Pharmacodynamics of a novel des-F(6)-quinolone, BMS-284756, against Streptococcus pneumoniae in the thigh infection model.
BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 10(5) to 10(6) CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (n = 8) ranged from 0.03 to 2 micro g/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, approximately 20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, approximately 40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S. pneumoniae, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, approximately 40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
Nicolau
David P
DP
Center for Anti-Infective Research, Office of Research, Division of Infectious Diseases, Hartford Hospital, Hartford, Connecticut 06102, USA. dnicola@harthosp.org
Mattoes
Holly M
HM
Banevicius
Maryanne
M
Xuan
Dawei
D
Nightingale
Charles H
CH
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D019540:Area Under Curve; D004195:Disease Models, Animal; D024841:Fluoroquinolones; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D011008:Pneumococcal Infections / Q000188:drug therapy* / Q000401:mortality; D011485:Protein Binding; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013848:Thigh
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D007211:Indoles; D015363:Quinolones; C419689:garenoxacin