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We tested the hypothesis that because of the different metabolic states of Mycobacterium tuberculosis (Mtb) in lesions, drugs in combination therapy often act effectively as monotherapy, leading to therapy failure and resistance emergence.Bactericidal and sterilizing activity studies were performed in the hollow fiber system of TB (HFS-TB) using the human equivalent dose of isoniazid (INH) 300 mg/day, rifampin (RIF) 600 mg/day, and pyrazinamide (PZA) 1.5 g/day either as monotherapy, two-, and three-drug combination for 28 days. The Mtb population (log 10 CFU/ml) for each drug, either monotherapy or combination, was compared using an analysis of variance.In the bactericidal activity studies, the microbial kill was driven by INH, followed by RIF, and PZA monotherapy failed. During the sterilizing activity, INH and RIF displayed similar microbial kill. The INH + RIF and RIF + PZA combinations were significantly different from each other but not from the INH + RIF + PZA combination. RIF and INH-resistant subpopulations did not increase despite premixing the inoculum with isogenic-resistant strains.Effective monotherapy arising from the selectivity of antibiotics against special Mtb sub-populations may not be the primary mechanism of resistance emergence. Different metabolic populations of Mtb were killed by more than one drug and were not under monotherapy when combination therapy was administered..

Introduction: β-lactam antibiotics are promising treatments for Mycobacterium avium complex (MAC) lung disease. We hypothesized that benzylpenicillin has efficacy against MAC., Methods: 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 max ) model for each sampling day, while two ordinary differential equations (ODEs) were used for the wild-type and penicillin-resistant mutants., Results: Benzylpenicillin killed >2.1 log 10 colony-forming unit (CFU)/mL below Day 0, better than azithromycin, ethambutol, and rifabutin. Efficacy was terminated by acquired resistance. Sigmoid E max 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 max 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., Conclusions: 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., Competing Interests: Conflict of interest: TG and GM are employees of Praedicare Inc (Dallas, TX, USA), a System of Systems-based drug development company. All other authors have nothing to declare., (© 2024 The Authors.)