The mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationship with effect of ciprofloxacin in treatment s.c. for three days varying doses and dosing intervals against a susceptible Escherichia coli (MIC, 0.032 mg/L). Further, a humanized dose of ciprofloxacin was administered for three days against three E. coli with low level resistance, i.e. MIC' s of 0.06, 0.25 and 1 mg/L, respectively. Against the susceptible isolate ciprofloxacin was highly effective in clearing the urine with daily doses from 10 mg/kg, but the dosing regimen had to be divided in at least two doses for optimal effect. Ciprofloxacin could not clear the urine or kidneys for the low level resistant strains. PKPD correlations with all strains combined showed for AUC24/MIC a slightly higher correlation with effect in urine and kidneys (R2, 0.71 and 0.69, respectively) than the %T>MIC (R2, 0.41 and 0.61, respectively). Equal correlations for the two PKPD indices were found for reduction of colony counts (CFUs) in the bladder tissue, but not even the highest dose of 28 mg/kg x 6 could clear the bladder tissue. In conclusion, ciprofloxacin is highly effective in clearing the urine and kidney tissue for fully susceptible E. coli, while even low level resistance in E.coli obscures this effect. While the effect of ciprofloxacin is mostly AUC/MIC driven against E. coli infection in the urinary tr act, the effect in urine depends on presence of ciprofloxacin in the urine during most of 24 hours.
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