The term 'entomophthoramycosis' classically refers to infections caused by members of the order Entomophthorales. A new subphylum, Entomophthoramycota, has been created to include Basidiobolomycetes, Neozygitomycetes and Entomophthoramycetes. Basidiobolomycetes encompass Basidiobolus spp., while the Entomophthoramycetes include Conidiobolus spp. Conidiobolus spp. characteristically cause rhinofacial entomophthoramycosis in apparently immunocompetent hosts. Conidiobolus spp. may also cause disseminated infection in immunocompromised patients. Basidiobolus spp. more typically cause subcutaneous entomophthoramycosis of the limbs, buttocks, back and thorax in immunocompetent patients. While once considered to be rare, there is an increasing number of reported cases of gastrointestinal infection caused by Basidiobolus spp. worldwide in countries such as United States, Thailand, Australia, Iran, Egypt and Saudi Arabia. These cases have clinical presentations similar to those of inflammatory bowel diseases, particularly Crohn's disease. Retroperitoneal, pulmonary, nasal and disseminated basidiobolomycosis have also been reported. Histology of entomophthoramycosis may reveal the Splendore-Hoeppli phenomenon. Culture of infected tissue remains the definitive method of laboratory diagnosis. However, molecular methods with specific DNA probes and panfungal primers, as well as real time PCR, are increasingly used to detect and identify these organisms in tissue. Treatment largely consists of therapy with antifungal triazoles. Surgery plays a selective role in the management of entomophthoramycosis, depending upon location, organism and extent of the infection.

Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits ( < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone ( < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone ( < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights ( = 0.764; < 0.001), and pulmonary infarct score ( = 0.911; < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.

No abstract

Combination therapy may be an alternative therapeutic approach for difficult-to-treat Candida infections with the aim of increasing efficacy of antifungal therapy. Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or polyenes for the treatment of invasive candidiasis has not been studied. We used Bliss independence drug interaction analysis and time-kill assays to examine the in vitro interactions of isavuconazole with amphotericin B or micafungin, an echinocandin, against strains of Candida albicans, Candida parapsilosis, Candida glabrata, Candida tropicalis, and Candida krusei. The Bliss independence-based drug interactions modeling showed that the combination of isavuconazole and micafungin resulted in synergistic interactions against C. albicans, C. parapsilosis, and C. krusei. The degree of synergy ranged from 1.8% to 16.7% (mean %ΔΕ value) with the highest synergy occurring against C. albicans (⊙SYN% = 8.8%-110%). Time-kill assays showed that the isavuconazole-micafungin combination demonstrated concentration-depended synergy against C. albicans and C. parapsilosis. The combined interaction by Bliss analysis between isavuconazole and amphotericin B was indifferent for C. albicans, C. parapsilosis, and C. tropicalis while for C. glabrata was antagonistic (-2% to -6%) and C. krusei synergistic (3.4% to 7%). The combination of isavuconazole-amphotericin B by time-kill assay was antagonistic against C. krusei and C. glabrata. Collectively, our findings demonstrate that combinations of isavuconazole and micafungin are synergistic against Candida spp., while those of isavuconazole and amphotericin B are indifferent in vitro.

No abstract