Comparison of fluconazole and amphotericin B for prevention and treatment of experimental Candida endocarditis

Abstract

Fluconazole and amphotericin B were compared in the prophylaxis and treatment of Candida albicans aortic endocarditis in a rabbit model. In the prophylaxis study, catheterized rabbits received, prior to intravenous (i.v.) challenge with C. albicans (2 x 107 blastospores), either no therapy, single-dose i.v. amphotericin B (1 mg/kg of body weight), single-dose fluconazole (50 mg/kg or 100 mg/kg i.v. or intraperitoneally [i.p.j), or fluconazole (50 mg/kg or 100 mg/kg i.v. or i.p.) with a second dose 24 h after inoculation. A single dose of amphotericin B was significantly more effective than either the one-or two-dose regimens of fluconazole at both 50 mg/kg (P < 0.001 and P < 0.03, respectively) and 100 mg/kg (P < 0.01 and P < 0.001, respectively) in the prevention of C. albicans endocarditis. In parallel treatment studies of established C. albicans endocarditis, i.v. amphotericin B (1 mg/kg) or i.p. fluconazole (50 mg/kg) was begun 24 or 60 h postinfection and continued daily for 9 or 12 days. At these dose regimens, amphotericin B was consistently more effective than fluconazole in reducing fungal vegetation densities, regardless of the timing of initiation of therapy. We also examined the efficacy of fluconazole at a daily dose of 100 mg/kg i.p. administered for 21 days in the treatment of established C. albicans endocarditis. When therapy was continued for 2 weeks or longer, fluconazole was more effective than no drug and approximately twice as effective as 12 days of amphotericin B in reducing intravegetation fungal densities. Our results suggest that amphotericin B is superior to fluconazole in both the prophylaxis and treatment of C. albicans endocarditis in the rabbit model. These findings may relate to the predominantly fungistatic activity of fluconazole against C. albicans in vitro.Once considered rare, endocardial infection with Candida albicans is being reported with increasing frequency, usually in the setting of open-heart surgery or intravenous (i.v.) drug abuse or in patients undergoing long-term i.v. therapy with antibiotics or hyperalimention (7,10,13,15,18). Even with early diagnosis, Candida endocarditis is difficult to eradicate with antifungal therapy alone, and valve replacement remains a requirement for cure in most patients (2, 15). While amphotericin B and flucytosine are synergistic in vitro against many strains of Candida and the combination has been successful in some patients without concomitant valve replacement (13), these agents are associated with significant nephrotoxicity and bone marrow suppression when used in combination (6,19). The toxicities associated with amphotericin B and flucytosine not only render their use problematic in the therapy of documented infection but also preclude their use as antifungal agents in the prophylaxis of patients at risk for Candida endocarditis. In contrast, fluconazole, a new antifungal bis-triazole, has limited toxicity and a favorable pharmacokinetic profile, attaining high concentrations in a wide variety of tissues (14). Fluconazole is c...

Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

“…However, although the serum levels were not tested, this possibility was contradicted by the fact that AmB was very effective at decreasing fungal densities in the kidneys. Moreover, previous studies using the same dosage of AmB in the endocarditis models also reported a very slow response of the infection (5,31,35,43,44).…”

Fungicidal Synergism of Fluconazole and Cyclosporine in Candida albicans Is Not Dependent on Multidrug Efflux Transporters Encoded by the CDR1 , CDR2 , CaMDR1 , and FLU1 Genes

“…The absence of polymorphonuclear phagocytes in endocarditis provides very stringent experimental conditions, and therapeutic success relies exclusively on the killing effect of the antimicrobial treatment. Given that previous studies of Candida experimental endocarditis described cure only after weeks of antifungal treatment, the sterilization of aortic valve vegetations recently reported in rats infected with parent strain CAF2-1 after a 5-day treatment with high doses of FLC-CY represented a clear proof of concept (4,11,28). The present work tested identical regimens, which, as in previous experiments, produced supratherapeutic blood FLC concentrations (i.e., trough levels up to 15 mg/liter, a concentration still compatible with that achieved with high-dose treatment in humans) and CY (i.e., trough levels up to 2.5 mg/liter, which is 5-to 10-fold the concentrations targeted in humans) (data not shown) (11).…”

Susceptibility to Thrombin-Induced Platelet Microbicidal Protein Is Associated with Increased Fluconazole Efficacy against Experimental Endocarditis Due to Candida albicans

“…The in vitro susceptibilities of the C. albicans 36082 s and 36082 r strains to FLU were determined by a previously published method (45). In the present study, an inoculum of 10 6 CFU/ml and an incubation temperature of 30°C were used to simulate readily achievable fungal densities and growth rates relevant to complex biomatrices, such as cardiac vegetations, respectively.…”