College answer

a)

Klebiella pneumoniae carbapenemase (KPC)

Metallo-beta-lactamases (MBL’s – e.g. New Delhi metallo-beta-lactamase)

OXA beta-lactamase

(Only one required)

b)

i.          Resuscitation and supportive treatment as indicated

ii.         Antimicrobial Therapy

Use of antimicrobial dependant on clinical status of patient – avoid treatment if possible

If treatment required recommendation is combination antimicrobial therapy Optimal combination is uncertain

Depends on further resistance pattern and enzyme present. Specialist ID opinion should be sought

Options:

1. Polymyxin-based regime (colistin or polymyxin B) 
2. Meropenem (including high dose infusion) if isolate has acceptable MIC to meropenem as part of combination therapy
3. Ceftazidime-avibactam (limited availability in Australia)
4. Aztreonam
5. Can consider tigecycline as part of combination therapy

iii.       Infection control procedures

Isolate patient in negative pressure room

1:1 nursing

Avoid unnecessary movement in and out of room

Have anteroom available

Dedicated equipment within room

Contact precautions in addition to standard precautions:

Signage

Strict hand hygiene

Wear gloves/gowns on entering room

Appropriate disposal of contaminated equipment

Appropriate infectious clean of surfaces and room post discharge Screening of other patients in unit.

Closed suction circuit if ventilated

Public health notification

Examiner Comments:

 Not well answered, with most attempts lacking structure, or understanding of all the relevant issues.

Discussion

a)

The fact that the college asked specifically which enzymes are responsible strongly implied that the college only wanted to hear the keywords "β-lactamase" or "carbapenemase", even though the Klebsiella strain they gave us was also resistant to aminoglycosides, fluoroquinolones, tetracyclines and cotrimoxazole. β-lactamase enzymes are classified according to a system called the Bush-Jacoby-Medeiros classification:

• Class A: resistance to monobactams, third-generation cephalosporins, 
  but these are inhibited by clavulanate and tazobactam, at least in vitro. To this class belongs KPC, the Klebsielle pneumoniae carbapenemase.
• Class B: resistance to penicillins, cephalosporins and carbapenems. NOT inhibited by clavulanate and tazobactam. These are the ones known as "metallo-beta-lactamases", because their active site contains a divalent metal cation, usually zink. This is the group to which belongs the "New Delhi" NDM-1 enzyme.
• Class C: resistance to cephalosporins; limited inhibition by clavulanate and tazobactam. These are the enzymes induced in ESCAPPM organisms
• Class D: "Oxacillinase"; resistance to carbapenems is slightly inhibited by clavulanate. These are also known as OXA  β-lactamase enzymes.

b)

Management might be summarised as follows:

Determine the result is clinically relevant

• Assess the volume of secretions and determine their significance (i.e. is this really an infection, or it just a coloniser? It's a "light" growth)
• Assess the clinical and radiological evidence for infection (is there a pneumonia, or is this result merely reflecting some sort of under-cuff microaspiration?)
• Assess the clinical and biochemical evidence for the systemic effect of this infection (are the inflammatory markers rising, is the patient developing haemodynamic instability?)

Supportive management, if the result is clinically relevant

• Optimise nutrition to minimise immunosuppressant effects of protein malnutrition
• Supplement micronutrients including vitamins 
• Cease all possible immunosuppressants

Non-antibiotic options

• Chest physiotherapy for secretion clearance
• Left and right alternating recovery position, to assist secretion drainage (or even prone)
• Work towards extubation (secretion clearance by cough is usually better than tracheal suction)
• Nebulise saline in addition to humidifying the circuit

Antibiotic options:

• Determine the need for antibiotics
• Antibiotic choice for KPC strains: colistin + meropenem + tigecyline or ceftazidime/avibactam (Hawkey et al, 2018).
• Other options:
  • Aztreonam
  • Temocillin
  • Ceftazidime-avibactam
  • Ceftolozane-tazobactam
  • Meropenem-vaborbactam
  • Eravacycline
  • Streptomycin
  • Fosfomycin
• Also it is possible to dose a carbapenem to MIC, eg. Pea et al (2017) who gave up to 13g/day of meropenem and had good success rates in killing carbamenemase producers
• Give the agents as an infusion to maintain a steady above-MIC concentration (for time-dependent killers)

Prevent contamination of other patients

• Hand hygiene
  • Soap and water for visibly contaminated hands
  • Alcohol-based rub for routine pre-and-post-contact hygiene
  • Monitoring of compliance should be performed
• Disposable gloves
• Disposable gowns
• Contaminated areas should be identified by obvious cautionary signs
• Routine disinfection of equipment between patient contacts
• Wherever possible, individualised equipment for every patient

Institution-level management

• Screening of all patients to identify reservoir for spread
• Routine surveillance cultures
• Decontamination of colonised health care workers
• Infection control specialty team, composed of ICU specialists, infectious diseases specialists, senior nursing staff, laboratory staff and administration staff.
• Allocated resources to MRO surveillance, compliance monitoring and education

The college in their answer mention that "recommendation is combination antimicrobial therapy" but do not specify whose recommendation that is. Presumably they were not referring to Hawkey et al (2018), as that statement came out approximately two weeks before the written paper. The authors admit that "most of the current evidence for the advantage of combination therapy ...derives from observational studies and reports". It is not totally clear that combination therapy is better than monotherapy, and studies tend to come up with wildly different contradictory conclusion, thereby generating some very confused systematic reviews (eg. Paul et al, 2014). The recommendations from Hawkey (2018) are:

• For KPC strains, colistin + meropenem + tigecyline or ceftazidime/avibactam
• For OXA strains, aztreonam or ceftazidime/avibactam as monotherapy
• For metallo-β-carbapenemase producers, colistin + fosfomycin, +/- tigecycline