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Mushtaq, Shazad, Vickers, Anna, Chaudhry, Aiysha, Woodford, Neil and Livermore, David M. 
ORCID: https://orcid.org/0000-0002-9856-3703
(2022)
Inoculum effects of cefepime/zidebactam (WCK 5222) and ertapenem/zidebactam (WCK 6777) for Enterobacterales in relation to β-lactamase type and enhancer effect, as tested by BSAC agar dilution.
Journal of Antimicrobial Chemotherapy, 77 (7).
1916–1922.
ISSN 0305-7453
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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 |
|---|---|
| Uncontrolled Keywords: | pharmacology,microbiology (medical),pharmacology (medical),infectious diseases ,/dk/atira/pure/subjectarea/asjc/3000/3004 |
| 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 (former - to 2023) Faculty of Medicine and Health Sciences > Research Groups > Epidemiology and Public Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 11 Apr 2022 16:30 |
| Last Modified: | 04 Apr 2023 01:38 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/84582 |
| DOI: | 10.1093/jac/dkac108 |
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