In vitro pharmacodynamic activity of gatifloxacin, gemifloxacin, moxifloxacin and levofloxacin against Streptococcus pneumoniae containing specific mutations in DNA gyrase and topoisomerase IV.
An in vitro pharmacodynatnic modeling apparatus (PDMA) generated specific bacterial kill profiles for single-dose regimens of gatifloxacin (GT), gemifloxacin (GM), moxifloxacin (MX) and levofloxacin (LV) against isolates of Streptococcus pneumoniae with specific QRDR profiles: SP-WT (no modifications); SP-C (changes in parC); and SP-AC (changes in both parC and gyrA). No differences in 3-log reduction time or total log reduction were observed among the four agents for SP-WT; however, LV failed to achieve a 3-log reduction in SP-C and SP-AC, and total log reduction after 12 hrs was minimal compared to the other agents. GM and MX required less time for 3-log reduction of SP-AC compared to GT, but total log reductions in SP-AC were similar among the three newer quinolone agents (GM > MX > GT). The study isolates with QRDR modifications greatly reduced LV activity. GM and MX maintained the greatest degree of activity against all study isolates and their activity was not adversely influenced by the genetic modifications in SP-C and SP-AC. The dual targeting characteristic of GM was also assessed, but did not offer significant advantages relative to MX and GT.
Garrison
Mark W
MW
Washington State University, College of Pharmacy, Spokane, WA 99202, USA. garrism@wsu.edu
Schimmels
Julie A
JA
Madaras-Kelly
Karl J
KJ
D000704:Analysis of Variance; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D003470:Culture Media; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009154:Mutation; D009287:Naphthyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D010597:Pharmacogenetics; D011008:Pneumococcal Infections / Q000175:diagnosis / Q000188:drug therapy; D011336:Probability; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics
D001372:Aza Compounds; D003470:Culture Media; D024841:Fluoroquinolones; D009287:Naphthyridines; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D000077266:Moxifloxacin