High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial.

Autor:	Gausi K; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Ignatius EH; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., De Jager V; TASK, Cape Town, South Africa., Upton C; TASK, Cape Town, South Africa., Kim S; Frontier Science Foundation, Brookline, Massachusetts., McKhann A; Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Moran L; Social & Scientific Systems, a DLH Company, Silver Spring, Maryland., Wiesner L; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., von Groote-Bidlingmaier F; TASK, Cape Town, South Africa., Marzinek P; Frontier Science Foundation, Amherst, New York., Vanker N; Social & Scientific Systems, a DLH Company, Silver Spring, Maryland., Yvetot J; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; and., Pierre S; GHESKIO Centers, Port-au-Prince, Haiti., Rosenkranz SL; Frontier Science Foundation, Brookline, Massachusetts., Swindells S; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; and., Diacon AH; Social & Scientific Systems, a DLH Company, Silver Spring, Maryland., Nuermberger EL; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Dooley KE; Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2024 Aug 01; Vol. 210 (3), pp. 343-351.
DOI:	10.1164/rccm.202311-2004OC
Abstrakt:	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 www.clinicaltrials.gov (NCT01936831).
Databáze:	MEDLINE
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