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

Abstract

Rationale: New regimens to shorten tuberculosis treatment and manage drug-resistant and human immunodeficiency virus infected tuberculosis patients 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 both drug-susceptible and drug-resistant tuberculosis.

Objective: 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-naïve, sputum smear-positive pulmonary tuberculosis patients 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 colony forming units/ml sputum estimated by joint non-linear mixed effects Bayesian regression modeling.

Measurements and main results: Estimated activities were 0.167 (95% CI: 0.075 - 0.257) for B-Pa-Z, 0.151 (95% CI: 0.071 - 0.232) for standard treatment, 0.124 (95% CI: 0.035 - 0.214) for B-Z-C, 0.115 (95% CI: 0.039 - 0.189) for B-Pa-Z-C, and 0.076 (95% CI: 0.005 - 0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI: -0.026 - 0.099). C had no activity alone (-0.017; 95% CI: -0.085 - 0.053) or in combinations. Treatments were well tolerated and safe. Interpretation B-Pa-Z, including two novel agents without resistance in prevalent M tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment.

Citation

Diacon, A.H.; Dawson, R.; von Groote-Bidlingmaier, F.; Symons, G.; Venter, A.; Donald, P.R.; van Niekerk, C.; Everitt, D.; Hutchings, J.; Burger, D.A.; Schall, R.; Mendel, C.M. Bactericidal Activity of Pyrazinamide and Clofazimine Alone and in Combinations with Pretomanid and Bedaquiline. American Journal of Respiratory and Critical Care Medicine (2015) : 150126100257004. [DOI: 10.1164/rccm.201410-1801OC]

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

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