{"doi":"10.1093/jac/dkaa412","title":"Optimizing pharmacokinetics/pharmacodynamics of β-lactam/β-lactamase inhibitor combinations against high inocula of ESBL-producing bacteria","abstract":"OBJECTIVES: Reduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria. METHODS: Three clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning. RESULTS: A concentration-dependent reduction in β-lactam MIC was observed (r2 ≥0.93). Regrowth could be suppressed in all six experiments using %T>MICi ≥73.6%, but only one out of six experiments below the threshold (P = 0.015). The exposures to suppress regrowth might be attained using the clinical dose of avibactam, but a much higher dose than the standard dose would be needed for tazobactam. CONCLUSIONS: A dense population of ESBL-producing bacteria could be suppressed by an optimized dosing regimen of selected β-lactam/β-lactamase inhibitor combinations. The reversibility of enzyme inhibition could play an important role in diminishing the inoculum effect. In vivo investigations to validate these findings are warranted.","journal":"Journal of Antimicrobial Chemotherapy","year":2020,"id":103490,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":505379,"name":"Henrietta Abodakpi","orcid":null,"position":1,"is_corresponding":false},{"id":439779,"name":"Weiqun Wang","orcid":"0000-0002-1295-8246","position":2,"is_corresponding":false},{"id":440838,"name":"Kimberly R. Ledesma","orcid":null,"position":3,"is_corresponding":false},{"id":505380,"name":"Paul R. Merlau","orcid":null,"position":4,"is_corresponding":false},{"id":439778,"name":"Katrina Chan","orcid":"0000-0002-4589-2781","position":5,"is_corresponding":false},{"id":505381,"name":"Rachel Altman","orcid":null,"position":6,"is_corresponding":false},{"id":343887,"name":"Truc T. Tran","orcid":"0000-0002-2696-4196","position":7,"is_corresponding":false},{"id":504316,"name":"Michael Nikolaou","orcid":"0000-0003-0241-6600","position":8,"is_corresponding":false},{"id":504317,"name":"Amelia K. Sofjan","orcid":"0000-0002-1349-7242","position":9,"is_corresponding":false},{"id":439780,"name":"Vincent H. Tam","orcid":"0000-0001-7071-5376","position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-18T22:42:48.999009Z","pmid":"33035321","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":[]}