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Antimicrobial Agents and Chemotherapy, July 2001, p. 2092-2097, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2092-2097.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacodynamic Assessment of Gatifloxacin against Streptococcus pneumoniae

Holly M. Mattoes,1 Maryanne Banevicius,1 Dadong Li,1 Christina Turley,1 Dawei Xuan,1 Charles H. Nightingale,1,2 and David P. Nicolau1,3,*

Department of Pharmacy Research,1 Office of Research,2 and Division of Infectious Diseases,3 Hartford Hospital, Hartford, Connecticut 06102

Received 12 June 2000/Returned for modification 22 October 2000/Accepted 15 April 2001

The pharmacodynamic parameters of peak serum drug concentration/MIC (peak/MIC) ratio and the area under the curve (AUC)/MIC ratio have been used to characterize in vivo drug exposure and its relationship to bacterial killing for the fluoroquinolones. Our study objectives were to describe the pharmacodynamic relationship between gatifloxacin exposure and outcome as assessed by bacterial density and survival in an immunocompromised murine thigh model of pneumococcal infection and to assess the relationship between drug exposure and these outcomes in an immunocompetent host. ICR mice were rendered neutropenic, and thigh infection was induced by intramuscular administration of 0.1 ml of 105 to 107 CFU of Streptococcus pneumoniae/ml. Mice received 1 to 5 mg of uranyl nitrate/kg of body weight at day -3 and were randomized to receive 10 to 80 mg of gatifloxacin/kg every 6 to 24 h orally, starting at 2 h postinoculation. Bacterial density studies were completed 24 h after initiation of therapy, and survival was assessed after 4 days of treatment. MICs for clinical isolates (n = 8) ranged from 0.25 to 1.0 µg/ml. Correlations were assessed between the change in bacterial density, as well as survival, and the AUC/MIC ratio, peak/MIC ratio, and the duration of time that serum drug concentration remained above the MIC. The best predictor of bacterial response was the AUC/MIC ratio for both outcome measures. There was greater efficacy, as measured by a decrease in log change in CFU as well as by survival data, in the immunocompetent mice compared to the immunocompromised mice. These data demonstrate (i) the appropriateness of the AUC/MIC ratio as a dynamic predictor of response to pneumococcal infection for the fluoroquinolones, (ii) that gatifloxacin AUC/MIC ratios of 30 to 40 appear to optimize bactericidal activity and survival in this model, and (iii) that immunocompetency of the host plays a role in efficacy.

* Corresponding author. Mailing address: Division of Infectious Diseases, Hartford Hospital, 80 Seymour St., Hartford, CT 06102. Phone: (860) 545-3941. Fax: (860) 545-3992. E-mail: dnicolau{at}harthosp.org.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2092-2097, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2092-2097.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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