Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.
Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA.
J Antimicrob Chemother. 2021 Jan 1;76(1):184-188. doi: 10.1093/jac/dkaa344.
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.
尽管沃博巴坦对 OXA-48 缺乏抑制活性，但由于其折点高于美罗培南单独使用的折点，约三分之一的携带 OXA-48 的肠杆菌科对美罗培南/沃博巴坦敏感。本研究评估了在中性粒细胞减少症小鼠大腿模型中，人类模拟美罗培南/沃博巴坦暴露对携带 OXA-48 的肠杆菌科的疗效。
评估了 26 株分离株[OXA-48（n=24）和 KPC（n=2）]。使用 CLSI 进行三次 MIC 检测。小鼠接受人类模拟的美罗培南/沃博巴坦、美罗培南或载体治疗 24 小时。在给药前 2 小时，每只大腿以约 1×107 CFU/mL 的剂量接种，24 小时后收获两只大腿。使用 24 小时时的平均对数 10 CFU/大腿和相对于 0 小时对照的 1 对数减少来评估疗效，这是一种成功治疗严重感染的预测替代标志物。
美罗培南/沃博巴坦 MIC 范围为 1 至 64 mg/L。0 小时的平均接种物为 5.77±0.26，而 24 小时时的对照为 8.26±1.53。与 KPC 相比，美罗培南/沃博巴坦导致细菌密度的平均变化（-1.10±0.26）增强，而美罗培南的平均变化（1.45±0.88）。与美罗培南相比，沃博巴坦对 OXA-48 分离株的平均变化没有增强（分别为-0.44±1.29 和-0.43±1.36）。对于美罗培南/沃博巴坦 MICs≥16（n=5）、8（n=5）、4（n=9）和≤2（n=5）mg/L的携带 OXA-48 的分离株，用两种药物分别有 0%、0%、44%和 60%的分离株达到目标减少≥1 对数。
这些数据表明，尽管 EUCAST 和 CLSI 解释的 MIC 敏感，但美罗培南/沃博巴坦和美罗培南的人类体内暴露导致对产 OXA-48 的肠杆菌科的活性相似，尽管不理想。因此，在没有基因型谱的情况下，治疗美罗培南/沃博巴坦敏感的肠杆菌科时应谨慎。
