Carbapenemase-producing Gram negatives – what are treatment options?

Guest posting from Professor Josh Davis, Infectious Diseases, John Hunter Hospital, NSW and Menzies Institute , Darwin, Dr Patrick Harris , NHMRC Early Career Fellow at The University of Queensland Centre for Clinical Research (UQCCR)

Carbapenemase-producing Enterobacterales (CPE),  Pseudomonas aeruginosa and Acinetobacter baumannii are usually resistant to most other antibiotics in addition to meropenem.  Treatment options are limited and potentially expensive.  In the first instance it is most important to decide whether treatment is indicated as in many patients,  detection of these organisms represents colonisation rather than infection.  The Ambler molecular class is a useful starting point as this predicts whether a particular carbapenemase can be inhibited by certain inhibitors.   CRE stands for carbapenem-resistant Enterobacterales.

AMBLER CLASS Class A Class B Class D
Key characteristic Serine group enzyme Metallo-betalactamase OXA-type
Key example(s) KPC, GES IMP, NDM, VIM OXA-48  (OXA-181, OXA-232 emerging)
Susceptibility features R to all beta-lactams R to all beta-lactams except aztreonam

May harbour other ESBLS, AmpC enzymes or KPCs encoding aztreonam resistance, and these are inhibited by avibactam.

Often, but not always R to all beta-lactams

(OXA does not confer cephalosporin R, but co-existing ESBL often present)

Inhibited by avibactam Yes No Yes
Inhibited by vaborbactam Yes No No
Inhibited by clavulanate and tazobactam Variable No No
Main Rx options Ceftazidime-avibactam Ceftazidime-avibactam plus Aztreonam

Cefiderocol

Ceftazidime-avibactam
Other Rx options Add Mero if Intermediate MIC

Meropenem-vaborbactam

Colistin plus meropenem (Mero MIC<=8)

Colistin plus tigecycline (Mero MIC>8)

IV fosfomycin

Often low level carbapenem resistance, so meropenem MICs may allow use (usually in combination where possible)
Notes CTX-M, TEM, SHV are class A b-lactamases but are NOT carbapenemases

Meropenem+colistin failed in RCT

Ceftazidime-avibactam plus Aztreonam has emerging supportive observational data*. Even in Aztreonam R isolates, the Avi likely restores Aztreonam S. The Ceftaz is not needed, so when Atztreonam/Avi becomes available it will Ceftaz/Avi+Aztreonam. Ceftazidime-avibactam is 2.5g q8h, extended infusion
  • Class C b-lactamases are cephalosporinases, as in ESCPPM group (ampC) may give rise to carbapenem resistance if combined ampC hyper-expression and porin changes;
  • Plazomicin a good option for CRE urosepsis if available;
  • Cefiderocol likely effective against most CREs but possible increased mortality in Acinetobacter infections.

*Falcone CID 2020, https://doi.org/10.1093/cid/ciaa586

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