Printable list of all infectious disease SAQs

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

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.

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
  • Vasopressor support
  • Careful fluid resuscitation, given that these patients are frequently severely dehydrated, but also acknowledging the fact that vigorous fluid resuscitation in malaria can lead to increased mortality
• 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
  • A 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.

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.

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.

References

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.

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.

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

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.

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.

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

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

• Septic shock
• DIC
• Acute adrenal haemorrhage (Waterhouse-Friedrichsen syndrome)
• Multiorgan system failure
• Meningitis
• Conjunctivitis
• Arthritis
• Pericarditis

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.

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

• Tracheal aspirate culture, BAL sample or PSB (protected specimen brush) - its all the same, it seems the method of sampling really does not influence survival.
• Blood cultures should be collected, but one does so with the knowledge that the organism cultured from the blood may not represent the organism causing the 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.

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.pneumoniae, H.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.

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

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.

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.

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.

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.

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

• Most species of Candida albicansare susceptible
• For susceptible organisms, fluconazole is at least equal (if not superior) to amphotericin.
• It has good oral bioavailability
• It has relatively low toxicity
• It seems to enhance the bactericidal activity of neutrophils

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.kruzei, C.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

• Fluconazole prophylaxis for surgical patients does not reduce mortality.
• Fluconazole as a co-antibiotic in septic shock seems to reduce mortality according to one small trial.
• In 2008, a similar trial compared empirical fluconazole to placebo, and was terminated due to a lack of primary endpoint difference (i.e. placebo was equally effective)

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.

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

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.

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

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.

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.

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:

• Broad spectrum antibiotics in particular clindamycin, quinolones, amoxycillin, cephalosporins

• Immunosuppressive therapy /Cytotoxic chemotherapy

• Gastric acid suppression

• Age > 65

• Prolonged hospitalisation

• Renal impairment

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.

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.

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.

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

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"

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

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.

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

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.

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.aphrophilus, H.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.

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

• Animal models predict benefit from steroids in ARDS.
• Human trials among early ARDS patients did not demonstrate any benefit (and suggested that there may be an increase in infectious complications).
• Human trials among late "fibroproliferative" ARDS patients demonstrated good evidence of harm rather than benefit, with greater incidence of muscular weakness.
• 2009 meta-analysis concluded that there might be some trend towards a mortality benefit, but without good quality evidence
• Another 2009 meta-analysis found a trend towards a small decrease in all-cause mortality in the group who received the lowest doses of steroids.

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.

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.

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.

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.

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

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.

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

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.

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

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

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

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.

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:

• Nitric oxide synthase induction by cytokines and endotoxin
• Direct vascular smooth muscle response to acidosis and hypoxia - this is mediated by theactivation of ATP-sensitive K⁺ channels, which which hyperpolarise the smooth muscle cell membranes, preventing contraction and producing vasoplegia.
• Inflammatory mediators produced by activated leucocytes
• Vasodilatory mediators (eg. histamine bradykinin and serotonin) produced by leukocytes and platelets
• Relative vasopressin deficiency
• Relative adrenal insufficiency, resulting in peripheral catecholamine insensitivity
• Acidosis, resulting in peripheral catecholamine insensitivity

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.

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,  Enterobacter, E. coli, Hafnia alvei, Lysobacter lactamgenus, Ochrobactrum anthropi, Proteus rettgeri,  Pseudomonas aeruginosa, Psychrobacter 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.

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.

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

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.

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:

• Viral myocarditis and respiratory infection (enterovirus or adenovirus)
• Leptospirosis
• Legionella pneumonia (yes, it can cause pericarditis and endocarditis)
• Q fever (which can cause endocarditis)
• Mycoplasma pneumoniae
• Streptococcus pneumonia and streptococcal endocarditis
• Brucellosis (arthralgia and fever in a cattle farmer)
• Malaria
• Sickle cell disease

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.

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:

• Acalculous cholecystitis
• Ischaemic hepatitis
• Pancreatitis
• Hepatic congestion due to right heart failure

Other causes of RUQ pain which neglect the raised bilirubin:

• Pancreatitis
• Duodenal or gastric ulceration
• Bowel ischaemia

Biochemical markers of sepsis include:

• CRP
• Procalcitonin
• LPS-binding protein
• sTREM-1
• Presepsin (sCD14-st)
• HMGB-1
• CD64 - although its not really a "biochemical marker" as it is expressed on the surface of neutrophils

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.

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.

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 anthracis, Corynebacterium 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.

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

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

Discussion

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

• Tigecycline
• Linezolid (particularly for MRSA pneumonia, where vancomycin penetrates poorly)
• Quinupristin/dalfopristin
• Daptomycin
• Fosfomycin (usually to enhance the effects of other drugs)
• Rifampicin/fusidic acid (particularly for deep bone and joint infections)
• Telavancin, dalbavancin and oritavancin
• Ceftobiprole and ceftaroline
• Iclaprim
• Trimethoprim/sulfamethoxazole
• Moxifloxacin

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.

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:
  • Procalcitonin may be useful in identifying occult infection; levels peak within 6-8 hours after the first appearance of endotoxin, and this it may identify patients with severe infection before blood cultures have time to incubate, and before more serious manifestations of sepsis have time to evolve.
  • Procalcitonin may be useful in discriminating between bacterial and non-infectious causes of inflammation, as its synthesis is triggered by bacterial endotoxin
• Evidence: what the recent trials say
  • The college answer quotes the PRORATA study which suggested that the use of procalcitonin could result in reduced antibiotic exposure.
  • There are others:
    • ProSEP study (2008)
    • PASS study (2008)
    • ProSICU study (2009)
    • ProVAP study (2009)
    • ProRATA study (2010)
    • SAPS study (2013)
  • Overall, according to a recent meta-analysis (2015)
  • • "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.

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.

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:
  • S.pneumoniae - but mainly in asplenic patients for some reason
  • S.aureus
  • H.influenzae
  • N.meningitides
  • Endocarditis of any bacterial aetiology
• 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.

College Answer

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

College Answer

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, Stenotrophomonas, Citrobacter, Acinetobacter, Serratia, Achromobacter 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.

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.

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.

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.

College Answer

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.

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.

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.

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:

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.

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.

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.

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?

• Broad spectrum antibiotics in particular clindamycin, quinolones, amoxycillin, cephalosporins

• Immunosuppressive therapy /Cytotoxic chemotherapy

• Gastric acid suppression

• Age > 65

• Prolonged hospitalisation

• Renal impairment

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.

College Answer

Discussion

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.

College Answer

a) Clinical features indicating poor prognosis

1. • 1. Common organisms
     • Streptococcus pneumonia
     • Legionella spp
     • Haemophilus influenza
     • Klebsiella pneumonia
     • Staphylococcus aureus
     • Respiratory viruses
     • Mycoplasma
   1. • Reasons for non-response
      1. • 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. 1. Complication of treatment
      1. • Antibiotic reaction
         • Superinfection
   2. Underlying disease
      1. • Cancer
         • Airway obstruction
         • Severe emphysema with bullae
2. Stopping antibiotics

1. • 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.

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

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.

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

• Need for isolation
• Potential for clinically significant VRE infection
• Potential for transmission of vancomycin resistance to S.aureus

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.

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.pneumoniae, H.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.

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.

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.

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.

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

• Rapid antigen tests range in sensitivity from 38.3% to 53.3% - thus, they dont actually excludeH1N1 - but they do confirm the diagnosis rapidly in a proportion of cases.
• Real time reverse transcriptase PCR (rRT-PCR)is the gold standard against which the rapid antigen tests are measured
• Diagnosis relies on the presence of a flu-like illness, as well as rRT-PCR confirmation.
  • The features of "flu-like illness" require respiratory symptoms and a history of fever (not necessarily a "documented" fever).

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

College Answer

a)

Not to give additional antibiotics

Consider removing / re-siting the femoral CVC depending on the patient’s condition

b)

1. 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:

• Coagulase-negative staph bacteraemia might sound quite rare (7 per 10,000 admissions) but is in fact the most common catheter-related bacteraemia.
• Cultures collected during CVC insertion are more likely to yield contaminants than peripheral blood cultures
• Significance of a coagulase-negative staph in a blood culture is determined by the presence of the clinical features of infection and in those cases one would be obliged to change the line. If it was a true bacteraemia, it will occur again in 20% of patients in whom the catheters remain in situ, compared to 3% in patients whose lines are changed.

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.

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.

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.

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.

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. Labetalol, magnesium 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.

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