title: Using In Vitro Dynamic Models To Evaluate Fluoroquinolone Activity against Emergence of Resistant Salmonella enterica Serovar Typhimurium.
abstract: The objectives of this study were to determine pharmacokinetic/pharmacodynamic (PK/PD) indices of fluoroquinolones that minimize the emergence of resistant Salmonella enterica serovar Typhimurium (S Typhimurium) using in vitro dynamic models and to establish mechanisms of resistance. Three fluoroquinolones, difloxacin (DIF), enrofloxacin (ENR), and marbofloxacin (MAR), at five dose levels and 3 days of treatment were simulated. Bacterial killing-regrowth kinetics and emergence of resistant bacteria after antibacterial drug exposure were quantified. PK/PD indices associated with different levels of antibacterial activity were computed. Mechanisms of fluoroquinolone resistance were determined by analyzing target mutations in the quinolone resistance-determining regions (QRDRs) and by analyzing overexpression of efflux pumps. Maximum losses in susceptibility of fluoroquinolone-exposed S Typhimurium occurred at a simulated AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 47 to 71. Target mutations in gyrA (S83F) and overexpression of acrAB-tolC contributed to decreased susceptibility in fluoroquinolone-exposed S Typhimurium. The current data suggest AUC/MIC (AUC/mutant prevention concentration [MPC])-dependent selection of resistant mutants of S Typhimurium, with AUC/MPC ratios of 69 (DIF), 62 (ENR), and 39 (MAR) being protective against selection of resistant mutants. These values could not be achieved in veterinary clinical areas under the current recommended therapeutic doses of the fluoroquinolones, suggesting the need to reassess the current dosing regimen to include both clinical efficacy and minimization of emergence of resistant bacteria.
authors.affiliation: Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Seung-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA.
authors.forename: Elias Gebru
authors.initials: EG
authors.lastname: Awji
authors.affiliation: Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea.
authors.forename: Na-Hye
authors.initials: NH
authors.lastname: Park
authors.affiliation: Laboratory of Veterinary Pharmacokinetics and Pharmacodynamics, College of Veterinary Medicine, Kyungpook National University, Daegu, South Korea parksch@knu.ac.kr.
authors.forename: Seung-Chun
authors.initials: SC
authors.lastname: Park
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013552:Swine; D019155:Veterinary Drugs / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D019155:Veterinary Drugs
keywords: PK/PD integration; Salmonella Typhimurium; acrAB-tolC; efflux pumps; fluoroquinolone; global regulator; gyrA; in vitro dynamic model; mutant prevention concentration; target mutation