{"doi":"10.1164/rccm.202311-2004oc","title":"High-Dose Isoniazid Lacks EARLY Bactericidal Activity against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized Phase II Clinical Trial","abstract":"Abstract 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).","journal":"American Journal of Respiratory and Critical Care Medicine","year":2024,"id":433853,"datarank":0.7411195219133899,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.345260922471101,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.345260922471101,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":12,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT01936831"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":501425,"name":"Elisa H. 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