Heterogeneity of the mutant selection window: selection of resistant Staphylococcus aureus at ciprofloxacin constant concentrations simulated close to the MIC or the mutant prevention concentration

Abstract number: R2267

Firsov A., Lubenko I., Smirnova M., Strukova E., Zinner S.

Objective: Expected enrichment of resistant mutants at antibiotic concentrations that fall into mutant selection window (MSW) might depend not only on the time inside the MSW but also on the position of the pharmacokinetic profile in the MSW. To test this hypothesis, the selection of ciprofloxacin (CIP)-resistant S. aureus was studied at CIP constant concentrations (CCs) simulated closer to the bottom of the MSW (slightly above the MIC –"lower case") and to the top of the MSW (slightly below the mutant prevention concentration (MPC) –"upper case").

Methods: Two meticillin-resistant strains of S. aureus, one with a wide MSW (ATCC 6538) and another with a narrow MSW (ATCC 43300) [respective MPC/MIC ratios are 16 and 4], were exposed to constant-rate infusion of CIP for 3 consecutive days. With S. aureus ATCC 6538 and ATCC 43300, simulated CCs were 1.3–2 times greater than the MICs ("lower case") and 1.5 times smaller than the MPCs ("upper case"). Bacterial growth on agar plates containing 2×–16×MIC of CIP was tested daily. Time courses of mutants grown on CIP-containing plates were expressed by areas under the bacterial mutant kinetic curves (AUBMCs) measured from the start to the end of the infusion.

Results: Susceptible sub-populations of S. aureus ATCC 43300 were completely replaced by mutants resistant to 2× and 4×MIC of CIP by the end of the infusion (both lower and upper cases – CC 0.75 and 1.5 mg/L, respectively). Similar replacement occurred with S. aureus ATCC 6538, but only in the lower case (CC 0.5 mg/L). In the upper case (CC 2.7 mg/L), CIP-resistant mutants of S. aureus ATCC 6538 were enriched later and to a lesser extent than in the lower case: for mutants resistant to 2–16×MIC of CIP, estimated AUBMCs were 2–3-fold smaller in the upper case than in the lower case. There were no "position-associated" differences in the enrichment of resistant S. aureus ATCC 43300, probably due to comparable CCs at both the lower and upper positions within the MSW.

Conclusion: A more rapid and pronounced enrichment of CIP-resistant staphylococci occurs with organisms exhibiting a wide MSW. The possible heterogeneity of the MSW should be considered to better predict the enrichment of staphylococcal resistance.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Location: Barcelona, Spain
Presentation type:
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