The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models

Objectives To explore whether the duration of in vitro simulated antibiotic exposure influences bacterial resistance, time-dependent amplification of resistant subpopulations of Staphylococcus aureus was studied in 10 day simulations in a dynamic model with daptomycin as a prototypic agent. Methods...

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Bibliographic Details
Published in:Journal of antimicrobial chemotherapy 2009-10, Vol.64 (4), p.815-820
Main Authors: Smirnova, Maria V., Vostrov, Sergey N., Strukova, Elena V., Dovzhenko, Svetlana A., Kobrin, Michael B., Portnoy, Yury A., Zinner, Stephen H., Firsov, Alexander A.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Antibiotics
Colony Count, Microbial
Drug resistance
Drug Resistance, Bacterial
Humans
in vitro studies
methodology
Microbial Sensitivity Tests - methods
Models, Theoretical
selection of resistant staphylococci
Selection, Genetic
Simulation
Staphylococcus aureus
Staphylococcus aureus - drug effects
Staphylococcus infections
Time Factors
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Summary:Objectives To explore whether the duration of in vitro simulated antibiotic exposure influences bacterial resistance, time-dependent amplification of resistant subpopulations of Staphylococcus aureus was studied in 10 day simulations in a dynamic model with daptomycin as a prototypic agent. Methods S. aureus ATCC 43300 was exposed to once-daily dosing of daptomycin at subtherapeutic ratios of 24 h area under the curve (AUC24) to the MIC (32 and 64 h). To provide an integral presentation of the time course of mutants grown on agar plates containing 2× and 4× the MIC of daptomycin, areas under the bacterial mutant kinetic curves (AUBCMs) were calculated. Results Daptomycin-resistant S. aureus mutants were enriched gradually over the entire treatment duration, with systematic increases in AUBCM and concomitant decreases in susceptibility. AUBCM analyses were also applied to resistance data reported from other studies with S. aureus exposed to daptomycin and garenoxacin over a wide range of AUC24/MIC ratios. Although the maximal AUBCMs were greater with longer than with shorter exposures, the treatment or observation durations did not influence the predicted anti-mutant AUC24/MIC ratios. Conclusions These findings suggest that the duration of in vitro simulated antibiotic exposure is important for estimates of the maximal enrichment of resistant mutants but not for the prediction of the anti-mutant AUC24/MIC ratio.
ISSN:0305-7453
1460-2091
DOI:10.1093/jac/dkp287