Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B

Abstract

A study was performed to assess the in vivo relevance of the in vitro antagonism between fluconazole and amphotericin B against Candida albicans. Combinations of fluconazole and amphotericin B were explored for their efficacies against acute (100% mortality in 2 to 5 days) or less acute (100% mortality in 30 days) invasive candidiasis infections in mice with healthy immune systems and immunocompromised mice. Treatment efficacy was assessed by protection from mortality and/or a reduction in the fungal burden in tissue. In models of acute infection in mice with healthy immune systems or less acute infection in immunocompromised mice, combinations of fluconazole and amphotericin B were superior to fluconazole alone, and the effects were at least additive. Combination therapy was at least as efficacious as amphotericin B alone. In a different model of less acute infection in mice with healthy immune systems, combinations of fluconazole and amphotericin B showed no interactions and were no better than either drug alone. We conclude that combination therapy with fluconazole and amphotericin B is not antagonistic in vivo, in contrast to published in vitro studies, and, consequently, suggest that combination therapy should be considered in the management of clinical candidiasis.

The Effect Of Combinations Of Antimycotics In A Mouse Model Of Systemic Candidiasis

“…[15] The mice were infected by injection of this inocula into a lateral tail vein. [2,3,15] Amphotericin B (Fungizone, Bristol-Myers Squibb), and fluconazole (Triflucan 100mg, Pfizer) were used, and prepared for injection as recommended by the manufacturer and terbinafine (Lamsil, Novartis) dissoluting in polyethylene glycol 200 and diluted in sterile distilled water. [17,18] The MICs for amphotericin B, fluconazole and terbinafine were determined by the broth microdilution method described by the National Committee for Clinical Laboratory Standards M27 A.…”

“…[1] Amphotericin B has traditionally been considered the cornerstone of therapy for deep-seated fungal infections and fungemia, but it has toxic side effects. [1][2][3][4] Despite advances, antifungal therapy with amphotericin B, the azoles or flucytosine has not been uniformly successful. Problems with toxicity, the emergence of resistant strains of Candida spp.…”

“…[5][6][7] This has increased the interest in using new drugs and drug combinations to enhance the efficacies of the drugs. [3,[7][8][9] Terbinafine is the first oral antimycotic in the allylamines class that inhibits ergosterol synthesis at the stage of squalene epoxidation. [10][11][12] Terbinafine demonstrates excellent in vitro activity against many fungal species.…”

Obstructive Renal Failure Caused by Bilateral Renal Candidiasis and Hypoplastic Renal Pelvises in a Preterm Infant: Case Presentation and Review of the Literature

“…Another option in renal failure is liposomal amphotericin B, but penetration of lipid form in renal tube is less and its efficacy on Candidal UTI is questionable (32). Although, fluconazole could be added to amphotericin B in case of renal failure or resistant organisms, it should be choosen as initial therapy for susceptible organisms (33)(34)(35)(36). When non-albicans Candida is probable, fluconazole is not as effective as amphotericin B (37).…”

Systemic Antifungal Therapy: Past, Present and Future

“…76 Sugar et al found the combination of fluconazole and amphotericin B was not antagonistic in vivo in mice with invasive candidiasis and suggested combination therapy be considered in management of clinical candidiasis. 77 Walsh et al reported that in-vitro combinations of amphotericin B and antifungal azoles were synergistic, additive, or indifferent in their interaction against P. boydii and antagonism was hot observed. 78 Combinations of antifungal drugs have proven to be the most effective approach for treating cryptococcal meningitis.…”