Pretomanid vs delamanid in a bedaquiline-linezolid regimen: efficacy in a high-burden tuberculosis mouse model

The bedaquiline, pretomanid, and linezolid (BPaL) regimen has shown significant efficacy in treating patients with multidrug-resistant and extensively drug-resistant tuberculosis. This study assessed whether delamanid, a closely related nitroimidazole, could replace pretomanid in the BPaL regimen by directly comparing the efficacy of bedaquiline, delamanid, and linezolid (BDL) and BPaL regimens in a high-burden preclinical Mycobacterium tuberculosis mouse model. Treatment with pretomanid and delamanid monotherapies and dual therapy with bedaquiline-linezolid was also conducted for comparison. Mice were treated for 2, 4, or 8 weeks, and treatment efficacy was assessed by reductions in lung colony-forming units (CFU), effect size, ribosomal RNA synthesis ratio (RS ratio), and histopathological changes. BPaL showed greater early reduction than BDL, with better CFU reduction kinetics on day 12 (3.96 log₁₀ CFU reduction for BPaL vs 2.89 log₁₀ CFU reduction for BDL, P < 0.001) and a lower RS ratio. By day 26, both BPaL and BDL reduced bacterial counts by nearly 6 log₁₀ CFU, and by day 54 of treatment, lung CFU levels in both groups had fallen below detectable levels. Histopathological analysis revealed slightly improved lung inflammation during early treatment in BPaL-treated mice compared to BDL. Plasma-drug levels were measured, confirming that exposures between regimens over the 24-h dosing interval were comparable and not significantly different. These results suggest that although pretomanid remains the preferred component of the BPaL regimen, delamanid could be a viable alternative if there are clinical reasons to substitute, including drug resistance or if pretomanid is unavailable or poorly tolerated.