Potential of high-dose cefepime/tazobactam against multiresistant Gram-negative pathogens

David Livermore*, Shazad Mushtaq, Marina Warner, Simon J. Turner, Neil Woodford

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Background: Early β-lactamase inhibitors were combined with established penicillins, but different combinations may be more appropriate to counter current β-lactamase threats, with development facilitated by the US Generating Antibiotic Incentives Now (GAIN) Act. Cefepime/tazobactam is especially attractive, combining an AmpC-stable cephalosporin with a clinically established inhibitor, active against ESBLs and suitable for high-dose administration. Methods: Organisms (n"563) were clinical isolates submitted to the UK national reference laboratory. MICs were determined by CLSI agar dilution with tazobactam at 4 mg/L and, for a subset, at 8 mg/L. Results: Cefepime/tazobactam 8+4 mg/L achieved coverage of 96%-100% of Enterobacteriaceae with penicillinases, AmpC, ESBL, K1 or OXA-48 β-lactamases. Even at 1+4 mg/L, the combination inhibited >94% of isolates with penicillinases, AmpC enzymes or ESBLs. Most Enterobacteriaceae with KPC and NDM carbapenemase were resistant at current cefepime breakpoints but 80% of those with VIM types were susceptible at 8+4 mg/L. Tazobactam did little to potentiate cefepime against non-fermenter groups, though gains were seen against AmpC-producing Acinetobacter spp. and Stenotrophomonas maltophilia. Increasing the tazobactam concentration to 8 mg/L gave further small increases in activity against Enterobacteriaceae groups. Conclusions: High-dose cefepime/tazobactam, justifying an 8+4 or 8+8 mg/L breakpoint, can achieve a carbapenem-like spectrum, with some additional coverage of OXA-48 (and maybe VIM) Enterobacteriaceae. Clinical evaluation is warranted.

Original languageEnglish
Article numberdkx360
Pages (from-to)126-133
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Volume73
Issue number1
DOIs
Publication statusPublished - 1 Jan 2018

Bibliographical note

Publisher Copyright:
© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

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