Baylor University Medical Center, Dallas, Texas, USA.
Department of Medicine, School of Medicine, the University of Texas at Tyler, Tyler, Texas, USA; Department of Cellular and Molecular Biology, Center for Biomedical Research, University of Texas Health Science Center, Tyler, Texas, USA.
Int J Antimicrob Agents. 2024 Sep;64(3):107204. doi: 10.1016/j.ijantimicag.2024.107204. Epub 2024 May 15.
Guideline-based therapy for Mycobacterium avium complex (MAC) pulmonary disease achieves sustained sputum conversion rates in only 43-53% of patients. Repurposing of β-lactam antibiotics such as ertapenem could expedite design of more efficacious regimens, compared to developing new drugs.
We performed an ertapenem exposure-response study in the hollow fibre system model of intracellular MAC (HFS-MAC). We recapitulated human-like intrapulmonary concentration-time profiles of eight once-daily intravenous doses of ertapenem over 28 days and performed repetitive sampling for drug concentration-time profiles and MAC burden. The % of time concentration persisted above MIC (%T) mediating either 50% or 80% of maximal effect (E, EC) were identified. The EC was used as target exposure in a 10 000 subject Monte Carlo experiments for ertapenem doses of 1G, 2G, or 4G administered once versus twice daily.
The ertapenem MIC ranged from 0.5 to 2 mg/L on three occasions. Ertapenem achieved a half-life of 4.04 ± 0.80 h in the HFS-MAC and killed a maximum of 2.17 log CFU/mL below day 0. The EC was %T of 75.9% (95% confidence interval: 68.43%-86.54%) and the EC was %T of 100%. Target attainment probability was >90% for 1G twice daily up to an MIC of 2 mg/L, while for 2G twice daily the susceptibility MIC breakpoint was 4-8 mg/L.
Ertapenem microbial kill below day 0 burden was better than guideline-based therapy drugs in the HFS-MAC in the past. Ertapenem is a promising drug for novel combination therapies for MAC lung disease.
基于指南的治疗方案可使 MAC 肺病患者的痰培养持续转化，但仅能达到 43-53%的患者。与开发新药相比，β-内酰胺类抗生素如厄他培南的再利用可以加快更有效的治疗方案的设计。
我们在中空纤维系统模型（HFS-MAC）中进行了一项厄他培南暴露-反应研究。我们模拟了人类肺内 28 天内每日一次静脉滴注 8 剂厄他培南的浓度-时间曲线，并进行了药物浓度-时间曲线和 MAC 负荷的重复采样。识别出了 50%或 80%最大效应（E、EC）时，浓度持续时间超过 MIC 的百分比（%T）。将 EC 用作厄他培南 1G、2G 或 4G 剂量一次或两次每日给药的 10000 名受试者蒙特卡罗模拟实验的目标暴露量。
厄他培南 MIC 在三个时间点分别为 0.5 至 2mg/L。厄他培南在 HFS-MAC 中的半衰期为 4.04±0.80h，在第 0 天之前最大减少了 2.17 对数 CFU/mL。EC 为 75.9%（95%置信区间：68.43%-86.54%），EC 为 100%。对于 1G 两次每日，MIC 为 2mg/L 时，目标达成概率>90%，而对于 2G 两次每日，敏感性 MIC 断点为 4-8mg/L。
与过去的 HFS-MAC 中基于指南的治疗药物相比，厄他培南在第 0 天之前的微生物杀灭效果更好。厄他培南是治疗 MAC 肺病新型联合疗法的有前途的药物。
