β-lactamases

Background

• Includes a spectrum of molecules that hydrolyze β-lactams, from penicillins to carbapenems
  • See also extended-spectrum β-lactamases and carbapenemases

Ambler Classification

• Classification based on amino acid sequences rather than function

Class	Binding Site	Examples	Inhibitors
A	serine	TEM, SHV, KPC, CTX-M, GES	clavulanic acid, tazobactam, avibactam, vaborbactam, relebactam
B	metallo	VIM, NDM, IMP
C	serine	AmpC, P99	avibactam, vaborbactam, relebactam
D	serine	OXA (oxacillinase) enzymes	avibactam (OXA-48), ±clavulanic aciid

Serine β-lactamases

• Amber classes A, B, and C are the serine β-lactamases
• Contain a serine residue at the active site
• Class A: inhibited by clavulanic acid or tazobactam
  • Constitutively expressed plasmid
  • Most common ESBL in Gram-negative bacteria
  • Resistance to 2nd and 3rd generation cephalosporins
  • Common in E. coli, Klebsiella, and Proteus spp.
  • Examples include:
    • Penicillinases: TEM-1 (common in GNBs), SHV-1
    • ESBLs: CTX-M, TEM-3
    • Carbapenemases: K. pneumoniae carbapenemase (KPC)
• Class C: not inhibited by clavulanic acid or EDTA, resistant to cefoxitin, inhibited by cloxicillin in vitro
  • AmpC = chromosomal
  • Often an inducible AmpC gene present in the genome
  • Common in Citrobacter, Serratia, and Enterobacter
• Class D: not inhibited by EDTA, variably inhibited by clavulanic acid; hard to identify
  • Common in Pseudomonas
  • Difficult to detect with routine screening
  • Examples include:
    • ESBLs: OXA-11
    • Carbapenemases: OXA-23, OXA-48

Metallo-β-lactamases

• Ambler Class B are the metallo-β-lactamases
• Contain a zinc ion at the active site
• Inhibited by EDTA, not inhibited by clavulanic acid
• Examples include:
  • Carbapenemases:
    • New Delhi metallo-beta-lactamase (NDM-1)
    • Imipenemases (IMP)
    • Verona integron-encoded metallo-β-lactamases (VIM)
    • L1 β-lactamase, present in the Stenotrophomonas maltophilia chromosome

Epidemiology

• The most common β-lactamase is TEM-1
• The most common carbapenemases in the US are KPCs, followed by NDM and OXA-48-like carbapenemases

Management

• Antibiotic therapy tailored to the resistance pattern
• Carbapenems, aminoglycosides, fluoroquinolones, and TMP-SMX typically work well