Deshpande D, Magombedze G, Srivastava S, Gumbo T
Baylor University Medical Center, Dallas, TX, USA.
Mathematical Modeling and AI Department, Praedicare Inc, Dallas, TX, USA.
IJTLD Open. 2024 Aug 1;1(8):362-368. doi: 10.5588/ijtldopen.24.0238. eCollection 2024 Aug.
β-lactam antibiotics are promising treatments for complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC.
Benzylpenicillin lung concentration-time profiles of seven doses in three dosing schedules were administered for 28 days using the hollow fiber system model of intracellular MAC (HFS-MAC). Data were analyzed using the inhibitory sigmoid maximal effect (E) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants.
Benzylpenicillin killed >2.1 log colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid E parameter estimates significantly differed between sampling days and were a poor fit. However, ODE model parameter estimates vs. exposure were a better fit. The exposure mediating E was 84.6% (95% CI 76.91-82.98) of time concentration exceeded the minimum inhibitory concentration (MIC). In Monte Carlo experiments, 24 million international units of benzylpenicillin continuous infusion achieved the target exposure in lungs of >90% of 10,000 subjects until an MIC of 64 mg/L, designated the susceptibility breakpoint.
Benzylpenicillin demonstrated a better bactericidal effect against MAC than guideline-recommended drugs before the development of resistance. Its role in combination therapy with other drugs with better efficacy than guideline-recommended drugs should be explored.
β-内酰胺类抗生素是治疗复杂性（鸟分枝杆菌复合群，MAC）肺部疾病的有前景的疗法。我们假设苄青霉素对MAC有效。
使用细胞内MAC的中空纤维系统模型（HFS-MAC），以三种给药方案给予七剂苄青霉素的肺浓度-时间曲线，持续28天。对每个采样日的数据使用抑制性S形最大效应（E）模型进行分析，同时对野生型和耐青霉素突变体使用两个常微分方程（ODE）。
苄青霉素在第0天以下杀灭>2.1 log菌落形成单位（CFU）/mL，优于阿奇霉素、乙胺丁醇和利福布汀。疗效因获得性耐药而终止。S形E参数估计在采样日之间有显著差异，拟合效果不佳。然而，ODE模型参数估计与暴露的拟合效果更好。介导E的暴露为时间浓度超过最低抑菌浓度（MIC）的84.6%（95%CI 76.91-82.98）。在蒙特卡洛实验中，2400万国际单位的苄青霉素持续输注在10000名受试者的肺部中，直到MIC为64mg/L（指定为敏感断点）时，>90%的受试者达到目标暴露。
在耐药性出现之前，苄青霉素对MAC的杀菌作用优于指南推荐药物。应探索其与疗效优于指南推荐药物的其他药物联合治疗中的作用。
