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JAC Advance Access originally published online on August 11, 2009
Journal of Antimicrobial Chemotherapy 2009 64(4):815-820; doi:10.1093/jac/dkp287
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

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

Maria V. Smirnova1, Sergey N. Vostrov1, Elena V. Strukova1, Svetlana A. Dovzhenko1, Michael B. Kobrin1, Yury A. Portnoy1, Stephen H. Zinner2 and Alexander A. Firsov1,*

1 Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, Russian Academy of Medical Sciences, 11 Bolshaya Pirogovskaya Street, Moscow, 119021 Russia 2 Mount Auburn Hospital, Harvard Medical School, Cambridge, MA, USA

Received 9 April 2009; returned 3 June 2009; revised 23 June 2009; accepted 14 July 2009

* Corresponding author. Tel: +7-495-708-3341; Fax +7-499-245-0295; E-mail: firsov{at}dol.ru

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 2x and 4x 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.

Keywords: selection of resistant staphylococci , in vitro studies , methodology


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