title: Pharmacodynamic assessment of gatifloxacin against Streptococcus pneumoniae.
abstract: 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 10(5) to 10(7) 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 microg/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.
authors.affiliation: Department of Pharmacy Research, Hartford Hospital, Hartford, Connecticut 06102, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Mattoes
authors.forename: M
authors.initials: M
authors.lastname: Banevicius
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Turley
authors.forename: D
authors.initials: D
authors.lastname: Xuan
authors.forename: C H
authors.initials: CH
authors.lastname: Nightingale
authors.forename: D P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D024841:Fluoroquinolones; D000077734:Gatifloxacin; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000209:etiology / Q000378:metabolism; D013290:Streptococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D000077734:Gatifloxacin