{"doi":"10.17615/0vfg-bd33","title":"Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii","abstract":"ABSTRACT Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B ( t 1/2 = 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an f AUC 0–24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections.","journal":"UNC Libraries","year":2020,"id":136102,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9497,"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":40493,"name":"Gauri G. Rao","orcid":"0000-0002-8704-7770","position":1,"is_corresponding":false},{"id":506148,"name":"Visanu Thamlikitkul","orcid":"0000-0002-0044-5988","position":2,"is_corresponding":false},{"id":350710,"name":"Alan Forrest","orcid":"0000-0003-2752-4819","position":3,"is_corresponding":false},{"id":298093,"name":"Jürgen B. Bulitta","orcid":"0000-0001-7352-3097","position":4,"is_corresponding":false},{"id":258541,"name":"Jian Li","orcid":"0000-0001-7953-8230","position":5,"is_corresponding":false},{"id":532664,"name":"Soon-Ee Cheah","orcid":null,"position":6,"is_corresponding":false},{"id":350708,"name":"Justin R. Lenhard","orcid":"0000-0002-2570-7593","position":7,"is_corresponding":false},{"id":300097,"name":"Patricia N. Holden","orcid":null,"position":8,"is_corresponding":false},{"id":350711,"name":"Roger L. Nation","orcid":"0000-0003-1492-8590","position":9,"is_corresponding":false},{"id":350709,"name":"Cornelia B. Landersdorfer","orcid":"0000-0003-0928-4743","position":10,"is_corresponding":false},{"id":298094,"name":"Brian T. Tsuji","orcid":"0000-0002-2413-2118","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:16:35.237665Z","pmid":null,"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":[]}