{"doi":"10.1128/aac.00287-25","title":"Drug development studies supporting zileuton as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity","abstract":"Glycopeptide, polymyxin, and aminoglycoside antibiotics are among the most commonly used agents to treat drug-resistant bacterial infections; however, their clinical use is hindered by nephrotoxicity. We previously reported that zileuton has the potential to attenuate antibiotic-associated nephrotoxicity in an animal model. Here, we further report the development of a parenteral formulation and exploration of dosing strategies for zileuton. The solubility, stability, and multi-dose safety of two zileuton formulations were evaluated. Zileuton serum and renal tissue pharmacokinetics were evaluated after a single dose and compared to steady state after 10 days. Different dosing strategies of zileuton to attenuate vancomycin-, polymyxin B-, and amikacin-associated nephrotoxicity were evaluated in rats over 10 days. Two formulations (1 and 10 mg/mL) showed good multi-dose safety, with no significant changes in serum creatinine, alanine transaminase, or body weight observed following doses of 12 mg/kg daily for 10 days. Zileuton was well-distributed into renal tissue, and serum exposure was comparable to humans after a typical dose (600-2,400 mg). No drug accumulation at steady state was observed. Zileuton was found to reduce nephrotoxicity associated with vancomycin, polymyxin B, and amikacin in a dose-dependent manner. With the same daily dose, dose fractionation resulted in similar renal protection compared to once-daily dosing. These preliminary studies support that zileuton has the potential to be used as a parenteral adjuvant to attenuate antibiotic-associated nephrotoxicity. This would allow the optimal use of glycopeptides, polymyxins, and aminoglycosides to treat difficult infections. Further studies are warranted to repurpose zileuton as a nephroprotectant.","journal":"Antimicrobial Agents and Chemotherapy","year":2025,"id":550799,"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":0.9529,"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":1144404,"name":"James E. Smith","orcid":"0009-0005-4330-9782","position":1,"is_corresponding":false},{"id":828288,"name":"Linh T. Vuong","orcid":null,"position":2,"is_corresponding":false},{"id":1043866,"name":"Nicholas S Teran","orcid":"0000-0001-7063-2191","position":3,"is_corresponding":false},{"id":1268283,"name":"Nazanin Pouya","orcid":null,"position":4,"is_corresponding":false},{"id":680715,"name":"David Sheikh‐Hamad","orcid":"0000-0003-4436-4191","position":5,"is_corresponding":false},{"id":554722,"name":"Xinli Liu","orcid":"0000-0002-1680-1561","position":6,"is_corresponding":false},{"id":1446702,"name":"Shama Kajiji","orcid":null,"position":7,"is_corresponding":false},{"id":439780,"name":"Vincent H. Tam","orcid":"0000-0001-7071-5376","position":8,"is_corresponding":false},{"id":796453,"name":"Cole S Hudson","orcid":"0000-0002-0284-4261","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:54:20.915388Z","pmid":"40626888","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":[]}