Printable list of all infectious disease SAQs

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Question 1c - 2000, Paper 1

A 50 year old man is brought into the Emergency Department after acute flexion injury to the neck while surfing.  He is unable to move both arms or legs and has a sensory level at C4·5.   He ls a heavy smoker with a history of chronic bronchitis.

(c) Two days later he develops fever, dirty sputum and basal CXR changes. 
What will you do? 

College Answer

A bread and butter ICU problem. ?nosocomial infection, but it has occurred early and may indicate aspiration pneumonia or exacerbation of his bronchitis leading to pneumonia. Is this infection? Other causes, a pulmonary infarct and sepsis elsewhere, should be considered.

The nosocomial pneumonia should be handled by tracheal aspirate, culture, antibiotics and physiotherapy. There is no strong evidence to support the routine use of covered brush, BAL techniques at this stage but bronchoscopy may aid sputum clearance if physiotherapy is ineffective. The likely pathogens and hence choice of antibiotics should be listed.   H.flu should be included considering his history.

The next problem is to consider how to prevent further episodes of infection:

- vigorous physiotherapy with assisted coughing

- early tracheostomy and surgical stabilisation should be considered

- can the patient be mobilised into a Philadelphia collar (if he has a stable spine and . complete lesion this may be possible)?

- can he be sat up?

is there a place for an Evac tube or Pitt tube to aspirate secretions from above the cuff?

Discussion

What would you do?...

  • Airway
    • ensure good quality regular tracheal aspiration of secretions
  • Breathing
    • ensure the patient is ona humidified circuit, preferably with a humidifier rather than HME
    • increase PEEP to recruit available alveoli
    • titrate FiO2 to normoxia
    • consider bronchoscopy to clear any obstructions
    • send sputum specimens for gram stain and microbiology
    • commence rotation therapy (alternate left and right recovery position)
  • Supportive management
    • ensure nasgastric tube is in appropriate position; consider advancing it to a post-jejunal location
    • ensure good quality regular oral hygiene
    • consider selective digestive tract decontamination
    • consider upright posture, whatever the spinal injury permits
  • Specific management
    • broad spectrum antibiotics
    • regular chest physiotherapy to assist clearance of secretions

References

Question 1 - 2000, Paper 1

List  briefly  ways in   which  clinical  illness  can  change  the  pharmacokinetics  and pharmacodynamics of antibiotic therapy.

College Answer

There are many reasons for variable antibiotic pharmacology in ICU patients. Critical illness affects drug absorption, distribution and clearance via changes in fluid compartments,  organ · function and plasma protein concentrations.

The question specifically refers to the effects of critical illness, not genetic polymorphisms, drug interactions etc. The answer required a list. It should have been comprehensive but without too much detail.

a)  Changed pharmacokinetics

i)          Absorption - unpredictable oral  bioavailability due  to  diarrhoea. ileus  and potentially slowed IMI absorption due to impaired peripheral blood flow. 
ii)        Distribution - volume of distribution commonly increased by increased total body water. Decreased protein binding may lead to shortened T and increased  free drug eg. ceftriaxone. 

iii)       Elimination: metabolism, biotransfonnation and excretion. 
Metabolism - may be slowed by acute hepatic impainnent or reduced hepatic blood flow.

Excretion - Nonrenal clearance (eg. hepatic) affected by bilary obstruction, renal clearance impaired by renal failure and variably restored by dialysis (eg. some detail on the effects on aminoglycoside dosing were expected).

b)   Pharmacodynarnics refers to the effects of the drug. Effects on organ systems may be both toxic and therapeutic. There is obviously a close interplay with kinetics. The ways that critical illness influences the pharmacodynamics of antibiotics therefore may include:

i)          Antibacterial effect potentially reduced by increased Vo. impaired tissue

blood flow etc or increased by failure to excrete. 

ii)        Renal - more susceptible to renal failure because of impaired renal blood flow, dehydration (eg.aminoglycosides, amphotericin). 

iii)       Cardiovascular - more susceptible to cardiovascular toxicity eg. bradycardia with vancomycin bolus.

iv)  CNS more susceptible to cerebral toxicity of high dose penicillins

Discussion

The list provided above, through marvellously comprehensive, is difficult for a tired trainee to recall in a pinch. I will adjust it to include fewer words.

  • Changed pharmacokinetics
    • Unpredictable oral absorption (ileus)
    • Unpredictable IM absorption (shock)
    • Increased volume of distribution (volume overload)
    • Increased free drug levels (hypoalbuminaemia)
    • Decreased renal clearance (renal failure)
    • Increased artifical clerarance (dialysis)
    • Decreased hepatic metabolism (hepatic failure or low hepatic flow)
  • Changed pharmacodynamics
    • Decreased tissue delivery of drug (shock)
    • Increased adverse effects due to decreased clearance

A more detailed answer is reproduced here from Question 10 from the second paper of 2015

Pharmacokinetic changes:

  • Factors which decrease the antibiotic peak concentration:
    • Suboptimal gut absorption.
    • Increased volume of distribution (patients are typically fluid-overloaded)
    • Poor penetration to the site of action (poor tissue perfusion and generalised oedema)
  • Factors which increase the antibiotic peak concentration
    • Increased free fraction (decreased protein binding due to low albumin)
    • Diminished clearance (renal and hepatic failure)
  • Factors which increase the antibiotic half-life
    • Diminished clearance (renal and hepatic failure)
  • Factors which decrease the antibiotic half-life
    • Renal replacement therapy (enhances clearance)
    • Increased hepatic clearance (hyperdynamic circulation)
    • Increased glomerular filtration rate (hyperdynamic circulation)
    • Increased rate of drug metabolism due to a "hypermetabolic state" induced by trauma,  burns and exogenous catecholamine infusions

Pharmacodynamic changes:

  • Increased nephrotoxicity from aminoglycosides, if the renal function is already impaired
  • Increased cardiotoxicity from bleomycin and vancomycin
  • Increased risk of QT prolongation and arrhythmia with fluoroquinolones in the context of cardiac ischaemia, profound hypothermia, or extreme electrolyte derangement
  • Increased bone marrow toxicity from linezolid, cotrimoxazole, gancyclovir, chloramphenicol, beta-lactams of all sorts...
  • With a disrupted blood-brain barrier, an increased risk of seizures from high-dose beta-lactams, due to enhanced penetration.  
  • Worsening shock due to dapsone-induced methaemoglobinaemia and thus diminished oxygen-carrying capacity.

References

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Mehrotra, Rina, Raffaele De Gaudio, and Mark Palazzo. "Antibiotic pharmacokinetic and pharmacodynamic considerations in critical illness." Intensive care medicine 30.12 (2004): 2145-2156.

 

Question 13 - 2000, Paper 1

A 35 year old man, recently returned from an African trek, is admitted with coma, severe hypoxia and dark urine.  A thick film of blood shows malarial parasites.  Outline your management over the first 48 hours

College Answer

This is a medical emergency with a potentially high mortality due to plasmodium falciparum. Initial management of acute severe malaria with these features should include: 
(a) Airway- the patient is unconscious so the airway will need to be secured.              - 
(b) Breathing - hypoventilation associated with the cerebral obtundation will necessitate IPPV 
to normalise PC02•  ARDS is common in this setting and will require titration of Fi02, PEEP 
and ventilatory mode (?PRVC,IRV etc). 
(c) Circulation - shock is not uncommon with severe malaria. Volume loading in clinical studies is usually counterproductive with associated worsening hypoxia. Inotropic support is usually indicated and renal failure my require CVVHD. 
(d) Diagnosis - secondary infection is uncommon, but other precipitants of deterioration should 
be excluded eg.. pneumonia. 
(e) Definitive therapy with antimalariais. Depending on known sensitivities from the area 
visited - quinine sulphate may be the treatment of choice  (IV  loading dose followed by eight hourly doses). 
(f)  Invasive monitoring. 
(g) Metabolic support- hypoglycaemia is common. 
(h) Exchange transfusion- not medically justified.

Discussion

This question vaguely resembles Question 20 from the second paper of 2009. However, the answer there is not set up in a "systematic" fashion. Here I will attempt a systematic approach.

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history
  • Airway
    • The patient is comatose. This mandates intubation.
  • Breathing/ventilation
    • Increased minute volume to compensate for metabolic acidosis
    • Adequate PEEP and FiO2 to maintain normoxia in the face of poor gas exchange, likely due to pulmonary involvement form malaria or aspiration due to obtundation
    • Lung protective strategy (given the frequency of ARDS in this setting)
  • Circulatory support
  • Supportive management
    • Sedation to comfort
    • Electrolyte correction
    • CVVHDF support of renal failure is a feature
    • Enteral feeding (given the prodorome likely featured a period of poor oral intake and vomiting)
    • Transfusion and blood product replacement to correct coagluopathy
  • Monitoring
    • Invasive hemodynamic monitoring with arterial line as minimum
  • Specific investigations
    • Confirmation of parasite species by PCR
    • Monitoring or organ dysfunction:
      • ABG
      • EUC /CMP
      • LFTs
      • Coags and fibrinogen
  • Specific management
    • 2010 guidelines statement by the WHO suggests the following management strategy for severe falciparum malaria:
      • Artemisinin derivatives are first line, as per the the AQUAMAT trial; previously to 2010 the guidelines did nto have enough evidence to recommend artsunate over quinine.
      • Quinine is second-line these days.

References

World Health Organization. "Severe falciparum malaria." Transactions of the Royal Society of Tropical Medicine and Hygiene 94 (2000): 1-90.

 

Riddle, Mark S., et al. "Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis." Clinical infectious diseases34.9 (2002): 1192-1198.

 

Reyburn, Hugh. "New WHO guidelines for the treatment of malaria." BMJ 340 (2010).

(the actual revised guidelines are available online for free)

 

Dondorp, Arjen M., et al. "Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial." The Lancet 376.9753 (2010): 1647-1657.

 

Trampuz, Andrej, et al. "Clinical review: Severe malaria." CRITICAL CARE-LONDON- 7.4 (2003): 315-323.

 

Maitland, Kathryn, et al. "Response to volume resuscitation in children with severe malaria*." Pediatric Critical Care Medicine 4.4 (2003): 426-431.

 

Maitland, Kathryn, et al. "Mortality after fluid bolus in African children with severe infection." New England Journal of Medicine 364.26 (2011): 2483-2495.

 

Question 2 - 2000, Paper 2

List the  mechanisms of  central  venous  catheter infection, and  llst the  measures you undertake to prevent this infection.

College Answer

Usual source of infection is the insertion site, hub, infusate or haematogenous spread from distant site. Major mechanisms causing CVC infection are therefore:

(1) Contamination during insertion. Prevented by:
•   Sterile precautions during insertion (gloves,.gown, mask, appropriate cutaneous antiseptic)

(2) Contamination of insertion site after insertion:
•  Use of subclavian site for insertion (rather than jugular or femoral)
• Adequately fix catheter to prevent movement
•  Use appropriate combination of dressings and observation of site (change dressing if soiled)
•  Avoid prolonged connection of solutions prone to contamination (lipid, propofol)
•  Remove catheter as soon as need for it diminishes

(3) Subsequent contamination due to breaking of sterile connections (multi-flows, 3-way taps):
•  Limit number of lumens, decrease breaks in system, clean injection ports before accessing system (eg. Alcohol), use alternate route for blood transfusion
• Use of anti-microbial impregnated catheters

(4) Subsequent contamination from systemic infection elsewhere:
•  Aggressive treatment of other infections, remove catheters as soon as possible
• Use of anti-microbial impregnated catheters

Discussion

The second part of this question is similar to Question 8 from the first paper of 2006, which asks the candidate to "Outline  strategies  you  would  incorporate  to  prevent  central  venous  catheter  related infection.". I reproduce the answer below, for convenience. A good article from 2002 reviews the risk factors for CVC infection, which resembles the college answer.

Mechanisms of CVC infections

  • Contamination during insertion
    • Unclean CVC being inserted with a substandard sterile technique
    • "Re-wiring" of an old line, rather than the insertion of a new line
  • Contamination of insertion site after insertion
    • Use of contaminated site, eg. groin
    • Poor care for dressings
    • Use of solutions prone to contamination (eg. propofol, lipid or TPN)
  • Contamination of lumen by breaking of sterile line connection
    • Poor line changing and port handling technique (one is supposed to use chlorhexidine-soaked gauze)
  • Haematogenous contamination of intravascular portion
    • Antimicrobial-impregnanted catheters are supposed to prevent this from happening
    • One may wish to be proactive about treating bacteraemia from organisms which are known to colonise plastic.

Prevention of CVC infections

This is a point-form synopsis of CVC features and practices associated with a decreased risk of CVC infection:

  • Subclavian lines.
  • Minimum number of lumens.
  • Use of dedicated lumens for lipid infusions.
  • Immunosuppressed patients or those with burns should have antibiotic-coated lines.
  • For insertion, use aseptic technique and maximal barrier precautions.
  • 0.5% chlorhexidine in 70% alcohol is the preferred cleaning agent.
  • Handle ends of administration sets with gauze soaked in chlorhexidine).
  • Review the line daily.
  • Remove the line as soon as possible.
  • Change lines early - ideally, every 7 days.
  • Sterile, transparent semipermeable dressings
  • Change dressings regularly (every 7 days for standard dressings)

References

Marschall, Jonas, et al. "Strategies to prevent central line–associated bloodstream infections in acute care hospitals: 2014 update." Strategies 35.7 (2014): 753-771.

 

ANZICS statement on prevention of central line associated infections

 

ANZICS statement on insertion and maintenance of CVCs

 

 

.LIFL have made as short a summary as one can manage without omitting vital facets of the overall strategy.

 

Safdar, Nasia, and Dennis G. Maki. "The pathogenesis of catheter-related bloodstream infection with noncuffed short-term central venous catheters."Intensive care medicine 30.1 (2004): 62-67.

 

Safdar, Nasia, Daniel M. Kluger, and Dennis G. Maki. "A review of risk factors for catheter-related bloodstream infection caused by percutaneously inserted, noncuffed central venous catheters: implications for preventive strategies."Medicine 81.6 (2002): 466-479.

Question 5 - 2000, Paper 2

Outline  the indications,  contraindications, side effects  and  details of  administration  for benzyl penicillin, ciprofloxacin and cotrimoxazole.

College Answer

Benzyl penicillin:
Indications: treatment of  infection with presumed susceptible organisms (eg.  Strep pyogenes, clostridium [Gram positive bacilli, Gram positive and Gram negative cocci and spirochaetes]). Prophylaxis of  bacterial  endocarditis  and  orthopaedic  trauma  or  surgery.  Prophyla.xjs after splenectomy.
Contraindications: previous adverse reactions (including  allergies)  to penicillin; infection with
organism not susceptible; high dose with renal dysfunction (CNS toxicity).
Side effects: include sensitivity reactions, superinfection (including pseudomembranous colitis), GI. upset, fitting, fever, interactions with other drugs, physical incompatibilities.
Administration: IV or IM. Reconstituted powder. Adult dose 1.2 to 24g over 24 brs in 4-6 doses.

Ciprofloxacin:
Indications: treatment of infection with presumed susceptible organisms (Gram  positive cocci and
Gram negative  bacilli  including  adjuvant  or  S<?le   use  for  resistant  organisms  [eg.  MRSA. pseudomonas, legionella]).
Contraindications: previous adverse reactions (including allergies) to quinolones (including nalidixic acid), pregnancy, children (?<18 years).
Side effects: include sensitivity reactions, superinfection (including pseudomembranous colitis), tendon rupture (esp. with steroids), Gl  upset, CNS stimulation, interactions with  other drugs (especially via inhibition ofP450 system), haematologic/liver enzyme effects.
Administration: IV - Adult dose 200-300 mg over 60 minutes, every 12 hours. Oral- Adult dose
250-750 mg every 12 hours.

Cotrimoxazole: (sulphamethoxazole + trimethoprim)
Indications: Seldom used as first line therapy in ICU but may be used for treatment of infection with susceptible organisms (Gram  positive cocci and Gram negative bacilli including adjuvant or sole use for resistant organisms [eg. pseudomonas, xanthomonas, pneumocysis]), and pneumocystis pneumonia (HIV, bone marrow transplant).
Contraindications: allergy to sulphonamides or trimetboprin (including allergies), blood dyscrasias,
marked renal or hepatic impairment, megaloblastic bone marrow.
Side effects: include sensitivity reactions (eg. photosensitivity), superinfection (including pseudomembranous colitis), GI upset, CNS effects, interactions with other drugs, haematologic
effects.

Administration: IV- Adult dose  75-100 mg/kg per day ofSMX (15-20 mg/kg!day TMP). m 3 or 4 doses. Oral (tablets or syrup) - Adult dose 800mg/160mg (DS) every  12 hours,  (? daily for prophylaxis).

Discussion

More recently, questions regarding fine detail of pharmacology for such drugs have been abandoned, perhaps reflecting that a vast wealth of such information is available rapidly through online media, and its perpetual storage in the brains of fellows is superfluous.

It does also seem as if some of these questions have migrated into the CICM Part I curriculum, where one might reasonably be expected to answer questions about basic pharmacology of common ICU drugs. The domain of fellowship seems to be more related to the validity of indications for the use of drugs, the interpretation of evidence behind broad trends in ICU management. These days, the candidate won't be expected to discuss the pharmacology of levosimendan; they will be asked to critically evaluate its use as a general vitality-enhancing tonic.  

Anyway. One can only tabulate the answer when the college answer is that good.

Features

Benzylpenicillin

Cotrimoxazole

Ciprofloxacin

Indications

Treatment of susceptible gram-positive organisms

Treatment of susceptible gram-positive and gram-negative organisms, including comminuty-acquired MRSA and PJP

Treatment of susceptible gram-positive and gram-negative  organisms

contraindications

Hypersensitivity to penicillin

Hypersensitivity to sulfonamides
Blood dyscrasias

Hypersensitivity to quinolones
pregnancy

side effects

Selection for resistant organisms
Gastrointestinal effects due to changes in gut flora

Selection for resistant organisms
Gastrointestinal effects due to changes in gut flora

Selection for resistant organisms
Gastrointestinal effects due to changes in gut flora
Tendon rupture
Interaction with other drugs

details of administration

1.2-2.4 g q4h

75-100/15-20 mg/kg/day in 3-4 divided doses

200-300mg tds

References

Question 10 - 2000, Paper 2

List your indication for the use of corticosteroids in the management of refractory shock.

College Answer

Candidates should demonstrate a good understanding of the background and current interest  in this area. The use of corticosteroids during refractory shock is undergoing a resurgence of interest following the publication of a number of interesting papers. A large RCT  assessing the use of high doses of steroids (eg. dexamethasone (Shock Pack 120mg] or methylprednisolone [2g]} in septic shock was associated  with no overall benefit, and indeed a higher mortality  in the subgroup with renal impairment. More recently, interest has developed  in the use of more  physiologic  doses of corticosteroids  (eg  120 to  240 mg  of  hydrocortisone)  to  treat a presumed  inadequate  intrinsic cortisol response in the presence of refractory shock. The aetiology of the cortisol deficiency could be due to adrenal, pituitary or hypothalamic.

Typical indications for physiologic doses (bolus or infusion) could include:
•  known previous steroid dependence,
•  recent steroid administration  (eg. course for > 1 week in last 6 months),
•  shock associated with coagulopathy (adrenal or pituitary haemorrhage more likely),
•  prolonged inotrope/vasopressor dependency (> a few days).
•  use of very high doses of inotropes/vasopressors to maintain acceptable goals.

Discussion

This question vaguely resembles Question 22 from the first paper of 2008: "Outline the evidence for the role of glucocorticoids  in ARDS and septic shock and the current controversies surrounding their use in these conditions". On a more sepsis-specific note, Question 16 from the first paper of 2013 asks "Discuss the potential role of corticosteroid administration as adjunctive treatment for septic shock" .

The issue of steroids in sepsis is treated with greater detail in another chapter.

One could evolve this answer into a critical evaluation of the use of steroids in refractory shock. The following is brief summary of their theorical benefits:

Theoretical benefits of steroids in shock

  • Reversal of relative adrenal insufficiency
  • Reversal of inflammatory overactivity
  • Reprogramming of the immune response
  • Improved responsiveness of α-1 receptors (thus, decreased catecholamine requirements)
  • Correction of vasoplegia by deactivation of nitric oxide synthase
  • Improved cardiac tolerance of bacterial endotoxin
  • Improved retention of resuscitation fluid

However, the college only asks you to list your indications. The candidate is not invited to prattle on about nitric oxide synthase.

Thus, a current list of indications would resemble the following:

  • Adrenal insufficiency
    • Due to primary hypoadrenalism
    • Due to withdrawal of chronic exogenous corticosteroids
    • Due to relative insufficiency during critical illness
  • Severe septic shock
    • If the shock state is refractory to vasopressors and fluid resuscitation
  • Shock states due to autoimmune inflammatory disease
    • Severe vasculitis with widespread SIRS
    • Severe autoimmune myocarditis with cardiogenic shock

References

Byhahn, C., V. Lischke, and K. Westphal. "Translaryngeal tracheostomy in highly unstable patients." Anaesthesia 55.7 (2000): 678-683.

 

Ambesh, Sushil P., et al. "Percutaneous tracheostomy with single dilatation technique: a prospective, randomized comparison of Ciaglia Blue Rhino versus Griggs’ guidewire dilating forceps." Anesthesia & Analgesia 95.6 (2002): 1739-1745.

 

Antonelli, Massimo, et al. "Percutaneous translaryngeal versus surgical tracheostomy: A randomized trial with 1-yr double-blind follow-up*." Critical care medicine 33.5 (2005): 1015-1020.

Question 14 - 2000, Paper 2

What  are  the  implications  for  ICU  practice of  the  increasing  incidence  of  antibiotic resistance?

College Answer

More focus on techniques for prevention and control:
•  hand washing practice, placement of hand basins, use of gloves, use of protective clothing
•  isolation  techniques  (standard  precautions,  transmission  based   precautions  [airborne, dropJet, contact])
•  increasing need for surveillance

More focus on judicious use of antibiotics (individual versus community needs)
•  appropriate initial cover, tailor quickly according to results of investigations, stop as soon as no longer  needed
•  reserve/restrict use of some  antibiotics (eg. vancomycin) with use of alternatives whenever possible

Need to alter antibiotic prescribing habits:
•  initial antibiotic regimen may not cover infecting organism
•  community acquired  organisms have more resistance eg. penicillin no longer always useful against streptococcus or haemophilus
•  third generation cephalosporios lose value after first week. in hospital
•  may have to use uncommonly used antibiotics (intravenous cotrimoxazole)
•  broader antibiotic use may increase superinfection (C difficile, fungi, etc.)
• antibiotics used for prophylaxis may  need to change  accordingly (? vancomycin for cardiac surgery)

Increased cost:
• newer antibiotics or combinations used to treat some resistant infections                          
•  additional susceptibility  testing required
•   invasive lines impregnated (antibacterial) or changed more frequently
•  ? prolonged ICU and hospital stay of nosocomial infections

Have no available antibiotics to treat infections with some resistant organisms.

Discussion

This is another very broad question. The candidate ought to have prepared a prefabricated rant in reponse to this. A solid basis for such a rant may be derived from articles such as this 2011 paper, which discuss the burden of multidrug resistance in the ICU. This question was from 2000, and the authors probably had something like this 1999 paper in mind.

In point form:

Preventative measures

  • Routine barrier and infection control process needs complicance monitoring and regular review.
  • Surveillance for MROs must be proactive.
  • Patient isolation should be practiced.

Antibiotic stewardship

  • Use of some antibiotics should be restricted/reserved
  • Broad spectrum antibiotics must be deployed intelligently
  • Antibiotics must be reviewed daily, and narrowed or discontinued when appropriate
  • Infectious diseases physicians should have greater input into prescribing practices
  • Perioperative prophylaxis needs to be rationalised
  • Antibiotic cycling may be helpful in preventing the emergeance of resistant strains

Healthcare costs

  • Increased cost of increased surveillance
  • Increased cost of extended spectrum susceptibility testing
  • Increased cost of increased use of consumables (eg. gloves, gowns, single room terminal cleaning)
  • Increased cost of exotic antibiotics
  • Increased cost of increased duration of hospital and ICU stay
  • Cost of developing and testing new antimicrobial agents

References

Elliott, T. S. J., and P. A. Lambert. "Antibacterial resistance in the intensive care unit: mechanisms and management." British medical bulletin 55.1 (1999): 259-276.

 

Brusselaers, Nele, Dirk Vogelaers, and Stijn Blot. "The rising problem of antimicrobial resistance in the intensive care unit." Annals of intensive care 1.1 (2011): 1-7.

 

Niederman, Michael S. "Impact of antibiotic resistance on clinical outcomes and the cost of care." Critical care medicine 29.4 (2001): N114-N120.

Question 1 - 2001, Paper 1

A patient presents with a red swollen leg and systemic signs of sepsis. You suspect necrotising fasciitis.  How will you confirm the diagnosis and what are the priorities of management?

College Answer

This question was generally well covered but candidates often failed to consider history and examination  as  part  of  the  diagnostic  process.  Necrotising  fasciitis  is  an  uncommon  soft  tissue infection, which is characterised by widespread fascial necrosis with relative sparing of skin and underlying muscle. It may be caused by a single virulent bacterium usually from skin or mixture of bacteria usually enteric.

The question was in two parts:

(a)        Confirm the diagnosis. Suspicion will be raised by history, examination and confirmed by investigations and surgical exploration. There may be a history of inciting event such as animal or insect bite, penetrating trauma, abdominal surgery, appendicitis, perineal surgery or trauma.

Early examination reveals an erythematous, tender, swollen area accompanied by local pain and fever.   The skin becomes smooth, shiny and tensely swollen. In a few days the skin darkens to a patchy, dusky blue as blisters and bullae develop. Frank gangrene may then develop.

Investigations reveal non-specific leukocytosis and positive blood cultures. X-ray may reveal subcutaneous air but early surgical exploration will confirm the diagnosis in the absence of resistance of normally adherent fascia to blunt dissection. There is a watery, thin (sometimes foul-smelling) pus in the subcutaneous space.

Other adjuncts include CT, MRI and full thickness biopsy. CT may show the subcutaneous air but MRI shows the extent of the fascial necrosis and guides limits of debridement. Biopsy helps differentiate fasciitis from cellulitis which is usually medically treated.

(b)       Management priorities are :

-     confirmation of diagnosis (history, examination, investigations)

-     resuscitation ( fluid, inotropes)

-     early and definitive surgery (the most important intervention)

-     antibiotics  to  cover  gram  positive,  gram  negative  and  anaerobic  organisms  before definitive                   cultures    are     available    (eg     ampicillin/gentamicin/metronidazole  or

clindamycin/gentamicin if penicillin allergic)

-     hyperbaric oxygen as an adjunct

Discussion

Though different in its wording, this question is functionally similar to Question 24 from the first paper of 2011, which asks the candidate to discuss the management of necrotising fasciitis in a diabetic. That diabetic also has a cellulitic thigh and features of systemic sepsis. In the Discussion section, the management priorities are outlined in a boring algorithmic fashion (A, B, C. )

References

Question 10 - 2002, Paper 1

Outline the aetiology, clinical manifestations and possible preventative measures for nosocomial infections in Intensive Care.

College Answer

Aetiology: dependent on cause.   Combination of overgrowth of endogenous flora, immune suppression, impairment of natural defences (eg. endotracheol tube, invasive catheters), and cross contamination  with  pathogens.     Commonest  are  pneumonia  (thought  related  to  aspiration  of organisms colonising oro-pharyngeal and gastric contents, decreased gastric pH, exposure to water borne organisms), surgical wound infections (contamination at time of surgery), sinusitis (tubes, immobility, nasal congestion),  line related sepsis (entry site contamination,  blood borne contamination, contamination of intravenous lines).

Clinical  manifestations:  apart  from systemic  manifestations  of sepsis  (leukocytosis/leukopaenia, fever, etc) are dependent on cause.   Pneumonia (purulent secretions, impaired oxygenation, radiological   infiltrates  etc.),  sinusitis  (purulent  discharge),  line  related  (local  inflammation). Diagnostic techniques are specific to cause.

Possible prevention: consider general infection control measures (including surveillance, continuous quality improvement, avoid un-necessary immunosuppression [steroids, glucose control], avoid un- necessary antibiotics).   Decrease cross infection (standard precautions [esp. hand washing] and transmission based precautions; cleaning/disinfection and sterilization of equipment; avoiding reuse of single  use items).   Pneumonia  (eg. semi-recumbent  position,  aspiration  above  cuff,  possibly selective decontamination, infrequent changing of circuit).   Line related (eg. sterile insertion, antibiotic/antiseptic   impregnated   lines,  perhaps  tunneling,   surveillance,   change  according   to protocol).

Discussion

This question is painfully broad. A good article reporting on the epidemiology of nosocomial infection in American ICUs is available, and using this substrate, one can attempt to boil the answer down into a point-form list. A notable reference is Hatcher and Dhillon's chapter for Ohs' Manual(Ch 70, p. 724)

Aetiology of nosocomial infection in ICU:

  • Pneumonia: VAP or HAP
  • Central line associated bacteraemia
  • UTI due to indwelling catheters
  • Sinusitis due to nasogastric tubes
  • Acalculous cholecystitis due to parenteral nutrition
  • Pressure area infections
  • Meningitis or ventriculitis due to EVD infection
  • C.difficile infections due to broad-spectrum antibiotic use
  • Surgical site infections

Clinical manifestations

  • Broadly speaking, these depend on where the infection is.
  • Fever
  • Inflammatory marker elevation
  • Shock and metabolic acidosis
  • Purulent discharge (pulmonary, urinary, or nasal)
  • Positive CSF gram stain and culture, decreased level of consciousness

Preventative measures

Non-specific measures

  • Scrupulous handwashing
  • Barrier precautions, gloves gowns and masks
  • Surveillance for MROs
  • Isolation precautions

Specific measures

  • Regular oral hygiene
  • Regular pressure area care
  • Minimisation of the duration of ventilation
  • Preventative strategies for VAP (eg. upright positioning)
  • Preventative strategies for central line contamination
  • Early removal of central lines
  • Rationalisation of antibiotics to prevent C.difficile infection
  • Control of hyperglycaemia
  • Rationalisation of immunosuppressive therapies
  • Perioperative antibiotics to prevent wound infection in high-risk patients

References

Oh's Manual:

Chapter 70  (pp. 724)  Nosocomial  infections by James  Hatcher  and  Rishi  H-P  Dhillon

 

Ak, Oznur, et al. "Nosocomial infections and risk factors in the intensive care unit of a teaching and research hospital: A prospecive cohort study." Medical Science Monitor 17.5 (2011): PH29-PH34.

 

Barnett, Adrian G., et al. "The increased risks of death and extra lengths of hospital and ICU stay from hospital-acquired bloodstream infections: a case–control study." BMJ open 3.10 (2013): e003587.

 

Doyle, Joseph S., et al. "Epidemiology of infections acquired in intensive care units." Seminars in respiratory and critical care medicine. Vol. 32. No. 02. © Thieme Medical Publishers, 2011.

 

ANZICS statement on VAP

 

ANZIC statement on central line insertion

 

Richards, Michael J., et al. "Nosocomial infections in combined medical-surgical intensive care units in the United States." Infection control and hospital epidemiology 21.8 (2000): 510-515.

 

Lepape, A. "Prevention of nosocomial infections in ICU. What is really effective?." Medicinski arhiv 57.4 Suppl 1 (2002): 15-18.

 

Question 1 - 2002, Paper 2

List the possible causes, and outline your principles of management of hyperthermia in the Intensive Care patient.

College Answer

•    Causes of hyperthermia (? specific temperature definition: eg. Core temperature > 38 °C) include: infection (bacteria, virus etc), inflammatory response (burns, pancreatitis etc), exertion (status epilepticus, posturing, delirium), auto-immune conditions (arthritis, inflammatory bowel disease), endocrine disorders (eg. hyperthyroidism/thyroid storm), malignancy (esp. haematological), drug associated (eg. overdose with cocaine, salicylates; withdrawal states eg. from alcohol, opiates; and occasionally drug fever) and unusual but requiring specific therapy: malignant hyperthermia (MH) and neuroleptic malignant syndrome (NMS). 

•    Principles of management include: treatment of underlying cause, and consideration of whether specific temperature lowering therapy is required. Obvious specific therapies
include antimicrobial therapy, chemotherapy (including corticosteroids). MH requires urgent removal of exposure to triggering agent, dantrolene (eg. 2.4 mg/kg IV and repeat according to protocol), aggressive cooling and fluid resuscitation. NMS requires removal of
responsible drugs (eg. phenothiazines, butyrophenones), symptomatic treatment and consideration of other specific therapies (eg. dantrolene, bromocriptine etc).


•    Mild to moderate elevations of temperature are generally not thought to be harmful.
Lowering of temperature (independent of the cause) may be beneficial in some circumstances (eg. for comfort), and may be indicated to avoid potential harm in other circumstances (eg. stroke, head injury, hypoxic injury). Aggressive management of temperature should be undertaken if temperature exceeds 39°C in children under 3 (increased risk of seizures) or 41°C in others (concern regarding long term effects on brain, rhabdomyolysis etc). Methods used may be simple (paracetamol, aspirin) or more complex (sponging through to ice packs and cooling blankets).

Discussion

As one of the readers (Sarah, you know who you are) had correctly pointed out, in their answer, the college examiner failed to distinguish between hyperthermia and fever, which are distinct entities. To borrow a turn of phrase from Still (1979), fever is a regulated increase in body temperature associated with an increased hypothalamic temperature setpoint and thermopreferendum (the behavioural preference for an environmental temperature), whereas in hyperthermia the body temperature is elevated above this preferred temperature. As such causes of elevated body temperature shoud be classified in terms of whether the temperature is elevated because of the body's thermoregulatory mechanisms, or in spite of them.  

However, for the purpose of answering questions on this topic, the trainees were not expected to discriminate between hypothermia and fever. In fact judging by the college answer, they really meant "fever" all along, as their answer has no mention of (for example) being in a fire as a cause of hyperthermia.   Paul Marik's excellent article on fever remains a definitive resource for the person trying to generate a broad range of differentials for fever specifically.

Firstly, the definition and measurement of fever. Marik suggests that the measurement of mixed venous blood with a PA catheter is the gold standard (in the face of all those heretics who think hypothalamic temperature is more important). The upper threshold for temperature is defined by the Society of Critical Care Medicine as 38.3°C

In summary, any process which releases IL-1, IL-6 and TNF-α will cause a fever. The process could be infectious or non-infectious.

Marik's article has a series of excellent (and extremely long) tables regarding the various differential causes of fever.

Highlights from these tables include the following:

  • Vascular causes
    • MI
    • PE
    • SAH
    • Gut ischaemia
    • DVT
  • Infectious causes
    • Systemic sepsis
    • Line-related
    • Acalculous cholecystitis
  • Neoplastic causes
    • Tumour-related pyrexia
    Drug-related
    • "Drug fever"
    • Neuroleptic-malignant syndrome
    • Serotonin syndrome
    • Drug withdrawal (alcohol)
  • Idiopathic/inflammatory
    • Malignant hyperthermia
    • Rhabdomyolysis
    • Pancreatitis
    • Gout
  • Autoimmune/allergic
    • Vasculitis
    • Anaphylaxis
    • Transfusion reaction
    • Transplant rejection
    • IV contrast reaction
  • Inflammatory causes

The answer for the management of a fever could be approached in a systematic manner.

  • Treat underlying cause:
    • Antibiotics for sepsis
    • Steroids for inflammatory/autoimmune states
    • Benzodiazepines for withdrawal
    • Dantrolene/bromocryptine/cyproheptadine
  • Treat the temperature:
    • One would wish to keep it under 41°C to prevent rhabdomyolysis, seizures and brain damage
    • Various cooling techniques are discussed elsewhere; in brief:
    • Ice bags, cold water sponges
    • Cooling blankets and vests
    • Cold IV fluids
    • Paracetamol/NSAIDs
    • Extracorporeal cooling

References

Marik, Paul E. "Fever in the ICU." Chest Journal 117.3 (2000): 855-869.

 

O'Grady, Naomi P., et al. "Practice guidelines for evaluating new fever in critically ill adult patients." Clinical infectious diseases 26.5 (1998): 1042-1059.

Question 8 - 2002, Paper 2

Outline the clinical manifestations, appropriate investigations, and treatment of acalculous cholecystitis.

College Answer

Clinical presentation is variable. Symptoms/signs include fever, leukocytosis with a left shift, abdominal pain, right upper quadrant mass, hyperbilirubinaemia, increased alkaline phosphatase and serum transaminases.
Additional investigations (assuming full blood count and liver function tests have already been performed) should include: ultrasonography (usually diagnostic), erect abdominal radiograph, and blood cultures. A radioisotope (HIDA) scan may be useful if diagnosis id still unclear and time permits.
Treatment involves broad spectrum antibiotics, though the definitive treatment is drainage. Percutaneous drainage (via ultrasound guidance) may be performed if the patient is too sick to transport, otherwise invasive techniques (laparoscopic or open) may be considered.

Discussion

This question is identical to Question 17 from the second paper of 2008.

References

Question 10 - 2002, Paper 2

Outline the diagnostic features, complications and treatment of patients  with meningococcal sepsis.

College Answer

•    Acute systemic meningococcal disease is usually manifest as meningitis &/or meningococcaemia. The diagnostic features include: history of sudden onset of fever/nausea/vomiting/headache/myalgias (sometimes intense), with rapid progression. Examination may reveal hypotension, tachycardia, diaphoresis, and discrete petechiae (initially 1-2 mm diameter; may coalesce). Shock is often profound with extreme vasoconstriction. Blood cultures and CSF cultures are often positive.
•    Complications include refractory shock, disseminated intravascular coagulation (including bleeding and major vessel thrombosis), cerebral oedema, and myocardial dysfunction.
•    Treatment is with immediate antibiotics. High dose penicillin (2 million units every 2 hours for adults) or chloramphenicol or 2nd or 3rd generation cephalosporins (according to sensitivities). Supportive care for shock (vasopressors and fluids) and other complications (eg. DIC, ARDS etc). Other unproven therapies may include plasmapheresis or activated protein C.

Discussion

A good NEJM review article is available which covers this territory well.

Diagnostic features of meningococcal sepsis

  • Abrupt onset of high fever
  • Myalgias, arthralgias, headache, decreased level of consciousness
  • Petechial or purpuric rash
    • progression to purpura fulminans
  • Hypotension and shock
  • Blood or CSF cultures positive for N.meningitidis

Complications of meningococcal sepsis

Management of meningococcal sepsis

  • Most strains are susceptible to penicillin
  • The Sanford Guide recomends ceftriaxone 2g bd or benzylpenicillin 2.4g q4h
  • Chloramophenicol is an alternative
  • Supportive management consists of vasopressor support and fluid resuscitiation, with correction of DIC-associated coagulopathy
  • Corticosteroids may be useful if there is meningitis
  • Plasma exchange may improve survival if commenced early, but the evidence for it is not robust.

References

Rosenstein, Nancy E., et al. "Meningococcal disease." New England Journal of Medicine 344.18 (2001): 1378-1388.

 

Mautner, L. S., and W. Prokopec. "Waterhouse-Friderichsen Syndrome."Canadian Medical Association journal 69.2 (1953): 156.

 

Kumar, Ajay, et al. "Plasma exchange and haemodiafiltration in fulminant meningococcal sepsis." Nephrology Dialysis Transplantation 13.2 (1998): 484-487.

 

 

Question 1c - 2003, Paper 1

A 50-year-old man with motor neurone disease presents to hospital  with respiratory distress following two (2) days of fever and malaise.  He is alert and anxious, and an arterial blood gas performed on oxygen (8L/min semi-rigid mask) revealed PaO2 45 mmHg, PaCO2  65 mmHg, pH 7.36 and HCO3 36 mmol/L.   He has used a motorised wheelchair for three (3) years but continues  to  work as  an  accountant.    His  attentive   wife states  that  they  have  discussed mechanical   ventilation   and   are  keen   for  him   to  receive   full  Intensive   Care  support.

•    On  day 7 of his admission  he become febrile,  develops a leukocytosis  and  a chest x-ray shows a new infiltrate in his left lower lobe.  Discuss the investigation  and management of this problem.

College Answer

Unfortunately nosocomial pneumonia is a common sequelae of mechanical ventilation after 7 days. A  standard approach should  be  considered, which  must  include some  culturing of  secretions (tracheal aspirates, or more invasive eg. bronchoscopic lavage or protected brush).  Gram stain may provide quantitative information of potential pathogens, as may quantitative cultures.  Antibiotics should be introduced if bacterial aetiology suspected, and should be appropriate to local factors (including usual bacterial sensitivities, previous antibiotic use and unit protocols) but should include cover for MRSA and resistant gram negatives for a specified period of time (eg. 3 days and review). Plan for review of antibiotics should be discussed.  Differential diagnosis includes other causes of WCC/temperature elevation (eg. line sepsis, UTI, sinus infection, pulmonary embolus, myocardial infarction etc.) and other causes of infiltrates (eg. collapse/atelectasis, pulmonary oedema and pulmonary embolus) and each may require specific investigation and treatment depending on other clinical  information.     This  event  provides  another  opportunity  to  revisit  the  direction  of management when necessary discussion regarding developments occurs with wife and family.

Discussion

This motor neuron disease patient has VAP, by the standard definition (any pneumonia which develops after 48 hrs on a ventilator can be called VAP).

A summary of ventilator-associated pneumonia is available in the Required Reading section.

Thus, a structured answer would look like this:

Exclusion of other sources of fever

  • Culture of the urine and a U/A
  • Examination of the abdomen, ultrasound of the gallbladder
  • Examination ± CT of the sinuses
  • Attention to central venous catheters

Investigations of VAP

Management:

  • Broad spectrum antibiotics until a pathogen is isolated - which should include cover for multiresistant organisms
  • Mechanical ventilation with small amount of PEEP, so as not to cause shunting of blood though the pus-filld lung
  • Suctioning of the secretions to improve clearance
  • Upright (45°) positioning to prevent further VAP
  • Strategies such as chlorhexidine mouthwashes and selective digestive tract decontamination are controversial

References

 

Ruíz, Mauricio, et al. "Noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome." American journal of respiratory and critical care medicine 162.1 (2000): 119-125.

 

Luna, Carlos M., et al. "Blood cultures have limited value in predicting severity of illness and as a diagnostic tool in ventilator-associated pneumonia." CHEST Journal 116.4 (1999): 1075-1084.

 

Kollef, Marin H., and Suzanne Ward. "The influence of mini-BAL cultures on patient outcomes implications for the antibiotic management of ventilator-associated pneumonia." CHEST Journal 113.2 (1998): 412-420.

 

Craven, Donald E., and Karin I. Hjalmarson. "Ventilator-associated tracheobronchitis and pneumonia: thinking outside the box." Clinical Infectious Diseases 51.Supplement 1 (2010): S59-S66.

 

Question 9 - 2003, Paper 1

List the potential  causes of diffuse pulmonary infiltrates in a patient  with AIDS, and outline how they would influence your management.

College Answer

Many potential causes should be considered.  High pressure pulmonary oedema (fluid overload: CPAP/PEEP, diurese, fluid restrict, remove blood; cardiac failure: diurese, vasodilate ± inotropes; acute ischaemia: nitrates, morphine ± betablockers, anticaogulants).  Low pressure pulmonary oedema/ARDS  (CPAP/PEEP, fluid restrict, diurese, treat underlyimg cause eg. sepsis).   Diffuse pneumonia (diffuse typical or atypical: CPAP/PEEP, likely to need invasive investigation [eg. lavage], diurese and fluid restrict, specific treatment [anti-agent therapy] according to underlying cause: bacteria [eg. strep or TB], viral [eg. CMV/influenza/SARS], protozoal [eg. pneumocystis], fungal [eg. cryptococcus]). Others: could uncommonly also be malignant (eg. Karposi’s sarcoma), pulmonary haemorrhage (eg. if low platelets: consider platelet transfusion) or auto- immune/vasculitic (consider steroids, immunosuppression).

Discussion

A good free full-text article is available to cover this terrain. In it, there is an excellent table, "Aetiology of pulmonary infections in HIV-infected patients". It also presents the incidence of the aetiology. Turns out, in 97% of cases the pulmonary infiltrates are infectious in nature. The bacterial pathogens are surprisingly mundane- its S.pneumoniaeH.influenzae and Legionella. Together they cover something like 60% of pulmonary infections. Pneumocystis accounts for another 20%, and viruses for 5%. Other fungal infections are surprisingly rare - 2% - and protozoal parasites represent only 0.5%.

Causes of diffuse pulmonary infiltrates in the AIDS patient, and a brief note on their specific treatment

Non-infectious:

  • Pulmonary oedema - PEEP and preload reduction
  • Diffuse alveolar haemorrhage - correction of coagulopathy
  • Malignant (eg. lymphangitis carcinomatosis) - dexamethasone
  • Autoimmune (vasculitis) - high dose steroids
  • Inflammatory - ARDS - lung-protective ventilation

Infectious:

  • Bacterial:
    • Streptococcus pneumoniae - ceftriaxone
    • Mycobacterium tuberculosis - standard cocktail
    • Mycoplasma pneumonia - azithromycin
    • Generally speaking, broad spectrum antibiotics which are narrowed when the pathogen is isolated
  • Viral
    • CMV - ganciclovir or foscarnet
    • VZV - acyclovir
    • HSV - acyclovir
    • Influenza - possibly oseltamivir
    • Human metapneumovirus - supportive management
  • Fungal:
    • Pneumocystis jirovecii - cotrimoxazole
      • This is the second most common cause of pneumonia, behind S.pneumoniae
    • Cryptococcus - fluconazole or amphotericin
  • Protozoal:
    • Toxoplasma gondii - pyrimethamine plus cotrimoxazole or sulfadiazine

References

Segal, Leopoldo N., et al. "HIV-1 and bacterial pneumonia in the era of antiretroviral therapy." Proceedings of the American Thoracic Society 8.3 (2011): 282-287.

 

Feldman, Charles. "Pneumonia associated with HIV infection." Current opinion in infectious diseases 18.2 (2005): 165-170.

 

Arora, V. K., and S. V. Kumar. "Pattern of opportunistic pulmonary infections in HIV sero-positive subjects: observations from Pondicherry, India." The Indian journal of chest diseases & allied sciences 41.3 (1998): 135-144.

 

Benito, Natividad, et al. "Pulmonary infections in HIV-infected patients: an update in the 21st century." European Respiratory Journal 39.3 (2012): 730-745.

Question 2a - 2003, Paper 2

A 65 year old man has been admitted to your Intensive Care Unit with a presumptive diagnosis of community acquired pneumonia. He is sedated, intubated and ventilated, and is haemodynamically stable.

(a)  What specific historical information would you attempt to obtain?  Discuss why.

College Answer

(a)       What specific historical information would you attempt to obtain?  Discuss why.

Specificity of typical or atypical in nature is poor; rapidity of onset (? Prognostic). Factors that might alter aetiology: recent or current hospitalisation, nursing home etc (more nosocomial like, including Gram negatives); areas associated with outbreaks (e.g. legionella); exposure to specific scenarios eg. Birds (psittacosis); exposure to communities with specific resistance patterns (eg. Drug resistant pneumococcus), risk for pseudomonas (structural lung disease e.g. bronchiectasis, corticosteroids, previous broad spectrum antibiotic use, undiagnosed HIV), visits to tropical areas (e.g. Burkholderia pseudomallei). Risk factors for poor prognosis: include age > 65, co-morbidities (eg. Diabetes, renal failure, neoplastic disease, alcoholism, immunosuppression).  Usual historical data  regarding  other  major  illnesses/comorbities,  drugs,  allergies,  etc.  Information  regarding specific immunosuppression may also allow better coverage of potential organisms: consider T cell dysfunction (e.g. AIDS, immunosuppressive therapy and risks of Pneumocystis and TB), neutropaenia (e.g Pseudomonas, Fungi), previous splenectomy etc.

Discussion

The first part of this question (the history of a pneumonia patient) closely resembles Question 26 from the first paper of 2006.

Contrary to custom, I will reproduce the answer here:

Patient's medical history of prognostic importance

  • smoking
  • COPD
  • heart disease, including CCF and pulmonary hypertension
  • exercise tolerance
  • immunesuppression, eg. corticosteroids
  • malignancy
  • vaccination history
  • history of exposure to TB, country of origin
  • end-stage organ failure, eg. cirrhosis or dialysis-dependent renal failure

Recent history of aetiological importance

  • swallowing difficulty, history of stroke
  • alcohol binges
  • haemoptysis
  • recent travel
  • recent gardening (Legionella)
  • recent bushwalking
  • exposure to birds or pets
  • recent chemotherapy
  • recent hospital stay
  • recent antibiotic use

Presenting history

  • rapidity of onset
  • associated symptoms eg. copious amounts of sputum, flu-like symptoms, hemoptysis, pleuritic chest pain, and so forth

References

 

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

 

Question 2b - 2003, Paper 2

A 65 year old man has been admitted to your Intensive Care Unit with a presumptive diagnosis of community acquired pneumonia. He is sedated, intubated and ventilated, and is haemodynamically stable.

(b) What specific investigations would you order?  Discuss why.

College Answer

(b)       What specific investigations would you order?  Discuss why.

Standard CXR to help delineate areas involved (possibly help with aetiology), and serve as baseline. Blood cultures (diagnose organism), and full blood examination (ideally with film to assess white cell morphology; white cell count may be high, low or normal).  Electrolytes including Creatinine (renal impairment, modify drugs) and liver function (organ involvement, modify drugs, help with aetiology). Gram stain (controversial) may help guide therapy, as may sputum culture. Pleural fluid should be tapped (for organism).  Legionella urinary antigen (and/or sputum immunofluorescence) may help confirm diagnosis.  Bronchoscopy and lavage or protected brush specimen may also help in aetiology.

Discussion

(b)       What specific investigations would you order?  Discuss why.

Of the following list of tests, the normal font identifies the college canon, and the  italicised ones were added by the deranged author.

  • CXR
  • Arterial blood gas
  • Blood cultures
  • FBC (for leucocyte morphology rather than their number)
  • EUC (to anticipate renal clearance problems)
  • LFTs (to anticipate hepatic clearance problems)
  • Blood culture
  • Sputum culture
  • Pleural fluid culture
  • Legionella urinary antigen
  • Pneumococcal urinary antigen
  • Bronchoscopic lavage specimen for culture
  • Respiratory viral swabs (NAT)
  • Inflammatory markers, eg. CRP and procalcitonin

The evidence and utility of these investigations can be examined in some greater detail:

  • CXR : according to the IDSA and BTS, "a demonstrable infiltrate by chest radiograph or other imaging technique... is required for the diagnosis of pneumonia".
  • ABG: recommended by the BTS for all patients receiving "emergency oxygen". In studies of random mixes of patients, ABG increased the chances of detecting clinically significant hypoxia. It is frightening to think that doctors need an ABG to accurately identify patients with clinically significant hypoxia, but in reality the blood gas result may sway one's decision regarding oxygen supplementation and intubation (eg. a patient who is tachypnoeic, and becoming hypercapnoeic due to fatigue).
  • Blood cultures: all the guidelines recommend that patients with pneumonia of ICU-level severity should get cultured. The specific caveat is that cultures should be collected "whenever the result is likely to change individual antibiotic management". The de-escalation of broad spectrum antibiotics would represent such a change.
  • Sputum culture is neither sensitive nor specific, but the BTS and IDSA recommend that we send purulent samples. Of particular interest are tracheal aspirate and BAL samples (as they might actually be representative of the infectious agent)
  • Pleural fluid culture is valuable if the patient already has empyema, or if one is suspected. This becomes of more interest in the pneumonia which fails to resolve.
  • Pneumococcal urinary antigen (specifically pneumococcal capsular polysaccharide antigen) has broad popularity and multiple advantages:
    • it has good sensitivity and specificity
    • it is not affected by prior antibiotic therapy (result is positive for up to a week after the commencement of antibiotic therapy)
    • its level is higher in more unwell patients
    • it is available earlier than cultures and Gram stains
  • Legionella urinary antigen only detects Legionella pneumophila, whereas there are about 19 other species which act as pathogens in man (particularly immunocompromised man). However, it is also positive more often in patients with severe infection. The assay occasionally cross-reacts with Campylobacter antigens.
  • FBC: the college recommends we look to the toxic granulation of neutrophils in order to make a diagnosis of infection, remarking that the WCC itself could be low, high, or normal. The BTS expand on this further in their Section 5.8 (iii19), quoting a 1990 paper by Holberg et al.  Apparently, among 418 adult Scandinavians, a WCC in excess of 15 was strongly associated with a bacterial (and specifically pneumococcal) pneumonia. It is unclear how this can be generalised to the typical 2015 Western Sydney scenario (150kg bong-smoking diabetic with sleep apnoea) ...but the FBC is probably still important.
  • EUC: not only to "modify drugs", as the college suggests. Renal function plays a role in the stratification of mortality risk (the CURB65 score), which in turn recommends for or against ICU admission.
  • LFTs are mentioned by the college because "organ involvement, modify drugs, help with aetiology". This is fairly accurate.  The BTS guideline mentions LFTs as a means of identifying Legionella cases (which tend to have deranged LFTs). Similarly, leptospirosis presents with a degree of hepatitis.   
  • Respiratory viral swabs (NAT) - locally, the viral swabs are tested (PCR) for several clinically important viruses, including influenza A and B, parainfluenza, RSV, rhinovirus, adenovirus and possibly one or two others. The BTS suggest that this PCR approach is superior to waiting for serological tests
  •  Inflammatory markers, eg. CRP and procalcitonin  are discussed in the BTS and ISDA guidelines. Salient points made by the societies include the following:
    • CRP which fails to fall by 50% byy day 3-4 is associated with an increased 30-day mortality
    •  CRP levels over 100 were 96% sensitive in identifying pneumonia in one poorly-designed study
    • Procalcitonin seems to be a sensitive marker of severe disease and bacterial (especially pneumococcal) aetiology.

References

Metlay, Joshua P., Wishwa N. Kapoor, and Michael J. Fine. quot;Does this patient have community-acquired pneumonia?: Diagnosing pneumonia by history and physical examination." Jama 278.17 (1997): 1440-1445.

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

Blum, Claudine Angela, et al. "Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial." The Lancet 385.9977 (2015): 1511-1518.

Lim, W. S., et al. "British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together." Thorax (2015): thoraxjnl-2015.

Lim, Wei Shen, et al. "BTS guidelines for the management of community acquired pneumonia in adults: update 2009." Thorax 64.Suppl 3 (2009): iii1-iii55.

Eccles, Sinan, et al. "Diagnosis and management of community and hospital acquired pneumonia in adults: summary of NICE guidance." BMJ 349 (2014): g6722.

The actual NICE recommendations (2014)

Lim, W. S., et al. "Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study." Thorax 58.5 (2003): 377-382.

Levin, Kenneth P., et al. "Arterial Blood Gas and Pulse Oximetry in Initial Management of Patients with Community‐acquired Pneumonia." Journal of general internal medicine 16.9 (2001): 590-598.

Venkatesan, P., and J. T. Macfarlane. "Role of pneumococcal antigen in the diagnosis of pneumococcal pneumonia." Thorax 47.5 (1992): 329-331.

Muder, Robert R., and L. Yu Victor. "Infection due to Legionella species other than L. pneumophila." Clinical infectious diseases 35.8 (2002): 990-998.

Johansson, Niclas, et al. "Procalcitonin levels in community-acquired pneumonia-correlation with aetiology and severity." Scandinavian journal of infectious diseases 46.11 (2014): 787-791.

 

Question 2c - 2003, Paper 2

A 65 year old man has been admitted to your Intensive Care Unit with a presumptive diagnosis of community acquired pneumonia. He is sedated, intubated and ventilated, and is haemodynamically stable.

(c) What empiric therapy would you commence (drugs, dosage, route and duration)?  Discuss why.

College Answer

One example would be: Erythromycin 1 g IV 6 hrly plus ceftriaxone 1 g IV daily. Covers common pathogens including atypicals and Haemophilus (but not pseudomonas, Pneumocystis, Burkholderia), well tolerated, reasonably cheap.

Discussion

Current guidelines recommend a broad-spectrum third generation cephalosprin (eg. ceftriaxone 1g bd) and a macrolide (eg. azithromycin 500mg daily). These should be given IV, for a minimum of 5 days (but more likely for 7)

The most recent NICE guidelines make the following recommendations for the British pneumonia patient with moderate or severe disease:

  • 7-10 days of antibiotics
  • Dual therapy (a β lactam and a macrolide) for severe pneumonia.

References

 

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

2014 National Institute for Health and Care Excellence (NICE) Pneumonia Guidelines

Question 2d - 2003, Paper 2

A 65 year old man has been admitted to your Intensive Care Unit with a presumptive diagnosis of community acquired pneumonia. He is sedated, intubated and ventilated, and is haemodynamically stable.

(d) What factors would make you subsequently change from your initial choice of antibiotic therapy?

College Answer

Altering initial format if other suspected pathogens (e.g. gentamycin and meropenem for Burkolderia; cotrimoxazole for Pneumocystis etc.). Allergies (become known or develop). Discover unexpected resistance pattern. Other organisms causative (eg. Mycobacterium TB). Develop nosocomial superinfection or develop resistance. Develop side effect related to drug (e.g. severe liver function abnormalities). Spectrum may be narrowed if specific organism

Discussion

What factors would cause you to change your antibiotic choice?

  • historical evidence pointing to a specific pathogen
  • microbiological identification of the pathogen, their sensitivities and resistances
  • failure to improve clinically with fevers and rising inflammatory markers in spite of antibiotic therapy 48-72hrs after commencement of antibiotics
  • patient intolerance of empiric antibiotic therapy due to side-effects

A better-worded question can be found in Question 18 from the first paper of 2012; the college wants to know "What are the possible reasons for non-response to empiric treatment for patients treated for severe community acquired pneumonia?" 

References

 

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

 

Question 1b - 2004, Paper 1

A 60-year-old woman has a right hemi-hepatectomy for invasive cholangio-carcinoma. She has been admitted to your unit for postoperative care.

b) On day 3, she has a rigor and blood cultures grow enterococcus faecalis.

How will you manage this?

College Answer

The rigor should demand culture of all possible sources: sputum, blood, urine, T Tube and other drains. Consideration of broad spectrum antibiotic cover should occur at that time. Once the definitive culture is known, specific therapy (ie amoxicillin or vancomycin) should be given and also, a reason why this gut organism has been grown should be elicited.

Discussion

This was the second part of one of those old "long answer questions".

Thus, one falls back on the old "approach to an unexplained fever in ICU". In short, you culture everything, and briefly think about non-infectious causes of fever, such as...

  • vasculitis
  • myocardial infarction
  • DVT/PE
  • SAH
  • malignancy, particularly haematological
  • etc, etc...

While looking for the source of infection, one may wish to use broad-spectrum antibiotics. Given the recent history of abdominal surgery, all eyes would be on the abdomen as a potential source, and Tazocin would probably be viewed as a reasonable choice of broad-spectrum antibiotic.

As soon as one has convinced themselves and others that E.faecalis is to blame, one should start specific therapy. For E.faecalis, ampicillin is usually enough according to antimicrobe.org.

Vancomycin is an odd choice. Its penetration into inflamed tissues is notoriously poor. And on top of that, it covers only Gram-positive organisms. Some of which will also be susceptible to ampicillin, so... why not use ampicillin? And some of the organisms - which are resistant to ampicillin - may also be resistant to vancomycin.

Enterococcal bacteraemia should be treated for a minimum of 2 weeks, even if there are no mechanical devices suspended in the bloodstream.

References

Poh, C. H., H. M. L. Oh, and A. L. Tan. "Epidemiology and clinical outcome of enterococcal bacteraemia in an acute care hospital." Journal of Infection 52.5 (2006): 383-386.

 

Bota, Daliana Peres, et al. "Body temperature alterations in the critically ill."Intensive care medicine 30.5 (2004): 811-816.

 

MAKI, DENNIS G., and WILLIAM A. AGGER. "Enterococcal bacteremia: clinical features, the risk of endocarditis, and management." Medicine 67.4 (1988): 248.

 

Question 3 - 2004, Paper 1

Critically evaluate the role of fluconazole in the management of the critically ill patient.

College Answer

Fluconazole is  an  azole  anti-fungal  agent  that  has  good  bioavailability (can  be  administered enterally). It has a proven role in treatment of candidal (skin/mucosal/systemic) and cryptococcal infections as an alternative to amphotericin. It has much less activity against other fungal pathogens (e.g. aspergillus species). Usual duration of therapy is until evidence of active fungal infection has subsided. Specific anti-fungal sensitivities may  be  required. Usually fluconazole is  very well tolerated,  but  observed  adverse  effects  include  an  increase  in  trans-aminase  enzymes,  other gastrointestinal & haematological problems, adrenal suppression, and rare cases of QT prolongation and torsades de pointes. As fluconazole is predominantly renally excreted as the unchanged drug, dose adjustment is required with renal impairment. Fluconazole is an inhibitor of the cytochrome P450 system, particularly the CYP2C, and as such may increase concentrations of various drugs (e.g. warfarin, theophylline, cyclosporin, oral hypoglycaemic agents, phenytoin, and midazolam). Recent interest has surrounded empiric therapy in patients with septic shock. One small prospective randomised study suggested improved 30 day and hospital mortality when 200 mg fluconazole was administered daily to patients with septic shock (due to either intra-abdominal source or nosocomial pneumonia) until resolution of shock. The majority of the benefits were attributable to the group with intra-abdominal sepsis. (Jacobs S et al. Crit Care Med 2003 31(7):1938-46)
Fluconazole  also  has  a  role  in  prophylactic  therapy  (e.g.  HIV  patients)  and  in  prolonged maintenance therapy (e.g. HIV patients with cryptococcal meningitis or recurrent oropharyngeal candidiasis).

Discussion

What do they mean, "critically evaluate fluconazole"?

Functionally, this question is analogous to "critically evaluate Thurday".

In contrast to other questions of this sort, which discuss the evidence behind some controversial practice or incompletely accepted study, this question asks about an azole antifungal drug.

Broadly, a summary of antifungal pharmacology is available to help answer similar quetsions in the future. It is difficult to approach this according to the classical template, but from the college answer it would seem that the examiners would have gladly accepted a list of uses for fluconazole, and some cautionary remarks about its elimination and interactions.

Definition

  • Fluconazole is a triazole antifungal agent.
  • Its effect is exerted by its inhibition of ergosterol synthesis in the fungal cell wall.

Rationale for use (...Indications for use?)

  • Fluconazole is an anti-yeast antifungal. It has good penetration into tissues, and is active against most forms of Candida albicans, as well as Cryptococcus.
  • Indications for IV fluconazole include systemic candidiasis with candidaemia and cryptococcal meningitis.
  • Indications also include severe localised infections, or infections of critical organs (eg. heart valves).

Advantages

Disadvantages

  • Most species of non-albicans Candida and most other fungi are not suceptible.
    • If one were called upon to mindlessly repeat rote-learned names of fluconazole-resistant yeasts, one would say C.kruzeiC.glabrata, and C.parapsilosis
  • Fluconazole needs adjustment in renal failure
  • It interacts with numerous other drugs by inhibiting the CYP450 system of metabolism
  • It may cause LFT derangement and QT prolongation.

Evidence

References

Rex, John H., M. G. Rinaldi, and M. A. Pfaller. "Resistance of Candida species to fluconazole." Antimicrobial Agents and Chemotherapy 39.1 (1995): 1.

 

Shorr, Andrew F., et al. "Fluconazole prophylaxis in critically ill surgical patients: A meta-analysis*." Critical care medicine 33.9 (2005): 1928-1935.

 

Sinnollareddy, Mahipal, et al. "Pharmacokinetic evaluation of fluconazole in critically ill patients." Expert opinion on drug metabolism & toxicology 7.11 (2011): 1431-1440.

 

Jacobs, Sydney, et al. "Fluconazole improves survival in septic shock: a randomized double-blind prospective study." Critical care medicine 31.7 (2003): 1938-1946.

 

Zervos, Emmanuel E., et al. "Fluconazole increases bactericidal activity of neutrophils through non-cytokine-mediated pathway." Journal of Trauma and Acute Care Surgery 41.3 (1996): 465-470.

 

Schuster, Mindy G., et al. "Empirical Fluconazole versus Placebo for Intensive Care Unit PatientsA Randomized Trial." Annals of internal medicine 149.2 (2008): 83-90.

Question 9 - 2004, Paper 2

Outline the causes, consequences and management of Vancomycin Resistant Enterococcus in the critically ill patient.

College Answer

Enterococci are intrinsically resistant to many antibiotics, but acquired resistance has more recently become a major problem. A genetic modification in the bacteria occurs, presumably as a result of exposure to vancomycin (more widespread recent use, including for penicillin resistant pneumococcus and its oral use for clostridium difficile). Resistance is readily transmitted between strains, with risk factors identified being previous treatment with anti- microbials (especially vancomycin, cephalosporins, and broad-spectrum antibiotics), increased length of stay, renal insufficiency, enteral tube feeding, prevalence of VRE colonised patients in the unit, and residents of long-term care facilities.

Consequences are determined by the presence of infection (UTI, bloodstream including endocarditis, and rarely respiratory infection), or just colonisation (main consequence being requirement for isolation and associated factors). Patients usually have significant pre- existing co-morbidities.

Management involves specific antibiotics if infected rather than colonised (depend on sensitivities: regimens may include one or more of ampicillin, tetracyclines, teicoplanin, quinolones, and quinupristin-dalfopristin), infection control related to the patient (isolation [avoiding direct contact], aggressive infection control, limiting broad spectrum antibiotics if possible, surveillance of patient until clear).

Discussion

This question is identical to Question 2 from the second paper of 2012 and closely resembles Question 26 from the first paper of 2007. The only difference is, in later years the examiners demonstrated an attachment to accuracy when they changed "causes" into "predisposing factors".

References

Question 13 - 2004, Paper 2

List the factors that would make you suspect Severe Acute Respiratory Syndrome in a patient with pneumonia, and outline your management strategy.

College Answer

SARS refers to a respiratory syndrome now known to be due to an infection with a novel coronavirus (SARS virus). Both the WHO and the CDC have published criteria for defining cases of SARS. The simpler WHO definition of a suspected case is someone who has fever (>38C), with cough or difficulty breathing, and either close contact with a person diagnosed as SARS or travel/residence (within 10 days of symptoms) in an area with recent local transmission of SARS. The CDC case definition adds radiographic findings in patients with respiratory illness without known aetiology. Patients often have non-specific symptoms (eg. malaise, headache and myalgias) but not gastrointestinal or neurological findings or a rash. SARS is still predominantly a diagnosis of exclusion.
Management: Prevention of disease transmission is crucial. Patients should be isolated in negative pressure rooms, and health care workers should wear masks (eg. N-95 respirator) to prevent airborne and droplet infection, and gowns/gloves/protective eyewear to prevent contact transmission (www.cdc.gov/ncidod/sars/ic.htm). Health care workers should be excluded from work if they develop symptoms within 10 days of exposure to a patient with SARS. No specific antiviral agents have been shown to be beneficial, though a number of antiviral agents and interferon have been tried (usually in combination with corticosteroids). General supportive care is the mainstay of treatment. As this is a diagnosis of exclusion, standard care (including antibiotics) for a severe respiratory illness should be considered. Confirmation of the disease is via antibodies to SARS virus or SARS RNA assays facilitates.

Discussion

SARS is an artifact of the past. However, this question touches upon some important points. It also interrogates the contemporary candidate's familiarity with the SARS coronavirus. The importance of this question may be greater with reference to the emerging MERS-CoV pathogen. All these horrendous viral pneumonias are lumped together into revision chapter, because

  • All are viruses without any specific treatment
  • All cause severe ARDS
  • All of these lifethreatening viral pneumonitis scenarios play out essentially the same.

Diagnostic criteria:

  • history of fever
  • at least one symptom of lower respiratory tract infection
  • pneumonia or ARDS on CXR
  • no alternative diagnosis

Supportive history

  • recent travel to affected region
  • contact with infected people
  • pregnancy

Clinical features

  • The incubation period lasted 2-10 days
  • persistent high fever, chills and rigor
  • malaise
  • myalgia
  • headache
  • dry cough
  • dyspnoea
  • diarrhoea
  • The patients did not report much sputum production, and were not complaining of sore throats or rhinorrhoea.

Investigations

  • Deranged LFTs, mainly ALT
  • Raised LDH
  • Raised CK
  • Lymphopenia
  • Features of DIC

Management:

  • Isolation facilities
  • Strict droplet and contact precautions (hand hygiene, gown, gloves, N95 masks and eye protection) for healthcare workers
  • Avoidance of nebulisers on general wards
  • Contact tracing and quarantine isolation for close contact
  • supportive ARDS management
  • ECMO may be necessary

References

Centers for Disease Control and Prevention (CDC. "Outbreak of severe acute respiratory syndrome--worldwide, 2003." MMWR. Morbidity and mortality weekly report 52.11 (2003): 226.

Centers for Disease Control and Prevention (CDC. "Outbreak of severe acute respiratory syndrome--worldwide, 2003." MMWR. Morbidity and mortality weekly report 52.11 (2003): 226.

Li, Wendong, et al. "Bats are natural reservoirs of SARS-like coronaviruses." Science 310.5748 (2005): 676-679.

Chan, Paul, Julian Tang, and David Hui. "SARS: clinical presentation, transmission, pathogenesis and treatment options." Clinical Science 110 (2006): 193-204.

Sharif-Yakan, Ahmad, and Souha S. Kanj. "Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives." PLoS pathogens 10.12 (2014): e1004457.

 

Question 2b - 2004, Paper 2

A 45-year-old intellectually handicapped man is admitted to your Intensive Care Unit for airway management.  He was nasally intubated for evacuation of a large dental abscess, which had caused airway compromise.

(b)       Within 24 hours he has become febrile, and has developed hypotension and bilateral large pleural effusions.  Describe your management of these problems.

College Answer

The development of a fever within 24 hours of an evacuation of a large dental abscess is not unexpected (infection/inflammation). It would be reasonable to repeat cultures (especially of blood and available sputum) but the antibiotic therapy started to cover the expected causative organisms should not need to be altered. Non-infective causes of fever are possible at this early stage but are less likely. Other sites of infection (seeded from the oral source are possible [eg. osteomyelitis, endocarditis]).


Hypotension should be treated on its merits and could be due to any of or a combination of: hypovoalemia (relative/absolute), cardiogenic (ischaemia, arrhythmia [tachy- or brady-]), obstructive (pulmonary emboli, pericardial collection, tension pneumothorax, large pleural collections) or distributive/vasodilatory (sepsis, anaphylaxis, sedation [removal of endogenous catecholamines , or direct effects]). Management depends on the specific causes but requires a systematic approach (including careful clinical examination, assessment of fluid status ± more invasive assessments [echocardiography, PA catheter or other assessment of cardiac output).


New, large, bilateral pleural effusions are unusual and should be confirmed on more than an Xray appearance (eg. ultrasound, CT scan). Definitive treatment would be drainage via intercostal tube insertion (which would also allow sampling of fluid to be sent for microscopy and culture, protein and electrolytes, and cytology). Specific causes to be considered can be divided into transudative (eg. congestive cardiac failure, low albumin, constrictive pericarditis, ascites) and exudative (eg. pneumonia, intra-abdominal abscesses, oesophageal rupture, chylothorax). Treatment needs to also address the underlying cause.

Discussion

A systematic approach is called for.

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history
  • Airway
    • Assess the volume of bronchial secretions; collect some for culture
  • Breathing/ventilation
    • Assess the effect these effusions are having on ventilation with an ABG and adjust ventilator settings to maintain normoxia and normocapnoea
  • Circulatory support
    • Systematically assess the causes of the hypotension
    • Start management with a fluid bolus; assess the need for vasopressors
    • ECG and TTE to rule out a cardiac cause of the effusion
  • Supportive management
    • Correct hypoalbuniaemia
    • Address the need for nutrition if the patient appears to be malnourished
  • Specific management
    • Culture blood and urine as well as sputum
    • Collect a sample of pleural fluid for analysis and culture
    • Consider adjusting the antibiotic regimen to cover a more broad range of pathogens
    • Consider a CT chest if the effusion fluid resembles something suspicious (eg. frank pus of a ruptured abscess, or chyle)

References

Question 7 - 2005, Paper 1

Compare and contrast the pharmacology of adrenaline,  dopamine and dobutamine when used by infusion for the treatment of septic shock.

College Answer

No human clinical trials have demonstrated any benefit to any particular vasoactive drug or combination in sepsis.

Adrenaline: endogenous adrenergic agonist, opaque ampoule (usually 1:1000 solution), administered  diluted   as   infusion,  rapidly  inactivated  by  liver   (Catechol  O-Methyl Transferase  and  Mono-Amine Oxidase),  duration  of  action  minutes,  activates  alpha-1,alpha-2, beta-1 and beta-2 receptors. Causes initial dose dependent increase in heart rate, cardiac output.   Blood pressure may not increase initially (beta-2 effects: smooth muscle vasodilatation, but also propensity for hypokalaemia, hypophosphataemia, hyperglycemia and increased lactate).   In higher doses vasoconstriction predominates.   May cause pulmonary arterial vasoconstriction. Dose range is unit dependant (eg. 1-30 microgram/min [0.01-0.5 microgram/kg/min]).  Caution with MOA inhibitors.  Central venous access for safety.

Dopamine: endogenous adrenergic agonist, ampoule 200mg/5 mL (with meta-bisulfite), administered  diluted   as   infusion,  rapidly  inactivated  by  liver   (Catechol  O-Methyl Transferase and Mono-Amine Oxidase), duration of action < 10 minutes.   At increasing dose range activates dopaminergic receptors (0.5 – 2 microgram/kg/min)(dopa-1 = sphlanchnic  vasodilatation  and   diuresis),   beta-1   receptors   (2-10   microgram/kg/min: increased heart rate, cardiac output), and finally alpha receptor activation (>10 microgram/kg/min: vasoconstriction, blood pressure elevation).   Indirect action also via release of noradrenaline.  May cause pulmonary arterial vasoconstriction and interacts with pituitary hormone release.   Caution with MAO inhibitors and phenytoin (hypotension, bardycardia). Central venous access required for safety.

Dobutamine:  exogenous  adrenergic  agonist  compound  resembling  dopamine.  Ampoule

250mg/20 mL (with meta-bisulfite) containing racemic mixture of levo and dextro enantiomers, administered diluted as infusion, rapidly inactivated (methylated and conjugated), with duration of action minutes.  Levo: alpha-1 agonist (pressor effect), with modest beta-2 effects. Dextro: beta-1 and beta-2 agonist with alpha-1 blocking activity. Combination of effects complex, but usually inotropic with some vasodilatation (ie. blood pressure may fall, and in sepsis commonly requires an additional vasoconstrictor eg. noradrenaline); pulmonary arterial vasodilatation rather than vasoconstriction.  Dose range

2.5 to 40 microgram/kg/min.  Overall vasodilation means can be administered safely via a peripheral vein.

Discussion

Again, a question where the answer works better as a table.

Features

Dopamine

Dobutamine

Adrenaline

Class

Endogenous catecholamine

Synthetic catecholamine

Endogenous catecholamine

Pharmacokinetics

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Half-life 2-3minutes
Metabolised by MAO and COMT

Receptor activity

Predominantly alpha-1 agonist activity;
Some beta-1 and beta-2 effects at high doses

Predominantly beta-1 receptor agonist at low doses, with more alpha-effects  as dose escalates
D-1 receptor agonist at low doses

Mixed non-selective alpha and beta agonist

Mechanism

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins

Increases intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Increases intracellular IP3, which in turn increases the availablility of intracellualr calcium to smooth muscle contractile proteins.

Additionally, the beta-effects increase intracellular cAMp, thus increasing the amount of intracellular calcium available for contractile elements.

Benefits in sepsis

Maintenance of vascular smooth muscle tone to maintain normotension

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Maintenance of vascular smooth muscle tone to maintain normotension

Increase cardiac contractility, thus increasing tissue perfusion

Adverse effects

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

Arrhythmogenic at the high doses required for treatment of severe sepsis

Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena

No evidence for any renal protective effects

The beta-2 vasodilatory effect may result in a decrease of blood pressure, which would be counterproductive in sepsis.

Increased cardiac oxygen demand due to increased contractility and heart rate may cause ischaemic phenomena

Peripheral vasoconstriction may worsen the microcirculatory shunting of sepsis

Lactic acidosis develops due to beta-2 and beta-3 effects

References

Beale, Richard J., et al. "Vasopressor and inotropic support in septic shock: an evidence-based review." Critical care medicine 32.11 (2004): S455-S465.

Oba, Yuji, and Nazir A. Lone. "Mortality benefit of vasopressor and inotropic agents in septic shock: A Bayesian network meta-analysis of randomized controlled trials." Journal of critical care 29.5 (2014): 706-710.

Wilkman, E., et al. "Association between inotrope treatment and 90‐day mortality in patients with septic shock." Acta Anaesthesiologica Scandinavica 57.4 (2013): 431-442.

Question 27 - 2005, Paper 2

Outline  the diagnostic  features of pseudomembranous colitis and list the likely causes in patients  in Intensive Care.

College Answer

Diagnostic features include: Watery Diarrhoea, Bloody diarrhoea, Pseudomembranes (may be passed with stool or may be visible on bowel mucosa on colonoscopy), Recent or current course of antibiotics, Abdominal tenderness, fever, increased WCC. Clostridium difficile infection can be asymptomatic.

Diagnosis confirmed by detection of clostridium difficile toxins (A &/or B) in stool (toxin present in 95% of patients with pseudomembranous colitis).

Other features on investigations: Plain AXR - mucosal thickening, "thumbprinting", or colonic distension; CT abdo – wall thickening, irregular bowel wall margin, pericolonic stranding, ascites. Features of complications include: electrolyte disturbances (low K, normal anion gap acidosis due to bicarbonate loss), hypoalbuminaemia, dehydration, toxic megacolon, perforation, pneumoperitoneum, possibly progressing to shock MOF.

Likely causes in patients in Intensive Care: Clostridium difficile infection; Overgrowth of clostridium due to eradication of other organisms; Antibiotics – particularly reported following clindamycin, cephalosporins (particularly 3rd generation), ampicillin/amoxycillin but can occur after any (less likely with ticarcillin/clavulanate, aminoglycosides, quinolones). More likely following shock and decreased gut perfusion, renal failure and in the old and debilitated or in patients with immunocompromise such as haematological malignancy or HIV infections.

Discussion

C.difficile infection is a favourite of the college, and appears frequently in the papers.

For instance, Question 3 from the first paper of 2013 asks even more detailed questions.

To bring together all the previously exmained aspects of pseudomembranous colitis, a summary ofC.difficile infection is available in the Required Reading section.

Diagnostic features:

  • Abdominal pain
  • Loose stools
  • History of broad spectrum antibiotics, particularly Clindamycin
  • Characteristic "thumbprinting" of bowel on plan Xrays
  • Inflamed appearance of bowel on CT
  • Direct confirmation of pseudomembranes on colonoscopy
  • C.difficile toxin A or B on stool PCR
  • Toxic megacolon
  • Perforation and pneumoperitoneum
  • Fever > 38°
  • Renal failure

Causes of pseudomembranous colitis in ICU:

Surely, the college - being composed of people with a certain respect for specificity- would be asking for the specific causes of pseudomembranous colitis. Of which there really is only one: C.difficile. The rest of the "likely causes" mentioned in the model answer are associated factors. The use of clindamycin does not "cause" this disease.

That said, not all pseudomembranous colitis is due to C.difficile infection.

Alternative pathogens include:

  • Strongyloides stercoralis
  • Staphylococcus aureus
  • Clostridium perfringens
  • Yersinia
  • CMV
  • Entamoeba
  • Listeria
  • All the enterohaemorrhagic diarrhoea organisms:
    • Salmonella
    • Shigella
    • Campylobacter
    • E.coli

Factors associated with C.difficile enterocolitis are as follows:

References

 

Loo, Vivian G., et al. "Host and pathogen factors for Clostridium difficile infection and colonization." New England Journal of Medicine 365.18 (2011): 1693-1703.

 

Thomas, Claudia, Mark Stevenson, and Thomas V. Riley. "Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review." Journal of antimicrobial chemotherapy 51.6 (2003): 1339-1350.

 

Anand, Ajay, and Aaron E. Glatt. "Clostridium difficile infection associated with antineoplastic chemotherapy: a review." Clinical Infectious Diseases 17.1 (1993): 109-113.

 

Cunningham, R., et al. "Proton pump inhibitors as a risk factor for Clostridium difficilediarrhoea." Journal of Hospital Infection 54.3 (2003): 243-245.

 

Pépin, Jacques, Louis Valiquette, and Benoit Cossette. "Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec." Canadian Medical Association Journal 173.9 (2005): 1037-1042.

 

Cunney, Robert J., et al. "Clostridium difficile colitis associated with chronic renal failure." Nephrology Dialysis Transplantation 13.11 (1998): 2842-2846.

 

Surawicz, Christina M., et al. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections." The American journal of gastroenterology 108.4 (2013): 478-498.

 

Henrich, Timothy J., et al. "Clinical risk factors for severe Clostridium difficile–associated disease." Emerging infectious diseases 15.3 (2009): 415.

 

FujitaniMD, Shigeki, W. Lance GeorgeMD, and A. Rekha MurthyMD. "Comparison of clinical severity score indices for Clostridium difficile infection."Infection Control and Hospital Epidemiology 32.3 (2011): 220-228.

 

Janvier, Jack, Susan Kuhn, and Deirdre Church. "Not all pseudomembranous colitis is caused by Clostridium difficile." The Canadian Journal of Infectious Diseases & Medical Microbiology 19.3 (2008): 256.

Question 8 - 2006, Paper 1

Outline  strategies  you  would  incorporate  to  prevent  central  venous  catheter  related infection.

College Answer

A number of different strategies should be considered. One approach to incorporate these follows:

Why? Confirm need for Central Venous Line (initial, and ongoing).

How? Pay attention to sterile insertion technique. Non occlusive dressing, transparent semipermeable dressing or dressing with topical disinfectant.

What? Use single lumen where possible; consider antibiotic impregnated line.

Where? Subclavian site preferentially over Internal Jugular or femoral; consider PICC lines

(peripherally inserted central catheters),

When remove? Daily site inspections, and consider early change.

Replace giving sets/lines regularly: blood and TPN giving sets 24hrly but other IV sets after 72 hrs

Twenty-two out of twenty-six candidates passed this question.

Discussion

This is one of those topics an intensivist is expected to be the master of. It is no wonder that the majority of candidates received a passing grade for their answers.

A recent SHEA/ADSA guidelines document (2014) is available for leasurely perusal. It, however, is too massive and fibrous to digest in a short span of time.

However, our very own ANZICS statement on insertion and maintenance of CVCs is a more concise and more manageable document. The following list of points is derived from this document.

This is a point-form synopsis of CVC features and practices associated with a decreased risk of CVC infection:

  • Intelligence use of CVCs (i.e. does the patient even need one?)
  • Subclavian lines.
  • Minimum number of lumens.
  • Use of dedicated lumens for lipid infusions.
  • Immunosuppressed patients or those with burns should have antibiotic-coated lines.
  • For insertion, use aseptic technique and maximal barrier precautions.
  • 0.5% chlorhexidine in 70% alcohol is the preferred cleaning agent.
  • Handle ends of administration sets with gauze soaked in chlorhexidine).
  • Review the line daily.
  • Remove the line as soon as possible.
  • Change lines early - ideally, every 7 days.
  • Sterile, transparent semipermeable dressings
  • Change dressings regularly (every 7 days for standard dressings)

References

Marschall, Jonas, et al. "Strategies to prevent central line–associated bloodstream infections in acute care hospitals: 2014 update." Strategies 35.7 (2014): 753-771.

 

ANZICS statement on prevention of central line associated infections

 

ANZICS statement on insertion and maintenance of CVCs

 

 

.LIFL have made as short a summary as one can manage without omitting vital facets of the overall strategy.

 

Question 26 - 2006, Paper 1

A 65 year old man has been admitted to your Intensive Care Unit with a presumptive diagnosis of community  acquired pneumonia.  He is sedated, intubated and ventilated, and   is  haemodynamically  stable.     List  specific  historical  information  you  would attempt to obtain and discuss why.

College Answer

Various specific pieces of historical information should be ought, including:
- Factors that might alter aetiology: recent or current hospitalisation, nursing home etc (more nosocomial like, including Gram negatives); areas associated with outbreaks (e.g. legionella); exposure to specific scenarios eg. Birds (psittacosis); exposure to communities with specific resistance patterns (eg. Drug resistant pneumococcus), risk for pseudomonas (structural lung disease e.g. bronchiectasis, corticosteroids, previous broad spectrum antibiotic use, undiagnosed HIV), recent travel (e.g. Burkholderia pseudomallei, SARS, bird flu).
- Information regarding specific immunosuppression may also allow better coverage of potential organisms: consider T cell dysfunction (e.g. AIDS, immunosuppressive therapy and risks of Pneumocystis and TB), neutropenia (e.g. Pseudomonas, Fungi), previous splenectomy etc.
- Risk factors for poor prognosis: include age > 65, co-morbidities (eg. Diabetes, renal failure, neoplastic disease, alcoholism, immunosuppression), and possibly rapidity of onset.
- Typical or atypical nature of symptoms is usually sought, but their specificity is poor.
- Usual historical data regarding other major illnesses/co-morbidities, drugs, allergies, etc.

Discussion

This strange question could be managed in a number of ways. Massive amounts of historic information may be relevant.

Lets try to consolidate this into a systematic answer

Patient's medical history of prognostic importance

  • smoking
  • COPD
  • heart disease, including CCF and pulmonary hypertension
  • exercise tolerance
  • immunesuppression, eg. corticosteroids
  • malignancy
  • vaccination history
  • history of exposure to TB, country of origin
  • end-stage organ failure, eg. cirrhosis or dialysis-dependent renal failure

Recent history of aetiological importance

  • swallowing difficulty, history of stroke
  • alcohol binges
  • haemoptysis
  • recent travel
  • recent gardening (Legionella)
  • recent bushwalking
  • exposure to birds or pets
  • recent chemotherapy
  • recent hospital stay
  • recent antibiotic use

Presenting history

  • rapidity of onset
  • associated symptoms eg. copious amounts of sputum, flu-like symptoms, hemoptysis, pleuritic chest pain, and so forth

References

Metlay, Joshua P., Wishwa N. Kapoor, and Michael J. Fine. "Does this patient have community-acquired pneumonia?: Diagnosing pneumonia by history and physical examination." Jama 278.17 (1997): 1440-1445.

 

Question 19 - 2006, Paper 2

Outline the strengths and weaknesses surrounding the Surviving Sepsis Campaign Guidelines of 2003 (which have been endorsed by the various National Societies of Critical Care Medicine).

College Answer

Strengths include

1)  A major document summarizing a large body of evidence towards the management of a common clinical problem akin to the BTF guidelines for neurotrauma

2)  Also provided access to a major literature review on the subject

Criticisms include

a)  Strength of evidence: More than 50% of recommendations are Level E (case reports, expert opinions, non-randomised historical controls)
b)  Only 5 had a Level A recommendation ( based on RCTs – which included avoiding supranormal DO2, avoiding high dose steroids etc)
c)  Extrapolation of evidence from non-septic studies

d)  Significant omissions : - Eg SDD
e)  Perception that the sepsis bundles suggested by the campaign may be an over interpretation
f)   That there was industry sponsorship in the development of this process

Discussion

In order to tailor this answer to the environment of late 2014-early 2015, I direct the gentle reader to Question 1 from the first paper of 2014, where the discussion answers this question with specific reference to the modern (2012) incarnation of the Surviving Sepsis Guidelines. The guidelines themselves have been subjected to a thorough autopsy at LITFL, and I merely summarise the key points into an easily retained morsel for the time-poor exam candidate.

Paul Marik tore apart the guidelines in 2011, and his article is the definitive source for this answer.

To answer this question to a satisfactory depth, a detailed critique of the 2012 Surviving Sepsis Guidelines is also available in the Required Reading section.

References

Question 25 - 2007, Paper 1

You are supervising a registrar during the insertion of a central line. He suffers a needle stick injury.
Outline your approach to this problem.

College Answer

Stop the procedure, ensure patient is safe and you take over care if required.

Advise the registrar of the following:

•           Wash the wound immediately with soap and water. Express any blood from the wound
•    Alert your supervisor and initiate the injury reporting system used in your workplace.
•    IdentifY the source patient,. who may need to be tested for HIV, hepatitis B, or
hepatitis C infections.

      Report to employee health services, or other designated treatment facility.
•    Get tested immediately and confidentially for HIV, hepatitisB, and hepatitis C infections.
•    Document the exposure in detail, for your own records as well as for the employer. When the source patient is unknown or tests positive for HIV, hepatitis B, or hepatitis C infection, get postexposure prophylaxis (PEP) in accordance with CDC guidelines.If the patient has HIV,start prophylaxis within two hours of exposure. For possible hepatitis C exposure, no treatment is currently recommended, but you may want to talk to a specialist about experimental postexposure prophylaxis.     .
•         Make sure to follow up with postexposure testing at six weeks, three months, and six months, and depending on the risat one year. If PEP is prescribed, you should be monitored  regularly for signs and symptoms of toxicity. Take precautions (especially by practicing safe sex) to prevent exposing others  until follow-up testing is complete.
•    Don't be afraid to seek additional information or a referral to an infectious disease specialist if you have any questions.

Discussion

LITFL have an approach to staff needlestick injuries.

David Tripp's notes for the fellowship exam are also a source of a nice point-form algorithm.

A list of definitive sources for this information would include the NSW Health Policy Directive: HIV, Hepatitis B and Hepatitis C - Management of Health CareWorkers Potentially Exposed, as well as the Westmead Children's Hospital procedure "Needlestick and Blood Exposure Injuries: Health Care Worker".

An answer to this question, as a summary of the abovementioned references:

Immediate management:

  • Abort the procedure
  • Ensure the patient is safe:
    • Take over the procedure and finish it yourself; or
    • Delegate the task to a competent sataff member
  • Ask the registrar to express blood from the wound
  • Wash the punctured area with soap and water
  • Report the incident

Risk assessment:

  • Is the patient known to have Hpe B, C, or HIV?

The following are associated with an increased risk of transmission:

  • Hollow needle
  • Large needle diameter
  • Needle was previously in an artery or vein
  • Absence of gloves 
  • Depth of wound 
  • Into artery or vein
  • Exposed to a large volume of blood
  • High blood titre of HIV, Hep B or C

Management

  • Document the Hep B immunisation status of the staff member
  • Perform antibody tests of both the staff member and the patient, with written consent
  • If the source is known to be Hep B C or HIV positive,
    • Solicit advice from infectious diseases authorities
    • Arrange appropriate vaccinations, antiretroviral prophylaxis and councelling
    • Arrange follow-up for the patient and staff member
  • Possible management strategies:
    • For Hep B, IV immunoglobulin may be appropriate
    • For Hep C, there is nothing.
    • For HIV, postexposure antiretroviral therapy is helpful (and needs to be commenced within 2 hours!)
  • Safe sex for 6 months
  • Follow-up testing: 6 weeks and 6 months 
  • Review unit guidelines and compliance
  • Offer emotional support to the staff member, and get help from infectious diseases authorities to aid post-exposure councelling

References

Wicker, Sabine, et al. "Determination of risk of infection with blood-borne pathogens following a needlestick injury in hospital workers." Annals of occupational hygiene 52.7 (2008): 615-622.

 

McGovern, Patricia. "Needlestick injuries among health care workers: a literature review." AAOHN Journal 47 (1999): 237-244.

 

NSW Health Policy Directive: HIV, Hepatitis B and Hepatitis C - Management of Health CareWorkers Potentially Exposed

 

Westmead Children's Hospital procedure: "NEEDLESTICK AND BLOOD EXPOSURE INJURIES: HEALTH CARE WORKER"

Question 26 - 2007, Paper 1

Outline the causes, consequences and management of Vancomycin Resistant Enterococcus in the critically ill patient.

College Answer

Causes:

1)  previous treatment with anti-microbials (especially vancomycin, cephalosporins, and broad-spectrum antibiotics),
2)  increased length of stay, renal insufficiency,
3)  enteral tube feeding,
4)  prevalence ofVRE colonised patients in the unit, and
5)  residents of long-term care facilities.

Consequences:

1)   potential transmission of resistance to Staph aureus
2)  are determined by the presence of infection (UTI, bloodstream includfug endocarditis, and rarely respiratory infection),
3)  or just colonisation (main consequence being requirement for isolation and associated factors

Management

Involves specific antibiotics if infected rather than colonised (depend on sensitivities: regimens may include one or more of ampicillin, tetracyclines, teicoplanin, quinolones, and quinupristin-dalfopristin),  infection control related to the patient (isolation [avoiding direct contact], aggressive infection control, limiting broad spectrum antibiotics if possible, surveillance of patient until clear).

Discussion

VRE is a much-beloved organism of the college examiners.

This question closely resembles Question 2 from the second paper of 2012.

References

Question 27 - 2007, Paper 1

Briefly outline the difficulties encountered in the clinical and laboratory  diagnosis of sepsis in the critical care unit.

College Answer

-Clinical: 
a) Fever and other SIRS criteria have low specificity 
b) No specific clinical signs of sepsis apart from specific syndromes such as endocarditis 
c) Elderly, immunocompromised and malnourished patients-do not manifest typical signs of sepsis 
d) Both infective and non infective causes of SIRS may coexist in the same patient and therefore presence of inflammation not always a reliable sign. 
e) Deep seated collections difficult to diagnose


-Laboratory 
a) Leukocytosis not specific as it is a marker of stress rather than infection 
b) Reliable diagnosis established by presence of organisms only in blood or in sterile tissues; but tissues may be difficult to obtain 
c) Administration of antibiotics frequently before diagnostic tests limits utility of cultures 
d) Cultures might sometimes take time for positive results to come back 
e) Tests such as PCR might not be universally available 
f) Serology tests frequently non specific 
g) Biomarkers such as procalcitonin and CRP and IL-6 do not have a high sensivity and specificity. 
h) Lack of consensus on criteria regarding what constitutes ventilator associated pneumonia, line sepsis etc.

Discussion

My own attempt to rewrite the answer to this question is non-superior to the college answer. It is surprisingly difficult to find any article which complains about how difficult it is to make the diagnosis of sepsis.

Clinical criteria for SIRS have poor specificity for sepsis

  • Not all septic patients are febrile or hypothermic. Many are normothermic.
  • Tachycardia can represent hypovolemia, anxiety, pain, or inotrope effect.
  • Tachypnoea may represent anxiety, pain or aseptic metabolic acidosis
  • Some patient groups will not be able to manifest clinical features of SIRS:
    • Malnourished patients
    • Immunocompromised
    • Therapeutically cooled
    • Elderly patients
    • Hypothyroid patients
  • Infectious and non-infectious causes of SIRS may co-exist

Infectious source may be unclear

  • The patient is sedated and cannot participate in history-taking.
  • There are no generic features of 'infection" to look for.
  • Specific features of infection may be obscured by other clinical findings
  • Criteria for the diagnosis of an infectious source are frequently not available (eg. central line associated bacteraemia, ventilator-associated pneumonia, etc).
  • Clinical features of specific syndromes may be shared by non-infectious pathology (eg. purpura fulminans)

The laboratory markers of sepsis are non-specific

  • All biochemical markers of sepsis can become elevated due to non-infectious causes.
  • Serology tests and PCR studies may not be organism-specific, or may require convalescent samples.
  • Microbiology is unreliable, because:
    • Sample may be difficult to obtain
    • Organism may be difficult to culture (eg. Treponema pallidum)
    • Sample may be sterilised by antibiotic therapy
    • A positive sample culture may represent colonisation rather than infection.
    • Cultures take time to develop, whereas sepsis evolves rapidly - empiric therapy must be commenced long before microbiology is available.

References

Claessens, Yann-Erick, and Jean-François Dhainaut. "Diagnosis and treatment of severe sepsis." Critical Care 11.Suppl 5 (2007): S2.

 

Lynn, Lawrence A. "The diagnosis of sepsis revisited-a challenge for young medical scientists in the 21st century." Patient safety in surgery 8 (2014): 1.

 

Vandijck, D. M., J. M. Decruyenaere, and S. I. Blot. "The value of sepsis definitions in daily ICU-practice." Acta Clinica Belgica 61.5 (2006): 220-226.

 

Question 1 - 2007, Paper 2

List key features in pathogenesis, clinical presentation and management of staphylococcal toxic shock syndrome.

College Answer

Pathogenesis

•    Due to toxin (TSST-1, 2 or 3) released by Staph and enteroxin

•    TSST acts as a superantigen activating T-cells directly with massive elevation of cytokines

•    Classically associated with tampon use but also seen with surgical procedures and wound infection, cellulitis, sinusitis, HIV

•    Very similar and cause seen with other bacteria (toxic shock like syndrome) such asStreptococci

Presentation

•    Initially myalgia, fever

•    Vasodilated shock and multiple organ dysfunction

•    Marked erythema with desquamation 7-14 days later

•    Edema due to capillary leak syndrome

•    Blood cultures usually negative

Management

•    Resuscitation and support including adequate fluids, inotropes/organ support…

•    Search for source which may be covert – drain abscess……remove tampon

•    There may be a role for IVIg to bind toxin

•    Antibiotics may not alter course but infection should be treated

•    Lincomycin/Clindamycin may have a particular role as it inhibits synthesis of bacterial toxins

Discussion

A nice case of this was presented in the NEJM in 2013. PLOS have a good review article which presents observational data regarding the typical clinical manifestations. Donald Low has recently published an excellent overview in Critical Care Clinics. A summary of toxic shock syndromescraped together from these sources is available in the Required Reading section.

Pathogenesis of toxic shock syndrome

Some staphylococci produce a characteristic protein (the Toxic Shock Syndrome Toxin, or TSST-1, 2 and 3).

  • TSST activates T-cells directly, acting as a "superantigen"
  • Massive inflammatory cytokine release is the result
  • Endothelial dysfunction and vasodilatory shock ensues, which is out of proportion to the severity of the initiating infection.

Risk factors for toxic shock syndrome

  • Being female
  • Use of tampons

In fact, in Low's article, staphylococcal TSS is separated into "mentsrual" and "non-menstrual" categories. Apparently, the tampon introduces oxygen, which is required for TSS-1 production.

  • Surgical wound infection
  • Mastitis
  • Sinusitis
  • Osteomyelitis
  • Burns
  • Compromised immune system (eg. HIV)

Clinical manifestations of toxic shock syndrome

According to the CDC, there are four stereotypical criteria for toxic shock syndrome, all of which must be met:

  • High fever (> 38.9°)
  • Hypotension and shock
  • Rash consistent with diffuse macular erythroderma
  • Desquamation, particularly of the palms and soles

There are also non-diagnostic associated features:

  • Rapid onset: ~ 2 days
  • Staphylococcus may grow in the blood (but blood cultures otherwise negative)
  • Multisystem organ involvement

Management

  • Vigorous resuscitation a'la Surviving Sepsis guidelines, or perhaps something evidence-based.
  • Source control
  • β-lactam antibiotics
  • Clindamycin as an adjunct (prevents the synthesis of TSST)
  • Intravenous immunoglobulin (to bind circulating TSST)
    The dose of IV IG has generally been either 2g/kg as one hit. If the patient has already been "well filled" (i.e. they are in florid pulmonary oedema) one may split the dose into three days, with 1g/kg on the first day and 0.5g/kg on each subsequent day.

References

Chan, Bob CY, and Paul Maurice. "Staphylococcal Toxic Shock Syndrome."New England Journal of Medicine 369.9 (2013): 852-852.

 

DeVries, Aaron S., et al. "Staphylococcal toxic shock syndrome 2000–2006: epidemiology, clinical features, and molecular characteristics." PLoS One 6.8 (2011): e22997.

 

Kare, M., and A. Dang. "Staphylococcal toxic shock syndrome." JAPI 56 (2008).

 

KEHRBERG, MARK W., et al. "Risk factors for staphylococcal toxic-shock syndrome." American journal of epidemiology 114.6 (1981): 873-879.

 

Parsonnet, Jeffrey. "Mediators in the pathogenesis of toxic shock syndrome: overview." Reviews of infectious diseases (1989): S263-S269.

 

Low, Donald E. "Toxic Shock Syndrome." Crit Care Clin 29 (2013): 651-675.

 

Brosnahan, Amanda J., and Patrick M. Schlievert. "Gram‐positive bacterial superantigen outside‐in signaling causes toxic shock syndrome." FEBS Journal278.23 (2011): 4649-4667.

 

Kulhankova, Katarina, Jessica King, and Wilmara Salgado-Pabón. "Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression." Immunologic research(2014): 1-6.

 

Question 13 - 2007, Paper 2

A 50 year old man presents to hospital with fever and an acute abdomen. He undergoes an emergency laparotomy. The findings at laparotomy include :
-     a perforated carcinoma in the splenic flexure
-     generalised faecal soiling of the peritoneum.
He undergoes a left hemicolectomy with a defunctioinng  colostomy.  Postoperatively he is transferred to intensive care because of septic shock.

a)  What antibiotic regime  will you consider and why?

b) Despite a 5 day course of antibiotics, he remains unwell with fever upto 38.50C, WCC 16.7 X 109/L. He is unable to tolerate oral feeds and is on TPN. List the likely intra-abdominal causes of persistent fever and leukocytosis?

c)  What investigations will you perform?

d) Blood cultures grow candida glabrata in one of the 3 bottles. List 4 factors which may have predisposed this patient  to develop this infection.

e) What antimicrobial therapy will you commence whilst waiting for sensitivities and why

f) Based on the culture report, list 1 other investigation you will perform the results of which might influence the prognosis and duration of antifungal treatment.

College Answer

a)  What antibiotic regime  will you consider and why?

Triple therapy or Timentin or Tazocin – to cover enterococcus, gram negatives and anaerobes. Some may consider adding fluconazole empirically, although this is not common. Vancomycin/gent flagyl if pen allergy

b) Despite a 5 day course of antibiotics, he remains unwell with fever upto 38.50C, WCC 16.7 X 109/L. He is unable to tolerate oral feeds and is on TPN. List the likely intra-abdominal causes of persistent fever and leukocytosis?

-     intra-abd collection / wound infection / abd wall cellulitis/acalculous cholecystitis, pancreatitis, stomal necrosis

c)  What investigations will you perform?

- Blood/urine/sputum/wound swab cultures
- CT abdomen
- Consider line change and line tips for c/s
Consider screening for a DVT
-consider a diagnostic relook laparotomy (this will carry a higher mark)

d) Blood cultures grow candida glabrata in one of the 3 bottles. List 4 factors which may have predisposed this patient  to develop this infection.

- Malignancy, abdominal soiling, TPN, recent broad spectrum therapy, presence of foreign body -CVL
-

e) What antimicrobial therapy will you commence whilst waiting for sensitivities and why

Voriconazole or amphotericin B, caspofungin. Fluconazole may not cover glabrata.

f) Based on the culture report, list 1 other investigation you will perform the results of which might influence the prognosis and duration of antifungal treatment.

Echocardiography – for vegetation. ophthalmic examination for retinal absecesses CT abdominal scan - liver abscess

Discussion

This question very closely resembles Question 18 from the second paper of 2011.

References

Question 21 - 2008, Paper 1

A 77 year old woman presents 6 months after elective coronary artery bypass grafting and aortic valve replacement feeling unwell over a few days with fever and rigors. You suspect infective endocarditis. The results of a septic screen are awaited.

a. List 5 clinical findings you may encounter when you examine her

b.  List 3 organisms that are commonly implicated

c.   What antibiotic would you choose in this patient?              

Over the next few days she develops progressive worsening of renal function. Her serum creatinine is twice baseline

d.  Outline the causes for his worsening renal function

e. What are the indications for valve replacement in prosthetic valve endocarditis?

College Answer

a. List 5 clinical findings you may encounter when you examine her
i.    New murmur
ii.  Skin rash
iii. Osler’s nodes – Tender nodules on pulps of fingers and toes
iv. Janeway lesions – non-tender haemorrhagic macules in the peripheries

v.  Roth spots – Retinal haemorrhages with a pale centre
vi. Splenomegaly
vii. New neurological signs

viii.Tender and swollen joints

b.  List 3 organisms that are commonly implicated
i.    Coagulase negative Staphylococcal sp. (CONS) / S. Epidermidis
ii.  S. Aureus (MSSA/MRSA)
iii. Streptococci (Viridans)
iv. HACEK organisms
Haemophilus aphrophilus, Haemophilus parainfluenzae and Haemophilus paraphrophilus
Actinobacillus actinomycetemcomitans
Cardiobacterium hominis Eikenella corrodens Kingella kingae

c.   What antibiotic would you choose in this patient?               )
AB guidlelines suggest Vanc + gent only. Additional cephalosporin +/- quinolone,
acceptable
Further therapy governed by MIC/cultures\

Over the next few days she develops progressive worsening of renal function. Her serum creatinine is twice baseline

d.  Outline the causes for his worsening renal function

Dehydration

Cardiac failure

Nephrotoxic agents

Sepsis
Immune mediated Glomerulonephritis

e.      What are the indications for valve replacement in prosthetic valve endocarditis?

Hemodynamic instability
Recurrent emboli
Root abscess

Discussion

a)

Clinical manifestations of infective endocarditis include the following:

  • Osler's nodes
  • Janeway lesions
  • Splinter haemorrhages
  • Roth spots
  • Focal neurological signs suggestive of embolic phenomena
  • A new murmur or a worsening of an old murmur
  • Splenomegaly
  • Glomerulonephritis
  • Arthralgia and arthritis
  • Elevated ESR, CRP or rheumatoid factor
  • Haematuria

A 2009 article has a table (Table 3) which lists these manifestations according to their prevalence among a large patient cohort.

Typical valve-eating organisms may include the following:

  • S.epidermidis and other coagulase-negative staphylococci
  • Streptococcus viridans
  • S.aureus
  • Enterococcus
  • Coxiella burnetii (Q fever)

HACEK organisms are mentioned, even though they are responsible for only about 3% of native valve endocarditis.

  • Haemophilus species: H.aphrophilusH.parainfluenzae and H.paraphrophilus
  • Actinobacillus and Aggregatobacter species
  • Cardiobacterium hominis
  • Eikenella corrodens
  • Kingella kingae

The abovementioned large scale cohort review also lists microbial aetiology of IE in their patient group (their Table 5).

c)

There are a few different recipes around for the empirical management of IE, which makes perfect sense as these recommendations would differ according to the prevailing microbiome:

  • The Sanford guide (Hong Kong) recommends vancomycin and gentamicin or vancomycin and ceftriaxone as empiric therapy for native valve endocarditis, or vancomycin, gentamicin and rifampicin "triple therapy" for prosthetic valves. This is one of the few cases when one might give 1mg/kg of gentamicin every 8 hours.
  • The eTG (Australia) recommend benzylpenicillin, flucloxacillin and gentamicin, substituting vancomycin for the beta-lactams wherever MRSA is suspected or where the patient has sepsis or septic shock. For prosthetic valves, vancomycin flucloxacillin and gentamicin are recommended.

Historically, the CICM examiners seem to use eTG for their antibiotic choices. In this question they only said "AB guidlelines suggest Vanc + gent" without specifying which "AB guidelines" they meant. The patient in that specific question was recovering from AVR, and was "unwell over a few days with fever and rigors", which warrants vancomycin according to the eTG. Since 2008, eTG have also added flucloxacillin to vancomycin, as there is thought to be some sort of synergistic effect (Tong et al, 2016)

Immediate valve replacement for IE has been practiced for decades.

Even then, the following criteria for urgent surgery were followed:

  • Haemodynamic instability
  • Aortic root abscess
  • Ongoing embolic phenomena

A 1994 article reports that " surgical replacement of the infected valve led to significantly lower mortality (23%) as compared with medical therapy alone (56%)". However, IE recurrence was observed in 30% of patients after 30 days, and 69% of patients after 60 days.

References

Murdoch, David R., et al. "Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis–Prospective Cohort Study." Archives of internal medicine 169.5 (2009): 463-473.

 

Richardson, JAMES V., et al. "Treatment of infective endocarditis: a 10-year comparative analysis." Circulation 58.4 (1978): 589-597.

 

Windsor, HARRY M., and MARK X. Shanahan. "Emergency valve replacement in bacterial endocarditis." Thorax 22.1 (1967): 25-33.

 

Yu, Victor L., et al. "Prosthetic valve endocarditis: superiority of surgical valve replacement versus medical therapy only." The Annals of thoracic surgery 58.4 (1994): 1073-1077.

 

Question 22 - 2008, Paper 1

Outline the evidence for the role of glucocorticoids  in ARDS and septic shock and the current controversies surrounding their use in these conditions

College Answer

ARDS  – ARDS part of the sepsis inflammatory response, fibroprolifeartive pahse associated with laying down of collagen, hence use of steroids to reduce the extent of these processes.
Lines of evidence: a) Meduri study (JAMA) cross over trial showed a reduction in lung injury score and improved mortality (small sample). (Candidates not expected to name authors, if they do get bonus marks)

b) Recent Meduri study : Reduction in LIS, length of stay and duration of IPPV

c) Recent ARDS net study:  the use of steroids was not associated with any benefit and there was an increased incidence of reintubation. Improves oxygenation faster, more ventilator and shock free days, but higher complications such as weakness, reintubation – no mortality advantage

Septic shock –
• one of the most controversial areas,
• Basis thought to be relative adrenal insufficiency (RAI)
• Basis of RAI diagnosis questionable, -doubts about validity of using plasma cortisol and the synacthen test.
• Shown to be of benefit in meningitis

• In septic shock – high dose steroids (30 mg/Kg) clearly increase mortality
• Low  dose  steroids  improve  shock  reversal  –   only  one  RCT  study  showed improvement (ANNANE) but study limitations- trial design, use of etomidate
• A     recent  multicentre-study  (CORTICUS)  demonstrated  a  lack  of  benefit  with steroids, although the study was underpowered.

Discussion

This old issue is easy to scoff at from the enlightened position we now occupy, but the pendulum of expert opinion keeps swinging.

Let us consider this answer from such a position.

As far as ARDS goes, steroids have long been viewed as harmful. The discussion of pharmacological management for ARDS goes into this in greater detail.

Steroids in sepsis have also seen their heyday come and go, and now have been degraded to the position of ancillary therapies in vasopressor-refractory shock, to treat some imaginary spectre of relative cortisol deficiency. Everybody now agrees that high dose steroids increase mortality, and that though the evidence for steroids in sepsis is pretty weak, nobody should ever die of sepsis without having tasted some steroids.

To finish with this would be pretty superficial. In general, thecomplicated issue of steroids in sepsisis dealt with in some detail in a dedicated chapter on this topic, nested within the greater discussion of the management of shock. This discussion is also relevant to the topic of relative adrenal insufficiencywhich is an endocrine curiosity found in severe disease states. The question of using steroids in refractory shock states is answered in the discussion of Question 12 from the second paper of 2000.

In brief, a list of acceptable indications is as follows:

  • Adrenal insufficiency
    • Due to primary hypoadrenalism
    • Due to withdrawal of chronic exogenous corticosteroids
    • Due to relative insufficiency during critical illness
  • Severe septic shock
    • If the shock state is refractory to vasopressors and fluid resuscitation
  • Shock states due to autoimmune inflammatory disease
    • Severe vasculitis with widespread SIRS
    • Severe autoimmune myocarditis with cardiogenic shock

Anyway, the above is time-wasting gibberish. The college asks us to outline the evidence and current controversies. Thus:

Steroids and sepsis

Evidence

2002 French study:

  • Significant improvement in mortality among 300 septic patients, from 70% to 58%.
  • Severely shocked patients, 1.1μg/kg/min (75ml/hr) of noradrenaline.

2008 CORTICUS trial:

  • No mortality difference associated with the use of steroids.
  • Moderately shocked patients, only 0.5μg/kg/min (35ml/hr) of noradrenaline.

2009 meta-analysis:

  • 17 trials; conclusion: there is a small mortality benefit.

The same analysis, excluding all but 6 well-designed trials:

  • Conclusion: steroids did not improve survival

2013 Surviving Sepsis Guidelines:

  • Grade 2B recommendation in favour of steroids, provided they are reserved for those patients who are refractory to fluids and vasopressors.
  • Rationale: survival only seems to be improved in patients whose mortality from sepsis is likely to be over 60%.

Current controversies

  • Disagreement regarding the dose of steroids: is 200mg of hydrocortisone too much?
  • Disagreement regarding the timing of steroids: if one waits for shock to become "vasopressor-refractory", one risks damage o organ systems which might theoretically have been prevented if steroids were given earlier
  • Disagreement regarding the early identification of patients who may benefit: the short synacthen test and random cortisol levels do not seem to identify those patients whose survival chances are likely to improve as the result of steroids
  • Contempt of Surviving Sepsis guidelines: though a good literature search, some have argued that their interpretation of the evidence has been immature and superficial. Nowithstanding the corporate whoring, and the questionable use of an international guidelines statement to sell Edwards Life Sciences ScvO2 monitoring products.

Steroids and ARDS

Evidence

Current controversies

  • ARDS is aetiologically heterogeneous, and trials of ARDS as an undifferentiated group may obscure the subgroup-specific benefit (eg. ARDS due to pulmonary sepsis end up in the same intervention group as ARDS due to autoimmune pneumonitis).
  • Increased mortality due to weakness-associated complications may obscure increased survival due to improved respiratory function
  • Increased weakness may confuse studies which look for decreased ventilator time; a steroid-weakened patient with improved lungs will take longer to wean, similarly to a non-weakned patient with ARDS-damaged lungs
  • ARDS and severe sepsis frequently co-exist, and severe sepsis frequently receives "stress dose" steroids, with an observed improvement in mortality and decreased duration of shock.

References

LITFL have an excellent page, summarising the current literature on steroids in sepsis.

Scott, W. J. M. "THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE: II. THE TOXIC EFFECT OF KILLED BACTERIA IN ADRENALECTOMIZED RATS." The Journal of experimental medicine 39.3 (1924): 457.

Annane, Djillali, et al. "A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin." Jama 283.8 (2000): 1038-1045.

Cooper, Mark S., and Paul M. Stewart. "Corticosteroid insufficiency in acutely ill patients." New England Journal of Medicine 348.8 (2003): 727-734.

Kass, Edward H., and Maxwell Finland. "Adrenocortical hormones and the management of infection." Annual review of medicine 8.1 (1957): 1-18.

Robson, HUGH G., and L. E. Cluff. "Experimental pneumococcal and staphylococcal sepsis: effects of hydrocortisone and phenoxybenzamine upon mortality rates." Journal of Clinical Investigation 45.9 (1966): 1421.

SIBBALD, WILLIAM J., et al. "Variations in adrenocortical responsiveness during severe bacterial infections: unrecognized adrenocortical insufficiency in severe bacterial infections." Annals of surgery 186.1 (1977): 29-33.

Marik, Paul E., and Gary P. Zaloga. "Adrenal insufficiency during septic shock*." Critical care medicine 31.1 (2003): 141-145.

Cohen, Jeremy, et al. "Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population." Intensive care medicine32.11 (2006): 1901-1905.

Annane, Djillali, et al. "Diagnosis of adrenal insufficiency in severe sepsis and septic shock." American journal of respiratory and critical care medicine 174.12 (2006): 1319-1326.

Kromah, Fatuma, et al. "Relative adrenal insufficiency in the critical care setting: debunking the classic myth." World journal of surgery 35.8 (2011): 1818-1823.

Siraux, Valérie, et al. "Relative adrenal insufficiency in patients with septic shock: comparison of low-dose and conventional corticotropin tests." CRITICAL CARE MEDICINE-BALTIMORE- 33.11 (2005): 2479.

Yaegashi, Makito, and Arthur J. Boujoukos. "The low-dose ACTH test in the ICU: Not ready for prime time." Critical Care 10.4 (2006): 313.

Annane, Djillali. "Corticosteroids for severe sepsis: an evidence-based guide for physicians." Annals of intensive care 1.1 (2011): 1-7.

Sprung, Charles L., et al. "Hydrocortisone therapy for patients with septic shock." New England Journal of Medicine 358.2 (2008): 111.

Vassiliadi, Dimitra A., et al. "Longitudinal assessment of adrenocortical responses to low-dose ACTH in critically ill septic patients." Endocrine Abstracts (2013) 32 P26

Annane, Djillali, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock." Jama 288.7 (2002): 862-871.

Barnes, Peter J., and Michael Karin. "Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases." New England Journal of Medicine336.15 (1997): 1066-1071.

Kashiwabara, Moto, et al. "Surgical trauma-induced adrenal insufficiency is associated with postoperative inflammatory responses." Journal of Nippon Medical School 74.4 (2007): 274-283.

Ehrchen, Jan, et al. "Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes." Blood 109.3 (2007): 1265-1274.

Boyer, A., et al. "Glucocorticoid treatment in patients with septic shock: effects on vasopressor use and mortality." International journal of clinical pharmacology and therapeutics 44.7 (2006): 309-318.

Szabo, Csaba, et al. "Attenuation of the induction of nitric oxide synthase by endogenous glucocorticoids accounts for endotoxin tolerance in vivo."Proceedings of the National Academy of Sciences 91.1 (1994): 271-275.

MACNICOL, MALCOLM F., ALAN H. GOLDBERG, and GEORGE HA CLOWES. "Depression of isolated heart muscle by bacterial endotoxin."Journal of Trauma and Acute Care Surgery 13.6 (1973): 554-558.

Romero-Bermejo, Francisco J., et al. "Sepsis-induced cardiomyopathy."Current cardiology reviews 7.3 (2011): 163.

Asfar, Pierre, Jan Tuckermann, and Peter Radermacher. "Steroids and Vasopressin in Septic Shock—Brother and Sister or Just Distant Cousins?*."Critical care medicine 42.6 (2014): 1531-1532.

Annane, Djillali, et al. "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review." Jama 301.22 (2009): 2362-2375.

Sligl, Wendy I., et al. "Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis." Clinical infectious diseases 49.1 (2009): 93-101.

Burnham, Ellen L., et al. "The Fibroproliferative Response in ARDS: Mechanisms and Clinical Significance." European Respiratory Journal (2013).

Borg, T., B. Gerdin, and J. Modig. "Prophylactic and Delayed Treatment with High‐Dose Methylprednisolone in a Porcine Model of Early ARDS Induced by Endotoxaemia." Acta anaesthesiologica scandinavica 29.8 (1985): 831-845.

Weigelt, John A., et al. "Early steroid therapy for respiratory failure." Archives of Surgery 120.5 (1985): 536.

Steinberg, K. P., et al. "Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome." New England Journal of Medicine354.16 (2006): 1671-1684.

Tang, Benjamin MP, et al. "Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis*."Critical care medicine 37.5 (2009): 1594-1603.

Belvitch, Patrick, and Steven M. Dudek. "Corticosteroids and Acute Respiratory Distress Syndrome: The Debate Continues*." Critical Care Medicine 41.7 (2013): 1813-1814.

Question 24.1 - 2008, Paper 1

With regards to antibiotic  dosing, look at these drug concentration versus time curves for antibiotics and answer the questions below:

 
a)  What does “A” represents, name one antibiotic for which this is important with regards to dosing?

b)  What does “B” represents, name one antibiotic for which this is important with regards to dosing?

c)  What does “C” represents, name one antibiotic for which this is important with regards to dosing?

College Answer

a)  What does “A” represents, name one antibiotic for which this is important with regards to dosing?
C MAX: Maximum concentration 
Aminiglycosides

b)  What does “B” represents, name one antibiotic for which this is important with regards to dosing?
AUC > MIC: Area under the curved where drug concentration is greater than MIC Quinilones

c)  What does “C” represents, name one antibiotic for which this is important with regards to dosing?
T>AUC above MIC: Time greater than Area under the curved where concentration is greater than MIC

Penicillins, Carbenepenems

Discussion

This question is based on Table 72.2 from Oh's Manual, "Pharmacodynamic properties of selected antibiotics". It can be found on page 739 of the new edition. The table, in turn, is based on a 2009 article by Roberts and Lipman. The article even has a graph of concentration over time, which resembles the graph in the question. It was published one year after this college paper. In it, an excellent section entitled "Kill characteristics of antibiotics" describes the below concepts very well. This article, in turn, draws on material from an even earlier article from 2003 by William A. Craig, which is even more detailed. For the time-poor exam candidate, a brief summary of antibiotic kill characteristics is compiled in the Required Reading section.

At a basic level, the activity of antibiotics is described by three statements, according to the most important factor in their pharmacokinetics:

  • Time dependent killing
    • This refers to the time spent marinading in a concentration over MIC - the "C" on the college graph
    • The antibiotics most affected by this are those which kill bacteria most effectively when the bacteria are about to divide.
    • Examples of this include β-lactams, carbapenems, monobactams, linezolid, linocosamides like clindamycin, and erythromycin.
  • Concentration dependent killing
    • This refers to the highest concentration reached.
    • Concentration dependent killing is a property of antibiotics which disable some sort of crucial step in bacterial metabolism or protein synthesis. The higher the concentration reached, the more synthetic enzyme molecules are inhibited.
    • Examples include aminoglycosides, metronidazole, daptomycin, and quinupristin/dalfopristin.
    • Maximum concentration is also important for fluoroquinolones.
  • Time and concentration dependent killing
    • This refers to antibiotics which rely on both time and concentration to kill bacteria - it is a property of those drugs which inhibit steps in DNA synthesis or replication, or other bacterial components which are crucial to cellular division.
    • Time is important because the inhibited enzymes are most active during cell division, and one must spend some time immersed in the drug in order to catch a large enough proportion of the bacteria at the point of replication.
    • Concentration is important because higher concentrations disable more of the target cell components.
    • Examples include fluoroquinolones, azithromycin, tetracyclines, glycopeptides, tigecycline, and to some extent linezolid.

References

Oh's Intensive Care Manual: Chapter 72  (pp. 738)  Principles  of  antibiotic  use  by Jeffrey  Lipman

 

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

 

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.

Question 24.2 - 2008, Paper 1

A patient  who has sepsis and renal impairment, secondary to intraabdominal collections has them drained, the early microbiology report is given below

Proteus mirabilis has been identified from the intra-abdominal pus sample. Antibiotic sensitivities as follows [Full report to follow]

Antibiotic

Sensitivity

Penicillin

R

Oxacillin

R

Cefotaxime

S

Ceftriaxone

S

Gentamicin

S

Vancomycin

R

What antibiotic would you choose to cover this organism?)

College Answer

Third generation cephalosporins although sensitive in vitro often will become resistant in vivo early – so should be avoided

Although not reported the empiric antibiotics of choice are (any of the following):

Quinilone

Pipercacillin / Tazobactam Ticarcillin and Clavulanate Imipenem / Meropenem

Gentamicin may worsen renal impairment, consider avoiding it. A single dose is acceptable

Discussion

Proteus vulgaris (the indole-positive Proteus species) and probably also Proteus mirabilis fall into the group of ESCAPPM organisms:

  • Enterobacter
  • Serratia
  • Citrobacrter
  • Acinetobacter (and Aeromonas)
  • Proteus
  • Providencia
  • Morganella

These bugs easily induce chromosomal cephalosporinases, and treatment with a cephalosporin will rapidly become ineffective.

ESCAPPM and HACEK bacteria are discussed elsewhere in the Required Reading section.

The college opts to avoid gentamicin in the renal impairment patient, but notes that a single dose is probably ok.

The first choices are combinations of extended spectrum β-lactam and β-lactamase inhibitor. Carbapenems and fluoroquinolones are mentioned.

The Stanford Guide recommends Tazocin, meropenem or ciprofloxacin. They permit the use of early generation cephalosporins, provided the infection is not lifethreatening.

References

 

O'Hara, Caroline Mohr, Frances W. Brenner, and J. Michael Miller. "Classification, identification, and clinical significance of Proteus, Providencia, and Morganella." Clinical microbiology reviews 13.4 (2000): 534-546.

 

Gram-negative Survey: 2004 Antimicrobial Susceptibility Report. Australian Group on Antimicrobial Resistance, 2006.

Question 24.3 - 2008, Paper 1

Name the organisms that makeup the ESCAPPM group of organisms.

College Answer

Enterobacter spp., Serratia spp., Citrobacter freundii, Acinetobacter spp., Proteus vulgaris, Providencia spp. and Morganella morganii.

Discussion

The ESCAPPM organisms are:

  • Enterobacter
  • Serratia
  • Citrobacrter
  • Acinetobacter (and Aeromonas)
  • Proteus
  • Providencia
  • Morganella

These are Gram-negative organisms with induceable chromosomal AmpC cephalosporinase/β-lactamase enzymes. Resistance to β-lactams and cephalosprins develops quickly in these species.

ESCAPPM and HACEK bacteria are discussed elsewhere in the Required Reading section.

References

BOYLE, ROBERT J., et al. "Clinical implications of inducible beta-lactamase activity in Gram-negative bacteremia in children." The Pediatric infectious disease journal 21.10 (2002): 935-939.

 

Sfakinos, John. "Detecting the dual presence of AmpC and ESBL enzymes."Microbiology Australia 30.5 (2009): 208-209.

 

Philippon, Alain, Guillaume Arlet, and George A. Jacoby. "Plasmid-determined AmpC-type β-lactamases." Antimicrobial agents and chemotherapy 46.1 (2002): 1-11.

Question 25.3 - 2008, Paper 2

A 36 year old cattle farmer was admitted to hospital with a flu like illness. 3 days after admission he developed arthralgia and  progressive shortness of breath. There was a soft systolic murmur over the precordium. Chest X-Ray showed bilateral infiltrates.

ECG showed non-specific ST-T changes. Troponin raised. Echo revealed decreased LV function.

Hb 90 G/L.

Reticulocytes 4% (0.5-2).

List  5 differential diagnoses for his presentation

College Answer

a)  Viral pneumonia

b)  Legionella

c)  Pneumococcal

d)  Q fever

e)  Mycoplasma

f)   Infective endocarditis

g)  Leptsopirosis

h)  Brucellosis

i)    Vasculitis (unlikely)

Discussion

This question closely resembles Question 25.4 from the second paper of 2009.

References

Question 11.2 - 2008, Paper 2

A previously well, 19 year old female presents with fever, headache, photophobia and neck stiffness.

a). List three (3) clinical features that would indicate  the need for a brain CT scan prior to lumbar puncture in this patient?

b) A lumbar puncture is performed. The initial results reveal:

Red blood cells

356 x 106/L

(0-5 x 106/L)

Polymorphs

3180 x 106/L

(0-5 x 106/L)

Mononuclear cells 
Protein

206 x 106/L 
2.96 g/L

(0.15 – 0.40 g/L)

Glucose

0.4 mmol/L

(2.5 – 5.6 mmol/L)

What are the three (3) most likely causative  organisms?

c) After 24 hours of appropriate therapy she develops new onset of generalised tonic-clonic seizures. List three (3) likely intracranial causes.

College Answer

a). List three (3) clinical features that would indicate  the need for a brain CT scan prior to lumbar puncture in this patient?

New onset seizures Immunocompromised state Abnormal level of consciousness
Focal neurological signs (signs suspicious of a space occupying lesion)
History of CNS disease (mass lesion, stroke, focal infection) Papilloedema

b)

Neisseria meningitidis

Streptococcus pneumoniae

Haemophilus influenzae

c) After 24 hours of appropriate therapy she develops new onset of generalised
tonic-clonic seizures. List three (3) likely intracranial causes.
Raised intracranial pressure
Cerebritis 
Cerebral abscess
Septic venous thrombosis

Discussion

The first part of this question closely resembles Question 25.1 from the second paper of 2009. The question is really asking, "what are the features of increased intracranial pressure in the presence of a space-occupying lesion?"

  • Hypertension and bradycardia
  • Focal neurological signs
  • Decreased level of consciousness
  • No previous history of epilepsy
  • Predisposition to infection (eg. immunocompromised state)
  • Papilloedema
  • History of stroke or intracranial space-occupying lesion

Then, the college tells you that the CSF is essentially pus, with numerous polymorphs and monocytes. Three causes of bacterial meningitis are asked for.

The main culprits are:

  • Listeria monocytogenes
  • Streptococcus pneumoniae
  • Neisseria meningitidis
  • Haemophilus influenzae

Seizures in meningitis are a signs of terrible intracranial processes. Either the brain itself is inflamed (cerebritis), or the patient has developed a cerebral venous sinus thrombus, or there is increased intracranial pressure, or an abscess has formed.

References

Tunkel, Allan R., et al. "Practice guidelines for the management of bacterial meningitis." Clinical infectious diseases 39.9 (2004): 1267-1284.

Oh's Intensive Care manual: Chapter   54  (pp. 597)  Meningitis  and  encephalomyelitis by Angus  M  Kennedy

Question 12 - 2008, Paper 2

A 45-year-old male is admitted from the ward to your high dependency unit for observation of his neurological state. On examination, his temperature is 38.°7C. His is confused and agitated with a GCS of 12. He has a stable respiratory and cardiovascular status. A blood culture showed Gram-positive cocci in both bottles.

His relevant background history is a splenectomy  following a motor vehicle accident 20 years ago, hypertension and mild asthma.

a)  What is the likely diagnosis and what other investigations would you order?

b) Outline  your specific treatment for this condition

c)  list 5 predisposing factors for this condition

d) what prophylactic measures could have been taken to prevent this condition  in this patient?

College Answer

a)  What is the likely diagnosis and what other investigations would you order?

pneumococcal bacteraemia likely meningitis

Investigations -

  • urine pneumococcal antigen
  • CT head
  • Routine bloods FBC/EUC/LFTS/CMP/COAGS/BSL
  • Lumbar Puncture – argument can be made for performing LP after CT or not performing an LP at all. Both responses are acceptable.
  • PCR for pneumococcus

b) Outline  your specific treatment for this condition

1) Empirical antibiotics ideally within 30 minutes
3rd generation cephalosporin Ceftriaxone 2 gm BD or cefotaxime 2gm tds
Plus Vancomycin 1 gm BD / 500 tds
Then target Pen 1.8 gm 4 hour if MIC < .125 gm/l      Cease Vancomycin if sensitive

2) Dexamethasone before or with antibiotics. Risk with altering vancomycin penetration for 4 days. 0.15gm /KG max 10 gm for 4 days.

c)  list 5 predisposing factors for this condition

Extreme of age <2 or >65
Chronic lung disease
Asplenia both functional and anatomic
Immunosuppression Transplant patients CSF leaks
Cochlear implants

d) what prophylactic measures could have been taken to prevent this condition  in this patient?

Vaccination 14 days before or 14 days post splenectomy (early vaccination not immunogenic)
Re vaccinate 5 year intervals
Patient’s penicillin/ amp daily for 2 years after splenectomy Antibiotics empirically if he develops temperature. (eg Augmentin) In this patient consider life long antibiotics orally

Discussion

This question vaguely resembles Question 9 from the first paper of 2013.

However, the end is slightly different. "What preventitive steps could have been taken?"

The college wants to hear about the postsplenectomy vaccines.

References

Reihsaus, E., H. Waldbaur, and W. Seeling. "Spinal epidural abscess: a meta-analysis of 915 patients." Neurosurgical review 23.4 (2000): 175-204.

Question 17 - 2008, Paper 2

Outline  the clinical manifestations, appropriate investigations, and treatment of acalculous  cholecystitis.

College Answer

Clinical presentation is variable and all signs and investigations lack sensitivity and specificity. Symptoms/signs include fever, leukocytosis with a left shift, abdominal pain, right upper quadrant mass, hyperbilirubinaemia, increased alkaline phosphatase and serum transaminases.

Additional investigations (assuming full blood count and liver function tests have already been performed) should include: ultrasonography (may be diagnostic) +/- CT abdomen and blood cultures. HIDA scans are reported to be useful in cases when diagnoses can’t be established with certainty.

Treatment involves broad spectrum antibiotics, though the definitive treatment is drainage. Percutaneous drainage (via ultrasound guidance) may be performed if the patient is too sick to transport, otherwise invasive techniques (laparoscopic or open) may be considered.

Discussion

Acalculous cholecystitis receives a detailed treatment elsewhere.

Clinical manifestations:

  • RUQ pain
  • High bilirubin
  • Cholestatic pattern of LFT elevation
  • Fever
  • Bacteraemia
  • Sympathetic right sided pleural effusion
  • Haemodynamic instability

Diagnostic investigations

  • Abdominal ultrasound
  • Abdominal CT
  • HIDA
  • Blood cultures
Options for Management of Acalculous Cholecystitis

Option

Advantages

Disadvantages

Conservative (antibiotics)
  • Few complications
  • May be the only option for high risk patients.
  • In a mixed (calculous and acalculous) group, 87% of conservatively managed patients recovered completely.
  • Patients with reasonably normal gall bladder function (over 40% GBEF) only need conservative management.
  • There is still an option to progress to one of the other treatment options.
  • May delay definitive treatment
  • The gallbladder may become necrotic and rupture, causing peritonitis
  • Patients with a severely infected gall bladder will continue to get worse, as source control has not been achieved.
Percutaneous cholecystostomy
Laparoscopic cholecystectomy
  • Fewer complications than open cholecystectomy
  • A definitive management option
  • Not an option in some patients, particularly morbidly obese patients and those with severe respiratory failure
  • Requires a surgeon familiar with the approach
  • May end up converting to open anyway, losing all benefits of the laparoscopic approach.
Open cholecystectomy
  • A definitive management option.
  • Allows for a thorough washout.
  • Accomodates weird anatomy and allows earlier maagement of surgical complications.
  • May be the only option for those with a gangrenous or perforated gall bladder.
  • Significant morbidity post operatively in the critically ill population (mortality may be up to 19%)

References

Laurila, Jouko, et al. "Acute acalculous cholecystitis in critically ill patients."Acta anaesthesiologica scandinavica 48.8 (2004): 986-991.

Wang, Ay-Jiun, et al. "Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis." Heart 1500 (2003): 8.

Boland, Giles W., et al. "Percutaneous cholecystostomy in critically ill patients: early response and final outcome in 82 patients." American Journal of Roentgenology 163.2 (1994): 339-342.

Question 25.1 - 2008, Paper 2

An 82 year old woman presents with fever, seizures and a history of anorexia, diarrhoea and vomiting.Following a normal CT scan of head, a lumbar puncture is performed.

The immediate results are as follows:

CSF slightly turbid in appearance. 
300 polymorphs /mm3,

240 monocytes/mm3 
Glucose           2.5mmol/l
Protein             0.6 g/l (0.2-0.4 g/l).

a) What is the likely diagnosis?

b) The microbiologist rings to inform you that the gram stain demonstrates numerous small non-branching Gram-positive bacilli. What is the likely diagnosis?

c) What are the appropriate antibiotics for this organism?

d) You discover the patient is allergic to your choice of antibiotic. Suggest an alternative antibiotic.

College Answer

a) What is the likely diagnosis?
Meningitis./ meningoencephalitis

b) The microbiologist rings to inform you that the gram stain demonstrates numerous small non-branching Gram-positive bacilli. What is the likely diagnosis?

Listeria monocytogenes infection

c) What are the appropriate antibiotics for this organism?

Ampicillin or Penicillin G.

d) You discover the patient is allergic to your choice of antibiotic. Suggest an alternative antibiotic.

IV Bactrim (cotrimoxazole, trimethoprim/sulphamethoxazole)./ Meropenem/ Linezolid-Rifamp combination

Discussion

This question closely resembles Question 25.2 from the second paper of 2009.

References

Question 25.2 - 2008, Paper 2

A patient who had been on meropenem and fluconazole for 6 days for intra- abdominal sepsis developed new fevers and grew a Gram negative organism in the blood. The initial sensitivities are given below. Further sensitivity testing will take another 24 hours.

Gentamicin

Tobramycin

Ampicillin

Imipenem

Ciprofloxacin

Ticarcillin

Gram negative

rods

R

R

R

R

R

R

List 3 likely causative  organisms of the new sepsis. What is an appropriate antibiotic for each of the listed organisms, whilst waiting for the final sensitivity report?

College Answer

Stenotrophomonas maltophilia  - Bactrim

Multi-resistant Acinetobacter – Amikacin/colistin

Multi-resistant pseudomonas / Burkholderia - Amikacin

Enterobacter/proteus - Amikacin

Discussion

This question is identical to Question 23.3 from the first paper of 2013, and to Question 25.3 from the second paper of 2009.

References

Question 25.1 - 2009, paper 1

A 74 year old woman presents with a perforated colonic cancer with widespread peritoneal contamination. She has a laparotomy, peritoneal washout, colonic resection and a defunctioning  ileostomy. On Day 6, she is noted to have an abdominal wall cellulitis, abdominal wall oedema and a positive blood culture growing Gram positive bacilli.


a) What is the likely diagnosis ?

b) What is the likely organism isolated in the blood culture?

ollege Answer

a) What is the likely diagnosis ?

Necrotising fasciitis

b) What is the likely organism isolated in the blood culture?
Clostridial species

Discussion

According to an authoritative source, "postoperative necrotizing fasciitis of the abdominal wall is usually caused by peritonitis in patients who have undergone multiple procedures for complications of emergency laparotomy" (Casali et al, 1980).

So, one might ask: what features of this SAQ history makes necrotising fasciitis the most likely diagnosis, rather than an uncomplicated wound infection with surrounding cellulitis? In summary, there is virtually nothing. All history we get can be broken down into component parts:

  • Old age (74 year old woman)
  • Malignancy
  • Perforated colon
  • Extensive faecal soiling ("widespread peritoneal contamination")
  • Extensive surgical intervention (laparotomy, peritoneal washout, colonic resection and a defunctioning  ileostomy) - what sounds like primary closure (no mention of an open abdomen)
  • Infection is taking place on Day 6
  • Clinically, it looks like abdominal wall cellulitis with oedema
  • The blood culture grew Gram positive bacilli.

Apart from the suspicious bacilli, this whole thing looks very much like a bog-standard wound infection.  The history barely resembles the case series presented by Casali et al (1980). The authors present twelve cases of necrotising fasciitis of which the majority were in young people, recovering from abdominal gunshot wounds (none of the right age for this SAQ, and none with malignant perforation). S.aureus and E.coli were the dominant organisms.  Digging around in the pile of literature, one may come across an article or two which describe a situation which resembles the college's scenario. Miyoshi et al (2008) present a review of the clinical features to be expected from post-operative necrotising fasciitis, and Huljev et al (2005) reviewed some historical data in their case report. Mixing the data from these authors, the following features are common to patients who develop post-operative necrotising fasciitis:

  • Most underwent colorectal surgery
  • In most, the timeframe was within 7 days of operation
  • Cellulitis-like features ("rubor of the skin and tenderness") were present in most (90%)
  • Abdominal wall oedema was present in 80%
  • Most were of old age
  • A malfunctioning immune system seems to be a predisposing factor (diabetes, AIDS, splenectomy and malnutrition were listed)

Other classical features (skin bullae, insensate skin, crepitations) were absent from the college history, making it difficult to guess what the examiners were thinking.

Now; of the Gram positive bacilli we know to be common pathogens, which are likely to be responsible for this wound infection? Let's review them and consider whether they are likely to be in that blood culture.

  • Corynebacterium diphtheriae (no)
  • Proprionibacterium sp. (very unlikely)
  • Nocardia asteroides (no)
  • Listeria monocytogenes (no)
  • Bacillus anthracis (hell no)
  • Clostridium sp. (the only one left)

The typical case will present as a polymicrobial zoo, and whereas Clostridium species will likely flourish in the smelly pockets of avascular fat necrosis, it is unlikely that they will be found in the blood culture, particularly as the blood is so well oxygenated (much of the time). It is more likely that Clostridium perfringens would the sole organism in the cultures of a patient with gas gangrene of the abdominal wall. If the college mentioned subcutaneous emphysema of the abdominal wall, there would be no guesswork involved in this question. This is supported by an article from 1966 (back in the day when surgeons actually palpated people's abdomens instead of scanning them). It reports on ten patients; nine had proper crackly gas gangrene due to C.perfringens or C.multifermentans. One patient with a C.tertium infection only had abdominal wall cellulitis, just like in the college question.

References

Casali, Robert E., et al. "Postoperative necrotizing fasciitis of the abdominal wall." The American Journal of Surgery 140.6 (1980): 787-790.

Huljev, D., and N. Kucisec-Tepes. "Necrotizing fasciitis of the abdominal wall as a post-surgical complication: A case report." WOUNDS-A COMPENDIUM OF CLINICAL RESEARCH AND PRACTICE 17.7 (2005): 169-177.

Rea, William J., and Walter J. Wyrick Jr. "Necrotizing fasciitis." Annals of surgery 172.6 (1970): 957.

Miyoshi et al. "Clinical Features of Postoperative Necrotizing Fasciitis" Journal of Abdominal Emergency Medicine Volume 28 (2008) Issue 5 Pages 649-654

Samel, S., et al. "Clostridial gas gangrene of the abdominal wall after laparoscopic cholecystectomy." Journal of Laparoendoscopic & Advanced Surgical Techniques 7.4 (1997): 245-247.

McSwain, Barton, John L. Sawyers, and MARION R. Lawler Jr. "Clostridial infections of the abdominal wall: review of 10 cases." Annals of surgery 163.6 (1966): 859.

Question 21 - 2009, paper 1

A 58 year old man is admitted to the Intensive Care Unit, intubated and ventilated. Haemodynamic monitors have been inserted and the following haemodynamic measurements have been recorded:

Mean arterial pressure                        53 mmHg

Central venous pressure                      15 mmHg

Cardiac output                                   6.8 L/min

Cardiac index                                       3.8 L/min/m2

21.1. Describe this circulatory disturbance.

21.2. Give five possible clinical scenarios consistent with the above circulatory dusturbance.

21.3. A review of the notes reveals that this man has a positive blood culture with Staph. aureus. Outline three mechanisms  that lead to vasodilation in sepsis?

21.4. Briefly outline what initial agent you will use to treat the circulatory disturbance and how would you initially titrate the dose of the agent

College Answer

21.1. Describe this circulatory disturbance.
Hyperdynamic circulation with moderate hypotension (Increased cardiac output and hypotension suggests low SVR). More information needed before labelling this as ‘shock’. If they mention vasodilated state that is also acceptable.
If they mention the word shock, that is incorrect .

21.2. Give five possible clinical scenarios consistent with the above circulatory dusturbance.

°     Septic shock
°     Non-septic inflammatory states
°     Pancreatitis
°     Burns
°     Post cardio-pulmonary bypass
°     Vasculitis
°     Thyrotoxicosis
°     Induced hypotension – nitroprusside, GTN
°     A-V fistula – trauma, Pagets etc
°     B1 deficiency
°     Severe liver disease
°     Severe anaemia
°     Spinal shock
°     Other
°     Anaphylaxis – data inconclusive
°     Poisonings – CO, CN

21.3. A review of the notes reveals that this man has a positive blood culture with Staph. aureus. Outline three mechanisms  that lead to vasodilation in sepsis?

°     Reduced Ca2+ entry into vascular SM myocyte due to membrane hyperpolarisation following K+ efflux via activated ATP-sensitive K+ channels.
°     Activation of inducible NO synthase, increasing NO production (cyclic GMP)
°     Relative deficiency of endogenous vasopressin
°     Relative adrenocortical insufficiency

21.4. Briefly outline what initial agent you will use to treat the circulatory disturbance and how would you initially titrate the dose of the agent

Lots of ways of doing this and any sensible answer is acceptable. Some units titrate mcg/kg/min, others will for example put 6 mg in 100 ml such that 1 ml/hr = 1 mcg/min

Candidate must comment on the need to confirm adequate volume before winding up the noradrenaline (or at least simultaneous Norad and volume replacement). Lots of ways to assess volume.

One reasonable titration scheme is:
°     Starting dose 0.1 mcg/kg/min
°     Usual dose range 0.05 to 0.5 mcg/kg.min
°     Titrated to MAP > 65 mm Hg
°     Higher MAP if pre-existing hypertension

Discussion

Noradrenaline in resuscitation of septic shock and the calculation of SVR are all discussed in a related chapter in the Required Reading section.

21.1 - This looks like a hyperdynamic circulation with decreased peripheral resistance. You can even calculate SVRI using the usual equation:

SVRI = ([MAP-RAP] × 79.9) / CI

Thus, the SVRI is ([59-15] × 79.9 )/ 3.8

= 925 dynes×sec/cm5/M2

That is pretty low - the normal range is 1800-2400.

21.2 Why would the peripheral resistance be so low?

  • Septic shock
  • Anaphyactic shock
  • Neurogenic (spinal) shock
  • Vasodilation due to SIRS following a global hypoxic/ischaemic injury
  • SIRS due to cardiopulmonry bypass
  • Vasodilation due to pharmacological agents (eg. nitrates)
  • Vasodilation due to severe liver disease

21.3 Mechanisms of vasodilation in sepsis:

21.4 is asking about noradrenaline. A good specific answer would provide doses. In order to sound professional, one should talk in terms of μg/kg/min. Thus, the patient could be started at 0.1μg/kg/min, which for a 100kg person ends up being about 10ml/hr of a standard dilution (6mg in 100ml). One would then titrate this dose up or down, depending on the individial response.

References

Ince, Can. "The microcirculation is the motor of sepsis." Critical Care 9.Suppl 4 (2005): S13.

 

Landry, Donald W., et al. "Vasopressin deficiency contributes to the vasodilation of septic shock." Circulation 95.5 (1997): 1122-1125.

 

Parrillo, Joseph E. "Pathogenetic mechanisms of septic shock." New England Journal of Medicine 328.20 (1993): 1471-1477.

 

Titheradge, Michael A. "Nitric oxide in septic shock."  Biochimica et Biophysica Acta (BBA)-Bioenergetics 1411.2 (1999): 437-455.

 

Landry, D. W., and J. A. Oliver. "The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog." Journal of Clinical Investigation 89.6 (1992): 2071.

 

Van Amersfoort, Edwin S., Theo JC Van Berkel, and Johan Kuiper. "Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock."Clinical microbiology reviews 16.3 (2003): 379-414.

 

Breil, I., et al. "Effects of bradykinin, histamine and serotonin on pulmonary vascular resistance and permeability." Acta physiologica scandinavica 159.3 (1997): 189-198.

 

Hanasawa, K., and M. Kodama. "[Sepsis and organ failure--its pathogenesis and treatment]." Nihon Geka Gakkai zasshi 99.8 (1998): 523-527.

 

Landry, Donald W., et al. "Vasopressin deficiency contributes to the vasodilation of septic shock." Circulation 95.5 (1997): 1122-1125.

 

Marik, Paul E., and Gary P. Zaloga. "Adrenal insufficiency during septic shock*." Critical care medicine 31.1 (2003): 141-145.

 

McGillivray-Anderson, Karen M., and J. E. Faber. "Effect of acidosis on contraction of microvascular smooth muscle by alpha 1-and alpha 2-adrenoceptors. Implications for neural and metabolic regulation." Circulation research 66.6 (1990): 1643-1657.

Question 25.2 - 2009, paper 1

56 year old man presents with pyelonephritis. Ultrasound reveals an obstructed right kidney. Percutaneous nephrostomy is performed.

Blood cultures: 2/2 bottles growing Enterobacter cloacae, sensitive to ceftriaxone

Pus from renal pelvis: Gram negative bacillus on microscopy. Cultures growing Enterobacter cloacae, sensitive to ceftriaxone, aminoglycoside, meropenem

What antibiotic will you choose and why?

College Answer

Choose an aminoglycoside or meropenem because it is an ESCAPM organism. (develop resistance to third gen cephalosporins)

Discussion

More correctly, the ESCAPPM organisms are:

  • Enterobacter
  • Serratia
  • Citrobacrter
  • Acinetobacter (and Aeromonas)
  • Proteus
  • Providencia
  • Morganella

These are Gram-negative organisms with induceable chromosomal AmpC cephalosporinase/β-lactamase enzymes. Resistance to β-lactams and cephalosprins develops quickly in these species. The linked article on this topic also identifies Chromobacterium violaceum,  EnterobacterE. coliHafnia alvei, Lysobacter lactamgenusOchrobactrum anthropiProteus rettgeri,  Pseudomonas aeruginosaPsychrobacter immobilis, Rhodobacter sphaeroides and Yersinia enterocolitica as carriers of the AmpC β-lactamase.

ESCAPPM and HACEK bacteria are discussed elsewhere in the Required Reading section.

If one does not wish to deal with the emergeance of resistance midway though the course of antibiotics, one will choose an aminoglycoside or carbapenem for this purpose.

References

BOYLE, ROBERT J., et al. "Clinical implications of inducible beta-lactamase activity in Gram-negative bacteremia in children." The Pediatric infectious disease journal 21.10 (2002): 935-939.

 

Sfakinos, John. "Detecting the dual presence of AmpC and ESBL enzymes."Microbiology Australia 30.5 (2009): 208-209.

 

Philippon, Alain, Guillaume Arlet, and George A. Jacoby. "Plasmid-determined AmpC-type β-lactamases." Antimicrobial agents and chemotherapy 46.1 (2002): 1-11.

Question 22 - 2009, paper 1

A 50 year old man, who had a heart lung transplant 8 years earlier, presents to your ICU with pneumonia. Discuss the clinical issues specific  to the heart lung transplant that will need consideration in your management of this patient.

College Answer

a) Opportunistic infections - This can result in a wide range of opportunistic organisms causing infection including Pneumocystis, Aspergillus and CMV. It will therefore require early aggressive investigation and broad spectrum bacterial, fungal and possibly viral cover.

b)  Immunosuppression :  Ongoing  immunosuppression will  need  to  be  carefully  managed  in consultation with the transplant unit

c) Cardiac issues- The transplanted heart is denervated. It is only responsive to directly acting drugs/hormones present in the circulation.   Normal compensatory cardiac autonomic reflexes are not present and therefore the heart is more sensitive to directly acting drugs and less able to rapidly respond to changes in intravascular volume.  This will clearly affect the ability to clinically assess a response to therapy and determine adequacy of therapy.

°     Altered ECG /rhytm strip patterns

°     Premature diffuse obliterative coronary atherosclerosis which results in impaired ventricular function

d) Respiratory issues - Impaired cough and clearance of secretions.
°     Impaired lung function due to Obliterative Bronchiolitis ( a manifestation of chronic rejection)
°     Bronchial or tracheal stenosis relating to the original anastomotic site.

e) Renal – altered renal function secondary to immunosuppressive drugs.
f) Altered adrenal function secondary to steroid use, need for steroid cover.

Discussion

It is difficult to answer such a question intelligently without the experience of having worked in a cardiac transplant unit.

Fortunately, there are good papers.

This question benefits from a structured approach, and the systems-based structure provided by the college is as good as any. I will attempt to reorganise this question into a locally familiar alphabetic algorithm. For a broader overview of complications following heart-lung transplantation, and specifically sepsis in the heart-lung transplant recipient, there are dedicated chapter in the Required Reading section.

Airway:

  • This patient may require intubation;
  • The risk of intubation in the immunocompromised patient must be weighed, as it places them at considerable risk of VAP.
  • On the other hand, clearance of secretions may not be satisfactory, and effort of breathing may be so great that the cardiac reserve is exhausted (as these people tend to have a rather fixed cardiac output).

Ventilation:

  • Respiratory function will be impaired because of the pneumonia.
  • The college also mentions obliterative bronchiolitis, which is a common feature of lung transplantation (it is a host vs graft chronic rejection syndrome)- in fact its the major cause of morbidity and mortality in long-term transplant patients. Obliterative bronchiolitis manifests as an obstructive respiratory disease, featuring an irreversible decrease in FEV1 which progressively worsens.

Circulation:

  • Myocardial ischaemia: the myocardia of these people tend to also be subjected to chronic rejection, and the consequence of this looks like an accelerated rate of coronary vascular disease. This is a mixture of normal coronary athersclerosis and a uniquely transplant-associated distal obliterative disease, which looks totally different histologically. A seriously unfortunate feature of this unique obliterative process is the fact that collateral circulation doesn't seem to form, in contrast to normal atherosclerotic narrowing. The upshot of all this is the predisposition of relatively young hearts to relatively severe ischaemic heart disease.
  • Increased responsiveness to infused inotropes: The denervated heart, in the absence of sympathetic stimulus, will grow vast numbers of catecholamine receptors. This is analogous to the skeletal muscle in the denervated legs of a spinal patient, which will overexpress acetylcholine receptors. Thus, inotropes will have an exaggerated effect on the transplanted heart.
  • Insensitivity to normal autonomic stimuli: Severed from the autonomic nervous system, the heart will no longer respond normally to changes in blood pressure, posture, or volume. There will not be a compensatory tachycardia when the patient is hypovolemic.

Renal and electrolyte abnormalities:

  • These patients like have been receiving steroids or cyclosporine-like drugs. 
  • The use of steroids will result in a hypernatremia, fluid retention, and hypokalemia.
  • Alternatively, the barupt withdrawal of steroids may produce hyponatremia and hyperkalemia
  • Renal function may be very poor, and drug clearance may be affected.
  • Cyclosporine may also cause a distal renal tubular acidosis.

Infectious agents:

  • In 60% of cases, pneumonia in the heart-lung trasplant recipient is due to an opportunistic pathogen.
  • The pathogens are as follows:
    • Opportunistic:
      • CMV
      • Aspergillus
      • Pneumocystis
      • Nocardia
    • Community-acquired
      • H.influenzae
      • S.pneumoniae
      • Moraxella catarrhalis
    • Hospital-acquired
      • Acinetobacter
      • Pseudomonas
      • Stenotrophomonas
      • Klebsiella
      • Legionella
      • E.Coli

Note how weirdly the range of bugs is arrayed. The community pathogens are fairly bog-standard, but the Stanford people found that gram-negatives dominated the hospital-acquired infectious lung flora.

Immunesuppression in the context of an acute infectious illness may have to be continued, because its cessation may result in catastrophic rejection.

References

Cisneros, J. M., et al. "Pneumonia after heart transplantation: a multiinstitutional study." Clinical infectious diseases 27.2 (1998): 324-331.

Reichenspurner, Hermann, et al. "Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation." The Annals of thoracic surgery 62.5 (1996): 1467-1473.

Gao, Shao-Zhou, et al. "Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings." Journal of the American College of Cardiology 12.2 (1988): 334-340.

Yusuf, S. A. L. I. M., et al. "Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade."Circulation 75.4 (1987): 696-704.

Question 25.3 - 2009, paper 1

Curves D and E represent concentrations after regular bolus administration of the same dose of an antibiotic to the same patient  at different points of time. What pharmacokinetic changes are noticed? List two clinical conditions that could explain the difference between E and D?

College Answer

a)  PK changes – Increased plasma concentrations with E for the same dose indicating reduced clearance and increased half life.

b)    Hepatic dysfunction , renal dysfunction

Discussion

This was easy marks. In the instance E, the clearance rate is decreased. You can see that with the first dose: even though the initial plasma concentration is the same after the first dose, curve D has a steeper slope, which suggests more rapid clearance (i.e. the concentration falls faster). Intermittent dosing in curve E results in a gradual increase of plasma concentration, with a higher steady-state concentration.

Two clinical conditions which might result in such a situation are hepatic impairment and renal impairment.

References

Question 29.1 - 2009, paper 1

A 29 year old man presents to the Emergency Department with a 2 day history of shortness of breath and hallucinations and one week history of a rash. Examination reveals that he is febrile (40.9oC), tachypnoeic (44 breaths per minute) and hypoxic on room air (SpO2 92%), tachycardic (120 beaths per minute) and hypotensive (90/45mmHg). He is resuscitated and transferred to intensive care:

a).What  is the likely pathogen  for the rash?

b) What specific treatment can be used?

c) What are the risk factors for developing a pneumonia from this pathogen?

d) What superimposed infection is likely?

College Answer

a).What  is the likely pathogen  for the rash?
Varicella Zoster Virus

b) What specific treatment can be used?
Acyclovir, famciclovir or valaciclovir

c) What are the risk factors for developing a pneumonia from this pathogen? 
Smoker, contact with index case, >100 spots, duration of fever, chronic lung disease, 3rd trimester pregnancy, immunosuppression

d) What superimposed infection is likely?
Staphylococcal Aureus

Discussion

a) This looks like the rash of Varicella zoster.

b) Aciclovir or famciclovir are the treatment of choice.Valaciclovir is an oral pro-drug of aciclovir, and one would probably be wanting to use the high-potency IV forms in this disease.

c)The following are known risk factors for Varicella pneumonia:

  • Immunocompromise
  • Pregnancy
  • Chronic lung disease
  • Adults (greater risk compared to children)
  • Smoking
  • Number of spots - over 100 (yes, somebody counted them)

Contact with an infected person is also mentioned. In one case series, such contact was mentioned by 16 of the varicella pneumonia patients, and only by 10 of the non-pneumonia patients.

d) Staphylococcal superinfection of the wounds classically follows the resolution of chickenpox, and can lead to some nasty complications.

 

References

Gogos, C. A., H. P. Bassaris, and A. G. Vagenakis. "Varicella pneumonia in adults, A review of pulmonary manifestations, risk factors and treatment."Respiration 59.6 (1992): 339-343.

 

Mohsen, A. H., and M. McKendrick. "Varicella pneumonia in adults." European Respiratory Journal 21.5 (2003): 886-891.

 

Ellis, M. E., K. R. Neal, and A. K. Webb. "Is smoking a risk factor for pneumonia in adults with chickenpox?." British medical journal (Clinical research ed.) 294.6578 (1987): 1002.

 

Mohsen, A. H., et al. "Lung function tests and risk factors for pneumonia in adults with chickenpox." Thorax 56.10 (2001): 796-799.

 

Fleisher, Gary, et al. "Life-threatening complications of varicella." American Journal of Diseases of Children 135.10 (1981): 896-899.

Question 9 - 2009, Paper 2

A 63 year old woman was admitted to the Intensive Care Unit 4 days ago following an out of hospital cardiac arrest. She was treated with urgent cardiac angiography and stenting of a significant left main coronary artery lesion.

On moderate sedation, she has started to obey commands  this morning. She is still intubated and ventilated. Currently on an FiO2 of 0.6, she has a PaO2 of 120 mm Hg (16kPa). She has a right internal jugular central line, left radial arterial line, and a right cephalic vein peripheral IV line – all inserted on admission. She is being treated with clopidogrel, ranitidine and intravenous heparin. She has been in atrial fibrillation since admission and this morning she developed a temperature of 38.8°C.

What are the likely causes of fever in this woman?

On examination, she has marked right upper quadrant tenderness and her bilirubin is 100 micromol/L  (N < 17 micromol/L).  What  are the  likely causes  of her abdominal tenderness?

Investigations   do  not  reveal  any  intra-abdominal pathology.  She  continues  to  have fever  and  a septic  screen  is negative.  

List  4 biochemical  (plasma)  markers of sepsis which have been suggested to help differentiate infectious from non-infectious  causes of fever.

College Answer

What are the likely causes of fever in this woman?

a.   Infectious
•    Chest
•    Line sepsis (peripheral and central lines)
•    Urinary sepsis
•    Sinusitis
•    Angiography site infection

b.  Non-infectious
•    Intra-abdominal conditions
1.  Mesenteric Ischaemia
2.  Acalculous cholecystitis

•    Haematoma secondary to anticoagulation
1. Groin following angiogram
2. Retroperitoneal

•    Pericarditis / Dressler’s (a bit too early)

c.   Drug fever
•    Heparin

On examination, she has marked right upper quadrant tenderness and her bilirubin is
100 micromol/L  (N < 17 micromol/L).  What  are the  likely causes  of her abdominal tenderness?

Possible diagnosis of acalculous cholecystitis

Also consider
1.  right heart failure/ischemic hepatitis
2.  pancreatitis
3.  perforated viscus
4.  calculous cholecystitis

Investigations   do  not  reveal  any  intra-abdominal pathology.  She  continues  to  have fever  and  a septic  screen  is negative.  

List  4 biochemical  (plasma)  markers of sepsis which have been suggested to help differentiate infectious from non-infectious  causes of fever.
1. CRP
2. Procalcitonin
3. Lipopolysaccharide binding protein (LBP)
4. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1)

Discussion

The non-specific differentials for fever are numerous. All the infectious and non-infectious causes of fever are discussed at length in the Required Reading section.

This patient's clues are an out of hospital cardiac arrest, a myocardial infarction, mechnical ventilation, and potentially dodgy lines.

Thus, the differentials can be narrowed:

Infectious causes:

  • Infectious pathology which triggered the arrest (and that could be anything - pneumonia, UTI, cholecystitis, what have you)
  • Aspiration pneumonia
  • Ischaemic bowel with gut translocation
  • Contaminated central line

Non-infectious causes:

  • Global hypoxic-ischamic SIRS
  • Groin haematoma post angiography
  • Retroperitoneal hematoma
  • Drug fever

The raised bilirubin and RUQ tenderness suggests that the candidate should form differentials around a dysfunctional liver or gall bladder; thus:

Other causes of RUQ pain which neglect the raised bilirubin:

  • Pancreatitis
  • Duodenal or gastric ulceration
  • Bowel ischaemia

Biochemical markers of sepsis include:

The whole range of biochemical markers of sepsis, together with their advantages and disadvantages, is discussed at length in the Required Reading section.

 

References

Povoa, P., et al. "C-reactive protein as an indicator of sepsis." Intensive care medicine 24.10 (1998): 1052-1056.

Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.

Opal, Steven M., et al. "Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock." Journal of Infectious Diseases 180.5 (1999): 1584-1589.

Shozushima, Tatsuyori, et al. "Usefulness of presepsin (sCD14-ST) measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria of systemic inflammatory response syndrome."Journal of Infection and Chemotherapy 17.6 (2011): 764-769.

Gámez‐Díaz, Laura Y., et al. "Diagnostic Accuracy of HMGB‐1, sTREM‐1, and CD64 as Markers of Sepsis in Patients Recently Admitted to the Emergency Department." Academic Emergency Medicine 18.8 (2011): 807-815.

Kwofie, L., et al. "Evaluation of circulating soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) to predict risk profile, response to antimicrobial therapy, and development of complications in patients with chemotherapy-associated febrile neutropenia: a pilot study." Annals of hematology 91.4 (2012): 605-611.

Gros, Antoine, et al. "The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients." Intensive care medicine 38.3 (2012): 445-452.

Gámez‐Díaz, Laura Y., et al. "Diagnostic Accuracy of HMGB‐1, sTREM‐1, and CD64 as Markers of Sepsis in Patients Recently Admitted to the Emergency Department." Academic Emergency Medicine 18.8 (2011): 807-815.

Calfee, Carolyn S., and Jérôme Pugin. "The search for diagnostic markers in sepsis: many miles yet to go." American journal of respiratory and critical care medicine 186.1 (2012): 2-4.

Question 20 - 2009, Paper 2

What are the clinical features of severe falciparum malaria in adults?  Briefly outline its treatment.

College Answer

The clinical features include:
History of recent travel to a malaria endemic zone
Impaired conscious state
Convulsions
Respiratory distress and ARDS

Shock and circulatory collapse

Jaundice
Severe hemoglobinuria
Severe anaemia

Treatment:
Two classes of drugs are available: Cinchona alkaloids and the artemisinin derivatives (latter may be superior in adults). Initially commenced as parenteral and switched to oral for a total of 7 days. Doxycycline is added to non-pregnant adults. If pregnant, then clindamycin is given in addition.

Supportive therapy of organ dysfunction

Specific other treatments:
a) No proven role for exchange transfusion in severe parasitemia, although used

b) risk of hypoglycemia with quinine

Discussion

Malaria in general is briefly summarised in the Required Reading section.

What the hell is "severe" malaria? The WHO in an excellent summary statement (2000) have suggested the following definition:

  • Prostration
  • Decreased level of consciousness
  • Respiratory distress
  • Pulmonary oedema
  • Seziures
  • Circulatory collapse
  • Coagulopathy
  • Jaundice
  • Haemoglobinuria
  • Severe anaemia

One can see that it closely resembles the college answer.

Furthermore, one wonders as to how a history of travel is a clinical feature.

Staying in the trend of using WHO recommendations for this answer, a 2010 guidelines statementsuggests the following management strategy for severe falciparum malaria:

  • Artemisinin derivatives are first line: IV artesunate "significantly reduced the risk of death compared to quinine" in the AQUAMAT trial; previously to 2010 the guidelines did nto have enough evidence to recommend artsunate over quinine.
  • Quinine is second-line, and the WHO reluctantly recommends it while reminding us that its position as a malaria treatment "was established before modern clinical trial methods were developed".
  • Doxycycline is recommended as a part f the "follow-on" treatment, when the intial critical illness settles and the patient can tolerate oral therapy. As always with tertracyclines, it is to be avoided in pregnancy or lactation.

As for exchange transfusion - it does not seem to improve survival, but the authors of the 2002 meta-analysis confess that there are no randomised controlled trials, and that the comparative cohort studies they reviewed had "significant problems with the comparability of treatment groups".

 

References

World Health Organization. "Severe falciparum malaria." Transactions of the Royal Society of Tropical Medicine and Hygiene 94 (2000): 1-90.

Riddle, Mark S., et al. "Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis." Clinical infectious diseases34.9 (2002): 1192-1198.

Reyburn, Hugh. "New WHO guidelines for the treatment of malaria." BMJ 340 (2010).

(the actual revised guidelines are available online for free)

Dondorp, Arjen M., et al. "Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial." The Lancet 376.9753 (2010): 1647-1657.

Trampuz, Andrej, et al. "Clinical review: Severe malaria." CRITICAL CARE-LONDON- 7.4 (2003): 315-323.

 

Question 25.2 - 2009, Paper 2

An 82 year old woman presents with fever, seizures and a history of anorexia, diarrhoea and vomiting.

In the above patient,  a lumbar puncture is performed following a normal CT scan of head. The immediate  results are as follows:

CSF slightly turbid in appearance

300 polymorphs /mm3,

240 monocytes/mm3

Glucose            2.5mmol/L

Protein             0.6 g/l (0.2-0.4 G/L).

a)          What is the likely diagnosis?

b)         The microbiologist rings to inform you that the gram stain demonstrates numerous small non-branching Gram-positive bacilli. What is the likely diagnosis?

c)         What are the appropriate antibiotics for this organism?

d)         You discover the patient  is allergic to your choice of antibiotic.  Suggest an alternative antibiotic.

College Answer

a)          What is the likely diagnosis?

Bacterial Meningitis./ meningoencephalitis.

b)         The microbiologist rings to inform you that the gram stain demonstrates numerous small non-branching Gram-positive bacilli. What is the likely diagnosis?

Listeria monocytogenes infection

c)         What are the appropriate antibiotics for this organism?

Ampicillin or Penicillin G.

d)         You discover the patient  is allergic to your choice of antibiotic.  Suggest an alternative antibiotic.

IV Bactrim (cotrimoxazole, trimethoprim/sulphamethoxazole)./ Meropenem/ Linezolid-Rifamp combination

Discussion

The CSF is infected-looking, that is for sure - even though the college does not provide us with an RBC count in the CSF, or with a peripheral BSL. The high protein and the presence of excessive monocytes suggests that meningitis is a likely diagnosis.

Small non-branching Gram-positive bacilli would probably be Listeria monocytogenes, given that meningitis is being discussed. Alternatives include Bacillus anthracisCorynebacterium diphtheriaeand Nocardia asteroides. However, these bugs are not renowened for their attacks on the cenral nervous system. Clostridium species are even less likely, as they do not thrive in the well-oxygenated environment of the brain.

The most appropriate antibiotics for this woman would be benzylpenicillin. Listeria is very sensitive to this basic antibiotic, and its CNS penetration is enhanced both by the huge doses used in this condition, and by the permeability of the blood-brain barrier in the context of infection. An alternative would be trimethoprim-sulfomethoxazole (Bactrim).

Seeking expert advice, one turns to the Sanford Guide. They recommend ampicillin together with gentamicin for acute Listeria meningitis. In case of allergy, they reach for Bactrim, meropenem or vancomycin.

 

References

 

Tunkel, Allan R., et al. "Practice guidelines for the management of bacterial meningitis." Clinical infectious diseases 39.9 (2004): 1267-1284.

 

Question 25.3 - 2009, Paper 2

A 56 year old patient  who has been on meropenem  and  fluconazole  for six days for intra-abdominal sepsis has developed new fevers and grown a Gram negative organism in the blood. The sensitivities are given below:

Gentamicin

Tobramycin

Ampicillin

Imipenem

Ciprofloxacin

Ticarcillin

Gram negative
rods

R

R

R

R

R

R

List  three  likely  causative   organisms  of  the  new  sepsis.  What   is  an  appropriate antibiotic for each of the listed organisms?

College Answer

1. Stenotrophomonas maltophilia - Bactrim
2. Multi-resistant Acinetobacter – Amikacin/colistin
3. Multi-resistant pseudomonas / Burkholderia - Amikacin
4. Enterobacter/proteus – Amikacin

Discussion

This question is identical to Question 23.3 from the first paper of 2013.

 

References

Question 25.4 - 2009, Paper 2

A 36 year old cattle farmer was admitted to hospital with a flu like illness. 3 days after admission he developed arthralgia and progressive shortness of breath. There was a soft systolic murmur over the precordium. Chest X-Ray showed bilateral infiltrates.

ECG showed non-specific ST-T changes. Troponin raised. Echo revealed decreased LV function.
Hb 90 G/L, reticulocytes 4%.

List 5 differential diagnoses for his presentation.

College Answer

1.  Viral pneumonia
2.  Legionella
3.  Pneumococcal
4.  Q fever
5.  Mycoplasma
6.  Infective endocarditis
7.  Vasculitis (unlikely)

Discussion

This is a pneumonia with bone marrow suppression, myocarditis (or pericarditis) and possibly some sort of connective tissue involvement. What could it be?

A list of differentials would include the following:

Those last two were suggested by a contributor, who ventured that they may be legitimate responses to the question. You don't get that impression that malaria or sickle cell disease are causing this picture from the history, but - does the biochemistry/haematology fit? Anaemia and reticulocytosis is all you get there. Anaemia and reticulocytosis could certainly be from malaria or sickle cell disease, but they could also be from a hundred other causes, so you'd not want to base your answer on those two findings solely. You could try to fit malaria in there because of the flu-like illness story (because that implies fevers). You could probably make this look like sickle cell more easily (spin the ST changes Xray changes and arthralgias into a sickle cell crisis). But, why the whole "cattle farmer" back story? And where is the jaundice you'd get with malaria and sickle cell disease?

But then, you look at what the college wrote in their answer. They've got a bunch of stuff in there which has no relationship with anaemia and reticulocytosis at any level. "Pneumococcal", they say. Mycoplasma.  In short, malaria and sickle cell disease are just as plausible as the college "model" differentials. 

Anyway, the links in the list presented above follow to the paper which describes cardiovascular involvement from that pathogen. However, one cannot rule out the idea that this patient has pulmonary oedema due to an acute mitral insufficiency due to infective endocarditis from some other agent.

 

References

Rajiv, C., et al. "Cardiovascular involvement in leptospirosis." Indian heart journal 48.6 (1995): 691-694.

Bowles, Neil E., et al. "Detection of viruses in myocardial tissues by polymerase chain reactionevidence of adenovirus as a common cause of myocarditis in children and adults." Journal of the American College of Cardiology 42.3 (2003): 466-472.

Nelson, D. P., et al. "Cardiac legionellosis." CHEST Journal 86.6 (1984): 807-808.

Wilson, H. G., et al. "Q fever endocarditis in Queensland." Circulation 53.4 (1976): 680-684.

SANDS, MILTON J., et al. "Pericarditis and perimyocarditis associated with active Mycoplasma pneumoniae infection." Annals of internal medicine 86.5 (1977): 544-548.

Aronin, Steven I., et al. "Review of pneumococcal endocarditis in adults in the penicillin era." Clinical Infectious Diseases 26.1 (1998): 165-171.\

Bax, H. I., et al. "Brucellosis, an uncommon and frequently delayed diagnosis."Neth J Med 65.9 (2007): 352-355.

Question 13 - 2010, Paper 1

13.1.   Apart  from  vancomycin,  list  three  antibiotics  that  have  activity  against  hospital acquired methicillin resistant staphylococcus aureus (MRSA).

13.2     List an example of each of the three main classes of systemic antifungal agents.


13.3.   Briefly outline the dosing adjustment and the monitoring necessary in patients with septic shock for each of the following  drug groups  in patients  with moderate  to severe renal dysfunction (without dialysis)

a) Aminoglycosides

b) Fluoroquinolones

c)  Beta Lactams

d)  Carbapenems

e)  Glycopeptides

College Answer

13.1.   Apart  from  vancomycin,  list  three  antibiotics  that  have  activity  against  hospital acquired methicillin resistant staphylococcus aureus (MRSA).

•     Linezolid
•     Talavancin
•    Streptogramins (not currently available in Australia)
•     tigecycline

13.2     List an example of each of the three main classes of systemic antifungal agents.

•     Polyenes e.g. Amphotericin B
•     Azoles e.g. Fluconazole
•     Echinocandins e.g. caspofungin, andulafungin, micafungin

13.3.   Briefly outline the dosing adjustment and the monitoring necessary in patients with septic shock for each of the following  drug groups  in patients  with moderate  to severe renal dysfunction (without dialysis)

a) Aminoglycosides

b) Fluoroquinolones

c)  Beta Lactams

d)  Carbapenems

e)  Glycopeptides

Aminoglycosides

High initial dose and monitor trough concentrations. Extend interval. May be necessary  to decrease dose and monitor with MIC data

Fluoroqinolones

Reduce     frequency     but      maintain dose. 
Monitor QT interval

Beta Lactams

Can reduce dose OR frequency
Monitoring unnecessary

Carbapenems

As for Beta Lactams

Glycopeptides

High   dosing   on   day   one   dose
adjustments according to Cmin and dependent on degree of renal dysfunction

Discussion

A good article on the antibiotic management options for MRSA lists the following substances:

So, really, we are spoilt for choice. MRSA in general is discussed in greater detail in the Required Reading section

As for the antifungal drugs, in brief summary:

  • Polyenes like amphotericin and nystatin weaken fungal cell walls by binding to ergosterol.
  • Azoles like fluconazole and voriconazole prevent the synthesis of ergosterol from lanosterol by inhibiting lanosterol 14 α-demethylase.
  • Echinocandins like caspofungin inhibit fungal cell wall synthesis by blocking the synthesis of glucan by 1,3-β glucan synthase.

Antifungal pharmacology is explored in luxurious detail by Russell E. Lewis in his 2011 article for the Mayo Clinic Proceedings. Some of this detail has been condensed into a summary of antifungal pharmacology, available in the Required Reading section,

Question 13.3 very closely resembles Question 15.2 from the second paper of 2013, and will receive no further attention here.

References

Holt, S., and K. Moore. "Pathogenesis and treatment of renal dysfunction in rhabdomyolysis." Intensive care medicine 27.5 (2001): 803-811.

 

Welte, Tobias, and Mathias W. Pletz. "Antimicrobial treatment of nosocomial meticillin-resistantStaphylococcus aureus (MRSA) pneumonia: current and future options." International journal of antimicrobial agents 36.5 (2010): 391-400.

 

Lewis, Russell E. "Current concepts in antifungal pharmacology." Mayo Clinic Proceedings. Vol. 86. No. 8. Elsevier, 2011.

Question 23 - 2010, Paper 1

Critically evaluate the role of Procalcitonin (PCT) as a biomarker in the diagnosis and management of sepsis.

College Answer

Diagnosis

•    PCT   is   synthesized   physiologically   by   thyroid   C   cells   but   in   sepsis   has extrathyroidal origin from the inflamed/infected tissue
•    The biochemical and clinical profile well described
•    It is easy to perform (Blood test), not too expensive and provides a quick answer in about 30 minutes. Blood cultures can take up to 24 hours.
•    PCT is no gold standard for infection. There number of reports of PCT elevation in non-septic SIRS, immediately after surgery and trauma.
•    Data from meta-analyisis  are conflicting,  some suggesting  it is superior to CRP, whilst others have concluded it is a weak biomarker in critical illness.
•    PCT    is    not    elevated    in    viral    infection,    autoimmune     disorders     and immunocompromised   patients  –  hence  empiric  therapy  still  the  way  in  these patients.
•    PCT does not tell you the site of infection/inflammation. History, clinical examination and other investigations like CT scan can.
•    PCT  is a biomarker  and  cannot  replace  good  history  taking,  systematic  clinical examination, appropriate investigations for the source of sepsis.

Management

Few prospective randomised studies using,PCT   as a guide to antibiotic therapy, have showed that prescription  rate and the cost of antibiotics  was reduced significantly  with similar outcomes compared to the conventional approach
(Mention  of the recent  Lancet  paper  (Jan2010  – ProRata  study and its conclusions  is worthy of extra credit).

Discussion

If one were to approach this in a structured fashion, the answer would resemble the following:

  • Introduction / definition:
    • Procalcitonin is the prohormone of calcitonin, normally synthesised by the C-cells of the thyroid gland, but produced ectopically by lung and intestine in the context of sepsis. As such, it is an attractive biomarker, and has been the subject of interesting research.
  • Rationale:
  • Evidence: what the recent trials say
      • "The optimal and most widely used procalcitonin cut-off value was 0.5 ng/mL with a corresponding sensitivity of 76% and specificity of 69%"
      • The authors concluded that procalcitonin had a "fair" diagnostic accuracy for bacteraemia.
      • According to an old meta-analysis (2004), it was more sensitive and more specific than CRP.
  • Advantages
    • Quick to perform the assay
    • More specific for bacterial sepsis than CRP
  • Disadvantages
    • Expensive
    • Optimal use requires serial measurements, which is even more expensive.
    • Confounded by non-infectious conditions, such as...
      • Extreme inflammatory stimuli:
        • Burns
        • Massive tissue necrosis
        • Tumour lysis
        • Cardiac or major abdominal surgery
        • Multi-organ system failure
      • Treatment with T-cell antibodies
      • End-stage renal failure (procalcitonin is chronically elevated)
    • No value in assessment of fungal or viral infections
    • No value in assessment of localised infections without a systemic response
    • There is disagreement as to what the negative cutoff value should be.
    • For the discrimination of infectious from non-infectious cause of fever, the clinical judgement of an ED physician is at least equally accurate, if not better.

References

Maruna, P., K. Nedelnikova, and R. Gurlich. "Physiology and genetics of procalcitonin." Physiological Research 49 (2000): S57-S62.

 

Delevaux, I., et al. "Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes?."Annals of the rheumatic diseases 62.4 (2003): 337-340.

 

Maniaci, Vincenzo, et al. "Procalcitonin in young febrile infants for the detection of serious bacterial infections." Pediatrics 122.4 (2008): 701-710.

 

Becker, Kenneth L., Richard Snider, and Eric S. Nylen. "Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations."Critical care medicine 36.3 (2008): 941-952.

 

Limper, Maarten, et al. "The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever." Journal of Infection 60.6 (2010): 409-416.

 

Höflich, R. Sabat C., and W. D. Döcke. "Massive elevation of procalcitonin plasma levels in the absence of infection in kidney transplant patients treated with pan-T-cell antibodies." Intensive Care Med 27 (2001): 987-991.

 

Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.

 

Hausfater, Pierre, et al. "Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department." Critical Care 11.3 (2007): R60.

 

Bouadma, Lila, et al. "Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial." The Lancet 375.9713 (2010): 463-474.

Question 21 - 2010, Paper 2

21.1      Outline     methods     for     diagnosing     CMV     infection     in     the     critically     ill immunocompetent  patient.

21.2      List risk factors for CMV infection in the above patient group.

21.3      List the effects of CMV infection on outcomes in immunocompetent  patients.

21.4      List drugs available for treating CMV infections.

College Answer

21.1      Outline     methods     for     diagnosing     CMV     infection     in     the     critically     ill immunocompetent  patient.

•    Viral cultures: Obsolete because of low sensitivity and time consuming nature.
•    Antigenemia: Direct detection of CMV protein pp65 using monoclonal antibodies.
Sensitive, quantitative but requires sufficient white cells in peripheral blood.
•    PCR assays: High sensitivity and rapid turnover time but not standardised.

21.2      List risk factors for CMV infection in the above patient group.

•    Mechanical ventilation.
•    Bacterial pneumonia and sepsis.
•    Corticosteroid use: Not clear.
•    Red cell transfusion: Immunomodulatory  effect of transfusion, rather than potential transmission of CMV.
•    Burns patients: Cell mediated immunity and T–helper 1 cells increase infection.

21.3      List the effects of CMV infection on outcomes in immunocompetent  patients.

•    Organ dysfunction: Increased  liver and renal failure.
•    Severe CMV disease: Pneumonitis, pneumonia, neurologic disease.
•    ICU stay prolonged
•    Mechanical ventilation duration increased
•    Increased incidence of bacterial or fungal infection
•    Mortality possibly increased

21.4      List drugs available for treating CMV infections.

•    Ganciclovir / valganciclovir.
•     Foscarnet.
•     Cidofovir.

Discussion

The topic of cytomegalovirus infection is explored in greater detail somewhere in the Required reading section.

To answer the question:

Diagnosis

These days, the diagnosis of CMV rests on the following tests:

  • Positive CMV antibodies (IgM) - sensitive for recent or acute infection
  • Qualitative PCR - very sensitive for the presence of CMV, but they do not distingusih between active and latent infection.
  • Quantitative PCR - ideal test, as it provides a quantitative assessment of viral load, and allows the monitoring of therapy.

Risk factors for the immunocompetent host (among the ICU population)

Critical illness in general seems to be a risk factor.

Searching through the references, one can find the following risk factors for reactivation:

  • Trauma
  • Burns
  • Severe critical illness (high APACHE score, over 27)
  • Blood transfusion
  • Mechanical ventilation
  • Severe sepsis
  • Prolonged ICU stay
  • Pregnancy

Consequences of CMV reactivation

The consequences of CMV in the immunocompetent host are detailed in an excellent article on this topic, published in 1997. For the paying customer, UpToDate also has a summary of CMV complications. In short, these complications consist of the following:

  • Colitis
  • Hepatitis
  • Encephalitis
  • Guillain-Barre syndrome
  • Pneumonitis (rare)
  • Pericarditis and myocarditis
  • Uveitis and retinitis

The college asks specifically about "outcomes". Some of the abovementioned complications can degrade cardiopulmonary performance and thus increase the duration of ventilation and length of ICU stay. Plus, the profound lethargy associated with CMV infection frustrates everything, from physiotherapy to ventilator weaning.

Indirect Consequences of CMV infection 
(from this 2013 article)

Immunocompetent host

  • Bacterial sepsis
  • Fungal sepsis
  • Cardiovascular disease
  • Prolonged ventilation
  • Prolonged ICU stay
  • Increased mortality from all causes

Immunocompromised (transplant) host

  • Chronic allograft nephropathy (renal transplant)
  • Hepatic artery thrombosis (liver transplant)
  • Accelerated Hep C recurrence (liver transplant)
  • Bronchiolitis obliterans (lung transplant)
  • New onset NIDDM
  • Post-transplant lymphoproliferative disease
  •  

Management of CMV infection

Ganciclovir, valganciclovir, foscarnet and cidofovir are the recommended antiviral agents.

The most recent guidelines recommend one start with ganciclovir, and convert to valganciclovir when the infection is under control. Foscarnet and cidofovir are reserved for ganciclovir-resistant mutants, owing to their nightmarish toxicity.

References

 

Chou, Suowen. "Newer methods for diagnosis of cytomegalovirus infection." Review of Infectious Diseases 12.Supplement 7 (1990): S727-S736.

Razonable, Raymund R., and Randall T. Hayden. "Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation."Clinical microbiology reviews 26.4 (2013): 703-727.

Vancikova, Z., and P. Dvorak. "Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review." Current drug targets. Immune, endocrine and metabolic disorders 1.2 (2001): 179-187.

Eddleston, M., et al. "Severe cytomegalovirus infection in immunocompetent patients." Clinical infectious diseases 24.1 (1997): 52-56.

Andrews, Peter A., Vincent C. Emery, and Chas Newstead. "Summary of the British Transplantation Society guidelines for the prevention and management of CMV disease after solid organ transplantation." Transplantation 92.11 (2011): 1181-1187.

Kotton, Camille N., et al. "Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation." Transplantation96.4 (2013): 333-360.

Jacobson, Mark A. "Review of the toxicities of foscarnet." JAIDS Journal of Acquired Immune Deficiency Syndromes 5 (1992): S11-17.

Lalezari, Jacob P., et al. "Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS." JAIDS Journal of Acquired Immune Deficiency Syndromes 17.4 (1998): 339-344.

Question 14.1 - 2010, Paper 2

A  75  year  old  man  was  admitted  3  days  post  prostatectomy  with  a  febrile illness. Examination revealed lower abdominal tenderness and a clinical photograph of his groins and external genitalia is shown below.

a)  What is shown in this picture below?

b)  List 2 important management steps

College Answer

a)  What is shown in this picture below?

Fournier’s gangrene.

b)  List 2 important management steps

Urgent surgical debridement
Use of meropenem  or other reasonable combinations

A clinical photograph of Fournier’s gangrene was supplied.

Discussion

The image above was stolen shamelessly from www.christem.com. No permission was asked for.

If they ask me to take it down, they do so with the knowledge that they have sent a very motivated man into the community with the explicit purpose of photographing genitals in early stages of decomposition. Cui bono?

One could get very clever about this condition, but the bottom line is simple. Surgical debridement is the only thing that saves lives in this condition. Broad spectrum antibiotics are of course mandatory, and meropenem is a good choice.

References

Eke, Ndubuisi. "Fournier's gangrene: a review of 1726 cases." British Journal of Surgery 87.6 (2000): 718-728.

Question 14.2 - 2010, Paper 2

a)   What  lesion  is shown  in the  picture  below  in  a patient  presenting  with septic shock?

b)   List 5 other causes of this lesion

College Answer

a)   What  lesion  is shown  in the  picture  below  in  a patient  presenting  with septic shock?

Purpura fulminans

b)   List 5 other causes of this lesion

•   Meningococcemia 
•  Post-splenectomy pneumococcemia
•   DIC 
•  Rickettsial infections
•  High dose inotropes
•   Endocarditis

A clinical photograph of purpura fulminans was supplied.

Discussion

This photograph of purpura fulminans was acquired legally (according to usage rights) fromwww.unboundedmedicine.com to whom I am grateful. The specific image is of a child suffering from menigococcal sepsis.

An excellent review presents a breakdown of the differential causes of puprura fulminans, which include the following:

  • DIC from any cause
  • Sepsis due to the following organisms:
  • MAHA (microangiopathic haemolytic anaemia)
  • TTP (thrombotic thrombocytopenic purpura)
  • Varicella infection
  • Rickettsial infection
  • Plasmodium falciparum malaria
  • Vasopressor excess
  • Warfarin-induced skin necrosis
  • Congenital Protein C anticoagulant pathway defect
  • Post-infectious purpura fulminans (due to autoimmune destruction of proteins C or S)

References

Gürses, Nuran, and Ismail Ilek. "Causes of purpura fulminans." The Pediatric infectious disease journal 14.6 (1995): 552.

 

Spicer, Thomas E., and Jerold M. Rau. "Purpura fulminans." The American journal of medicine 61.4 (1976): 566-571.

 

Chalmers, E., et al. "Purpura fulminans: recognition, diagnosis and management." Archives of disease in childhood 96.11 (2011): 1066-1071.

Question 17.1 - 2010, Paper 2

For each of the microbes listed below; list the most appropriate antibiotic(s) of choice for treatment of infection resulting from these organism.

Pathogen

Antibiotic

Candida glabrata

 

Clostridium perfringens

 

Listeria monocytogenes

 

Meningococcus

 

Multiresistant acinetobacter

 

Nocardia

 

Penicillin intermediate pneumococcus

 

Vancoymcin resistant enterococcus

 

College Answer

Pathogen

Antibiotic

Candida glabrata

Voriconazole or amphotericin or caspofungin

Clostridium perfringens

Penicillin/ meropenem/ flagyl

Listeria monocytogenes

Penicillin/Ampicillin

Meningococcus

Penicillin/ceftriaxone

Multiresistant acinetobacter

Amikacin, Polymyxins,

Nocardia

Sulfonamides

Penicillin intermediate pneumococcus

Ceftriaxone or Vancomycin

Vancoymcin resistant enterococcus

Linezolid , Daptomycin

Discussion

This question closely resembles Question 15.1 from the second paper of 2013.

The only difference is the renaming of "menigococcus" into the more scientific-sounding Neisseria meningitides.

References

Question 17.2 - 2010, Paper 2

List the most likely pathogens which may be encountered in patients admitted with severe sepsis in the following clinical circumstances.

Clinical circumstance

Pathogen

Encephalitis following a flying fox bite

 

Gram  negative  sepsis  in  a  patient recently  returned  from  Papua  New Guinea during the wet season

 

Gram  negative  sepsis  in a patient  who has been on meropenem  for a week

 

Meningitis in a post splenectomy patient

 

College Answer

Clinical circumstance

Pathogen

Encephalitis following a flying fox bite

Lyssa virus  or rabies virus or rhabdo virus

Gram  negative  sepsis  in  a  patient recently  returned  from  Papua  New Guinea during the wet season

Melioidosis / Acinetobacter

Gram  negative  sepsis  in a patient  who has been on meropenem  for a week

Stenotrophomonas or multi- resistant pseudomonas or acinetobacter

Meningitis in a post splenectomy patient

Pneumo or meningococcus,

Discussion

This is another game of "Name That Microbe".

Flying foxes carry Lyssavirus, which resembles rabies and can completely destroy your brain.

It takes little imagination to surmise that PNG during the rainy season is not exactly a sterile place to be. However, I shamefully confess I had no idea what the endemic gram-negatives look like. Fortunately, a Google Scholar search for the string "papua new guinea gram negative rainy season" yielded this article on melioidosis as the first result. In short, it is a dangerous predominantly pulmonary infection by Burkholderia pseudomallei.

The patient who has been marinading in meropenem will likely have an ESBL meropenem-resistant gram negative bug - probably something from the Enterobacteriaceae family. Potential candidates include Enterobacter, StenotrophomonasCitrobacterAcinetobacterSerratiaAchromobacter and so on and so forth.

Meningitis in the asplenic person is likely due to an encapsulated organism - and statistially speaking, this is most likely going to be S. pneumoniae, although N.meningitides or H.influenzae are also potential culprits.

References

Fraser, Graeme C., et al. "Encephalitis caused by a Lyssavirus in fruit bats in Australia." Emerging infectious diseases 2.4 (1996): 327.

 

Currie, Bart J., et al. "The epidemiology of melioidosis in Australia and Papua New Guinea." Acta tropica 74.2 (2000): 121-127.

Question 17.3 - 2010, Paper 2

List the factors which result in failure in resolution of sepsis despite antibiotic therapy.

College Answer

List the factors which result in failure in resolution of sepsis despite antibiotic therapy.

•        wrong antibiotic choice
•        delayed administration of antibiotics
•        Inadequate source control
•        inadequate antimicrobial blood levels
•        inadequate penetration of the antimicrobial to the target site,
•        antimicrobial neutralization or antagonism,
•        superinfection or unsuspected secondary bacterial infection,
•        nonbacterial infection, and
•        noninfectious source of illness

Discussion

In 1972, Garrod Pollock and Cargill all published separate articles in the same edition of the British Medical Journal, exploring the reasons behind antibiotic failure.

In short, they came up with this list:

  • Wrong antibiotics
  • Inadequate dose of the right antibiotic
  • Inappropriately infrequent administration of antibiotics
  • Wrong route (poor absorption)
  • Enhanced metabolism (eg. due to drug interaction or CYP450 activation)
  • Increased clearance (eg. due to dialysis)
  • Inadequate source control
  • Poor tissue penetration of an otherwise sensible antibiotic (eg. daptomycin might be a great choice for VRE, but it is useless in the lung where it becomes inactivated by surfactant)
  • Development of in-vivo resistance (eg. the way Klebsiella seems to suddenly develop a resistance to β-lactams)
  • There is no infection, or the infection is not bacterial.

The Garrod article is beautiful. In a literary manner more consistent with earlier times, Garrod writes of chloramphenicol: "Chloramphenicol is the only antibiotic which when given in the normal way to apparently normal people is capable of killing them". Today's lame robotic authors should take heed.

A more extensive exploration of the reasons behind antibiotic treatment failure can be found in the Required Reading section.

References

Garrod, L. P. "Causes of failure in antibiotic treatment." British medical journal4.5838 (1972): 473.

Pollock, A. V. "Causes of failure in antibiotic treatment." British medical journal4.5843 (1972): 790.

Cargill, J. S. "Causes of failure in antibiotic treatment." British medical journal4.5843 (1972): 791.

Question 7 - 2011, Paper 1

As director of ICU, the general manager of your hospital asks you to review your  current  infection  control  policy  following  an  increase  of  200%  in  the number of newly acquired  MRSA infections  during an ICU admission  in the past 2 months.

Outline your approach to this request.

College Answer

1.

Obtain relevant details of the increase in infection rate- is it a real increase i.e. is there an increase in the rate of MRSA per 100 or 1000 admissions or have the no of admission  gone up significantly  too, clinical  relevance  of finding i.e. is the 200% related to case mix changes, no of patients, demographics and type of patients, duration of ICU stay, details of ICU stay/ procedures/  antibiotic  usage, genetic of MRSA- community acquired/ hospital acquired, is MRSA same or similar to the prevalent strain or is it a new strain

2.

Review  current  infection  control  policy-  when  it  was  written,  people  involved  in writing it, MRO rate at the time of writing policy.

3.

Get expert help- infectious disease specialists, infection control specialist either from your hospital or from elsewhere.

4.

For a review team with yourself, 1 or 2 other intensivists form your ICU, ICU nursing mangers and 1 0r 2 nurses and infectious diseases/ infection control experts.

5.

Review cases, review previous policy, review experience in peer hospitals in your vicinity  and in your state if available,  perform  a literature  review of the evidence base on this topic.

6.

Document all above in the form of a report with key findings and recommendations- key finding should include- clinical relevance of findings, cohort of patients affected, current  rate  of  MRSA  in  your  hospitals  compared  to  peer  hospitals,  postulated causes for the current increase, possible causes why current infection control policy may not have been effective, antibiotic usage and their impact on the increase in MRSA.  Recommendations   include-  infection  control  i.e.  hand  washing,  vector control  if  relevant,  rigorous  cleaning  of  bed  spaces  and  areas  of  clinical  use. Antibiotic  use review,  consider  antibiotic  stewardship,  employing  appropriate  staff for infection control e.g. cleaners, infection control nurse, regular infectious diseases consultant   rounds.  May  need  to  prepare  business   case  if  any  new  staff  or equipment will be needed. Also regular review of rates and distribution of these to all staff should be considered.

7.

Discuss report with staff in your ICU for comments or any suggestions.

8.

Submit report to general manager

Discussion

You run a gross ICU. It is encrusted with scank, and you will need to clean it. However, a suggestion to nuke the site from orbit would probably be frowned upon by the humourless examiners.

The college answer is comprehensive in its attention to administrative detail. I will merely make an attempt to summarise it.

  • Investigate the validity of the reported colonisation rate
  • Investigate the demographics of the colonised patients
  • Investigate the origin of the patients (which ward are they coming from?)
  • Revisit the current infection control policy: is it time to rewrite it?
  • Get expert opinions from infectious diseases and infection control specialists
  • Form a multidisciplinary review panel (ICU specilists, ID physicians, NUMS and RNs)
  • Review the current literature on infection control
  • Rewrite infection control policy
  • Educate the staff regarding the new policy
  • Implement rigorous standards regarding hand washing and bed space cleaning
  • Monitor the effects of the implemented policies

Previously successful coccus pogroms in Europe have reported on the efficacy of certain specific measures, which have included the following:

  • Introduction of alcohol-based hand rub
  • Single rooms for infected patients
  • Explicit signs identifying MRSA-infected rooms
  • Wearing gloves and gowns when entering patient rooms

A more detailed review of strategies to prevent the transmission of MROs can be found in the Required Reading section

References

Widmer, A. F. "Infection control and prevention strategies in the ICU." Intensive care medicine 20.4 (1994): S7-S11.

Eggimann, Philippe, and Didier Pittet. "Infection control in the ICU." Chest Journal 120.6 (2001): 2059-2093.

Lucet, Jean-Christophe, et al. "Successful long-term program for controlling methicillin-resistant Staphylococcus aureus in intensive care units." Intensive care medicine 31.8 (2005): 1051-1057.

 

Question 11 - 2011, Paper 1

The organisms below were isolated and demonstrated antimicrobial sensitivities as listed.

Enterococcus faecalis

Drug

Sensitivity

Ampicillin

R

Chlorampenicol

R

Ciproflxacin

R

Erythromycin

R

Gentamicin

R

Nitrofurantoin

R

Cotrimoxazole

R

Teicoplanin

R

Vancomycin

R

Klebsiella pneumoniae

Drug

MIC (µg/ml)

Cefpodoxime

≥ 2

Ceftazidime

≥ 2

Aztreonam

≥ 2

Cefotaxime

≥ 2

Ceftriaxone

≥ 2

a)     What is the significance of these results?

b)    List 1 appropriate antimicrobial in each case.

c)     List   the   strategies   available   to   reduce   the   development   of   these organisms in ICUs.

College Answer

Van A VRE
Linezolid, Daptomycin, (Tigecycline, Quinupristin-dalfopristin)

ESBL
Carbapenem     (imipenem,     meropenem,     and     perhaps     ertapenem),      Colistin, Aminoglycosides, Ciprofloxacin

c)     List   the   strategies   available   to   reduce   the   development   of   these organisms in ICUs.

Strategies to improve the efficacy and utilization of antimicrobial therapy
•    Antibiotic evaluation committees
•    Protocols and guidelines to promote appropriate antimicrobial utilization
•    Hospital formulary restrictions of broad-spectrum agents
•    Substitution of narrow-spectrum antibiotics (such as first generation cephalosporins and aminoglycosides)
•    Mandatory consultations with infectious diseases specialists
•    Antibiotic cycling by regularly cycling different antimicrobial classes

Infection control measures
•    Handwashing   compliance:   Alcohol-based   hand   wash   is  more   effective   than traditional soap and water in cleansing hands of bacteria
•    Barrier precautions with gloves and gowns
•     Isolation
•    Surveillance for multidrug-resistant bacteria for the early identification and control
•    Monitoring   and   disseminating   the   incidence   and   prevalence   of   isolation   of multidrug-resistant bacteria
•    Limiting LOS and invasive devices (idc / ett/  vascular)

Discussion

a) The Enterococcus is a VRE, and the Klebsiella possesses a β-lactamase which seems to lyse extended spectrum cephalosporins, which makes it an ESBL organism.

b) The Enterococcus can be managed with linezolid, tigecycline or daptomycin. 

The Klebsiella may still be sensitive to carbapenems and it may still be somewhat susceptible to extended spectrum β-lactams (such as Tazocin), but if all else fails there are always amikacin and colistin up your sleeve.

c) Strategies for the prevention and spread of multi-resistant organisms?

A CICM trainee should be able to issue forth a torrential stream of evidence-based antibiotic stewardship strategies and infection control protocols.

Prevent emergence of antibiotic resistance:

  • Limit use of broad-spectrum agents
  • Limit use of multiple antibiotics
  • Use narrow-spectrum agents whenever sensitivities are available
  • Rationalise duration of antibiotics to prevent over-long courses
  • Invitation to infectious diseases physicians to take part in antibiotic decisionmaking
  • Antibiotic class cycling

According to a 2011 review, antimicrobial stewardship interventions beyond 6 months were associated with reductions in antimicrobial resistance rates, which suggests that the above strategies can be rapidly effective.

Prevent cross-contamination:

  • Screening of patients during their ICU stay
  • Introduction of alcohol-based hand rub
  • Single rooms for infected patients
  • Explicit signs identifying MRSA-infected rooms
  • Wearing gloves and gowns when entering patient rooms

References

Gniadkowski, M. "Evolution and epidemiology of extended‐spectrum β-lactamases (ESBLs) and ESBL‐producing microorganisms." Clinical microbiology and infection 7.11 (2001): 597-608.

Huskins, W. Charles, et al. "Intervention to reduce transmission of resistant bacteria in intensive care." New England Journal of Medicine 364.15 (2011): 1407-1418.

Kollef, Marin H., and Victoria J. Fraser. "Antibiotic resistance in the intensive care unit." Annals of internal medicine 134.4 (2001): 298-314.

Kaki, Reham, et al. "Impact of antimicrobial stewardship in critical care: a systematic review." Journal of antimicrobial chemotherapy 66.6 (2011): 1223-1230.

 

Question 24 - 2011, Paper 1

A 38-year-old  man with type 1 diabetes  mellitus  presents  with two days  of severe thigh pain.  You are called to see him because of hypotension.   On examination  he is drowsy,  BP 80/60 mmHg,  HR 140/min  and temperature  of 40.2°C.   There is gross swelling on the medial aspect of his right thigh with clear cellulitis and visible central necrosis.

Describe  the management  priorities  in the first  24 hours  and briefly  justify your responses.

College Answer

1.   Resuscitation
•    High flow oxygen,
•    Support BP with fluids +/- vasopressors
•    Measure & fix BSL

2.   Antibiotics
•    The  presentation  is  that  of  necrotising  fasciitis.   T1DM  a  significant  risk  factor.
Group A streptococcus (type 2) or polymicrobial aerobic and anaerobic organisms (type1) are both possible.  Initial cover should be broad and include an extended spectrum  beta-lactam  or  meropenem,  and  clindamycin.  Clindamycin  suppresses toxin formation from GAS, has other favourable in-vitro effects (facilitating phagocytosis).
•    Further survey: extent of cellulitis, perineal involvement.

3.   Surgical Referral and post-operative management
•    Requires urgent debridement, with removal of dead/infected tissue back to bleeding tissue
•    Takes priority over other therapies including hyperbaric O2
•    Expectation of major blood loss and massive transfusion
•    Likely to be highly unstable post-operatively with major support requirement
•    Routine ICU care of patient with severe sepsis

4.   Specific Therapies
Intravenous Immunoglobulin
•    In vitro neutralisation of streptococcal super-antigens and clostridial toxins
•    Streptococcal toxic shock syndrome (with or without nec. fasc.) listed as “emerging”
indication for IVIG by ARCBS, and available for use

5.   Hyperbaric O2
•    Observational studies only
•    Conflicting   results   with   both   reduction   and   increases   in   mortality   seen   cf. observational controls
•    Possible reduction in need for debridement
•    Usually bd to tds dives of 90 min at 3 atm.
•    Severe organ failure may limit logistics

Discussion

So, the college has presented us with a picture of a diabetic who clearly has a necrotising fasciitis.

A boringly algorithmic answer to this question would look something like this:

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
  • Airway
    • Assess the need for intubation in the context of a potentially decreased level of consciousness
  • Breathing/ventilation
    • Assess efficacy of spontaneous breathing, and the need for mechanical ventilation.
    • Administer supplemental oxygen at a high flow- it may not be particularly helpful at atmospheric pressure, but hyperoxia does seem to retard the growth of anaerobic organisms.
  • Circulatory support
    • Administer a 20-30ml/kg fluid bolus
    • Secure central venous access and commence vasopressors- start with noradrenaline
    • Aim for a MAP over 65mmHg
  • Specific investigations
    • A full panel of blood tests including blood cultures, CK and an ABG
    • A CT scan of the lower limbs and pelvis, as a prelude to surgical intervention
  • Supportive management
    • Continue fluid resuscitation and vasopressors in pursuit of haemodynamic goals
    • Ensure normoglycaemia and normoxia
    • Correct acid base balance
    • Attend to organ system failure - consider early dialysis if there is rhabdomyolysis
  • Monitoring
    • Admit to ICU
    • Commence continuous blood pressure monitoring via arterial line
    • Assess for ketosis/ketoacidosis - this is a Type 1 diabetic, and this is exactly the sort of trigger that would produce a DKA.
  • Specific management
    • Commence broad spectrum antibiotics. In this case, the choice is clindamycin plus anycillin or anypenem. The addition of clindamycin is well supported - particularly with Group A streptococci, where it inhibits the bacterial synthesis of endotoxin.
    • Immediately contact surgical services for source control - debridement is the single most useful management strategy; everything else is fairly cosmetic in terms of decreasing mortality.
    • Consider IV immunoglobulin (i.e. if this is a streptococcal toxic shock syndrome - which manifests as massive cardiovascular collapse and organ system failure very early in the infective process). The use of IVIG in this setting has been well studied, and though those European investigators didn't reach statistical significance in their primary endpoit (mortality), they did note a significant decrease in organ failure scores in the IVIG group.
    • Consider an early referral to a specialist centre where hyperbaric oxygen therapy can be carried out. This management strategy historically did not seem to reduce either mortality or the number of debridements. However, recent data suggests that they were doing it wrong in the 1990s, and modern hyperbaric oxygen therapy seems to be associated with a 50% reduction in mortality (from 9.4% to 4.5%).

The key points to remember are:

  • Source control
  • Clindamycin
  • IV immunoglobulin
  • Hyperbaric oxygen

References

Hasham, Saiidy, et al. "Necrotising fasciitis.Bmj 330.7495 (2005): 830-833.

Mulla, Zuber D. "Treatment options in the management of necrotising fasciitis caused by Group A Streptococcus." Expert opinion on pharmacotherapy 5.8 (2004): 1695-1700.

Darenberg, Jessica, et al. "Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial." Clinical infectious diseases 37.3 (2003): 333-340.

Brown, D. Ross, et al. "A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy." The American journal of surgery 167.5 (1994): 485-489.

Soh, Chai R., et al. "Hyperbaric oxygen therapy in necrotising soft tissue infections: a study of patients in the United States Nationwide Inpatient Sample." Intensive care medicine 38.7 (2012): 1143-1151.

 

Question 18 - 2011, Paper 2

A 50-year-old man presents to hospital with fever and an acute abdomen. He undergoes an emergency laparotomy, the findings of which include perforated carcinoma in the splenic
flexure and generalized faecal soiling of the peritoneum. He undergoes a left hemicolectomy with a defunctioning colostomy. Post-operatively he is transferred to the intensive care unit because of septic shock.

a) What antibiotic regimen will you consider and why?

Despite a five-day course of antibiotics he remains unwell with fever up to 38.50C, WCC 16.7 x 109 /l. He is unable to tolerate oral feeds and is on TPN.

b) List the likely abdominal causes of persistent fever and leukocytosis?

Blood cultures show Candida glabrata in one of the three bottles.

c) List 4 predisposing factors for this infection in this patient.

d) What antibiotic therapy will you commence whilst waiting for sensitivities and why?

e) Based on the culture report, give one other investigation, the results of which might influence the prognosis and duration of antifungal treatment, and the rationale for your choice.

College Answer

a) What antibiotic regimen will you consider and why?

  • Triple therapy or Timentin or Tazocin – cover enterococcus, gram negatives and anaerobes.
  • May consider adding empiric fluconazole
  • Vancomycin, gentamicin, metronidazole if penicillin allergic

Despite a five-day course of antibiotics he remains unwell with fever up to 38.50C, WCC 16.7 x 109 /l.

He is unable to tolerate oral feeds and is on TPN.


b) List the likely abdominal causes of persistent fever and leukocytosis?

  • Intra-abdominal collection
  • Wound infection
  • Acalculous cholecystitis
  • Pancreatitis
  • Stomal necrosis


Blood cultures show Candida glabrata in one of the three bottles.
c) List 4 predisposing factors for this infection in this patient.

  • Malignancy
  • Abdominal soiling
  • TPN
  • Recent broad spectrum antibiotic therapy
  • Indwelling CVC

d) What antibiotic therapy will you commence whilst waiting for sensitivities and why?

  • Voriconazole or amphotericin B or caspafungin
  • Candida glabrata may not be sensitive to fluconazole


e) Based on the culture report, give one other investigation, the results of which might influence the prognosis and duration of antifungal treatment, and the rationale for your choice.

  • Echocardiography – vegetations
  • CT / USS abdomen – liver abscess
  • Ophthalmic examination – retinal abscesses

Discussion

This question refers to the management of faecal peritonitis.

 The first part asks for empirical antibiotic therapy in abdominal sepsis. The "triple therapy" this refers to is the well known ampicillin-gentamicin-metronidazole combination. There is reference to the fact that single broad agent therapy may be equivalent in its efficacy to the standard multidrug regimen. As a single agent, Tazocin (piperacillin/tazobactam) is a fine choice. Perhaps it will not cover some of the more resistant enterococci, but their low pathogenicity makes it unlikely that they will pose a problem. And it will certainly wipe the floor with most of the gram-negatives.

The second part asks for the potential causes of fever in the feed-intolerant post-laparotomy patient. Acalculous cholecystitis and pancreatitis should be mentioned. Stomal necrosis is another possibility.

The presence of Candida glabrata in the blood cultures is explored; the candidate is invited to produce a list of factors which predispose post-operative patients to such an infection. A good article on this exact subject is available. It had found that non-albicans candidaemia is associated with CVCs and multiple antibiotic therapy. TPN also seems to all but triple the risk of non-albicans candidaemia. There is also an association with malignancy, which is biased by the fact that most studies of candidaemia have been performed in solid or hematological cancer patients. The college answer doesnt mention renal failure (because the scenario patient does not have it), but this is another significant risk factor.

Thus, in summary, risk factors for non-albicans candidaemia are as follows:

  • Repeated abdominal surgeries
  • Exposure to broad-spectrum antibiotics
  • Exposure to fluconazole
  • Diabetes
  • CVC insertion
  • TPN use
  • Malignancy
  • Renal failure

One ought to also mention that specifically the use of fluconazole may select for a fluconazole-resistant species such as C.glabrata. The next question asks which agent is the most appropriate empirical therapy for this yeast, and voriconazole or liposomal amphotericin are valid answers.

The last question asks the candidate to think about the complications of candidaemia.

One can list a few:

  • Candida endopthalimitis/retinitis
  • Candia endocarditis
  • Hepatosplenic abscesses
  • Pulmonary cavitating lesions
  • CNS involvement (meningitis or abscesses)
  • Candida arthritis

Candida endocarditis is the most feared complication, and it seems that the most common pathogen (28%) is a non-albicans species.

Candida endophthalmitis (specifically, retinitis) occurs via haematogenous seeding, and is enough of a problem for the Infectious Diseases Society of America to issue recommendations regarding early retinal examination for these patients.

The whole business of scanning the abdomen for collections is laudable, but I am not sure why the college has latched on to the idea of looking specifically for hepatic abscesses. This seems more a feature of liver transplant recipients.

References

Harris, Anthony D., et al. "Risk factors for nosocomial candiduria due to Candida glabrata and Candida albicans." Clinical infectious diseases 29.4 (1999): 926-928.

Lee, Ingi, et al. "Risk factors for fluconazole-resistant Candida glabrata bloodstream infections." Archives of internal medicine 169.4 (2009): 379-383.

D M Mosdell, D M Morris, A Voltura, D E Pitcher, M W Twiest, R L Milne, B G Miscall, and D E Fry Antibiotic treatment for surgical peritonitis. Ann Surg. 1991 November; 214(5): 543–549.

Chow, Jennifer K., et al. "Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit."Clinical infectious diseases 46.8 (2008): 1206-1213.

Chow JK, Golan Y, Ruthazer R, Karchmer AW, Carmeli Y, Lichtenberg DA, Chawla V, Young JA, Hadley S.Risk factors for albicans and non-albicans candidemia in the intensive care unit.Crit Care Med. 2008 Jul;36(7):1993-8.

Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, Rangel-Frausto MS, Rinaldi MG, Saiman L, Wiblin RT, Wenzel RP; National Epidemiology of Mycoses Survey(NEMIS) Study Group. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. The National Epidemiology of Mycosis Survey. Clin Infect Dis. 2001 Jul 15;33(2):177-86. Epub 2001 Jun 20.

Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, Filler SG, Fisher JF, Kullberg BJ, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD; Infectious Diseases Society of America.Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009 Mar 1;48(5):503-35. doi: 10.1086/596757.

 

Question 19 - 2011, Paper 2

Critically evaluate the role of fluid resuscitation in critically ill patients with sepsis.

College Answer

1) Hypotension a feature of sepsis


2) Hypotension –multifactorial – leaky capillaries, vasoplegia, myocardial dysfunction, NO,
adrenergic failure


3) Fluid resuscitation can only treat one component of sepsis.


4) Current guidelines for the acute management of severe sepsis in pediatric and adult patients place prime importance on early, rapid, and substantial infusion of intravenous fluids. The immediate aim is to correct a possible fluid responsive hypodynamic circulation. Beyond this, the common assumption is that expansion of effective circulating volume will attenuate hypotension, distress) and clinical evidence of impaired peripheral perfusion.


5) Evidence that +ve fluid balance associated with worse outcomes in sepsis (SOAP study) and ALI


6) FEAST study – first RCT- compared albumin, saline and no fluid resus – Mortality at 48 hrs clearly higher in the fluid resuscitation groups. Caveats – paediatric study, 48 hr end point, no ICU package.


7) In adults – a post hoc analysis of the SAFE study showed that adminstration of albumin as
compared to saline reduced the risk of death in severe sepsis.


8) Other points to mention are – fluid should include blood products to a target Hb and
conservative rather than liberal approach in presence of ALI. End points of fluid resuscitation
are difficult


Summary statement: Fluid resuscitation is clearly indicated to treat acute hypotensive episodes. Beyond that, an assessment of causes of ongoing hypotension in sepsis must be evaluated for and treated. Robust RCTs in adults are lacking but use of albumin is preferred to saline

Discussion

The topic of fluid resusicitation in sepsis enjoys a more detailed discussion in the Required Reading section.

Let us first deconstruct the college answer.

Points 1 and 2 set the mood, so to speak. there is no mention of the fluid resuscitation studies here, merely a backdrop as to why it may be neccessary.

Point 3 mentions that fluid resuscitation only treats one component of sepsis, restoring an adequate effective intravascular volume.

Point 4 sensibly repeats the Surviving Sepsis dogma ("early, rapid, and substantial infusion of intravenous fluids") but then degenerates somewhat. The circulation in sepsis is generaly held to be hyperdynamic. Volume restoration (pouring water into an ever-enlarging leaky bucket) is an early goal of management insofar as it allows organ perfusion to continue unimpaired even as the vessels dilate abominably, and third space losses increase.

Point 5 refers to the SOAP study, which found that a positive fluid balance was a strong predictor for death from sepsis in the ICU. The odds ratio of mortality in Europe increased by 1.1 for every added litre of cumulative fluid balance in the first 72 hours.

Point 6 adds the FEAST study which also questions the use of fluid boluses in sepsis. In order to appease the proponents of wet intensive care, the savvy candidate will mention study limitations (such as the absence of ICU facilities for it to run in, the relative mildness of the septic shock, the prevalence of malaria in the population group, and the difficulty generaising these findings to an adult population).

Point 7 raises the recent meta-analysis of albumin as a resuscitation fluid for patients with sepsis. Delaney et al (2011)  found that albumin is better than saline. One may argue that almost any sterile isotonic fluid would be better than saline. Moreover, this meta-analysis compared albumin to "control fluid" which was hydroxyethyl starch or gelofusine in 14 of the 17 analysed studies. Thus, albumin is better than starch. I thank Luke (you know who you are) for pointing out that albumin is also better than cyanide. So, hardly a convincing victory for albumin in 2011. Most recently, the ALBIOS investigators also found no outcome difference among the "mildly septic" shock patients, though perhaps with some subtle benefits among the group with severe illness.

Point 8 returns to Surviving Sepsis guidelines to mention the maintenance of hematocrit above 0.30 with blood products, as well as mentioning the value of conservative fluid management in ALI.

Lastly, the use of "balanced" crystalloids in the resuscitation of sepsis has recently (in 2014) been shown to improve mortality. In fact, "Mortality was progressively lower among patients receiving larger proportions of balanced fluids".

Overall, the successful candidate would have ranted at length about the SOAP, SAFE and FEAST trials, before coming to the conclusion that fluid resuscitation is mandatory, careful, guided by end-points, and that albumin is preferred to saline.

Thus, a model answer would look like this:

Introduction:

  • Fluid resuscitation has been the traditional starting point in the resuscitation of sepsis
  • The choice of fluids and the required volume remain topics of debate

Rationale:

  • Fluid resuscitation maintains intravascular volume and organ perfusion pressure
  • Fluid resuscitation maintains preload, ensuring an adequate cardiac output
  • Fluid resuscitation improves microvascular perfusion and thus tissue oxygen delivery
  • Haemodilution decreases blood viscosity, which may also improve microcirculatory flow

Evidence:

  • Recent evidence regarding the choice of fluids (SAFE, ALBIOS) has demonstrated the non-inferiority of crystalloid as compared to colloid in terms of mortality; however, haemodynamic goals appear to be achieved faster with human albumin.
  • There is some argument (on the basis of subgroup analysis) that albumin use may be associated with increased survival in sepsis.
  • There is a strong argument against fluid over-resuscitation, and it is known that every 1 L of positive fluid balance at day 3 after admission is associated with an increase in mortality.

Summary

  • Fluid resuscitation is an important part of the resuscitation of sepsis
  • It should be guided by dynamic markers of fluid responsiveness
  • It should be guided by haemodynamic goals and surrogate markers of tissue perfusion (eg.lactate)
  • Its use should be curtailed to prevent excessively positive fluid balance

References

An excellent resource for this topic are the chapters in Oh's Manual dealing with severe sepsis (ch 61, by A Raffaele de Gaudio) and with the immunocompromised host (ch 59, by Steve Wesselingh and Martyn A H French).

 

An older, yet similarly respectable source is Shoemaker (2005); Chapter 155 (Infections in the immunocompromised patient) by Andrew Githaiga, Magdaline Ndirangu and David L. Paterson covers this topic with great detail.

 

The Surviving Sepsis Campaign has these published guidelines to peruse.

 

Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006 Feb;34(2):344-53.

 

Maitland K, et al and the FEAST Trial Group. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 May 26.

 

Delaney, Anthony P., Arina Dan, John McCaffrey, and Simon Finfer. "The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis*." Critical care medicine 39, no. 2 (2011): 386-391.

 

Raghunathan, Karthik, et al. "Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis." Critical care medicine (2014).

 

Caironi, Pietro, et al. "Albumin replacement in patients with severe sepsis or septic shock." New England Journal of Medicine 370.15 (2014): 1412-1421.

 

Question 25 - 2011, Paper 2

With respect to malaria:


a) Describe the laboratory confirmation of this condition

b) List 2 firstline drugs from different classes given parenterally in the treatment of the severe form of this disease

c) List the acute complications of this disease

College Answer

a) Describe the laboratory confirmation of this condition
Thick and thin blood smears (give diagnosis and parasite load)
Rapid diagnostic tests utilising malarial antigens (dependents on specific test)


b) List 2 firstline drugs from different classes given parenterally in the treatment of the severe form of this disease
Cinchona alkaloids (quinine and quinidine)
Artemisinin derivatives (artesunate, artemether).


c) List the acute complications of this disease
• Cerebral Involvement with or without convulsions
• Respiratory Failure - acute respiratory distress syndrome (ARDS)
• Circulatory collapse
• Renal failure, hemoglobinuria ("black water fever")
• Hepatic failure
• Haematological
• Disseminated intravascular coagulation
• Severe anemia secondary to Haemaolysis
• Thrombocytopenia
• Metabolic
• Hypoglycemia
• Severe Acidosis
• Hyponatraemia
• Splenic Rupture

Discussion

This question dips into one's general knowlege of infectious diseases.

Obviously, unless specifically schooled in the infectious arts, the candiate would not be able to regurgitate a very large amount of information regarding this disease. For such candidates, I have compiled a brief summary of malaria in the Required Reading section.

a) Describe the laboratory confirmation of this condition

  • Thick and thin films
  • Rapid diagnostic tests (RDTs) looking for parasite antigens such as parasite-specific lactate dehydrogenase (pLDH), or aldolase.

Usually thick and thin films are enough. Oh's Manual describes them as the gold standard. The thin films help the parasitologist identify the parasite species because they are visible within the red cells. The thick films have a layer of lysed red cells and with the parasites floating free one can do a head-count and estimate the parasite load. The American CDC has a wonderful set of cartoonish guides to help a semi-skilled practitioner to correctly prepare the thick and thin slides. This is a labour-intensive technique; in contrast, the rapid antigen tests can give an answer within 20 minutes, but does not give a parasite count (and so cannot be used to monitor the effects of therapy)


b) List 2 firstline drugs from different classes given parenterally in the treatment of the severe form of this disease
The college answer lists cinchona alkaloids (eg. chloroquine) and artemisinin derivatives (eg. artemethrin).

From the two-line answer, it would seem that a detailed understanding of the pharmacotherapy of malaria is not required. A certain CDC document can shed some light on the alternative drugs, without being excessively detailed. According to the CDC, in addition to the cinchona drugs and artemisinin family, one could also add tetracyclines (eg doxycycline), napthoquinones (eg. atovaquone) and lincosamides (eg. clindamycin).

The WHO has released a set of guidelines in 2010 which make recommendations of first and second line agents. This boc


c) List the acute complications of this disease
The college answer lists complications in no specific order. I would like to organise my answer according to a puerile alphabetic template.

  • A) - ...nothing much happens to the airway in malaria, provided one's brain is not swarming with parasites.
  • B) - ARDS
  • C) - Shock, circulatory collapse (and maybe a ruptured spleen)
  • D) - Encephalitis, maybe with seziures and decreased level of consciousness (swarming, parasites, etc)
  • E) - Severe metabolic acidosis, hyperkalemia, hyponatremia
  • F) - Hemoglobinuria, leading to acute tubular necrosis and acute renal failure
  • G) - Acute hepatitis and syntheic liver failure; hypoglycaemia
  • H) - Haemolysis, thrombocytopenia, DIC
  • I) - High fever and rhabdomyolysis die to rigors

The Required Reading entry on malaria contains this table, which is a more comprehensive answer:

Complications of Severe Malaria

System

Complications

Respiratory

  • ARDS
  • Pulmonary oedema

Circulatory

  • Shock, circulatory collapse
  • Cardiac failure due to anaemia
  • Haemorrhagic shock due to coagulopathy or splenic rupture

Neurological

  • Generalised weakness
  • Decreased level of consciousness
  • Increased ICP
  • Seizures
  • Hepatic encephalopathy

Endocrine

  • Hypoglycaemia
  • Hyperkalemia
  • Hyponatremia
  • Acidosis (predominantly, lactic)
  • Rhabomyolysis

Renal

  • Haemoglobinuria, leading to acute tubular necrosis
  • Acute renal failure due to circulatory collapse
  • ATN due to rhabdomyolysis

Gastrointestinal

  • Hepatosplenomegaly
  • Splenic rupture
  • Hepatic failure
  • GI tract bleeding

Haematological

  • Disseminated intravascular coagulation
  • Thrombocytopenia
  • Haemolytic anaemia

Immunological

  • Hyperpyrexia (temperatures over 40°C)
 

References

World Health Organization. Guidelines for the treatment of malaria. World Health Organization, 2006.

We dont have a CDC here in Australia, and so I link to the CDC site for details about standardised diagnosis and treatment of malaria. This page has links to downloadable PDF documents with decisionmaking flowcharts et cetera. One particularly useful document is this set of Guidelines for Clinicians.

WHO. Guidelines for the treatment of malaria. 2nd ed. Geneva: WHO; 2010. Online.

Question 3 - 2012, Paper 1

a) List the patient-related risk factors associated with the development of Clostridium difficile enterocolitis
 
b) List two tests that can be used for diagnosis of Clostridium difficile enterocolitis.
 
c) List four markers of severity of disease in Clostridium difficile enterocolitis
 
d) What are other possible causes of infective diarrhoea in the critically ill?

College Answer

a) Patient-related risk factors

  • Broad spectrum antibiotics in particular clindamycin, quinolones, amoxycillin, cephalosporins
  • Immunosuppressive therapy /Cytotoxic chemotherapy
  • Gastric acid suppression
  • Age > 65
  • Prolonged hospitalisation
  • Renal impairment
  • Prior GI surgery

b) Diagnostic tests

  • Faecal culture determination of the toxigenic status of the infecting C. difficile isolate
  • Screening EIA to detect C. difficile glutamate dehydrogenase (GDH)
  • EIAs to detect toxins A and/or B
  • Cell culture cytotoxicity assays that directly detect stool cytotoxic activity
  • PCR-based assays to detect conserved gene targets within the pathogenicity locus of C. difficile

c) Markers of severity

  • Clinical
    • Fever (> 38.5°C), rigors
    • Haemodynamic instability
    • Peritonitis or evidence of bowel perforation
    • Ileus or toxic megacolon
  • Laboratory
    • White blood cell count >15 × 109/L and < 20% neutrophils
    • Elevated lactate level
    • Rise in creatinine level (> 50% above baseline)
    • Albumin level < 25 mg/L
  • Other investigations
    • Large intestine distension, colonic wall thickening, fat stranding, unexplained ascites (imaging)
    • Pseudomembranous colitis (colonoscopy)

d) Other infective causes of diarrhoea

  • Viruses –Norovirus, adenovirus, CMV (rotavirus in children)
  • Bacterial pathogens – Campylobacter, E.Coli, cholera, salmonella Protozoa – Cryptosporidium, Giardia
  • Parasitic -Strongyloides

Discussion

This question favours the candidate who has a very detailed understanding of C. difficile infection. A long rant about C.difficile is available in the Required Reading section.

The risk factors for C.difficile infection are discussed here, in a NEJM article.

Where did the college answer get its evidence from, you ask?

As for diagnosis of C.difficile, the current recommendations are:

  • PCR is better than toxin A or B identification
  • You should only test loose stools
  • You should not re-test

Markers of "severe" enterocolitis, which means the sort that ends up either killing you or results in a colectomy, are deliniated in this retrospective study. They are as follows:

  • age >70 years
  • maximum leukocyte count >20,000 cells/mL
  • minimum albumin level <25 g/L
  • maximum creatinine level >200 mcg/L
  • small bowel obstruction or ileus
  • CT evidence of colorectal inflammation

To this list, another study adds more markers of severity:

  • Fever (>38.0°)
  • Abdominal distension

References

Loo, Vivian G., et al. "Host and pathogen factors for Clostridium difficile infection and colonization." New England Journal of Medicine 365.18 (2011): 1693-1703.

 

Thomas, Claudia, Mark Stevenson, and Thomas V. Riley. "Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review." Journal of antimicrobial chemotherapy 51.6 (2003): 1339-1350.

 

Anand, Ajay, and Aaron E. Glatt. "Clostridium difficile infection associated with antineoplastic chemotherapy: a review." Clinical Infectious Diseases 17.1 (1993): 109-113.

 

Cunningham, R., et al. "Proton pump inhibitors as a risk factor for Clostridium difficilediarrhoea." Journal of Hospital Infection 54.3 (2003): 243-245.

 

Pépin, Jacques, Louis Valiquette, and Benoit Cossette. "Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec." Canadian Medical Association Journal 173.9 (2005): 1037-1042.

 

Cunney, Robert J., et al. "Clostridium difficile colitis associated with chronic renal failure." Nephrology Dialysis Transplantation 13.11 (1998): 2842-2846.

 

Surawicz, Christina M., et al. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections." The American journal of gastroenterology 108.4 (2013): 478-498.

 

Henrich, Timothy J., et al. "Clinical risk factors for severe Clostridium difficile–associated disease." Emerging infectious diseases 15.3 (2009): 415.

 

FujitaniMD, Shigeki, W. Lance GeorgeMD, and A. Rekha MurthyMD. "Comparison of clinical severity score indices for Clostridium difficile infection."Infection Control and Hospital Epidemiology 32.3 (2011): 220-228.

Question 6 - 2012, Paper 1

A 33-year-old abattoir worker presented to the Emergency Department with a 2 week history of increasing shortness of breath and haemoptysis. He had previously been fit and well. 

On examination he is alert, normotensive but tachypnoeic (35 breaths per minute), centrally 
cyanosed (SaO2 85% on 10L/min O2) and tachycardic (120 beats per minute). Auscultation reveals a systolic murmur at the lower left sternal edge and coarse inspiratory crackles bibasally. The remainder of the examination was unremarkable. 

His chest radiograph demonstrates bibasal consolidation.

List the most likely differential diagnoses, and for each diagnosis, list the specific investigations needed to confirm the diagnosis and the specific treatment required.

College Answer

Cause

Investigation

Treatment

Pneumonia
Bacterial         

  • S. pneumonia,
  • H. _nfluenza
  • K. pneumonia

Sputum MC&S
Blood Culture

3rd Generation cephalosporin
(or similar) plus
Azithromycin (or similar)

Atypical          
Viral- Influenza

Serology / PCR
Viral PCR

± Oseltamivir / Ribavarin

Other infective
Infective endocarditis
Leptospirosis

TTE/TOE, bld culture
Serology, PCR

Antibiotics  surgery
Doxycycline / cefotaxime /
benzyl penicillin

Q fever            
Anthrax          

Serology for C. burnetii
Blood culture

Doxycycline, ciprofloxacin
Doxycycline, ciprofloxacin,
benzyl penicillin

Vasculitis                    
Goodpasture’s syndrome
Wegener’s
granulomatosis

Anti-GBM Abs

cANCA

) Steroids
) Plasmapheresis
) Cyclophosphamide

Cardiovascular
Acute mitral regurgitation
Pulmonary infarction

TTE/TOE, screen for acute MI
CTPA, V/Q scan

Surgery
Anticoagulation

Discussion

This question favours the candidate with a physician background.

Really, it's a pub trivia question. "Which bugs can cause pneumonia and haemoptysis in an abbatoir worker?" Most physicians would immeadiately yell "Q Fever!" And that would be the most likely explanation. It tends to produce an atypical pneumonia and endocarditis.

Instead of delving into the specifics of Q Fever, the college model answer unfocuses broadly on thedifferentials of haemoptysis, with an infectious flavour. Table 1 in the linked article lists the usual suspects. That is the concise version.

A less concise version is presented in the answer to Question 2 from the first paper of 2012 (yes, this exact same paper)

References

 

Talwar, D., et al. "Massive hemoptysis in a respiratory ICU: causes, interventions and outcomes-Indian study." Critical Care 16.Suppl 1 (2012): P81.

 

Maurin, M., and D. fever Raoult. "Q fever." Clinical microbiology reviews 12.4 (1999): 518-553.

 

Bidwell, JACOB L., and Robert W. Pachner. "Hemoptysis: diagnosis and management.Am Fam Physician 72.7 (2005): 1253-1260.

Question 18 - 2012, Paper 1

  • List the clinical features that indicate a poor prognosis in a patient with community-acquired pneumonia?
  • List 5 common organisms causing severe community acquired pneumonia in immunocompetent adults.
  • what are the possible reasons for non-response to empiric treatment for patients treated for severe community acquired pneumonia?
  • Briefly outline your approach to stopping antibiotics given for CAP responding to empiric treatment in ICU? 

College Answer

a) Clinical features indicating poor prognosis

      1. Common organisms
      • Streptococcus pneumonia
      • Legionella spp
      • Haemophilus influenza
      • Klebsiella pneumonia
      • Staphylococcus aureus
      • Respiratory viruses
      • Mycoplasma
      • Reasons for non-response
        • Wrong diagnosis
        • Cardiac failure
        • PE
        • Pulmonary haemorrhage
        • Wrong antibiotics
        • Resistant organism e.g.: MRSA
        • Wrong organism: e.g.: viral pneumonitis
        • Wrong dose
        • Under dosing (gentamicin, vancomycin)
        • Wrong interval (vancomycin, cephalosporins)
      1. Complication of the disease
        • Empyema
        • Lung abscess
    1. Complication of treatment
        • Antibiotic reaction
        • Superinfection
    2. Underlying disease
        • Cancer
        • Airway obstruction
        • Severe emphysema with bullae
  1. Stopping antibiotics
    • Evidence in area is complicated, but in resolving CAP- 7-10 days most common in studies
    • 5 days seems the minimum
    • More than 8 days may be associated with super infection with resistant organisms.
    • Pseudomonas- may need 15 days Legionella 3 weeks
    • Biomarkers e.g. procalcitonin in some RCTS

Discussion


a) Clinical features indicating poor prognosis

Now, one might cynically presume that the table presented in the college answer was crudely cut-and-pasted from some paper.

One might be absolutely correct. 

It was the 2007 version of the IDSA guidelines. This is probably a table we candidates were expected to memorise.  Since this paper has come out, in fact an updated form of guidelines has become available (Metlay, 2019), and in case you want to see what the difference between the documents is, they helpfully summarised it for you. Fortunately, they did not change the content of their "Criteria for Defining Severe Community-acquired Pneumonia", which is what that table actually is. 

List 5 common organisms causing severe community acquired pneumonia in immunocompetent adults.

Again, this is a direct transcription of Table 6 from the same paper.

  • Streptococcus pneumoniae
  • Mycoplasma pneumoniae
  • Haemophilus influenzae
  • Chlamidophyla pneumonia
  • Respiratory viruses

What are the possible reasons for non-response to empiric treatment for patients treated for severe community acquired pneumonia?

The college answer is sub-optimal, as it revolves around the inaccuracy of diagnosis and inadequacy of treatment. Question 7 from the second paper of 2012 looks indepth at the causes of treatment failure for community acquired pneumonia, and the investigations for treatment-refractory pneumonia; the college answer and discussion offered there are far superior.

In brief:

  • Wrong disease
    • PE
    • Cardiac failure
    • Autoimmune pneumonitis
  • Wrong antimicrobial agents
    • Resistant organism
    • Viral pneumonia
    • Atypical pneumonia
  • Wrong use of antimicrobial agents
    • Underdosing
    • Inappropriate dose interval
    • Poor penetration into lung tissue
  • Patient and disease factors which predict poor response to antibiotics:
    • Elderly patient
    • Multiple comorbidities
    • Alcoholism
    • Smoking (and COPD)
    • Multilobar pneumonia
    • Bacteraemia
    • Empyema and lung abscess
    • Legionella pneumonia
    • Polymicrobial pneumonia
  • Organisms which are known to respond poorly to antibiotics
    • Mycobacterium tuberculosis
    • Nocardia
    • Actinomyces israelii
    • Aspergillus
    • Coxiella burnetii (Q fever)
    • Chlamydia psittaci (psittacosis)
    • Leptospira interrogans (leptospirosis)
    • Pseudomonas pseudomallei (melioidosis)

Briefly outline your approach to stopping antibiotics given for CAP responding to empiric treatment in ICU?

Where, do you ask, did the college get those time intervals? Who said 5 days is minimum?
Well.
It was in the same paper.

The guidelines are:

  • Minimum of 5 days
  • Stop after 72 hrs of haemodynamic stability without fevers
  • Pseudomonas typically needs 15 days

The procalcitonin RCT mentioned is a famous study where antibiotic therapy was deescalated according to a procalcitonin level (anything less than 0.25mic/L was grounds for deescalation).

References

Bartlett, John G., et al. "Practice guidelines for the management of community-acquired pneumonia in adults." Clinical infectious diseases 31.2 (2000): 347-382.

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

Christ-Crain, Mirjam, et al. "Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial." American journal of respiratory and critical care medicine 174.1 (2006): 84-93.

Metlay, Joshua P., et al. "Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America." American journal of respiratory and critical care medicine 200.7 (2019): e45-e67.

Question 30 - 2012, Paper 1

You are looking after a 54 year old man post cadaveric liver transplantation with impaired graft function and failure to progress. A large subhepatic bile collection was drained percutaneously on day 7 when he was started on piperacillin-tazobactam. Culture of the drain fluid reveals heavy growth of Enterococcus spp.

  • What activity does piperacillin have against Enterococcus spp?
  • The Provisional report is that the Enterococcus is resistant to Vancomycin. List 3 antibiotics would you consider in this situation.
  • What are the main toxicities of each of the antibiotics you have listed in your answer to b)?
  • Which antibiotic would you select, and why?

College Answer

a) Piperacillin:

Piperacillin activity is similar to penicillin, and less than that of ampicillin. Enterococci are relatively penicillin resistant; E. faecium is more resistant than E. faecalis. Most VRE have high-level resistance to β-lactams (and aminoglycosides).

b) Antibiotics:

The main options would be:

  • teicoplanin
  • linezolid
  • tigecycline
  • daptomycin
  • ceftaroline (E.faecalis not faecium)

c) Main toxicities of each of the antibiotics:

  • Teicoplanin: relatively little toxicity, less than vancomycin; thrombocytopenia, anaemia, renal or hepatic dysfunction
  • Linezolid: mitochondrial toxin, hence thrombocytopenia, anaemia, peripheral or ocular neuropathy, lactic acidosis, serotonin syndrome
  • Tigecycline: nausea & vomiting; teratogenic; catabolic, FDA reports increased risk of death in HAP or VAP compared to alternative treatments
  • Daptomycin: myopathy
  • Ceftaroline: no significant toxicity

d) Antibiotic:

A reasoned answer is required. Linezolid may be preferred over teicoplanin due to its greater efficacy and better tissue penetration (it is poorly protein bound, so volume of distribution approximates to total body water). No dosage reduction is necessary in renal or hepatic failure. Van A resistance is common in Australia, so many VRE are teicoplanin resistant. Tigecycline and daptomycin generally regarded as third line drugs. Ceftaroline new to practice and limited experience to date.

Discussion

VRE seems to be a topic favoured by the CICM examiners.

This bunch of cocci were previously known as Group D streptococci. They are not particularly pathogenic, but their intrinsic resistance to antibiotics makes them interesting to the intensivist.

a) Enterococci have intrinsic resistance to β-lactam antibiotics due to the low affinity of their penicillin-binding proteins for penicillin. Interestingly, piperacillin has approximately the same activity as benzylpenicillin against these enterococci; ticarcillin and cephalosporins have about four times less activity, and are thus essentially useless.

b) Antibiotic choices and their toxicities

Antibiotic     Toxicity
Teicoplanin
  • Thrombocytopenia
  • Rarely, red man syndrome
  • Rarely, nephrotoxicity
Linezolid
Daptomycin
  • Myopathy, with raised CK
  • Nephrotoxicity
Tigecycline
  • Nausea and vomiting were the most commonly reported side effects, and organ toxicity seems to be mild.
  • The college answer mentions a certain FDA warning about using tigecycline in hospital-acquired pneumonia, especially VAP. This is based on a mortality difference of 1%; but it was an increase from 3.0% to 4.0%, which is a 25% increase in relative risk of death.
Ceftaroline
  • Little is known about the toxicity of ceftaroline, because infectious diseases physicians reserve it for the most dire of circumstances, and thus nobody has had much of a chance to use it.
  • The studies say that it "demonstrated a safety profile similar to that of comparator drugs".
  • A notable weirdness is the sudden emergence of a positive Coombs test during treatment, which did not evolve into haemolytic anaemia.

As to this specific biliary sepsis patient? Their collection is VRE infected, and one needs a drug with good tissue penetration. The college have chosen linezolid.

References

Hollenbeck, Brian L., and Louis B. Rice. "Intrinsic and acquired resistance mechanisms in enterococcus." Virulence 3.5 (2012): 421-433.

Kaye, Donald. "Enterococci: biologic and epidemiologic characteristics and in vitro susceptibility." Archives of Internal Medicine 142.11 (1982): 2006-2009.

Wilson, A. P. R. "Comparative safety of teicoplanin and vancomycin."International journal of antimicrobial agents 10.2 (1998): 143-152.

Lawrence, Kenneth R., May Adra, and P. Ken Gillman. "Serotonin toxicity associated with the use of linezolid: a review of postmarketing data." Clinical infectious diseases 42.11 (2006): 1578-1583.

Attassi, Kinan, et al. "Thrombocytopenia associated with linezolid therapy."Clinical infectious diseases 34.5 (2002): 695-698.

Bressler, Adam M., et al. "Peripheral neuropathy associated with prolonged use of linezolid." The Lancet infectious diseases 4.8 (2004): 528-531.

Rucker, Janet C., et al. "Linezolid-associated toxic optic neuropathy."Neurology 66.4 (2006): 595-598.

Vinh, Donald C., and Ethan Rubinstein. "Linezolid: a review of safety and tolerability." Journal of Infection 59 (2009): S59-S74.

Arbeit, Robert D., et al. "The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections." Clinical Infectious Diseases38.12 (2004): 1673-1681.

Raja, Aarti, et al. "Daptomycin." Nature Reviews Drug Discovery 2.12 (2003): 943-944.

Stein, Gary E., and William A. Craig. "Tigecycline: a critical analysis." Clinical infectious diseases 43.4 (2006): 518-524.

Stein, Gary E., and Timothy Babinchak. "Tigecycline: an update." Diagnostic microbiology and infectious disease 75.4 (2013): 331-336.

Saravolatz, Louis D., Gary E. Stein, and Leonard B. Johnson. "Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus." Clinical infectious diseases 52.9 (2011): 1156-1163.

 

Question 7 - 2012, Paper 2

A 67 year old male, having presented with a presumptive diagnosis of Community Acquired Pneumonia (CAP) remains intubated and in need of mechanical ventilation at Day 5 of his admission to hospital.

  • Outline the factors that may affect the expected rate of resolution of their CAP
  • Outline your approach, and indication for, the diagnostic evaluation of non-resolving pneumonia
 

College Answer

a) Host factors

Alcoholism, older age, and the presence of comorbid diseases such as diabetes and chronic obstructive lung disease. In addition, disorders of immune function, particularly AIDS and syndromes associated with deficient humoral immunity, can be associated with delayed resolution of pneumonia.

Severity of CAP Pathogen:

In general, resolution is more rapid with Mycoplasma pneumoniae, non-bacteremic Streptococcus pneumoniae, Chlamydophila (formerly Chlamydia) species, and Moraxella catarrhalis than with other organisms

(note to Examiners – don’t need to list all of these, just indicate that some organisms associated with rapid resolution, and which some of those organism are)

Unusual pathogen:

Such as: Mycobacterium tuberculosis, Nocardia, Actinomyces israelii, Aspergillus, Coxiella burnetii (Q fever), Chlamydia psittaci (psittacosis), Leptospira interrogans (leptospirosis), Pseudomonas pseudomallei (melioidosis)

Antibiotic Resistance

Development of complications from initial CAP

The two main forms of sequestered focus preventing adequate resolution of pneumonia are empyema and lung abscess.

Non-infectious aetiology to initial CAP and/or underlying lung disease

Respiratory Malignancy, lymphoma, Granulomatosis with polyangiitis (Wegener's), Diffuse alveolar hemorrhage, Bronchiolitis obliterans-organizing pneumonia (BOOP), Acute or Chronic eosinophilic pneumonia, Acute interstitial pneumonia, Pulmonary alveolar proteinosis, Sarcoidosis, Systemic lupus erythematosus, Heart failure, Pulmonary embolism

b)

Chest CT to look for sequestered areas of infection or for findings that suggest an alternative diagnosis.

Fiberoptic bronchoscopy patients – lesions, mechanicals respiratory lesion, unusual pathogen

Thoracoscopic or open lung biopsy

Discussion

Outline the factors that may affect the expected rate of resolution of their CAP

This is a question regarding a community-acquired pneumonia which meets with treatment failure.

There is a good article about that. It lists the following factors, which were identified as predictors of poor response to antibiotics:

  • Elderly patient
  • Multiple comorbidities
  • Alcoholism
  • Smoking (and COPD)
  • Multilobar pneumonia
  • Bacteraemia
  • Empyema and lung abscess
  • Legionella pneumonia
  • Polymicrobial pneumonia

However, the college goes even further. They list pathogens which are expected to resolve rapidly:

  • Strep pneumoniae
  • Moraxella catarrhalis
  • Chlamidophyla
  • Mycoplasma pneumoniae

They then list pathogens which are expected to respond poorly to antibiotic therapy:

  • Mycobacterium tuberculosis
  • Nocardia
  • Actinomyces israelii
  • Aspergillus
  • Coxiella burnetii (Q fever)
  • Chlamydia psittaci (psittacosis)
  • Leptospira interrogans (leptospirosis)
  • Pseudomonas pseudomallei (melioidosis)

They then mention offhand that a list of pathogens of this magnitude was not expected from the candidates.

Then, they cheat.

The discussion turns to non-infectious aetiology for the respiratory failure, which is somewhat unfair (as the candidates would have been focussing on pneumonia). However, the savvy graduate would have noticed the sneaky word "presumptive" in the question text. This patient does not have a confirmed diagnosis. So, their respiratory failure could be totally non-infectious. The following differentials are suggested:

  • Vasculitis (eg. Wegeners)
  • Malignancy (eg. lung primary, mets or lymphoma)
  • Alveolar haemorrhage
  • BOOP
  • Alveolar proteinosis
  • SLE
  • Heart failure
  • PE
  • Sarcoidosis
  • Eosinophilic pneumonia

This is a broad list, and the key message is that one should read the question carefully.

Outline your approach, and indication for, the diagnostic evaluation of non-resolving pneumonia

A list of investigations can be generated.

  • High-resolution CT
  • Bronchoalveolar lavage, with culture, gram stain, PCR for atypical bacterial fungal and viral pathogens
  • Serology for atypical bacterial fungal and viral pathogens
  • Investigations for immune compromise, including HIV serology and blood film to consider hematological malignancy
  • Bronchoscopy for sampling
  • Lung biopsy if other diagnostic modalities fail to yield an answer

References

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

Leroy, O., et al. "A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit."Intensive care medicine 21.1 (1995): 24-31.

Oster, Gerry, et al. "Initial treatment failure in non-ICU community-acquired pneumonia: risk factors and association with length of stay, total hospital charges, and mortality." Journal of medical economics 16.6 (2013): 809-819.

Menendez, Rosario, and Antoni Torres. "Treatment failure in community-acquired pneumonia." CHEST Journal 132.4 (2007): 1348-1355.

Question 2 - 2012, Paper 2

Outline the predisposing factors, consequences and management of the critically ill patient with Vancomycin Resistant Enterococcus (VRE).
 

 

College Answer

Predisposing factors

Previous treatment with anti-microbials (especially vancomycin, cephalosporins and broad-spectrum antibiotics)

Increased length of stay

Renal impairment

Long-term IV access

Enteral tube feeding

Prevalence of VRE colonized patients in the ICU

Resident of long-term care facility 
Decreased staff : patient ratios

Consequences

Potential transmission of resistance to Staph aureus

Determined by site of infection if present (eg UTI, bloodstream including endocarditis and rarely respiratory infection) 
Need for isolation

Management

Specific antibiotics if infected rather than colonized depending on sensitivities (Van A resistant to vancomycin and teicoplanin; Van B sensitive to teicoplanin) – options include linezolid, daptomycin, quinupristin-dalfopristin, tigecycline. 
Probiotics may have a role.

Infection control including isolation, contact precautions and PPE, and general infection control measures including surface and environmental cleaning, antibiotic stewardship, screening of contacts and patient surveillance until swabs are negative.

Precautions should continue on discharge from ICU

Discussion

VRE comes up often in this exam. One should become intimately familiar with its behaviour and temperament.

Risk factors for VRE colonisation:

  • Proximity to other VRE patients - especially those with diarrhoea
  • Advanced age
  • Severe underlying illness
  • Inter-hospital transfer
  • Nursing home residency
  • Extended hospitalization
  • Specialized nutritional support
  • Central venous catheterization
  • Haematologic malignant tumours
  • Solid organ allograft
  • Chronic haemodialysis
  • Antibiotic exposure to vancomycin, third-generation cephalosporins, metronidazole, and any antibiotics with anti-anaerobic activity.
  • Exposure to multiple antibiotics
  • Prolonged duration of antibiotic therapy

Consequences of VRE colonisation

Management of the colonised patient

  • Isolation
  • Protective equipment
  • Scrupulous attention to cleaning areas where the patient has been
  • Surveillance swabs until the patient tests negative

Management of the clinically relevant VRE infection

  • Linezolid
  • Daptomycin
  • Tigecycline

References

Bonten, Marc JM, et al. "Epidemiology of colonisation of patients and environment with vancomycin-resistant enterococci." The Lancet 348.9042 (1996): 1615-1619.

MacIntyre, C. Raina, et al. "Risk factors for colonization with vancomycin-resistant enterococci in a Melbourne hospital." Infection control and hospital epidemiology 22.10 (2001): 624-629.

Tornieporth, Nadia G., et al. "Risk factors associated with vancomycin-resistant Enterococcus faecium infection or colonization in 145 matched case patients and control patients." Clinical infectious diseases 23.4 (1996): 767-772.

Karki, Surendra, et al. "Prevalence and risk factors for VRE colonisation in a tertiary hospital in Melbourne, Australia: a cross sectional study." Antimicrob Resist Infect Control 1.1 (2012): 31.

DeLisle, Sylvain, and Trish M. Perl. "Vancomycin-resistant enterococci: a road map on how to prevent the emergence and transmission of antimicrobial resistance." Chest journal 123.5_suppl (2003): 504S-518S.

Patel, Robin. "Clinical impact of vancomycin-resistant enterococci." Journal of Antimicrobial Chemotherapy 51.suppl 3 (2003): iii13-iii21.

Noble, W. C., Zarina Virani, and Rosemary GA Cree. "Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus ." FEMS Microbiology letters93.2 (1992): 195-198.

Question 3.3 - 2012, Paper 2

The following is a CSF sample from a 56-year-old woman with severe rheumatoid arthritis who has presented with fever, malaise and altered mental state

Parameter

Value

Normal Range

Cell count

75 cells / mm3*

0 – 5

(90% lymphocytes)

Protein

890 mg/L*

170 – 550

Glucose

2.0 mmol/L*

2.8 – 4.5

Gram stain

Negative

Describe 4 further tests you would perform upon the CSF to establish an infective cause.

 

College Answer

  • Herpes Simplex PCR
  • Mycobacterium Tuberculosis PCR 
  • Mycobacterial Stain and Cultures
  • India Ink Stain, Cryptococcal Ag 
  • Fungal cultures
  • Bacterial PCR

Discussion

The question is really asking, "what pathogens can cause a meningitis, but wont be picked up on a routine gram stain?" The answer is "anything that is not a classical bacterium". This is what one might call "aseptic meningitis". LITFL has an excellent summary of this topic.

The list contains the following bugs:

  • Mycobacteria:
    • M.tuberculosis
  • Fungi:
    • Cryptococcus neoformans
  • Viruses:
    • HSV
    • VZV
    • CMV
    • HIV
    • Enterovirus
  • Random:
    • Treponema pallidum
    • Borrelia burgdorferi (Lyme disease)

Additionally, one might wish to consider non-infectious causes, such as lymphoma, vasculitis, or drug-induced meningitis (eg. due to cotrimoxazole or azathiaprine)

Interestingly, the most likely causes of CSF lymphocytosis are the common meningitis pathogens -S.pneumoniaeH.influenzae and N.meningitides.

The richness of this pathology is serenaded in a dedicated chapter on meningitis.

References

Powers, William J. "Cerebrospinal fluid lymphocytosis in acute bacterial meningitis." The American journal of medicine 79.2 (1985): 216-220.

Question 9 - 2013, Paper 1

A 56-year-old male, with a previous splenectomy, presents with an altered mental state but a stable cardiorespiratory status. He is pyrexial with a temperature of 38.4°C.

Blood cultures taken on admission show gram-positive cocci in both bottles.

  • What is the likely diagnosis and what other specific investigations would you order?
  • Outline your specific treatment for this condition.
  • List five factors that predispose to this condition.
  • What follow-up treatment will you recommend for this man on hospital discharge?

College Answer

Pneumococcal bacteraemia – probably meningitis

Investigations: 
CT head ± lumbar puncture

PCR for pneumococcus

Urine pneumococcal antigen (Routine bloods)

b) 
Empiric antibiotics – ideally within 30 minutes

3rd generation cephalosporin + vancomycin (steroids may limit penetration to CSF) or rifampicin

May change to penicillin if susceptible

Alternative regime – any reasonable combination

Dexamethasone before or with first dose of antibiotics

c)

Age <2 or >65 years

Chronic lung disease

Asplenic – functional or post splenectomy

Immunosuppression 
Transplant recipient

CSF leak 
Cochlear implants

d)

Vaccination and re-vaccinate at 5 year intervals 
Empiric antibiotics if develops temperature and consider life long antibiotic therapy in this patient.

Discussion

a) The asplenic man is prone to infections by encapsulated organsisms. S.pneumoniae is the likely culprit. One would want a CT brain and LP; a urinary pneumococcal antigen should confirm the pathogen.

b) Immediate management should consist of dexamethasone, vancomycin and ceftriaxone.

c) Predisposing factors to pneumococcal meningitis:

  • Immunosuppression
  • Splenectomy
  • Extremes of age (very young and very old)
  • Intracranial implants, eg. cochlear implants
  • A CSF leak, for any reason
  • Cochlear implants
  • Sickle cell disease
  • Unvaccinated patient

d) Post splenectomy vaccination and chronic oral suppression antibiotics will be required.

The specific details of precisely which vaccinations are required are available in the splenectomy chapter of the Required Reading section. A lot of spleen-associated wank is there, including references to such hard-hitting medical sources as the Japanese Journal of Ichthyology.

References

Kastenbauer, Stefan, and Hans‐Walter Pfister. "Pneumococcal meningitis in adults Spectrum of complications and prognostic factors in a series of 87 cases." Brain 126.5 (2003): 1015-1025.

Selby, C. D., and P. J. Toghill. "Meningitis after splenectomy." Journal of the Royal Society of Medicine 82.4 (1989): 206-209.

Fraser, David W., et al. "Risk factors in bacterial meningitis: Charleston County, South Carolina." Journal of infectious Diseases 127.3 (1973): 271-277.

Reefhuis, Jennita, et al. "Risk of bacterial meningitis in children with cochlear implants." New England Journal of Medicine 349.5 (2003): 435-445.

Lynch 3rd, J. P., and George G. Zhanel. "Streptococcus pneumoniae: epidemiology, risk factors, and strategies for prevention." Seminars in respiratory and critical care medicine. Vol. 30. No. 2. 2009.

Question 16 - 2013, Paper 1

Discuss the potential role of corticosteroid administration as adjunctive treatment for septic shock.

College Answer

Controversial unresolved topic, conflicting evidence.

Background:

In septic shock, cytokines may suppress the cortisol response to adrenocorticotropin hormone and in almost half of the patients this causes poor adrenal activity. Tissues possibly become resistant to corticosteroids because of fewer corticosteroid receptors or receptors with lower affinity.

Mechanism:

  1. Treatment of deficiency - concept of CIRCI possibly associated with increased mortality
  2. Pharmacological effects on immune system through nuclear factor kappa B
  3. Up-regulation of receptors for vasopressors such as noradrenaline
  4. A possible interaction with vasopressin treatment has been identified but this needs further research

Indications:

Concept of CIRCI unclear and use of short Synacthen test to determine who may benefit from steroids is controversial

Surviving Sepsis Campaign Guidelines 2012 reoommend 200mg hydrocortisone /24hr for septic shock only if fluid resuscitation and vasopressor therapy have been inadequate to restore haemodynamic stability (grade 2C). Further recommendations are not to use the short Synacthen test, to taper hydrocortisone when vasopressors are no longer required and not to use steroids in sepsis without shock

Clear role for steroids in patients who are overtly hypoadrenal (as opposed to CIRCI) and Waterhouse-Friderichsen Syndrome

Steroid treatment is recommended as early adjunctive treatment in bacterial meningitis but studies evaluating role of steroids in bacterial meningitis with septic shock are lacking and recommendations advise treatment as per septic shock

Consider additional supplementation in patients already on steroid therapy

Treatment effects:

The use of low-dose corticosteroids in septic shock significantly reduces shock duration. No improvement in mortality has been shown except for a possible reduction in 28-day mortality in the subgroup of patients who received a prolonged course (defined as more than 5 days) of low-dose corticosteroids.

Possible adverse effects include: impaired glucose control, increased fungal infection, myopathy and poor wound healing.

Studies using low-dose corticosteroids have not shown an increase in the risk of gastrointestinal bleeding, superinfection, or acquired neuromuscular weakness compared with placebo, but may not have been adequately powered to observe significant differences in side effects.

The use of corticosteroids may affect glucose metabolism and the need for insulin administration.

Discussion

Relative adrenal insufficiency and the use of corticosteroids in severe septic shock are treated with brief summaries in the Required reading section.

Steroids in shock generally are asked about in Question 12 from the second paper of 2000.

Evidence for steroids in sepsis, and controversies surrounding their use, are asked about in Question 22 from the first paper of 2008: "Outline the evidence for the role of glucocorticoids  in ARDS and septic shock and the current controversies surrounding their use in these conditions".

In brief:

  • Introduction / definition:
    • A certain group of sepsis patients may benefit from the administration of steroids, with improvement in mortality.
  • Rationale: 
    Steroids may produce the following beneficial actions in severe shock: 
    • Reversal of relative adrenal insufficiency
    • Reversal of inflammatory overactivity
    • Reprogramming of the immune response
    • Improved responsiveness of α-1 receptors (thus, decreased catecholamine requirements)
    • Correction of vasoplegia by deactivation of nitric oxide synthase
    • Improved cardiac tolerance of bacterial endotoxin
    • Improved retention of resuscitation fluid
  • Evidence:
    • 2002 French study:
      • Significant improvement in mortality among 300 septic patients, from 70% to 58%.
      • Severely shocked patients, 1.1μg/kg/min (75ml/hr) of noradrenaline.
    • 2008 CORTICUS trial:
      • No mortality difference associated with the use of steroids.
      • Moderately shocked patients, only 0.5μg/kg/min (35ml/hr) of noradrenaline.
    • 2009 meta-analysis:
      • 17 trials; conclusion: there is a small mortality benefit.
    • The same analysis, excluding all but 6 well-designed trials:
      • Conclusion: steroids did not improve survival
    • 2013 Surviving Sepsis Guidelines:
      • Grade 2B recommendation in favour of steroids, provided they are reserved for those patients who are refractory to fluids and vasopressors.
      • Rationale: survival only seems to be improved in patients whose mortality from sepsis is likely to be over 60%.
  • Advantages
    • Cardiovascular improvement (decreased vasopressor dose)
    • Decreased organ system dysfunction
    • Earlier withdrawal of vasopressor support
    • Possibly, decreased mortality in selected patients
  • Disadvantages
    • Hyperglycaemia
    • Fluid retention
    • Possibly, increased risk of nosocomial infection
    • Steroid myopathy and delayed ventilator weaning
    • Increased risk of gastric ulceration
  • Own practice:
    • practice according to the Surviving Sepsis guidelines, or local policy.

References

Surviving Sepsis Guidelines

Annane, Djillali, et al. "Corticosteroids in the treatment of severe sepsis and septic shock in adults: a systematic review." Jama 301.22 (2009): 2362-2375.

Sligl, Wendy I., et al. "Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis." Clinical infectious diseases 49.1 (2009): 93-101.

Annane, Djillali. "Corticosteroids for severe sepsis: an evidence-based guide for physicians." Annals of intensive care 1.1 (2011): 1-7.

Sprung, Charles L., et al. "Hydrocortisone therapy for patients with septic shock." New England Journal of Medicine 358.2 (2008): 111.

Vassiliadi, Dimitra A., et al. "Longitudinal assessment of adrenocortical responses to low-dose ACTH in critically ill septic patients." Endocrine Abstracts (2013) 32 P26

Annane, Djillali, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock." Jama 288.7 (2002): 862-871.

Question 19 - 2013, Paper 1

You are contacted by a rural physician seeking advice regarding a 35-year-old female who is 28/40 pregnant and has been intubated for acute respiratory failure with a possible diagnosis of H1N1 influenza A.
 
Briefly discuss how you would confirm the diagnosis and outline the priorities regarding the immediate management of this case.

College Answer

Diagnosis

Diagnosis of H1N1 is taken against background of pre-test probability (season, signs and symptoms of flu-like illness, possible exposure, other confirmed cases) and the sensitivity and specificity of laboratory test.

rRT-PCR is most sensitive and specific.

Rapid antigen tests and Immunofluorescent antibody testing are not specific for different flu A subtypes

Serology useful for identifying patients post infection

Confirmation of the diagnosis of H1N1 influenza A (CDC case definition) requires influenza-like illness with laboratory-confirmed H1N1 influenza A virus detection by real-time reverse transcriptase PCR or culture.

Treat as positive in interim if test results uncertain

Management Priorities

Arrange transfer to appropriate centre with combined ICU/obstetric care

Isolation, negative pressure room, contact precautions

Antiviral treatment: antiviral oseltamivir – important not to delay treatment in pregnancy

Obstetric input and counseling patient and partner.

Pregnancy increases the likelihood of the development of severe disease.

Early delivery likely either spontaneous or therapeutic so commence etamethasone/dexamethasone for foetal lung maturation

Supportive management: as indicated mechanical ventilation using lung protective strategies, vasopressor support if hypotensive etc.

Discussion

This question comes in the wake of the H1N1 pandemic, and may never appear again. Writing in mid-2015, one might expect that we are more likely to get an Ebola question. These pandemic questions usually appear about 18 months after the end of the outbreak, to lull the candidates into a false sense of security.

In summary:

Diagnosis of H1N1 influenza

Management of H1N1 influenza

  • ABC management - intubation and ventilation as needed, using lung-protective strategies
  • Oseltamivir - though it has recently come under fire, its use may still contribute to survival in patients at greatest risk of death. And it seems vaguely safe in pregnancy.
  • Isolation
  • Airborne precautions
  • O&G consultation
  • Preparation of the foetus for delivery with corticosteroids
  • Preparation for transfer to a large ICU

References

Vasoo, Shawn, Jane Stevens, and Kamaljit Singh. "Rapid antigen tests for diagnosis of pandemic (Swine) influenza A/H1N1." Clinical infectious diseases49.7 (2009): 1090-1093.

Balish, A., et al. "Evaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) virus-United States, 2009." Morbidity and Mortality Weekly Report 58.30 (2009): 826-829.

Gerrard, John, et al. "Clinical diagnostic criteria for isolating patients admitted to hospital with suspected pandemic influenza." The lancet 374.9702 (2009): 1673.

Dunstan, H. J., et al. "Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study." BJOG: An International Journal of Obstetrics & Gynaecology 121.7 (2014): 901-906.

Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2545

Question 23.1 - 2013, Paper 1

A 55-year-old obese male with dysuria and hypotension was admitted to the ICU 12 hours previously. He had a femoral central venous catheter inserted in the Emergency Department on admission. Your registrar has reported that blood cultures collected through the CVC at the time of insertion growing Staphylococcus epidermidis.

  • What advice will you give the registrar regarding the blood culture result?
  • List two groups of patients in whom this result would be a concern.

College Answer

a)

Not to give additional antibiotics

Consider removing / re-siting the femoral CVC depending on the patient’s condition

b)

    1. Immunocompromised patients with intravascular devices
    2. Patients with surgical implants
    3. Patients high risk for endocarditis
    4. Low weight neonates and elderly

Discussion

Key points about the first part of this question:

Key points about the risk factors for clinically significant S.epidermidis bacteraemia:

  • Anyone at risk of native valve endocarditis
  • Anyone with artifical valves
  • Anyone with a history of rheumatic heart disease
  • Anyone who is immunosuppressed
  • Anyone with an implated pacemaker, or any other surgical implant
  • Any low birth infant
  • Any elderly person (>65 years of age)

In any case, the question clearly points our way to urosepsis. The guy had dysuria, which is not usually a feature of staphylococcal endocarditis so severe that it would cause haemodynamic collapse and ICU admission.

References

De Leon, Samuel Ponce, and Richard P. Wenzel. "Hospital-acquired bloodstream infections with Staphylococcus epidermidis: review of 100 cases."The American journal of medicine 77.4 (1984): 639-644.

Haslett, T. M., et al. "Microbiology of indwelling central intravascular catheters."Journal of clinical microbiology 26.4 (1988): 696-701.

Stohl, Sheldon, et al. "Blood cultures at central line insertion in the intensive care unit: comparison with peripheral venipuncture." Journal of clinical microbiology 49.7 (2011): 2398-2403.

Beekmann, Susan E., Daniel J. Diekema, and Gary V. Doern. "Determining the clinical significance of coagulase-negative staphylococci isolated from blood cultures." Infection control and hospital epidemiology 26.6 (2005): 559-566.

Raad, Issam, et al. "Impact of central venous catheter removal on the recurrence of catheter-related coagulase-negative staphylococcal bacteremia."Infection control and hospital epidemiology (1992): 215-221.

Raad, Issam, et al. "Management of the catheter in documented catheter-related coagulase-negative staphylococcal bacteremia: remove or retain?."Clinical infectious diseases 49.8 (2009): 1187-94.

Chu, Vivian H., et al. "Emergence of coagulase-negative staphylococci as a cause of native valve endocarditis." Clinical infectious diseases 46.2 (2008): 232-242.

Blot, François, et al. "Earlier positivity of central-venous-versus peripheral-blood cultures is highly predictive of catheter-related sepsis." Journal of clinical microbiology 36.1 (1998): 105-109.

Question 23.2 - 2013, Paper 1

A 61-year-old male fisherman presented to the Emergency Department with hypotension, three days after falling on a coastal slipway and suffering extensive abrasions to both lower limbs. These abrasions are now progressing and transforming into haemorrhagic bullae. The patient is now admitted to the ICU for organ support.

  • What is the most likely causative organism?
  • What is the specific treatment required in this case?

College Answer

a)

  • Vibrio vulnificus or V parahaemolyticus

b)

  • Surgical debridement of necrotic tissue including amputation if indicated.
  • Antibiotic therapy – 3rd generation cephalosporin + a tetracycline OR Ciprofloxacin OR Meropenem OR any reasonable antibiotic choice

Discussion

This question requires the candidate to be familiar with a fairly rare pathogen.

a) Vibrio vulnificus is strongly suggested by the keywords "fisherman" and "coastal slipway".

b) A tetracycline, ciprofloxacin or meropenem are all good choices.

The Sanford Guide recommends doxycycline together with ceftriaxone, with ciprofloxacin as an alternative sole agent.

References

Strom, Mark S., and Rohinee N. Paranjpye. "Epidemiology and pathogenesis of Vibrio vulnificus." Microbes and infection 2.2 (2000): 177-188.

Bross, Michael H., et al. "Vibrio vulnificus infection: diagnosis and treatment."American family physician  volume 76, number 4 (2007): 539-544.

Question 23.3 - 2013, Paper 1

A 56-year-old patient who has been on Meropenem and Fluconazole for six days for intra-abdominal sepsis has developed new fevers and blood cultures have shown a Gram negative organism. The sensitivities are given below:

Gentamicin

Tobramycin

Ampicillin

Imipenem

Ciprofloxacin

Ticarcillin

Gram

negative

bacillus

R

R

R

R

R

R

  • List three likely causative organisms for the new episode of sepsis.
  • For each organism listed give an appropriate antibiotic.

College Answer

  • Stenotrophomonas maltophilia · Co-trimoxazole
  • Multi-resistant Acinetobacter · Amikacin / Colistin
  • Multi-resistant pseudomonas spp · Amikacin
  • Enterobacter spp - Amikacin
  • Proteus spp - Amikacin

Any other reasonable combination accepted

Discussion

The college recognises the many different ways to skin a cat, and accepts any reasonable combination.

However, the savvy candidate will recognise that imipenem is the specific antibiotic listed there.

There are some Gram-negative bacteria which are intriniscally imipenem-resistant, but which are still susceptible to other carbapenems (provided they are antibiotic-naive). Generally, there are only a few bugs which have an intrinsic imipenem resistance. Specifically, these would include any intracellular organisms, such as Chlamydia.

This list is small, and it also includes organisms which are not relevant to this question.

  • Stenotrophomonas maltophila
  • Pseudomonas maltophilia
  • Pseudomonas cepacia 
  • Enterococcus faecium
  • MRSA

Potentially, one could spew out a list of gram negative bacteria and preamble each name on the list with the words "multi-resistant":

  • Acinetobacter
  • Stenotrophomonas
  • Serratia
  • Klebsiella
  • Enterobacter
  • Pseudomonas
  • Citrobacter

Then, one can add the antibiotics. Most of these bugs will be susceptible to amikacin or colistin.Serratia Citrobacter and Acinetobacter have a particular weakness for co-trimoxazole.

"Any other reasonable combination accepted."

References

Giamarellou, Helen, and Garyphallia Poulakou. "Multidrug-resistant gram-negative infections." Drugs 69.14 (2009): 1879-1901.

Falagas, Matthew E., Sofia K. Kasiakou, and Louis D. Saravolatz. "Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections." Clinical infectious diseases 40.9 (2005): 1333-1341.

Kimberly D. Boeser, PharmD "Are all carbapenems the same?Infectious Disease News, November 2008

Zhanel, George G., et al. "Comparative review of the carbapenems." Drugs67.7 (2007): 1027-1052.

Braveny, I. "In vitro activity of imipenem—a review.European journal of clinical microbiology 3.5 (1984): 456-462.

Question 12 - 2013, paper 2

A 67-year-old female has presented acutely with a diagnosis of tetanus. She sustained a laceration one week earlier while gardening and has now developed generalised spasms and respiratory distress.
 
Outline your specific management of this patient including management of the anticipated complications of tetanus.

College Answer

This case is consistent with a diagnosis of severe generalized tetanus.

Management comprises:

  • Airway management with intubation and mechanical ventilation. Respiratory distress is most likely due to involvement of muscles of respiration and/or laryngospasm but pneumonia should be looked for and treated. Early tracheostomy may be indicated.

Neutralisation of unbound toxin

  • Human tetanus immune globulin 3000-6000 units IM (some authorities advocate 500 units).

Source control and limitation of toxin production

  • Debridement and cleaning of wound
  • Appropriate antibiotics for 7-10 days – penicillin, 3rd generation cephalosporins (nb both GABA antagonists which may aggravate symptoms), metronidazole, erythromycin, doxycycline

Control of spasms

  • Sedation with benzodiazepines +/- neuromuscular blockers. Intrathecal baclofen has been used. Avoid stimulation

Management of autonomic dysfunction

  • Cause of death if respiratory failure avoided by intubation and ventilation
  • Magnesium sulphate has been shown to be effective and labetalol (dual alpha and beta blocker) has also been used.
  • Clonidine may be useful.

Initiation of full active tetanus immunization (with diphtheria and pertussis) given at site separate from TIG injection.

Salient points

Management of tetanus:

  • ABCs
  • neutralise toxin with IM immunoglobulin
  • control sympathetic storm with labetalol/magnesium/clonidine
  • kill Clostridium with metronidazole and control the source

Discussion

This question would have killed most people.

Oh well. One approaches this as any other "outline your management" question.

A more generic discussion of tetanus is carried out in the Required Reading section.

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
  • Airway
    • Intubate the patient for airway protection; laryngospasm is likely.
    • NIV with high PEEP could be a temporising measure
  • Breathing/ventilation
    • Adequate ventilator support with MV titrated to accomodate the increased CO2production in the context of increased muscular metabolic acivity.
  • Circulatory support
    • Tetanus is characterised by massive sympathetic stimulation, with tachycardia and hypertension. Labetalolmagnesium sulfate and clonidine have been used as antagonists.
  • Specific management
    • Administration of human tetanus immunoglobulin
    • Administration of antibiotics targeted at Clostridium tetani (metronidazole and benzylpenicillin)
    • Source control by wound debridement
    • Control of spasms with a neuromuscular junction blocker or benzodiazepine
    • Tetanus immunisation

References

Rodrigo, Chaturaka, Deepika Fernando, and Senaka Rajapakse. "Pharmacological management of tetanus; an evidence based review." Crit Care18 (2014): 217.

Cook, T. M., R. T. Protheroe, and J. M. Handel. "Tetanus: a review of the literature." British Journal of Anaesthesia 87.3 (2001): 477-487.

Wesley, A. G., et al. "Labetalol in tetanus." Anaesthesia 38.3 (1983): 243-249.

Attygalle, D., and N. Rodrigo. "Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients*." Anaesthesia 57.8 (2002): 778-817.

Question 14 - 2013, paper 2

Critically evaluate the use of selective decontamination of the digestive tract (SDD) in the ICU.

College Answer

Introductory statement:

SDD is a prophylactic strategy to prevent or minimise the incidence of nosocomial infection from endogenous organisms and to prevent or minimise cross-infection by the application of non-absorbable oral and enteric antibiotics and parenteral antibiotics.

Classically SDD has four components:

  • Administration of orobase and enteral antibiotics (eg polymixin B, tobramycin and amphotericin)
  • Parenteral antibiotic eg cefotaxime
  • Good hygiene to prevent cross-contamination
  • Microbiological surveillance of throat swabs and faecal samples

Variations exist.

  • Oropharyngeal eradication only (SOD). 
  • Enteral only. 
  • Oral and enteral only. 
  • Different antibiotics.

OR any reasonable and adequate introduction.

Rationale:

Nosocomial infections cause significant morbidity and mortality in the ICU. These infections arise from a limited number of potentially pathogenic micro-organisms (PPM) carried by healthy individuals (eg Staph aureus, E coli and C albicans) and opportunistic, aerobic Gram-negative bacilli (eg Klebsiella, Pseudomonas Acinetobacter) that colonise individuals when critically ill.

The goal of SDD is to prevent or eradicate, if already present, at the start of ICU admission, the carriage of PPMs from the oropharynx and GI tract, leaving the indigenous flora, which protect against overgrowth with resistant bacteria, largely undisturbed.

Arguments against;

  • SDD might lead to increased antibiotic resistance of colonising bacteria
  • There is already a significant overuse of antimicrobial therapy

Evidence:

Over 60 RCTs with >15,000 patients (mostly in Europe) show benefits in terms of:

  • mortality (NNT ~18)
  • overall infection
  • lower airway infections
  • blood stream infections
  • oropharyngeal carriage
  • rectal carriage
  • MODS
  • ICU length of stay

Patient groups studied include general ICU, burns, gastrointestinal surgery and transplant patients.

  • The evidence does not suggest an increase in MROs
  • However the number of trials with good scientific methods are few
  • In the trials that suggested benefit, there was baseline variance in patient demographics and overall care
  • The trials that suggest benefit have been conducted in areas with a low prevalence of multi-resistant organisms (northern Europe).
  • There is a suggestion that selective oral decontamination is equally as effective as SDD, so the iv cephalopsporins are not required

Await the results of the international multi-centre RCT SuDDICU.

Summary statement and Personal approach:

Any reasonable statement of candidate’s own approach, for example

  • Risk benefits
  • Adoption by communities vs. units
  • Protocols driven by local flora and practice vs. world evidence
  • Not widely used in intensive care practice in ANZ
  • The need for a definitive trial, especially in the ANZ community

Discussion

Rationale

  • Critical illness causes an overgrowth of normal and opportunistic flora.
    • Specifically, the organisms which enjoy a population explosion are exactly those which are known to cause common nosocomial infections: predominantly oropharyngeal and upper GI organisms.
  • Increased population of this flora leads to the proliferation of multiple bacterial clones, which is an ideal environment for developing antimicrobial resistance.
  • Thus, it stands to reason that if one were to eradicate these organisms, one would reduce the incidence of nosocomial infection in critical illness, and reduce the incidence of antimicrobial resistance.

Protocol

  • There is no agreed-upon protocol.
  • Usual antibiotics are the "PTA" cocktail:
    • polymyxin E
    • tobramycin
    • amphotericin B
      • The SuDDICU authors have complained that these days its harder and harder to get "good old fashioned amphotericin" and the more recent trials have used nystatin instead, which is a poorly absorbed polyene antifungal (i.e. from the same class), cheap and already enjoying universal popularity as a treatment for oral candidiasis.
  • This goop is applied to the oral cavity, and injected down the NG tube.
  • Vancomycin can be added if there are high local rates of colonisation
  • A controversial step is the addition of a short course of IV antibiotics.
  • This is usually a broad spectrum cephalosporin eg. cephotaxime, and it is used for 4 days only. Many study protocols omit this.
  • Surveillance cultures of the throat and rectum are recommended

The beneficial effects are expected to manifest in the following ways:

  • Decreased incidence of VAP.
  • Decreased incidence of pseudocyst infection in acute pancreatitis.
  • Decreased systemic infection rate in cases of gastrointestinal haemorrhage.
  • Decreased incidence of spontaneous bacterial peritonitis in patients with ascites.
  • Protection against early gram-negative sepsis following liver transplantation

Potential drawbacks:

  • May result in increased rates of antimicrobial resistance
  • Expensive in terms of antibiotic doses, staff workload, and processing of surveillance samples
  • Local flora may not respond to standard antibiotic cocktails

Evidence:

  • To date, there are numerous RCTs - LITFL counted 60, with over 15,000 patients. A recent (2013) meta-analysis has identified 64 studies.
  • The studies have revealed that
    • There is a mortality benefit (OR = 0.73, NNT = 18)
    • Specificaly, the largest trial to date (de Smet, 2009) found an all-cause mortality reduction by 3.5%, from an absolute rate of 27.5% down to 25%.
    • Length of stay is decreased
    • VAP incidence is decreased by 72%
    • The "full-scale" SDD protocol (with a short course of IV antibiotics) is superior to the "limited" SDD where only the oropharynx is decontaminated (and both strategies are superior to oral chlorhexidine)
    • A 2004 Cochrane review found that whereas the "full-scale" SDD decreases the incidence of respiratory tract infections and mortality, the use of oropharyngeal decontamination alone had no effect on mortality- only on incidence of pneumonia.

Critique of the evidence

  • The studies all suffer from heterogeneity and poor experimental design.
  • Outcome definitions vary considerably, especially as there is no universally accepted definition of VAP.
  • Most of the studies were conducted in countries with a lower local MRSA prevalence (Germany and the Netherlands). In these affluent Norther European nations, rates of multiresistant organism colonization would not be representative.
  • Placebo solutions may have been microbial vehicles in these studies, increasing the incidence of VAP among the control group.
  • There are no good studies of the effect of SDD on the development of multi-resistant organisms (but poor-quality studies suggest that there is no effect).

Local practice

  • There is little support for this practice among the Australian intensivist community.
  • The practice has been regarded with scepticism in Australian ICUs, and there has been no broad department-level support for it here. Opponents cite paucity of good quality evidence and non-generalisability of European data in local intensive care units.

References

Marshall, John C. "Gastrointestinal flora and its alterations in critical illness."Current Opinion in Critical Care 5.2 (1999): 119.

van Saene, H. K. F., et al. "Microbial gut overgrowth guarantees increased spontaneous mutation leading to polyclonality and antibiotic resistance in the critically ill." Current drug targets 9.5 (2008): 419-421.

Camus, Christophe, et al. "Short-Term Decline in All-Cause Acquired Infections With the Routine Use of a Decontamination Regimen Combining Topical Polymyxin, Tobramycin, and Amphotericin B With Mupirocin and Chlorhexidine in the ICU: A Single-Center Experience*." Critical care medicine 42.5 (2014): 1121-1130.

Daneman, Nick, et al. "Effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis." The Lancet infectious diseases 13.4 (2013): 328-341.

Price, Richard, Graeme MacLennan, and John Glen. "Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis." BMJ: British Medical Journal 348 (2014).

Petros, Andy J., et al. "2B or Not 2B for Selective Decontamination of the Digestive Tract in the Surviving Sepsis Campaign Guidelines." Critical care medicine 41.11 (2013): e385-e386.

Hurley, James C. "Paradoxical ventilator associated pneumonia incidences among selective digestive decontamination studies versus other studies of mechanically ventilated patients: benchmarking the evidence base." Crit Care15 (2011): R7.

Ochoa-Ardila, María E., et al. "Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: a 5-year prospective cohort study." Intensive care medicine 37.9 (2011): 1458-1465.

Hurley, James C. "The perfidious effect of topical placebo: A calibration of Staphylococcus aureus Ventilator Associated Pneumonia incidence within Selective Digestive Decontamination (SDD) studies versus the broader evidence base." Antimicrobial agents and chemotherapy (2013): AAC-00424.

Liberati, Alessandro, et al. "Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care." Cochrane Database Syst Rev 1 (2004).

Safdar, Nasia, Adnan Said, and Michael R. Lucey. "The role of selective digestive decontamination for reducing infection in patients undergoing liver transplantation: A systematic review and meta‐analysis." Liver transplantation10.7 (2004): 817-827.

Derde, L. P. G., and M. J. M. Bonten. "Controlling antibiotic resistance in intensive care units." Netherlands Journal of Critical Care, VOLUME 19 - NO 1 - FEBRUARY 2015

De Smet, A. M. G. A., et al. "Decontamination of the digestive tract and oropharynx in ICU patients." New England Journal of Medicine 360.1 (2009): 20.

Cuthbertson, B. H., et al. "A study of the perceived risks, benefits and barriers to the use of SDD in adult critical care units (The SuDDICU study)." Trials 11.1 (2010): 117.

Question 15.1 - 2013, paper 2

For each of the microbes listed below, list the most appropriate antibiotic(s) for treatment of infection resulting from these organisms:

  1. Candida glabrata
  2. Clostridum perfringens
  3. Listeria monocytogenes
  4. Neisseria meningitides
  5. Multi-resistant Acinetobacter
  6. Nocardia
  7. Penicillin-intermediate pneumococcus
  8. Vancomycin-resistant enterococcus

College Answer

Organism

Agent

Candida glabrata

Voriconazole or caspafungin or Amphotericin B

Clostridium perfringens

Peniciliin or Meropenem or Metronidazole

Listeria monocytogenes

Penicillin or Ampicillin

Neisseria meningitides

Ceftriaxone or Penicillin (high dose)

Multi-resistant Acinetobacter

Amikacin. Polymixins

Nocardia

Sulphonamides

Penicillin-intermediate pneumococcus

Ceftriaxone or Vancomycin

Vancomycin-resistant enterococcus

Linezolid or Daptomycin

Discussion

Elsewhere, there is a large list of important microorganisms.

More specifically, there is also a tabulated short-list of important pathogens and their antibiotic remedies.

The table from the college answer is difficult to expand upon. It seems important, but one cannot list every possible microorganism in a table with the drugs routinely used to treat them. That is what the Sanford Guide is for; this is why we have a vast array of electronic databases to guide our antimicrobial decisionmaking. In view of the rapid availability of accurate reference information, one wonders about the value of a question which tests the candidate's ability to recall lists of microbes and their antibiotic susceptibilities.

References

For the antibiotic choices, I have used the Sanford Guide.

Local practice may vary (wildly).

Question 15.2 - 2013, paper 2

Briefly outline the dosing adjustment and the monitoring necessary for each of the following drug groups in patients with established septic shock and moderate to severe renal dysfunction (without dialysis):

  1. Aminoglycosides
  2. Fluoroquinolones
  3. Beta-Lactams
  4. Carbapenems
  5. Glycopeptides

College Answer

  • Aminoglycosides
    • High initial dose and monitor trough concentrations. Extend interval. May be necessary to decrease dose and monitor with MIC data
  • Fluoroqinolones
    • Reduce frequency but maintain dose.
    • Monitor QT interval
  • Beta Lactams
    • Can reduce dose OR frequency
    • Monitoring unnecessary
  • Carbapenems
    • As for Beta Lactams
  • Glycopeptides
    • High dosing on day one dose adjustments according to Cmin and dependent on degree of renal dysfunction

Discussion

Another question which relies on memory rather than on the capacity to reason. However, the classes of antibiotics discussed here are common ones, and one should be intuitively familiar with their use.

In a brief summary:

  • Beta-lactams can be either dose-adjusted or interval-adjusted
  • Carbapenems can be either dose-adjusted or interval-adjusted
  • Aminoglycosides keep the same dose, and are interval-adjusted (with monitoring of drug levels)
  • Fluoroquinolones keep the same dose, and are interval-adjusted (with monitoring of the QT interval)
  • Glycopeptides keep the same dose, and are interval-adjusted (with monitoring of drug levels)

References

McKenzie, Cathrine. "Antibiotic dosing in critical illness." Journal of antimicrobial chemotherapy 66.suppl 2 (2011): ii25-ii31.

Ulldemolins, Marta, et al. "Antibiotic dosing in multiple organ dysfunction syndrome." CHEST Journal 139.5 (2011): 1210-1220.

Lipman, J. "Towards better ICU antibiotic dosing." Critical Care and Resuscitation 2000; 2: 282-289 .

Trotman, Robin L., et al. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy." Clinical infectious diseases 41.8 (2005): 1159-1166.

Question 16 - 2013, paper 2

Critically evaluate the role of Early Goal Directed Therapy (EGDT) in septic shock.

College Answer

EGDT definition:

Within 6 hours of presentation to the Emergency Department intensive monitoring of specific circulatory parameters with the aggressive management of these parameters to specified targets:

Parameters

  • CVP ³ 8-12 mmHg
  • MAP 65 – 90 mmHg
  • Urine output ³ 0.5 ml/kg/hr
  • Mixed venous oxygen saturation ³ 65% / ScvO2 ³ 70%
  • Haematocrit ³ 30%

Interventions

  • Reduce work of breathing by early use of mechanical ventilation
  • Fluid resuscitation
  • Use of vasoactive medication
  • Transfusion

Rationale:

The principle of applying EGDT for septic shock is based on the observations that:

  • Early treatment for Myocardial Infarction, Acute Ischaemic Stroke and
  • Trauma improves patient outcomes.
  • Patients presenting to ED with sepsis have measurable O2 deficit
  • Evidenced by high lactate and high ScvO2.
  • For septic shock the hypothesis is that early optimization of the compromised
  • Septic circulation may reduce mortality.

Evidence:

The evidence for the intervention is based on an American, single-centre RCT (Rivers 2001) and a recent Chinese multicenter study supporting EGDT -

Surviving Sepsis Guidelines: Grade 1C (inconsistent results, well done observational studies/control RCTs) recommendation

Limitations of Rivers study include the following:

Study population limited to ED presentations and did not include ward patients Single centre

Non-blinded 
Control group had an above-average mortality rate

Unclear which interventions are most important – whole EGDT protocol or one single component

Target parameters are restrictive

Use of ScvO2 and pressure monitoring has not been tested in the target population Transfusion target to improve DO2 contradicts restrictive transfusion practice and may be associated with increased mortality in the critically ill

Results of ANZ ARISE and related international studies (ProCESS and ProMISE) Awaited

Adverse effects:

Protocols for implementing EGDT usually result in more fluid being administered, more use of vasoactive medication and more use of blood transfusion.

Therefore potential adverse effects relate to:

  • Fluid overload
  • Arrhythmias
  • Adverse effects of blood transfusion

Proscriptive targets may not suit all (eg higher MAP needed for elderly patients, lower MAP and Hct targets for young, fit patients).

Statement of Candidate’s Own Practice:

Summary statement including any reasonable strategy.

Discussion

Also LITFL have an excellent autopsy of this technique. Additonally, Paul Marik recently published an opinion piece in CHEST which is an excellent summary of modern approaches to the acute management of sepsis. Lastly, the ProCESS and ARISE studies have now added damning empirical evidence to the theoretical objections.

Upon my initial inspection, the college answer seemed extremely detailed, and seemed unlikely to be reproduced by the time-starved exam candidate.

A succinct version would be better... but, in an attempt to create one, my version also became hideously bloated. There is simply no way to approach this answer without a vast amount of detail.

Such was the extent of this bloat, that the original answer to this question has mutated into a whole chapter on the merits and demerits of early goal-directed therapy.

An then was re-summarised again.

Thus:

  • Introduction / definition:
    • Goals of early goal-directed therapy:
      • CVP  8-12 mmHg
      • MAP 65 – 90 mmHg
      • Urine output >0.5 ml/kg/hr
      • Mixed venous oxygen saturation >65%,
        • or ScvO2 >70%
      • Haematocrit >30%
  • Rationale:
    • Septic patients present with shock and evidence of poor tissue oxygen delivery
    • Poor tissue oxygwen delivery results in organ system failure
    • Duration and magnitude of poor oxygen delivery correlates with severity of organ injury
    • Organ system failure correlates with increased mortality
    • Thus, early correction of the tissue oxygen delivery deficit should improve mortality by decreasing the incidence and severity of organ system failure.
  • Criticism of early goal-directed therapy, and specifically of the trial rationale and methodology:
    • Single centre study
    • Non-blinded
    • Only enrolled ED patients
    • Control group had an above-average mortality rate
    • This mortality rate - a reduction from 46.5% to 30.5% - was still higher than the average rate in Australian ICUs (which do not practice early goal-directed therapy)
    • The whole protocol was the test intervention, and it is unclear which particular goals should be prioritised.
    • The use of ScvO2 is controversial - it is not validated as an endpoint of management in sepsis, and it may not be a good surrogate for mixed venous saturation
    • Lactate monitoring is non-inferior to ScvO2
    • The only independently validated time-critical intervention is early antibiotic administration
    • Transfusion target to improve DO2 contradicts restrictive transfusion practice and may be associated with increased mortality in the critically ill
    • Hemodynamic end-points used in this trial do not address sepsis-induced microvascular hemodynamic changes
  • Support for early goal-directed therapy:
    • A multi-centre study from 2010 duplicated Rivers' results (15.7% improvement in mortality)
    • EGDT has been incorporated into the Surviving Sepsis guidelines
  • Contradictory studies in the literature:
  • Advantages of using this approach in one's own practice
    • The hemodynamic goals are laudable - at least MAP is a physiological parameter worth pursuing.
    • If one is comfortable with the methodology of the trial, the improvement in survival (16%) is substantial
    • Individual use of the EGDT strategy is validated by its incorporation into the Surviving Sepsis guidelines
  • Disadvantages of using this approach in one's own practice
    • You end up using more fluids and blood products
    • You end up resorting to more vasopressors and inotropes.
    • The use of EGDT was trialled in the ED population only.
    • There does not appear to be any benefit in the ICU setting (ProCESSARISE).
  • Summary: the key points for one's practice
    • Early aggressive resuscitation of shock is important, no matter the cause
    • Though individual components of EGDT have been criticised, MAP and perhaps oter hemodynamic goals can be incorporated into practice which also involves other parameters (such as lactate).

References

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Jones, Alan E., et al. "The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis." Critical care medicine 36.10 (2008): 2734.

Kumar, Anand, et al. "Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*." Critical care medicine 34.6 (2006): 1589-1596.

Early Goal-Directed Therapy Collaborative Group of Zhejiang Province. "The effect of early goal-directed therapy on treatment of critical patients with severe sepsis/septic shock: A multi-center, prospective, randomized, controlled study." Zhongguo wei zhong bing ji jiu yi xue= Chinese critical care medicine= Zhongguo weizhongbing jijiuyixue 22.6 (2010): 331.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Power, GSarah, et al. "The Protocolised Management in Sepsis (ProMISe) trial statistical analysis plan." Critical Care and Resuscitation 15.4 (2013): 311.

Delaney, Anthony P., et al. "The Australasian Resuscitation in Sepsis Evaluation (ARISE) trial statistical analysis plan." Critical Care and Resuscitation 15.3 (2013): 162.

Marik, Paul E. "Early Management of Severe Sepsis: Concepts and Controversies." CHEST Journal 145.6 (2014): 1407-1418.

Peake, Sandra L., et al. "Goal-directed resuscitation for patients with early septic shock." The New England journal of medicine 371.16 (2014): 1496.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Question 22 - 2013, paper 2

Critically evaluate the role of vasopressin in septic shock.

College Answer

Introductory statement:

Vasopressors have a role in septic shock to offset hypotension caused by vasoplegia. Vasopressin is an endogenous neuroendocrine peptide that acts on multiple receptors with multiple effects including potent vasoconstriction

Rationale for use of vasopressin in septic shock:

Low levels of vasopressin have been demonstrated in patients with septic shock (compared to cardiogenic shock).

Infusion of vasopressin reduces the need for other vasoactive medication and increases both urine output and creatinine clearance.

In septic shock, exogenous vasopressin appears to act preferentially on V1 receptors on the smooth muscle of the vasculature rather than the renal V2 receptors.

Patients with septic shock may be relatively catecholamine resistant and not respond well to nor-adrenaline and potentially respond better to vasoactive agents acting at different receptors.

Evidence:

The largest study to date is an International RCT (VASST) Patients: Septic shock on low dose nor-adrenaline infusion

Intervention: Vasopressin vs. Comparator: Noradrenaline (Other doses of open-label vasopressors given according to clinical indication)

Outcome: No effect on the primary outcome of 28-day mortality. Subgroup of those with less severe shock appeared to benefit.

Potential adverse effects:

  • Ischaemia: Cardiac/Gastrointestinal/Cutaneous 
  • Reduction in cardiac output 
  • Liver function abnormalities 
  • Platelet dysfunction

Opinion:

  • Vasopressin may benefit patients when it is started early, but the subgroup benefit may be a chance finding and needs to be interpreted with caution.
  • Higher doses of vasopressin (fixed dose infusion used in the studies) may be needed for patients with more severe shock.
  • Either way there is a clear need to monitor closely for adverse effects if vasopressin is used for septic shock.

Discussion

An extensive elaboration of vasopressin and its properties can be found elsewhere.

  • Introduction / definition:
    • Vasopressin is an important adjunct to the management of septic shock, and works synergistically with catecholamine vasopressors.
  • Rationale:
    • Vasopressin acts on V1 and V2 receptors, of which the V1 receptors are responsible for its vasoconstrictor properties.
    • Activation of these receptors leads to vasoconstriction which is synergistic with the vasoconstriction form catecholamine vasopressors, thus decreasing catecholamine requirements.
    • Vasopressin does not have proarrhythmic properties of catecholamine agents, and may be used as a catecholamine-sparing agent
    • Vasopressin receptor sensitivity is unchanged in the setting of severe acidosis, while catecholamine receptors lose their sensitivity.
    • There is also a concept of "relative vasopressin insufficiency" which suggests that in states of severe shock the endogenous secretion of vasopressin is inadequate, and vasopressin needs to be supplemented in order to maintain an adequate vasopressor response.
  • Evidence: what the recent trials say
    • The VASST trial had demonstrated that vasopressin alone is not inferior to noradrenaline as a vasopressor in septic shock
  • Advantages
    • Decreased catecholamine requirements
    • Maintained activity in severe acidosis
    • Non-arrhythmogenic
    • Promotes the retention of resuscitation fluid
  • Disadvantages
    • Causes splanchnic vasoconstriction, which may promote anastomotic breakdown and worsening of gut ischaemia.
    • Causes increased peripheral vasoconstriction, which may result in ischaemia of the extremities
    • May cause cardiac ischaemia due to coronary vasoconstriction
    • Requires central venous access to administer
  • Own practice:
    • Vasopressin is useful as an adjunct in severe shock states which feature low peripheral vascular resistance, and should be added to catecholamine vasopressors in situations of increased catecholamine requirements or catecholamine resistance.
 

References

Landry, Donald W., et al. "Vasopressin deficiency contributes to the vasodilation of septic shock." Circulation 95.5 (1997): 1122-1125.

Sharshar, Tarek, et al. "Depletion of neurohypophyseal content of vasopressin in septic shock*." Critical care medicine 30.3 (2002): 497-500.

Dünser, Martin W., et al. "Arginine Vasopressin in Advanced Vasodilatory Shock A Prospective, Randomized, Controlled Study." Circulation 107.18 (2003): 2313-2319.

Question 11 - 2014, Paper 1

A 65-year-old male is admitted to your intensive care unit from the haematology ward with hypotension and diarrhoea (1.5L/day). He received an allogeneic stem cell transplant 18 days ago as part of his treatment for multiple myeloma.
 
On arrival to the ICU he is febrile, tachypnoeic, with a tachycardia and hypotension and a distended abdomen, which is diffusely mildly tender.

Blood results on ICU admission are as follows:
 

 

Parameter

Patient Value

Normal Adult Range

Sodium

137 mmol/L

135 – 145

Potassium

4.8 mmol/L

3.5 – 5.0

Chloride

99 mmol/L

95 – 105

Bicarbonate

16 mmol/L*

22 – 32

Urea

21 mmol/L*

3.0 – 8.5

Creatinine

146 micromol/L*

40 – 90

Albumin

19 G/L*

36 – 52

Bilirubin

33 micromol/L*

0 – 18

Alanine Aminotransferase (ALT)

49 IU/L*

0 – 30

Aspartate Aminotransferase (AST)

140 IU/L*

0 – 30

Alkaline Phosphatase (ALP)

120 IU/L*

30 – 100

Gamma Glutamyl Transferase (GGT)

225 IU/L*

0 – 35

Haemoglobin

84 G/L*

115 – 165

Platelets

12 x 109/L*

150 – 400

White Cell Count

0.1 x 109/L*

4 – 11

Neutrophils

0.0 x 109/L*

2.0 – 7.5

FiO2

0.4

pH

7.37

7.35 – 7.45

PCO2

28 mmHg*

35 – 45

PO2

108 mmHg

HCO3

16 mmol/L*

24 – 31

Base excess

-8 mmol/L*

-3 – +3

Lactate

8.1 mmol/L*

< 2.2

Glucose

6.2 mmol/L

3.0 – 7.8

Calcium

1.24 mmol/L

1.2 – 1.3

a) Outline your management priorities.

b) List the likely causes of diarrhoea in this patient.

College Answer

NB: Important points in bold.

a)
This is a critically ill, immunocompromised patient with febrile neutropenia following a stem cell transplant. There is evidence of septic shock with evidence of organ dysfunction (lactic acidosis, renal, hepatic and bone marrow dysfunction)
Management priorities: resuscitation, determination of relevant history, appropriate investigations and definitive therapy.

i. Resuscitation
 Assessment of work of breathing & NIV, if required.
 Assessment of volume status/responsiveness & cardiac output, IV access and fluid resuscitation, invasive central venous and arterial lines with platelet cover, vasoconstrictor/inotrope therapy aiming for appropriate goals.
 Early antibiotic therapy.

ii. Relevant history
 Organ specific symptoms.
 Information about transplant, related chemotherapy, current medications.
 Prior infections/colonisations.
 Consideration of non-infectious causes - e.g. pancreatitis .

iii. Investigations
 Detailed clinical examination, source of sepsis.
 Blood cultures-peripheral and through existing central lines, urine, stool cultures, removal of existing lines if likelihood of infection and tip for culture.
 Investigation for diarrhoea- stool for ova, cysts, parasites, C diff toxin, P/R examination, proctosigmoidoscopy (caution due to thrombocytopenia).
 Erect AXR – rule out perforated viscous and surgical review, if indicated.
 Other relevant imaging based on history and examination- chest x-ray, abdominal ultrasound/CT.

iv. Therapy 
 Empiric antibiotic therapy within an hour- either based on existing cultures or colonisation, allergies, recent antibiotic use, local antibiograms. Otherwise established febrile neutropenia protocol - Antipseudomonal, anti-staphylococcal and antifungal therapy. Dose adjustment for organ function. 
 Source control where possible, removal of existing lines, catheters. 
 Management of diarrhoea- fluid and electrolyte correction, loperamide if cultures negative. 
 G-CSF (haematology guidance), platelet transfusion if < 20,000 or active bleeding/pre-procedure. 
 Management of symptoms- pain, nausea, mucositis. 
 Establishment of nutrition- Parenteral nutrition if severe mucositis or diarrhoea, trace element supplementation.

b) Possible causes of diarrhoea: 
 Infectious 
o Bacterial- Clostridium difficile, salmonella, shigella, E coli including ESBL. 
o Viral - CMV, rotavirus, adenovirus, norovirus. 
o Parasitic – cryptosporidium, microsporidia, giardia. 
o Fungal- candida.

 Non-Infectious 
o Acute Graft versus Host Disease. 
o Neutropenic enterocolitis (Typhilitis). 
o Drugs- antibiotic related, opioid withdrawal, promotility agents, tacrolimus (thrombotic microangiopathy), chemotherapy conditioning regime for stem cell transplant. 
o Severe hypoalbuminaemia .

Discussion

a)

This question is broadly about the resuscitation of sepsis, but the patient has specific issues which need to be addressed, and one would not do well if one simply applied an algorithmic approach.

The issues are:

  • Septic shock (likely from an abdominal source)
  • Multi-organ system failure
    • Acute renal failure
    • Hepatic insufficiency
    • Bone marrow failure
    • Respiratory failure
  • Lactic acidosis

A structured approach:

Immediate management:

A) - assessment of the urgent need for intubation

B) - Support of oxygenation with NIV or high flow nasal prongs

    • if the patient is mechanically ventilated, minute volume must take into account the need for compensation in this metabolic acidosis

C) - Hemodynamic control:

    • Vigorous fluid resuscitation with combination of balanced crystalloid and albumin, as directed by dynamic assessment of fluid responsiveness
    • Arterial blood pressure monitoring
    • Central venous access
    • Vasopressor support as indicated
    • Reassessment of resuscitation efficacy (lactate)

D) - Adequate analgesia

E) - Correction of electrolyte abnormalities

F) - Monitoring of urine output and renal function; CRRT support as indicated

G) - Nutritional support (ideally, enteral)

H) - Haematological interventions:

    • Maintenance of Hb over 70g/L
    • Consultation with haematology regarding the need for G-CSF
    • Replacement of clotting factors
    • Correction of thrombcytopenia as required by invasive procedures

I) - Early administration of broad-spectrum antibiotics

Investigations:

  • Blood, urine, sputum, stool cultures
  • C.difficile toxin stool test
  • CXR and AXR
  • CT of the abdomen (if permitted by patient stability)
  • Removal of old central venous catheters, or at least cultures from their lumens

b)

Causes of Diarrhoea
In the Bone Marrow Transplant Recipient

Infectious

Non-Infectious

Viruses

  • Rotavirus
  • Norovirus
  • Adenovirus
  • Cytomegalovirus

Bacteria:

  • Clostridium difficile
  • Shigella
  • Salmonella
  • Campylobacter
  • E.coli
  • Aeromonas

Parasites

  • Giardia
  • Cryptosporidium
  • Microsporidium

Fungi

  • Candida

     

Immunosuppressant therapy

  • Cytotoxic drugs
  • Tacrolimus
  • Whole-body irradiation

Consequences of BMT

  • Neutropenic enterocolitis
  • Graft vs host disease

ICU therapy

  • Pro-motility agents
  • High caloric feeds
  • Lactulose
  • Opioid withdrawal
  • Broad spectrum antibiotics

References

Timothy A. Woods. "Diarrhea." Chapter 88 in: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990.

Cox, George J., et al. "Etiology and outcome of diarrhea after marrow transplantation: a prospective study." Gastroenterology 107.5 (1994): 1398-1407.

Question 14 - 2014, Paper 1

With regards to Clostridium difficile (C. difficile) infection in critically ill patients:

a) What are the risk factors for development of this condition?

b) What complications can occur as a result of this infection?

c) How is the diagnosis of C. difficile and its complications established?

d) Briefly outline the options for prevention and treatment.

College Answer

a) Risk factors:
 Exposure to antibiotics
 Clindamycin
 Cephalosproins
 Fluoroquinolones
 Extended spectrum penicillins
 Extremes of age
 Immunosuppression
 Proton pump inhibitors and H2 antagonists
 Nursing home or group care home

b) Complications:
 Related to the diarrhoea
o Hypovolaemia
o Electrolyte disturbance; hypokalaemia, hypomagnesaemia
 Related to the intestinal infection
o Sepsis and septic shock
o Perforation
o Toxic megacolon
o Bleeding

c) Diagnosis:
Clinical and investigation:
 Clinical findings
o Diarrhoea, but may have severe disease without diarrhoea
o Abdominal pain, colic in nature
o Fever
o Shock
 Microbiology
o Stool; C. difficile toxin (false negatives problematic)
o PCR for C. difficile (false positives problematic)
o ELISA for C difficile glutamate dehydrogenase
 Sigmoidoscopy, colonoscopy
o Pseudomembranes
 CT scan
o Abdominal and pelvis
o Oral and ivi contrast
o Helps to diagnose complications such as toxic megacolon, perforation and exclude differential diagnosis

d)
Prevention and treatment:
Prevention
 Antibiotics stewardship, limitation of broad spectrum antibiotics
 Isolation of C diff positive cases with notices advising contact precautions
 Limit spread with hand washing with soap and water, alcohol hand rub is ineffective
Treatment
 Supportive care and resuscitation
 Specific
o Medical
 Antibiotics;

Oral vancomycin (250 – 500 mg enteral q6h)
o Metronidazole oral or ivi
o Tigecycline

o Surgical
 For perforation or toxic megacolon
 Subtotal colectomy
o Monoclonal antibodies and vaccine under development
o Faecal transplant
 More for recurrent infection than for acute severe illness

Examiners' comments: Overall, candidates' knowledge of this topic was limited.

Discussion

This question resembles several other C.difficile questions:

They usually ask about the same things.

Oh well, here we go again.

Risk factors for C.difficile infection

The risk factors for C.difficile infection are discussed here, in a NEJM article.

References

Question 1 - 2014, Paper 1

Outline the strengths and limitations of the current Surviving Sepsis Campaign Guidelines, using examples to illustrate your points.

College Answer

Strengths:

  • The guidelines are formulated by an international panel of experts reviewing and grading the evidence.
  • Use of the Grading of Recommendations Assessment Development and Evaluation (GRADE) for guideline development.
    • GRADE separates the assessment of the quality of the evidence from the ultimate strength of the recommendations (allows for strong recommendations when the quality of evidence is weak or weak recommendations when the quality of evidence is strong, particularly when patient values and preferences may strongly factor into the equation).
  • Intensivists may use as a decision-making tool in their practice as:
    • Information to aid practice
    • An established source of references
    • The current recommendations may generate areas for future research and consensus statements for this high-risk and high-cost patient group.

Limitations

  • The GRADE system, although transparent, is still subjective. Recommendations depend greatly on the values and preferences of the committee members.
  • Guidelines attempt to include nearly every aspect of critical care potentially related to sepsis, thereby losing focus in the process and becoming a general ICU guideline.
  • A narrower guideline dedicated to sepsis-specific management might be more useful.
  • Complexity and diversity of sepsis may defy a single guideline for all cases.
  • Guidelines may rapidly become out-dated
  • E.g. the 2012 guidelines on prone positioning for patients with PaO2/FiO2 ratios < 100 despite such manoeuvres (Grade 2C). This would now potentially be (1B)
  • Recommends use of proton pump inhibitors over histamine-2 receptor antagonist for stress ulcer prophylaxis (grade 2C), although the emerging consensus suggests that this approach may not be beneficial and indeed may even be harmful.
  • There are recommendations that may be considered controversial.
    E.g. Conservative fluid strategy in patients with sepsis-induced adult respiratory distress syndrome in the absence of evidence of tissue hypo perfusion (grade 1C)
  • Early Goal Directed Therapy (EGDT) is strongly recommended, but potentially has a limited evidence base.
  • The guidelines emphasize 'bundles' of care for sepsis resuscitation, although the evidence behind some of the bundled recommendations is not strong, for example using central venous pressure readings to guide volume resuscitation.
  • Significant risk that bundles will be utilised as quality measures with which intensivists (who may validly disagree with some of the recommendations) treating sepsis will be assessed/benchmarked.

Examiners' comments: Candidates appeared to have a lack of understanding of the SSC Guidelines and were unable to discuss their strengths and weaknesses. Many candidates focused on EGDT alone.

Discussion

In response to the Examiner's comment, one might counter by saying that the SSG are so heavily based upon EGDT that a discussion of one is by necessity a discussion of the other. The examiners would counter by pointing out that only 9% of people passed.

It may well be that these candidates in their susceptible state had erroneously conflated this question with Question 16 from the second paper of 2013, having obviously done all the past papers back to front.

A long rambling critique of the EGDT approach is already available elsewhere, and the reader will not be subjected to it here. A distillate of expert opinion regarding the SSG is also available. What follows below is a summary of that summary, hopefully incorporating the important points made in the college model answer.

Advantages of the SSG

High quality of the presented package

  • Excellent literature search and summary.
  • A good source of literature references
  • Produced by an international panel of experts.
  • GRADE system makes it easier for clinicians to assess the strength of a recommendation.
  • GRADE system separates quality of the evidence from the strength of recommendations.

Evidence in defence of the guidelines

Criticisms of the SSG

Arguments against bundled care in general:

  • All-or-none bundles may promote harmful therapies together with helpful ones.
  • Marketing of such bundles may propagate unhelpful therapies.
  • There is no evidence that "bundle synergy" exists.
  • The quality of care might end up being measured according to bundle compliance.

Objections on the basis of methodology:

  • Many of the recommendations are not based in high-level evidence
  • None of the recommendations are based in Level 1 evidence.
  • The GRADE system is subjective.
  • GRADE system separates quality of the evidence from the strength of recommendations, which allows one to make strong recommendations on the basis of weak evidence.

Objections to the guidelines themselves:

  • The guidelines digress significantly from sepsis, and creep across into other areas of ICU management.
  • Controversial recommendations are made, which may not be supported by evidence:
    • There is no survival benefit from routine ScvO2 monitoring (SSG authors agree)
    • There is no survival benefit from routine dobutamine use.
  • The emphasis on EGDT is not supported by strong evidence.

Objections to the evidence offered in support of widespread implementation:

  • Benefit of SSG implementation is found mainly in"before-and-after" trials, subject to publication bias, patient selection bias, temporal bias, and the Hawthorne effect.
  • Frequently only one specific component was independently associated with a treatment effect.
  • Often a treatment effect was found in spite of poor compliance with the bundle.

Empirical evidence against the use of the guidelines:

References

Vo, Mai, and Jeremy M. Kahn. "Making the GRADE: how useful are the new Surviving Sepsis Campaign guidelines?." Critical Care 17.6 (2013): 328.

Marik, Paul E., Karthik Raghunathan, and Joshua Bloomstone. "Counterpoint: are the best patient outcomes achieved when ICU bundles are rigorously adhered to? No." CHEST Journal 144.2 (2013): 374-378.

Dellinger, R. Phillip, and Sean R. Townsend. "Rebuttal From Drs Dellinger and Townsend." CHEST Journal 144.2 (2013): 378-379.

Marik, Paul E., Karthik Raghunathan, and Joshua Bloomstone. "Rebuttal From Dr Marik et al." CHEST Journal 144.2 (2013): 379-380.

Chawla, Shalinee, and Jonas P. DeMuro. "Current controversies in the support of sepsis." Current opinion in critical care 20.6 (2014): 681-684.

Marik, Paul E. "Surviving sepsis: going beyond the guidelines." Annals of intensive care 1.1 (2011): 1-6.

Marik, Paul E. "Surviving sepsis." Critical care medicine 41.10 (2013): e292-e293.

Marik, Paul E. "Early management of severe sepsis: concepts and controversies." CHEST Journal 145.6 (2014): 1407-1418.

Kevin Klauer. "Sepsis: Unbundling the Bundle" in EP Monthly on May 24, 2012.

Priebe, Hans-Joachim. "Goal-directed resuscitation in septic shock." The New England journal of medicine 372.2 (2015): 189-189.

Kaukonen, Kirsi-Maija, et al. "Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012."Jama 311.13 (2014): 1308-1316.

Levy, Mitchell M., et al. "Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study." The Lancet infectious diseases 12.12 (2012): 919-924.

"Australia’s high survival rates shed doubt on global sepsis guidelines" - a press release by Monash University, home of ARISE.

Ferrer, Ricard, et al. "Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain." Jama 299.19 (2008): 2294-2303.

Barochia, Amisha V., et al. "Bundled care for septic shock: an analysis of clinical trials." Critical care medicine 38.2 (2010): 668.

Question 3.2 - 2014, Paper 1

A 74-year-old femle presents with perforated colonic cancer and widespread peritoneal contamination. She has a laparotomy, peritoneal washout, colonic resection and formation of a defunctioning ileostomy. On day 6, she is noted to have abdominal wall cellulitis, abdominal wall oedema and a positive blood culture growing Gram positive bacilli.


a) What is the likely diagnosis?
b) What is the likely organism isolated in the blood culture?

College Answer

a) Necrotising fasciitis.
b) Clostridial species.

Discussion

This question is essentially identical to Question 25.1 from the first paper of 2009, the sicussion section from that SAQ is reproduced here with no modification:

According to an authoritative source, "postoperative necrotizing fasciitis of the abdominal wall is usually caused by peritonitis in patients who have undergone multiple procedures for complications of emergency laparotomy" (Casali et al, 1980).

So, one might ask: what features of this SAQ history makes necrotising fasciitis the most likely diagnosis, rather than an uncomplicated wound infection with surrounding cellulitis? In summary, there is virtually nothing. All history we get can be broken down into component parts:

  • Old age (74 year old woman)
  • Malignancy
  • Perforated colon
  • Extensive faecal soiling ("widespread peritoneal contamination")
  • Extensive surgical intervention (laparotomy, peritoneal washout, colonic resection and a defunctioning  ileostomy) - what sounds like primary closure (no mention of an open abdomen)
  • Infection is taking place on Day 6
  • Clinically, it looks like abdominal wall cellulitis with oedema
  • The blood culture grew Gram positive bacilli.

Apart from the suspicious bacilli, this whole thing looks very much like a bog-standard wound infection.  The history barely resembles the case series presented by Casali et al (1980). The authors present twelve cases of necrotising fasciitis of which the majority were in young people, recovering from abdominal gunshot wounds (none of the right age for this SAQ, and none with malignant perforation). S.aureus and E.coli were the dominant organisms.  Digging around in the pile of literature, one may come across an article or two which describe a situation which resembles the college's scenario. Miyoshi et al (2008) present a review of the clinical features to be expected from post-operative necrotising fasciitis, and Huljev et al (2005) reviewed some historical data in their case report. Mixing the data from these authors, the following features are common to patients who develop post-operative necrotising fasciitis:

  • Most underwent colorectal surgery
  • In most, the timeframe was within 7 days of operation
  • Cellulitis-like features ("rubor of the skin and tenderness") were present in most (90%)
  • Abdominal wall oedema was present in 80%
  • Most were of old age
  • A malfunctioning immune system seems to be a predisposing factor (diabetes, AIDS, splenectomy and malnutrition were listed)

Other classical features (skin bullae, insensate skin, crepitations) were absent from the college history, making it difficult to guess what the examiners were thinking.

Now; of the Gram positive bacilli we know to be common pathogens, which are likely to be responsible for this wound infection? Let's review them and consider whether they are likely to be in that blood culture.

  • Corynebacterium diphtheriae (no)
  • Proprionibacterium sp. (very unlikely)
  • Nocardia asteroides (no)
  • Listeria monocytogenes (no)
  • Bacillus anthracis (hell no)
  • Clostridium sp. (the only one left)

The typical case will present as a polymicrobial zoo, and whereas Clostridium species will likely flourish in the smelly pockets of avascular fat necrosis, it is unlikely that they will be found in the blood culture, particularly as the blood is so well oxygenated (much of the time). It is more likely that Clostridium perfringens would the sole organism in the cultures of a patient with gas gangrene of the abdominal wall. If the college mentioned subcutaneous emphysema of the abdominal wall, there would be no guesswork involved in this question. This is supported by an article from 1966 (back in the day when surgeons actually palpated people's abdomens instead of scanning them). It reports on ten patients; nine had proper crackly gas gangrene due to C.perfringens or C.multifermentans. One patient with a C.tertium infection only had abdominal wall cellulitis, just like in the college question.

References

Casali, Robert E., et al. "Postoperative necrotizing fasciitis of the abdominal wall." The American Journal of Surgery 140.6 (1980): 787-790.

Huljev, D., and N. Kucisec-Tepes. "Necrotizing fasciitis of the abdominal wall as a post-surgical complication: A case report." WOUNDS-A COMPENDIUM OF CLINICAL RESEARCH AND PRACTICE 17.7 (2005): 169-177.

Rea, William J., and Walter J. Wyrick Jr. "Necrotizing fasciitis." Annals of surgery 172.6 (1970): 957.

Miyoshi et al. "Clinical Features of Postoperative Necrotizing Fasciitis" Journal of Abdominal Emergency Medicine Volume 28 (2008) Issue 5 Pages 649-654

Samel, S., et al. "Clostridial gas gangrene of the abdominal wall after laparoscopic cholecystectomy." Journal of Laparoendoscopic & Advanced Surgical Techniques 7.4 (1997): 245-247.

McSwain, Barton, John L. Sawyers, and MARION R. Lawler Jr. "Clostridial infections of the abdominal wall: review of 10 cases." Annals of surgery 163.6 (1966): 859.

Question 3.3 - 2014, Paper 1

A 56-year-old male presents with pyelonephritis. Ultrasound reveals an obstructed right kidney. Percutaneous nephrostomy is performed.


Blood cultures show 2/2 bottles growing Enterobacter cloacae, sensitive to ceftriaxone.

What antibiotic will you choose and why?

College Answer

Choose an aminoglycoside or meropenem because it is an ESCAPPM organism and will develop resistance to third gen cephalosporins.

Discussion

This has come up before. Many times.

Previous near-identical questions asking about ESCAPPM organisms include:

ESCAPPM and HACEK bacteria are discussed elsewhere in the Required Reading section.

References

Question 1 - 2014, paper 2

You are asked to review a 47-year-old male in the Emergency Department with hypotension that has not responded to rapid infusion of 2 litres intravenous crystalloid. On examination his temperature is 40°C, he is warm peripherally with a respiratory rate of 24 breaths per minute, an arterial oxygen saturation of 98% on room air, a heart rate of 140 beats per minute, and a blood pressure of 80/40 mmHg with an arterial lactate concentration of 6 mmol/L.
Describe the steps for the initial haemodynamic management of this patient, including a brief discussion of the underlying evidence for each step.

College Answer

Step 1

Initial fluid resuscitation

  • Give more volume 1000 – 2000 ml or 20 ml/kg up to minimum 30 ml/kg in total
  • Evidence:
    • Surviving sepsis guidelines recommendation
    • Rivers et al EGDT study although ProCESS (NEJM May 2014) showed no outcome benefit from protocolised care in septic shock
    • Usual care in ICU based upon physiological reasoning with relative volume depletion due to vasodilation in sepsis
  • Avoid starch
  • Evidence:
    • 6S and CHEST studies
  • Probably just use crystalloid (0.9% NaCl or Hartmanns)
  • Evidence:
    • SAFE – no difference with albumin or crystalloid
  • Consider 4% albumin
  • Evidence:
    • SSG recommendation for refractory hypotension in sepsis
  • Blood transfusion if bleeding/low haemoglobin
  • Evidence:
    • Rivers EGDT recommend target haematocrit 30%
    • SSG aim for haemoglobin 70-90 g/L
    • TRICC and Patient Blood Management Guidelines recommend transfusion trigger at Hb <70 g/L

Step 2

Assess response and need for more fluid

  • Monitoring:
  • Clinical reassessment after fluid bolus; HR, BP, peripheral perfusion, urine output
    Lactate clearance
  • Evidence:
    • SSG recommends ongoing fluid resuscitation according to response using dynamic or static variables
    • Jones et al JAMA 2010 lactate clearance had no additional benefit in addition to ScvO2 for guiding resuscitation in sepsis
  • Arterial line and target MAP >? 60 mmHg ? 65 mmHg
  • Evidence:
    • Asfar et al NEJM Mar 2014 no outcome benefit in 65-75 mmHg MAP v 80-85 mmHg MAP except higher MAP with pre-existing hypertension had less renal replacement therapy but more atrial fib
  • CVC and target CVP >8-12 mmHg
  • Evidence:
    • Convention but no good evidence (Marik meta-analyses 2008 and 2013)
    • EGDT/SSG recommends CVP >8-12 but very controversial regarding use of static pressure measurements to determine fluid responsiveness.
  • Use of dynamic measure of fluid responsiveness
    E.g. Passive leg raising, PPV, echo
  • Evidence:
    • Many small physiological studies but no large RCTs with patient oriented outcomes to guide practice
  • ScvO2 or SvO2
  • Evidence:
    • ScvO2 in SSG / supported by RCT evidence. SvO2 requires PAC and not commonly used in this particular scenario
  • PAC and PAOP
  • Evidence:
    • PAC-Man study and Connors SUPPORT study JAMA 1996 - PA catheters do not improve / may worsen outcome

Step 3
Commence vasopressors

  • If hypotensive and not responsive to further filling will need vasopressor, probably noradrenaline
    as first line, but adrenaline probably acceptable
  • Evidence:
    • SSG/ EGDT study
    • CAT study showed no real difference in outcomes with adrenaline v noradrenaline

Step 4
Consider adequacy of cardiac output

  • Consider Echo, ScvO2, SvO2, PiCCO or other measure of cardiac output
  • If low consider inotrope as well as vasopressor - either dobutamine or adrenaline
  • Evidence:
    • Low cardiac output (absolute or relative) is common in sepsis, inotropic support recommended in SSG and in the EGDT resuscitation algorithm
    • PAC-Man and SUPPORT study

Step 5
Refractory hypotension

  • Consider vasopressin 0.03 u/min
  • Evidence:
    • VASST study NEJM 2008 did not demonstrate an improvement in outcome with additional
      vasopressin in patients receiving low dose noradrenaline.
    • Not recommended as first line vasopressor
  • If hypotensive following fluid resuscitation and vasopressors, consider hydrocortisone 200mg daily.
  • Evidence:
    • Very mixed evidence to use of steroids (Annane JAMA 2002 - Pro) and CORTICUS NEJM 2008 - No support for hydrocortisone). Erring to no benefit. Awaiting results of ADRENAL ANZICS CTG study

Additional Examiners’ Comments: Candidates omitted resuscitation end-points and assessment of fluid responsiveness. Some candidates did not describe the management of septic shock

Discussion

This college answer was used as the foundation of an evidence-based summary (Resuscitation of the Septic Shock patient) which can be found in the Required Reading section. One can do little to improve on the model answer, as it is succinct yet comprehensive. The summary merely expands upon it with references.

In brief:

Step 1: Fluid resuscitation and antibiotics

Step 2: Assess need for further fluid resuscitation

The college examiners made much of the candidates' failure to suggest resuscitation endpoints and fluid responsiveness assessment methods.

End-point of resuscitation:

Step 3: Vasopressors

  • Noradrenaline is the first choice (SSG)
  • Adrenaline is the second choice (CATSSSG)

Step 4: Assess adequacy of cardiac output

Inotrope options:

Step 5: Refractory hypotension

Step 6: Innovative therapies

References

Dellinger, R. Phillip, et al. "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012." Intensive care medicine 39.2 (2013): 165-228.

Weinstein, Melvin P., et al. "The clinical significance of positive blood cultures: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults. I. Laboratory and epidemiologic observations." Review of infectious diseases 5.1 (1983): 35-53.

Kumar A, Roberts D, Wood KE et al "Duration of hypotension prior to initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock." Crit Care Med(2006)34:1589–1596

Myburgh, John A., et al. "Hydroxyethyl starch or saline for fluid resuscitation in intensive care." New England Journal of Medicine 367.20 (2012): 1901-1911.

Finfer, Simon, et al. "A comparison of albumin and saline for fluid resuscitation in the intensive care unit." N Engl j Med 350.22 (2004): 2247-2256.

Caironi, Pietro, et al. "Albumin replacement in patients with severe sepsis or septic shock." New England Journal of Medicine 370.15 (2014): 1412-1421.

Raghunathan, Karthik, et al. "Association between the choice of IV crystalloid and in-hospital mortality among critically ill adults with sepsis*." Critical care medicine 42.7 (2014): 1585-1591.

Holst, Lars B., et al. "Lower versus higher hemoglobin threshold for transfusion in septic shock." New England Journal of Medicine 371.15 (2014): 1381-1391.

Bourquin, Vincent, et al. "Use of high-volume haemodiafiltration in patients with refractory septic shock and acute kidney injury." Clinical Kidney Journal 6.1 (2013): 40-44.

Cornejo, Rodrigo, et al. "High-volume hemofiltration as salvage therapy in severe hyperdynamic septic shock." Intensive care medicine 32.5 (2006): 713-722.

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Peake, Sandra L., et al. "Goal-directed resuscitation for patients with early septic shock." The New England journal of medicine 371.16 (2014): 1496.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Asfar, Pierre, et al. "High versus low blood-pressure target in patients with septic shock." New England Journal of Medicine 370.17 (2014): 1583-1593.

Marik, Paul E., and Rodrigo Cavallazzi. "Does the central venous pressure predict fluid responsiveness? An updated meta-analysis and a plea for some common sense*." Critical care medicine 41.7 (2013): 1774-1781.

An excellent resource for this topic is a paper by Marik, Paul E. "Hemodynamic parameters to guide fluid therapy." Transfusion Alternatives in Transfusion Medicine 11.3 (2010): 102-112.

Cavallaro, Fabio, et al. "Diagnostic accuracy of passive leg raising for prediction of fluid responsiveness in adults: systematic review and meta-analysis of clinical studies." Applied Physiology in Intensive Care Medicine 1. Springer Berlin Heidelberg, 2012. 225-233.

Zhang, Zhongheng, et al. "Accuracy of stroke volume variation in predicting fluid responsiveness: a systematic review and meta-analysis." Journal of anesthesia25.6 (2011): 904-916.

Biais, Matthieu, et al. "Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach."Critical Care 18.6 (2014): 587.

Kumar, Anand, et al. "Pulmonary artery occlusion pressure and central venous pressure fail to predict ventricular filling volume, cardiac performance, or the response to volume infusion in normal subjects." Critical care medicine 32.3 (2004): 691-699.

Marik, Paul E., et al. "Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature*." Critical care medicine 37.9 (2009): 2642-2647.

Hanson, Josh, et al. "The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study."Malaria journal 12.1 (2013): 348.

Zhang, Zhongheng, et al. "Ultrasonographic Measurement of the Respiratory Variation in the Inferior Vena Cava Diameter Is Predictive of Fluid Responsiveness in Critically Ill Patients: Systematic Review and Meta-analysis." Ultrasound in medicine & biology (2014).

Monnet, Xavier, et al. "Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients."Critical care medicine 37.3 (2009): 951-956.

Mandeville, Justin C., and Claire L. Colebourn. "Can transthoracic echocardiography be used to predict fluid responsiveness in the critically ill patient? A systematic review." Critical care research and practice (2012). Article ID 513480, 9 pages

Jones, Alan E., et al. "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial." Jama 303.8 (2010): 739-746.

Vallée, Fabrice, et al. "Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock?." Intensive care medicine 34.12 (2008): 2218-2225.

Mallat, Jihad, et al. "Central venous-to-arterial carbon dioxide partial pressure difference in early resuscitation from septic shock: a prospective observational study." European Journal of Anaesthesiology (EJA) 31.7 (2014): 371-380.

Ospina-Tascón, G. A., et al. "0032. Relationship between microcirculatory alterations and venous-to-arterial carbon dioxide differences in patients with septic shock." Intensive Care Medicine Experimental 2.Suppl 1 (2014): O5.

Russell, James A., et al. "Vasopressin versus norepinephrine infusion in patients with septic shock."New England Journal of Medicine 358.9 (2008): 877-887.

Annane, D., et al. "Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: aárandomised trial." Lancet 370 (2007): 676-684.

Morelli, Andrea, et al. "Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial." Critical Care 12.6 (2008): R143.

De Backer, Daniel, et al. "Comparison of dopamine and norepinephrine in the treatment of shock." New England Journal of Medicine 362.9 (2010): 779-789.

Martin, Claude, et al. "Effect of norepinephrine on the outcome of septic shock." Critical care medicine 28.8 (2000): 2758-2765.

Morelli, Andrea, et al. "Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial." JAMA 310.16 (2013): 1683-1691.

Connors, Alfred F., et al. "The effectiveness of right heart catheterization in the initial care of critically III patients." Jama 276.11 (1996): 889-897.

Vieillard-Baron, Antoine. "Septic cardiomyopathy." Annals of intensive care 1.1 (2011): 1-7.

Hunter, J. D., and M. Doddi. "Sepsis and the heart." British journal of anaesthesia 104.1 (2010): 3-11.

Barton, Phil, et al. "Hemodynamic effects of iv milrinone lactate in pediatric patients with septic shock: A prospective, double-blinded, randomized, placebo-controlled, interventional study." CHEST Journal 109.5 (1996): 1302-1312.

Morelli, Andrea, et al. "Levosimendan for resuscitating the microcirculation in patients with septic shock: a randomized controlled study." Crit Care 14.6 (2010): R232.

Orme, Robert M. L’E., et al. "An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial." Trials 15.1 (2014): 199.

Ducrocq, Nicolas, et al. "Comparison of equipressor doses of norepinephrine, epinephrine, and phenylephrine on septic myocardial dysfunction." Survey of Anesthesiology 56.6 (2012): 277-278.

Bihari, D., S. Prakash, and A. Bersten. "Low-dose vasopressin in addition to noradrenaline may lead to faster resolution of organ failure in patients with severe sepsis/septic shock." Anaesthesia and intensive care 42.5 (2014): 671.

Sharshar, Tarek, et al. "Circulating vasopressin levels in septic shock." Critical care medicine 31.6 (2003): 1752-1758.

Patel, Gourang P., and Robert A. Balk. "Systemic steroids in severe sepsis and septic shock." American journal of respiratory and critical care medicine185.2 (2012): 133-139.

Todd, JAMES K. "Toxic shock syndrome." Clinical microbiology reviews 1.4 (1988): 432-446.

Darenberg, Jessica, et al. "Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial." Clinical Infectious Diseases 37.3 (2003): 333-340.

Linnér, Anna, et al. "Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study." Clinical Infectious Diseases 59.6 (2014): 851-857.

STEINHORN, DAVID M., MICHAEL F. SWEENEY, and LISA K. LAYMAN. "Pharmacodynamic response to ionized calcium during acute sepsis." Critical care medicine 18.8 (1990): 851-857.

DESAI, TUSAR K., et al. "A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit." Critical care medicine 16.6 (1988): 578-582.

Jang, David H., Lewis S. Nelson, and Robert S. Hoffman. "Methylene blue for distributive shock: a potential new use of an old antidote." Journal of Medical Toxicology 9.3 (2013): 242-249.

Yunge, Mauricio, and Andy Petros. "Angiotensin for septic shock unresponsive to noradrenaline." Archives of disease in childhood 82.5 (2000): 388-389.

Chawla, Lakhmir S., et al. "Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study." Crit Care 18 (2014): 534.

Kimmoun, Antoine, and Bruno Levy. "Angiotensin II: a new approach for refractory shock management?." Critical Care 18.6 (2014): 694.

Cariou, Alain, Christophe Vinsonneau, and Jean-François Dhainaut. "Adjunctive therapies in sepsis: an evidence-based review." Critical care medicine 32.11 (2004): S562-S570.

Question 3.1 - 2014, paper 2

With regards to antibiotic dosing:
Look at the diagram below, representing antibiotic drug concentration versus time, and answer the questions below:

drug concentration versus time curves for antibiotics

a) What does “A” represent? Name one class of antibiotic for which this is important with regards to dosing.

b) What does “B” represent? Name one class of antibiotic for which this is important with regards to dosing.

c) What does “C” represent? Name one class of antibiotic for which this is important with regards to dosing.

College Answer

a)
C MAX: Maximum concentration
Aminoglycosides

b)
AUC > MIC: Area under the curved where drug concentration is greater than MIC
Quinilones

c)
T>AUC above MIC: Time greater than Area under the curved where concentration is greater than MIC
Penicillins, Carbenepenems

Discussion

This question is identical to Question 24.1 from the first paper of 2008.

For the curious, the relevant references are reproduced below.

Additionally, an indepth exploration of antibiotic pharmacokinetics occurs in the Required Reading section.

References

Oh's Intensive Care Manual: Chapter 72  (pp. 738)  Principles  of  antibiotic  use  by Jeffrey  Lipman

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.

Question 3.2 - 2014, paper 2

Look at the diagram below, representing antibiotic drug concentration against time. Curves D and E represent concentrations after regular bolus administration of the same dose of an antibiotic to the same patient at different points of time

a) What pharmacokinetic changes are demonstrated in D and E?

b) List the clinical conditions that could explain the difference between E and D.

College Answer

a)
PK changes – Increased plasma concentrations with E relative to D for the same dose indicating reduced clearance and increased half-life.

b)
Hepatic dysfunction
Renal dysfunction

Discussion

The question itself is reasonably straightforward to answer. The drug is clearly accumulating; its concentration is increasing.

Pharmacokinetics of antibiotic dosing and the challanges of antibiotic dosing in renal failure are discussed in greater detail elsewhere. More detail regarding pharmacokinetics in the context of continuous renal replaceemnt therapy can be found in the Required Reading section for the renal failure and dialysis SAQs.

In brief, the following factors influence antibiotic clearance in critical illness:

Factors which decrease the antibiotic peak dose:

  • Poor gut absorption
  • Increased volume of distribution
  • Poor penetration to the site of action

Factors which increase the antibiotic peak dose:

  • Decreased protein binding
  • Diminished clearance mechanisms

Factors which increase the antibiotic half-life

  • Decreased renal clearance
  • Decreased hepatic clearance
  • Decreased overall metabolism (eg. hypothermia)

Factors which decrease the antibiotic half-life

  • Renal replacement therapy
  • Increased hepatic clearance, eg. enzymes induced by drug interactions

References

Oh's Intensive Care Manual: Chapter 72  (pp. 738)  Principles  of  antibiotic  use  by Jeffrey  Lipman

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Craig, William A. "Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid." Infectious disease clinics of North America 17.3 (2003): 479-501.

Craig, William A. "Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men." Clinical infectious diseases (1998): 1-10.

Question 3.3 - 2014, paper 2

List the factors that result in failed resolution of sepsis despite antibiotic therapy.

College Answer

Wrong antibiotic choice
Delayed administration of antibiotics
Inadequate source control
Inadequate antimicrobial blood levels
Inadequate penetration of the antimicrobial to the target site,
Antimicrobial neutralization or antagonism,
Superinfection or unsuspected secondary bacterial infection,
Non-bacterial infection
Non-infectious source of illness

Discussion

The question is, "why aren't my antibiotics working?"

Several possibilities exist; this list is duplicated in the Required Reading section.

There is no infection.

The infection is not susceptible to antibiotics

  • There is a viral cause of illness, without an accepted antiviral therapy.
  • The infection is fungal, protozoal, parasitic, or algal (yes, by algae).
  • The source of infection is subject to severe circulatory neglect (eg. an ischaemic toe) in which case surgical source control is the only way to manage it.

You are using the wrong antibiotics.

  • The drug is plainly inappropriate for its application (eg. nitrofurantoin for pneumonia).
  • The drug would normally be appropriate, but this organism happens to be resistant.

You are using the wrong route of administration.

  • The oral drug may not be getting absorbed due to the sluggish gut of critical illness
  • The IV drug is not effective in treating an infection in the gut lumen (eg. IV vancomycin instead of oral vancomycin for C.difficile infection

Your antibiotic dosing is inappropriate

  • The dose is too small, and does not reach far enough over MIC
  • The dosing interval is too long
  • The administration was delayed (in septic shock, every hour counts)
  • The course was too brief
  • You have failed to adjust for increased clearance by dialysis
  • You must by neccessity use a lower dose, or shorten the course, due to unacceptable toxicity (Garrod dryly remarks that "treatment may reasonably be said to have failed when a patient dies as a direct result of it").

Source control is inadequate

  • The source is subject to surgical neglect
  • The debridement was incomplete (more surgery is needed)
  • The clearance of secretions in pneumonia is poor (more physiotherapy is needed)

Antibiotic penetration to the target site is poor

  • The chosen antibiotic happens to penetrate that specific tissue poorly.
  • The tissue in question has poor blood supply (the ischaemic toe again)

Antibiotic activity is being inhibited

Some examples:

  • Acidic environments inhibit the activity of macrolides and aminoglycosides
  • Lung surfactant inhibits daptomycin

Antibiotic antagonism has developed

  • Classically, it is said that giving a bacteriostatic antibiotic together with a bactericidal one will result in antagonism, as the bacteriostatic drug prevents the bacteria from reproducing, and the bactericidal drug can only kill bacteria while they are trying to reproduce.

Antibiotics are working just fine, but the clinical state has deteriorated anyway

  • For instance, you have destroyed the streptococci, but the streptococcal toxic shock syndrome has laid to waste your patient's organ systems, giving the overall impression of treatment failure.

References

Garrod, L. P. "Causes of failure in antibiotic treatment." BMJ 4.5838 (1972): 473-476.

Cargill, J. S. "Causes of failure in antibiotic treatment." BMJ 4.5843 (1972): 791-791.

Pollock, A. V. "Causes of failure in antibiotic treatment." BMJ 4.5843 (1972): 790-791.

García, Miguel Sánchez. "Early antibiotic treatment failure." International journal of antimicrobial agents 34 (2009): S14-S19.

Cunha, Burke A., and Antonio M. Ortega. "Antibiotic failure." The Medical clinics of North America 79.3 (1995): 663-672

Arancibia, Francisco, et al. "Antimicrobial treatment failures in patients with community-acquired pneumonia: causes and prognostic implications."American journal of respiratory and critical care medicine 162.1 (2000): 154-160.

Sanders, E., and P. F. Jurgensen. "Remediable causes of failure of" appropriate" antimicrobial therapy." Postgraduate medicine 50.5 (1971): 161. -Not available even as an abstract! Oh well, it was 1971.

Cox, G. Erika, J. D. Wilson, and Pamela Brown. "Protothecosis: a case of disseminated algal infection." The Lancet 304.7877 (1974): 379-382.

Question 7 - 2014, paper 2

A 28-year-old Australian aid worker, returns from the Philippines’ flood disaster and is subsequently admitted to your ICU. Twelve days following her return she developed fevers, headaches and severe myalgias. This continued for a week, and then improved. Despite feeling weak she remained well for three days before deteriorating again.

On clinical examination the following is evident:

She appears unwell, respiratory rate 24 breaths per minute; bibasal crackles on auscultation, heart rate 102 beats per minute, blood pressure 92/45 mmHg, cool peripheries, conjunctival suffusion, and mild meningism. She is confused but with no focal neurological signs.

Results of investigations are as follows:

Haemoglobin 86 g/L*

115 – 160

White blood cell 21 x 109/L with a left shift*

4.0 – 11.0

Platelets 95 x 109/L*

140 – 400

International Normalised Ratio (INR) 1.6*

0.8 – 1.2

Activated partial thromboplastin time (APTT) 39 seconds*

30 – 34

Creatine kinase (CK) 3000 U/L*

< 100

Urea 19.0 mmol/L*

2.1 – 7.1

Creatinine 350 µmol/L*

46 – 90

Alanine aminotransferase (ALT) 272 U/L*

< 34

Aspartate aminotransferase (AST) 240 U/L*

< 31

Gamma glutamyl transferase (GGT) 92 U/L*

< 38

Alkaline phosphatase (ALP) 300 U/L*

42 – 98

Bilirubin 87 µmol/L*

4.0 – 12.0

a) List the features on the history, examination and results of investigations, given above, that are in keeping with a diagnosis of leptospirosis in this patient.

b) Briefly describe the natural course of this disease.

c) Discuss the specific treatment of this patient for this condition.

College Answer

a)
Contracted in a flooding tropical environment
1. Biphasic pattern of illness
2. Conjunctival suffusion
3. The combination of hepatitis and renal failure in the setting of a tropical febrile illness.

b)
The natural course of leptospirosis falls into 2 distinct phases:
A. Septicaemic - During this stage, which lasts about 4-7 days, the patient experiences fever,
chills, weakness, and myalgias. Other symptoms include sore throat, cough, chest pain,
haemoptysis, rash, frontal headache, photophobia, mental confusion, and other symptoms of
meningitis.
B. Immune - This stage occurs as a consequence of the body's immunologic response to
infection and lasts 0-30 days or more. Aseptic meningitis, renal failure, cardiomyopathy,
pulmonary manifestations, uveitis.

During a brief period of 1-3 days between the 2 phases, the patient shows some improvement.
Weil syndrome is the severe form of leptospirosis and primarily manifests as profound jaundice,
renal dysfunction, hepatic necrosis, pulmonary dysfunction, and hemorrhagic diathesis - occurs at the
end of the first stage and peaks in the second stage.

c)
Penicillin (1.5 million units IV every 6 hours) OR
Doxycycline (100 mg IV twice daily) OR
Ceftriaxone (1 to 2 g IV once daily), OR
Cefotaxime (1 g IV every 6 hours).
The duration of treatment in severe disease is usually seven days.
Initiation of antibiotic treatment may be associated with the Jarisch-Herxheimer reaction
(inflammatory reaction to endotoxins released by bacterial lysis)

Use of intravenous corticosteroid therapy has been proposed given the vasculitic nature of severe
leptospirosis, particularly in the setting of pulmonary involvement; however there is insufficient
evidence for routine use of corticosteroids.

Discussion

The college's model answer is both brief and comprehensive.

One can only add general remarks and references, fleshing the answer out somewhat to include the general clinical features and diagnosis. Of course, the candidate at the exam should answer the question they asked, rather than blabbering about microagglutination.

In brief:

Clinical features of Leptospirosis in general; particularly of Phase 1 (early disease)

  • History of travel to a tropical flood-prone area
  • Conjunctival suffusion
  • Headache, particularly retroorbital
  • Myalgia, particularly of the lower back and calf.

Clinical features of Weil's disease in particular (Phase 2)

  • Jaundice
  • Bleeding diathesis
  • Hepatosplenomegaly and hepatic necrosis
  • Renal failure
  • Pulmonary haemorrhage
  • Aseptic meningitis
  • Uveitis
  • Cholecystitis
  • Pancreatitis
  • Myocarditis
  • Rhabodomyolysis

Laboratory diagnosis

Natural course of the disease

  • Incubation period: 5-14 days.
  • Leptospiraemia (Phase 1) - 1 week. Oh's Manual calls it the "Septicaemic phase"
    • Characterised by fevers, myalgia, conjunctival effusion, etc.
  • A brief break in symptoms usually follows.
  • Leptospiruria (Phase 2) - up to 1 month. Oh's Manual calls it the "Immune phase"
    • Weil's disease usually appears around the beginning of Phase 2.

Antibiotic management

References

Oh's Manual: Chapter 73  (pp. 743) Tropical  diseases  by R. Sivakumar  and  M.  E.  Pelly

Smith, James KG, et al. "Leptospirosis following a major flood in Central Queensland, Australia." Epidemiology and infection 141.03 (2013): 585-590.

World Health Organization. "Human leptospirosis: guidance for diagnosis, surveillance and control." (2003).

Toyokawa, Takao, Makoto Ohnishi, and Nobuo Koizumi. "Diagnosis of acute leptospirosis." Expert Rev Anti Infect Ther. 2011 Jan;9(1):111-21.

Palaniappan, Raghavan UM, Subbupoongothai Ramanujam, and Yung-Fu Chang. "Leptospirosis: pathogenesis, immunity, and diagnosis." Current opinion in infectious diseases 20.3 (2007): 284-292.

Dolhnikoff, Marisa, et al. "Pathology and pathophysiology of pulmonary manifestations in leptospirosis." Brazilian Journal of Infectious Diseases 11.1 (2007): 142-148.

Kobayashi, Y. "Human leptospirosis: management and prognosis." Journal of postgraduate medicine 51.3 (2005): 201.

Ferreira, Ana Sofia, et al. "Direct Detection and Differentiation of Pathogenic Leptospira Species Using a Multi-Gene Targeted Real Time PCR Approach."PloS one 9.11 (2014): e112312.

Brett‐Major, David M., and Rodney Coldren. "Antibiotics for leptospirosis." The Cochrane Library (2012).

Bryceson, Anthony DM. "Clinical pathology of the Jarisch-Herxheimer reaction." Journal of infectious Diseases 133.6 (1976): 696-704.

Question 9 - 2014, paper 2

A 65-year-old male with a background history of chronic obstructive pulmonary disease has been ventilated for ten days for respiratory failure related to community-acquired pneumonia. He develops a new fever and a sputum sample is positive for Aspergillus spp.

a) Discuss the difficulties in confirming a diagnosis of invasive pulmonary aspergillosis (IPA) in this patient.

b) What findings on history and examination are associated with increased risk of IPA?

c) What investigations are used to confirm a diagnosis of IPA?

College Answer

a)
Inavsive pulmonary aspergillosis is an important diagnosis to make as the mortality of the disease is
high.
In ICU patients it is more difficult due to;

  • symptoms and signs difficult in these patients
  • classic radiology signs difficult in ventilated patients
  • biopsy often not able to be done
  • Occurs in immune competent patients where there may be a low index of suspicion for this diagnosis
  • Colonisation is common in patients, and so distinguishing colonisation from invasive disease may be difficult

b)
Background history

  • Neutropenia > 10 days and immunosuppressed
  • HIV,
  • Haematological or oncological malignancy treated with cytotoxics
  • Congenital or acquired immunodeficiency
  • Prolonged steroid use,
  • Chronic airflow limitation
  • Bone marrow transplant,
  • Cirrhosis or acute hepatic failure,
  • Solid organ transplant,
  • Chronic renal failure

Acute clinical features

  • Fever refractory > 3 days Rx
  • Pleuritic chest pain
  • Pleural rub
  • Dyspnea
  • Haemoptysis
  • Worsening respiratory insufficiency in spite of adequate antibiotic and ventilator support

c)
Radiology

  • CT scan:
  • Halo sign (pulmonary mass surrounded by ground glass)
  • Air crescent sign (crescentic radiolucencies around a nodular consolidation)

Respiratory secretions-BAL

  • Microscopy showing branched hyphae
  • Galactomannan antigen
  • PCR
  • MALDI tof

Blood

  • PCR
  • Galactomannan Ag; low sensitivity and difficult to interpret in immune competent patients and
  • interaction with Tazocin
  • MALDI tof

Biopsy

Discussion

Invasive aspergillosis is discussed at greater lengths in the Required Reading section.

Briefly,

a) Discuss the difficulties in confirming a diagnosis of invasive pulmonary aspergillosis (IPA) in this patient. (applied in general, to all ICU patients)

  • ICU patients will have nonspecific signs, buried under other signs, and often no history.
  • Radiological diagnosis may be obscured by othr pathology, or may be logistically difficult
  • Biopsy is frequently impossible
  • Immunocompetent individuals are not suspected, yet may still develop the disease
  • Clinically insignificant colonisation is common, but will yield the same positive diagnostic results as active invasive disease.
  • Diagnostic test accuracy may be confounded by many factors, eg. concurrent β-lactam therapy.

b) What findings on history and examination are associated with increased risk of IPA?

Clinical Features and Associated Findings in Aspergillosis

Pulmonary:

  • An asthma-like clinical picture
  • Haemoptysis
  • Chronic cough

Extrapulmonary: immunocompromised host

  • endopthalmitis
  • endocarditis
  • Eosinophilia
  • Elevated serum IgE
  • Spherical lesions on CXR
  • Incidental lesions on CT
Risk Factors for Invasive Aspergillosis
(from Meersseman et al, 2007)

Low risk

Intermediate risk

High risk

  • Heart, kidney, liver transplant
  • Burns
  • Stay in ICU > 21 days
  • Malnutrition
  • Cardiac surgery
  • Short term steroids
  • Bone marrow transplant (auto)
  • COPD
  • Cirrhosis
  • Solid malignancy
  • HIV
  • Lung transplant
  • Chronic steroids
  • Chronic immunesuppression
  • Bone marrow transplant (allo)
  • Neutropenia
  • Haem malignancy

c) What investigations are used to confirm a diagnosis of IPA?

  • Serum galactomannan (poor sensitivity/specificity, many false positives)
  • BAL galactomannan (better sensitivity and specificity
  • BAL PCR (more sensisitve but less specific than BAL galactomannan)
  • Microscopy, to identify hyphae
  • Radiological findings:
    • "Halo sign" on CT
    • Pulmonary nodule on CXR
    • Wedge-like haemorrhagic pulmonary infarcts
    • Air crescents following resolution

References

ROSENBERG, MICHAEL, et al. "Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis." Annals of Internal Medicine 86.4 (1977): 405-414.

Soubani, Ayman O., and Pranatharthi H. Chandrasekar. "The clinical spectrum of pulmonary aspergillosis." CHEST Journal 121.6 (2002): 1988-1999.

Sherif, Rami, and Brahm H. Segal. "Pulmonary aspergillosis: clinical presentation, diagnostic tests, management and complications." Current opinion in pulmonary medicine 16.3 (2010): 242.

Meersseman, Wouter, et al. "Invasive aspergillosis in the intensive care unit."Clinical Infectious Diseases 45.2 (2007): 205-216.

Trof, R. J., et al. "Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients." Intensive care medicine 33.10 (2007): 1694-1703.

Mennink-Kersten, Monique ASH, J. Peter Donnelly, and Paul E. Verweij. "Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis." The Lancet infectious diseases 4.6 (2004): 349-357.

Musher, Benjamin, et al. "Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid." Journal of Clinical Microbiology 42.12 (2004): 5517-5522.

Pfeiffer, Christopher D., Jason P. Fine, and Nasia Safdar. "Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis." Clinical Infectious Diseases 42.10 (2006): 1417-1727.

Patmore, J. V., H. D. Goff, and S. Fernandes. "Cryo-gelation of galactomannans in ice cream model systems." Food Hydrocolloids 17.2 (2003): 161-169.

Wald, Anna, et al. "Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation." Journal of Infectious Diseases 175.6 (1997): 1459-1466.

Escuissato, Dante L., et al. "Pulmonary infections after bone marrow transplantation: high-resolution CT findings in 111 patients." American Journal of Roentgenology 185.3 (2005): 608-615.

Nucci, Marcio, et al. "Early diagnosis of invasive pulmonary aspergillosis in hematologic patients: an opportunity to improve the outcome." haematologica98.11 (2013): 1657-1660.

Acosta, J., et al. "A prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of (1→ 3)–β–d‐glucan chromogenic assay in serum samples." Clinical Microbiology and Infection 17.7 (2011): 1053-1060.

Izumikawa, Koichi, et al. "Bronchoalveolar lavage galactomannan for the diagnosis of chronic pulmonary aspergillosis." Medical mycology 50.8 (2012): 811-817.

Boonsarngsuk, Viboon, et al. "False-positive serum and bronchoalveolar lavage Aspergillus galactomannan assays caused by different antibiotics."Scandinavian journal of infectious diseases 42.6-7 (2010): 461-468.

Digby, Justin, et al. "Serum glucan levels are not specific for presence of fungal infections in intensive care unit patients." Clinical and diagnostic laboratory immunology 10.5 (2003): 882-885.

Hage, Chadi A., et al. "Plasmalyte as a cause of false-positive results for Aspergillus galactomannan in bronchoalveolar lavage fluid." Journal of clinical microbiology 45.2 (2007): 676-677.

Buess, Michael, et al. "Aspergillus-PCR in bronchoalveolar lavage for detection of invasive pulmonary aspergillosis in immunocompromised patients." BMC infectious diseases 12.1 (2012): 237.

Heng, Siow-Chin, et al. "Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in patients with haematological malignancies." Diagnostic microbiology and infectious disease 79.3 (2014): 322-327.

Franquet, Tomás, et al. "Spectrum of Pulmonary Aspergillosis: Histologic, Clinical, and Radiologic Findings 1." Radiographics 21.4 (2001): 825-837.

Kim, Kihyun, et al. "Importance of open lung biopsy in the diagnosis of invasive pulmonary aspergillosis in patients with hematologic malignancies." American journal of hematology 71.2 (2002): 75-79.

Blot, Stijn I., et al. "A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients." American journal of respiratory and critical care medicine 186.1 (2012): 56-64.

Question 18 - 2014, paper 2

a) What is the endothelial glycocalyx? Outline its potential importance in sepsis.

b) Name factors that can disrupt the endothelial surface layer (ESL).

c) What are the effects of glycocalyx disruption?

College Answer

a)
The endothelial glycocalyx forms the basal skeleton that in vivo interacts dynamically with plasma
constituents forming an endothelial surface layer (ESL)
 forms the interface between the vessel wall and moving blood
 protein-free space below the glycocalyx
 maintenance of the vascular permeability barrier
 mediation of shear-stress-dependent nitric oxide production
 retention of vascular protective enzymes (e.g. superoxide dismutase)
 retention of coagulation inhibition factors (e.g. antithrombin, the protein C system and tissue
factor pathway inhibitor)
 modulation of the inflammatory response by preventing leukocyte adhesion and binding
various ligands (e.g. chemokines, cytokines and growth factors)

b)
Glycocalyx shedding and disruption is associated with:
 TNFα, redox stress and oxidised lipoproteins,
 ischaemia/reperfusion
 hyperglycaemia, hypernatremia
 hypervolemia,
 trauma, surgery,
 artificial colloids such as hydroxyethyl starch

c)
Effects of glycocalyx damage
 capillary leak
 edema
 hypercoagulability
 inflammation
 loss of vascular responsiveness
 platelet aggregation

Discussion

A more thorough examination of what the glycocalyx is can be found in the Required Reading section.

The college answer is pretty good. That is pretty much everything you can be expect to remember in the ten-minute episode of exam panic dedicated to this question.

An idealised response furnished with references would resemble the following:

a) What is the endothelial glycocalyx? Outline its potential importance in sepsis.

  • The glycocalyx is a thin (500-1000nm) hydrated gel-like layer on the luminal surface of the vascular endothelium
  • It is composed of a vast variety of macromolecules, including glycoproteins, polysaccharides, proteoglycans, glycosaminoglycans, plasma proteins, enzymes and enzyme inhibitors, growth factors, cytokines, amino acids, cations and water.
  • Glycocalyx degradation may be resposible for much of the organ damaged observed in sepsis.
  • Concentration of glycocalyx components shed into the bloodstream correlates with sepsis severity.

b) Name factors that can disrupt the endothelial surface layer (ESL).

c) What are the effects of glycocalyx disruption?

References

A much more complete list of references is available elsewhere.

Those of key importance are:

Reitsma, Sietze, et al. "The endothelial glycocalyx: composition, functions, and visualization." Pflügers Archiv-European Journal of Physiology 454.3 (2007): 345-359.

Burke-Gaffney, Anne, and Timothy W. Evans. "Lest we forget the endothelial glycocalyx in sepsis." Critical Care 16.2 (2012): 121.

Becker, Bernhard F., et al. "Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential." Cardiovascular research (2010): cvq137.

VanTeeffelen, Jurgen W., et al. "Endothelial glycocalyx: sweet shield of blood vessels." Trends in cardiovascular medicine 17.3 (2007): 101-105.

Ait-Oufella, H., et al. "The endothelium: physiological functions and role in microcirculatory failure during severe sepsis." Applied Physiology in Intensive Care Medicine 2. Springer Berlin Heidelberg, 2012. 237-249.

Alphonsus, C. S., and R. N. Rodseth. "The endothelial glycocalyx: a review of the vascular barrier." Anaesthesia 69.7 (2014): 777-784.

Question 29.1 - 2014, paper 2

List the clinical signs on examination that would support the diagnosis of infective
endocarditis in a patient with fever and a new murmur.

College Answer

Janeway lesions (small, non-tender erythematous or haemorrhagic macular or nodular lesions on the
palms or soles)
Roth spots (retinal haemorrhages with pale or white centres
Oslers nodes (painful, red raised lesions found on the hands and feet)
Splinter haemorrhages
Clubbing
Splenomegaly
Petechiae

Discussion

An excellent review article form 2009 lists the following clinical features:

  • Osler's nodes
  • Janeway lesions
  • Splinter haemorrhages
  • Roth spots
  • Focal neurological signs suggestive of embolic phenomena
  • A new murmur or a worsening of an old murmur
  • Splenomegaly
  • Glomerulonephritis
  • Arthralgia and arthritis
  • Elevated ESR, CRP or rheumatoid factor
  • Haematuria

The abovementioned article has a table (Table 3) which lists these manifestations according to their prevalence among a large patient cohort. The emphasis of the article is on endocarditis "in the 21st century", implying that the endocarditis of the previous centuries was substantially different. This is certainly true. One need only refer to the 1885 Gulstonian Lectures by William Osler to see what infective endocarditis looked like in the pre-antibiotic era (in short, it was uniformly fatal). For a relatively recent 20th century perspective, one can turn to a 1983 review of the state-of-the art diagnosis and therapy for the previous 25 years.

References

Murdoch, David R., et al. "Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis–Prospective Cohort Study." Archives of internal medicine 169.5 (2009): 463-473.

Richardson, JAMES V., et al. "Treatment of infective endocarditis: a 10-year comparative analysis." Circulation 58.4 (1978): 589-597.

Windsor, HARRY M., and MARK X. Shanahan. "Emergency valve replacement in bacterial endocarditis." Thorax 22.1 (1967): 25-33.

Yu, Victor L., et al. "Prosthetic valve endocarditis: superiority of surgical valve replacement versus medical therapy only." The Annals of thoracic surgery 58.4 (1994): 1073-1077.

Brandenburg, Robert O., et al. "Infective endocarditis—a 25 year overview of diagnosis and therapy." Journal of the American College of Cardiology 1.1 (1983): 280-291.

Pruitt, R. D. "William Osler and his Gulstonian Lectures on malignant endocarditis." Mayo Clinic Proceedings. Vol. 57. No. 1. 1982.

Kang, Duk-Hyun, et al. "Early surgery versus conventional treatment for infective endocarditis." New England Journal of Medicine 366.26 (2012): 2466-2473.

Thuny, Franck, et al. "Management of infective endocarditis: challenges and perspectives." The Lancet 379.9819 (2012): 965-975.

Question 28 - 2015, Paper 1

Critically evaluate the role of Early Goal Directed Therapy (EGDT) in septic patients.

College Answer

Definition of EGDT –This is a protocolised approach to sepsis that refers to sequentially targeting a series of haemodynamic targets with the use of fluids, vasopressors/dilators, inotropes and blood within the first six hours of presentation. This follows early appropriate antibiotic therapy and source control where appropriate.

The 3 major trials:

Rivers (NEJM 2001) – single centre, randomised trial of 263 patients with severe sepsis or septic shock compared a protocol – including targeting ScVO2 > 70%, CVP 8-12 mmHg, MAP > 65 mmHg and urine output > 0.5mL/kg/hour – to conventional therapy that targeted CVP, MAP and urine output only. Both groups initiated therapy (including antibiotics) within 6 hours of presentation. Mortality was lower in the group where all 4 targets were used (31% Vs 47%), suggesting that targeting SCVo2, CVP, MAP and urine output was a superior strategy.

Critique – There was an emphasis on use of blood transfusion (haematocrit>30) and dobutamine in order to reach the ScVO2 target, which is controversial. Results may not be generalisable due to inclusion of significant number of sick patients/late presentations with liver and heart disease that may have potentially biased the outcome favourably (resulting in very high mortality in control group as well as treatment group – higher than that seen in other settings). “Hawthorne effect” in intervention group patients who were managed by a senior, experienced clinician.

ProCESS (NEJM 2014) – multicentre, randomised trial of 1341 patients (U.S. based) with septic shock reported no mortality benefit with protocol-based therapies. The study had 3 arms – a protocol-based therapy that used all of the EGDT targets (ScvO2, CVP, MAP, urine output, central access required), a protocol-based standard therapy arm (MAP, urine output, central access not required) and a ‘’usual care’’ (no protocol) arm.

ARISE (NEJM 2014) – multicentre, randomised trial of 1600 patients conducted in Australia and New Zealand. The study had 2 arms – the EGDT group and the usual-care group. Patients in the EGDT group received a larger mean volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group and were more likely to receive vasopressor infusions, red-cell transfusions, and dobutamine. There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay between the 2 groups.

Critique for ProCESS and ARISE – There are a number of proposed explanations for the negative results from ProCESS and ARISE. Antibiotics were administered early (70 to 100% before randomisation) in all randomisation groups. The trials were conducted in academic centres during an era of education and training regarding sepsis management. Central line placement was common in patients receiving protocol-based and usual care (>50%).

ProMISe due out soon

Conclusion

Conflicting evidence regarding the value of protocol-based therapy for sepsis with larger multi- centre trials not demonstrating the originally reported benefit.

Results of the ProMISe (UK) trial awaited.

Surviving Sepsis Guidelines still recommend central venous access for CVP/ScvO2 measurement together with MAP and urine output in all patients with severe sepsis. The Guidelines were created before the publication of ARISE and ProCESS.

The optimal target to guide fluid management is unknown. However, it may be reasonable to aim for certain physiological targets when resuscitating patients with severe sepsis, rather than have no therapeutic targets.

OR any reasonable conclusion.

Additional comments:

Candidates were not expected to provide specific details of the trials, such as patient numbers.
(Note: ProMISe trial findings subsequently published in NEJM April 2015: 1260 patients with early septic shock randomised to EGDT or usual care did not show improved outcome in EGDT protocol group)

Discussion

The previous incarnation of this SAQ (Question 16 from the second paper of 2013) focused on deconstructing the original protocol as published by Rivers et al. (2001). The locally available critique has much material on that subject. In 2015, more evidence became available (in fact about 4200 patients worth of EGDT-related trial material was published) and so the model answer expected by the college has also changed. The last time this came up in the exam only 9% of the candidates passed; the encouragingly high pass rate in 2015 suggests that everybody has done the past papers several times over.

The following resources are required for answering this question:

In summary:

Goals of goal-directed therapy:

  • CVP  8-12 mmHg
  • MAP 65 – 90 mmHg
  • Urine output >0.5 ml/kg/hr
  • Mixed venous oxygen saturation >65% / ScvO2 >70%
  • Haematocrit >30%

Rationale for early goal-directed therapy

  • Poor oxygen delivery to organs (another words, shock) leads to multi-organ system failure.
  • Duration of shock correlates with severity of organ dysfunction.
  • Severity of organ dysfunction
  • Patients with sepsis frequently have shock- they present with a high lactate, deranged oxygen extraction and suboptimal hemodynamic parameters.
  • Ergo, early normalisation of oxygen delivery should improve survival in septic shock, by decreasing the incidence of multi-organ system failure.

Trials mentioned by the college:

ProCESS trial (2013): n=1341; multicentre RCT (31 US hospitals)

  • 3 arms: protocol-based therapy (full EGDT), protocol-based standard care, and some sort of  "anything goes" non-protocol therapy
  • The primary end point was 60-day in-hospital mortality.
  • Mean APACHE II score was about 20.8
  • Outcome for this were 21.0% mortality (EGDT), 18.2% (standard protocol) and 18.9% (anything goes).
  • There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support.

ARISE trial (2014): n=1600; multicentre RCT (50 Australian hospitals)

  • 2 arms: protocol-based therapy (full EGDT), and "anything goes" non-protocol therapy.
  • The primary outcome was all-cause mortality within 90 days.
  • Mean APACHE II score was about 15.8
  • Rates of death were 18.6% (EGDT) and 18.8% (standard)
  • Again, there was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay.

 ProMISE trial (2015): n=1260; multicentre RCT (56 UK hospitals)

  • 2 arms: protocol-based therapy (full EGDT), and "anything goes" non-protocol therapy.
  • The primary outcome was all-cause mortality at 90 days.
  • Mean APACHE II score was about 18.0
  • Rates of death were  29.5% (EGDT) and 29.2% (standard)

Meta-analysis (2015) - Angus, Barnato, Bell, Bellomo et al...

  • The authors of the ProCESS, ProMISE and ARISE trials scraped the databases for abstracts. Of 2395 eligible abstracts, only five RCTs met the inclusion criteria, totalling 4735 patients. Of these, the ProCESS, ProMISE and ARISE trials contributed 4201. The remaining 532 patients came from the Rivers trial and the lesser-known Jones trial (2010) which actually had more patients than Rivers.
  • In summary, EGDT was not associated with decreased mortality, but it was associated with increased admission to ICU.
  • Did this increase in ICU admissions improve the organ system function of admitted patients? No it did not. The same organ system support requirements were the same, except for the fact that the EGDT group got more vasopressors.

Since the publication of these trials, and since the first paper of 2015 was sat in March, the Surviving Sepsis Guidelines have changed slightly, and they no longer insist on CVP or ScvO2 targets. These previously mandatory goals have become reduced to suggestions; one may serially assess the patient with a "focused exam", or one may choose to look at CVP, ScvO2 , bedside TTE, or passive leg raise.

References

Rivers, Emanuel, et al. "Early goal-directed therapy in the treatment of severe sepsis and septic shock." New England Journal of Medicine 345.19 (2001): 1368-1377.

Peake, Sandra L., et al. "Goal-directed resuscitation for patients with early septic shock." The New England journal of medicine 371.16 (2014): 1496.

Yealy, Donald M., et al. "A randomized trial of protocol-based care for early septic shock." The New England journal of medicine 370.18 (2014): 1683-1693.

Mouncey, Paul R., et al. "Trial of early, goal-directed resuscitation for septic shock." New England Journal of Medicine 372.14 (2015): 1301-1311.

Angus, D. C., et al. "A systematic review and meta-analysis of early goal-directed therapy for septic shock: the ARISE, ProCESS and ProMISe Investigators." Intensive care medicine (2015): 1-12.

Jones, Alan E., et al. "Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial." Jama 303.8 (2010): 739-746.

Question 5 - 2015, Paper 1

You are supervising a registrar who suffers a needle stick injury during the insertion of a central line in a patient with a history of intravenous drug use.

Outline your approach to this problem.

College Answer

Immediate Response:

  • Stop the procedure
  • Ensure patient is safe
  • Takeover / delegate patient management as required

Further response:

  • Wash the registrar’s wound immediately with soap and water
  • Express any blood from the wound
  • Initiate injury-reporting system used in the workplace
  • Patient may need to be consented and then tested for HIV, hepatitis B, Hepatitis C
  • Refer registrar to designated treatment facility: Emergency Department / Infectious Disease Physician / 
Immunology as per hospital protocol
  • With consent, registrar to be tested immediately and confidentially for HIV, hepatitis B and C
  • Document the exposure in detail for your own record and for the employer
  • If the patient is HIV positive, post exposure prophylaxis needs to be started within two hours of the 
exposure.
  • For possible Hepatitis C exposure, no treatment is recommended but advice must be obtained 
from Infectious Disease Specialist
  • If the source patient tests positive for HIV, hepatitis B, hepatitis C, get post-exposure prophylaxis in 
accordance with CDC guidelines and as per recommendations from Infectious Disease Specialist or other 
expert.
  • Registrar to have follow up with post exposure testing
  • Advise re: taking precautions (including safe sex) to prevent exposing others until follow up testing is 
complete.
  • If exposed to blood borne pathogen, he/she should not donate blood for six months until cleared

Counselling:

  • While definitive testing is essential, counsel the registrar that the risk factors for infection are: deep injury, visible blood on devices, and needle placement in a vein or artery, lower risk with solid suture needle.

Related to procedure:

  • Review of registrar’s technique, equipment used, unit policy for procedural training, assessment of competency, etc.

Additional comments:
Candidates who failed did not give enough detail, e.g. “take bloods” without specifying for which investigations.

Discussion

This question is near-identical to Question 25 from the first paper of 2007. LITFL have an approach to staff needlestick injuries. David Tripp's notes for the fellowship exam are also a source of a nice point-form algorithm. A list of definitive sources for this information would include the 2017 NSW Health Policy Directive: HIV, Hepatitis B and Hepatitis C - Management of Health CareWorkers Potentially Exposed, as well as the Westmead Children's Hospital procedure "Needlestick and Blood Exposure Injuries: Health Care Worker". A NM

Immediate management:

  • Abort the procedure
  • Ensure the patient is safe:
    • Take over the procedure and finish it yourself; or
    • Delegate the task to a competent staff member
  • Ask the registrar to express blood from the wound
  • Wash the punctured area with soap and water
  • Report the incident

Risk assessment:

  • Is the patient known to have Hpe B, C, or HIV?

The following are associated with an increased risk of transmission:

  • Hollow needle
  • Large needle diameter
  • Needle was previously in an artery or vein
  • Absence of gloves 
  • Depth of wound 
  • Into artery or vein
  • Exposed to a large volume of blood
  • High blood titre of HIV, Hep B or C

Management

  • Document the Hep B immunisation status of the staff member
  • Perform antibody tests of both the staff member and the patient, with written consent
  • If the source is known to be Hep B C or HIV positive,
    • Solicit advice from infectious diseases authorities
    • Arrange appropriate vaccinations, antiretroviral prophylaxis and councelling
    • Arrange follow-up for the patient and staff member
  • Possible management strategies:
    • For Hep B, IV immunoglobulin may be appropriate
    • For Hep C, there is nothing.
    • For HIV, postexposure antiretroviral therapy is helpful (and needs to be commenced within 2 hours!)
  • Safe sex for 6 months
  • Follow-up testing: 6 weeks and 6 months 
  • Review unit guidelines and compliance
  • Some health districts include mandatory central notification of all health care worker exposure events
  • Offer emotional support to the staff member, and get help from infectious diseases authorities to aid post-exposure councelling

References

Wicker, Sabine, et al. "Determination of risk of infection with blood-borne pathogens following a needlestick injury in hospital workers." Annals of occupational hygiene 52.7 (2008): 615-622.

McGovern, Patricia. "Needlestick injuries among health care workers: a literature review." AAOHN Journal 47 (1999): 237-244.

2017 NSW Health Policy Directive: HIV, Hepatitis B and Hepatitis C - Management of Health CareWorkers Potentially Exposed

Westmead Children's Hospital procedure: "NEEDLESTICK AND BLOOD EXPOSURE INJURIES: HEALTH CARE WORKER"

Question 11 - 2015, Paper 1

With respect to community-acquired bacterial meningitis in Australia and New Zealand:

a) List two common pathogens encountered AND the empirical antimicrobial therapy of choice in EACH the following contexts:

  1.  Neonate aged < 1month
  2.  Immunocompetent adult aged 35 years
  3. Adult aged 48years on steroids
  4. Immunocompetent adult aged 85 years

(70% marks)

b) Briefly discuss the role of adjunctive corticosteroids in the management of meningitis.

(30% marks)

College Answer

Pathogens

Neonate aged < 1 month

  • Gp B Strep (agalactiae)
  • E. coli
  • Listeria

Immunocompetent adult aged 35 years

  • Strep. pneumoniae
  • N. meningitidis

Adult aged 48 years on steroids

  • Listeria
  • Gram negative bacilli
  • [TB]

Immunocompetent adult aged 85 years

  • Strep pneumoniae
  • N meningitides
  • Listeria
  • Aerobic GNB

Antimicrobial Therapy

Neonate aged < 1month
Amoxycillin/Ampicillin + 3rd generation cephalosporin (OR Amox/Amp + aminoglycoside)

Immunocompetent adult aged 35 years
3rd generation cephalosporin + Vancomycin

Adult aged 48 years on steroids
Vancomycin + Ampicillin + either Cefepime or Meropenem

Immunocompetent adult aged 85 years
3rd generation cephalosporin + Vancomycin + Ampicillin NB Some protocols substitute Rifampicin for Vancomycin.

b)

Multiple studies and meta-analyses conflicting results with mortality and neurological sequelae. Neurological sequelae seen in up to 50% of survivors of community-acquired meningitis.

Cochrane review 2013:
Overall –

  • Trend to reduction in mortality
  • Reduced rate of hearing loss
  • Reduced rate of short-term neurological sequelae 
subgroup analyses –
  • Reduced hearing loss in children with h influenza only
  • Favourable effect on mortality with s pneumonia only
  • No effect in low income countries, except possibly for tb meningitis
 
 

Approach to use of adjunctive steroids

  • Adults in developed world – suspected or proven pneumococcus. Therefore commence steroids in all and discontinue if proven to not be pneumococcus.
  • Children – suspected or proven H influenza, although many recommendations do include steroids for suspected pneumococcal or meningococcal as well. 
Given prior to, or with first dose of antibiotics. Continued for 4 days.
  •  

Potential side-effects of steroids
 

  • Concern that steroids may reduce antibiotic penetration into CSF (esp Vancomycin) – controversial. 
  • Generic SEs – e.g. hyperglycaemia, GI bleed, immunosuppression etc.

Additional comments:
Overall  candidates  had  poor  knowledge  about  the  causative  organisms  and  appropriate antimicrobial agents in the setting of bacterial meningitis.

Discussion

a)

Pathogens of Meningitis according to Host Age and Immune Status
Host group Microbial enemies Appropriate antibiotics
(CICM model answer)
Appropriate antibiotics
(Therapeutic Guidelines)
Neonates
  • S. agalactiae
    (group B)
  • E.coli
  • L. monocytogenes

Ampicillin
+ Ceftriaxone
or + aminoglycoside

Cefotaxime
+  ampicillin
 
Adults
  • S. pneumoniae
  • L.monocytogenes
  • N. meningitidis
  • H. influenzae
Ceftriaxone
+ Vancomycin
Ceftriaxone or cefotaxime
Immunosuppressed adults
  • L.monocytogenes
  • Gram negative bacilli
  • Tuberculosis
Vancomycin
+ Ampicillin
+ Cefepime or meropenem
Ceftriaxone or cefotaxime
+ Benzylpenicillin for Listeria
+ vancomycin (most of the time)
The elderly
  • S. pneumoniae
  • L.monocytogenes
  • N. meningitidis
  • Klebsiella sp.
  • E.coli
Ceftriaxone
+ Ampicillin
+ Vancomycin
Ceftriaxone or cefotaxime
+ Benzylpenicillin for Listeria
+ vancomycin (most of the time)
 

Therapeutic Guidelines recommend slightly different drugs; benzylpenicillin is substituted for ampicillin and vancomycin is only offered to those with unidentified gram positive cocci in their CSF, or whenever an LP is not available. Aminoglycosides are not mentioned.

eTG give their references as the 2014 NSW Health guidelines, and this 2004 article by Tunkel et al from Clinical infectious diseases. It is unclear what happened to the candidates whose antibiotic choices agreed with Therapeutic Guidelines but not with the college.

The neonates get cefotaxime instead of ceftriaxone, for some reason. Dr Alistair Burns has pointed out to me that this is probably because ceftriaxone can cause worsening jaundice. Ceftriaxone clearance is around 50% biliary, leading to biliary sludge formation. Furthermore it is over 90% albumin-bound, which means it displaces bilirubin from albumin making more bilirubin bioavailable to cause havoc in the jaundiced neonate. This is supported by a review article from Furyk et al (2011), and an older article by Carla M. Odio (1995). The biliary sludging is not much of an issue, but the kernicterus is a genuine concern. The difference between these two third-gen cephalosporins becomes less important among older children, and it seems that ceftriaxone is still used on neonates in resource-poor settings (it is much cheaper) without a significant increase in adverse effects.

b)

The college are quotting this 2013 Cochrane review by Brouwer et al  was able to include 4121 participants from twenty-five trials.

  • The mortality benefit was statistically non-significant
  • Deafness was reduced (RR 0.67) as were neurological sequelae of all sorts (RR 0.83).
  • Mortality improved in the S.pneumoniae patients only
  • In children, protection against hearing loss was only seen in the H.influenzae group.
  • In third world countries, there was no benefit for anybody, except for those with tuberculosis meningitis.
  • Subgroup analysis of high quality studies did not show any effect on severe hearing loss.
  • There was an increased risk of recurrent fever, but no other side effects.

Still, the overall conclusion that corticosteroids should still be given to patients in high-income countries.

Adverse effects of corticosteroids in meningitis are mentioned in this 1996 article by Townsend et al. In brief, the only major concern is that corticosteroids may rapidly normalise the blood brain barrier function, decreasing the penetration of antibiotics into the CSF. This phenomenon is known purely from rabbit models. Might I add that in those models the decreased concentration of ampicillin in the rabit CSF was still well above MIC for the E.coli they injected into the rabbits. In the one known human study (Paris et al, 1994) with eleven meningitic children the CSF concentration of ceftriaxone was also unaffected. In short,  the evidence to feed these concerns is far from convincing.

In summary::

  • Dexamethasone should be given to all adult meningitis patients in the developed world.
  • Most guidelines recommend the same for children
  • It should be given before the first dose of antibiotics
  • It should be given for 4 days, or less if the meningitis is proven non-streptococcal (or non-Haemophilus, in the case of children)
  • The daily dose should be 0.6mg/kg.

References

Oh's Intensive Care manual: Chapter   54  (pp. 597)  Meningitis  and  encephalomyelitis by Angus  M  Kennedy

Van de Beek, D., et al. "Corticosteroids for acute bacterial meningitis."Cochrane Database Syst Rev 1 (2007).

Brouwer, Matthijs C., et al. "Corticosteroids for acute bacterial meningitis." Cochrane Database Syst Rev 6 (2013).

Lee, Bonita E., and H. Dele Davies. "Aseptic meningitis." Current opinion in infectious diseases 20.3 (2007): 272-277.

Beer, R., P. Lackner, and B. Pfausler. "Nosocomial ventriculitis and meningitis in neurocritical care patients." Journal of neurology 255.11 (2008): 1617-1624.

Korinek, A-M., et al. "Prevention of external ventricular drain–related ventriculitis." Acta neurochirurgica 147.1 (2005): 39-46.

NSW Health. Infants and children: acute management of bacterial meningitis: clinical practice guideline. North Sydney: NSW Ministry of Health; 2014.

Tunkel, Allan R., et al. "Practice guidelines for the management of bacterial meningitis." Clinical infectious diseases 39.9 (2004): 1267-1284.

Townsend, Gregory C., and W. Michael Scheld. "The use of corticosteroids in the management of bacterial meningitis in adults." Journal of Antimicrobial Chemotherapy 37.6 (1996): 1051-1061.

Paris, Maria M., et al. "Effect of dexamethasone on therapy of experimental penicillin-and cephalosporin-resistant pneumococcal meningitis." Antimicrobial agents and chemotherapy 38.6 (1994): 1320-1324.

Furyk, J. S., O. Swann, and E. Molyneux. "Systematic review: neonatal meningitis in the developing world." Tropical Medicine & International Health16.6 (2011): 672-679.

Odio, Carla M. "Cefotaxime for treatment of neonatal sepsis and meningitis."Diagnostic microbiology and infectious disease 22.1 (1995): 111-117.

Question 19 - 2015, Paper 1

With respect to patients with HIV disease admitted to Intensive Care for a non-HIV related cause:

a)  What relevant information about the patient’s HIV disease would you elicit from the history, examination and investigations to assist management? (50% marks)

b)  Discuss the issues associated with the administration of antiretroviral therapy in the Intensive Care Unit. (50% marks)

College Answer

History

  • Duration of disease
  • Treating physician
  • h/o AIDS defining illnesses
  • h/o opportunistic or other infections, Hep B/C status
  • h/o IVDU
  • h/o malignancy
  • Weight loss
  • Medication history
    • antiretrovirals, compliance
    • side effects with ART
    • prophylaxis against opportunistic infections

Clinical Examination

  • Nutritional state/wasting
  • Stigmata of IVDU
  • Oropharyngeal candidiasis, herpes simplex lesions
  • Assessment for cardiovascular risk and disease

Investigations

  • recent CD4 & viral load
  • nadir CD4 and peak viral load
  • ART drug resistance tests
  • Previous chest x-ray- old TB/MAC, chronic changes
  • ECG- looking for ischaemic changes, (risk of accelerated atherosclerosis)

b)

No prospective studies evaluating safety, efficacy & timing of ART in the ICU

1) ART interruption- Difficulty with administering oral drugs in the critically ill especially with GI dysfunction. No parenteral preparations. Treatment interruption can lead to resistance mutations (effects seen up to 3 months after). Interruption also has HIV- specific and non-HIV specific risks (cardiovascular, renal, liver)

2) Toxicities and Side Effects- Dose adjustment required with organ failure (renal or hepatic). Specific toxicities and complications such as lactic acidosis, pancreatitis, liver failure, cardiovascular disease and hypersensitivity reactions.

3) Drug Interactions- With commonly used ICU drugs such as midazolam, PPIs, H2 blockers, amiodarone.(specific names of drugs not required)

4) Immune Reconstitution Syndrome- May complicate new initiation of ART in ICU. Worsens respiratory failure from PJP or TB. Worsens neurological status from Cryptococcus or TB. Increased risk soon after commencement of ART and with low CD4 counts.

Discussion

a)

What relevant information is required to manage this patient?

History

Prognosis-defining features:

  • duration of disease
  • AIDS-defining illnesses
  • IV drug use
  • Malignancy
  • Weight loss
  • Compliance with meds
  • PJP prophylaxis
  • Side effects of the ART

Examination

  • Nutritional state
  • Stigmata of IVDU
  • oral candida
  • Oral heres simplex
  • Cardiovascular disease
  • Respiratory disease (eg. COPD)
     

Investigations

  • CD4 count
  • viral load
  • historical nadir
  • CXR (for TB, PJP)
  • ECG (accelerated atheroma)
  • ART drug resistances
     

b)

In brief, as far as ART is concerned:

  • If they are already on antiretroviral drugs, those should continue.
  • However:
    • None are parenteral.
    • Many of them won't get absorbed properly (all are capsule drugs)
    • Alkalinised stomach content will not permit adequate absorption
    • Feeds need to be paused for the administration of many of them, leading to sub-optimal nutrition.
    • Metabolism and clearance will be altered
    • Some will interact with ICU medications (eg. protease inhibitors potentiate the effects of midazolam)
  • If they are not on antiretroviral drugs, and are admitted for some non-HIV related problem, then one can safely defer starting them until after the critical illness has resolved.
  • They may not know they have HIV. Up to 40% of patients admitted to ICU with a complication of HIV don't know they are infected.
  • If they are admitted with an infectious complication of untreated HIV, then antiretroviral drugs should be started as early as possible (it seems to result in less AIDS progression and decreased mortality with no increase in adverse events)
  • Exceptions to this rule are cryptococcal meningitis and TB meningitis, because:
    • Drug interactions are prohibitive.
    • A severe inflammatory syndrome (Immune Reconstituion Inflammatory Syndrome, IRIS) can develop.

Manifestations of IRIS may include:

  • ARDS
  • Vasodilated shock
  • Fevers and rigors
  • Worsening of progressive multifocal leukoencephalopathy
  • Worsening of CNS tuberculosis infection (or pulmonary, for that matter)
  • Worsening of CMV retinitis
  • Exacerbation (or de novo emergeance) of VZV encephalitis
  • Worsening of cryptococcal meningitis

ART might have numerous side effects:

  • All of these drugs are hepatotoxic
  • Didanosine and stavudine cause pancreatitis
  • NRTIs cause lactic acidosis
  • Tenofovir and indinavir are nephrotoxic
  • Nevirapine causes Stevens-Johnson syndrome

References

Oh's Manual:  Chapter 68  (pp. 710) HIV  and  acquired  immunodeficiency  syndrome  by Alexander  A  Padiglione  and  Steve  McGloughlin

Zolopa, Andrew R., et al. "Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial." PloS one 4.5 (2009): e5575.

Huang, Laurence, et al. "Intensive care of patients with HIV infection." New England Journal of Medicine 355.2 (2006): 173-181.

Murdoch, David M., et al. "Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options."AIDS research and therapy 4.1 (2007): 9.

Bajwa, Sukhminder Jit Singh, and Ashish Kulshrestha. "The potential anesthetic threats, challenges and intensive care considerations in patients with HIV infection.Journal of pharmacy & bioallied sciences 5.1 (2013): 10.

Duggal, Abhijit, et al. "OUTCOMES OF HIV PATIENTS REQUIRING INVASIVE MECHANICAL VENTILATION AS COMPARED TO PATIENTS WITH AIDS." CHEST Journal 136.4_MeetingAbstracts (2009): 115S-a.

Question 21.2 - 2015, Paper 1

A previously healthy 65-year-old female presents with headache, fever and altered level of consciousness. A CT Brain scan is normal and an LP is performed showing the following results:

Parameter Patient Value Normal Adult Range
Opening pressure 22 cm H2O* 5 – 15
White Blood Cell Count 240 cells/μL*(75% mononuclear) 0–5
Red Blood Cell Count 1 cell/μL 0–5
Protein 800 mg/L* 150 – 400
Cerebrospinal Fluid Glucose 3.0 mmol/L 2.5 – 4.4
Serum Glucose 6.0 mmol/L 4.2 – 6.9

The patient is currently treated solely with Ceftriaxone 2g 12 hourly.

Give the three most likely infectious causes that would require additional specific treatment, and give the treatment of each of these conditions.

(40% marks)

College Answer

  • Listeria                               Benzylpenicillin 2.4g Q4H or Ampicillin  2g ivi Q4-6H
  • HSV                                    Aciclovir 10mg/Kg Q8H 
  • Resistant pneumococcus:  Vancomycin load 25-35mg/kg and reasonable ongoing dosing regimen)
  • TB                                       Isoniazid plus rifampicin plus ethambutol plus pyrazinamide
  • Cryptococcus                     Amphotericin

Discussion

This is another one of these "match the bug with an appropriate agent" questions, much like Question 11 from the first paper of 2011 or Question 17.1 from the second paper of 2010.

The only new issue raised in this question (when compared to all the other questions of this sort) is the mention of HSV meningitis requiring 10mg/kg qid of aciclovir, and the naming of all the drugs from the tuberculosis cocktail (isoniazid, rifampicin, ethambutol and pyrazinamide).

Interestingly, in this question the Listeria is managed with benzylpenicillin, whereas a meningitis question from the same paper (Question 11 from the first paper of 2015) lists ampicillin instead.

References

Question 25 - 2015, Paper 1

Your intensive care unit has had a noticeable increase in the rate of ventilator - associated pneumonia (VAP). A number of cases involve multi - resistant organisms.

Outline the strategies you would recommend implementing in your unit in an effort to reduce the incidence of VAP.

Explain the rationale for each recommended quality improvement strategy in your answer.

College Answer

Infection control procedures

Review routine infection control procedures e.g. hand washing, personal protection (gloving, gowning etc.), isolation policies for MDR organisms and airborne pathogens.

Benefits include a reduction in transmission of organisms from patient to staff and staff to patients hence reducing colonisation. Generally evidence of benefit exists for many of these strategies (e.g. hand washing) and there is also evidence of poor or less than perfect compliance.

Robust infection control governance and systems are also mandatory under new National Standards for Safety and Quality in Healthcare (Standard 3) including the need for regular audit and feedback. 

Direct patient care strategies to prevent VAP

The presence of an endotracheal tube, micro aspiration and poor clearance of respiratory secretions is thought to the key to pathogenesis of VAP. Therefore the implementation of a so- called ‘VAP bundle’ or similar is worth considering (although not all elements have a high level of evidence).

Strategies include:

  • Remove tube at earliest possible time
  • Elevate head of bed >30 degrees
  • Daily mouth care (meticulous dental care and/or Chlorhexidine mouthwash)
  • Minimise circuit manipulation
  • Appropriate cuff pressures

May also consider:

  • ETTs with subglottic suctioning
  • Selective digestive decontamination
  • Limiting the use of PPIs
  • Weaning and sedation protocols

Antibiotic stewardship

Implement antibiotic stewardship including review of current prescribing practice, consideration of regular infectious diseases input, ICU and hospital specific antibiogram to guide antibiotic use and possible regulation of prescription of certain antibiotic classes.

No high level evidence of benefit for individual patients but generally considered to be important to avoid overuse of broad spectrum antibiotics in particular and limit the development of MDR pathogens. Good antibiotic stewardship may also increase the adequacy of empiric antibiotic cover, which is associated with improved mortality.

Environmental cleaning and decontamination

Review of cleaning procedures and compliance with Australian regulations regarding the surrounding environment is warranted.

For example:

  • Staphylococcus remains viable on dry surfaces and be transmitted to staff and patients hence the entire bedspace including high surfaces must be cleaned regularly.
  • Aspergillus may be transmitted via airborne spread of spores particularly to immunosuppressed patients in the setting of construction or renovation.
  • Serratia has been linked to spread via sinks particularly if non-compliant with current design regulations.

Ongoing measurement and audit program

Ongoing measurement and feedback of clinically relevant processes and outcomes is a key to any quality improvement strategy and essential to demonstrate future improvement.

Problems exist with definitions for VAP including poor reliability and gaming of results. Even so review of existing data and data quality with appropriate statistical measures is important to be able to distinguish common cause from special cause variation.

It should not necessarily be assumed that the current increase in cases is based on reliable data or that it is statistically significant.

Equally important is allocation an appropriate clinician (nurse or doctor) with the responsibility and time to champion the cause and provide regular feedback to other staff.

This would likely be included in a wider quality and safety or infection control portfolio.

Additional comments:
Candidates were expected to give a clear statement of each strategy with a mature explanation
of the rationale, not just state, for example, “VAP bundle”

Discussion

Below, a table is reproduced from the ventilator-associated pneumonia (VAP) chapter in the required reading section of the site. It concerns the organisation-level strategies to reduce the risk of VAP. In addition to this, there are direct bedisde strategies, which are as follows:

Strongly evidence-based advice

  • Early extubation, avoidance of intubation
  • Avoidance of reintubation
  • Avoid NG tubes
  • Use of higher cuff pressures (~ 20cmH2O)
  • Use of above-the-cuff subglottic suction
  • Minimised sedation and paralysis
  • Sit them up to 45° (avoid being supine)

Advice based on weak evidence

  • Consider using post-pyloric feeds
  • Consider selective digestive decontamination
  • Reduce the use of stress ulcer propylaxis.
Organisation-Level Strategies for the Prevention of VAP
Strategies Specific interventions Rationale and literature support
Education
  • Distribution of materials
  • Meetings
  • Outreach visits

According to the abovequoted review (Crnich et al, 2005) this has a  modest and shortlived effect on the process of care. Furthermore, most survey respondents (in a 2004 systematic review) felt that they were only sufficiently resourced to disseminated printed material and to hold informal lunchtime meetings.

Infection control procedures
  • Hand-washing
  • PPE
  • Isolation policies for resistant organisms

The literature in support of this is Standard 3, ACSQHC: this stuff is actually as mandatory as your compulsory annual fire training. The rationale for it is that scupulous attention to infection control might prevent VAP by preventing the transmission of multi-resistant organisms.

Does it help with VAP? Probably,. At least one study (Koff et al, 2011) has found an improvement in VAP after the introduction of a comprehensive hand hygiene program.

Antibiotic stewardship
  • Regulated antibiotic prescribing
  • Mandatory ID input
  • Review of prescribing practice

The college hastens to add that there "is no high level evidence" to demonstrate that antibiotic stewardship has very much effect on the rates of VAP. In fact some reasonable quality studies do exist (Gruson et al, 2000). The authors were able to decrease both their VAP rates and the incidence of multi-resistant bacteria by starting a program of antibiotic supervision and regular rotation. However, this was a French hospital where the random wanton use of ceftazidime and ciprofloxacin was rampant prior to the study protocol.

Environmental
decontamination

  •  Compliance with the (already strict) practice protocols
  • Air filtration
  • Hygiene of the ventilator circuit
  • Decontamination of potable tap water
  • Single-use airway devices

This does not refer exclusively to the "terminal cleanining" of a bed space, and is inclusive of the ventilator tubing, the bed itself, the bedside sink, the room air conditioner filter, etc etc. But the bed space is probably the most important: for example, This Irish infection control protocol (2011) cites a brilliant review from Respiratory Care (Crnich et al, 2005). Crnich et al produce a massive table of environmental factors which influence the risk of VAP, including contaminated respiratory equipment, poor ambient air filtration, dislogement of Aspergillus spores during construction activities, and so forth. The review quotes evidence for the importance of these factors among its 388 references.

Audit of activities
  • Reliable definition of VAP, consistent over the course of audit
  • Data collection protocol
  • Scheduled reviews
  • Allocation of auditor responsiilities

Is there a point to this? To many it seems like pointless busywork. Indeed, a widely cited 2004 meta-analysis (Grimshaw et al, 2004) found that "the effect of audit and feedback on improving professional practice was small to moderate", and that "variability in the study quality and reporting transparency makes it difficult to recommend widespreaduse of audit and feedback". This was not specific to infection control, but pertaining to the broader tendency of healthcare staff to spontaneously self-organise into committees and auditing bodies.

References

Koff, Matthew D., et al. "Reduction in ventilator associated pneumonia in a mixed intensive care unit after initiation of a novel hand hygiene program." Journal of critical care 26.5 (2011): 489-495.

Gruson, Didier, et al. "Rotation and restricted use of antibiotics in a medical intensive care unit: impact on the incidence of ventilator-associated pneumonia caused by antibiotic-resistant gram-negative bacteria." American journal of respiratory and critical care medicine 162.3 (2000): 837-843.

Crnich, Christopher J., Nasia Safdar, and Dennis G. Maki. "The role of the intensive care unit environment in the pathogenesis and prevention of ventilator-associated pneumonia." Respiratory Care 50.6 (2005): 813-838.

Sinuff, Tasnim, et al. "Ventilator-associated pneumonia: improving outcomes through guideline implementation." Journal of critical care 23.1 (2008): 118-125.

Grimshaw, J. M., et al. "Effectiveness and efficiency of guideline dissemination and implementation strategies." International Journal of Technology Assessment in Health Care 21.01 (2005): 149-149.

Question 27 - 2015, Paper 1

Discuss the factors that may affect your choice of antimicrobial agent in a critically ill septic patient, giving examples where relevant.

College Answer

Patient Factors

  • History of current acute illness
  • Allergies
  • Previous antibiotic exposure
  • Co-morbidities like immunocompetence, Diabetes.
  • Social history e.g. nursing home resident, alcohol/drug abuse, occupation, contact with birds/animals, travel

Organism

  • Sensitivity profile
  • Inducible beta-lactamase producers (e.g. ESCAPPM)
  • Tendency to develop resistance to antimicrobial during treatment course e.g. Pseudomonas aeruginosa
  • Intracellular (e.g. aminoglycosides poorly active against strictly intracellular bacteria e.g. Rickettsia, Chlamydia, Coxiella burnetti)

Site of infection

  • Organs with non-fenestrated capillaries (e.g. brain, prostate, anterior chamber of eye) – poor penetration of non lipid-soluble drugs
  • Biliary and urinary sepsis – select drugs with hepatic (e.g. ceftriaxone) and urinary excretion (cefotaxime) respectively
  • Lung – e.g. daptomycin inactivated by surfactant, vancomycin poor penetration

Organ dysfunction

  • Renal or hepatic dysfunction may result in decreased elimination and increased toxicity

Toxicity

  • Renal and ototoxicity of aminoglycosides
  • Renal toxicity of vancomycin
  • Neurotoxicity of imipenem

Drug interactions

  • Synergy – beta lactams and aminoglycosides
  • Pharmacodynamic interactions e.g. macrolides plus other agents causing prolongation of QT

Non anti-microbial effects of antimicrobial

  • Anti-inflammatory effect of macrolides – may underlie outcome benefit when combined with beta lactams for bacteraemic pneumococcal pneumonia
  • Inhibition of toxin synthesis in toxic-shock syndrome by clindamycin and linezolid

Hospital factors

  • Local microbiology/ecology
  • Ability of monitoring drug levels (TDM)
  • Presence of an ID physician / Antibiotic Stewardship team in the hospital and their policies

Route of administration

  • Certain routes of administration may be unreliable in critically ill patients and drugs which can only be administered by that route are less desirable e.g. inhaled zanamivir

Cost

  • Cost-effectiveness of the antibiotic

Bactericidal vs bacteriostatic

Theoretical benefit from bactericidal drugs. Controversial whether there is a clinical benefit

Additional comments:

Candidates were not expected to provide long lists of antimicrobial agents but to mention some examples where relevant. Overall, the question was poorly answered with superficial answers showing a lack of depth of understanding of the topic. Some wrote about dosing and dose adjustment but not about the choice of antimicrobial agent. Some candidates included key phrases e.g., “time dependent killing” without any demonstration of understanding of how that concept affected the choice of antibiotic.

Discussion

This vaguely worded broad question was answered poorly. This is not because the trainees were unaware of the influence of susceptibilities or drug interactions on antibiotic choice, but because they could not guess what exactly the examiners wanted from them.

The tabulated answer below was largely derived from an article by  Surbhi et al (2011) from the Mayo Clinic Proceedings.

Factors which Influence the Choice of Antibiotic Therapy
Factors Discussion and examples
Disease specifics Travel history
  • Geography of endemic regions (eg. leptospirosis)
  • Known ongoing outbreaks (eg. Ebola, H1N1, MERS)
Occupational exposure
  • Abbatoir workers (Coxiella burnetii)
  • Fisherman (Vibrio vulnificus)
  • Cattle farmers (Brucella sp.)
Recreational exposure
  • IV drug use (endocarditis)
  • Pets or animal exposure (eg. psittacosis or toxoplasma)
  • Bushwalking (eg. tick-borne disease)
  • Alcoholism (prognostic importance in community-acquired pneumonia)
Recent antimicrobial use
  • Was it the right antibiotic? i.e. was the course of antibiotics ineffective because of poor agent choice?
  • Did it select for a specific group of organisms?
  • Prophylaxis vs. endemic pathogens (eg, malaria)
Empiric vs. definitive
  • Are we convinced of the diagnosis?
  • Is there a need to cover broadly?
Urgency and timing
  • Septic patient (every hour delay is associated with a 1% mortality increase)
Reliability of cultures
  • Are we sure we cultured the correct pathogen?
  • Is a polymicrobial infection possible (eg. diabetic foot)?
Host factors Clearance
  • Decreased renal clearance (by renal failure)
  • Increased renal clearance (by dialysis, or in pregnancy)
  • Decreased hepatic clearance (eg. cirrhosis)
  • Exotically altered clearance (eg. plasma exchange, haemoperfusion, adsorption on to ECMO circuit surfaces, and so forth).
Age
  • Paediatric dosing needs to be adjusted to weitght
  • Geriatric dosing needs to account for change in volume of distribution and clearance
Genetic variation
  • Genetic differences in side effects from antibiotics
  • Congenital idiosyncracies preventing the use of certain antibiotics (eg. G6PD deficiency resulting in haemolysis when exposed to dapsone or nitrofurantoin)
  • Hepatic enzyme defects
Pregnancy and lactation
  • Early pregnancy teratogenesis (eg. nitrofurantoin, chloramphenicol, sulfonamides)
  • Late pregnancy teratogensis (eg. tetracyclines)
Immunocomptence
  • Steroid use
  • Post-splenectomy, unvaccinated (susceptible to encapsulated organisms)
  • Chemotherapy
  • Solid organ or bone marrow transplantation
   
Allergies
  • Fatal hypersensitivity reaction vs. some sort of mild scaly rash with a little itching.
Organism factors Susceptibility
  • ESCAPPM, MRO, etc
  • Community prevalence of drug resistance
  • Tendency to develop resistance during treatment
Biology
  • Intracellular pathogen vs. extracellular
  • Unusual life cycle (eg. helminthes, malaria) - need to kill the eggs or dormant cocoons or whatnot
Source control
  • Success of therapy overall is largely determined by this
Duration of therapy
  • Short course, eg. in urosepsis
  • Long course, eg. osteomyelitis
Assessment of response
  • To repeat the cultures, or not?
  • Is there a point in monitoring serology?
Drug factors Cost
  • Fluconazole: $57.99 AUD for 28 capsules (200mg)
  • Anidulafungin: ~$ 300 AUD per single 200mg dose.
  • Cost of monitoring the drug levels
  • How much is a life worth? you amoral monsters, etc.
Toxicity
  • Risk vs benefit
  • Some drugs (eg. chloramphenicl) are uniformly  "too toxic for use", as there are less toxic alternatives in almost every situation.
Bioavailability
  • Convenience of oral dosing
  • Certainty of IV dosing
  • Altered absorption via GI tract in context of critical illness, shock states, low flow, what have you.
Site penetration
  • Basic chemistry of the drug influences this aspect. Eg:
  • Penetration to the CSF (lipophilicity)
  • Exclusive distribution into the circulating volume, (hydrophilicity, or high serum protein binding)
  • Weird organ preference (eg. the strange affinity of fluoroquinolones for the prostate)
  • Exclusion of a drug from a specific organ (eg. the inactivation of daptomycin by lung surfactant)
Bactericidal vs bacteriostatic
  • Some agents are bacteriostatic against one pathogen and bactericidial against another
  • There may not be any in-vivo difference
Synergistic combination
  • Need for multiple agent therapy (eg. in Pseudomonas)
  • Unquestioned need for synergy (eg. cocktail for TB)
  • Advantage from synergy (eg. ampicillin with gentamicin for enterococci)
  • Need for broad-spectrum coverage (in which case you use multiple agents to start with, and then narrow the spectrum of cover)
  • Need for polymicrobial coverage (eg. surgical triple therapy, or in context of bone marrow transplant)
  • Need to prevent emergence of resistance (eg. the argument offered to defend the use of selective digestive tract decontamination; also, a genuine argument for the use of  rifampicin and fusidic acid together)

References

LONGACRE, AB. "Factors influencing the choice of antibiotics in therapy." The New Orleans medical and surgical journal 103.4 (1950): 160-167.

Leekha, Surbhi, Christine L. Terrell, and Randall S. Edson. "General principles of antimicrobial therapy." Mayo Clinic Proceedings. Vol. 86. No. 2. Elsevier, 2011.

Question 10 - 2015, Paper 2

Outline how the pathophysiological changes in septic shock affect the pharmacokinetics and pharmacodynamics of commonly used antimicrobials.

College Answer

The major changes in pharmacokinetic parameters of critically ill patients include alterations in volume of distribution (Vd) and clearance (Cl). Subsequently, these alterations affect the concentrations of antimicrobials in the body and the extent to which they are cleared.

The Vd is the volume in which the total amount of drug would have to be evenly distributed in to equal the same concentration as in the plasma. The toxins produced by various bacteria often lead to endothelial damage and result in increased capillary permeability. This leads to the phenomenon of “third spacing” where fluid shifts into the interstitial space from the intravascular space. These fluid shifts will increase the Vd of hydrophilic antimicrobials. Generally speaking, hydrophilic antimicrobials have a low Vd and therefore are greatly affected by these fluid shifts. Since lipophilic antimicrobials have a larger Vd, they typically distribute further into tissues and are less affected by these fluid shifts.

Patients in the ICU often have hypotension as a result of septic shock, which requires the administration of fluid boluses. Additionally, heart failure and renal failure lead to more oedematous states where patients can retain large amounts of fluid. These situations also lead to increases in Vd of hydrophilic drugs.

Changes in protein binding can also have a substantial effect on the Vd, especially for drugs that are highly protein bound. Only unbound or free drug is microbiologically active. Hypoalbuminemia in critically ill patients can result in decreased binding of drugs and subsequently higher free concentrations of drugs. While free drug will distribute into tissues, critically ill patients often have greater amounts of fluid in the interstitial space causing the antimicrobial concentrations in the tissues to remain low.

The administration of large volumes of fluid and use of vasopressors leads to a hypermetabolic state in which cardiac output and glomerular filtration rate are increased. The term often used to describe this enhanced elimination is augmented renal clearance. These physiological changes affect the clearance of drugs and can lead to sub-therapeutic levels of antimicrobials that are typically cleared by the kidneys. In contrast, decreased organ perfusion in the presence of end organ damage can lead to kidney and/or liver failure in which concentrations of these antimicrobials would be increased. Inadequate clearance or metabolism of these drugs would lead to accumulation and potential toxicity. Typically, equations such as Cockroft-Gault are used to estimate renal function; however, these are often not good predictors of renal function in critically ill patients due to the acute and rapid changes such patients often experience. Since many antimicrobials are dosed based on renal function it is even more challenging to ensure adequate doses are being administered. The most accurate way to calculate renal function is the use of 8- or 12-hour creatinine collections. In situations where renal replacement therapy is utilized, careful consideration of timing and supplemental dosing post-dialysis would be needed depending on the antimicrobial agent

Discussion

The college model answer to this question is a excessive block of prose, which cannot be expected from the trainees under any sort of exam conditions. Instead, a more streamlined point-form answer is suggested. In essence, the college ask about septic shock, but then go on to discuss pharmacological changes which are common to all critically ill patients.

These are as follows:

Pharmacokinetic changes:

  • Factors which decrease the antibiotic peak concentration:
    • Suboptimal gut absorption.
    • Increased volume of distribution (patients are typically fluid-overloaded)
    • Poor penetration to the site of action (poor tissue perfusion and generalised oedema)
  • Factors which increase the antibiotic peak concentration
    • Increased free fraction (decreased protein binding due to low albumin)
    • Diminished clearance (renal and hepatic failure)
  • Factors which increase the antibiotic half-life
    • Diminished clearance (renal and hepatic failure)
  • Factors which decrease the antibiotic half-life
    • Renal replacement therapy (enhances clearance)
    • Increased hepatic clearance (hyperdynamic circulation)
    • Increased glomerular filtration rate (hyperdynamic circulation)
    • Increased rate of drug metabolism due to a "hypermetabolic state" induced by trauma,  burns and exogenous catecholamine infusions

Pharmacodynamic changes:

  • Increased nephrotoxicity from aminoglycosides, if the renal function is already impaired
  • Increased cardiotoxicity from bleomycin and vancomycin
  • Increased risk of QT prolongation and arrhythmia with fluoroquinolones in the context of cardiac ischaemia, profound hypothermia, or extreme electrolyte derangement
  • Increased bone marrow toxicity from linezolid, cotrimoxazole, gancyclovir, chloramphenicol, beta-lactams of all sorts...
  • With a disrupted blood-brain barrier, an increased risk of seizures from high-dose beta-lactams, due to enhanced penetration.  
  • Worsening shock due to dapsone-induced methaemoglobinaemia and thus diminished oxygen-carrying capacity.

As such, this model answer to a question about sepsis would have also answered Question 1 from the first paper of 2000, which asks about pharmacological changes in critical illness in a broader sense. There are a few pharmacological peculiarities which dveelop exclusively (or almost exclusively) in the context of sepsis, and these are sumarised below using the excellent article by De Paepe et al (2002)

Change to pharmacology which are unique to sepsis and septic shock

  • Increased volume of distribution due to sepsis-associated "capillary leak" results in a decreased effective concentration of antimicrobials.
  • Decreased bioavailability of basic drugs: because α-1-acid glycoprotein is an acute phase reactant
  • Increased penetration of formerly impenetrable tissues due to their inflamed state, as in the enhanced penetration of β-lactams into the CNS which is associated with meningitis
  • Impaired hepatic metabolism due to inhibition of CYP-450 enzymes by  endotoxin-mediated release of nitric oxide

References

Craig, William A. "Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men." Clinical infectious diseases (1998): 1-10.

Ulldemolins, Marta, et al. "Antibiotic dosing in multiple organ dysfunction syndrome." CHEST Journal 139.5 (2011): 1210-1220.

Trotman, Robin L., et al. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy." Clinical infectious diseases 41.8 (2005): 1159-1166.

Drusano, George L. "Antimicrobial pharmacodynamics: critical interactions of'bug and drug'." Nature Reviews Microbiology 2.4 (2004): 289-300.

De Paepe, Peter, Frans M. Belpaire, and Walter A. Buylaert. "Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock." Clinical pharmacokinetics 41.14 (2002): 1135-1151.

Piafsky, Kenneth M., et al. "Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1 acid glycoprotein." New England Journal of Medicine 299.26 (1978): 1435-1439.

Muller, Claudia M., et al. "Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin." The Journal of the American Society of Anesthesiologists 84.6 (1996): 1435-1442.

Question 12 - 2015, Paper 2

Outline the strengths and limitations of the current Surviving Sepsis Campaign Guidelines, using examples to illustrate your points.

College Answer

Strengths:

The guidelines are formulated by an international panel of experts reviewing and grading the evidence.

Use of the Grading of Recommendations Assessment Development and Evaluation (GRADE) for guideline development.

o GRADE separates the assessment of the quality of the evidence from the ultimate strength of the recommendations (allows for strong recommendations when the quality of evidence is weak or weak recommendations when the quality of evidence is strong, particularly when patient values and preferences may strongly factor into the equation).

Intensivists may use as a decision-making tool in their practice as: Information to aid practice

An established source of references Reduce variations in clinical practice

The current recommendations may generate areas for future research and consensus statements for this high-risk and high-cost patient group.

Limitations

The GRADE system, although transparent, is still subjective. Recommendations depend greatly on the values and preferences of the committee members.

Guidelines attempt to include nearly every aspect of critical care potentially related to sepsis, thereby losing focus in the process and becoming a general ICU guideline.

A narrower guideline dedicated to sepsis-specific management might be more useful. Complexity and diversity of sepsis may defy a single guideline for all cases.

Guidelines may rapidly become out-dated

E.g. the 2012 guidelines on prone positioning for patients with PaO2/FiO2 ratios < 100 despite such manoeuvres (Grade 2C). This would now potentially be (1B)

Recommends use of proton pump inhibitors over histamine-2 receptor antagonist for stress ulcer prophylaxis (grade 2C), although the emerging consensus suggests that this approach may not be beneficial and indeed may even be harmful.

There are recommendations that may be considered controversial

E.g. Conservative fluid strategy in patients with sepsis-induced adult respiratory distress syndrome in the absence of evidence of tissue hypo perfusion (grade 1C)

The guidelines emphasize ‘bundles’ of care for sepsis resuscitation, although the evidence behind some of the bundled recommendations is not strong, for example using central venous pressure readings to guide volume resuscitation.

Significant risk that bundles will be utilised as quality measures with which Intensivist (who may validly disagree with some of the recommendations) treating sepsis will be assessed/benchmarked.

Discussion

Again, this was brought up in the wake of three recent publications. The increasingly mindless rote-learned answer to these multiplying questions is offered below, and is largely identical to the discussion sections of Question 19 from the second paper of 2006 and Question 1 from the first paper of 2014.

Advantages of the SSG

High quality of the presented package

  • Excellent literature search and summary.
  • A good source of literature references
  • Well presented and easily accessible website.
  • Produced by an international panel of experts reviewing and grading the evidence.
  • GRADE system makes it easier for clinicians to assess the strength of a recommendation.

Evidence in defence of the guidelines

Criticisms of the SSG

Arguments against bundled care in general:

  • Marik et al: "Systematic promotion of evidence illustrates the power of bundles to magnify ineffective therapies."
  • All-or-none bundles may promote harmful therapies together with helpful ones. People end applying evidence-based treatment together with unsupported treatment. Remember Xigris, propagated by the SSG despite abundant evidence against its use.
  • There is no evidence that "bundle synergy" exists.
  • The quality of care might end up being measured according to bundle compliance, which is dangerously divorsed from actual "quality".

Objections on the basis of methodology:

  • Many of the recommendations are not based in high-level evidence
  • None of the recommendations are based in Level 1 evidence.
  • The GRADE system is subjective.

Objections to the guidelines themselves:

  • The guidelines digress significantly from sepsis, and creep across into other areas of ICU management.
  • Controversial recommendations are made, which may not be supported by evidence:
    • There is no survival benefit from routine ScvO2 monitoring (SSG authors agree)
    • There is no survival benefit from routine dobutamine use.
  • The emphasis on EGDT is not supported by strong evidence.

Objections to the evidence offered in support of widespread implementation:

  • All the trials demonstrating a benefit from SSG implementation were "before-and-after" trials.
    • These are chronically subject to publication bias, patient selection bias, temporal bias, and the Hawthorne effect.
  • All the trials tested the whole bundle, but frequently only one specific component was independently associated with a treatment effect (eg. early administration of antibiotics in the Edusepsis study from Spain)
  • The offered studies demonstrate a treatment effect in spite of poor adherence to the bundle (again Edusepsis - as an example mentioned by Marik et al - 5% decrease in mortality was attributed to the six-hour bundle, but the sites only complied with it 10% of the time).

Empirical evidence against the use of the guidelines:

References

Vo, Mai, and Jeremy M. Kahn. "Making the GRADE: how useful are the new Surviving Sepsis Campaign guidelines?." Critical Care 17.6 (2013): 328.

Marik, Paul E., Karthik Raghunathan, and Joshua Bloomstone. "Counterpoint: are the best patient outcomes achieved when ICU bundles are rigorously adhered to? No." CHEST Journal 144.2 (2013): 374-378.

Dellinger, R. Phillip, and Sean R. Townsend. "Rebuttal From Drs Dellinger and Townsend." CHEST Journal 144.2 (2013): 378-379.

Marik, Paul E., Karthik Raghunathan, and Joshua Bloomstone. "Rebuttal From Dr Marik et al." CHEST Journal 144.2 (2013): 379-380.

Chawla, Shalinee, and Jonas P. DeMuro. "Current controversies in the support of sepsis." Current opinion in critical care 20.6 (2014): 681-684.

Marik, Paul E. "Surviving sepsis: going beyond the guidelines." Annals of intensive care 1.1 (2011): 1-6.

Marik, Paul E. "Surviving sepsis." Critical care medicine 41.10 (2013): e292-e293.

Marik, Paul E. "Early management of severe sepsis: concepts and controversies." CHEST Journal 145.6 (2014): 1407-1418.

Kevin Klauer. "Sepsis: Unbundling the Bundle" in EP Monthly on May 24, 2012.

Priebe, Hans-Joachim. "Goal-directed resuscitation in septic shock." The New England journal of medicine 372.2 (2015): 189-189.

Kaukonen, Kirsi-Maija, et al. "Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012."Jama 311.13 (2014): 1308-1316.

Levy, Mitchell M., et al. "Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study." The Lancet infectious diseases 12.12 (2012): 919-924.

"Australia’s high survival rates shed doubt on global sepsis guidelines" - a press release by Monash University, home of ARISE.

Ferrer, Ricard, et al. "Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain." Jama 299.19 (2008): 2294-2303.

Barochia, Amisha V., et al. "Bundled care for septic shock: an analysis of clinical trials." Critical care medicine 38.2 (2010): 668.

Hicks, Peter, et al. "The surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. An assessment by the Australian and New Zealand Intensive Care Society." Anaesthesia and intensive care 36.2 (2008): 149-151. - this article was also published in Critical care and Resuscitation - and this version is available for free.

Question 19 - 2015, Paper 2

a)    Interpret the three pharmacodynamic (PD) profiles, labelled Scenario 1, Scenario 2 and Scenario 3, shown below. (40% marks)

b)    For each PD profile, describe how you would optimise the dose and/or frequency of antibiotic if prescribing:

i)    a beta lactam

ii)    an aminoglycoside

(60% marks)

College Answer

a)

Comments:
Scenario 1

  • Drug concentration does not reach MIC
  • Ineffective dose

Scenario 2.

  • Drug concentration is well above MIC.
  • Repeat dose maintains the concentration above MIC but increases the AUC: MIC ratio.

Scenario 3

  • Peak drug concentration is well above MIC
  • Significant period of interval between doses where drug level is below MIC

b)
Methods to optimise:

(i) Beta Lactam agents:

Scenario 1

  • Increase dose
  • More frequent dosing
  • Consider continuous infusion after an appropriate loading dose

Scenario 2

  • Decrease dose
  • Less frequent dosing intervals
  • Continuous infusion

Scenario 3

  • More frequent dosing interval
  • Continuous infusion

(ii)    Aminoglycosides

Scenario 1

  • Increase dose

Scenario 2

  • Prolong dosing interval
  • Therapeutic drug monitoring to avoid drug toxicity

Scenario 3

  • No change
  • Could consider higher dose.

Discussion

Obviously, in Scenario 1 the antibiotics will never be effective as the MIC is never achieved, and in Scenario 2 the antibiotics will kill the bugs shortly before they kill the patient with toxicity. In Scenario 3, one might argue that nothing needs to change for antibiotics with concentration-dependent killing; whereas those with time-dependent killing should probably be dosed more regularly (or given as an infusion).

This would work best as a table:

Drug profile Time-dependent killers Concentration-dependent killers
MIC not achieved Increase dose
Decrease dosing interval
Increase dose
Dose accumulation Decrease dose
Increase dosing interval
Increase dosing interval
MIC achieved but prolonged sub-MIC time Decrease dose AND increase dosing frequency Do nothing (fine like this)

In regard to the college answers, one might add that "continuous infusion" is the correct answer to any sort of dose adjustment problem when it comes to time-dependent killers, and "therapeutic drug monitoring" can never be a wrong answer in a dose adjustment question. Kill characteristics of antibiotic agents are discussed elsewhere.

References

Question 22 - 2015, Paper 2

A  health  care  worker,  recently  returned  from  West  Africa,  presents  to  the  Emergency  Department  with fevers,  vomiting  and  diarrhoea.    Her  vital  signs  are  normal  on  presentation.    Blood  tests  have  not  been taken, and venous access has not been established.

Your state and hospital’s Ebola response plan has been activated, and the patient is due to be transferred to the state quarantine hospital.  For logistic reasons this cannot occur for 24 hours, and you (with approval from ICU medical and nursing directors) have agreed to admit the patient to your ICU as this is the site of your hospital’s only suitable isolation rooms.  Outline your management for this first 24-hour period.

College Answer

Ensure appropriate isolation prior to transfer:

  • negative pressure room with appropriate venting activated checked, and operational
  • ante-room with facilities for donning and doffing of PPE
  • separate toilet and hygiene facilities
  • adequate PPE supplies ideally staffed by an “opt-in” model
  • rehearse donning and doffing procedures with observed and guided doffing

Ensure appropriate staff safety:

  • intervention and observations to a minimum
  • blood tests are contraindicated unless sent to a designated laboratory with appropriate containment facilities

Specific Patient Management:

  • focussed clinical examination to determine both physiologic disturbance and to look for other diagnoses (malaria, typhoid)
  • empiric antibiotics for typhoid etc. and antimalarials
  • strategy to maintain adequate fluid intake (oral, or iv with appropriate precautions)
  • active symptom management of nausea & vomiting, diarrhoea (often profuse), pain
  • no blood tests unless logistics allow

Other:

  • staff welfare and de-brief
  • family support

Additional Examiners’ Comments:
Most  answers  were  very  superficial ,  lacking  consideration  of  the  detail  needed  to  describe  adequate isolation practices and were not at specialist level

Discussion

If anyone wants to know what a "specialist level" answer is supposed to look like, they can read this recent 2014 article on severe Ebola by West et al, as it contains - in greater detail - the sort of issues that were brought up  briefly in the college answer.

Thus, the management of the Ebola patient can be divided into four major domains:

  • Protect the public (isolate the patient)
  • Protect your staff
  • Supportive management
  • Specific therapies

Protect the public: epidemic control measures ( see the NSW Health Ebola document)

  • Specific plans regarding transfer of confirmed cases to a dedicated facility.
  • Dedication of a specific "VHF designated" facility, where specialist staff are concentrated.
  • Dedicated isolation rooms, with specific features:
  • Single room with door closed
  • Ideally, a negative pressure room
  • Own bathroom; not connected to central sewer (special disposal arrangements)
  • Strict limits on visitors (none!)
  • Special arrangements for disposal of patient's wastes and disposable equipment

Protect your staff: personal protective equipment

  • Staff training for VHF personal protective equipment (PPE).
  • Specific instructions to transport and retrieval staff trained in VHF PPE.
  • Surgical scrubs (not your comfy home clothes)
  • Disposable long sleeve gown
  • Face shield
  • Surgical hood
  • P2/N95 mask or disposable powered air purifying respirator (PAPR) hood
  • Fluid repellent below-knee boot covers
  • Double gloves with long cuffs

Supportive management

  1. Intubation may be required in case of significant respiratory failure.
    Specific problems may arise:
    1. Greatest risk of aerosol transmission will be to the airway operator, who would need to be appropriately protected
    2. Coagulopathy could create a post-intubation haemoptysis problem due to relatively trivial airway trauma
    3. Frequent suctioning could cause enough airway trauma to produce lower airway haemorrhage
  2. Respiratory support
    1. Copious volumes of fluid resuscitation may produce pulmonary oedema
    2. NIV may be sufficient initially, but has a greater potential to aerosolize secretions.
    3. Invasive ventilation is the preferred method.
    4. The invasively ventilated patient should be ventilated with lung-protective ventilation.
    5. Expired gas from the patient should pass through a HEPA or equivalent filter.
    6. Extracorporeal life support is not advised (expecting haemorrhagic complications)
  3. Circulatory support
    1. Aggressive volume repletion with isotonic fluids
    2. Ebola can be complicated by adrenal necrosis; "stress dose" steroids should be considered early
    3. Standard noradrenaline is probably going to play a role.
  4. Neurological dysfunction
    1. These patients may be obtunded for a variety of reasons.
    2. Of the reasons one needs to exclude, the most important are:
      1. Intracranial haemorrhage in the coagulopathic patient
      2. Seizures (including non-convulsive status)
      3. If not obtunded, they may be in pain, feeling isolated, and frightened beyond belief.
      4. Experts recommend videoconferencing facilities be made available to permit contact with loved ones
  5. Electrolyte abnormalities
    1. Massive fluid and electrolyte loss is to be expected
    2. Apart from anticipating and correcting it, no specific recommendations can be made
  6. Fluid balance and renal failure
    1. Vast volumes of crystalloid may be used; so you better use a balanced solution.
    2. ATN is present on post-mortem of Ebola victims, and is thought to originate from the shock state- correcting the haemodynamic derangement is therefore a priority.
    3. Standard indications for renal replacement therapy apply.
    4. All effluent must be disposed of in some sort of formalised fashion (like the rest of the Ebola patient material, one cannot simply put it in the routine medical waste bins)
  7. Nutrition
    1. If this is a person originating from the characteristic part of Africa where Ebola is endemic, premorbid malnutrition needs to be considered.
    2. Thus, refeeding syndrome needs to be watched for
    3. No specific recommendations can be made other than to watch for haemorrhagic complications of NGT insertion
  8. Correction of coagulopathy
    1. If substantial bleeding has occurred, the DIC must be supported with blood products. Tranexamic acid may play a role.

Specific therapies

  • Many of these therapies have been approved by the American FDA only because of the ongoing emergency situation. Some are barely in Phase I trials.
  • Several experimental therapies exist:
    • Brincidofivir (in vitro activity)
    • ZMapp monoclonal antibody cocktail
    • TKM-Ebola an interfering RNA molecule used to block expression of two viral replication genes
    • Convalescent whole blood
    • To date, none are exactly evidence-based.

References

Question 1 - 2016, Paper 1

Discuss the role of systemic antibiotic therapy in patients with severe acute pancreatitis

College Answer

Background / Rationale:

Systemic antibiotics in severe acute pancreatitis (SAP) have a potential role in three areas:

  • Infected pancreatic necrosis 
    • Necrotising pancreatitis develops in about 15% and approx. half of these become infected with increased mortality
    • Majority of pancreatic infections are from gut derived organisms and may be polymicrobial. Common organisms include E coli, Klebsiella species, Enterobacter species, Proteus, Pseudomonas aeruginosa, Bacteroides species and Enterococcus
    • Should be suspected in patients with pancreatic necrosis who fail to improve after 7-10 days of hospitalisation
  • Extra-pancreatic infections
    • Common (up to 20% of patients with SAP), e.g. bloodstream, pneumonia, UTI and associated with increased mortality
  • Prophylaxis
    • Theoretically antibiotics could prevent or decrease infection rates and decrease mortality
    • Use of prophylactic antibiotics in SAP is controversial

Disadvantages:

  • Development of resistant strains of bacteria and selection of fungal infections.

Evidence and Practice Guidelines:

  • Infected pancreatic necrosis
    • In suspected infected necrosis or pancreatic abscess, use antibiotics in association with minimally invasive drainage or open surgery.
    • Therapeutic guidelines recommend Tazocin OR if allergic to penicillin’s 3rd generation cephalosporin and metronidazole OR meropenem OR quinolone and metronidazole.
  • Extra-pancreatic infections
    • Antibiotics should be prescribed as clinically indicated.
  • Use of prophylactic antibiotics in pancreatitis
    • Controversial
    • Cochrane meta-analysis in 2010:
      • Trends towards increased survival and reduced rates of infections of pancreatic necrosis but not statistically significant
      • Trend towards less incidence of non-pancreatic infections
      • Of subgroup analysis regarding antibiotic therapy, only imipenem had statistically decreased infection rates of necrotic pancreas but no mortality benefit
      • Issues with under powering of studies, not limited to necrotic pancreatitis and heterogeneity of patients
      • Prophylactic antibiotics in established necrosis of acute pancreatitis not recommended.

Summary statement:

  • In suspected infected pancreatic necrosis treat with surgical/percutaneous/endoscopic drainage and broad-spectrum antibiotics
  • Routine use of prophylactic antibiotics with sterile necrosis to prevent infected necrosis is not recommended
  • Antibiotics as indicated for extra-pancreatic infections
  • Routine use of prophylactic antibiotics in severe acute pancreatitis is not recommended

Discussion

The correct answer to this question is "role? there is none". However, it is a ten-mark SAQ. So, here is an example of how to say "none" using approximately extra 400 words.

Potential uses of antibiotics in pancreatitis

  • Prophylaxis to prevent infection of the necrotic pancreas
  • Prophylaxis to prevent infection of the pancreatic pseudocyst
  • Treatment of infected pancreatic necrosis
  • Coincidental use of these antibiotics to treat an unrelated extrapancreatic infection

Coincidental treatment of extrapancreatic infection

  • Brown et al (2014): incidence of  infectious complications = 32%
  • Commonest infections were respiratory (9.2%) and bacteraemia (8.4%).
  • Half of bacterial cultures of pancreatic necrosis are of non-enteric origin.
  • Ergo, pancreatic nnecrosis easily gets infected from extrapancreatic sources.
  • However, this seems to have no effect on severity or mortality of the pancreatitis.

Treatment of infected pancreatic necrosis

  • "Pancreatic necrosis" is non-enhancing areas of the pancreas
  • 8-12% of patients develop infected necrosis (Mike Larvin, 2008)
  • Infection of the pancreatic necrosis tends to be confirmed late (19-21 days following onset).
  • Survivors from early organ system failure may still die if pancreatic necrosis later becomes infected.
  • Organ system failure tends to be worse and mortality tends to be higher.
  • Confirmation of the diagnosis is invasive, i.e. by samples and culture.
  • CT-guided aspiration has pros (Banks, 2005) and cons (Pappas, 2005).
  • If the patient is haemodynamically unstable and the infected pancreas is held responsible, CT-guided or gastroscopic drainage offers both a diagnosis (confirming infection) and souirce control.
  • If infection is confirmed by Gram stain, the best choice of antibiotics is probably meropenem.

Arguments for the use of prophylactic antibiotics in severe pancreatitis

  • Pancreatic necrosis promotes bacterial growth
  • Surgical source control is difficult or impossible
  • Diagnosis of sepsis is difficult (in the presense of SIRS)
  • Sepsis is a major cause of death in severe pancreatitis
  • Non-pancreatic infection plays a major role in this mortality.
  • Thus, prophylactic antibiotics should reduce mortality, even if by treating extrapancreatic infections
  • This practice is common: Baltatziz et al (2016) found antibiotic prophylaxis was used in 44-88% of the surveyed units.

Counterarguments to the routine use of prophylactic of antibiotics

  • Penetration into the collection will be poor.
  • Treatment of extrapancreatic infections with panreas-penetrating antibiotics results in overuse of meropenem.
  • The use of antibiotics will promote the overgrowth of resistant organisms, and select for species which will subsequently be more difficult to eradicate. The college answer mentions fungus as one of the options.

Evidence

  • Jafri et al (2009):no improvement in mortality, risk of pancreatic pseudocyst infection or need for surgical intervention.- Hoqwever, the risk of extrapancreatic infection was reduced by 15%, NNT =7.
  • Parent et al (2016): meta-analysis; only low quality studies show any treatment effect.
  • The Cochrane analysis referred to by the college is Villatoro et al (2010), whose conclusion was also "no benefit"

Antibiotic choice (if you felt compelled to give them)

  • All antibiotics penetrate the necrotic tissue, but most end up not achieving MIC (Bassi et al, 1994).
  • Drugs which achieve a high concentration in pancreatic tissue :
    • Imipenem (and thus also meropenem)
    • Metronidazole
    • Fluoroquinolones (specifically, pefloxacin)
  • Drugs which are known to penetrate poorly:
    • Aminoglycosides
    • Beta-lactams

Guidelines and "own practice"

  • This practice is not supported by the American College of Gastroenterology guidelines (2013)
  • Antibiotics should not be routinely given to patients with severe acute pancreatitis
  • Clinical evidence of sepsis (including sepsis of other origin, eg. urinary or pulmonary) should be promptly treated with appropriate antibiotics (not pancreas-specific antibiotics)
  • It may be possible to sample the collection by CT-guided aspiration; if the Gram-stain is positive this will be the deciding factor

References

Maheshwari, Rahul, and Ram M. Subramanian. "Severe Acute Pancreatitis and Necrotizing Pancreatitis." Critical care clinics 32.2 (2016): 279-290.

Baltatzis, Minas, et al. "Antibiotic use in acute pancreatitis: Global overview of compliance with international guidelines." Pancreatology (2016).

Parent, Brodie, and E. Patchen Dellinger. "Antibiotic Prophylaxis for Acute Necrotizing Pancreatitis." Difficult Decisions in Hepatobiliary and Pancreatic Surgery. Springer International Publishing, 2016. 433-449.

Tenner, Scott, et al. "American College of Gastroenterology guideline: management of acute pancreatitis." The American journal of gastroenterology 108.9 (2013): 1400-1415.

Jiang, Kun, et al. "Present and future of prophylactic antibiotics for severe acute pancreatitis." World J Gastroenterol 18.3 (2012): 279-84.

Jafri, Nadim S., et al. "Antibiotic prophylaxis is not protective in severe acute pancreatitis: a systematic review and meta-analysis." The American Journal of Surgery 197.6 (2009): 806-813.

Bassi, C., et al. "Behavior of antibiotics during human necrotizing pancreatitis." Antimicrobial agents and chemotherapy 38.4 (1994): 830-836.

Brown, Lisa A., et al. "A systematic review of the extra-pancreatic infectious complications in acute pancreatitis." Pancreatology 14.6 (2014): 436-443.

Larvin, Mike. "Management of infected pancreatic necrosis." Current gastroenterology reports 10.2 (2008): 107-114.

Banks, Peter A. "Pro: computerized tomographic fine needle aspiration (CT-FNA) is valuable in the management of infected pancreatic necrosis." The American journal of gastroenterology 100.11 (2005): 2371.

Pappas, Theodore N. "Con: computerized tomographic aspiration of infected pancreatic necrosis: the opinion against its routine use." The American journal of gastroenterology 100.11 (2005): 2373.

Villatoro, Eduardo, Mubashir Mulla, and Mike Larvin. "Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis." The Cochrane Library (2010).

Question 5 - 2016, Paper 1

Critically evaluate the role of corticosteroids in the management of severe community-acquired pneumonia.

College Answer

Rationale / Indications

Conventional & generally accepted indications include:

  • Pneumonia complicating exacerbated COPD
  • PJP infection with lung infiltrates (data from HIV population, and by extrapolation to other immunosuppressed groups)
  • Patients who are on long term corticosteroids or otherwise have adrenal suppression
  • (With less certainty) those with shock states and vasoplegia as a catecholamine sparing strategy

Outside of these groups, in a general population with CAP:

  • The basis for use is as an adjunctive therapy in hospitalised patients to reduce inflammation and improve morbidity or mortality.
  • Some patients with CAP fail to resolve, and progress to cryptogenic organising pneumonia, (COP) with case series showing response to corticosteroids (and relapse on early cessation 
  • Conflicting evidence in the fibro-proliferative phase of ARDS
  • Now several studies randomising patients to early use in uncomplicated CAP

Potential adverse effects

  • Super-added infection
  • Muscle weakness / Proximal myopathy / Critical illness polyneuromyopathy
  • Difficulty weaning from ventilatory support

Evidence

A 2015 Meta-analyses (Siemieniuk et al, 2015):

  •   3% decrease in all-cause mortality, 
  •   5% decrease rate of mechanical ventilation
  •  Reduced hospital length of stay by 1 day.
  •  Critique of metanalysis
    • Trials included in metanalyses have been small
    • had high heterogeneity
    • Insufficient power to analyse mortality.
    • Many exclusions
      •  (e.g. immunocompromised patients at risk of superinfection, pregnant women, GI bleeding within 3 months as well as patients with neuropsychiatric conditions prone to psychotic side effects of steroids)
    • Small overall effect

A recent RCT (Blum et al, Lancet 2015, 392 pt per group) showed a shorter time to reach a composite endpoint of ‘clinical stability’ with Prednisolone 50mg daily for 7 days.  

Another RCT (Torres et al, JAMA 2015, 60 pt per group) showed that Methylprednisolone 0.5mg/kg 12h for 5 days reduced risk of “treatment failure” compared with placebo in patients with severe CAP and high CRP levels

Practical (Translational) Issues

  • No clear data on exact steroid and regimen
    • There is no definitive data on what type of steroid to give and whether to give continuously or in a tapering regimen and for how long.
    •  In the idiopathic pneumonia group (COP) steroid tapering can be associated with abrupt relapse
  • Pathogen dependent response to steroids
    • Pneumonia due to pathogens like the influenza virus and aspergillus may be associated with worse outcomes with steroid use, PCP better
  • Studies in progress that may help
    • The ESCAPE study by the Department of Veterans affairs is assessing the role of steroids in CAP with either placebo, methyl prednisolone 40 mg per day or 20 mg per day for 7 days followed by tapering over 13 days on all cause 60 day mortality.

Summary statement (For example)

  • Subgroups where steroids would be conventional therapy (COPD, PJP)
  • Not yet accepted therapy
  • Treatment effect small
  • But no evidence of adverse effect and demonstrated safety.
  • Listed as practice changing update in Up-to-Date
  • Should ideally be a conjoint decision with clinician responsible for post ICU management

Additional comments:

Candidates were lacking in knowledge relating to the evidence for steroids in severe CAP. The detail in above template was not required for a pass mark. Satisfactory answer for a pass mark was expected to include:

  • Accepted indications for steroids in CAP
  • Some reference to rationale for use in other groups with CAP
  • Potential adverse effects
  • Some reference to evidence

Discussion

Rationale  for the use of steroids

  • Much of the organ system effects of pneumonia may be related to the inflammatory reaction
  • Anti-inflammatory drugs like steroids may reduce the release of cytokines, thereby dampening the SIRS response
  • Modulation of the pro-inflammatory response should lead to a more rapid resolution of clinical features
  • Similar rationale has been successfully applied to other infectious illnesses, for instance in the use of dexamethasone for pneumococcal meningitis
  • Other pulmonary infections benefit from corticosteroids:
    • COPD complicated by pneumonia: patients with pneumonia may have underlying COPD or asthma which may be unrecognised in the community, and which will improve with steroids as a "collateral benefit".
    • Pneumocystis jirovecii pneumonia (PJP): even in non-HIV patients, around 30mg/d of prednisone seems to reduce ICU stay and duration of mechanical ventilation (Pareja et al, 1998).
    • Cryptogenic organising pneumonia (1mg/kg/day of prednisolone, according to a multinational guideline from 2008)
    • Fibro-proliferative phase of ARDS - but the evidence is not convincing; there may be some sort of effect if the steroids are given between 7 and 1 days following onset, accroding to Steinberg et al (2006)
    • Acute eosinophilic pneumonia ( Davis et al, 1986)
  • Other extrapulmonary pathology will benefit from steroids:

Arguments against the use of steroids

  • The systemic inflammatory response to pneumonia has constructive facets, as it mobilises the immune retaliation against the pathogens
  • The metabolic side effects (eg. hyperglycaemia, hypernatremia, adrenal suppression) may be a disadvantage to severely septic patients
  • The possibility of exacerbating muscle weakness may be a disadvantage with using corticosteroids in mechanically ventilated patients
  • Some forms of pneumonia are known to get worse with steroids, eg. Influenza where mortality is doubled (Rodrigo et al, 2015 ) and Aspergillus  (Parody et al, 2009 - although this was a study of bone marrow transplant patients)

Evidence regarding use of steroids

  • Torres et al : compared methylprednisolone (n = 61) or placebo (n = 59) for 5 days.
    • Less treatment failure with steroids (13% vs 31%)
    • No difference in mortality
    • Major criticism:
      • The placebo group has more intubated patients, and more septic shock
      • Only ~ 20-25% of the patients received proper dual antibiotic therapy
      • Only 57% of the patients had a CRP above 15
      • The study recruited over 8 years, an average of 5 patients per center per year.
      • The primary treatment difference between groups was radiographic progression between days 3 and 5, which may represent something completely clinically irrelevant.
  • Blum et al: 785 patients randomised to 50mg prednisolone or placebo
    • "Median time to clinical stability was shorter in the prednisone group" - 3.0 days vs. 4.4
    • Not specifically ICU patients - all CAP admissions were enrolled
    • "Clinical stability" was a composite endpoint
  • The college answer has quoted a 2015 meta-analysis by Siemieniuk et al, who (including the above data) suggested that the use of corticosteroids may reduce
    • mortality by 3%
    • need for mechanical ventilation by 5%
    • hospital stay by 1 day

References

Metlay, Joshua P., Wishwa N. Kapoor, and Michael J. Fine. quot;Does this patient have community-acquired pneumonia?: Diagnosing pneumonia by history and physical examination." Jama 278.17 (1997): 1440-1445.

Mandell, Lionel A., et al. "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults." Clinical infectious diseases 44.Supplement 2 (2007): S27-S72.

Blum, Claudine Angela, et al. "Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial." The Lancet 385.9977 (2015): 1511-1518.

Lim, W. S., et al. "British Thoracic Society community acquired pneumonia guideline and the NICE pneumonia guideline: how they fit together." Thorax (2015): thoraxjnl-2015.

Lim, Wei Shen, et al. "BTS guidelines for the management of community acquired pneumonia in adults: update 2009." Thorax 64.Suppl 3 (2009): iii1-iii55.

Eccles, Sinan, et al. "Diagnosis and management of community and hospital acquired pneumonia in adults: summary of NICE guidance." BMJ 349 (2014): g6722.

The actual NICE recommendations (2014)

Lim, W. S., et al. "Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study." Thorax 58.5 (2003): 377-382.

Levin, Kenneth P., et al. "Arterial Blood Gas and Pulse Oximetry in Initial Management of Patients with Community‐acquired Pneumonia." Journal of general internal medicine 16.9 (2001): 590-598.

Venkatesan, P., and J. T. Macfarlane. "Role of pneumococcal antigen in the diagnosis of pneumococcal pneumonia." Thorax 47.5 (1992): 329-331.

Muder, Robert R., and L. Yu Victor. "Infection due to Legionella species other than L. pneumophila." Clinical infectious diseases 35.8 (2002): 990-998.

Johansson, Niclas, et al. "Procalcitonin levels in community-acquired pneumonia-correlation with aetiology and severity." Scandinavian journal of infectious diseases 46.11 (2014): 787-791.

Annane, Djillali. "Corticosteroids and pneumonia: time to change practice." The Lancet 385.9977 (2015): 1484-1485.

Siemieniuk, Reed AC, et al. "Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis." Annals of internal medicine (2015).

Torres, Antoni, et al. "Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial." JAMA 313.7 (2015): 677-686.

Blum, Claudine Angela, et al. "Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial." The Lancet 385.9977 (2015): 1511-1518.

Wunderink, Richard G. "Corticosteroids for Severe Community-Acquired Pneumonia: Not for Everyone." JAMA 313.7 (2015): 673-674.

Bartlett, John G., et al. "Practice guidelines for the management of community-acquired pneumonia in adults." Clinical infectious diseases 31.2 (2000): 347-382.

Christ-Crain, Mirjam, et al. "Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial." American journal of respiratory and critical care medicine 174.1 (2006): 84-93.

Wunderink, Richard G., and Grant W. Waterer. "Community-acquired pneumonia." New England Journal of Medicine 370.6 (2014): 543-551.

Li, Meiling, et al. "Risk factors for slowly resolving pneumonia in the intensive care unit." Journal of Microbiology, Immunology and Infection (2014).

Sialer, Salvador, Adamantia Liapikou, and Antoni Torres. "What is the best approach to the nonresponding patient with community-acquired pneumonia?." Infectious disease clinics of North America 27.1 (2013): 189-203.

COJOCARU, Manole, et al.  "Pulmonary manifestations of systemic autoimmune diseases." Maedica 6.3 (2011): 224.

Kuru, Tünay, and Joseph P. Lynch. "Nonresolving or slowly resolving pneumonia." Clinics in chest medicine 20.3 (1999): 623-651.

Kyprianou, Andreas, et al. "The challenge of non resolving pneumonia." Postgrad Med 113.1 (2003): 79-92.

Rome, Lauren, Ganesan Murali, and Michael Lippmann. "Nonresolving pneumonia and mimics of pneumonia." Medical clinics of North America 85.6 (2001): 1511-1530.

Menéndez, Rosario, and A. Torres. "Evaluation of non-resolving and progressive pneumonia." Intensive Care Medicine. Springer New York, 2003. 175-187.

Oster, Gerry, et al. "Initial treatment failure in non-ICU community-acquired pneumonia: risk factors and association with length of stay, total hospital charges, and mortality." Journal of medical economics 16.6 (2013): 809-819.

Pareja, Jaime G., Robert Garland, and Henry Koziel. "Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia." CHEST Journal 113.5 (1998): 1215-1224.

Rodrigo, Chamira, et al. "Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis." Journal of Infectious Diseases 212.2 (2015): 183-194.

Parody, Rocio, et al. "Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or after hematopoietic stem cell transplantation: single‐center analysis and validation of the seattle, french, and strasbourg prognostic indexes." American journal of hematology 84.9 (2009): 571-578.

Bradley, B., et al. "Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society (vol 63, Suppl V, pg v1, 2008)." Thorax 63.11 (2008): 1029-1029.

Davis, William B., Henry E. Wilson, and Robert L. Wall. "Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious etiology." CHEST Journal 90.1 (1986): 7-10.

Steinberg, Kenneth P., et al. "Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome." New England Journal of Medicine 354.16 (2006): 1671-1684.

Question 12 - 2016, Paper 1

Three patients with diarrhoea, positive for Clostridium difficile, have been identified in your ICU.

Describe your approach to specific patient treatment, and infection control and prevention strategies for this problem.

College Answer

Treatment:

  • Immediate goal is to alleviate the active symptoms of diarrhoea and colitis.
  • Ultimate goal is restoration of normal gut flora.
  • Discontinue all unnecessary antibiotics.
  • Fluid and electrolyte replacement as indicated to compensate for GI losses
  • Antibiotic therapy
    • First line agent is PO metronidazole especially in milder disease.
    • Second Line is PO vancomycin for patients with more severe disease, or who are intolerant or do not respond to metronidazole. There has been recent debate that vancomycin should possibly be first line therapy, due to increasing treatment failure rates with metronidazole not seen with vancomycin. Cost and increasing nosocomial vancomycin resistance are other issues within this debate.
  • Assess for complications of colitis – severe sepsis or toxic megacolon
  • Faecal transplant should be considered to restore normal gut flora

Infection Control and Prevention Strategies:

  • The ultimate goal in combating disease is prevention/eradication.
  • Specific infection control measures, and thus a Unit Policy, are very important MUST be instituted, championed and audited.
    • Isolation of CDI patients in single rooms or cohorted together o Hand Hygiene – The “5 Moments of Hand Hygiene”.
      • Soap and water
      • Not alcohol-based hand rubs (don’t kill the spores) 
    • Contact Precautions.
      • Gown and glove.
    • Environmental cleaning and disinfection.
      • Ammonium-based disinfectants are not sporicidal
      • Solutions must include unbuffered hypochlorite (bleach), which is sporicidal. In other words, chlorine-based solutions.
    • Restriction of antimicrobial use.
  • Education, via a widespread campaign, and audit, of staff and compliance will be important.
  • Consider the introduction of a formal CDI Team which would help educate, raise awareness, implement and audit your policy
  • Consider the introduction of CDI Bundles similar to other hospitals 
    • Education Bundle
    • Prevention Bundle
    • Treatment Bundle
  • Introduction of an Antibiotic Stewardship Program would help monitor appropriate antibiotic use and cessation etc.
  • Consider restricting the use of gastric acid suppressive agents. Multiple large trials now support the association between CDI and PPI use. One would have to weigh up the riskbenefit on a patient-to-patient basis though.
  • Finally there are ongoing trials looking at the use of probiotics for the prevention of CDI. Their role is unclear at present.

Discussion

Approach to specific patient treatment:

Mild-moderate C.difficile infection:

  • Treat empirically in the absence of positive results, if the pre-test suspicion is strong.
  • Stop the inciting antibiotics
  • Give oral metronidazole for 10 days
    • Change metronidazole to vancomycin if there is no response in 5-7 days
  • For severe infection, just give oral vancomycin straight away(125mg qid for 10 days)
  • Vancomycin enemas are an option
  • Avoid anti-diarrhoea medications

Severe and complicated C.difficile infection:

  • CT of the abdomen is indicated
  • Oral vacomycin PLUS intravenous metronidazole are indicated
  • If there is significant abdominal distension, the vancomycin should be given as an enema

Recurrent C.difficile infection:

  • First recurrence: treat in the same way as the first episode
  • Second recurrence: change to vancomycin
  • Third recurrence: consider a faecal microbiota transplant

When to consider surgery:

  • Hypotension requiring vasopressor therapy
  • Clinical signs of sepsis and organ dysfunction
  • WCC in excess of 50
  • Lactate in excess of 5mmol/L
  • Failure to improve on medical therapy after 5 days

Supportive management:

  • Manage the diarrhoea
    • This includes stool management systems, rectal tubes etc.
  • Manage the symptoms of colitis
    • Adequate pain relief
  • Restore fluid and electrolyte imbalance 

Infection control:

Active surveillance cultures

  • Identifies the "reservoir" for spread
  • Allows precautions to be cost-effectively focused on the reservoir.
  • The health care workers themselves may become colonised reservoirs.
  • Performed on all patients, on admission, and then peridoically (eg. weekly).
  • In facilities found to have a high prevalence on initial sampling, a facility-wide culture survey is indicated.

Contact precautions

  • Hand hygiene
    • Soap and water for visibly contaminated hands
    • Alcohol-based rub for routine pre-and-post-contact hygiene
    • Monitoring of compliance should be performed
  • Disposable gloves
  • Disposable gowns
  • Patients colonised by C.difficile may be cohorted together.
  • Contaminated areas should be identified by obvious cautonary signs

Eradication of existing colonies

  • Effective treatment of existing cases
  • Decontamination of colonised health care workers
  • Environmental disinfection
  • Routine disinfection of equipment between patient contacts
  • Wherever possible, individualised equipment for every patient

Prevention of C.difficile outbreaks

Barrier methods:

A change in prescribing culture:

Organisation-level changes to improve infection control

Organisation

  • Infection control specialty team, composed of ICU specialists, infectious diseases specialists, senior nursing staff, laboratory staff and administration staff.
  • Allocated resources to MRO surveillance, compliance monitoring and education
  • "Champions" - staff allocated to promote the existing policies and monitor adherence

Education

  • "Widespread campaign", as recommended by the SAQ model answer
  • Awareness-rasing posters
  • Lunchtime meetings
  • Promulgated reading material
  • Education bundle as a part of mandatory employee training

Data collection and audit

  • Data collection and MRO colonisation record
    • Records of MRO results allow colonised patients to be identified early
  • Regular review of collected information, resistance and transmission patterns
  • Regular audit of the efficacy of implemented strategies
  • Regular comparison of policies to those of peer hospitals
  • Regular reevaluation and amendment of infection control policies

References

Oh's Manual: Chapter 70  (pp. 724)  Nosocomial  infections by James  Hatcher  and  Rishi  H-P  Dhillon - totally useless; there is literally just one paragraph devoted to it here.

Surawicz, Christina M., et al. "Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections." The American journal of gastroenterology 108.4 (2013): 478-498.

Lawrence, Steven J., et al. "Clostridium difficile in the intensive care unit: epidemiology, costs, and colonization pressure." Infection Control 28.02 (2007): 123-130.

Deshpande, Abhishek, et al. "Association between proton pump inhibitor therapy and Clostridium difficile infection in a meta-analysis." Clinical Gastroenterology and Hepatology 10.3 (2012): 225-233.

Question 25 - 2016, Paper 1

A 38-year-old male with type 1 diabetes mellitus presents with two days of severe thigh pain. You are called to see him because of hypotension. On examination he is drowsy, BP 80/60 mmHg, HR 140 beats/min and temperature of 40.2°C. There is gross swelling on the medial aspect of his right thigh with obvious cellulitis and visible central necrosis.

Describe the management priorities in the first 24 hours and briefly justify your responses.

College Answer

Resuscitation

  • High-flow oxygen,
  • Support BP with fluids +/- vasopressors 
  • Measure & fix BSL
  • Other organ support as indicated e.g. CRRT

Antibiotics

  • The presentation is that of necrotising fasciitis. T1DM a significant risk factor. 
  • Until microbial aetiology and sensitivities are known, broad-spectrum antibiotics should be administered that cover the most common aetiologies of type I infection (mixed infections with anaerobes such as Bacteroides or Peptostreptococcus with a facultative anaerobe such as Enterobacteriaceae [Escherichia coli, Enterobacter, Klebsiella, Proteus], MRSA, or non-group A streptococcus), and also type II (group A streptococcus) infection.
  • Appropriate initial antibiotic regime is Vancomycin / Meropenem / Clindamycin with Pip-Tazo OR Ceftriaxone and Metronidazole OR Ciprofloxacin and Metronidazole as alternatives to Meropenem. Clindamycin is bacteriostatic, has synergistic effect with Vancomycin, inhibits bacterial toxin synthesis by GAS and has a post-antibiotic effect.
  • When further micro information is available, antibiotic therapy should be narrowed to appropriately target the causative organism(s)

Surgical Referral and post-operative management

  • Requires urgent debridement, with removal of dead/infected tissue back to bleeding tissue
  • Takes priority over other therapies including hyperbaric O2
  • Expectation of major blood loss and massive transfusion
  • Likely to be highly unstable post-operatively with major support requirement

Routine ICU care of patient with severe sepsis

Specific Therapies

  • Intravenous Immunoglobulin
    • In vitro neutralisation of streptococcal super-antigens and clostridial toxins
    • Streptococcal toxic shock syndrome (with or without nec. fasc.) listed as “emerging” indication for IVIG by ARCBS, and available for use 
  • Hyperbaric O2
    • Observational studies only
    • Conflicting results with both reduction and increases in mortality seen cf.
    • Observational controls
    • Possible reduction in need for debridement Usually bd to tds dives of 90 min at 3 atm.
    • Severe organ failure may limit logistics

Discussion

This question is identical to Question 24 from the first paper of 2011.

The discussion section from that previous question is reproduced below, to simplify revision

A boringly algorithmic answer to this question would look something like this:

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
  • Airway
    • Assess the need for intubation in the context of a potentially decreased level of consciousness
  • Breathing/ventilation
    • Assess efficacy of spontaneous breathing, and the need for mechanical ventilation.
    • Administer supplemental oxygen at a high flow- it may not be particularly helpful at atmospheric pressure, but hyperoxia does seem to retard the growth of anaerobic organisms.
  • Circulatory support
    • Administer a 20-30ml/kg fluid bolus
    • Secure central venous access and commence vasopressors- start with noradrenaline
    • Aim for a MAP over 65mmHg
  • Specific investigations
    • A full panel of blood tests including blood cultures, CK and an ABG
    • A CT scan of the lower limbs and pelvis, as a prelude to surgical intervention
  • Supportive management
    • Continue fluid resuscitation and vasopressors in pursuit of haemodynamic goals
    • Ensure normoglycaemia and normoxia
    • Correct acid base balance
    • Attend to organ system failure - consider early dialysis if there is rhabdomyolysis
  • Monitoring
    • Admit to ICU
    • Commence continuous blood pressure monitoring via arterial line
    • Assess for ketosis/ketoacidosis - this is a Type 1 diabetic, and this is exactly the sort of trigger that would produce a DKA.
  • Specific management
    • Commence broad spectrum antibiotics. In this case, the choice is clindamycin plus anycillin or anypenem. The addition of clindamycin is well supported - particularly with Group A streptococci, where it inhibits the bacterial synthesis of endotoxin.
    • Immediately contact surgical services for source control - debridement is the single most useful management strategy; everything else is fairly cosmetic in terms of decreasing mortality.
    • Consider IV immunoglobulin (i.e. if this is a streptococcal toxic shock syndrome - which manifests as massive cardiovascular collapse and organ system failure very early in the infective process). The use of IVIG in this setting has been well studied, and though those European investigators didn't reach statistical significance in their primary endpoit (mortality), they did note a significant decrease in organ failure scores in the IVIG group.
    • Consider an early referral to a specialist centre where hyperbaric oxygen therapy can be carried out. This management strategy historically did not seem to reduce either mortality or the number of debridements. However, recent data suggests that they were doing it wrong in the 1990s, and modern hyperbaric oxygen therapy seems to be associated with a 50% reduction in mortality (from 9.4% to 4.5%).

The key points to remember are:

  • Source control
  • Clindamycin
  • IV immunoglobulin
  • Hyperbaric oxygen

References

Marron, Conor D., et al. "Perforated carcinoma of the caecum presenting as necrotising fasciitis of the abdominal wall, the key to early diagnosis and management." BMC surgery 6.1 (2006): 11.

Casali, Robert E., et al. "Postoperative necrotizing fasciitis of the abdominal wall." The American Journal of Surgery 140.6 (1980): 787-790.

Rea, William J., and Walter J. Wyrick Jr. "Necrotizing fasciitis." Annals of surgery 172.6 (1970): 957.

Samel, S., et al. "Clostridial gas gangrene of the abdominal wall after laparoscopic cholecystectomy." Journal of Laparoendoscopic & Advanced Surgical Techniques 7.4 (1997): 245-247.

McSwain, Barton, John L. Sawyers, and MARION R. Lawler Jr. "Clostridial infections of the abdominal wall: review of 10 cases." Annals of surgery 163.6 (1966): 859.

Hasham, Saiidy, et al. "Necrotising fasciitis.Bmj 330.7495 (2005): 830-833.

Mulla, Zuber D. "Treatment options in the management of necrotising fasciitis caused by Group A Streptococcus." Expert opinion on pharmacotherapy 5.8 (2004): 1695-1700.

Darenberg, Jessica, et al. "Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial." Clinical infectious diseases 37.3 (2003): 333-340.

Brown, D. Ross, et al. "A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy." The American journal of surgery 167.5 (1994): 485-489.

Soh, Chai R., et al. "Hyperbaric oxygen therapy in necrotising soft tissue infections: a study of patients in the United States Nationwide Inpatient Sample." Intensive care medicine 38.7 (2012): 1143-1151.

Majeski, James A., and J. Wesley Alexander. "Early diagnosis, nutritional support, and immediate extensive debridement improve survival in necrotizing fasciitis." The American Journal of Surgery 145.6 (1983): 784-787.

Bilton, Bradley D., et al. "Aggressive surgical management of necrotizing fasciitis serves to decrease mortality: a retrospective study." The American Surgeon 64.5 (1998): 397-400.

Wong, Chin-Ho, et al. "Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality." The Journal of Bone & Joint Surgery 85.8 (2003): 1454-1460.

Norrby-Teglund, Anna, et al. "Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach." Scandinavian journal of infectious diseases 37.3 (2005): 166-172.

Carapetis, Jonathan R., et al. "Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group A streptococcal infections." Clinical Infectious Diseases (2014): ciu304.

Levett, Denny, Michael H. Bennett, and Ian Millar. "Adjunctive hyperbaric oxygen for necrotizing fasciitis." The Cochrane Library (2015).

Eke, Ndubuisi. "Fournier's gangrene: a review of 1726 cases." British Journal of Surgery 87.6 (2000): 718-728.

Question 30.1 - 2016, Paper 1

A 52-year-old male diabetic presents with a week-long history of fever, headache, confusion, facial nerve palsy with pain and a black, purulent nasal discharge. He is referred to ICU for his deteriorating level of consciousness.

Give the most likely diagnosis.   (20% marks)

List four predisposing factors.    (10% marks)

List the specific management of this condition.         (40% marks)

College Answer

a) 

  • Rhinocerebral mucormycosis or fungal sinus infection with cerebral spread.

b)                                                                   

  • HIV/AIDs Diabetes
  • Cancer – lymphoma
  • Renal failure
  • Organ transplantation
  • Long term steroid or immunosuppressive therapy
  • Cirrhosis
  • Deferoxamine therapy
  • Iron overload
  • Burns

c)

  • Investigation with MRI or CT to determine the extent of the spread. 
  • Blood culture and biopsy to obtain tissue for fungal culture +/- Surgical debridement if amenable
  • Amphotericin B
  • Possibly hyperbaric oxygen therapy.

Discussion

a) "Give the most likely diagnosis" for 20% of the mark really only gives enough time for two words. Fortunately, you only need one: mucor. Not much else presents as encephalitis/meningitis "and a black, purulent nasal discharge".

Having said this, "mucor mimics" do exist. Firstly, it could be another Zygomycete (Branscomb, 2002, lists Rhizopus, Absidia,  Saksenaea and Cunninghamella). Secondly, it could be a bacterial infection causing necrotising fasciitis,  or it could be the black eschar of an airway burn, or the patient might have recently had a nasogastric tube which had produced a nasty intranasal pressure area with necrosis. But these are not especially plausible. 

b) List four predisposing factors is worth only 10% of the marks, but these are reasonably easy to earn. The college have already given you one, by volunteering a history of diabetes. Mucor likes to extend along blood vessels, and even more so when the vessels are full of sugar. In total, Branscomb (2002) lists the following nine predisposing factors:

  • Acidosis
  • Uncontrolled diabetes mellitus
  • Leukemia
  • Lymphoma
  • AIDS
  • Severe malnourishment
  • Severe burns
  • Cytotoxic therapy
  • Immune suppression from corticosteroid use

In addition to this, the college also add

  • Renal failure
  • Cirrhosis
  • Deferoxamine therapy
  • Iron overload

c), "List the specific management of this condition" calls for some additional thinking, as it is worth 40%. Interestingly, the college had listed imaging and cultures in this section, even though those (undoubtedly important) elements are investigations which don't themselves manage anything. Still, if one is expected to list the investigations, they would be:

  • Investigations of the underlying predisposing factors
    • HbA1c
    • FBC to look for neutropenia
    • HIV test
  • Imaging and endoscopy:
    • MRI or CT  of the head and sinuses
    • CT venogram to look for involvement of the cavernous sinus
    • Nasendoscopy to look for necrotic tissue from which a sample can be taken
  • Microbiology
    • Tissue culture is gold standard. Mucor in blood is rather difficult to find as - even if it is in there - it tends to be outcompeted by bacteria on standard blood culture media, and special cultures are required (Sabouraud’s dextrose agar or brain-heart infusion agar).
    • The most sensitive investigation would be histological section of a sizeable chunk, as the hyphae are aseptate and rather fragile (i.e. they may not survive a scraping sample). Histology will demonstrate characteristic fungal elements and arterial invasion with necrosis.

Craig et al (2019) give an excellent overview of management options, classifying them in the following manner: 

  • Surgical
    • Extensive debridement, "until bleeding is seen"
    • This typically results in disfigurement
    • The patient needs to be agreeable to that possibility, particularly where the orbit is involved 
  • Antifungal therapy
  • Reversal of predisposing condition
    • Control of the diabetes
    • Transfusion of ranulocytes or GM-CSF if neutropenic
    • Antiretroviral therapy if AIDS

References

Craig, John R. "Updates in management of acute invasive fungal rhinosinusitis." Current opinion in otolaryngology & head and neck surgery 27.1 (2019): 29-36.

Branscomb, Robert. "An overview of mucormycosis." Laboratory Medicine 33.6 (2002): 453-455.

Tragiannidis, A., and A. H. Groll. "Hyperbaric oxygen therapy and other adjunctive treatments for zygomycosis." Clinical Microbiology and Infection 15 (2009): 82-86.

Question 30.2 - 2016, Paper 1

65-year-old female with rheumatoid arthritis has been admitted to ICU with an acute confusional state following a two-day history of fever and headache.

Investigations reveal:

Blood culture:         Gram-positive bacilli at 24 hours.

a) Give the most likely causative organism.         (10% marks)

b) Give the specific therapy for this condition.          (10% marks)

c) List three risk factors for this condition.           (10% marks)

College Answer

a)

Diagnosis: Listeria monocytogenes                                                                                                                      

b)

Treatment:                                                                                                                                             

Benzylpenicillin 2.4 g IV, 4-hourly    

Or

Trimethoprim+sulfamethoxazole 160+800 mg IV, 6-hourly (in case of penicillin allergy)

 c) Risk Factors:       

Extremes of age

Pregnancy

Immunosuppression

Malignancy

Discussion

a)

The question is designed poorly. Gram-positive rods - in which bottle? Cultured how? An excellent 2001 article by Von Graevenitz  allows us to consider the following as realistic differentials:

  • Misidentified organism
    • Gram-positive cocci misidentified as bacilli: typically, diplococci (eg. Streptococcus sp.) or coccobacilli (eg. Haemophilus sp.)
  • Contaminants from the skin
    • Corynebacterium sp., eg. C.jeikeum (aerobic; a skin saprophyte)
    • Propionibacterium acnes. (aerobic)
    • Numerous others, eg. Arcanobacterium sp., Actinomyces sp., etc
  • Clinically insignificant contaminants from other sources:
    • Genitourinary source, eg. when the culture is staken from a groin stab - for example, Lactobacillus sp. (aerobic) or Gardenerella vaginalis (anaerobic)
    • Oral source or unrelated oral bacteraemia, eg. Rothia dentocariosa
  • CNS infection
    • Listeria monocytogenes (aerobic)
    • Nocardia asteroides (aerobic)
  • Severe systemic infection with septic encephalopathy
    • Clostridium species, eg. C.perfringens, C.difficile (anaerobic) 
  • Rare and unlikely pathogens:
    • Bacillus anthracis (aerobic)
    • Corynebacterium diphteriae (aerobic)
    • C.tetani  and C.botulinum (anaerobic)

But of course, if the college asks about a gram-positive rod, it's always going to be Listeria m., because the college loves Listeria.

b)

Listeria is equisitely sensitive to penicillin. The high dose recommended by the college answer seems to come from the Sanford recommendations for treating listerial meningitis. Cotrimoxazole is a valid alternative.

According to Troxler et al (2000), all Listeria species are innately resistant to cephalosporins and aztreonam. They are also all innately sensitive to penicillins of all kinds, as well as aminoglycosides cabapenems glycopeptides and lincosamides. In a theoretical real-life situation, one's panic in the face of an unknown CNS infection often leads to the choice of a vancomycin/meropenem combination: if it turns out to be Listeria, this combination would still be appropriate, even if it is inelegantly overpowered. 

c)

From J Rocourt (1996) and Schuchat et al (1992)

  • Patient risk factors
    • Malignancy
    • Pregnancy
    • Organ transplantat recipient
    • HIV/AIDS
    • Corticosteroid therapy
    • Anything that interferes with T-cell mediated immunity
    • Extremes of age (neonates, the elderly)
  • Food risk factors
    • ​Soft cheese
    • Food "purchased from store delicatessen counters"
    • Undercooked chicken
    • Broadly speaking, foods which are "ready to eat", stored at refrigeration temperature for prolonged periods

References

Schuchat, Anne, et al. "Role of foods in sporadic listeriosis: I. Case-control study of dietary risk factors." Jama 267.15 (1992): 2041-2045.

Rocourt, J. "Risk factors for listeriosis." Food Control 7.4 (1996): 195-202.

McKew, Genevieve, et al. "“Probable contaminants” no more: rapid identification of Gram-positive rods leads to improved clinical care." Journal of clinical microbiology 51.5 (2013): 1641-1641.

Von Graevenitz, A. "Antimicrobial therapy of infections with aerobic Gram‐positive rods." Clinical Microbiology and Infection 7.s4 (2001): 43-46.

Troxler, R., et al. "Natural antibiotic susceptibility of Listeria species: L. grayi, L. innocua, L. ivanovii, L. monocytogenes, L. seeligeri and L. welshimeri strains." Clinical microbiology and infection 6.10 (2000): 525-535.

Question 2 - 2016, Paper 2

Discuss the diagnosis and early management of necrotising fasciitis associated with Group A
Streptococcal (GAS) infection.

College answer

The management of necrotizing fasciitis associated with Group A Streptococcal infection consists of 

  • Diagnosis, 
  • Antibiotic therapy, 
  • Supportive therapy for associated shock, and 
  • Prompt surgical intervention. 

Diagnosis History

  • Necrotising infections are likely to have pain far in excess of superficial appearance
  • May have history of recent trauma, cuts, wounds or IVDU
  • Predisposition: diabetes, peripheral vascular disease, immunosuppression, steroid use
  • May have history of systemic symptoms; fever, chills, nausea, myalgia, headache

Examination Local 

  • Red, swollen, tender, area, dark discoloration of the skin
  • Bullous formation and areas of necrosis are late signs

Systemic

  • Signs of systemic toxicity and organ failure may be present (renal impairment, coagulopathy, liver abnormalities, acute respiratory distress, erythematous rash)

Investigations

  • Culture of swabs, tissue in selective media
  • PCR
  • Frozen section biopsy at time of surgery
  • Blood culture
  • CT or MRI may show extent of infection
  • Routine investigations: ABG, FBC, Coags and fibrinogen, LFTs, EUC, lactate
  • Streptozyme test – need antibody production. Better at detecting post-streptococcal disease like PSGN, rheumatic fever o
    • Anti-streptolysin (ASO) 
    • Anti-hyaluronidase (AHase) 
    • Anti-streptokinase (ASKase) 
    • Anti-nicotinamide-adenine dinucleotidase (anti-NAD) 
    • Anti-DNAse B antibodies
  • Rapid Antigen Detection test – more useful for diagnosis of pharyngitis

Antibiotic therapy

  • Group A Strep. remain susceptible to beta-lactam antibiotics.  
  • Penicillin is still drug of choice
  • Clindamycin should be added to the regimen as clindamycin may be more effective in invasive infections. The efficacy of clindamycin is unaffected by the size of the inoculum and the stage of bacterial growth. Clindamycin also inhibits the production of toxin by streptococci. 
  • In a patient where the initial microbiology is uncertain a broad spectrum antibiotic – such as meropenem should be considered.

Supportive management

  • Often requires monitoring in an intensive care unit with insertion of arterial and central lines, aggressive fluid resuscitation, inotropic support, invasive respiratory support and not infrequently renal replacement therapy. 
  • IVIG is of benefit in TSS to help limit spread of disease and improve mortality. 
  • Hyperbaric oxygen therapy may be considered but is adjunctive and other therapy should not be delayed.  

Prompt Surgery

  • Early and extensive surgical intervention is key with remove all affected tissue. 
  • Daily returns to operating theatres until there is no longer further evidence of spread are often necessary

Additional Examiners‟ Comments:

Many candidates‟ answer contained lists of facts with very little clinical perspective. Although the pass rate overall was good, much better marks would have been possible if candidates actually read the question and discussed the diagnosis and early management rather than just reciting textbook facts. 

Discussion

This question closely resembles the generic mass of necrotising fasciitis questions, such as  Question 25 from the first paper of 2016, Question 24 from the first paper of 2011 and Question 1 from the first paper of 2001. The unique features are the question about diagnosis and the reference to Group A Streptococci specifically. Moreover, the question and college answer seem to jump back and forth between the American and the British spelling of "necrotising", suggesting that at least some of the college answer was cut and pasted from somewhere. This brings into question the seriousness of the comment about mindlessly reciting textbook facts. In any case, the pass rate was 94%, which means the marking criteria did not contain anything which might have tested "clinical perspective".

The diagnosis can be discussed in terms of history, examination, biochemistry, microbiology, imaging and anatomical pathology. The definitive resource for this is probably Wong et al (2005). However, much of the summary below actually comes from the 1995 article by McHenry et al, and represents the historical and clinical features found in a retrospective case series of necrotising fasciitis patients.

Features of history

  • Rapidly develping symptoms
  • Reasonably young patients
  • Previously healthy
  • History of minor trauma, eg. scratch, bruise
  • Initial injury is frequently trivial and blunt rather than penetrating
  • Intense pain and tenderness over the involved skin and underlying muscle
  • Pain is out of proportion to physical findings
  • Risk factors may be apparent: diabetes, alcoholism, obesity, steroid use.

Features of physical examination

  • At the earliest stages, necrotising facsiitis is indistinguishable from severe cellulitis.
  • Severe pain on palpation is an early feature
  • The affected tissue is oedematous and has a "wooden, hardened feel"
  • Erythema is present early.
  • Skin "blebs", i.e. bullae with clear fluid develop as skin ischaemia progresses, and these become haemorrhagic in a late presentation
  • Crepitus on palpation is another late sign
  • Decreased sensation of the overlying skin develops late in the course, and the skin may appear clearly gangrenous

Biochemical features

  • Acute renal failure
  • Coagulopathy; DIC
  • Raised inflammatory markers (WCC, CRP)
  • Hypocalcemia
  • Metabolic (lactic) acidosis
  • Rapid antigen detection test for Group A Strep: this is mainly for pharyngitis (Gerber et al, 2004), but has been used to achieve a rapid diagnosis of lifethreatening GAS soft tissue infection (Ault et al, 1996)
  • "Streptozyme" tests; which, according to a 2009 book chapter by Gould and Reeves are "generally not helpful except as paired acute and convalescent titres", which means the patient will be long dead if you wait for these to become diagnostic of necrotising fasciitis. Oh well, here'es a list of theem anyway, directly from Question 2 from the second paper of 2016​
    • Anti-streptolysin (ASO) 
    • Anti-hyaluronidase (AHase) 
    • Anti-streptokinase (ASKase) 
    • Anti-nicotinamide-adenine dinucleotidase (anti-NAD) 
    • Anti-DNAse B antibodies

Radiological appearance

  • CT findings:
    • Deep fascial thickening
    • Contrast enhancement
    • Fluid and gas in the soft tissue planes in and around the superficial fascia
  • Ultrasound findings:
    • Thickening and distortion of the deep fascia
    • Fluid collections along the deep fascia
  • MRI findings
    • Deep fascial thickening
    • Deep fascial fluid collections
    • Hyperintense T2W signal within the muscles

Surgical findings

  • The presence of grayish necrotic fascia
  • A lack of resistance to blunt dissection: i.e. the normally firmly adherent superficial fascia just sort of falls apart under gentle traction your hands.
  • Lack of bleeding of the fascia during dissection
  • The presence of foul smelling ‘dishwater’ pus.

Histopathology

  • The histologic criteria for diagnosis as described by Stamenkovic and Lew (1984) were as follows:
    • Necrosis of the superficial fascia
    • Polymorphonuclear infiltration of the dermis and fascia
    • Fibrinous thrombi of arteries and veins coursing through the fascia
    • Angiitis with fibrinoid necrosis of arterial and venous walls
    • Presence of microorganisms within the destroyed fascia and dermis
    • An absence of muscle involvement.

Microbiology

  • S.pyogenes is frequently the organism found on tissue culture
  • Blood cultures are also frequently positive

As for the management: the key points to remember are:

  • Source control
  • Clindamycin
  • IV immunoglobulin
  • Hyperbaric oxygen

That's the specific management. The supportive management is boring and algorithmic. The suitably boring and algorithmic answer to Question 25 from the first paper of 2016 is reproduced below. The candidates were offered a necrotising fasciitis in a diabetic leg, and were invited to "describe the management priorities in the first 24 hours".

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
  • Airway
    • Assess the need for intubation in the context of a potentially decreased level of consciousness
  • Breathing/ventilation
    • Assess efficacy of spontaneous breathing, and the need for mechanical ventilation.
    • Administer supplemental oxygen at a high flow- it may not be particularly helpful at atmospheric pressure, but hyperoxia does seem to retard the growth of anaerobic organisms.
  • Circulatory support
    • Administer a 20-30ml/kg fluid bolus
    • Secure central venous access and commence vasopressors- start with noradrenaline
    • Aim for a MAP over 65mmHg
  • Specific investigations
    • A full panel of blood tests including blood cultures, CK and an ABG
    • A CT scan of the lower limbs and pelvis, as a prelude to surgical intervention
  • Supportive management
    • Continue fluid resuscitation and vasopressors in pursuit of haemodynamic goals
    • Ensure normoglycaemia and normoxia
    • Correct acid base balance
    • Attend to organ system failure - consider early dialysis if there is rhabdomyolysis
  • Monitoring
    • Admit to ICU
    • Commence continuous blood pressure monitoring via arterial line
    • Assess for ketosis/ketoacidosis - this is a Type 1 diabetic, and this is exactly the sort of trigger that would produce a DKA.
  • Specific management
    • Commence broad spectrum antibiotics. In this case, the choice is clindamycin plus anycillin or anypenem. The addition of clindamycin is well supported - particularly with Group A streptococci, where it inhibits the bacterial synthesis of endotoxin.
    • Immediately contact surgical services for source control - debridement is the single most useful management strategy; everything else is fairly cosmetic in terms of decreasing mortality.
    • Consider IV immunoglobulin (i.e. if this is a streptococcal toxic shock syndrome - which manifests as massive cardiovascular collapse and organ system failure very early in the infective process). The use of IVIG in this setting has been well studied, and though those European investigators didn't reach statistical significance in their primary endpoit (mortality), they did note a significant decrease in organ failure scores in the IVIG group.
    • Consider an early referral to a specialist centre where hyperbaric oxygen therapy can be carried out. This management strategy historically did not seem to reduce either mortality or the number of debridements. However, recent data suggests that they were doing it wrong in the 1990s, and modern hyperbaric oxygen therapy seems to be associated with a 50% reduction in mortality (from 9.4% to 4.5%).

References

Chelsom, J., et al. "Necrotising fasciitis due to group A streptococci in western Norway: incidence and clinical features." The Lancet 344.8930 (1994): 1111-1115.

McHenry, Christopher R., et al. "Determinants of mortality for necrotizing soft-tissue infections." Annals of surgery 221.5 (1995): 558.

Wong, Chin-Ho, and Yi-Shi Wang. "The diagnosis of necrotizing fasciitis." Current opinion in infectious diseases 18.2 (2005): 101-106.

Ault, Mark J., Joel Geiderman, and Richard Sokolov. "Rapid identification of group A streptococcus as the cause of necrotizing fasciitis." Annals of emergency medicine 28.2 (1996): 227-230.

Gerber, Michael A., and Stanford T. Shulman. "Rapid diagnosis of pharyngitis caused by group A streptococci." Clinical microbiology reviews17.3 (2004): 571-580.

Gould, Kate, and David Reeves, eds. Managing skin and soft tissue infections: expert panel recommendations on key decision points. Oxford University Press, 2003.

Question 6 - 2016, Paper 2

Critically evaluate the utility of monitoring procalcitonin (PCT) levels for the diagnosis and management of sepsis in the ICU.

College answer

Introductory statement

  • PCT is the pro-peptide of calcitonin, produced by the parafollicular cells of the thyroid and neuroendocrine cells of lung and intestine, and has been studied as a sepsis biomarker to help with the diagnosis/exclusion of sepsis and to guide the time course of antibiotic therapy

Rationale

  • PCT is secreted in low concentrations in health (plasma level <0.1 ng/ml)
  • Rises in response to pro-inflammatory stimulus, especially of bacterial origin, mostly from neuroendocrine cells of lungs and intestine
  • Lag time of 2 – 4 hours after onset of sepsis, peaking at 24 – 36 hours
  • Does not rise significantly with viral and non-infectious inflammations
  • To exclude sepsis a cut-off plasma level of ≤ 0.2 ng/ml is used with levels ≥0.5 ng/ml suggesting sepsis
  • Circulating levels halve daily when the infection is controlled

Advantages

  • Theoretical use for diagnosis of bacterial infections, differential diagnosis of inflammatory response  Predictor of outcome – high levels correlate with organ dysfunction and persistently high levels associated with higher mortality
  • Correlation with extent and severity of bacterial infections
  • Guide duration of antibiotic therapy
  • Faster response than waiting for incubation of blood cultures
  • Better at discriminating sepsis from SIRS than CRP or cytokines
  • Better diagnostic marker of bacterial sepsis than CRP
  • Relatively cheap although more expensive than CRP

Disadvantages

  • Increases in non-septic inflammatory conditions with massive necrosis e.g. major trauma, tumour lysis, cardiogenic shock and case report of massive amphetamine overdose
  • Not useful for identifying viral or fungal infections or localised infections without systemic involvement
  • May not be elevated in immunocompromised
  • Serial measurements needed with added cost
  • May be no better than experienced clinician in differentiating infectious from non-infectious cause of fever
  •  

Evidence

  • Conflicting
  • Meta-analysis – Hoeboer et al 2015
  •             Approx. 60 studies
  •             Concluded low PCT values could be used to rule out bacteraemia
  • Further studies needed on safety and efficacy of PCT as single diagnostic tool
  •  
  • Studies using PCT algorithms to guide duration of therapy
  • PRORATA
  •             Multi-centre RCT approx. 600 patients
  •             No difference in outcome but PCT algorithm group used fewer antibiotics 
  • ProGUARD
  •             Used lower level of PCT for initiation and cessation of antibiotics  No difference between 2 arms on antibiotic duration
  •  
  • PASS
  •             Danish multi-centre RCT with 1200 patients
  •             Use of PCT algorithm for escalation of antibiotic therapy 
  •             Did not improve survival
  •          Associated with more organ failure and longer ICU stay
  •  
  • SAPS – Lancet 2016
  •              Dutch study with approx. 1600 patients
  •             Used PCT guided algorithm
  •             Found reduction in antibiotic use and mortality benefit

Summary Statement For example:

  • The evidence for the efficacy of PCT as a biomarker in sepsis is conflicting. Low values may be helpful in ruling out bacterial infection. Some studies show a benefit in using PCT algorithms to guide antibiotic therapy duration. In my practice I use PCT levels as a biomarker of sepsis judiciously in conjunction with careful clinical assessment and other elements of antibiotic stewardship on a caseby-case basis.

An acceptable answer addressed the following:

  • Rationale for the use of PCT
  • Pros and cons
  • Some reference to the evidence
  • Statement of candidate‟s own practice

Additional Examiners‟ Comments:

Most candidates were extremely vague and failed to deliver specific information. While often times the information provided was at least partially correct it was very non-specific and more in keeping with general comment rather than the knowledge expected of a specialist. Very few candidates demonstrated even a passing knowledge of the relevant literature.

Discussion

This question is in many ways identical to Question 23 from the first paper of 2010.

The discussion section was copy-pasted below to simplify revision.

  • Introduction / definition:
    • Procalcitonin is the prohormone of calcitonin, normally synthesised by the C-cells of the thyroid gland, but produced ectopically by lung and intestine in the context of sepsis. As such, it is an attractive biomarker, and has been the subject of interesting research.
  • Rationale:
  • Evidence: what the recent trials say
  • Advantages
    • Quick to perform the assay
    • More specific for bacterial sepsis than CRP
    • Getting cheaper
    • Predictor of outcome - high levels associated with higher mortality and unexpected ICU readmission (Zhou et al, 2016)
    • Persistently high levels are associated with worse organ dysfunction (Hatherill et al, 2000 - as well as many other studies which confirmed this association)
    • Guides antibiotic therapy in the absence of better guesses (eg. where infectious diseases physicians are not available for an opinion)
    • Accurate in identifying bacterial sepsis -a meta-analysis by Wacker et al (2013) found an AUROC of 0.85, and Meynaar et al (2011) found a positive predictive value of 88%.
    • Better than CRP for bacterial sepsis (higher sensitivity, similar specificity - Simon et al, 2004)
  • Disadvantages
    • Expensive
    • Optimal use requires serial measurements, which is even more expensive.
    • Confounded by non-infectious conditions, such as...
      • Extreme inflammatory stimuli:
        • Burns
        • Massive tissue necrosis
        • Tumour lysis
        • Cardiac or major abdominal surgery
        • Multi-organ system failure
      • Treatment with T-cell antibodies
      • End-stage renal failure (procalcitonin is chronically elevated)
    • No value in assessment of fungal or viral infections
    • No value in assessment of localised infections without a systemic response
    • There is disagreement as to what the negative cutoff value should be.
    • For the discrimination of infectious from non-infectious cause of fever, the clinical judgement of an ED physician is at least equally accurate, if not better.

References

Maruna, P., K. Nedelnikova, and R. Gurlich. "Physiology and genetics of procalcitonin." Physiological Research 49 (2000): S57-S62.

Delevaux, I., et al. "Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes?."Annals of the rheumatic diseases 62.4 (2003): 337-340.

Maniaci, Vincenzo, et al. "Procalcitonin in young febrile infants for the detection of serious bacterial infections." Pediatrics 122.4 (2008): 701-710.

Becker, Kenneth L., Richard Snider, and Eric S. Nylen. "Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations."Critical care medicine 36.3 (2008): 941-952.

Limper, Maarten, et al. "The diagnostic role of procalcitonin and other biomarkers in discriminating infectious from non-infectious fever." Journal of Infection 60.6 (2010): 409-416.

Höflich, R. Sabat C., and W. D. Döcke. "Massive elevation of procalcitonin plasma levels in the absence of infection in kidney transplant patients treated with pan-T-cell antibodies." Intensive Care Med 27 (2001): 987-991.

Wacker, Christina, et al. "Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis." The Lancet infectious diseases 13.5 (2013): 426-435.

Hausfater, Pierre, et al. "Serum procalcitonin measurement as diagnostic and prognostic marker in febrile adult patients presenting to the emergency department." Critical Care 11.3 (2007): R60.

Bouadma, Lila, et al. "Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial." The Lancet 375.9713 (2010): 463-474.

Question 9 - 2016, Paper 2

You are asked to review a confused 65-year-old female in the Emergency Department, who has presented with abdominal pain and vomiting. She has a history of ischaemic heart disease and atrial fibrillation.

On examination she is jaundiced, mildly confused and has right upper quadrant tenderness. Her vital signs, after 4 litres intravenous 0.9% saline, are as follows:
 

  • Temperature 39.5°C
  • Respiratory rate 30 breaths/min
  • SpO2 92% on 15 L/min oxygen via a reservoir mask
  • Heart rate 120 beats/min (atrial fibrillation)
  • Blood pressure 88/48 mmHg

An abdominal ultrasound scan shows a dilated common bile duct and enlarged gall bladder with mural oedema.

Outline your management of this patient

College answer

The patient is most likely to have acute ascending cholangitis, which needs rapid resuscitation and definitive treatment.

  1. Admit to the intensive care unit
  2. Provide resuscitative and organ supportive care. 
  • Resuscitate, investigate and treat simultaneously.
  • Actively consider the need intubation and ventilation given her respiratory failure, confusion and haemodynamic instability, 
  • Central venous and arterial lines need to be inserted and monitoring commenced.

Blood taken for investigations:

FBC, Coags, UECs, LFTs, ABGs, cultures

  • No further intravenous fluid bolus
  • Commence vasopressor support, aiming for a MAP > 65mmHg.
  • Ensure referral to gastroenterology team for further investigation and management
  • Consider MRCP or abdominal CT scan if diagnosis uncertain
  1. Commence broad-spectrum empiric antibiotic therapy. 

Need good gram negative, gram positive and include anaerobic cover if very unwell:

Examples include: amoxycillin and gentamicin and metronidazole piperacillin/tazobactam

  1. Source control with decompression & drainage of her biliary tract.
    • By most recent international guidelines this is Grade III (severe) acute cholangitis and thus the biliary tree must be urgently decompressed and drained. 
    • This can be done either endoscopically (ERCP) or percutaneously. 
    • Open surgery is not indicated in this situation. 
    • ERCP +/- sphincterotomy (provided the patient is not coagulopathic) is the gold standard and the best method of decompression and drainage.
  • Additional Examiners‟ Comments:
  • Candidates‟ description of the management of the case was superficial with lack of perspective or explanation of rationale, e.g. “I would assess the airway…may need to regularly assess” with no indication as to why, causes for concern, what they would look for etc. There was poor discussion and/or explanation of airway management, source control techniques, fluid assessment, antibiotic choice, differential diagnosis of hypoxia, impact of co-mobidities. There was over-emphasis on the utility of echo before addressing the basics of oxygenation.

Discussion

This patient has to have some sort of biliary sepsis, because she manifests not only Charcot's Triad (abdominal pain, jaundice and fever), but the full Reynolds pentad (same, but with confusion and hypotension).

Immediate resuscitation

  • A: intubate the confused uncooperative patient
  • B: ventilate with mandatory mode
  • C: insert CVC, arterial line;
      - assess the need for further fluid resuscitation
      - commence vasopressors if  it appears that the patient is well filled
  • D: commence sedation and analgesia
  • E: correct electrolyte derangements and acidosis
  • F: Assess renal function; insert IDC
  • G: NGT for gastric decompression
  • H: keep Hb >70
  • I: broad spectrum antibiotics

Confirmation / investigation of cholangitis

  • Repeat LFTs
  • Inflammatory markers
  • CT of the abdomen ( the patient still has not me TG13 criteria, insofar as she has no evidence of any bile duct stone or mass).  Possible causes of duct obstruction could include stones (commonest), tumour, abscess, vascular malformation or parasites. Each might call for a different approach.
  • MRCP (can detect non-calcified stones more easily than CT, and is more sensitive for making the diagnosis of malignant obstruction)

Specific management

  • Antibiotics: Sanford Guide recommends Tazocin or Meropenem.
    Of the patients with cholangitis, 70-80% will respond to conservative management (i.e. they get better with antibiotics and are clinically well by the time they get to have an ERCP).
  • ERCP: the treatment of choice whenever feasible (stent or sphincterotomy)
  • Percutaneous transhepatic cholangiography (PTCC): the bile duct can be decompressed by inserting a needle into the liver and draining the pus that way. PTC can also be used to put stents in, image the duct, extract stones, etc.
  • Percutaneous cholecystostomy:  if the gall bladder is accessible, the simplest thing would be to put a drain into it (just as in the case of acalculous cholecystitis)
  • Surgical decompression by T-tube:  if ERCP is impossible, inserton of a T-tube has a lower complication rate than open cholecystectomy and exploration.
  • Surgical cholecystectomy and exploration of CBD:  this is the approach which led to the mortality rates in excess of 50% during the 1960s and 70s.
  • Cholecystectomy: ultimately, the gall bladder must be removed, but it should ideally happen when the inflammation has settled down. Acute cholecystitis makes this organ friable and difficult to handle laparoscopically, and the morbidity from open procedures is much greater. Thus, if you can afford to wait, you really should.
  • Oncology referral:  in the event that the CBD was compressed by a head of pancreas mass or somesuch

Supportive management

  • Mechanical ventilation - mandatory mode while severely septic; then weaning off the ventilator
  • Haemodynamic support with vasopressors
  • Management of AF with amiodarone
  • Vigilant monitoring for myocardial infarction with daily ECGs
  • Nutrition - post-ERCP, one should be able to commence NG diet
  • Adequate analgesia
  • PPI, heparin, etc

References

Laurila, Jouko, et al. "Acute acalculous cholecystitis in critically ill patients."Acta anaesthesiologica scandinavica 48.8 (2004): 986-991.

Wang, Ay-Jiun, et al. "Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis." Heart 1500 (2003): 8.

Boland, Giles W., et al. "Percutaneous cholecystostomy in critically ill patients: early response and final outcome in 82 patients." American Journal of Roentgenology 163.2 (1994): 339-342.

Question 28 - 2016, Paper 2

A 52-year-old male, who had a heart-lung transplant 5 years earlier, is admitted to your ICU with suspected community-acquired pneumonia (CAP).

Outline the key clinical issues specific to this clinical situation that will need consideration in this patient's management.

College answer

Respiratory failure in a cardiopulmonary transplant patient is most commonly due to infection, rejection or a combination of the two and has a high mortality. A multi-disciplinary approach with quaternary level consultation is warranted including the transplant unit and infectious diseases. 
 
Issues related to pneumonia 
Causative organisms- Opportunistic infections e.g. PJP, CMV, Aspergillus, Scedosporium as well as other bacterial, viral or atypical causes of community-acquired pneumonia. 
Early aggressive investigation – appropriate specimens/nasopharyngeal swabs and PCR testing, CXR, CT scan, bronchoscopy and consideration of lung biopsy 
Early aggressive antimicrobial therapy – To cover standard CAP organisms and likely opportunistic organisms eg co-trimoxazole, ganciclovir, antifungal agents. Steroid therapy if severe PJP 
 
Issues related to respiratory function 
Need to rule out rejection (cellular or antibody mediated)- often treated empirically for both infection and rejection. Enhanced antibody response developed to combat infection may result in concurrent antibody mediated rejection (AMR).  
Impaired cough and clearance of secretions. 
Impaired lung function due to obliterative bronchiolitis (a manifestation of chronic rejection)- small airway disease 
Bronchial or tracheal stenosis relating to the original anastomotic site may be present- large airway disease 
 
Issues related to immunosuppression 
On-going immunosuppression will need to be carefully managed in consultation with the transplant unit  
Stress dose steroids if associated shock 
Therapeutic drug monitoring of immunosuppression 
 
Issues related to cardiac function 
The transplanted heart is denervated. It is only responsive to directly acting drugs/hormones present in the circulation.  
Normal compensatory cardiac autonomic reflexes are not present and therefore the heart is more sensitive to directly acting drugs and less able to rapidly respond to changes in intravascular volume.  
Careful titration of fluid boluses needed- likely diastolic dysfunction. 
Difficult to clinically assess response to and adequacy of therapy 
Premature diffuse obliterative coronary atherosclerosis occurs resulting in impaired ventricular function 
 
Issues related to other organ function 
Renal – altered renal function secondary to calcineurin inhibitors 
Altered adrenal function secondary to steroid use. Consider need for steroid cover 
Glycaemic control with increased steroid dose 
Other co-morbidities and issues related to reason for heart-lung transplant, e.g. vascular disease, diabetes 
 
Other 
Early referral to transplant centre  
Involvement of multi-disciplinary team – transplant unit, ID, respiratory, cardiology, physiotherapy Psychological support of patient and next of kin 
 
Valid points not mentioned in the template were given credit 
 
Additional Examiners' Comments: 
Candidates who did not pass had knowledge gaps in this area. 

Discussion

This question is almost identical to Question 22 from the first paper of 2009.  Therefore, the discussion section from this previous question can be safely reproduced here with virtually no modification. For a broader overview of complications following heart-lung transplantation, and specifically sepsis in the heart-lung transplant recipient, there are dedicated chapter in the Required Reading section:

Anyway: a systems-based approach to discussing the "key clinical issues":

Airway:

  • This patient may require intubation;
  • The risk of intubation in the immunocompromised patient must be weighed, as it places them at considerable risk of VAP.
  • On the other hand, clearance of secretions may not be satisfactory, and effort of breathing may be so great that the cardiac reserve is exhausted (as these people tend to have a rather fixed cardiac output).

Ventilation:

  • Respiratory function will be impaired because of the pneumonia.
  • The college also mentions obliterative bronchiolitis, which is a common feature of lung transplantation (it is a host vs graft chronic rejection syndrome)- in fact its the major cause of morbidity and mortality in long-term transplant patients. Obliterative bronchiolitis manifests as an obstructive respiratory disease, featuring an irreversible decrease in FEV1 which progressively worsens.

Circulation:

  • Myocardial ischaemia: the myocardia of these people tend to also be subjected to chronic rejection, and the consequence of this looks like an accelerated rate of coronary vascular disease. This is a mixture of normal coronary athersclerosis and a uniquely transplant-associated distal obliterative disease, which looks totally different histologically. A seriously unfortunate feature of this unique obliterative process is the fact that collateral circulation doesn't seem to form, in contrast to normal atherosclerotic narrowing. The upshot of all this is the predisposition of relatively young hearts to relatively severe ischaemic heart disease.
  • Increased responsiveness to infused inotropes: The denervated heart, in the absence of sympathetic stimulus, will grow vast numbers of catecholamine receptors. This is analogous to the skeletal muscle in the denervated legs of a spinal patient, which will overexpress acetylcholine receptors. Thus, inotropes will have an exaggerated effect on the transplanted heart.
  • Insensitivity to normal autonomic stimuli: Severed from the autonomic nervous system, the heart will no longer respond normally to changes in blood pressure, posture, or volume. There will not be a compensatory tachycardia when the patient is hypovolemic.

Renal and electrolyte abnormalities:

  • These patients like have been receiving steroids or cyclosporine-like drugs. 
  • The use of steroids will result in a hypernatremia, fluid retention, and hypokalemia.
  • Alternatively, the barupt withdrawal of steroids may produce hyponatremia and hyperkalemia
  • Renal function may be very poor, and drug clearance may be affected.
  • Cyclosporine may also cause a distal renal tubular acidosis.

Infectious agents:

  • In 60% of cases, pneumonia in the heart-lung trasplant recipient is due to an opportunistic pathogen.
  • The pathogens are as follows:
    • Opportunistic:
      • CMV
      • Aspergillus
      • Pneumocystis
      • Nocardia
    • Community-acquired
      • H.influenzae
      • S.pneumoniae
      • Moraxella catarrhalis
    • Hospital-acquired
      • Acinetobacter
      • Pseudomonas
      • Stenotrophomonas
      • Klebsiella
      • Legionella
      • E.Coli

Note how weirdly the range of bugs is arrayed. The community pathogens are fairly bog-standard, but the Stanford people found that gram-negatives dominated the hospital-acquired infectious lung flora.

Immunesuppression in the context of an acute infectious illness may have to be continued, because its cessation may result in catastrophic rejection.

  • Autonomic disconnection:
    • No cardiovascular response to hypotension; thus, sepsis or spinal/epidural anaesthesia result in massive hypotension
    • Atropine has no effect on heart rate
    • Digoxin has no effect on heart rate
    • There is no bradycardia in response to cholinergic drugs, eg. neostigmine
    • There is no reflex tachycardia in response to GTN
  • Adenosine has an exaggerated effect, and one should use 1mg doses
  • Inotropes have an exaggerated effect, perhaps with the exception of isoprenaline (?)
  • Coronary artery disease is accelerated in these people

References

Cisneros, J. M., et al. "Pneumonia after heart transplantation: a multiinstitutional study." Clinical infectious diseases 27.2 (1998): 324-331.

Reichenspurner, Hermann, et al. "Stanford experience with obliterative bronchiolitis after lung and heart-lung transplantation." The Annals of thoracic surgery 62.5 (1996): 1467-1473.

Gao, Shao-Zhou, et al. "Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings." Journal of the American College of Cardiology 12.2 (1988): 334-340.

Yusuf, S. A. L. I. M., et al. "Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade."Circulation 75.4 (1987): 696-704

Question 15.2 - 2017, Paper 1

This is the second part of a multi-part SAQ. The first part was as follows:

You are called to review a 48-year-old male in the post-operative recovery unit (PACIJ) who has just undergone resection of a TSH-secreting pituitary adenoma via a trans-sphenoidal approach. He is febrile (38.5'C) and is hypertensive (160/50 mmHg) with tachycardia (130 beats/min) and hyper-dynamic circulation, and is hyper-reflexic.

Give the likely diagnosis.        (10% marks)

List your immediate pharmacological management.            (30% marks)

The patient subsequently recovered and was discharged home. He re-presented two weeks later with increasing drowsiness, confusion, fevers, neck stiffness and a clear nasal discharge.

Give the likely diagnosis.        (10% marks)

Briefly outline your immediate management.          (30% marks)

College answer

c) CSF leak post-surgery with meningitis

d)

  • Intubation for airway protection if indicated and ventilatory support
  • Haemodynamic resuscitation / support as indicated
  • Blood cultures LP (post CT scan)
  • Broad-spectrum antibiotics with CNS penetration (e.g. meropenem and vancomycin)
  • Referral to neurosurgery / ENT (ID input)

Discussion

The previous question using this stem had the patient develop a thyroid storm following the resection of a TSH-secreting adenoma, a rare complication. The complication in the SAQ is more common. 

This is basal meningitis due to a dural breach. The breach has allowed filthy nose organisms into the brain, and now they swarm though the meninges. 

Management of this:

  • Obviously, ABCs
  • Confirm CSF leak by testing the clear discharge for β-transferrin
  • Lumbar CSF drain - to decrease the volume of CSF leak and to allow the CSF fistula to heal
  • Antibiotics (see below)
  • Instructions to avoid blowing one's nose 
  • If the lumbar drainage fails to control the leak, a surgical repair of the defect may be attempted (eg. by using some sort of patch).

As far as choice of antibiotics goes, it is unclear wherther one should treat this as a meningitis following base of skull fracture (which it pathophysiologically resembles) or post-surgical meningitis (which it ontologically is).  In the former, S.pneumoniae and H.influenzae are the dominant organisms, whereas in post-operative cases the bug is either S.aureus or S.epidermides. In either case, vacomycin and ceftriaxone are recommended by the Sanford Guide. In both cases, dexamethasone (0.15mg/kg) is recommended. 

References

Ciric, Ivan, et al. "Complications of transsphenoidal surgery: results of a national survey, review of the literature, and personal experience."Neurosurgery 40.2 (1997): 225-237.

Van Aken, M. O., et al. "Cerebrospinal fluid leakage during transsphenoidal surgery: postoperative external lumbar drainage reduces the risk for meningitis." Pituitary 7.2 (2004): 89-93.

Nishioka, H., J. Haraoka, and Y. Ikeda. "Risk factors of cerebrospinal fluid rhinorrhea following transsphenoidal surgery.Acta neurochirurgica 147.11 (2005): 1163-1166.

Black, Peter McL, Nicholas T. Zervas, and Guillermo L. Candia. "Incidence and management of complications of transsphenoidal operation for pituitary adenomas." Neurosurgery 20.6 (1987): 920-924.

Mathias, Tiffany, et al. "Contemporary approach to the diagnosis and management of cerebrospinal fluid rhinorrhea.The Ochsner Journal 16.2 (2016): 136-142.

Question 14 - 2017, Paper 1

A 45-year-old male has been in ICU for 10 days for necrotising pancreatitis. He has been treated for eight days with vancomycin, meropenem and caspofungin in appropriate dosages. He has been febrile and hypotensive for 24 hours and has had a change in vascular access.

The following three scenarios describe different potential results from his blood cultures:

Scenario 1 :

His blood cultures from the previous day become positive with a Gram-negative bacillus. The line tips show no growth.

List four likely identities for the Gram-negative bacillus, AND give an appropriate choice of antimicrobial for each.   (60% marks)

Scenario 2:

His blood cultures from the previous day become positive with a Gram-positive coccus. The line tips show no growth.

List three likely identities for the Gram-positive coccus, AND give an appropriate choice of antimicrobial for each.   (30% marks)

Scenario 3:

His blood cultures from the previous day become positive with a yeast.

Give the  likely identity for the yeast, AND suggest an appropriate antimicrobial agent.

(10% marks)

College answer

a) Scenario 1

  • Stenotrophomonas maltophilia- environmental organism with low virulence Treatment is cotrimoxazole, ticarcillin clavulanic acid
  • Multi-resistant Acinetobacter baumanii
    Low virulence overall- though recent cases of high virulence community acquired cases in USA
    Treatment is complex- Colistin, Tigecycline
  • Multi-resistant E.coli
  • Multi-resistant K. pneumonia (or metalloprotein betalactamase secreting GNB) – virulent with high mortality- combination treatment which includes carbapenem, colistin, rifampicin and tetracycline – new agents such as avibactam and cefiderocol show promise
  • Multiresistant Pseudomonas aeruginosa
  • Metalloprotein beta-lactamase secreting GNB
    Acceptable answer
    Treatment will depend on extended susceptibilities- colistin and amikacin are potential options

b) Scenario 2

  • Vancomycin resistant Enterococcus faecalis
  • Vancomycin resistant Enterococcus faecium
  • Staphylococcus aureus with intermediate susceptibility to Vancomycin (VISA)
  • Vancomycin resistant Staphylococcus aureus (VRSA) (not yet reported in Australia but candidates should get credit if they mention it)

c) Scenario 3

  • The likely yeast in this setting is Candida glabrata (would accept Kruzei or Tropicalis, or other resistant organism. Simply stating caspofungin resistant organism did not score marks), Scedesporium acceptable
  • Treatment would be with Amphotericin

Discussion

Scenario 1 :

His blood cultures from the previous day become positive with a Gram-negative bacillus. The line tips show no growth.

List four likely identities for the Gram-negative bacillus, AND give an appropriate choice of antimicrobial for each.   (60% marks)

So, there are Gram-negative rods in the blood, and the lines are clean. The bugs you choose to answer this question would probably be at least to some extent resistant to carbapenems. The colleges offers a selection of classics, such as S.maltophila and A.baumanii. All the other choices offered by the college are simply familiar Gram-negative bugs prefaced with the words "Multi-Resistant".

Other possible appropriate bugs with antibiotics listed in parentheses are offered below.

  • Bacteroides fragilis (metronidazole)
  • Pseudomonas maltophilia (a fluoroquinolone, eg. ciprofloxacin)
  • Pseudomonas cepacia (a fluoroquinolone, eg. ciprofloxacin)

Scenario 2:

His blood cultures from the previous day become positive with a Gram-positive coccus. The line tips show no growth.

List three likely identities for the Gram-positive coccus, AND give an appropriate choice of antimicrobial for each.   (30% marks)

So, there are Gram-positive cocci in the blood, and the lines are clean. The cocci would have to be resistant to vancomycin. Or, as an unwelcome detour into the territory of common sense, the trainee could sacrifice 10% of the grade here by suggesting that the peripheral blood cultures might be contaminated by a coagulase-negative staph (surely that would attract zero marks because the model answer does not countenance such a possibility). Anyway, the college examiners appear to have lost interest in giving antibiotic recommendations after the first scenario. For those of us still paying attention, the appropriate antibiotics are listed in parentheses.

  • Enterococcus faecium, or E.faecalis i.e. VRE  (linezolid, or daptomycin, or tigecycline)
  • Vancomycin-intermediate MRSA, i.e. VISA (tigecycline, or telavancin, or ceftaroline)
  • VRSA (tigecycline, or telavancin, or ceftaroline)
  • Leuconostoc mesenteroides (tigecycline)

Scenario 3:

His blood cultures from the previous day become positive with a yeast.

Give the  likely identity for the yeast, AND suggest an appropriate antimicrobial agent.

(10% marks)

This would have to be a yeast sufficiently resistant to caspofungin so as to survive an eight-day course and still be causing systemic fungaemia (yeastaemia?). In actual fact, this could be any albicans or non-albicans Candida with an Fks1 mutation (conferring a 1000-fold decrease in susceptibility).  Treatment would be with something like amphotericin, the old go-to of fungicidal therapy.

References

Perlin, David S. "Resistance to echinocandin-class antifungal drugs.Drug Resistance Updates 10.3 (2007): 121-130.

Kumar, Randhir, et al. "METHICILLIN AND VANCOMYCIN RESISTANCE AMONG STAPHYLOCOCCUS AUREUS STRAINS ISOLATED FROM PATIENTS ATTENDING TERTIARY CARE HOSPITAL IN EASTERN BIHAR." JOURNAL OF EVOLUTION OF MEDICAL AND DENTAL SCIENCES-JEMDS 6.12 (2017): 914-917.

Question 6 - 2017, Paper 2

With respect to a patient presenting with clinical features suggestive of tetanus:

a) List six other potential differential diagnoses other than tetanus that you would consider.
(30% marks)
 
b) How would you confirm the diagnosis of tetanus?                                            

(30% marks)
 
c)
Excluding  general  supportive  measures  (e.g. airway  management),  describe  the  specific management of tetanus.
(40% marks)

College answer

a)    The differential includes:                                              
•    Strychnine poisoning 
•    Drug induced dystonia 
•    Dental/local infections 
•    Stiff person syndrome 
•    Hypocalcaemia 
•    Malignant Hyperthermia 
•    Stimulant Use 
•    Serotonin syndrome 
•    Seizure disorder 
•    Psychiatric disorders 
 
 
b)    The diagnosis is a clinical one.                                          
•    Appropriate History 
•    Vaccinations status 
•    Tetanus prone wound 
•    Appropriate clinical features 
•    C tetani is cultured from the wound in only 1/3 of cases. There are no specific lab tests to confirm the diagnosis 
 
c)    Passive immunisation.                                               
Human antitetanus immunoglobulin (HIG) has now largely replaced antitetanus serum (ATS) of horse origin as it is less antigenic.it is recommended that HIG  be administered to unimmunised patients or those where their immunisation status is unknown if they present with contaminated wounds 
 
Eradication of the organism.  
•    Wound care. The infected site should the cleaned and all necrotic tissue should be debrided.  
•    Antibiotics .As tetanus spores are destroyed by antibiotics they should be administered.  
•    Recommendations include Metronidazole, penicillin and erythromycin. 

Management of spasms 
•    Intra thecal Baclofen 
•    Magnesium 
•    Diazepam 
•    Muscle relaxants with mechanical ventilation

Management of autonomic dysfunction 
•    Sedation 
•    Alpha and beta blockers 
 

Note: Mention of Human Antitetanus Immunoglobulin was considered essential to score a passing mark 

Discussion

Differentials for whole-body rigidity, opisthotonos and trismus:

  • Intracranial catastrophe - increased tone an all 4 limbs should make on think of something happening in the brain stem. The generally increased tone and the spasming arm flexion makes one think of decerebrate posturing. However one does not normally develop a risus sardonicus while having a bilateral brainstem lesion. Most relevantly, one should not be fully alert during an episode of decerebrate posturing.
  • Strychnine poisoning - but where does one get a hold of strychnine these days? It is no longer available widely; nowadays most countries which still use it tend to limit its sales. In California, for example it is used as a mole and gopher poison.
  • Local temporomandibular disease, causing masseter spasm
  • Local oral disease causing masseter spasm
  • Epilepsy
  • Stiff person syndrome
  • Dystonia
  • Hypocalcemia
  • Serotonin syndrome
  • Sympathomimetics

Confirmation of the diagnosis of tetanus:

  • Clinically:  the physical findings are quite characteristic. Henderson et al (1998) described a case series where only one case in eleven was misdiagnosed in the ED. "Laboratory results and cultures are of little diagnostic value", the authors concluded.
  • The "spatula test" which is where you poke the patient's posterior pharyngeal wall to elicit a masseter spasm; Apte & Karnad (1995) found it had 100% specificity and 94% sensitivity. 
  • Wound culture might occasionally grow C.tetani (in 30% of cases)
  • Serum antitoxin level: you can't test for the actual tetanospasmin, but you can test for the antitoxin immunoglobulin; levels above 0.1 IU should be protective, so very low levels demonstrate susceptibility and therefore raise the level of clinical suspicion.

Management of tetanus:

  • Even though the college sternly warned the exam candidates against talking about generic stuff like airway management, it is actually an important part of the specific management for tetanus because these people usually develop laryngospasm and stridor. 
  • Disable the toxin: passive immunisation with tetanospasmin antibodies
    • this will bind circulating toxin only;
    • all the toxin already within the CNS will continue to have its effects, i.e. the symptoms will not resolve
  • Destroy the bacterium and its spores: both are sensitive to metronidazole, and thus there is usually a good response. Benzylpenicillin is also added.
  • Control the spasms. Usually a neuromuscular junction blocker or benzodiazepine infusion is needed. The college also mention intrathecal baclofen 
  • Control the sympathetic nervous system. Usually, an infusion of labetalol, magnesium sulfate or clonidine is required.

References

Rodrigo, Chaturaka, Deepika Fernando, and Senaka Rajapakse. "Pharmacological management of tetanus; an evidence based review." Crit Care18 (2014): 217.

Cook, T. M., R. T. Protheroe, and J. M. Handel. "Tetanus: a review of the literature." British Journal of Anaesthesia 87.3 (2001): 477-487.

Wesley, A. G., et al. "Labetalol in tetanus." Anaesthesia 38.3 (1983): 243-249.

Attygalle, D., and N. Rodrigo. "Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients*." Anaesthesia 57.8 (2002): 778-817.

Henderson, Sean O., et al. "The presentation of tetanus in an emergency department." The Journal of emergency medicine 16.5 (1998): 705-708.

Apte, Nitin M., and Dilip R. Karnad. "The spatula test: A simple bedside test to diagnose tetanus." The American journal of tropical medicine and hygiene 53.4 (1995): 386-387.

Question 14 - 2017, Paper 2

With respect to gram positive infections in the ICU:


a) What type of infections are commonly caused by Coagulase-negative Staphylococci (CoNS)?(10% marks)

b) What are the differences in clinical presentation between infections with CoNS and those with staphylococcus aureus? (40% marks)

c) What blood culture findings would suggest true bacteraemia rather than contamination with CoNS?(40% marks)

d) What empirical antimicrobial therapy is preferred for suspected CoNS infections? (10% marks) 

College answer

a)    What infections are commonly caused by Coagulase-negative Staphylococcal Infections? 
•    Coagulase-negative Staphylococci (CoNS) commonly cause prosthetic device infections, such as:
o Prosthetic heart valves,
 o Prosthetic joints
o Vascular grafts
o Intra-vascular devices
o CNS shunts  
 
b)    Compared to Staphylococcus Aureus infections, what different clinical presentation is expected from infection with coagulase-negative staphylococci?                     
•    CoNS are less virulent than staphylococcus aureus, and hence: 
o    Signs of localised infection are subtle
o Rate of disease progression is slow
o Systemic findings are limited. 
o    Fever may be absent
o Acute phase reactants, may be normal or slightly elevated. 
o    Abscess formation commoner with S. Aureus
o Patients with S Aureus usually sicker 
 
c)    What blood culture findings (in addition to clinical suspicion) would suggest true bacteraemia rather than contamination with CoNS?                           
•    Multiple isolations of the same strain from separate cultures 
•    Growth of the strain within 48 hours 
•    Bacterial growth in both aerobic and anaerobic bottles. 
 
d)    Empirical antimicrobial therapy                                    
•    CoNS are usually resistant to Methicillin; hence, Vancomycin is the preferred empirical therapy. 
 

Discussion

Most of this discussion section (and the associated CoNS revision chapter) were generated using the comprehensive review by Davidson and Low at antimicrobe.org. 

a)

Specific infections caused by these organisms:

  • Urinary tract infections
  • Central or peripheral venous catheter related infections,
  • VP shunt infections
  • Pneumonia, 
  • Endophthalmitis
  • Surgical wound infections
  • Mastitis or breast abscess
  • Osteomyelitis
  • Native and prosthetic valve endocarditis
  • Prosthetic joint infections
  • Infections of pacemaker leads

b)

Classically, because these organisms are low virulence skin organisms, infections due to them are

  • indolent
  • superficial
  • related to breakdown of the skin barrier properties
  • limited to areas which are sequestered from the immune system
  • more common among immunocompromised hosts
  • less likely to stimulate a vigorous immune response

In contrast, S.aureus infection tends to progress more rapidly, cause more severe infections, affect relatively healthy people, stimulate a vigorous SIRS response, and occasionally produce a toxic-shock-like superantigen-driven syndrome.

c)

Blood culture findings suggestive of a true CoNS bacteraemia:

  • Number of positive cultures
  • Simultaneous cultures: Of a set of two cultures taken at the same time but from different sites, both grow the same CoNS. 
  • Rapid time to culture growth (i.e. large inoculum): Kassis et al (2009) found that a time to positive culture of less than 16 hours was suggestive of a large organisms count as measured by "colony-forming units".
  • Quantitative blood culture: a colony count <10 CFUs suggests contamination; Kassis et al (2009) found that of these patients had a good outcome even if they didn't get any antibiotics and their central line was left in situ.

The college answer refers to "bacterial growth in both aerobic and anaerobic bottles" as one of the parameters suggestive of "true" bacteraemia. Looking for evidence in support of this one lands on the influential and highly-referenced article by Kirchoff et al (1985), which documents 26 months of blood cultures from the University of Michigan Medical Center. The authors reported that "coagulase-negative staphylococci grew in both aerobic and anaerobic bottles in 85% of blood culture sets drawn during episodes of bacteremia, but in only 30% of the cultures thought to be contaminated".  Kirchoff et al also seem to be the reference for the "positive within 48 hours" comment. 

d)

The Sanford Guide recommends vancomycin as empiric therapy. Most CoNs (80-90%) are resistant to "classical" β-lactams, but sensitive to antistaphylococcal ones like flucloxacillin. Cephazolin and linezolid are alternatives. If a prosthetic device is infected but needs to remain in situ, rifampicin may be used over a long course.

References

John Jr, Joseph F., R. J. Davidson, and Donald E. Low. "Staphylococcus epidermidis and other Coagulase-Negative Staphylococci.Antimicrobial Therapy 1.

Foster, Timothy. "Staphylococcus." (1996).

Kassis, Christelle, et al. "Differentiating culture samples representing coagulase-negative staphylococcal bacteremia from those representing contamination by use of time-to-positivity and quantitative blood culture methods.Journal of clinical microbiology 47.10 (2009): 3255-3260.

Weinstein, M. P. "Contaminated or not? Guidelines for interpretation of positive blood cultures. WebM&M. January 2008. Agency for Healthcar Research and Quality, Rockville, MD." (2008).

Al-Mazroea, Abdulhadi Hassan. "Incidence and clinical significance of coagulase negative Staphylococci in blood." Journal of Taibah University Medical Sciences 4.2 (2009): 137-147.

Kirchhoff, Louis V., and John N. Sheagren. "Epidemiology and clinical significance of blood cultures positive for coagulase-negative staphylococcus." Infection Control & Hospital Epidemiology 6.12 (1985): 479-486.

Question 18 - 2017, Paper 2

You are supervising a registrar who suffers a needle stick injury during the insertion of a central line in a patient with a history of intravenous drug use.

Outline your approach to this problem. 

College answer

Immediate Response: 

  • Stop the procedure 
  • Ensure patient is safe 
  • Takeover / delegate patient management as required

Further response: 

  • Wash the registrar’s wound immediately with soap and water
  • Express any blood from the wound
  • Initiate injury-reporting system used in the workplace
  • Patient may need to be consented and then tested for HIV, hepatitis B, Hepatitis C 
  • Refer registrar to designated treatment facility: Emergency Department / Infectious Disease
  • Physician / Immunology as per hospital protocol 
  • With consent, registrar to be tested immediately and confidentially for HIV, hepatitis B and C
  • Document the exposure in detail for your own record and for the employer 
  • If the patient is HIV positive, post exposure prophylaxis needs to be started within two hours of the exposure. 
  • For possible Hepatitis C exposure, no treatment is recommended but advice must be obtained from Infectious Disease Specialist 
  • If the source patient tests positive for HIV, hepatitis B, hepatitis C, get post-exposure prophylaxis in accordance with CDC guidelines and as per recommendations from Infectious Disease Specialist or another expert. 
  • Registrar to have follow up with post exposure testing 
  • Advise re: taking precautions (including safe sex) to prevent exposing others until follow up testing is complete. 
  • If exposed to blood borne pathogen, he/she should not donate blood for six months until cleared

Counselling: While definitive testing is essential, counsel the registrar that the risk factors for infection are: deep injury, visible blood on devices, and needle placement in a vein or artery, lower risk with solid suture needle. Related to procedure: Review of registrar’s technique, equipment used, unit policy for procedural training, assessment of competency, etc. 

Discussion

This question is identical to Question 5 from the first paper of 2015 and very similar to Question 25 from the first paper of 2007, except in 2007 this patient was not yet an IV drug user. The answer to these questions is reproduced here with minimal modification, reflecting the fact that the college examiners had also cut and pasted their model answer from the first paper of 2015.

Immediate management:

  • Abort the procedure
  • Ensure the patient is safe:
    • Take over the procedure and finish it yourself; or
    • Delegate the task to a competent staff member
  • Ask the registrar to express blood from the wound
  • Wash the punctured area with soap and water
  • Report the incident

Risk assessment:

  • Is the patient known to have Hpe B, C, or HIV?

The following are associated with an increased risk of transmission:

  • Hollow needle
  • Large needle diameter
  • Needle was previously in an artery or vein
  • Absence of gloves 
  • Depth of wound 
  • Into artery or vein
  • Exposed to a large volume of blood
  • High blood titre of HIV, Hep B or C

Management

  • Document the Hep B immunisation status of the staff member
  • Perform antibody tests of both the staff member and the patient, with written consent
  • If the source is known to be Hep B C or HIV positive,
    • Solicit advice from infectious diseases authorities
    • Arrange appropriate vaccinations, antiretroviral prophylaxis and councelling
    • Arrange follow-up for the patient and staff member
  • Possible management strategies:
    • For Hep B, IV immunoglobulin may be appropriate
    • For Hep C, there is nothing.
    • For HIV, postexposure antiretroviral therapy is helpful (and needs to be commenced within 2 hours!)
  • Safe sex for 6 months
  • Follow-up testing: 6 weeks and 6 months 
  • Review unit guidelines and compliance
  • Offer emotional support to the staff member, and get help from infectious diseases authorities to aid post-exposure councelling

References

Question 21 - 2017, Paper 2

After 14 days in ICU with a diagnosis of community-acquired pneumonia, a patient's signs and symptoms have not improved despite antimicrobial therapy.

a) List the factors that might be responsible for the slow resolution. (60% marks) 

b) Outline your assessment to identify the cause of the slow resolution. (40% marks)

College answer

Factors contributing to non-resolution or delayed resolution of pneumonia

  1. Host factors: 
  2. Agent (organism factors)
  3. Extent of disease
  4. Due to Complication of Pneumonia
  5. Incorrect Diagnosis: Diseases mimicking pneumonia

Host factors:

  • Age > 60
  • H/o Smoking
  • Comorbidities: COPD, CCF, DM, CRF, alcoholism
  • Malnutrition
  • Immunosuppressed host 
  • Underlying lung disease

Agent or Organism factors

  • Resistant organism: especially in patients treated with beta lactams in the recent past, hospitalised in last 3 months, pneumonia in the last 1 year.
  • Nosocomial pneumonia: MRSA in a hospitalised patient, with indwelling IV catheters, dialysis patients etc. Pseudomonas aerogenosa infection,  
  • Unusual pathogen: TB, atypical mycobacterium, nocardia, actinomyceces, Pneumocystis jiroveci,
  • Fungal: Aspergillus, Cryptococcus, and Histoplasma etc

Extent of disease

  • Bilateral multi-lobar pneumonia
  • Associated with bacteraemia

As a result of Complications of pneumonia.

  • Empyema
  • Abscess
  • Metastatic infection such as infective endocarditis
  • ARDS/fibrotic lung disease

Diseases mimicking pneumonia

  • Malignancy
  • Systemic vasculitis
  • Collagen vascular disorder
  • Pulmonary oedema, CCF, heart failure with preserved EF, mitral regurgitation
  • Drug induced pneumonitis
  • Radiation pneumonitis
  • Hypersensitivity Pneumonitis.

b)                                                                                                                                             

Assessment will involve history, examination and investigations to delineate which of the causes from the above list may be contributing.

 History: 

  • Detailed history of travel, pets, occupation, medication, addiction and family history
  • Past medical history; e.g. radiation for lymphoma or breast cancer, systemic disease e.g., RA
  • Allergies
  • Medications

Examination: 

  • Looking for signs of complication and signs suggestive of other systemic illness such as collagen vascular disorders.
  • Assess for other sources of sepsis e.g. abscess, infectious endocarditis, catheter-related

Investigation:

Will depend upon the findings of the history and examination. Specific respiratory investigations may include: 

  • Repeat Tracheal aspirates- Send for fungal and cultures for unusual organisms
  • Bronchoscopic aspirates both for infectious causes and cytology
  • US guided pleural tap If fluid present
  • CT Chest: High resolution chest CT to detect parenchymal abnormalities, including emphysema, airspace disease, interstitial disease, and nodules o Chest CT also detects sequestered foci of infection, such as lung abscess and empyema, and helps direct biopsy procedures.
  • Thoracoscopic or open Lung biopsy: If bronchoscopy is non diagnostic and failure to improve and large specimens are required then open lung biopsy can be resorted to.

Other investigations may include:

  • Echocardiography
  • Vasculitis screen
  • EPG, IEPG, immunology screen, HIV serology

Discussion

Factors Associated with Treatment Failure
in Community-Acquired Pneumonia

Wrong disease

  • Abscess
  • Empyema
  • Vasculitis (eg. Wegeners)
  • Malignancy (eg. lung primary, mets or lymphoma)
  • Alveolar haemorrhage
  • BOOP
  • Alveolar proteinosis
  • SLE
  • Heart failure
  • PE
  • Sarcoidosis
  • Eosinophilic pneumonia

Wrong antimicrobial agents

  • Underdosing
  • Inappropriate dose interval
  • Poor penetration into lung tissue
  • Viral pneumonia
  • Atypical pneumonia, or a resistant organism:
    • Mycobacterium tuberculosis
    • Nocardia
    • Actinomyces israelii
    • Aspergillus
    • Coxiella burnetii (Q fever)
    • Chlamydia psittaci (psittacosis)
    • Leptospira interrogans (leptospirosis)
    • Pseudomonas pseudomallei (melioidosis)

Predictors of poor response to antibiotics:

  • Elderly patient
  • Multiple comorbidities
  • Alcoholism
  • Smoking (and COPD)
  • Multilobar pneumonia
  • Bacteraemia
  • Empyema and lung abscess
  • Legionella pneumonia
  • Polymicrobial pneumonia

A brilliant article on this topic is offered from Clinics in Chest Medicine (Kuru and Lynch, 1999), but unfortunately it is behind a paywall.  The next best source is probably the UpToDate page on nonresolving pneumonia. Again, access to the latter requires the exchange of money. This LITFL article, however, is free.

  • Culture again! You have selected some sort of Horrendomonas with your empirical therapy, and it will require a different antibiotic cocktail.
  • TTE: the contribution of cardiogenic pulmonary oedema to the respiratory failure needs to be considered.
  • CT chest; particularly high-resolution CT: it will reveal the full extent of the pneumonia, and it will unveil new cavitating lesions, loculated collections and bronchial masses.
  • Sputum eosinophils: eosinophilic pneumonitis may be to blame.
  • Acid-fast bacilli: it would be embarrassing to miss tuberculosis
  • Aspergillus investigations as well as the other fungi
  • CMV, VZV, HSV - PCR on sputum (though inlikely in an immunocompetent host)
  • Autoimmune screen; perhaps this "pneumonia" is in fact a pulmonary manifestation of a systemic autoimmune disease, eg. SLE, RA, Sjögren's syndrome, mixed connective tissue disease, Wegener's granulomatosis, Churg-Strauss syndrome, Goodpasture's syndrome,  ankylosing spondylitis, and so on and so forth.
  • Bronchoscopy: it will reveal any bronchial obstruction, and it may allow the lavage of a lobe, thereby collecting valuable specimens.
  • Lung biopsy: Even though this is invasive, it may be indicated in situations where the diagnosis is uncertain and the potential treatments are aggressive and mutually incompatible (eg. high dose steroids vs. high dose antibiotics)

References

Li, Meiling, et al. "Risk factors for slowly resolving pneumonia in the intensive care unit." Journal of Microbiology, Immunology and Infection (2014).

Sialer, Salvador, Adamantia Liapikou, and Antoni Torres. "What is the best approach to the nonresponding patient with community-acquired pneumonia?." Infectious disease clinics of North America 27.1 (2013): 189-203.

COJOCARU, Manole, et al.  "Pulmonary manifestations of systemic autoimmune diseases." Maedica 6.3 (2011): 224.

Kuru, Tünay, and Joseph P. Lynch. "Nonresolving or slowly resolving pneumonia." Clinics in chest medicine 20.3 (1999): 623-651.

Kyprianou, Andreas, et al. "The challenge of non resolving pneumonia." Postgrad Med 113.1 (2003): 79-92.

Rome, Lauren, Ganesan Murali, and Michael Lippmann. "Nonresolving pneumonia and mimics of pneumonia." Medical clinics of North America 85.6 (2001): 1511-1530.

Menéndez, Rosario, and A. Torres. "Evaluation of non-resolving and progressive pneumonia." Intensive Care Medicine. Springer New York, 2003. 175-187.

Oster, Gerry, et al. "Initial treatment failure in non-ICU community-acquired pneumonia: risk factors and association with length of stay, total hospital charges, and mortality." Journal of medical economics 16.6 (2013): 809-819.

Pareja, Jaime G., Robert Garland, and Henry Koziel. "Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia." CHEST Journal 113.5 (1998): 1215-1224.

Rodrigo, Chamira, et al. "Effect of corticosteroid therapy on influenza-related mortality: a systematic review and meta-analysis." Journal of Infectious Diseases 212.2 (2015): 183-194.

Parody, Rocio, et al. "Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or after hematopoietic stem cell transplantation: single‐center analysis and validation of the seattle, french, and strasbourg prognostic indexes." American journal of hematology 84.9 (2009): 571-578.

Bradley, B., et al. "Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society (vol 63, Suppl V, pg v1, 2008)." Thorax 63.11 (2008): 1029-1029.

Davis, William B., Henry E. Wilson, and Robert L. Wall. "Eosinophilic alveolitis in acute respiratory failure. A clinical marker for a non-infectious etiology." CHEST Journal 90.1 (1986): 7-10.

Steinberg, Kenneth P., et al. "Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome." New England Journal of Medicine 354.16 (2006): 1671-1684.

Question 22 - 2017, Paper 2

Critically evaluate the use of selective decontamination of the digestive tract (SDD) in the ICU.

College answer

Introductory statement  
SDD is a prophylactic strategy to prevent or minimise the incidence of nosocomial infection from endogenous organisms and to prevent or minimise cross-infection by the application of nonabsorbable oral and enteric antibiotics and parenteral antibiotics.  
Classically SDD has four components:  

  • Administration of orobase and enteral antibiotics (e.g. polymixin B, tobramycin and amphotericin)  
  • Parenteral antibiotic e.g. cefotaxime 
  • Good hygiene to prevent cross-contamination 
  • Microbiological surveillance of throat swabs and faecal samples Variations exist 
    Oropharyngeal eradication only (SOD) Enteral only Oral and enteral only Different antibiotics OR any reasonable and adequate introduction 

 
Rationale 
Nosocomial infections cause significant morbidity and mortality in the ICU. These infections arise from a limited number of potentially pathogenic micro-organisms (PPM) carried by healthy individuals (e.g. Staph aureus, E coli and C albicans) and opportunistic, aerobic Gram-negative bacilli (e.g. Klebsiella, Pseudomonas Acinetobacter) that colonise individuals when critically ill. The goal of SDD is to prevent or eradicate, if already present, at the start of ICU admission, the carriage of PPMs from the oropharynx and GI tract, leaving the indigenous flora, which protect against overgrowth with resistant bacteria, largely undisturbed. 
 
Arguments against; 

  • SDD might lead to increased antibiotic resistance of colonising bacteria 
  • There is already a significant overuse of antimicrobial therapy 
  •  

Evidence 

  • Over 60 RCTs with >15,000 patients (mostly in Europe) show benefits in terms of: 
  • mortality (NNT ~18) 
  • overall infection 
  • lower airway infections 
  • blood stream infections 
  • oropharyngeal carriage 
  • rectal carriage 
  • MODS 
  • ICU length of stay Patient patients. 
  • The evidence does not suggest an increase in MROs 
  • However the number of trials with good scientific methods are few 
  • In the trials that suggested benefit, there was baseline variance in patient demographics and overall care 
  • The trials that suggest benefit have been conducted in areas with a low prevalence of multiresistant organisms (northern Europe). 
  • There is a suggestion that selective oral decontamination is equally as effective as SDD, so the iv cephalopsporins are not required
  • Await the results of the international multi-centre RCT SuDDICU 

 
Summary statement and Personal approach Any reasonable statement of candidate’s own approach, for example 

  • Risk benefits 
  • Adoption by communities vs. units 
  • Protocols driven by local flora and practice vs. world evidence 
  • Not widely used in intensive care practice in ANZ 
  • The need for a definitive trial, especially in the ANZ community 
     

Discussion

This question is identical to Question 14 from the second paper of 2013. The answer has been reproduced below without any alterations. The college had also made minimal effort to change the answer since 2014, except where they deleted the middle words from the phrase "Patient groups studied include general ICU, burns, gastrointestinal surgery and transplant patients", leaving behind only "Patients patients" in an amusing proofreader fail.

Rationale

  • Critical illness causes an overgrowth of normal and opportunistic flora.
    • Specifically, the organisms which enjoy a population explosion are exactly those which are known to cause common nosocomial infections: predominantly oropharyngeal and upper GI organisms.
  • Increased population of this flora leads to the proliferation of multiple bacterial clones, which is an ideal environment for developing antimicrobial resistance.
  • Thus, it stands to reason that if one were to eradicate these organisms, one would reduce the incidence of nosocomial infection in critical illness, and reduce the incidence of antimicrobial resistance.

Protocol

  • There is no agreed-upon protocol.
  • Usual antibiotics are the "PTA" cocktail:
    • polymyxin E
    • tobramycin
    • amphotericin B
      • The SuDDICU authors have complained that these days its harder and harder to get "good old fashioned amphotericin" and the more recent trials have used nystatin instead, which is a poorly absorbed polyene antifungal (i.e. from the same class), cheap and already enjoying universal popularity as a treatment for oral candidiasis.
  • This goop is applied to the oral cavity, and injected down the NG tube.
  • Vancomycin can be added if there are high local rates of colonisation
  • A controversial step is the addition of a short course of IV antibiotics.
  • This is usually a broad spectrum cephalosporin eg. cephotaxime, and it is used for 4 days only. Many study protocols omit this.
  • Surveillance cultures of the throat and rectum are recommended

The beneficial effects are expected to manifest in the following ways:

  • Decreased incidence of VAP.
  • Decreased incidence of pseudocyst infection in acute pancreatitis.
  • Decreased systemic infection rate in cases of gastrointestinal haemorrhage.
  • Decreased incidence of spontaneous bacterial peritonitis in patients with ascites.
  • Protection against early gram-negative sepsis following liver transplantation

Potential drawbacks:

  • May result in increased rates of antimicrobial resistance
  • Expensive in terms of antibiotic doses, staff workload, and processing of surveillance samples
  • Local flora may not respond to standard antibiotic cocktails

Evidence:

  • To date, there are numerous RCTs - LITFL counted 60, with over 15,000 patients. A recent (2013) meta-analysis has identified 64 studies.
  • The studies have revealed that
    • There is a mortality benefit (OR = 0.73, NNT = 18)
    • Specificaly, the largest trial to date (de Smet, 2009) found an all-cause mortality reduction by 3.5%, from an absolute rate of 27.5% down to 25%.
    • Length of stay is decreased
    • VAP incidence is decreased by 72%
    • The "full-scale" SDD protocol (with a short course of IV antibiotics) is superior to the "limited" SDD where only the oropharynx is decontaminated (and both strategies are superior to oral chlorhexidine)
    • A 2004 Cochrane review found that whereas the "full-scale" SDD decreases the incidence of respiratory tract infections and mortality, the use of oropharyngeal decontamination alone had no effect on mortality- only on incidence of pneumonia.

Critique of the evidence

  • The studies all suffer from heterogeneity and poor experimental design.
  • Outcome definitions vary considerably, especially as there is no universally accepted definition of VAP.
  • Most of the studies were conducted in countries with a lower local MRSA prevalence (Germany and the Netherlands). In these affluent Norther European nations, rates of multiresistant organism colonization would not be representative.
  • Placebo solutions may have been microbial vehicles in these studies, increasing the incidence of VAP among the control group.
  • There are no good studies of the effect of SDD on the development of multi-resistant organisms (but poor-quality studies suggest that there is no effect).

Local practice

  • There is little support for this practice among the Australian intensivist community.
  • The practice has been regarded with skepticism in Australian ICUs, and there has been no broad department-level support for it here. Opponents cite paucity of good quality evidence and non-generalisability of European data in local intensive care units.

References

Marshall, John C. "Gastrointestinal flora and its alterations in critical illness."Current Opinion in Critical Care 5.2 (1999): 119.

van Saene, H. K. F., et al. "Microbial gut overgrowth guarantees increased spontaneous mutation leading to polyclonality and antibiotic resistance in the critically ill." Current drug targets 9.5 (2008): 419-421.

Camus, Christophe, et al. "Short-Term Decline in All-Cause Acquired Infections With the Routine Use of a Decontamination Regimen Combining Topical Polymyxin, Tobramycin, and Amphotericin B With Mupirocin and Chlorhexidine in the ICU: A Single-Center Experience*." Critical care medicine 42.5 (2014): 1121-1130.

Daneman, Nick, et al. "Effect of selective decontamination on antimicrobial resistance in intensive care units: a systematic review and meta-analysis." The Lancet infectious diseases 13.4 (2013): 328-341.

Price, Richard, Graeme MacLennan, and John Glen. "Selective digestive or oropharyngeal decontamination and topical oropharyngeal chlorhexidine for prevention of death in general intensive care: systematic review and network meta-analysis." BMJ: British Medical Journal 348 (2014).

Petros, Andy J., et al. "2B or Not 2B for Selective Decontamination of the Digestive Tract in the Surviving Sepsis Campaign Guidelines." Critical care medicine 41.11 (2013): e385-e386.

Hurley, James C. "Paradoxical ventilator associated pneumonia incidences among selective digestive decontamination studies versus other studies of mechanically ventilated patients: benchmarking the evidence base." Crit Care15 (2011): R7.

Ochoa-Ardila, María E., et al. "Long-term use of selective decontamination of the digestive tract does not increase antibiotic resistance: a 5-year prospective cohort study." Intensive care medicine 37.9 (2011): 1458-1465.

Hurley, James C. "The perfidious effect of topical placebo: A calibration of Staphylococcus aureus Ventilator Associated Pneumonia incidence within Selective Digestive Decontamination (SDD) studies versus the broader evidence base." Antimicrobial agents and chemotherapy (2013): AAC-00424.

Liberati, Alessandro, et al. "Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care." Cochrane Database Syst Rev 1 (2004).

Safdar, Nasia, Adnan Said, and Michael R. Lucey. "The role of selective digestive decontamination for reducing infection in patients undergoing liver transplantation: A systematic review and meta‐analysis." Liver transplantation10.7 (2004): 817-827.

Derde, L. P. G., and M. J. M. Bonten. "Controlling antibiotic resistance in intensive care units." Netherlands Journal of Critical Care, VOLUME 19 - NO 1 - FEBRUARY 2015

De Smet, A. M. G. A., et al. "Decontamination of the digestive tract and oropharynx in ICU patients." New England Journal of Medicine 360.1 (2009): 20.

Cuthbertson, B. H., et al. "A study of the perceived risks, benefits and barriers to the use of SDD in adult critical care units (The SuDDICU study)." Trials 11.1 (2010): 117.

Question 26 - 2017, Paper 2

Discuss strategies to limit antimicrobial resistance (AMR) in the ICU.

College answer

Factors driving antimicrobial resistance (AMR) include inappropriate use of antibiotics, inadequate monitoring and surveillance, poor infection control practices and failing antibiotic pipeline. 
 
Strategies to limit AMR include: 
1. Antimicrobial Stewardship 
Appropriate antimicrobial prescribing (right indication, right drug(s), right dose, right dosing regime, right duration) 
Liaison with microbiology / infectious diseases team 
Knowledge of local antibiograms 
Streamlining to narrow spectrum drugs / oral agents when appropriate Education of staff 
Computer-assisted prescribing 
Prescribing protocols 
Cycling of antibiotics (uncertain benefit) 
Antimicrobial prescribing committee 
 
2. Infection control 
Hand hygiene 
Barrier precautions 
Environmental cleaning 
Isolation / cohorting of patients 
Surveillance / screening / monitoring 
Appropriate staff:patient ratios 
Limit indwelling devices / appropriate asepsis for insertion etc 
Care bundles to reduce VAP, reduce time on ventilator, early enteral feeding etc 
 
3. Other 
Vaccination programs 
Adequate source control e.g. surgical drainage of abscesses Future directions include: 
More rapid and accurate diagnosis of sepsis 
Advances in genomics 
Immunomodulating agents  
Use of bacteriophages 
Use of antibiotics in agriculture and animal husbandry 
New drug development 
Synergistic combinations of antibiotics and drugs with no antimicrobial effect (eg minocycline and loperamide enhances action against staph aureus) 
 

Discussion

Prevention of resistance development

  • Use of some antibiotics should be restricted/reserved
    • Use in agriculture and animal husbandry needs to be limited
  • Broad spectrum antibiotics must be deployed intelligently
    • Rapid diagnostic methods to guide rapid de-escalation
  • Antibiotics must be reviewed daily, and narrowed or discontinued when appropriate
  • Infectious diseases physicians should have greater input into prescribing practices
  • Perioperative prophylaxis needs to be rationalised
  • Antibiotic cycling may be helpful in preventing the emergeance of resistant strains
  • Combination therapy may be relevant to some species (eg. rifampicin plus fusidic acid, rather than either one as a sole agent).
  • Selective digestive tract decontamination could potentially be useful
  • Scrupulous attention to source control (i.e. do not use antibotics as a substitute for source control)

Prevention of MRO transmission:

  • Routine barrier and infection control process needs complicance monitoring and regular review.
  • Surveillance for MROs must be proactive.
  • Patient isolation should be practiced
  • Decolonisation may be used in certain circumstances

Prevention of clinically relevant MRO infections in colonised patients

  • Careful monitoring of indwelling devices
  • Vaccinations

Management of MRO infections

  • Multi-drug cocktails might be helpful
  • Use of a higher concentration of a drug may defeat resistance 
  • MIC monitoring may guide dosing
  • New drugs may need to be developed
  • Novel drug combinations which exploit a synergy between antibiotics and non-antibiotic drugs - the college mention minocycline with loperamide but there are numerous others (Worthington, 2013)
  • Non-drug (eg. bacteriophage, immunoglobulin, hyperbaric oxygen) therapy may become necessary

References

Elliott, T. S. J., and P. A. Lambert. "Antibacterial resistance in the intensive care unit: mechanisms and management." British medical bulletin 55.1 (1999): 259-276.

Brusselaers, Nele, Dirk Vogelaers, and Stijn Blot. "The rising problem of antimicrobial resistance in the intensive care unit." Annals of intensive care 1.1 (2011): 1-7.

Niederman, Michael S. "Impact of antibiotic resistance on clinical outcomes and the cost of care." Critical care medicine 29.4 (2001): N114-N120.

Kollef, Marin H., and Victoria J. Fraser. "Antibiotic resistance in the intensive care unit." Annals of internal medicine 134.4 (2001): 298-314.

Spellberg, Brad, John G. Bartlett, and David N. Gilbert. "The future of antibiotics and resistance." New England Journal of Medicine 368.4 (2013): 299-302.

Di Bella, Stefano, and Nicola Petrosillo. "Management of antibiotic resistance in the intensive care unit setting from an international perspective."Microbiology Australia 35.1 (2014): 63-65.

Worthington, Roberta J., and Christian Melander. "Combination approaches to combat multidrug-resistant bacteria." Trends in biotechnology 31.3 (2013): 177-184.

Question 2 - 2018, Paper 1

You are asked to review a 54-year-old female in the Emergency Department who has community acquired pneumonia. The chest X-ray shows multi-lobar consolidation.
Outline the factors that will influence your decision regarding admission to the Intensive Care Unit (ICU) for this patient.

College answer

Intensive Care admission will be required for this patient if they need: 

  • interventions that cannot be provided elsewhere in the hospital (e.g. invasive mechanical ventilation, vasopressor support, etc), or 
  • require a high level of monitoring to allow early detection of deterioration and early intervention. 

The factors that will influence the decision to admit this patient include

  1. Patient factors 
  2. ICU factors
  3. Hospital facorts

1. The patient factors include: 

History 

Presence of one or more of these features may alter the balance of risk and therefore the inclination to admit to ICU

  • Background:
    • Comorbidities, baseline function o Previous or known respiratory disease
    • Malignancy o Smoking  o Immune competence
  • History of current illness o Rapid progression of symptoms  o Contact and travel history
    • Response to therapy thus far

Examination

  • Overall clinical impression at the time of review
  • Signs of respiratory distress
  • Signs of other acute or chronic organ failure

Investigations

  • Routine venous blood o hyponatraemia, elevated creatinine, abnormal LFTs, DIC, anaemia…
  • ABG 

o A-a gradient, acidaemia, CO2

  • ECG
  • CXR

Severe Community acquired Pneumonia scoring systems

  • There are several of these:
    • PSI o CURB-65
    • ATS criteria
    • SMART-COP
  • None have sufficient sensitivity or specificity to be used alone

2.         ICU Factors include

  • Local admission policy and culture
  • Bed and nursing staff availability
  • Specific bedspace availability (if isolation required)

3.         Hospital Factors

  • Bed availability and capability (e.g. is there a respiratory high dependency unit?)
  • Monitoring facilities on ward
  • Oxygen delivery capability of ward (?HFNP)

Medical, nursing staff and ancillary support staff (e.g., physiotherapy) capability of the ward

Summary

The decision to admit the patient to the ICU will depend on the intersection between how sick the patient currently is, the best prediction of the likely clinical course over the next 24 hours, the capacity of the ICU to admit further patients and the capacity of the ward in that particular hospital to care for a moderately unwell patient with the potential to deteriorate and require further invasive interventions. 

Examiners Comments:

Overall answered well, with good answers considering patients background morbidities as well as local hospital and ICU factors.

Discussion

"local admission policy and culture" is an excellent euphemistic way of saying either "we are an obstructive and unhelpful ICU" or "we admit anything". 

This question can be answered in a couple of different ways, depending on how you interpret it. One way would be to discuss the risk stratification (where patients at the greatest risk of death would be admitted to ICU), which would then lead to the discussion of whichever scoring systems you feel most comfortable with. The other way would be to start the discussion in terms of hospital resources and capacity. The college clearly wanted a large amount of the latter. Their model answer leaves little to improve upon. To be different in a totally arbitrary way which does not necessarily produce a better answer, one might reclassify the factors influencing ICU admission decisions into two broad groups: illness severity and resource requirement

Illness severity

  • Pneumonia severity:
    • Mortality as predicted by scoring systems (see below)
    • Level of respiratory support required (i.e. does the patient require HFNP, NIV or intubation?)
  • Acute comorbidity
    • Level of haemodynamic support required (i.e. does the patient need vasopressors, and if yes, then is there anywhere other than the ICU where they can be administered? The answer is usually no). 
    • Coesisting organ system dysfunction (i.e. acute renal failure, liver dysfunction, DIC, etc)
  • Chronic comorbidity
    • Chronic cardiac disease (likely to decompensate)
    • Chronic respiratory disease (lower reserve)
    • Immunosuppression
    • Fraily (i.e. is the patient unlikely to survive irrespective of whether or not they come to ICU?) 

Resource requirements

  • Skills
    • Level of cover (ward vs. ICU) - availability of respiratory physician, after-hours anaesthetic cover in the event that intubation becomes necessary
    • Ward staff may not be familiar with HFNP/NIV even if this were available outside the ICU
    • ICU staff may not be sufficiently experienced with prone ventilation 
  • Manpower
    • ​​​​​​​Sufficient nursing ratio to care for this complex patient
    • Respiratory or infectious diseases physicians may not be available (eg. small regional hospital)
    • An intensivist may not be available (small regional units are often run by physicians or anaesthetists)
  • Bed space logistics
    • A single isolation room might be required
    • Telemetry or hardwired monitoring may not be available outside the ICU in smaller centres
    • ​​​​​​​
  • Equipment
    • HFNP-enabled gas supply may not be available in the ward areas
    • The ICU may not be resourced to care for a patient who requires dialysis (small regional centres) or ECMO (most centres other than large tertiary units).
    • The pharmacy may have neither prostacycline nor nitric oxide

In an idealised setting, with an infinite number of 1:1 nurses and single rooms, pneumonia severity would be the only factor which needs to be considered. The severity of pneumonia is assessed by means of various scoring systems, which attempt to predict mortality. These are worth discussing in detail. 

Pneumonia severity scoring systems:

Of the possible risk stratification tools, one may need to commit to just one for the purposes of this question. There are many:

The college, in their answer to Question 18 from the first paper of 2012, used the IDSA/ATS document (to the extent that they cut and pasted the criteria directly into their model answer with zero modification).  These are reproduced below:

Which of these tools is best? According to a 2010 meta-analysis by Chalmers et al, they are all much the same. Niederman (2009), in a narrative review, suggests that these tools mainly differ according to the intended application.  The old PSI and the NICE guideline-recommended CURB65 score are both very good at identifying good for low-morality patients and there therefore better in the ED and the GP clinic. The IDSA/ATS guidelines and the SMART‐COP tool are probably better at identifying the patients at need of ICU care. For the purposes of completeness, the SMARRT-COP tool is included below:

SMART-COP

In case you want to use it, the CURB 65 score is calculated by giving 1 point for each of the following prognostic features:

  • confusion (abbreviated Mental Test score 8 or less, or new disorientation in person, place or time
  • raised blood urea nitrogen (over 7 mmol/litre)
  • raised respiratory rate (30 breaths per minute or more)
  • low blood pressure (diastolic 60 mmHg or less, or systolic less than 90 mmHg)
  • age 65 years or more.

Patients are stratified for risk of death as follows:

  • 0 or 1: low risk (less than 3% mortality risk)
  • 2: intermediate risk (3‑15% mortality risk)
  • 3 to 5: high risk (more than 15% mortality risk).

Whichever guidelines you use, ICU admission should be considered for the high risk patients, i.e. those at greatest risk of mortality. One might also add that ICU admission would be inappropriate for patients in whom mortality is expected to be inevitable regardless of treatment, and that should probably also factor into the decision.

References

Question 4 - 2018, Paper 1

a)    How would you diagnose Spontaneous Bacterial Peritonitis (SBP)?    (30% marks)
b)    List four common organisms causing SBP.    (20% marks)
c)    Other than SBP, list six common causes of decompensation of chronic liver disease.
(30% marks)
d)    In a patient with suspected SBP, microscopy of ascitic fluid is reported as showing gram positive cocci, gram negative bacilli and fungal elements. What is the likely diagnosis? (20% marks)

College answer

a) How would you diagnose Spontaneous Bacterial Peritonitis (SBP)?  (3 marks)

Occurs in patients with cirrhosis and ascites

Signs and symptoms of fever, abdominal pain, abdominal tenderness, altered mental status, hypotension. May be relatively asymptomatic and requires high degree of suspicion.

Diagnosis confirmed by paracentesis:

Neutrophil count > 250 cells/mm3 

Positive culture

Other tests that may be used in diagnosis include: Albumin, Total protein, glucose, and LDH

Other causes of peritonitis should be excluded.

 

b) List 4 common organisms causing SBP (2 marks)

E. coli

Klebsiella

Strep pneumoniae

Enterococci

c) Other than SBP List 6 common causes of decompensation of chronic liver disease (3 marks)

Upper GI Bleeding

Alcohol consumption / alcoholic hepatitis

Dehydration / over diuresis

Protein load

Constipation

Portal vein thrombosis

HCC

d) In a patient with suspected SBP microscopy of ascitic fluid is reported as showing gram positive cocci, gram negative bacilli and fungal elements.  What is the likely diagnosis? (2 marks)

Bowel perforation

Examiners Comments:

Overall answered well – candidates should be careful to read the question and just give the number of answers that are required: extra answers do not gain marks.

Discussion

a) The question "how'd you diagnose that" could be interpreted two ways. One might try to give the laboratory diagnostic criteria for spontaneous bacterial peritonitis:

  • Ascitic fluid neutrophil count must be > 250/mm3
  • Positive ascitic bacterial culture (for one organism only)
  • No other obvious (eg. surgical) source for these bacteria

Alternatively, one might respond that the diagnosis of SBP is made by performing paracentesis, which results from having a clinical suspicion in any patient who manifests the following features, on the background of the following risk factors:

  • Risk factors
    • Child-Pugh Grade C cirrhosis
    • Ascitic fluid protein level less than 10g/L
    • Gastrointestinal bleeding
    • Urinary tract infection
    • Intestinal bacterial overgrowth
    • Invasive devices: central lines, peripheral cannulae, IDCs 
    • Previous SBP episodes
  • Clinical features
    • Fever: 68%
    • Abdominal pain 49%
    • Tenderness on abdominal palpation 39%
    • Rebound tenderness 10%
    • Decreased level of consciousness 54%

b) According to Koulaouzidis et al (2009), here is a list of organisms most usually responsible for the classic monomicrobial SBP:

  • E. coli 37%
  • K. pneumoniae 17%
  • Misc gram-positives 14%
  • S. pneumoniae  12%
  • Misc. gram-negatives 10%
  • S. viridans 9%%

c) Apart from SBP, the following causes of acute decompensation are listed in Kim et al (2013)

  • Sepsis
  • Reactivation of a hepatitis virus (eg. hep B, C)
  • Alcohol
  • Drug-induced toxicity
  • Gastrointestinal haemorrhage
  • Surgery
  • Portal vein thrombosis
  • Ischaemic insult of any sort (eg. shock)
  • Autoimmune hepatitis
  • Wilson disease

Would a TIPS procedure be one of the causes of acute decompensation of liver disease? Would that earn any marks? It is difficult to say.  It certainly would cause a worsening of hepatic encephalopathy (usually), but portal hypertension and ascites should be improved.  These consensus recommendations describe decompensation as " variceal haemorrhage, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, hepatopulmonary syndrome and jaundice. ". Of the official college answers, a couple of the answers (UGI bleeding, portal load) would also mainly give you encephalopathy by itself. Furthermore, people who discuss complications of TIPS describe hepatic decompensation as one of the rare but well-documented possibilities (Suhocki et al, 2015) - where the shunt either reverses portal flow or causes ischaemia by squishing the major vessels accidentally.  

d) If the patient's ascitic fluid has multiple organisms, there are two possible explanations:

  1. The needle punctured the gut and some gut content was aspirated inadvertently into the culture bottles
  2. The patient has a perforated gut and has secondary bacterial peritonitis

In the latter case, mortality without surgery is essentially 100%. Some sort of urgent abdominal imaging would then be called for, to exclude this differential. If there is no evidence of surgical pathology, the zoo can be managed with the aforementioned broad-spectrum drugs without fear of complications: Runyon, the world guru on SBP, in his UpToDate article writes  "we have never encountered an episode of this variant in which surgical intervention was required."

References

Such, Jose, and Bruce A. Runyon. "Spontaneous bacterial peritonitis." Clinical infectious diseases (1998): 669-674.

Foris, Lisa A., and Melanie T. Stapleton. "Spontaneous Bacterial Peritonitis." (2017).

Koulaouzidis, Anastasios, Shivaram Bhat, and Athar A. Saeed. "Spontaneous bacterial peritonitis." World Journal of Gastroenterology: WJG 15.9 (2009): 1042.

Runyon, Bruce A. "Chapter 91. Ascites and Spontaneous Bacterial Peritonitis." (2002). 

Kim, Tae Yeob, and Dong Joon Kim. "Acute-on-chronic liver failure." Clinical and molecular hepatology 19.4 (2013): 349.

Suhocki, Paul V., et al. "Transjugular intrahepatic portosystemic shunt complications: prevention and management." Seminars in interventional radiology. Vol. 32. No. 2. Thieme Medical Publishers, 2015.

Question 20 - 2018, Paper 1

This organism was grown from an endotracheal tube (ETT) aspirate of a 67-year-old male with pneumonia.

Culture:

Light growth of Klebsiella pneumoniae

Antimicrobial Susceptibility

  • Amp / Amoxycillin   R
  • Amox/clav acid         R
  • Cefazolin                   R 
  • Cefotaxime                R  
  • Cotrimoxazole           R
  • Ciprfofloxacin           R
  • Gentamicin               R
  • Meropenem              R
  • Tigecycline               R
  • Ertapenem                R

What are the enzymes potentially responsible for antibiotic resistance? (10% marks)

How would you manage this clinical scenario? (90% marks)


 

College answer

a)

Klebiella pneumoniae carbapenemase (KPC)

Metallo-beta-lactamases (MBL’s – e.g. New Delhi metallo-beta-lactamase)

OXA beta-lactamase

(Only one required)

b)

i.          Resuscitation and supportive treatment as indicated

ii.         Antimicrobial Therapy

Use of antimicrobial dependant on clinical status of patient – avoid treatment if possible

If treatment required recommendation is combination antimicrobial therapy Optimal combination is uncertain

Depends on further resistance pattern and enzyme present. Specialist ID opinion should be sought

Options:

  1. Polymyxin-based regime (colistin or polymyxin B) 
  2. Meropenem (including high dose infusion) if isolate has acceptable MIC to meropenem as part of combination therapy
  3. Ceftazidime-avibactam (limited availability in Australia)
  4. Aztreonam
  5. Can consider tigecycline as part of combination therapy

iii.       Infection control procedures

Isolate patient in negative pressure room

1:1 nursing

Avoid unnecessary movement in and out of room

Have anteroom available

Dedicated equipment within room

Contact precautions in addition to standard precautions:

Signage

Strict hand hygiene

Wear gloves/gowns on entering room

Appropriate disposal of contaminated equipment

Appropriate infectious clean of surfaces and room post discharge Screening of other patients in unit.

Closed suction circuit if ventilated

Public health notification

Examiner Comments:

 Not well answered, with most attempts lacking structure, or understanding of all the relevant issues.

Discussion

a)

The fact that the college asked specifically which enzymes are responsible strongly implied that the college only wanted to hear the keywords "β-lactamase" or "carbapenemase", even though the Klebsiella strain they gave us was also resistant to aminoglycosides, fluoroquinolones, tetracyclines and cotrimoxazole. β-lactamase enzymes are classified according to a system called the Bush-Jacoby-Medeiros classification:

  • Class A: resistance to monobactams, third-generation cephalosporins, 
    but these are inhibited by clavulanate and tazobactam, at least in vitro. To this class belongs KPC, the Klebsielle pneumoniae carbapenemase.
  • Class B: resistance to penicillins, cephalosporins and carbapenems. NOT inhibited by clavulanate and tazobactam. These are the ones known as "metallo-beta-lactamases", because their active site contains a divalent metal cation, usually zink. This is the group to which belongs the "New Delhi" NDM-1 enzyme.
  • Class C: resistance to cephalosporins; limited inhibition by clavulanate and tazobactam. These are the enzymes induced in ESCAPPM organisms
  • Class D: "Oxacillinase"; resistance to carbapenems is slightly inhibited by clavulanate. These are also known as OXA  β-lactamase enzymes.

b)

Management might be summarised as follows:

Determine the result is clinically relevant

  • Assess the volume of secretions and determine their significance (i.e. is this really an infection, or it just a coloniser? It's a "light" growth)
  • Assess the clinical and radiological evidence for infection (is there a pneumonia, or is this result merely reflecting some sort of under-cuff microaspiration?)
  • Assess the clinical and biochemical evidence for the systemic effect of this infection (are the inflammatory markers rising, is the patient developing haemodynamic instability?)

Supportive management, if the result is clinically relevant

  • Optimise nutrition to minimise immunosuppressant effects of protein malnutrition
  • Supplement micronutrients including vitamins 
  • Cease all possible immunosuppressants

Non-antibiotic options

  • Chest physiotherapy for secretion clearance
  • Left and right alternating recovery position, to assist secretion drainage (or even prone)
  • Work towards extubation (secretion clearance by cough is usually better than tracheal suction)
  • Nebulise saline in addition to humidifying the circuit

Antibiotic options:

  • Determine the need for antibiotics
  • Antibiotic choice for KPC strains: colistin + meropenem + tigecyline or ceftazidime/avibactam (Hawkey et al, 2018).
  • Other options:
    • Aztreonam
    • Temocillin
    • Ceftazidime-avibactam
    • Ceftolozane-tazobactam
    • Meropenem-vaborbactam
    • Eravacycline
    • Streptomycin
    • Fosfomycin
  • Also it is possible to dose a carbapenem to MIC, eg. Pea et al (2017) who gave up to 13g/day of meropenem and had good success rates in killing carbamenemase producers
  • Give the agents as an infusion to maintain a steady above-MIC concentration (for time-dependent killers)

Prevent contamination of other patients

  • Hand hygiene
    • Soap and water for visibly contaminated hands
    • Alcohol-based rub for routine pre-and-post-contact hygiene
    • Monitoring of compliance should be performed
  • Disposable gloves
  • Disposable gowns
  • Contaminated areas should be identified by obvious cautionary signs
  • Routine disinfection of equipment between patient contacts
  • Wherever possible, individualised equipment for every patient

Institution-level management

  • Screening of all patients to identify reservoir for spread
  • Routine surveillance cultures
  • Decontamination of colonised health care workers
  • Infection control specialty team, composed of ICU specialists, infectious diseases specialists, senior nursing staff, laboratory staff and administration staff.
  • Allocated resources to MRO surveillance, compliance monitoring and education

The college in their answer mention that "recommendation is combination antimicrobial therapy" but do not specify whose recommendation that is. Presumably they were not referring to Hawkey et al (2018), as that statement came out approximately two weeks before the written paper. The authors admit that "most of the current evidence for the advantage of combination therapy ...derives from observational studies and reports". It is not totally clear that combination therapy is better than monotherapy, and studies tend to come up with wildly different contradictory conclusion, thereby generating some very confused systematic reviews (eg. Paul et al, 2014). The recommendations from Hawkey (2018) are:

  • For KPC strains, colistin + meropenem + tigecyline or ceftazidime/avibactam
  • For OXA strains, aztreonam or ceftazidime/avibactam as monotherapy
  • For metallo-β-carbapenemase producers, colistin + fosfomycin, +/- tigecycline 

References

Nordmann, Patrice, Gaelle Cuzon, and Thierry Naas. "The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria." The Lancet infectious diseases 9.4 (2009): 228-236.

Hawkey, Peter M., et al. "Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/healthcare Infection Society/british Infection Association Joint Working Party." Journal of Antimicrobial Chemotherapy 73.suppl_3 (2018): iii2-iii78.

MacVane, Shawn H. "Antimicrobial resistance in the intensive care unit: a focus on gram-negative bacterial infections." Journal of intensive care medicine 32.1 (2017): 25-37.

Schneider, Elena K., et al. "Antibiotic–non-antibiotic combinations for combating extremely drug-resistant Gram-negative ‘superbugs’." Essays in biochemistry 61.1 (2017): 115-125.

Question 1 - 2018, Paper 2

With respect to Clostridium Difficile (CD) colitis:

  1. List five risk factors for infection. (10% marks)
  2. What infection control measures would you take in a patient diagnosed with CD?  (30% marks)
  3. Outline the approach to diagnosis and pharmacological management of severe CD colitis. Include the rationale for Faecal Microbial Transplantation and under what circumstances you would consider its use.  (60% marks)

College answer

a) List 5 risk factors for infection. 
Antimicrobial use, especially fluoroquinolones, clindamycin, broad spectrum penicillins and cephalosporins. (Specific antibiotics expected) 
Increasing age use of PPI,  
inflammatory bowel disease,  
organ transplants, chemotherapy, chronic kidney disease, immune deficiency exposure to an infected individual,  Nursing home/health care facility resident 
 

b) What infection control measures would you take in a patient diagnosed with CD?  

Strict contact precautions  Isolation in single room 
PPE: healthcare workers should wear gloves, gowns, 5 moments of hand hygiene should be observed 
Use of soap and water more effective than alcohol based had wash (spores are resistant to killing by alcohol) in outbreak situations. Use of disposable equipment when possible 
Post discharge disinfection of the room  

c) Outline the approach to diagnosis and pharmacological management for severe CD colitis. Include the rationale for Faecal Microbial Transplantation and under what circumstances you would consider its use.

Diagnosis: 

Diarrhoea 
Radiographic evidence of ileus or megacolon 
Positive stool testing - either ELISA or PCR 
Presence of pseudomembranes on sigmoidoscopy 
 
Pharmacological Management 
 
Severe CD colitis – oral vancomycin (or fidaxamicin) and iv metronidazole. 

Fidaxamicin may be an alternative if vancomycin is not available or not tolerated. Vancomycin can be given rectally if there is severe ileus 
 
Faecal Microbial Transplantation (FMT)  

The human colonic microbiota, which provides colonization resistance against bacterial pathogens, is a key determinant in the pathogenesis of C. difficile. After exposure to oral antibiotics, a decline in faecal microbial diversity is common and may last many months. FMT reconstitutes healthy microbiota. 
Primarily indicated for recurrent disease that has not responded to antibiotic treatment 
 
Examiners Comments: 
 
Candidates need to read the question carefully; part c) specified severe infection which was not addressed in some answers. 

 

Discussion

This question falls into the growing group of SAQs which ask for a considerable amount of detail about this organism, known commonly as Clostridium difficile  because of a post-Linnaean convention of binomial nomenclature where we do not capitalise the species name, even when it is based on an otherwise capitalised personal or place name. That nerdgasm notwithstanding, the question itself is fairly similar to all the others before it, and contains all the familiar elements (risk factors, infection control measures, diagnosis and management). The only novel curveball was the additional need to discuss a faecal microbiota transplant, which was also weirdly capitalised. It is unclear how much of the 60% mark was allocated to the discussion of this exotic therapy.

Risk factors for C.difficile colitis (from Deshpande et al, 2015, and Leffler et al, 2015, where paragraphs of the latter bear a striking resemblance to the college answer, suggesting its origin)

  • Renal impairment
  • Severe underlying illness (i.e. ICU patients in general)
  • Non-surgical gastrointestinal procedures
  • Presence of an NG tube
  • Inflammatory bowel disease
  • exposure to an infected individual
  • Nursing home/health care facility resident 

Infection control measures:

Diagnosis

Clinical suspicion

  • Watery diarrhoea (≥3 loose stools in 24 hours)
  • History of antibiotic exposure 
  • Fever, abdominal pain, distension

Radiological diagnosis:

  • Bowel dilatation
  • Mural thickening and haustral fold thickening ("thumbprinting")
  • Toxic megacolon
  • Perforation and free intraperitoneal gas

Biochemical diagnosis: the current recommendations are:

  • PCR is better than toxin A or B identification
  • You should only test loose stools
  • You should not re-test.

Sigmoidoscopy (endoscopic diagnosis)

  • Pseudomembranes
  • Confirming biopsy and culture

Pharmacological management

Mild-moderate C.difficile infection:

  • Treat empirically in the absence of positive results, if the pre-test suspicion is strong.
  • Stop the inciting antibiotics
  • Give oral metronidazole for 10 days
    • Change metronidazole to vancomycin if there is no response in 5-7 days
  • For severe infection, just give oral vancomycin straight away(125mg qid for 10 days)
  • Vancomycin enemas are an option
  • Avoid anti-diarrhoea medications

Severe and complicated C.difficile infection:

  • CT of the abdomen is indicated
  • Oral vacomycin PLUS intravenous metronidazole are indicated
  • If there is significant abdominal distension, the vancomycin should be given as an enema

Recurrent C.difficile infection:

  • First recurrence: treat in the same way as the first episode
  • Second recurrence: change to vancomycin
  • Third recurrence: consider a faecal microbiota transplant

Faecal microbial transplant

Rationale:

  • C.difficile colitis is characterised by a loss of colonic biodiversity, which is attributed to the abuse of broad-spectrum antibiotics
  • Processed stool from healthy donors can promote a restoration of this "dysbiosis"

Circumstances for use:

  • Guidelines (ISDA/SHEA, 2018) recommend faecal microbiota transplantation for patients with multiple recurrences of C.difficile infection who have failed appropriate antibiotic treatments

References


Parker C, Tindall B, Garrity G. " International Code of Nomenclature of Prokaryotes" November 2015, International Journal of Systematic and Evolutionary Microbiology

Deshpande, Abhishek, et al. "Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis." infection control & hospital epidemiology 36.4 (2015): 452-460.

Leffler, Daniel A., and J. Thomas Lamont. "Clostridium difficile infection." New England Journal of Medicine 372.16 (2015): 1539-1548.

McDonald, L. Clifford, et al. "Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)." Clinical infectious diseases 66.7 (2018): e1-e48.

Question 4 - 2018, Paper 2

What are the principles involved in determining the loading dose and dosing frequency of antimicrobials in patients undergoing continuous veno-venous haemodiafiltration (CVVHDF)? 

College answer

Initial doses of drugs depend on the volume of distribution of the drug. For most antibiotics this is either unchanged or increased in critically ill patients with renal failure, so the initial dose should be a standard dose or higher. 
 
Subsequent dosing depends on clearance and PK-PD relationships. 
 
Clearance will depend on hepatic function (for those drugs that are hepatically metabolized) and residual renal function and clearance by CVVHDF (renally excreted drugs). 
 
Clearance by CVVHDF depends on ultrafiltration rate + dialysis flow rate (=effluent rate) and saturation coefficient. 
 
Saturation coefficient/sieving is predominantly dependent on protein binding and to a lesser extent on membrane material. 
 
Residual renal function can be estimated from measured creatinine clearance, but this will overestimate the clearance of drugs that undergo significant tubular reabsorption (e.g. fluconazole, colistin). 
 
The clearance determines the appropriate infusion rate (or dose and frequency) for time dependent antibiotics, dosing interval for concentration dependent antibiotics. 
 
Information on dosing frequency can be obtained from therapeutic drug monitoring during therapy Give no marks for molecular size (antibiotics are relatively small molecules) or discussions related to choosing antibiotics. 
 

Discussion

In summary,  these are the  General Principles of Antibiotic Dose Adjustment in CRRT:

  • Antibiotics with time-dependent killing:
    • if the drug is rapidly cleared by CRRT, the dosing interval should be decreased (i.e. the doses need to be given more frequently)
  • Antibiotics with concentration-dependent killing:
    • if the drug is rapidly cleared by CRRT, the actual dose should be increased, and dosing interval should remain more or less the same.
  • If the RRT is intermittent (eg. SLED):
    • the antibiotics should be given after the end of each session.

In detail:

Specifics of Antibiotic Dose Adjustment in CRRT

Drugs with a large volume of distribution, which do not rely on renal clearance

  • Ceftriaxone
  • Moxifloxacin
  • Clindamycin
  • Linezolid
  • Quinupristin
    /dalfopristin
  • Voriconazole
  • Clavulanate

Theoretically, these drugs should not need any changes to their dosing.

The amount of free drug dissolved in body water is normally so laughably small that renal (or renal-like) mechanisms can never play an important role in their clearance.

Drugs with a large volume of distribution, which do rely on renal clearance

  • Levofloxacin
  • Ciprofloxacin
  • Colistin
  • Amphotericin (liposomal)

These drugs should be given with an increased dosing interval.

The renal clearance of these drugs is usually reliant on some sort of exchange pump or active transport mechanism in the tubule. The CRRT filter is of course a dumb porous membrane without any sort of fancy pumps, and it will only filter the free fraction, of which there may not be much.

For some reason, Pea and Furlanut give only levofloxacin as an example of a drug affected in this way. Levofloxacin is excreted partially by tubular secretion, which may explain this sort of pharmacokinetics. Ciprofloxacin could probably also be included in this category, but its elimination is variably reliant on non-renal elimination routes (eg. faecal and biliary). The function of these elimination pathways is going to be wildly erratic in the critically ill population, so its uncertain how any given dose of ciprofloxacin is going to behave during CRRT.

Lastly, colistin seems to be a renally cleared drug with a massive volume of distribution, and its clearance by CRRT is poor in comparison to renal clearance. However, the issue is complicated by the fact that it avidly adsorbs onto the haemofilter membrane.

Drugs with a small volume of distribution, which do not rely on renal clearance

  • Ceftriaxone
  • Moxifloxacin
  • Clindamycin
  • Linezolid
  • Quinupristin
    /dalfopristin

This is a largely theoretical category.

Theoretically, these drugs would not need any adjustment to their dosing in CRRT, in comparison to a renally "normal" individual. Their small volume of distribution makes them easily available for renal (or dialytic) clearance, but the normal mechanisms they rely on for clearance remain unimpaired in renal failure.

Practically speaking, most drugs which have a small volume of distribution are also easily cleared renally, in part because they end up being filtered freely by the glomerulus, and not reabsorbed. Thus, this category really only applies to those drugs like adenosine, which are degraded rapidly by plasma enzymes, never even making it to the glomerulus. A discussion of their CRRT excretion is therefore completely meaningless.

Drugs with a small volume of distribution, which do rely on renal clearance

  • β-lactams
  • Carbapenems
  • Aminoglycosides
  • Most cephalosporins
  • Glycopeptides
  • Fluconazole

Theoretically, these drugs should not need any changes to their dosing.

These drugs should be cleared easily by CRRT, because normally they are cleared by glomerular filtration (with a little help from tubular secretion). The glomerular filtration is a renal excretion mechanism which should be well modelled by the CRRT circuit.

In fact, for some of these drugs the CRRT clearance is better than the normal renal clearance, and an increased dose/frequency may be required. Fluconazole is a classic example of a drug which requires an up-adjustment of daily dose if the CRRT dose exceeds 2L/hr.

References

McKenzie, Cathrine. "Antibiotic dosing in critical illness." Journal of antimicrobial chemotherapy 66.suppl 2 (2011): ii25-ii31.

Ulldemolins, Marta, et al. "Antibiotic dosing in multiple organ dysfunction syndrome." CHEST Journal 139.5 (2011): 1210-1220.

Chertow, Glenn M., et al. "Guided medication dosing for inpatients with renal insufficiency." Jama 286.22 (2001): 2839-2844.

Linton, A. L., and D. H. Lawson. "Antibiotic therapy in renal failure."Proceedings of the European Dialysis and Transplant Association. Vol. 1. 1970.

Question 20 - 2018, Paper 2

Outline the features of the Immune Reconstitution Inflammatory Syndrome (IRIS) in patients with Human Immunodeficiency Virus (HIV) infection with regards to:

  1. Definition
  2. Pathogenesis 
  3. Risk factors
  4. Differential diagnosis 
  5. Clinical features 
  6. Management

College answer

Definition

A collection of inflammatory disorders associated with paradoxical worsening of pre-existing infectious process following initiation of antiretroviral therapy primarily in HIV-infected patients.  It has also been described in patients receiving therapy for TB.

Pathogenesis

HIV infection produces CD4+ T cell immune suppression.

HIV half-life is generally between 1-4 days

With commencement of antiretroviral therapy there is greater than 90% reduction of HIV viral burden within 1-2 weeks.

CD4+ T lymphocyte count rapidly increases over the first 3-6 weeks

Increased lymphocyte activity then leads to systemic or local inflammatory reactions at the site or sites of pre-existing infection (known or unknown)

Risk Factors

Lower CD4 counts at time of initiation of therapy

High viral load at time of initiation of therapy

More significant response to antiretroviral therapy

Differential diagnoses 

Progression of initial opportunistic infection

New opportunistic infection

Drug toxicity

Clinical features 

Most patients develop symptoms within 1 week to a few months after the initiation of antiretroviral therapy.  Symptoms can be localised or systemic.  Features are similar to the primary infection.

Depend on the site and organism involved.  Commonly:

Pneumocystis jerovicii: fever, cough, dyspnoea, hypoxia and progressive radiographic pulmonary opacification.  BAL: large numbers of inflammatory cells

Cryptococcus: CNS: fever, headache, neck stiffness, photophobia. Pulmonary: lung lesions, hypoxia, respiratory failure and ARDS

TB: clinical or radiological pulmonary deterioration, lymphadenopathy, enlarging intracranial lesions

Others (any reasonable description OK): TB, MAC, CMV (uveitis), JC virus, Hepatitis B&C – worsened LFT’s. with fevers, seats anorexia; Kaposi sarcoma, toxoplasmosis (CNS)

Management 

Supportive

Continue antiretroviral therapy

Treat the underlying opportunistic infection

Severe symptoms = steroid therapy

Discussion

The college definition seems to be paraphrased from the opening paragraphs of Sharma & Soneja (2011), where it is described as a "paradoxical worsening of an existing infection or disease process".  Suggested definitions (French et al, 2004; Robertson et al, 2006) generally require some combination of the following features:

  • Temporal relationship with antiretroviral treatment
  • Worsening of inflammation
  • Symptoms not explained by new infection or worsening of a previous infection
  • Increase in CD4 count or decrease in HIV RNA copies

Obviously such HIV-centric definitions do not take into account the fact that IRIS can occur in several other conditions (eg. with tuberculosis).

Pathogenesis of IRIS is well-described in the IRIS article from UpToDate, from which the college answer appears to draw most of its inspirations.  For the purposes of regurgitating a point-form summary of what happens, the causes of IRS can be summarised thus:

  • The loss of CD-4 TH cells results  in a diminished immune response against a variety of antigens
  • As a consequence, with a very low CD4 cell count there may be infections with opportunistic pathogens which are sub-clinical and unrecognised
  • As HAART is started, HIV viral load rapidly decreases by as much as 90%  (as HIV has a short 1-4 day half life) and CD4 counts increase (over 3-6 weeks)
  • As CD4 counts increase, antigen-specific immune response pathways are restored
  • Thus, clinically silent opportunistic infections suddenly become clinically apparent as the immune response to them returns to normal
  • This typically manifests as inflammation of the locally affected tissues, or potentially as systemic inflammatory response resembling septic shock.

Risk factors for IRS  (according to Shellburn et al, 2005include:

  • Low CD4 counts at baseline
  • High HIV viral load at baseline
  • Highly active antiretroviral therapy (HAART)
  • Rapid drop of HIV RNA counts (i.e. vigorous response to HAART)
  • Infection with characteristic agents:
    • M. tuberculosis
    • M. avium complex
    • C. neoformans
    • P. jirovecii
    • VZV
    • HSV
    • CMV
    • Hepatitis viruses

Differential diagnosis (From Beshuizen et al, 2009):

  • Treatment failure of ART
  • Failure of treatment of an opportunistic infection
  • An alternative opportunistic infection.
  • Drug interactions
  • Drug toxicity

Clinical manifestations may include:

  • ARDS
  • Worsening of Pneumocystis pneumonia
  • Vasodilated shock
  • Fevers and rigors
  • Worsening of progressive multifocal leukoencephalopathy
  • Worsening of CNS tuberculosis infection (or pulmonary, for that matter)
  • Worsening of CMV retinitis and uveitis
  • Exacerbation (or de novo emergence) of VZV encephalitis
  • Worsening of cryptococcal meningitis (rising ICP)
  • Enlargement of CNS lesions due to M.tuberculosis
  • Worsening liver function due to IRIS reaction against Hep B or Hep C
  • Typically, features develop rapidly (within 90 days) of commencing HAART.

Management of IRIS (from Konishi et al, 2010)

  • Major management principles
    • Continue HAART 
    • Aggressively treat the opportunistic infection against which the reconstitution response has developed
    • Wait: most of the time, IRIS resolves over days or weeks
  • Specific therapy
    • NSAIDs
    • Corticosteroids (0.5-1.0mg/kg/day of prednisolone)
    • Infliximab, anti-TNF-α monoclonal antibody (Richaud et al, 2015)
    • Adalimumab, another kind of anti-TNF-α monoclonal antibody (Lwin et al, 2018)
  • Supportive therapy
    • Vasopressors, lung-protective ventilation, ICP management, FASTHUG
  • Worst case scenario
    • Interrupt HAART therapy

References

Mayer, Kenneth H., and Martyn A. French. "Immune reconstitution inflammatory syndrome: a reappraisal." Clinical Infectious Diseases 48.1 (2009): 101-107.

Sharma, Surendra K., and Manish Soneja. "HIV & immune reconstitution inflammatory syndrome (IRIS)." The Indian journal of medical research 134.6 (2011): 866.

French, Martyn A., Patricia Price, and Shelley F. Stone. "Immune restoration disease after antiretroviral therapy." Aids18.12 (2004): 1615-1627.

Robertson, Jaime, et al. "Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy.Clinical infectious diseases 42.11 (2006): 1639-1646.

Shelburne, Samuel A., et al. "Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy." AIDS 19.4 (2005): 399-406.

Beishuizen, S. J., and S. E. Geerlings. "Immune reconstitution inflammatory syndrome: immunopathogenesis, risk factors, diagnosis, treatment and prevention." Neth J Med 67.10 (2009): 327-331.

Konishi, M., K. Uno, and E. Yoshimoto. "Management of immune reconstitution inflammatory syndrome." Nihon rinsho. Japanese journal of clinical medicine 68.3 (2010): 508-511.

Richaud, Clémence, et al. "Anti-tumor necrosis factor monoclonal antibody for steroid-dependent TB-IRIS in AIDS." Aids 29.9 (2015): 1117-1119.

Lwin, Nilar, Michael Boyle, and Joshua S. Davis. "Adalimumab for corticosteroid and infliximab-resistant immune reconstitution inflammatory syndrome in the setting of TB/HIV coinfection." Open forum infectious diseases. Vol. 5. No. 2. US: Oxford University Press, 2018.

Question 21 - 2018, Paper 2

You are asked to review a confused 65-year-old female in the Emergency Department, who has presented with abdominal pain and vomiting. She has a history of ischaemic heart disease, obstructive airways disease and atrial fibrillation. 
 
On examination she is jaundiced, mildly confused and has right upper quadrant tenderness. 
 
Her vital signs, after 4 litres intravenous 0.9% saline, are as follows: 
 
Temperature           39.5oC  
Respiratory rate          30 breaths/min 
SpO2                 92% on 15 L/min O2 via a reservoir mask  
Heart rate                120 beats/min (atrial fibrillation)  
Blood pressure          88/48 mmHg  
 
An abdominal ultrasound scan shows a dilated common bile duct and enlarged gall bladder with mural oedema. 
 
Outline your management of this patient. 
 

College answer

The patient is most likely to have acute ascending cholangitis, which needs rapid resuscitation and definitive treatment. 
 
a)    Admit to the intensive care unit 
Provide resuscitative and organ supportive care.  
•    Resuscitate, Investigate and Treat simultaneously. 
•    Actively consider the need intubation and ventilation given her respiratory failure, confusion and haemodynamic instability,  
•    Central venous and arterial lines need to be inserted and monitoring commenced. Blood taken for investigations: 
FBC, Coags, UECs, LFTs, ABGs, cultures • No further intravenous fluid bolus 
•    Commence vasopressor support, aiming for a MAP > 65mmHg. 
•    Ensure referral to gastroenterology team for further investigation and management 
•    Consider MRCP or abdominal CT scan if diagnosis uncertain 
 
b)    Commence broad-spectrum empiric antibiotic therapy.  
Need good gram negative, gram positive and include anaerobic cover if very unwell: 
Examples include: amoxycillin and gentamicin and metronidazole piperacillin/tazobactam 
 
c)    Source control with decompression & drainage of her biliary tract. 
•    By most recent international guidelines this is Grade III (severe) acute cholangitis and thus the biliary tree must be urgently decompressed and drained.  
•    This can be done either endoscopically (ERCP) or percutaneously.  
•    Open surgery is not indicated in this situation.  
•    ERCP +/- sphincterotomy (provided the patients is not coagulopathic) is the gold standard and the best method of decompression and drainage. 
 
 
Examiner Comments: 
 
Many candidates gave further fluid boluses despite the history of marginal oxygenation and previous administration of 4l crystalloid, without any assessment of likelihood of the patient being fluid responsive. 

 

Discussion

This question is identical to Question 9 from the second paper of 2016 in every way, with the exception of the examiner's comments at the end of the answer (which are less snarky this time). In 2016, the pass rate was still quite good (65%). The discussion section to Question 9 from 2016 is reproduced below with zero modification.

This patient has to have some sort of biliary sepsis, because she manifests not only Charcot's Triad (abdominal pain, jaundice and fever), but the full Reynolds pentad (same, but with confusion and hypotension).

Immediate resuscitation

  • A: intubate the confused uncooperative patient
  • B: ventilate with mandatory mode
  • C: insert CVC, arterial line;
      - assess the need for further fluid resuscitation
      - commence vasopressors if  it appears that the patient is well filled
  • D: commence sedation and analgesia
  • E: correct electrolyte derangements and acidosis
  • F: Assess renal function; insert IDC
  • G: NGT for gastric decompression
  • H: keep Hb >70
  • I: broad spectrum antibiotics

Confirmation / investigation of cholangitis

  • Repeat LFTs
  • Inflammatory markers
  • CT of the abdomen ( the patient still has not me TG13 criteria, insofar as she has no evidence of any bile duct stone or mass).  Possible causes of duct obstruction could include stones (commonest), tumour, abscess, vascular malformation or parasites. Each might call for a different approach.
  • MRCP (can detect non-calcified stones more easily than CT, and is more sensitive for making the diagnosis of malignant obstruction)

Specific management

  • Antibiotics: Sanford Guide recommends Tazocin or Meropenem.
    Of the patients with cholangitis, 70-80% will respond to conservative management (i.e. they get better with antibiotics and are clinically well by the time they get to have an ERCP).
  • ERCP: the treatment of choice whenever feasible (stent or sphincterotomy)
  • Percutaneous transhepatic cholangiography (PTCC): the bile duct can be decompressed by inserting a needle into the liver and draining the pus that way. PTC can also be used to put stents in, image the duct, extract stones, etc.
  • Percutaneous cholecystostomy:  if the gall bladder is accessible, the simplest thing would be to put a drain into it (just as in the case of acalculous cholecystitis)
  • Surgical decompression by T-tube:  if ERCP is impossible, inserton of a T-tube has a lower complication rate than open cholecystectomy and exploration.
  • Surgical cholecystectomy and exploration of CBD:  this is the approach which led to the mortality rates in excess of 50% during the 1960s and 70s.
  • Cholecystectomy: ultimately, the gall bladder must be removed, but it should ideally happen
  • Oncology referral:  in the event that the CBD was compressed by a head of pancreas mass or somesuch

Supportive management

  • Mechanical ventilation - mandatory mode while severely septic; then weaning off the ventilator
  • Haemodynamic support with vasopressors
  • Management of AF with amiodarone
  • Vigilant monitoring for myocardial infarction with daily ECGs
  • Nutrition - post-ERCP, one should be able to commence NG diet
  • Adequate analgesia
  • PPI, heparin, etc

References

Laurila, Jouko, et al. "Acute acalculous cholecystitis in critically ill patients."Acta anaesthesiologica scandinavica 48.8 (2004): 986-991.

Wang, Ay-Jiun, et al. "Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis." Heart 1500 (2003): 8.

Boland, Giles W., et al. "Percutaneous cholecystostomy in critically ill patients: early response and final outcome in 82 patients." American Journal of Roentgenology 163.2 (1994): 339-342.

Question 30.1 - 2018, Paper 2

a)    List six clinical signs on examination that would support the diagnosis of infective endocarditis in a patient with fever and a new murmur.     (30% marks) 

College answer

•    Janeway lesions (small, non-tender erythematous or haemorrhagic macular or nodular lesions on the palms or soles) 
•    Roth spots (retinal haemorrhages with pale or white centres) 
•    Oslers nodes (painful, red raised lesions found on the hands and feet)  
•    Splinter haemorrhages  
•    Clubbing  
•    Splenomegaly  
•    Petechiae 
 

Discussion

This question, and the college answer, are identical to  Question 29.1 from the second paper of 2014.

An excellent review article form 2009 lists the following clinical features:

  • Osler's nodes
  • Janeway lesions
  • Splinter haemorrhages
  • Roth spots
  • Focal neurological signs suggestive of embolic phenomena
  • A new murmur or a worsening of an old murmur
  • Splenomegaly
  • Glomerulonephritis
  • Arthralgia and arthritis
  • Elevated ESR, CRP or rheumatoid factor
  • Haematuria

The abovementioned article has a table (Table 3) which lists these manifestations according to their prevalence among a large patient cohort. The emphasis of the article is on endocarditis "in the 21st century", implying that the endocarditis of the previous centuries was substantially different. This is certainly true. One need only refer to the 1885 Gulstonian Lectures by William Osler to see what infective endocarditis looked like in the pre-antibiotic era (in short, it was uniformly fatal). For a relatively recent 20th century perspective, one can turn to a 1983 review of the state-of-the art diagnosis and therapy for the previous 25 years.

References