Designing fluoroquinolone breakpoints for Streptococcus pneumoniae by using genetics instead of pharmacokinetics-pharmacodynamics.
We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.
Smith
H J
HJ
Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Canada. smithhj14@hotmail.com
Noreddin
A M
AM
Siemens
C G
CG
Schurek
K N
KN
Greisman
J
J
Hoban
C J
CJ
Hoban
D J
DJ
Zhanel
G G
GG
D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001372:Aza Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077734:Gatifloxacin; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D000077266:Moxifloxacin; D009154:Mutation / Q000235:genetics; D015242:Ofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics*
D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D004269:DNA, Bacterial; D024841:Fluoroquinolones; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D004250:DNA Topoisomerases, Type II; D000077734:Gatifloxacin; D000077266:Moxifloxacin