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JAC Advance Access published online on September 1, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg401
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

Emergence of resistant Streptococcus pneumoniae in an in vitro dynamic model that simulates moxifloxacin concentrations inside and outside the mutant selection window: related changes in susceptibility, resistance frequency and bacterial killing

Stephen H. Zinner 1 , Irene Yu. Lubenko 2 , Deborah Gilbert 3 , Kelly Simmons 3 , Xilin Zhao 4 , Karl Drlica 4 , and Alexander A. Firsov 2 *

1 Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA
2 Department of Pharmacokinetics & Pharmacodynamics, Gause Institute of New Antibiotics, 11 Bolshaya Pirogovskaya Street, Moscow, 119021 Russia
3 Roger Williams Medical Center, Providence, RI
4 Public Health Research Institute, Newark, NJ, USA

* Corresponding author. E-mail: firsov{at}dol.ru.

Received 13 March 2003 ; revised 1 July 2003 ; accepted 6 July 2003

Abstract

Objectives: According to the mutant selection window (MSW) hypothesis, resistant mutants are selected or enriched at antibiotic concentrations above the MIC but below the mutant prevention concentration (MPC). To test this hypothesis, Streptococcus pneumoniae ATCC 49619 (MIC 0.1 mg/L; MPC 0.5 mg/L) was exposed to moxifloxacin concentrations below the MIC, above the MPC and between the MIC and MPC, i.e. within the MSW.

Methods: Daily administration of moxifloxacin for 3 consecutive days was mimicked using a two-compartment dynamic model with peripheral units containing a starting inoculum of 108 cfu/mL S. pneumoniae. Changes in susceptibility were examined by repeated MIC determinations and by plating the specimens on agar containing zero, 2 x MIC, 4 x MIC and 8 x MIC of moxifloxacin.

Results: Both in terms of the MIC and resistance frequency, S. pneumoniae resistance developed at concentrations that fell inside the MSW [ratios of 24 h area under the curve (AUC24) to MIC between 24 and 47 h]. A Gaussian-like function fitted the AUC24/MIC-dependent increases in MIC and resistance frequency with central points at AUC24/MICs of 38 and 42 h, respectively, where resistant mutants are enriched selectively. Selective enrichment of resistant mutants was not seen at AUC24/MICs <10 h or >100 h.

Conclusions: These data suggest that AUC24/MICs >100 h may protect against the selection of resistant S. pneumoniae mutants. Since the usual 400 mg dose of moxifloxacin provides much higher AUC24/MIC (270 h), it is expected to prevent mutant selection at clinically achievable concentrations. Also, these data provide further support for the MSW hypothesis.


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