title: The effect of pharmacokinetics on the bactericidal activity of ciprofloxacin and sparfloxacin against Streptococcus pneumoniae and the emergence of resistance.
abstract: The pharmacokinetics of ciprofloxacin and sparfloxacin were simulated in vitro and the effects of pharmacodynamic parameters on bactericidal activity and the emergence of quinolone resistance were examined for Streptococcus pneumoniae. Simulated serum concentrations of ciprofloxacin 500 mg bd were more rapidly bactericidal than sparfloxacin 200 mg bd, despite lower values for the key pharmacodynamic parameters (AUC/MIC and C(max)/MIC). This was possibly related to the slower oral absorption of sparfloxacin, which delayed achievement of the MIC compared with ciprofloxacin. In addition, sparfloxacin was shown to have similar bactericidal activity to ciprofloxacin when tested at the same concentrations, despite its four-fold better potency in MIC terms. The emergence of resistance following exposure to ciprofloxacin appeared to be dependent on the C(max)/MIC ratio and the AUC above the MIC, but not the AUC/MIC ratio. Resistance (at least four-fold increase in MIC) developed when the C(max)/MIC ratio was less than four or the AUC above the MIC was less than 10, and the resulting cultures regrew fully. In contrast, pneumococci with a two- to four-fold increase in sparfloxacin MIC were selected in the presence of serum concentrations of sparfloxacin despite a C(max)/MIC ratio higher than 12, but these isolates remained clinically susceptible by breakpoint MIC and their growth was inhibited by repeated dosage of sparfloxacin. Nevertheless, the selection of pneumococci with reduced susceptibility, and the possibility of further mutation to highly resistant strains supports the use of quinolones that rapidly eradicate pneumococci at conventional doses and achieve concentrations, in both serum and tissues, which exceed at least 4 x MIC.
authors: Chemotherapy Research Unit, Department of Life Sciences, University of East London, Romford Road, London E15 4LZ, UK.
authors: C E
authors: CE
authors: Thorburn
authors: D I
authors: DI
authors: Edwards
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002939:Ciprofloxacin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D024841:Fluoroquinolones; D006801:Humans; D008826:Microbial Sensitivity Tests; D013296:Streptococcus pneumoniae / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D002939:Ciprofloxacin; C061363:sparfloxacin