{"doi":"10.1093/infdis/jiaf303","title":"The Kinetics of Bedaquiline Diffusion in Tuberculous Cavities Open a Window for the Emergence of Resistance","abstract":"BACKGROUND: Cavitary tuberculosis is difficult to cure and constitutes a site of relapse. Bedaquiline has been a wonder drug in the treatment of multidrug-resistant tuberculosis, but emergence of resistance threatens the sustainability of its success. We designed site-of-disease pharmacokinetic studies to spatially resolve the penetration of bedaquiline, and 2 next-generation diarylquinolines, TBAJ876 and TBAJ587, in cavities. METHODS: Rabbits with established cavitary tuberculosis received the study drugs. A laser-capture microdissections scheme was developed to measure drug concentrations as a function of distance from blood supply in caseum. To simulate drug coverage in patient cavities, the data were modeled, and parameter estimates were linked to clinical plasma pharmacokinetic models. RESULTS: Pharmacokinetic-pharmacodynamic simulations in caseum revealed that bedaquiline reaches steady state and efficacious concentrations in deep caseum after several weeks to months and lingers at subtherapeutic concentrations up to 3 years after therapy ends. TBAJ876 and TBAJ587, achieve bactericidal concentrations in caseum layers more rapidly and shorten the window of suboptimal concentrations post treatment compared to bedaquiline. CONCLUSIONS: The slow kinetics of diffusion of bedaquiline into and out of caseum creates spatiotemporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ587 and TBAJ876 predict reduced opportunities for resistance development.","journal":"The Journal of Infectious Diseases","year":2025,"id":519672,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9557,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":355785,"name":"Jacqueline P. Ernest","orcid":"0000-0002-7664-7287","position":1,"is_corresponding":false},{"id":458979,"name":"Firat Kaya","orcid":"0000-0001-8655-2065","position":2,"is_corresponding":false},{"id":1388628,"name":"Connie Silva","orcid":null,"position":3,"is_corresponding":false},{"id":458978,"name":"Jansy P. Sarathy","orcid":"0000-0002-1532-146X","position":4,"is_corresponding":false},{"id":618617,"name":"Landry Blanc","orcid":"0000-0001-5622-356X","position":5,"is_corresponding":false},{"id":455378,"name":"Marjorie Z. Imperial","orcid":"0000-0001-7434-3012","position":6,"is_corresponding":false},{"id":270338,"name":"Martin Gengenbacher","orcid":"0000-0002-0208-5920","position":7,"is_corresponding":false},{"id":691232,"name":"Min Xie","orcid":"0000-0002-9770-5351","position":8,"is_corresponding":false},{"id":294414,"name":"Matthew Zimmerman","orcid":"0000-0002-6229-0571","position":9,"is_corresponding":false},{"id":477426,"name":"Gregory T. Robertson","orcid":"0000-0001-7157-4034","position":10,"is_corresponding":false},{"id":1032665,"name":"Danielle Weiner","orcid":null,"position":11,"is_corresponding":false},{"id":584801,"name":"Laura E. Via","orcid":"0000-0001-6074-9521","position":12,"is_corresponding":false},{"id":89001,"name":"Clifton E. Barry","orcid":"0000-0002-2927-270X","position":13,"is_corresponding":false},{"id":455381,"name":"Radojka M. Savić","orcid":"0000-0003-3143-5579","position":14,"is_corresponding":false},{"id":283116,"name":"Véronique Dartois","orcid":"0000-0001-9470-5009","position":15,"is_corresponding":false},{"id":620611,"name":"Annamarie E. Bustion","orcid":"0000-0002-7380-3619","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:49:18.751199Z","pmid":"40464735","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}