Inhibitory and Fungicidal Effects of Antifungal Drugs against Aspergillus Species in the Presence of Serum

Abstract

bGiven the high protein binding rates of antifungal drugs and the effect of serum proteins on Aspergillus growth, we investigated the in vitro pharmacodynamics of amphotericin B, voriconazole, and three echinocandins in the presence of human serum, assessing both inhibitory and fungicidal effects. In vitro inhibitory (IC) and fungicidal (FC) concentrations against 5 isolates of Aspergillus fumigatus, Aspergillus flavus, and Aspergillus terreus were determined with a CLSI M38-A2-based microdilution method using the XTT methodology after 48 h of incubation at 35°C with a medium supplemented with 50% human serum. In the presence of serum, the IC and FC of amphotericin B and the IC of echinocandins were increased (1.21-to 13.44-fold), whereas voriconazole IC and FC were decreased (0.22-to 0.90-fold). The amphotericin B and voriconazole FC/IC ratios did not change significantly (0.59-to 2.33-fold) in the presence of serum, indicating that the FC increase was due to the IC increase. At echinocandin concentrations above the minimum effective concentration (MEC), fungal growth was reduced by 10 to 50% in the presence of human serum, resulting in complete inhibition of growth for some isolates. Thus, the in vitro activities of amphotericin B and echinocandins were reduced, whereas that of voriconazole was enhanced, in the presence of serum. These changes could not be predicted by the percentage of protein binding, indicating that other factors and/or secondary mechanisms may account for the observed in vitro activities of antifungal drugs against Aspergillus species in the presence of serum.

Administration of Zinc Chelators Improves Survival of Mice Infected with Aspergillus fumigatus both in Monotherapy and in Combination with Caspofungin

“…The inhibition of A. fumigatus by human serum agrees with previous findings (55) and is due to the fact that it contains fungal inhibitors (58). The effectiveness of phenanthroline was not affected by any of the sera; however, all tested sera reduced the effectiveness of both clioquinol and TPEN, an effect also observed on other antifungal compounds such as amphotericin B and echinocandins (55). This may be due to binding by albumin or other plasma proteins (59,60), though there are likely to be other, unknown factors affecting their efficacy as well (57).…”

“…For these reasons, we decided to compare the effects of the presence or absence of human and other animal sera on A. fumigatus and zinc chelators, as this may provide information regarding their in vivo efficacy. The inhibition of A. fumigatus by human serum agrees with previous findings (55) and is due to the fact that it contains fungal inhibitors (58). The effectiveness of phenanthroline was not affected by any of the sera; however, all tested sera reduced the effectiveness of both clioquinol and TPEN, an effect also observed on other antifungal compounds such as amphotericin B and echinocandins (55).…”

“…Blood serum can affect the growth of different Aspergillus strains to various degrees, as well as the efficacy of different antifungal compounds, either positively or negatively (55); this can vary depending on which species the serum originates from (56). Additionally, there is a correlation between the efficacy of certain antifungals in the presence of serum in vitro and in vivo (57).…”

In Vitro Fungicidal Activities of Anidulafungin, Caspofungin, and Micafungin against Candida glabrata, Candida bracarensis, and Candida nivariensis Evaluated by Time-Kill Studies

“…Only anidulafungin reached the fungicidal endpoint (36.54 h at 0.5 g/ml) against C. nivariensis. The repercussions of protein binding on the in vitro killing should be very similar for the three echinocandins as the protein binding is Ͼ96% for all of them (23).…”

Characterization of the acivicin effects on trichothecene production by <i>Fusarium graminearum</i> species complex

“…After 16 h of pre-incubation (reaching the exponential growth phase), 1% (v/v) of the pre-culture was transferred to YS_60 medium. Because media compositions affect antibiotic titers (Clavaud et al, 2012;Doern et al, 1986;Elefanti et al, 2013), we sought to clarify whether the inhibitory activity of acivicin against Difco TM yeast extract lot number 4216756 was used for the preparation of the YS_60 medium. Acivicin obtained from a different manufacturer (Enzo Life Sciences) was used to confirm the results obtained in the previous study.…”