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.
In: The Journal of antimicrobial chemotherapy, Jg. 77 (2022-06-29), Heft 7, S. 1916-1922
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Zugriff:
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.
(© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Titel: |
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.
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Autor/in / Beteiligte Person: | Mushtaq, S ; Vickers, A ; Chaudhry, A ; Woodford, N ; Livermore, DM |
Zeitschrift: | The Journal of antimicrobial chemotherapy, Jg. 77 (2022-06-29), Heft 7, S. 1916-1922 |
Veröffentlichung: | 1997- : London : Oxford University Press ; <i>Original Publication</i>: London, New York, Academic Press., 2022 |
Medientyp: | academicJournal |
ISSN: | 1460-2091 (electronic) |
DOI: | 10.1093/jac/dkac108 |
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