Examining effective monotherapy hypothesis for TB therapy failure and resistance emergence

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 (log₁₀ 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..