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- Title
Drug Exposure and Minimum Inhibitory Concentration Predict Pulmonary Tuberculosis Treatment Response.
- Authors
Zheng, Xubin; Bao, Ziwei; Forsman, Lina Davies; Hu, Yi; Ren, Weihua; Gao, Yazhou; Li, Xuliang; Hoffner, Sven; Bruchfeld, Judith; Alffenaar, Jan-Willem
- Abstract
Background Prospective studies correlating pharmacokinetic/pharmacodynamic (PK/PD) indices to clinical responses are urgently needed. This study aimed to find clinically relevant PK/PD thresholds that can be used for treatment optimization. Methods Pharmacokinetic sampling and minimum inhibitory concentration (MIC) measurements were performed for patients with culture-confirmed tuberculosis (TB). Classification and regression tree (CART) analysis was applied to obtain PK and/or PD thresholds for first-line drugs predictive of 2-week/month culture conversion, treatment outcome determined at 6–8 months, acute kidney injury (AKI), and drug-induced liver injury (DILI). Least absolute shrinkage and selection operator (LASSO) logistic regression was used for model development and validation. Results Finally, 168 and 52 patients with TB were included in development and validation cohorts for analysis, respectively. Area under the concentration-time curve (AUC)/MIC below CART-derived thresholds for pyrazinamide of 8.42, pyrazinamide of 2.79, or rifampicin of 435.45 were the predominant predictors of 2-week culture conversion, 2-month culture conversion, or treatment success, respectively. Isoniazid AUC >21.78 mg · h/L or rifampicin AUC >82.01 mg · h/L were predictive of DILI or AKI during TB treatment. The predictive performance of trained LASSO models in the validation cohort was evaluated by receiver operating characteristic curves and ranged from 0.625 to 0.978. Conclusions PK/PD indices and drug exposure of TB drugs were associated with clinical outcome and adverse events. The effect of CART-derived thresholds for individualized dosing on treatment outcome should be studied in a randomized controlled trial.
- Subjects
TUBERCULOSIS prognosis; DRUG therapy for tuberculosis; PYRAZINAMIDE; REGRESSION analysis; TREATMENT effectiveness; LIVER diseases; ANTITUBERCULAR agents; DRUG monitoring; LOGISTIC regression analysis; RIFAMPIN; RECEIVER operating characteristic curves; MICROBIAL sensitivity tests; ACUTE kidney failure; PHARMACODYNAMICS
- Publication
Clinical Infectious Diseases, 2021, Vol 73, Issue 9, pe3520
- ISSN
1058-4838
- Publication type
Article
- DOI
10.1093/cid/ciaa1569