Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania

Abstract

Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class' purported bactericidal activity early in treatment. We tested whether <i>Mycobacterium tuberculosis</i> killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable <i>M. tuberculosis</i> 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). <i>M. tuberculosis</i> killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted <i>M. tuberculosis</i> killing of -0.17 (95% confidence interval [CI] -0.23 to -0.12) for the injectable bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI -1.05 to -0.20) log₁₀ eCFU/ml for the injectable bedaquiline-containing regimen (<i>P</i> = 0.019), -0.35 (95% CI -0.65 to -0.13) log₁₀ eCFU/ml for the all-oral bedaquiline-based regimen (<i>P</i> = 0.054), and -0.29 (95% CI -0.78 to +0.22) log₁₀ eCFU/ml for the RHZE regimen (<i>P</i> = 0.332). Thus, <i>M. tuberculosis</i> killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.