{"doi":"10.3389/fphar.2025.1682477","title":"Tigecycline pharmacodynamics in the hollow fiber system of Mycobacterium avium-complex lung disease and the utility of MICs and time-kill studies in drug development","abstract":"Background Guideline-based therapy (GBT) drugs for Mycobacterium avium -complex (MAC) lung disease (LD) were chosen in part because they have low minimum inhibitory concentrations (MICs). Despite these low MICs, GBT achieves 6-month sustained sputum culture conversion in only 43% of patients. Methods First, we co-incubated tigecycline with MAC for 7 days in time-kill studies and calculated the exposure mediating 50% of maximal effect (E max ), or EC 50 . Next, we performed tigecycline exposure-effect studies in the hollow fiber system of MAC (HFS-MAC) inoculated with the reference ATCC#700898 isolate. Third, we performed an exposure-effect study in the HFS-MAC inoculated with five clinical isolates. Finally, the target exposure (EC 80 ) was used to identify a clinical dose of inhaled tigecycline for MAC-LD in 10,000 virtual subject Monte Carlo experiments (MCE). Results In time-kill studies, the EC 50 was 0–24 h area under the concentration-time curve-to-MIC (AUC 0–24 /MIC) of 174 for extracellular and 4.56 for intracellular MAC (p < 0.001). In the HFS-MAC inoculated with ATCC#700898, the EC 50 statistically differed between sampling days. However, studies with five different isolates demonstrated a stable and robust day-to-day EC 50 (%CV = 18.18%), with an EC 80 AUC 0–24 /MIC of 33.65. The E max was 4.84 log 10 CFU/mL. In MCE, tigecycline inhalational doses of 35–40 mg/day achieved the EC 80 target in >90% of virtual patients, with an MIC breakpoint of 256 mg/L. Conclusion Instead of static time-kill studies with a reference strain, inclusion of multiple MAC isolates in HFS-MAC studies improves the precision of pharmacokinetic/pharmacodynamic parameter estimates. Tigecycline administered via the inhalational route could contribute to the treatment of MAC-LD.","journal":"Frontiers in Pharmacology","year":2025,"id":548453,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9614,"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":267029,"name":"Shashikant Srivastava","orcid":"0000-0002-8786-8851","position":1,"is_corresponding":false},{"id":267039,"name":"Tawanda Gumbo","orcid":"0000-0001-7592-8012","position":2,"is_corresponding":false},{"id":1081692,"name":"Devyani Deshpande","orcid":"0000-0002-1665-7619","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T02:53:58.530220Z","pmid":"41311832","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":[]}