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 were 0.167 (95% confidence interval [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 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe. CONCLUSIONS: 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. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).
RCT Entities:
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 were 0.167 (95% confidence interval [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 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe. CONCLUSIONS: 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. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).
Entities:
Keywords:
antitubercular agents; drug evaluation; tuberculosis
Authors: Melisa J Willby; Maria Wijkander; Joshua Havumaki; Kartee Johnson; Jim Werngren; Sven Hoffner; Claudia M Denkinger; James E Posey Journal: Antimicrob Agents Chemother Date: 2017-12-21 Impact factor: 5.191
Authors: Gustavo E Velásquez; Meredith B Brooks; Julia M Coit; Henry Pertinez; Dante Vargas Vásquez; Epifanio Sánchez Garavito; Roger I Calderón; Judith Jiménez; Karen Tintaya; Charles A Peloquin; Elna Osso; Dylan B Tierney; Kwonjune J Seung; Leonid Lecca; Geraint R Davies; Carole D Mitnick Journal: Am J Respir Crit Care Med Date: 2018-09-01 Impact factor: 21.405