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

Objectives Combinations of PBP3-active beta-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 x 10(3) to 3-6 x 10(5) cfu/spot. Isolates, principally Klebsiella spp., were chosen as having previously tested resistant to zidebactam or its cefepime combination, and by beta-lactamase type. Results MICs of zidebactam, tested alone, were strongly inoculum dependent regardless of beta-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 x 10(4) 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.