Fig. 2: Time–kill kinetics predict in vivo outcomes of M. tuberculosis drug regimens.
a, ASCT-based time–kill kinetics of PBS-starved M. tuberculosis (mc27000) exposed to 65 drug regimens, with the following regimens highlighted: isoniazid-rifampicin (HR, dark blue), isoniazid-rifampicin-ethambutol-pyrazinamide (HREZ, light blue), bedaquiline-pretomanid-linezolid (BPaL, red) and bedaquiline-pretomanid-pyrazinamide (BPaZ, purple). b, Areas under the kill curve for M. tuberculosis drug regimens, averaged across three M. tuberculosis starvation conditions (mean ± s.e.m.), with individual drugs indicated. c, Drug regimens were previously classified as similar to standard-of-care (SOC) or better than SOC on the basis of their performance in relapsing mouse models (RMM), bactericidal mouse models (BMM) of common mouse strains, the granulomatous C3HeB/FeJ mouse strain and in clinical studies30,31. Time–kill curves (AUC averaged across three M. tuberculosis starvation models) of similar-to-SOC drug regimens were compared with better-than-SOC regimens using a two-sided Mann–Whitney U-test. Each dot represents a drug regimen (colours indicate drug regimens in a). Boxplots show the median, interquartile range and total range (central line, box and whiskers, respectively) of AUC values (RMM: n = 46, P = 2.7 × 10−5; BMM common strains: n = 48, P = 0.0015; BMM C3HeB/FeJ: n = 15, P = 0.0047; clinical bactericidal activity: n = 14, P = 0.020). *P < 0.05, **P < 0.01, ****P < 0.0001; NS, not significant. d, Median MICs of drug regimens, calculated from the MICs of individual drugs (averaged from mc27000 and H37Ra strains), were compared between similar-to-SOC and better-than-SOC regimens. Sample sizes, statistical tests and box plots are identical to those described in c. BgMM, BMM C3HeB/FeJ.
