Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria

Mushtaq, Shazad, Garello, Paolo, Vickers, Anna, Woodford, Neil and Livermore, David M. (2021) Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria. International Journal of Antimicrobial Agents, 57 (5). ISSN 0924-8579

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Abstract

Objectives: Piperacillin/tazobactam has long been a broad-spectrum ‘workhorse’ antibiotic; however, it is compromised by resistance. One response is to re-partner tazobactam with cefepime, which is easier to protect, being less β-lactamase labile, and to use a high-dose and prolonged infusion. On this basis, Wockhardt are developing cefepime/tazobactam (WCK 4282) as a 2+2 g q8h combination with a 90-min infusion.  Methods: The activity of cc cefepime/tazobactam was assessed, with other tazobactam combinations as comparators, against 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, as submitted to the UK National Reference Laboratory. These were categorised by carbapenemase-gene detection and interpretive reading of phenotypes, with MICs determined by British Society for Antimicrobial Chemotherapy agar dilution.  Results: Although higher breakpoints may be justifiable, based on the pharmacodynamics, the results were reviewed against current cefepime criteria. On this basis, cefepime/tazobactam was broadly active against Enterobacterales with AmpC enzymes and extended-spectrum β-lactamases (ESBLs), even when they had ertapenem resistance, suggesting porin loss. At 8+8 mg/L, activity extended to > 90% of Enterobacterales with OXA-48 and KPC carbapenemases, although the MICs for KPC producers belonging to the international Klebsiella pneumoniae ST258 lineage were higher; metallo-β-lactamase producers remained resistant. Cefepime/tazobactam was less active than ceftolozane/tazobactam against Pseudomonas aeruginosa with AmpC de-repression or high-level efflux but achieved wider antipseudomonal coverage than piperacillin/tazobactam. Activity against other non-fermenters was species-specific.  Conclusion: Overall, cefepime/tazobactam had a spectrum exceeding those of piperacillin/tazobactam and ceftolozane/tazobactam and resembling or exceeding that of carbapenems. Used as a ‘new-combination of old-agents’ it has genuine potential to be ‘carbapenem-sparing’.

Item Type: Article
Uncontrolled Keywords: beta-lactamase inhibitors,beta-lactamases,tazobactam,tazobactam,tazobactam,microbiology (medical),infectious diseases,pharmacology (medical) ,/dk/atira/pure/subjectarea/asjc/2700/2726
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 09 Mar 2021 00:42
Last Modified: 11 May 2021 00:12
URI: https://ueaeprints.uea.ac.uk/id/eprint/79406
DOI: 10.1016/j.ijantimicag.2021.106318

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