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Antimicrobial Agents and Chemotherapy, March 2003, p. 1088-1095, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1088-1095.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Activities of Moxifloxacin against, and Emergence of Resistance in, Streptococcus pneumoniae and Pseudomonas aeruginosa in an In Vitro Pharmacokinetic Model

Alasdair P. MacGowan,* Chris A. Rogers, H. Alan Holt, and Karen E. Bowker

Bristol Centre for Antimicrobial Research and Evaluation,University of Bristol and ,1 North Bristol NHS Trust, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom3

Received 22 January 2002/ Returned for modification 16 September 2002/ Accepted 15 November 2002

The pharmacodynamics of moxifloxacin against Streptococcus pneumoniae and Pseudomonas aeruginosa were investigated in a pharmacokinetic infection model. Three strains of S. pneumoniae, moxifloxacin, and two strains of P. aeruginosa were used. Antibacterial effect and emergence of resistance were measured for both species over a 72-h period using an initial inoculum of about 108 CFU/ml. At equivalent area under the curve (AUC)/MIC ratios, S. pneumoniae was cleared from the model while P. aeruginosa was not. For S. pneumoniae, the area under the bacterial kill curve up to 72 h could be related to AUC/MIC ratio using an inhibitory maximum effect (Emax) model (concentration required for 50% Emax [EC50], 45 ± 22; r2, 0.97). For P. aeruginosa even at the highest AUC/MIC ratio (427), bacterial clearance was insufficient for the EC50 to be calculated. Emergence of resistance occurred with P. aeruginosa but not to any significant extent with S. pneumoniae. Emergence of resistance in P. aeruginosa as measured by population analysis profile (PAP-AUC) was dependent on drug exposure and time of exposure. In weighted least-squares regression analysis AUC/MIC ratio was predictive of PAP-AUC. When emergence of resistance was measured by the time for the colony counts on media containing antibiotic to increase by 2 logs, again AUC/MIC was the best predictor of emergence of resistance. However, for both experiments using S. pneumoniae and P. aeruginosa the correlation between all the pharmacodynamic parameters was high. These data indicate that for a given fluoroquinolone the magnitude of the AUC/MIC ratio for antibacterial effect is dependent on the bacterial species. Emergence of resistance is dependent on (i) species, (ii) duration of drug exposure, and (iii) drug exposure. A single AUC/MIC ratio magnitude is not adequate to predict antibacterial effect or emergence of resistance for all bacterial species.

* Corresponding author. Mailing address: Bristol Centre for Antimicrobial Research and Evaluation, Department of Medical Microbiology, Southmead Hospital, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. Phone: 44 (0) 1179595652. Fax: 44 (0) 1179593154. E-mail: macgowan_a{at}southmead.swest.nhs.uk.

Antimicrobial Agents and Chemotherapy, March 2003, p. 1088-1095, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.1088-1095.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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