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 TB in BALB/c mice compared to 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 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 BMZ alone. Among severely ill C3HeB/FeJ mice with caseous pneumonia and cavitation, BPaMZ increased median survival (≥60 vs. 21 days) and reduced median lung CFU by 2.4 log10 at 1 month compared to 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.

Comparative Efficacy of the Novel Diarylquinoline TBAJ-587 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis

“…Importantly, we did not observe selection of higher level, or "second-step" BDQ resistance despite treating the Rv0678 mutant infection with BDQ or TBAJ-587 alone. This is likely a function of the low frequency of viable spontaneous atpE mutants and their fitness costs observed in vivo (27). were formulated in 20% hydroxypropyl-β-cyclodextrin solution acidified with 1.5% 1N HCl.…”

“…At D0, the mean frequencies of CFU able to grow on agar containing 0.06 and 0.25 µg/ml of BDQ were 4.2x10 -5 and 1.8x10 -5 , respectively. Plates containing BDQ 0.06 µg/ml were used to quantify the resistant subpopulation at subsequent time points, based on prior evidence of its effectiveness for quantifying mutants with low-level resistance to BDQ (27). All mice infected with M. tuberculosis H37Rv and treated with BDQ monotherapy at 25 mg/kg for one or two months demonstrated selective amplification of BDQ-resistant CFU, which represented approximately 3% and 18% of the recovered CFU after one and two months, respectively (Table 1).…”

Comparative efficacy of the novel diarylquinoline TBAJ-587 and bedaquiline against a resistantRv0678mutant in a mouse model of tuberculosis

“…Importantly, we did not observe selection of higher level, or “second-step” BDQ resistance despite treating the Rv0678 mutant infection with BDQ or TBAJ-587 alone. This is likely a function of the low frequency of viable spontaneous atpE mutants and their fitness costs observed in vivo (31). Although atpE mutations have been identified in a small number of BDQ-resistant clinical isolates to date (32, 33), Rv0678 mutations have been more prevalent.…”

“…The laboratory strain, M. tuberculosis H37Rv, and a spontaneous bedaquiline-resistant mutant with an IS 6110 insertion in Rv0678 at aa116/nt349 were used in this study. The Rv0678 mutant was previously identified as BDQ-8 when it was isolated from an untreated mouse infected by H37Rv (31). The Rv0678 mutation and the absence of other mutations in genes associated with drug resistance were confirmed by whole genome sequencing.…”

Evaluation of pharmacokinetic‐pharmacodynamic relationships and selection of drug combinations for tuberculosis

“…Finally, the addition of PMD to BZ does not yield an improvement in EBA 7–14 (from 0.152 to 0.146) 49 . Overall, these results indicate that whilst the use of PMD as companion drug may contribute to a lower relapse rate, 50 it does not appear to improve the overall antimicrobial activity of the combination.…”