Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline

Rationale: New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis.Objectives: To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B.Methods: Groups of 15 treatment-naive, sputum smear–positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling.Measurements and Main Results: Estimated activities...