In Vitro Synergy Testing of Anidulafungin with Itraconazole, Voriconazole, and Amphotericin B against Aspergillus spp. and Fusarium spp

Abstract

The in vitro interactions of anidulafungin with itraconazole, voriconazole, and amphotericin B were evaluated by using the checkerboard method. For Aspergillus spp., anidulafungin with amphotericin B showed indifference for 16/26 isolates, while anidulafungin with either azole showed a synergy trend for 18/26 isolates. All drug combinations showed indifference for 7/7 Fusarium sp. isolates.Invasive fungal infections due to molds are becoming more prevalent in immunocompromised patients (21). Among the invasive mold infections, Aspergillus spp. and Fusarium spp. are particularly challenging to manage, due to aggressive courses and high mortality (11,20).Since 1959, amphotericin B deoxycholate (AMBD) had been considered the "gold standard" for the treatment of fungal infections. However, due to high failure rates and significant toxicity (6), other agents are being explored today both singly and in combination therapy. Among the azoles, itraconazole (ITR) continues to show some promise against Aspergillus spp. (3). Voriconazole (VOR), a novel azole (11), is perhaps the current "gold standard" for the treatment of invasive aspergillosis, although success rates are still less than optimal (5, 8). The echinocandins (caspofungin, anidulafungin [ANID], and micafungin) inhibit 1,3-␤-D-glucan synthesis and have in vitro and in vivo activity against Candida and Aspergillus spp. (4,16,17). In the clinical setting, caspofungin appears to be at least as effective as AMBD for salvage therapy of invasive aspergillosis compared to historical controls (13).Due to the high mortality and lack of an ideal drug for these diseases, combination therapy has been an attractive possibility that has recently received much attention in medical mycology. Early studies have shown in vitro and in vivo advantages of several combinations. Arikan et al. (2) showed additive to synergistic effects of caspofungin with AMBD in vitro against Aspergillus and Fusarium spp. In a guinea pig model, colony counts of Aspergillus spp. and the number of culture-positive tissues were reduced after treatment with VOR and caspofungin compared with either of the agents alone (10). Similarly, Petraitis et al. showed that the combination of micafungin and ravuconazole in a rabbit model had synergistic effects against invasive aspergillosis (18).The purpose of this study was to evaluate the in vitro interactions of ITR, VOR, and AMBD with ANID against Aspergillus spp. and Fusarium spp. as preliminary work to support further in vivo and clinical research on these combinations.Isolates. Twenty-six clinical isolates of Aspergillus spp. and seven clinical isolates of Fusarium spp. were used. The species distribution was as follows: eight isolates of Aspergillus flavus,

Molecular Phylogenetic Diversity, Multilocus Haplotype Nomenclature, and In Vitro Antifungal Resistance within theFusarium solaniSpecies Complex

“…Consistent with the findings of Azor et al (6) and others (5,15,26,41,44,48,49), the 10 antifungals tested in the present study showed very poor in vitro activities against 19 phylogenetically diverse members of the FSSC. The most significant finding from the susceptibility testing is that the polyene AMB showed the highest activity against members of the FSSC (Table 4); however, the MICs for AMB were highly varied.…”

“…Even though the triazole VORI exhibited poor in vitro activity against phylogenetically diverse members of the FSSC in the present and prior studies (6,15), VORI has been used successfully to treat some patients where AMB therapy failed to be efficacious (42). Because FSSC isolates have been reported to exhibit greater resistance to antifungals than other fusaria in some studies (15,41,49) but not others (26,44), future in vitro susceptibility tests need to evaluate these findings by use of sufficient numbers of isolates that have been characterized phylogenetically via MLST (37) so that statistically significant conclusions can be drawn. In addition, studies are needed to evaluate whether and to what extent species-and strain-specific differences in antifungal susceptibility exist within Fusarium (26).…”

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

“…Indifference was also reported when VOR was combined with the echinocandin CAS (16). In vitro synergy between VOR and ANI was only demonstrated in studies providing alternative interpretations of MIC endpoints being prominent growth reduction endpoints (32).…”

In Vitro Interaction between Fluconazole and Triclosan against Clinical Isolates of Fluconazole-Resistant Candida albicans Determined by Different Methods

“…In the checkerboard assay, the FICI model has been frequently used to determine the interaction between antifungal drugs (7,9,12,17,21,23). The ⌬E model is a useful method for characterizing drug interactions.…”