Inoculum effects of cefepime/zidebactam (WCK 5222) and ertapenem/zidebactam (WCK 6777) for Enterobacterales in relation to ββ-lactamase type and enhancer effect, as tested by BSAC agar dilution

Mushtaq, Shazad, Vickers, Anna, Chaudhry, Aiysha, Woodford, Neil and Livermore, David M. (2022) Inoculum effects of cefepime/zidebactam (WCK 5222) and ertapenem/zidebactam (WCK 6777) for Enterobacterales in relation to ββ-lactamase type and enhancer effect, as tested by BSAC agar dilution. Journal of Antimicrobial Chemotherapy. ISSN 0305-7453

[img] PDF (Ziddy inoc effect revision) - Accepted Version
Restricted to Repository staff only until 4 April 2023.

Request a copy

Abstract

Objectives: Combinations of PBP3-active β-lactams with developmental diazabicyclooctanes (DBOs), e.g. zidebactam, remain active against many MBL producers via an enhancer effect. We explored how this activity is affected by inoculum. Materials and methods: MICs of zidebactam and its cefepime and ertapenem combinations (WCK 5222 and WCK 6777, respectively) were determined by BSAC agar dilution at inocula from 3–6 × 103 to 3–6 × 105 cfu/spot. Isolates, principally Klebsiella spp., were chosen as having previously tested resistant to zidebactam or its cefepime combination, and by β-lactamase type. Results: MICs of zidebactam, tested alone, were strongly inoculum dependent regardless of β-lactamase type; MICs of its cefepime and ertapenem combinations likewise were strongly inoculum dependent—rising ≥32-fold across the inoculum range tested—but only for MBL producers. Combination MICs for isolates with non-MBLs, including those with OXA-48 (where the enhancer effect remains critical for ertapenem/zidebactam) were much less inoculum dependent, particularly for cefepime/zidebactam. MBL producers frequently moved between putative ‘susceptible’ (MIC ≤ 8 + 8 mg/L) and ‘resistant’ (MIC > 8 + 8 mg/L) categories according to whether the inoculum was at the high or low end of BSAC’s acceptable (1–4 × 104 cfu/spot) range. Conclusions: The activity of zidebactam combinations against MBL producers, which strongly depends on the enhancer effect, is inoculum dependent. Animal data suggest consistent in vivo activity even in high-inoculum pneumonia models. Contingent on this being supported by clinical experience, the combination behaviour may be best represented by the MICs obtained at the lower end of BSAC’s inoculum range.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 11 Apr 2022 16:30
Last Modified: 26 Apr 2022 16:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/84582
DOI: 10.1093/jac/dkac108

Actions (login required)

View Item View Item