TY - JOUR
T1 - Experimental basis for use of fluconazole for preventive or early treatment of disseminated candidiasis in granulocytopenic hosts
AU - Walsh, Thomas J.
AU - Lee, James
AU - Aoki, Shizuko
AU - Mechinaud, Françoise
AU - Bacher, John
AU - Lecciones, Julius
AU - Thomas, Vanessa
AU - Rubin, Marc
AU - Pizzo, Philip A.
N1 - Funding Information:
This work was supported in part by grants from Glaxo (Research Triangle Park, N.C.), the Upjohn Company (Kalamazoo, Mich.), and Pfizer Central Research (Groton, Conn.).
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 1990/3
Y1 - 1990/3
N2 - To determine the potential for the use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, we investigated its activity and pharmacokinetics in models of acute, subacute, and chronic forms of disseminated candidiasis in persistently granulocytopenic rabbits. Fluconazole was administered for systemic prophylaxis, early treatment, and delayed treatment. Single-dose and steady-state plasma pharmacokinetics, tissue penetration, and dose-response studies of the investigational compound were studied in subacutely infected granulocytopenic rabbits. Fluconazole was more effective when used for systemic prophylaxis or early treatment of disseminated candidiasis than for delayed treatment. Fluconazole was as effective as amphotericin B plus flucytosine in preventive and early treatment of disseminated candidiasis but was significantly less effective than amphotericin plus flucytosine in the treatment of chronic candidiasis. Dose-response studies demonstrated that the antifungal effect of fluconazole was dose- and time-dependent. Studies of the pharmacokinetics of fluconazole in rabbits demonstrated a long half-life in plasma and a large volume of distribution, properties that correspond to the attainment of high levels of penetration into tissues at multiple organ sites. We conclude that fluconazole is effective for prevention and early treatment of disseminated candidiasis in persistently granulocytopenic rabbits and that the evaluation of its use in preventive or early treatment of disseminated candidiasis in carefully designed clinical trials is warranted.
AB - To determine the potential for the use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, we investigated its activity and pharmacokinetics in models of acute, subacute, and chronic forms of disseminated candidiasis in persistently granulocytopenic rabbits. Fluconazole was administered for systemic prophylaxis, early treatment, and delayed treatment. Single-dose and steady-state plasma pharmacokinetics, tissue penetration, and dose-response studies of the investigational compound were studied in subacutely infected granulocytopenic rabbits. Fluconazole was more effective when used for systemic prophylaxis or early treatment of disseminated candidiasis than for delayed treatment. Fluconazole was as effective as amphotericin B plus flucytosine in preventive and early treatment of disseminated candidiasis but was significantly less effective than amphotericin plus flucytosine in the treatment of chronic candidiasis. Dose-response studies demonstrated that the antifungal effect of fluconazole was dose- and time-dependent. Studies of the pharmacokinetics of fluconazole in rabbits demonstrated a long half-life in plasma and a large volume of distribution, properties that correspond to the attainment of high levels of penetration into tissues at multiple organ sites. We conclude that fluconazole is effective for prevention and early treatment of disseminated candidiasis in persistently granulocytopenic rabbits and that the evaluation of its use in preventive or early treatment of disseminated candidiasis in carefully designed clinical trials is warranted.
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U2 - 10.1093/clinids/12.Supplement_3.S307
DO - 10.1093/clinids/12.Supplement_3.S307
M3 - Article
C2 - 2184509
AN - SCOPUS:0025253978
SN - 0162-0886
VL - 12
SP - S307-S317
JO - Reviews of infectious diseases
JF - Reviews of infectious diseases
ER -