Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study

Abstract

Background Treatment of rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) requires multiple drugs and outcomes remain suboptimal. Some drugs are associated with improved outcome, however whether particular pharmacokinetic-pharmacodynamic relationships predict outcome is unknown. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh and Russian Federation receiving therapy with local regimens were enrolled from June, 2016 to July, 2018. Serum was collected after two, four, and eight weeks for each drug’s area under the concentration-time curve (AUC0-24) and quantitative susceptibility of the Mycobacterium tuberculosis isolate measured by minimum inhibitory concentrations (MIC). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (OR) for association with favorable treatment outcome and hazard ratios (HR) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into four clusters by AUC0-24/MIC exposures. Results Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome [OR 3.75 (1.21, 11.56), p = 0·022], while levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg*h/L were associated with faster culture conversion [HR > 1·0, p < 0.05]. Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed those with lowest multidrug exposures had slowest culture conversion. Conclusion Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs – fluoroquinolones, pyrazinamide, clofazimine – were predictive and should be optimized to improve clinical outcome.

Why do we use 100 mg of clofazimine in TB and NTM treatment?

“…In 105 patients with MDR-TB receiving clofazimine, an AUC/MIC ratio of >50 was associated with faster time to sputum culture conversion. 10 A similar correlation between higher AUC/MIC ratios and 2 and 6 month culture conversion was recorded in 136 MDR-TB patients receiving clofazimine. 38 A similar signal was observed in NTM disease.…”

“… 7 Achieving adequate exposures fast seems important, as clofazimine shows exposure-driven sterilizing and a treatment-shortening effect in TB in mouse models 8 , 9 and in patients with MDR-TB. 10 …”

Outcome of anti-tubercular therapy on rifampicin sensitive non-HIV patients with tubercular cervical lymphadenopathy in Bangladesh

“…These symptoms are consistent with findings from multiple studies. 15,16 However, a study in Nigeria reported that knowledge about TB was a significant factor affecting treatment adherence and outcomes, implying that clinical presentations alone may not be sufficient indicators of treatment success. 17 In terms of treatment duration, most participants had a TB presentation lasting more than one month (61.38%).…”