Interaction between Posaconazole and Amphotericin B in Concomitant Treatment against Candida albicans In Vivo

Abstract

The interaction of posaconazole and amphotericin B was evaluated in concomitant treatment of Candida albicans systemic infections in immunocompetent mice by using four strains of C. albicans with different susceptibilities to fluconazole. Posaconazole and amphotericin B were each tested at four dose levels alone and in all possible combinations against each C. albicans strain. Survival curves of mice treated with combinations of posaconazole and amphotericin B were statistically compared with those of mice treated with the component monotherapies. Of the 64 total combinations evaluated against the C. albicans strains (16 combinations per strain), 20.3% were more effective in prolonging mouse survival than both of the monotherapies, 45.3% were more effective than one of the monotherapies, and 32.8% were similar to both monotherapies. No evidence of antagonism was observed between posaconazole and amphotericin B in this mouse model, consistent with in vitro results against the same strains.The clinical use of azoles in combination with amphotericin B (AMB) is still controversial because of the potential for antagonism between the two drugs (9,12,18,22). This potential comes from their mechanisms of action; azoles block ergosterol biosynthesis, while AMB causes membrane damage by binding to ergosterol. Various experimental fungal infection models have been used to address the issue of combinational dosing, but the results have been mixed. In systemic candidiasis models in mice with Candida albicans, Louie et al. (11) observed antagonism between the triazole fluconazole (FLC) and AMB, while Sugar and Liu (23) reported antagonism between another triazole, itraconazole, and AMB. Louie et al. (10,12) also found that FLC was antagonistic to AMB therapy against experimental C. albicans endocarditis, endophathalmitis, and pyelonephritis in rabbits. However, Sanati et al. (17) did not observe antagonism when FLC and AMB were used in combination against C. albicans in invasive candidiasis in neutropenic mice or in endocarditis in rabbits. Sugar et al. (21) reported no antagonism between FLC and AMB in invasive candidiasis with C. albicans in immunocompetent or immunocompromised mice.Posaconazole (POS) is a broad-spectrum antifungal triazole which recently completed phase III clinical trials (7). The experiments described in this report were performed to determine the interaction between POS and AMB in concomitant combination therapy against systemic C. albicans infection in mice.( MATERIALS AND METHODSAntifungal agents. POS clinical oral suspension was used in these experiments, and dilutions were made in sterile water for injection. AMB (Fungizone) was obtained from Apothecon, Bristol-Myers Squibb, Princeton, N.J., and prepared according to the manufacturer's directions.C. albicans strains and in vitro activity testing. All C. albicans strains were from the Schering-Plough Research Institute fungal culture collection and included one FLC-susceptible (FLC-S) strain C43, one FLC-susceptible, dosedependent (FLC S-DD) strai...

Posaconazole Enhances the Activity of Amphotericin B against Aspergillus Hyphae In Vitro

“…were comparable to those presented in previously published reports (3,7,9,14,22). The in vitro activities of POS in combination with AMB against conidia of Aspergillus ranged from indifferent (88% of isolates) to…”

“…Clinical studies confirm that POS has a favorable safety profile during treatment of seriously ill patients with invasive fungal infections (3,9,17). POS appears to be well tolerated (9,17), making this substance a promising candidate for use for the prevention and treatment of fungal infections in immunocompromised patients.…”

“…POS was recently approved for use for the treatment of patients with invasive infections that are refractory to other antifungal agents (17). The high rate of mortality from mold infections and the relatively limited efficacies of the current agents have produced a significant interest in the use of polyene-and azole-based combinations for these difficult-to-treat infections (3,5,11,19). The present study evaluated the antifungal activity of either POS or VRZ, alone and in combination with AMB, against the conidia and hyphae of Aspergillus spp.…”

“…POS appears to be well tolerated (9,17), making this substance a promising candidate for use for the prevention and treatment of fungal infections in immunocompromised patients. The lack of antagonism in vitro and in vivo (3,4,14,21) suggests that POS-AMB and VRZ-AMB may be used as combination therapies for the treatment of fungal infections.…”

“…gistic; FIC Ն1 to Յ4, indifferent; and FIC Ͼ4, antagonistic (3). Also, the metabolic activity of drug-treated hyphae was determined by their ability to reduce the tetrazolium compound 3-(4,5-dimethl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT), as described elsewhere (13).…”