title: Predictors of bacterial resistance using in vitro dynamic models: area under the concentration-time curve related to either the minimum inhibitory or mutant prevention antibiotic concentration.
abstract: OBJECTIVE
  To examine the predictive power of the ratios of the 24 h AUC (AUC24) to the mutant prevention concentration (MPC) and the MIC, the selection of ciprofloxacin-resistant mutants of Pseudomonas aeruginosa was studied in an in vitro dynamic model.
  
  
  METHODS
  Four clinical isolates of P. aeruginosa with MPC/MIC ratios from 5.6 to 32 were exposed to twice-daily ciprofloxacin for 3 days over a 100- to 200-fold range of the AUC24/MIC ratio.
  
  
  RESULTS
  The emergence of P. aeruginosa resistance to ciprofloxacin was concentration dependent: mutants resistant to 2-16 × MIC were enriched at antibiotic concentrations between the MIC and MPC, but not at concentrations below the MIC or above the MPC. Both AUC24/MIC and AUC24/MPC relationships with the area under the bacterial mutant concentration-time curve (AUBCM) were bell-shaped. These relationships predict highly variable 'anti-mutant' AUC24/MIC and AUC24/MPC ratios: e.g. with mutants resistant to 2 × MIC the ratios ranged from 220 to 1100 and from 7 to 180 h, respectively. Using combined data for the four studied organisms, correlations between AUBCM and AUC24/MIC or AUC24/MPC were established (r(2) = 0.75 and 0.65, respectively). Much stronger correlation was observed between AUC24/MIC and the area between the cut-off level at 10(8) cfu/mL and the time-kill curve (ABBC) as an integral index of the antimicrobial effect of ciprofloxacin on the parental strains (r(2) = 0.93).
  
  
  CONCLUSIONS
  Findings obtained with ciprofloxacin-exposed P. aeruginosa are consistent with the mutant selection window hypothesis. AUC24/MIC and AUC24/MPC relationships with resistance were more bacterial strain specific than AUC24/MIC relationships with fluoroquinolone-induced killing of susceptible cells.
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Strukova
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia.
authors.forename: Yury A
authors.initials: YA
authors.lastname: Portnoy
authors.affiliation: Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Zinner
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow 119021, Russia Department of Pharmaceutical and Toxicological Chemistry, I. M. Sechenov First Moscow State Medical University, Moscow, Russia firsov@dol.ru.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Firsov
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D009154:Mutation; D011552:Pseudomonas Infections / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000302:isolation & purification; D012641:Selection, Genetic
chemical_list: D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin