Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis

Abstract

Novel regimens combining bedaquiline and pretomanid with either linezolid (BPaL regimen) or moxifloxacin and pyrazinamide (BPaMZ regimen) shorten the treatment duration needed to cure tuberculosis (TB) in BALB/c mice compared to that of the first-line regimen and have yielded promising results in initial clinical trials. However, the independent contribution of the investigational new drug pretomanid to the efficacy of BPaMZ has not been examined, and its contribution to BPaL has been examined only over the first 2 months of treatment. In the present study, the addition of pretomanid to BL increased bactericidal activity, prevented emergence of bedaquiline resistance, and shortened the duration needed to prevent relapse with drug-susceptible isolates by at least 2 months in BALB/c mice. Addition of pretomanid to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in a 1-log₁₀ greater CFU reduction after 1 month of treatment and/or reduced the number of mice relapsing in each of 2 experiments in BALB/c mice and in immunocompromised nude mice. Bedaquiline-resistant isolates were found at relapse in only one BMZ-treated nude mouse. Treatment of infection with a pyrazinamide-resistant mutant in BALB/c mice with BPaMZ prevented selection of bedaquiline-resistant mutants and reduced the proportion of mice relapsing compared to that for BMZ treatment alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 versus 21 days) and reduced median lung CFU by 2.4 log₁₀ at 1 month compared to the level for BMZ. In conclusion, in 3 different mouse models, pretomanid contributed significantly to the efficacy of the BPaMZ and BPaL regimens, including restricting the selection of bedaquiline-resistant mutants.

Keywords: bedaquiline; linezolid; moxifloxacin; murine model; pretomanid; pyrazinamide; resistance.

FIG 1

Proportion of relapses and individual mouse lung CFU counts after treatment of infection with M. tuberculosis H37Rv for 1 month (M1), 1.5 months (M1.5), 2 months (M2), and 3 months (M3) with each regimen. Regimen symbols: BMZ, open triangles; BPaMZ, solid circles; BL, open squares; and BPaL, solid diamonds. Horizontal black lines indicate the medians.

FIG 2

Proportion of relapses and individual mouse lung CFU counts (with medians) after treatment of infection with M. tuberculosis pncA A146V mutant for 2 months (M2) and 3 months (M3) with each regimen. BMZ, open black circles; BPaMZ, solid black circles.

FIG 3

Survival of C3HeB/FeJ mice infected with M. tuberculosis HN878 from the onset of treatment with BMZ or BPaMZ.

FIG 4

Lung CFU counts assessed during treatment in infected C3HeB/FeJ mice. Data points indicate individual mouse CFU counts. Horizontal black lines indicate the medians.

FIG 5

Lung histopathology in C3HeB/FeJ mice before and during treatment with BPaMZ (left) or BMZ (right) beginning 4 weeks postinfection with M. tuberculosis HN878. Hematoxylin and eosin (H&E) and Ziehl-Neelsen (AFB) staining were performed on lung tissue sections. Low-power views of an entire lung section (upper) and higher-power views of individual granulomas or cavitary lesions (lower) from representative mice in each group are shown. D0, treatment initiation (4 weeks postinfection); W2, status after 2 weeks of treatment; M1, status after 1 month of treatment; M2, status after 2 months of treatment.