title: Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models.
abstract: There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant K. pneumoniae mutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBCM) were bell shaped. These relationships predict highly variable "antimutant" AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC24/MIC ratio.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Strukova
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, Russia.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.affiliation: Institute of Antimicrobial Chemotherapy, Smolensk State Medical University, Smolensk, Russia.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Romanov
authors.affiliation: Institute of Antimicrobial Chemotherapy, Smolensk State Medical University, Smolensk, Russia.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Edelstein
authors.affiliation: Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, Gause Institute of New Antibiotics, Moscow, Russia firsov@dol.ru.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009154:Mutation
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin