Pulmonary Distribution and Lesion Penetration of Antimicrobials in Patients with Nontuberculous Mycobacterial Disease

Abstract Background The intrapulmonary pharmacokinetics of antimicrobial agents used to treat nontuberculous mycobacterial (NTM) pulmonary disease remain poorly characterized, limiting the optimization of dosing regimens. This study characterized the plasma and intrapulmonary pharmacokinetics of azithromycin, ethambutol, rifampicin, clofazimine, and amikacin, as well as their penetration into pulmonary lesion sites. Methods We prospectively enrolled patients undergoing guideline-based treatment for NTM pulmonary disease who were indicated for surgical resection at a single center in Japan. Drug concentrations were measured in the plasma and lung samples, and analyzed using a population pharmacokinetic model. The lung lesion site, cavity, or nodule/bronchiectatic were evaluated as covariates of the plasma-to-lung partition ratios. Results Twenty-four patients were enrolled in the study. Antimicrobial agents other than rifampicin and amikacin accumulate in the lungs at concentrations > 40-fold higher than those in the plasma. Notably, the intrapulmonary half-life of ethambutol, which has not been well-characterized to date, is estimated to be approximately 2 months, indicating prolonged retention within the lungs. Evaluation of drug penetration into cavities and nodular/bronchiectatic lesions showed no clearly reduced concentration compared to that of normal lung tissue. However, in the single case where the caseum was obtained, azithromycin, ethambutol, and rifampicin levels exhibited clearly lower concentrations. Conclusions Ethambutol shows a prolonged intrapulmonary half-life, suggesting sustained lung exposure even with intermittent dosing. The absence of clearly reduced drug penetration into lesion sites suggests that lesion phenotype alone may have limited value in guiding drug selection. Key points Ethambutol exhibited a prolonged intrapulmonary half-life of 2 months. Clofazimine continued to accumulate in the lung for at least 3 years. Evaluation of drug penetration into pulmonary lesions showed no clearly reduced concentration compared to that of normal tissue.