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- Title
Artificial intelligence–derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.
- Authors
Pasipanodya, Jotam G; Smythe, Wynand; Merle, Corinne S; Olliaro, Piero L; Deshpande, Devyani; Magombedze, Gesham; McIlleron, Helen; Gumbo, Tawanda
- Abstract
Background In the experimental arm of the OFLOTUB trial, gatifloxacin replaced ethambutol in the standard 4-month regimen for drug-susceptible pulmonary tuberculosis. The study included a nested pharmacokinetic (PK) study. We sought to determine if PK variability played a role in patient outcomes. Methods Patients recruited in the trial were followed for 24 months, and relapse ascertained using spoligotyping. Blood was drawn for drug concentrations on 2 separate days during the first 2 months of therapy, and compartmental PK analyses was performed. Failure to attain sustained sputum culture conversion at the end of treatment, relapse, or death during follow-up defined therapy failure. In addition to standard statistical analyses, we utilized an ensemble of machine-learning methods to identify patterns and predictors of therapy failure from among 27 clinical and laboratory features. Results Of 126 patients, 95 (75%) had favorable outcomes and 19 (15%) failed therapy, relapsed, or died. Pyrazinamide and rifampicin peak concentrations and area under the concentration-time curves (AUCs) were ranked higher (more important) than gatifloxacin AUCs. The distribution of individual drug concentrations and their ranking varied significantly between South African and West African trial sites; however, drug concentrations still accounted for 31% and 75% of variance of outcomes, respectively. We identified a 3-way antagonistic interaction of pyrazinamide, gatifloxacin, and rifampicin concentrations. These negative interactions disappeared if rifampicin peak concentration was above 7 mg/L. Conclusions Concentration-dependent antagonism contributed to death, relapse, and therapy failure but was abrogated by high rifampicin concentrations. Therefore, increasing both rifampin and gatifloxacin doses could improve outcomes. Clinical Trials Registration NCT002216385.
- Subjects
WEST Africa; SOUTH Africa; DRUG therapy for tuberculosis; TUBERCULOSIS mortality; ANTIBIOTICS; ARTIFICIAL intelligence; CULTURES (Biology); DRUG interactions; GENETIC techniques; MACHINE learning; RIFAMPIN; SPUTUM; DISEASE relapse; RANDOMIZED controlled trials; TREATMENT effectiveness; PYRAZINAMIDE
- Publication
Clinical Infectious Diseases, 2018, Vol 67, pS284
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/ciy610