Antifungal Combinations against Simulated Candida albicans Endocardial Vegetations

Abstract

The in vitro effects of flucytosine (5FC), liposomal amphotericin B (L-AmB), and micafungin (Mica) combinations against two Candida albicans strains that simulated 24-hour-old endocardial vegetations were studied. Mica was superior to 5FC or L-AmB, and the 5FC-L-AmB-Mica combination was superior to all other treatments for one strain but no different from the dual combination of L-AmB-Mica for the other strain.Candida species can adhere to cell surfaces and form a three-dimensional community of microorganisms encased in an exopolymeric matrix known as biofilm (5). Biofilm can form on native and prosthetic heart valves to cause infective endocarditis. Candida albicans is the most common fungus linked to the development of infective endocarditis and is associated with a mortality rate in excess of 50% (6). Candida albicans organisms within biofilm have decreased cell membrane ergosterol content, have reduced expression of ergosterol biosynthetic genes, express higher levels of genes involved in amino acid and nucleotide metabolism, and upregulate efflux pumps (5, 9). These alterations may explain the poor activity of antifungals such as fluconazole and amphotericin that target ergosterol. Unlike these agents, the echinocandins target the cell wall of Candida species through inhibition of ␤-1,3-glucan synthase. A growing body of evidence suggests that echinocandins are active against Candida albicans biofilm (1, 4,7,8,11,[13][14][15]. However, cell wall integrity pathways and glucan-associated changes can also occur, which could limit echinocandin activity against Candida biofilm (10). As a consequence, combination antifungal therapy remains a rational approach to treatment of Candida endocarditis while possibly limiting emergence of resistance.The effectiveness of combination antifungal therapy for Candida endocarditis is difficult to assess clinically. Animal models provide valuable data but are not always necessary for initial assessment. Replication of antifungal pharmacokinetics to mimic the human profile cannot be easily accomplished in animal models. Also, evaluation of the interaction of antifungals requires large sample sizes and can lead to unnecessary animal testing with limited information gain. In contrast, in vitro models provide an alternative, more rapid, and controlled environment for the assessment of antifungal combinations. My coworkers and I previously determined the activity of flucytosine (5FC), micafungin (Mica), and voriconazole as single agents and in combinations against Candida species by using an in vitro model of infective endocarditis (11). This work demonstrated the poor activity of voriconazole and the superior activity of 5FC and Mica against developing Candida biofilm. As a consequence, the present study was performed to test the interaction of 5FC, Mica, and liposomal amphotericin B (L-AmB) against mature (24-hour-old) C. albicans human platelet fibrin clots that simulated endocardial vegetations (SEVs).Two C. albicans isolates, ATCC 14053 (CA1) and a clinical isolate (CA2) obtai...

Anti-Biofilm Strategies: How to Eradicate Candida Biofilms?

“…By contrast with the previous study in 2008, they measured the antifungal effects only at one time point and used the standard definition of synergism. These data revealed that micafungin was uniquely active against mature C. albicans biofilms, while flucytosine was not [46]. This is in contrast to the data in the previous report, where flucytosine was markedly active against C. albicans biofilms [45].…”

“…The triple combination of flucytosine/liposomal amphotericin B/micafungin was superior to all other treatments for one isolate but not different from the dual combination liposomal amphotericin B/micafungin for the other isolate. Although no clear pattern of interaction between these agents was seen, the superior activity of micafungin against 24h-old C. albicans biofilms relative to flucytosine and liposomal amphotericin B was apparent for both isolates [46]. In conclusion, and supported by earlier reports [19], these data demonstrated the activity of echinocandins when used alone or in combination with polyenes against C. albicans biofilm.…”

“…The indifference of amphotericin B/caspofungin is in line with the previous data of Bachmann and coworkers [42]. In addition, Pai and coworkers performed studies of various antifungal combinations against simulated Candida endocardial vegetations [45,46]. Current medical management includes combination use of amphotericin B and flucytosine followed by prolonged suppression with fluconazole [47,48].…”

Novel strategies to fightCandidaspecies infection

“…Several studies support the combination of echinocandins with other antifungal drugs to treat C. albicans biofilms (Bink et al, 2011;Kuhn et al, 2002b;Pai, 2009). For example, synergy effects were found for micafungin and fluconazole, voriconazole or liposomal amphotericin B against Candida species (Espinel-Ingroff et al, 2009;Nishi et al, 2009;Olson et al, 2005).…”

Current pharmacological concepts for wise use of echinocandins in the treatment ofCandidainfections in septic critically ill patients

“…Combination therapy with liposomal amphotericin B plus flucytosine is currently recommended for the treatment of Candida endocarditis [5]. However, it is worth noting that some experimental data showed that the addition of an echinocandin (micafungin) to the combination of liposomal amphotericin B plus flucytosine may be even more fungicidal against simulated C. albicans endocardial vegetations than the combination of liposomal amphotericin B plus flucytosine [46]. This support the idea that a combination therapy with three antifungal agents characterized by different mechanisms of action might improve current treatment of Candida endocarditis, which is a highmorbidity and -mortality disease.…”