David Czock1, F M Rasche. 1. University Hospital Ulm, Medical Department, Division of Nephrology, Robert-Koch-Str. 8, D-89070 Ulm, Germany. david.czock@medizin.uni-ulm.de
Abstract
BACKGROUND: Dose adjustments of antimicrobial drugs are necessary in renal failure. One method of dose adjustment is to reduce the dose and the other is to prolong the administration interval in proportion to the reduced drug clearance. Pharmacokinetically, both methods involve an identical drug exposure but pharmacodynamically there may be differences. It is not known which dose adjustment method is preferable in patients with renal failure. METHODS: We performed simulations using a published mechanism-based pharmacokinetic/ pharmacodynamic model of ciprofloxacin effects on growth and death of Escherichia coli bacteria. Ciprofloxacin 500 mg every 12 hrs was selected as the standard dose. In renal failure either the dose was reduced (250 mg every 12 hrs) or the administration interval was prolonged (500 mg every 24 hrs) in proportion to the reduced ciprofloxacin clearance. Simulations were done with use of a commercial software package. RESULTS: In normal renal function, using the standard dose, bacterial eradication was predicted on day 3. In renal failure, bacterial eradication was predicted on day 3 when using the interval prolongation scheme but only on day 6 when using the dose reduction scheme. The relationship between the efficacies of these 3 dosage schemes could have been predicted by AUC above MIC and AUIC, but not by AUC/MIC or time above MIC. CONCLUSION: Prolongation of the administration interval may be the preferable dose adjustment method in renal failure with ciprofloxacin. We hypothesize that these results may be transferable to other so-called dose-dependent antimicrobial drugs.
BACKGROUND: Dose adjustments of antimicrobial drugs are necessary in renal failure. One method of dose adjustment is to reduce the dose and the other is to prolong the administration interval in proportion to the reduced drug clearance. Pharmacokinetically, both methods involve an identical drug exposure but pharmacodynamically there may be differences. It is not known which dose adjustment method is preferable in patients with renal failure. METHODS: We performed simulations using a published mechanism-based pharmacokinetic/ pharmacodynamic model of ciprofloxacin effects on growth and death of Escherichia coli bacteria. Ciprofloxacin 500 mg every 12 hrs was selected as the standard dose. In renal failure either the dose was reduced (250 mg every 12 hrs) or the administration interval was prolonged (500 mg every 24 hrs) in proportion to the reduced ciprofloxacin clearance. Simulations were done with use of a commercial software package. RESULTS: In normal renal function, using the standard dose, bacterial eradication was predicted on day 3. In renal failure, bacterial eradication was predicted on day 3 when using the interval prolongation scheme but only on day 6 when using the dose reduction scheme. The relationship between the efficacies of these 3 dosage schemes could have been predicted by AUC above MIC and AUIC, but not by AUC/MIC or time above MIC. CONCLUSION: Prolongation of the administration interval may be the preferable dose adjustment method in renal failure with ciprofloxacin. We hypothesize that these results may be transferable to other so-called dose-dependent antimicrobial drugs.
Authors: Samir K Gupta; Suzanne K Swan; Thomas Marbury; William Smith; Sherwyn Schwartz; Karen Kolz; David L Cutler Journal: Br J Clin Pharmacol Date: 2007-06-06 Impact factor: 4.335