Antifungal Activity of Micafungin in Serum

The aim of this study was to compare the in vitro and in vivo activities of micafungin, caspofungin, and anidulafungin against Candida glabrata. The MICs against 28 clinical isolates showed that the overall susceptibilities to caspofungin and to micafungin were not statistically different in the absence of human serum, whereas the isolates were less susceptible to micafungin than to caspofungin in its presence. Minimum fungicidal concentrations, as well as time-kill experiments, showed that caspofungin was more active than anidulafungin, while micafungin was superior to either caspofungin or anidulafungin without serum; its addition rendered caspofungin and micafungin equally effective. A murine model of systemic candidiasis against a C. glabratasusceptible isolate was performed to study the effects of all three echinocandins, and kidney burden counts showed that caspofungin, micafungin, and anidulafungin were active starting from 0.25, 1, and 5 mg/kg of body weight/day, respectively. Two echinocandin-resistant strains of C. glabrata were selected: C. glabrata 30, a laboratory strain harboring the mutation Fks2p-P667T, and C. glabrata 51, a clinical isolate harboring the mutation Fks2p-D666G. Micafungin activity was shown to be as effective as or more effective than that of caspofungin or anidulafungin in terms of MICs. In vivo studies against these resistant strains showed that micafungin was active starting from 1 mg/kg/day, while caspofungin was effective only when administrated at higher doses of 5 or 10 mg/kg/day. Although a trend toward colony reduction was observed with the highest doses of anidulafungin, a significant statistical difference was never reached. Candida glabrata has recently been reported to be the second most common cause of invasive candidiasis, and there are increasing amounts of data showing its important role in determining either superficial or deep-seated infections (4, 18). Systemic infections due to C. glabrata are characterized by a high mortality rate, and they are difficult to treat due to reduced susceptibility of the species to azole drugs, especially to fluconazole (26). According to the published guidelines, amphotericin B can be used to treat infections due to C. glabrata, especially in profoundly immunocompromised hosts (22). Fortunately, the species also appears to be highly susceptible to the echinocandins (i.e., caspofungin, anidulafungin, and micafungin), making these agents valuable alternatives as first-line therapy against this Candida species (22). Interestingly, patients suffering from systemic candidiasis due to C. glabrata showed a trend, although not a significant one, to a better clinical outcome when treated with micafungin (87%) rather than with caspofungin (67%) (23).The three echinocandin antifungal agents anidulafungin, caspofungin, and micafungin have a unique mechanism of action, inhibiting ␤-1,3-D-glucan synthase, an enzyme that is necessary for the synthesis of ␤-1,3-D-glucan polymers, essential components of the cell walls of several fungi (8).Althou...

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Comparative Effects of Micafungin, Caspofungin, and Anidulafungin against a Difficult-To-Treat Fungal Opportunistic Pathogen, Candida glabrata

Spreghini

Orlando²,

Sanguinetti

et al. 2012

“…The in vivo equilibrium may be shifted to the left arm (toward free drug) since free drug is constantly eliminated. This equilibrium might also be affected by the type (reversible versus nonreversible) and the strength (weak or strong) of protein binding, like the reversible and weak interaction of micafungin with serum proteins which was used to explain the smaller MIC increase than predicted by the percentage of protein binding (25). Finally, in vivo the volume of drug distribution is much larger than the volume of infection, whereas in vitro the opposite is true.…”

Section: Discussionmentioning

confidence: 99%

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

Elefanti

Mouton

Krompa

et al. 2013

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.

“…It is well established that echinocandin drugs bind to serum proteins at very high levels (98% for ANF, 96.5% for CSF, and 99.8% for MCF) (17,24,38,42). However, it is not clear whether echinocandins are active only as unbound free drug or whether these drugs are also active when complexed with protein.…”

Section: Discussionmentioning

confidence: 99%

Improved Detection of Candida sp. fks Hot Spot Mutants by Using the Method of the CLSI M27-A3 Document with the Addition of Bovine Serum Albumin

García‐Effrón¹,

Park²,

Perlin³

2011

Echinocandins are highly bound to serum proteins, altering their antifungal properties. The addition of 50% human serum to the MIC assay improves the identification of echinocandin-resistant Candida spp. harboring fks hot spot mutations. However, this modification cannot readily be applied to the method of the CLSI M27-A3 document due to safety and standardization difficulties. The aim of this study was to evaluate commercial bovine serum albumin (BSA) as a safe and standardized alternative to human serum. A collection of 28 echinocandin-susceptible strains, 10 Candida parapsilosis sensu lato strains (with naturally reduced echinocandin susceptibility), and 40 FKS hot spot mutants was used in this work. When RPMI 1640 was used for susceptibility testing, wild-type strains and fks mutants showed MIC range overlaps (؊2, ؊1, and ؊3 2-fold-dilution steps separated these populations for anidulafungin, caspofungin, and micafungin, respectively). On the other hand, the addition of BSA to RPMI 1640 differentially increased echinocandin MIC values for these groups of strains, allowing better separation between populations, with no MIC range overlaps for any of the echinocandin drugs tested. Moreover, the use of RPMI-BSA reduced the number of fks hot spot mutant isolates for which MIC values were less than or equal to the upper limit for the wild type (very major errors) from 9, 2, and 7 with RPMI alone to 3, 0, and 3 for anidulafungin, caspofungin, and micafungin, respectively. When RPMI-BSA was used to study the susceptibility of C. parapsilosis sensu lato species to echinocandins, the strains behaved as anidulafungin-and micafungin-resistant isolates (MIC, >8 g/ml). These data support the need for a revision of the CLSI protocol for in vitro testing of echinocandin susceptibility in order to identify all or most of the fks hot spot mutants. Also, caspofungin could be used as a surrogate marker of reduced susceptibility to echinocandins.