Activity of faropenem against cephalosporin-resistant Enterobacteriaceae

Background: There is a need for new oral agents active against extended-spectrum β-lactamase (ESBL) producers, as these increasingly cause community-onset infections. We therefore evaluated faropenem, a penem in Phase III development, against recently collected oxyimino-cephalosporin-resistant bacteria. Methods: We tested 847 consecutive cephalosporin-resistant Enterobacteriaceae collected at 16 centres in South-East England in 2004, 501 of them with CTX-M enzymes; we also tested reference strains and transconjugants with acquired β-lactamases and various modes of AmpC expression. MICs were determined by the BSAC agar dilution method. Results: Modal MICs of faropenem for Escherichia coli or Klebsiella spp. with CTX-M or non-CTX-M ESBLs or high-level AmpC enzyme were 0.5-1 mg/L, with over 95% of producers susceptible to ≤2 mg/L. Modal MICs for Enterobacter and Citrobacter spp. with ESBLs or derepressed AmpC were 2-4 mg/L, although around 5% of AmpC-derepressed Enterobacter spp. required faropenem MICs of 16 mg/L. MICs of 8-16 mg/L were seen also for most AmpC-derepressed Serratia spp. isolates. Derepression of AmpC in isogenic mutant series typically raised faropenem MICs by one doubling dilution; among the β-lactamases introduced into E. coli, only NMC-A (Class A) and IMP (Class B) carbapenemases caused substantive rises in faropenem MICs. Conclusions: Faropenem has good activity against E. coli and Klebsiella spp. with ESBLs, including the CTX-M types now proliferating in Europe, but was less active against AmpC-derepressed and ESBL-producing Enterobacter spp. Its clinical utility will depend on levels achieved in the urinary tract, the site of most of the community infections caused by ESBL producers, and more work is needed in this area.