Efficacy of human-simulated exposures of meropenem/vaborbactam and meropenem against OXA-48 β-lactamase-producing Enterobacterales in the neutropenic murine thigh infection model.

Abstract

Despite vaborbactam lacking inhibitory activity against OXA-48, approximately a third of OXA-48-harbouring Enterobacterales test susceptible to meropenem/vaborbactam due to its higher breakpoint than meropenem alone. The present study evaluated the efficacy of human-simulated exposures of meropenem/vaborbactam against OXA-48-harbouring Enterobacterales in the neutropenic murine thigh model. Twenty-six isolates [OXA-48 (n = 24) and KPC (n = 2)] were evaluated. MICs were conducted in triplicate per CLSI. Mice received human-simulated regimens of meropenem/vaborbactam, meropenem or vehicle for 24 h. Mice were inoculated with ∼1 × 107 cfu/mL in each thigh 2 h prior to dosing and both thighs were harvested at 24 h. Efficacy was assessed using mean log10 cfu/thigh at 24 h and the achievement of 1 log10 reduction relative to 0 h control as an established surrogate marker predictive of success for serious infections. Meropenem/vaborbactam MICs ranged from 1 to 64 mg/L. The mean inoculum at 0 h was 5.77 ± 0.26 compared with 8.26 ± 1.53 for controls at 24 h. As anticipated for KPCs, meropenem/vaborbactam resulted in enhanced mean ± SD change in bacterial density (-1.10 ± 0.26), compared with meropenem (1.45 ± 0.88). Vaborbactam did not enhance mean ± SD change against OXA-48 isolates compared with meropenem (-0.44 ± 1.29 and -0.43 ± 1.36, respectively). For OXA-48-harbouring isolates with meropenem/vaborbactam MICs ≥16 (n = 5), 8 (n = 5), 4 (n = 9) and ≤2 (n = 5) mg/L, 0%, 0%, 44% and 60% of isolates achieved the target reduction ≥1 log10 with either agent, respectively. These data highlight that meropenem/vaborbactam and meropenem humanized exposures in vivo resulted in similar, albeit poor, activity against OXA-48-producing Enterobacterales despite susceptible MICs per EUCAST and CLSI interpretation. As a result, caution is warranted when treating meropenem/vaborbactam-susceptible Enterobacterales without a genotypic profile.