Carbapenemases

Background

• Enzymes that hydrolyze carbapenems
• Includes members of all Ambler classes, which are in Bush-Jacoby classes 2df, 2f, 3a, and 3b
  • Class A (2f): KPC, IMI
  • Class B (3a and 3b): NDM, IMP, VIM
  • Class C: AmpCs (occasionally weakly active against carbapenems)
  • Class D (2df): OXA-48

Identification

• Screening is done by identifying isolates with decreased susceptibility to one or more carbapenems
  • Testing "not susceptible" to ertapenem is the most sensitive indicator
  • Typically also resistant to third-generation cephalosporins, as well, with the exception of SME in Serratia marcescens and IMI
• A modified Hodge test can confirm the presence of a carbapenemase, but is no longer routinely recommended
• Modified carbapenem inactivation method (mCIM)
  • Place meropenem disc in a suspension of the test isolate, and incubate at 35ºC for 4 hours
  • Remove disc, squeezing out excess fluid, and place on a lawn of susceptible Escherichia coli
  • Positive for carbapenemase if zone diameter is clear ≤15 mm (or pinpoint colonies up to 18 mm)
  • Negative if zone diameter is clear ≥19 mm
  • Indeterminate if clear diameter 16 to 18 mm, or pinpoint colonies ≥19 mm
• EDTA-modified carbapenem inactivation method (eCIM)
  • Only done if mCIM is positive, to test for metallo-β-lactamases
  • As above for mCIM, but adds EDTA to the tube
  • Positive for metallo-β-lactamase if zone diameter increases ≥5 mm from mCIM
    • Ignore pinpoint colonies within any zones of inhibition in the eCIM
• Double disc diffusion (using Rosco discs)
  • Class A: attenuated by boronic acid
  • Class B: attenuated by diploconic acid
  • Class C: attenuated by both cloxacillin and boronic acid
  • Class D: not attenuated by boronic acid, diploconic acid, or cloxacillin
    • Needs special discs, or PCR testing

Inhibitors

• Avibactam: active against ESBLs, AmpCs, KPC, and OXA-48, but not MBLs and other OXAs
  • Only inhibitor with some activity against class D (OXAs)
• Relebactam: active against ESBLs, AmpCs, and KPC, but not OXA-48, VIM, GES, or MBLs
• Tazobactam: active against Pseudomonas, but limited activity against carbapenemases otherwise
• Vaborbactam: active against KPC, but limited activity against MBLs and OXA-48, Pseudomonas, or Acinetobacter

Specific Carbapenemases

• Class A carbapenemases
  • KPC (Klebsiella pneumoniae carbapenemase) is the most common carbapenemase, located on a plasmids and found most commonly in Klebsiella pneumoniae
  • GES-1 (Guiana extended spectrum) is located on plasmids
  • SME (Serratia marcescens enzyme) is chromasomal and found in Serratia marcescens
  • NMC-A (not metalloenzyme carbapenemase) is chromasomal and found in Enterobacter cloacae
  • IMI-1 (imipenem-hydrolyzing β-lactamase) is chromasomal and found in Enterobacter cloacae and confers resistance to carbapenems but possibly not to cephalosporins1
• Class B carbapenemases (metallo-β-lactamases)
  • VIM-2 (Verona integron-encoded metallo-β-lacamase) is the most common metallo-β-lactamase worldwide, is on a multiple-intergron cassette, and is mostly found in Pseudomonas aeruginosa
  • IMP (active on imipenem) is on a conjugative plasmid and is mostly found in Pseudomonas aeruginosa but has also been found in Enterobacterales
  • NDM (New Delhi metallo-β-lactamase) is transmitted by horizontal gene transfer and is most commonly found in Escherichia coli, Klebsiella pneumoniae, and other Enterobacterales
  • SPM-1 (Sao Paulo metallo-β-lactamase) has been found in Pseudomonas aeruginosa in Brazil
  • GIM-1 (German imipenemase) is in a class 1 integron on a plasmid and has been found in Pseudomonas aeruginosa
  • SIM-1 (Seoul imipenemase) is in a class 1 integron and has been found in Pseudomonas species and Acinetobacter species
• Class D
  • Found mostly in Acinetobacter baumannii complex

Management

• Directed by susceptibility testing
• See also carbapenem-resistant organisms