Raaijmakers J, Salillas S, Aarnoutse R, Svensson E, Te Brake L, Stemkens R, Wertheim H, Hoefsloot W, van Ingen J
Radboudumc Community for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Microbiology, Pediatrics, Radiology and Public Health, Faculty of Medicine, University of Zaragoza, Zaragoza, Aragon, Spain.
Antimicrob Agents Chemother. 2025 May 7;69(5):e0146424. doi: 10.1128/aac.01464-24. Epub 2025 Apr 14.
Bedaquiline has been proposed as a second-line drug to treat pulmonary disease caused by complex. Based on synergy and interactions, a logical regimen would combine bedaquiline and clofazimine as additions to an ethambutol-azithromycin backbone. Here, we evaluate the added benefit of bedaquiline in a regimen of azithromycin, ethambutol, and clofazimine. THP-1 cells infected with ATCC 700898 were seeded in a hollow-fiber model and exposed to a regimen of azithromycin, ethambutol, and clofazimine with or without bedaquiline for 3 weeks. Epithelial lining fluid pharmacokinetic profiles of azithromycin and ethambutol were simulated, while an average steady-state concentration was sought for clofazimine and bedaquiline. Pharmacokinetics and pharmacodynamics were monitored throughout the experiment. Both regimens led to sustained bacterial killing (both intracellular and extracellular) throughout the experiment. No difference in kill rate was observed between the two therapies. The extracellular kill rate for the 3-drug regimen was 0.65 (95% CI 0.63-0.67) and for the 4-drug regimen 0.65 (95% CI 0.64-0.67). The intracellular kill rate was 0.48 (95% CI 0.46-0.50) for the 3-drug regimen and 0.48 (95% CI 0.46-0.50) for the 4-drug regimen. Macrolide-tolerant subpopulations were observed with both treatment regimens at day 21. Bedaquiline does not add killing activity to a clofazimine-ethambutol-azithromycin regimen and did not improve suppression of the emergence of macrolide resistance, which makes its role as a second-line agent doubtful.
贝达喹啉已被提议作为治疗由[具体病菌名称缺失]引起的肺部疾病的二线药物。基于协同作用和相互作用，合理的治疗方案是将贝达喹啉和氯法齐明添加到以乙胺丁醇-阿奇霉素为主的治疗方案中。在此，我们评估了贝达喹啉在阿奇霉素、乙胺丁醇和氯法齐明治疗方案中的附加益处。用美国典型培养物保藏中心（ATCC）700898感染的THP-1细胞接种于中空纤维模型中，并暴露于含或不含贝达喹啉的阿奇霉素、乙胺丁醇和氯法齐明治疗方案中3周。模拟了阿奇霉素和乙胺丁醇的上皮衬液药代动力学特征，同时寻求氯法齐明和贝达喹啉的平均稳态浓度。在整个实验过程中监测药代动力学和药效学。两种治疗方案在整个实验过程中均导致持续的细菌杀灭（细胞内和细胞外）。两种治疗方法之间未观察到杀灭率的差异。三联药物治疗方案的细胞外杀灭率为0.65（95%置信区间0.63 - 0.67），四联药物治疗方案为0.65（95%置信区间0.64 - 0.67）。三联药物治疗方案的细胞内杀灭率为0.48（95%置信区间0.46 - 0.50），四联药物治疗方案为0.48（95%置信区间0.46 - 0.50）。在第21天，两种治疗方案均观察到大环内酯耐受亚群。贝达喹啉并未增强氯法齐明 - 乙胺丁醇 - 阿奇霉素治疗方案的杀菌活性，也未改善对大环内酯耐药性出现的抑制作用，这使得其作为二线药物的作用存疑。
