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.
Highlights
The World Health Organization (WHO) estimates that 10.4 million people developed active tuberculosis (TB) in 2016, and 1.67 million people died from it [1]
After 1 month of treatment, the addition of PMD to bedaquiline, moxifloxacin, and pyrazinamide (BMZ) resulted in an additional reduction of approximately 1 log10 in both BALB/c and nude mice (P Ͻ 0.01). Both regimens resulted in significantly greater decreases in lung CFU counts in BALB/c mice compared to counts in nude mice, with additional 1.1-log10 reductions observed in BALB/c mice after 1 month of treatment with both BPaMZ and BMZ (P Ͻ 0.01)
Both regimens were identified in a comprehensive screening program seeking to identify broad-spectrum regimens containing two or more novel agents with minimal preexisting resistance in our high-dose aerosol infection model in BALB/c mice [4, 6]
Summary
The World Health Organization (WHO) estimates that 10.4 million people developed active tuberculosis (TB) in 2016, and 1.67 million people died from it [1]. The combination of bedaquiline (BDQ), pretomanid (PMD), moxifloxacin (MXF), and PZA (regimen abbreviated as BPaMZ) had bactericidal and sterilizing activity superior to that of RIFϩINHϩPZA in a murine model of TB, shortening the duration of treatment required to prevent relapse by 2.5 to 3.5 months [4]. The combination of BDQ, PMD, and linezolid (LZD) (regimen abbreviated as BPaL) has superior bactericidal and sterilizing activity compared to that of RHZE in a murine TB model [6] It does not cure mice as rapidly as BPaMZ, this regimen has a greater spectrum of activity and has recently shown promising efficacy as an all-oral 6-month regimen in patients (Nix-TB trial) with extensively drug-resistant TB [7]. This model may be more representative of TB in patients with immunocompromising diseases such as human immunodeficiency virus (HIV) or following iatrogenic immunosuppression who have an increased risk of treatment failure and relapse, especially those not receiving antiretroviral therapy [17]
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