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

• Published in: Journal of antimicrobial chemotherapy Vol. 71; no. 3; pp. 678 - 684
• Main Authors: Strukova, Elena N, Portnoy, Yury A, Zinner, Stephen H, Firsov, Alexander A
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.03.2016
• Subjects: Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibiotics; Area Under Curve; Bacteria; Ciprofloxacin - administration & dosage; Ciprofloxacin - pharmacokinetics; Ciprofloxacin - pharmacology; Drug resistance; Drug Resistance, Bacterial; Gram-negative bacteria; Humans; Microbial Sensitivity Tests; Models, Theoretical; Multidrug resistant organisms; Mutation; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - isolation & purification; Pseudomonas Infections - microbiology; Selection, Genetic
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkv387

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. 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. 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). 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.