Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model

In vivo pharmacodynamic parameters have been described for a variety of ant ibacterials, These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of out come and the magnitude of that parameter associated with efficacy, Very lit tle is known about pharmacodynamics for antifungal agents. We utilized a ne ntropenic mouse model of disseminated candidiasis to correlate pharmacodyna mic parameters (percent time above MIG [T > MIG], area under the concentrat ion time curve [AUG]/MIC ratio, and peak serum level/MIC ratio) for amphote ricin B in vivo with efficacy, as measured by organism number in homogenize d kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mi ce were nonlinear, Serum half-lives ranged from 13 to 27 h, Infection was a chieved by intravenous inoculation with 10(6) CFU of yeast cells per mi via the lateral tail vein of neutropenic mice. Groups of mice were treated wit h fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h, Increasing d oses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphote ricin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIG. Nonlinear regression analysis was us ed to determine which pharmacodynamic parameter best correlated with effica cy. Peak serum level in relation to the MIG (peak serum level/MIC ratio) wa s the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coeffi cient of determination [R-2] = 90 fo 93%; AUC/MIC ratio, R-2 = 49 to 69%; T > MIG, R-2 = 67 to 85%), The total amount of drug necessary to achieve var ious microbiological outcomes over the treatment period was 4,8- to 7.6-fol d smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses, Given the n arrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regime ns.