التفاصيل البيبلوغرافية
| العنوان: |
High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial. |
| المؤلفون: |
Gausi, Kamunkhwala, Ignatius, Elisa H., De Jager, Veronique, Upton, Caryn, Kim, Soyeon, McKhann, Ashley, Moran, Laura, Wiesner, Lubbe, von Groote-Bidlingmaier, Florian, Marzinek, Philip, Vanker, Naadira, Yvetot, Joseph, Pierre, Samuel, Rosenkranz, Susan L., Swindells, Susan, Diacon, Andreas H., Nuermberger, Eric L., Denti, Paolo, Dooley, Kelly E. |
| المصدر: |
American Journal of Respiratory & Critical Care Medicine; 8/1/2024, Vol. 210 Issue 3, p343-351, 9p |
| مصطلحات موضوعية: |
ISONIAZID, MULTIDRUG-resistant tuberculosis, TUBERCULOSIS, CLINICAL trials, BACTERICIDAL action, MYCOBACTERIUM tuberculosis |
| مستخلص: |
Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration–time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than in inhA-mutated M.tb. The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15–20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registered with (NCT01936831). [ABSTRACT FROM AUTHOR] |
|
Copyright of American Journal of Respiratory & Critical Care Medicine is the property of American Thoracic Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
