{"doi":"10.1093/jac/dkaf431","title":"Pharmacodynamic studies of taniborbactam (VNRX-5133) combined with cefepime against β-lactamase–producing Gram-negative bacteria in a neutropenic murine thigh infection model","abstract":"BACKGROUND: Taniborbactam (VNRX-5133) is a novel boronate-based β-lactamase inhibitor that directly inhibits all four classes of β-lactamases. We studied the pharmacodynamics of taniborbactam in combination with cefepime against β-lactamase-producing Enterobacterales and Pseudomonas aeruginosa. METHODS: In vitro, cefepime/taniborbactam combination was assessed with a checkerboard broth microdilution method against two ESBL-producing Enterobacterales and one AmpC- and one VIM-producing P. aeruginosa isolates (cefepime MIC 16-256 mg/L). In vivo, neutropenic infected mice were treated with cefepime, every 2 h for 24 h, alone or in combination with taniborbactam at q2h, q4h and q8h dosing intervals. Single dose escalation and dose-fractionation experiments were conducted in order to describe plasma pharmacokinetics and pharmacodynamics of taniborbactam, respectively. RESULTS: In vitro, reversal of phenotypic resistance to cefepime was found at taniborbactam ≤0.03 and 0.25 mg/L for ESBL-producing E. coli and K. pneumoniae, and at 0.125 and 2 mg/L for VIM- and AmpC constitutively-producing P. aeruginosa, respectively. In vivo, cefepime alone marginally reached stasis against Enterobacterales and AmpC-producing P. aeruginosa. Taniborbactam restored cefepime's static effect against all isolates and its 1 log10 kill effect against all strains except the K. pneumoniae isolate. The percentage of time above free concentration threshold (%fT > Ct) best described taniborbactam efficacy (R2 = 0.50-0.80). At high cefepime exposures, area under the free concentration-time curve (fAUC) performed equally well (R2 0.49-0.70). A 40%-50% and 60%-100% fT > Ct of taniborbactam was associated with stasis and 1 log10 kill, respectively, at taniborbactam concentrations where reversal of cefepime resistance was found in vitro. CONCLUSIONS: Taniborbactam restored cefepime's activity against resistant Gram-negative bacteria in a time- and concentration-dependent manner at low and higher cefepime exposures, respectively.","journal":"Journal of Antimicrobial Chemotherapy","year":2025,"id":535940,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"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":119975,"name":"Maria Siopi","orcid":"0000-0002-5924-1007","position":1,"is_corresponding":false},{"id":1420791,"name":"Marilena Tsala","orcid":null,"position":2,"is_corresponding":false},{"id":1420792,"name":"Claudia Lagarde","orcid":null,"position":3,"is_corresponding":false},{"id":1420793,"name":"Wendy Kloezen","orcid":null,"position":4,"is_corresponding":false},{"id":1420794,"name":"Anouk E Muller","orcid":null,"position":5,"is_corresponding":false},{"id":119988,"name":"Joseph Meletiadis","orcid":"0000-0002-8869-1509","position":6,"is_corresponding":false},{"id":1420790,"name":"Panagiota-Christina Georgiou","orcid":null,"position":0,"is_corresponding":true}],"reference_count":28,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41533743","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":[]}