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

Abstract

In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with 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 doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold 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 narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.

FIG. 1

Concentrations of amphotericin B in serum after subcutaneous doses of 20, 10, 5, 2.5, and 0.625 mg/kg in neutropenic infected mice. Each symbol represents the geometric mean ± standard deviation of serum levels from three mice.

FIG. 2

In vivo PAE of amphotericin B at doses of 4, 1, and 0.25 mg/kg against C. albicans in neutropenic mice. Each symbol represents the mean ± standard deviation from two mice (four kidneys).

FIG. 3

Relationship between the 24-h total dose for three lengthening dosing intervals and log₁₀ CFU/kidney in a neutropenic mouse model of disseminated candidiasis. Each symbol represents data from two mice (four kidneys).

FIG. 4

(A) Relationship between T > MIC and log₁₀ CFU/kidney after 72 h of therapy. Each symbol represents data from two mice (four kidneys). (B) Relationship between the 72-h AUC/MIC ratio and log₁₀ CFU/kidney after 72 h of therapy. Each symbol represents data from two mice (four kidneys). (C) Relationship between the peak serum level/MIC ratio and log₁₀ CFU/kidney after 72 h of therapy. Each symbol represents data from two mice (four kidneys).