Pharmacodynamic assessment based on mutant prevention concentrations of fluoroquinolones to prevent the emergence of resistant mutants of Streptococcus pneumoniae.
The objective of this study was to investigate the relationship between pharmacokinetic and pharmacodynamic parameters, on the basis of the mutant prevention concentration (MPC) concept, and the emergence of resistant mutants of Streptococcus pneumoniae to fluoroquinolone antibacterials. Some clinical isolates with various MIC and MPC values of moxifloxacin and levofloxacin were exposed under conditions simulating the time-concentration curves observed when moxifloxacin (400 or 80 mg, once a day) or levofloxacin (200 mg, twice a day) was orally administered by using an in vitro pharmacodynamic model. The decrease in susceptibility was evaluated by altering the population analysis profiles after moxifloxacin or levofloxacin treatment for 72 h. When the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MPC and peak concentration (C(max))/MPC were above 13.41 and 1.20, respectively, complete eradication occurred and no decrease in susceptibility was observed. On the other hand, when AUC(0-24)/MPC and C(max)/MPC were below 0.84 and 0.08, respectively, the susceptibility decreased. However, the time inside the mutant selective window and the time above the MPC did not show any correlation with the decrease in susceptibility. These results suggest that AUC(0-24)/MPC and C(max)/MPC are important parameters for predicting the emergence of resistant mutants and that higher values indicate greater effectiveness.
Homma
Tomoyuki
T
Infectious Diseases, Discovery Research Laboratories, Shionogi & Co., Ltd. 3-1-1, Futaba-cho, Toyonaka, Osaka 561-0825, Japan. tomoyuki.honma@shionogi.co.jp
Hori
Toshihiko
T
Sugimori
Giichi
G
Yamano
Yoshinori
Y
D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D000077266:Moxifloxacin