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 Mycobacterium tuberculosis 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 M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis 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 M. tuberculosis 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 (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 the RHZE regimen (P = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.
Highlights
Measurement of pulmonary tuberculosis (PTB) treatment response in areas of endemicity largely depends on sputum smear microscopy [1]
Among 296 serial sputa analyzed, 104 sputa came from 13 patients who received an injectable but bedaquiline-free regimen, 72 sputa were from 9 patients who received an injectable bedaquiline-containing regimen, 64 from 8 patients who received an alloral bedaquiline-based regimen, and 56 sputa from 7 patients who were treated for drug-sensitive TB with conventional RHZE
Adjusting for bacterial load, initial killing rate, silicosis, chest cavity, HIV status, and gender, the hazard ratios (HR) for M. tuberculosis killing were 12.37 and 14.31 for patients who received an alloral bedaquiline versus injectable bedaquiline-containing regimens, respectively (Table 4)
Summary
Measurement of pulmonary tuberculosis (PTB) treatment response in areas of endemicity largely depends on sputum smear microscopy [1]. Patients with RR/MDR-TB are typically monitored for cultured growth in Lowenstein-Jensen (LJ) solid medium or the Mycobacteria Growth Indicator Tube (MGIT) liquid culture system This culture system is sensitive, with a detection limit of 10 to 100 CFU/ml of sputum, yet it is prone to contamination and can take up to 8 weeks to determine a definitive positive or negative result, thereby limiting the ability to take appropriate and timely clinical action [4]. TB-MBLA is a real-time quantitative PCR (RT-qPCR) assay that detects and quantifies killing of 16S rRNA from both viable replicating and dormant M. tuberculosis in patient sputum during treatment [14] It is rapid and results are available within 24 h, thereby allowing informed clinical assessment of patient progress [14, 17]. We tested the hypothesis that M. tuberculosis killing rates from the sputum, as measured by TB-MBLA, correlated with time-to-culture conversion but were dependent upon the composition of the RR/MDR-TB antibiotic regimen
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