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

Livermore, David M. ORCID: https://orcid.org/0000-0002-9856-3703, Mushtaq, Shazad, Warner, Marina, Turner, Simon J. and Woodford, Neil (2018) Potential of high-dose cefepime/tazobactam against multi-resistant Gram-negative pathogens. Journal of Antimicrobial Chemotherapy, 73 (1). pp. 126-133. ISSN 0305-7453

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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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Public Health and Health Services Research
Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health
Depositing User: Pure Connector
Date Deposited: 07 Sep 2017 05:06
Last Modified: 22 Oct 2022 03:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/64768
DOI: 10.1093/jac/dkx360

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