title: Fluoroquinolone resistance in Streptococcus pneumoniae: area under the concentration-time curve/MIC ratio and resistance development with gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin.
abstract: The potential for resistance development in Streptococcus pneumoniae secondary to exposure to gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin at various levels was examined at high inoculum (10(8.5) to 10(9) log10 CFU/ml) over 96 h in an in vitro pharmacodynamic (PD) model using two fluoroquinolone-susceptible isolates. The pharmacokinetics of each drug was simulated to provide a range of free areas under the concentration-time curves (fAUC) that correlated with various fluoroquinolone doses. Potential first (parC and parE)- and second-step (gyrA and gyrB) mutations in isolates with raised MICs were identified by sequence analysis. PD models simulating fAUC/MICs of 51 and<or=60, 34 and 37, <or=82 and<or=86, and<or=24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations. For each fluoroquinolone a delay of first- and second-step mutations was observed with increasingly higher fAUC/MIC ratios and recovery of topoisomerase mutations in S. pneumoniae was related to the fAUC/MIC exposure. Clinical doses of gatifloxacin, gemifloxacin, and moxifloxacin exceeded the fAUC/MIC resistance breakpoint against wild-type S. pneumoniae, whereas those of levofloxacin (500 and 750 mg) were associated with first- and second-step mutations. The exposure breakpoints for levofloxacin were significantly different (P<0.001) from those of the newer fluoroquinolones gatifloxacin, gemifloxacin, and moxifloxacin. Additionally, moxifloxacin breakpoints were significantly lower (P<0.002) than those of gatifloxacin. The order of resistance development determined from fAUC/MIC breakpoints was levofloxacin>gatifloxacin>moxifloxacin=gemifloxacin, which may be related to structural differences within the class.
authors.affiliation: Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Department of Pharmacy Practice, School of Medicine, Wayne State University, 259 Mack Ave., Detroit, MI 48201, USA.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: LaPlante
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rybak
authors.forename: Brian
authors.initials: B
authors.lastname: Tsuji
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.forename: Glenn W
authors.initials: GW
authors.lastname: Kaatz
mesh_terms: D019540:Area Under Curve; D001372:Aza Compounds / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D024841:Fluoroquinolones / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D000077266:Moxifloxacin; D009287:Naphthyridines / Q000494:pharmacology; D015242:Ofloxacin / Q000494:pharmacology; D011008:Pneumococcal Infections / Q000382:microbiology; D011804:Quinolines / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D009287:Naphthyridines; D011804:Quinolines; D064704:Levofloxacin; D015242:Ofloxacin; D000077734:Gatifloxacin; D000077735:Gemifloxacin; D000077266:Moxifloxacin