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

• Published in: Clinical infectious diseases 2023-02, Vol.76 (3), p.497-505
• Main Authors: Heysell, Scott K, Mpagama, Stellah G, Ogarkov, Oleg B, Conaway, Mark, Ahmed, Shahriar, Zhdanova, Svetlana, Pholwat, Suporn, Alshaer, Mohammad H, Chongolo, Anna M, Mujaga, Buliga, Sariko, Margaretha, Saba, Sabrina, Rahman, S M Mazidur, Uddin, Mohammad Khaja Mafij, Suzdalnitsky, Alexey, Moiseeva, Elena, Zorkaltseva, Elena, Koshcheyev, Mikhail, Vitko, Serhiy, Mmbaga, Blandina T, Kibiki, Gibson S, Pasipanodya, Jotam G, Peloquin, Charles A, Banu, Sayera, Houpt, Eric R
• Format: Article
• Language: English
• Subjects: Adult; Antitubercular Agents - pharmacokinetics; Antitubercular Agents - therapeutic use; Clofazimine - therapeutic use; Humans; Major; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Prospective Studies; Pyrazinamide - pharmacokinetics; Pyrazinamide - therapeutic use; Rifampin - pharmacology; Rifampin - therapeutic use; Tuberculosis, Multidrug-Resistant - drug therapy; Tuberculosis, Pulmonary - drug therapy
• ISSN: 1058-4838; 1537-6591
• DOI: 10.1093/cid/ciac511

Abstract Background Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. Methods Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug’s area under the concentration-time curve over 24 hours (AUC0–24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0–24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 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; 95% confidence interval, 1.21–11.56; P = .022); 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 < .05). Other individual drug exposures were not predictive. Clustering by AUC0–24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. Conclusions 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. Clinical Trials Registration NCT03559582. In a multicountry, prospective cohort treated with standardized regimens for rifampin-resistant/multidrug-resistant tuberculosis, serum pharmacokinetics and Mycobacterium tuberculosis minimum inhibitory concentrations were variable, yet parameters to certain drugs—fluoroquinolones, pyrazinamide, clofazimine—were predictive of clinical outcome.