Mycobactericidal effect of different regimens measured by molecular bacterial load assay among people treated for multidrug-resistant tuberculosis in Tanzania

Abstract

Background : Rifampicin 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 Mycobacterium tuberculosis (Mtb) killing rates measured by molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Methods : Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at day 0, 3, 7, 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable Mtb 16S rRNA in sputum for estimation of colony-forming-unit per mL (eCFU/mL). Mtb killing rates were compared among regimens using nonlinear-mixed-effects modelling of repeated measures. Results : Thirty-seven patients produced 296 serial sputa: 13 patients received an injectable-containing but bedaquiline-free reference regimen, 9 received an injectable and 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 Mtb killing of -0.17 (95% CI; -0.23 to -0.12) for the injectable-containing but bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI; -1.05 to -0.20) log10 eCFU/mL for the injectable and bedaquiline-containing regimen (p = 0.019), -0.35 (95% CI; -0.65 to -0.13) log10 eCFU/mL for the all-oral bedaquiline-based regimen (p = 0.054), and -0.29 (95% CI; -0.78 to +0.22) log10 eCFU/mL for RHZE (p = 0.332). Conclusion : Mtb killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.