Objectives Ceftazidime/avibactam is not active against MBL-producing bacteria. Combining ceftazidime/avibactam or avibactam with aztreonam can counter the resistance of MBL-producing Enterobacterales. The aim of this study was to evaluate whether the addition of avibactam could reduce or close the mutant selection window (MSW) of aztreonam in Escherichia coli and Klebsiella pneumoniae harbouring MBLs; MSW is a pharmacodynamic (PD) parameter for the selection of emergent resistant mutants. Methods In vitro susceptibility of 19 clinical isolates to ceftazidime/avibactam, aztreonam alone, and in co-administration (aztreonam/ceftazidime/avibactam and aztreonam/avibactam) was determined, as well as the mutant prevention concentration (MPC). The fraction of time within 24 h that the free drug concentration was within the MSW (fTMSW) and the fraction of time that the free drug concentration was above the MPC (fT>MPC) in both plasma and epithelial lining fluid (ELF) were determined from simulations of 10 000 profiles. The joint PTA was used to derive a joint cumulative fraction of response (CFR). Results All isolates were resistant to ceftazidime/avibactam or aztreonam. Combining aztreonam and avibactam or ceftazidime/avibactam resulted in synergistic bactericidal activities against all isolates. Synergism was primarily due to the aztreonam/avibactam combination. For aztreonam/avibactam dosing regimens evaluated in clinical trials, fT>MPC values were >90% and >80%, whereas fTMSW measures were <10% and <20% in plasma and ELF, respectively. The CFR was 100% for aztreonam/avibactam against the collection of clinical isolates. Conclusions Effective antimicrobial combination optimized the PD parameters measuring selection for emergent mutants by increasing fT>MPC and reducing fTMSW.

中文翻译：

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氨曲南/阿维巴坦对筛选含有丝氨酸和新德里金属-β-内酰胺酶的大肠杆菌和肺炎克雷伯菌的药效学指标的影响

目的 头孢他啶/阿维巴坦对产生 MBL 的细菌没有活性。将头孢他啶/阿维巴坦或阿维巴坦与氨曲南联合使用可以对抗产生 MBL 的肠杆菌的耐药性。本研究的目的是评估添加阿维巴坦是否可以减少或关闭氨曲南在含有 MBLs 的大肠杆菌和肺炎克雷伯菌中的突变选择窗口 (MSW)；MSW 是用于选择紧急耐药突变体的药效学 (PD) 参数。方法 测定 19 株临床分离株对头孢他啶/阿维巴坦、氨曲南单独和联合给药（氨曲南/头孢他啶/阿维巴坦和氨曲南/阿维巴坦）的体外敏感性，以及突变预防浓度（MPC）。测定了 24 小时内游离药物浓度在 MSW 内的时间分数 (fTMSW) 和在血浆和上皮衬里液 (ELF) 中游离药物浓度高于 MPC 的时间分数 (fT＞MPC)来自 10 000 个配置文件的模拟。联合 PTA 用于得出联合累积响应分数 (CFR)。结果所有菌株均对头孢他啶/阿维巴坦或氨曲南耐药。将氨曲南和阿维巴坦或头孢他啶/阿维巴坦联合使用对所有分离物产生协同杀菌活性。协同作用主要是由于氨曲南/阿维巴坦组合。对于在临床试验中评估的氨曲南/阿维巴坦给药方案，fT＞MPC值＞90％和＞80％，而血浆和ELF中的fTMSW测量值分别＜10％和＜20％。氨曲南/阿维巴坦对临床分离株收集的 CFR 为 100%。结论 有效的抗微生物组合通过增加 fT＞MPC 和减少 fTMSW 优化了测量出现突变体选择的 PD 参数。