gms | German Medical Science

The approval of echinocandins and new azoles during the last decade caused a breakthrough in the therapy of fungal infections. Nevertheless, fungal pathogens, especially Candida spp., are becoming more resistant. Azole and echinocandin resistance rates are increasing worldwide. Furthermore, multidrug resistance, i.e., strains resistant to two or more classes of antifungal agents, are increasingly reported. Thus, new antifungals, particularly those with novel mechanisms of action, are urgently needed.

Currently, several candidates are in different phases of clinical development. Isavuconazole is an azole drug with an antifungal spectrum similar to that of voriconazole, but with longer plasma half-life. It is currently under development as oral and i.v. formulations in phase III studies of invasive candidiasis, invasive aspergillosis and rare mold infections. New formulations of posaconazole including aqueous solution for i.v. application based on β-cyclodextrin as solubilizer and a solid oral tablet with pH-sensitive polymer matrix and enhanced bioavailability have successfully passed phase I studies. New posaconazole formulations are appreciated given the variable pharmacokinetics of the approved oral suspension, mainly due to absorption issues. MK-3118 (enfumafungin derivative), an oral glucan synthase inhibitor with in vitro and in vivo activity against Candida and Aspergillus species, has been successful in phase I. MGCD290 is an oral small molecule which targets the Hos2 fungal enzyme and, thus, potentiates and broadens the activity of azoles, especially fluconazole. MGCD290 has entered phase II with indication of vulvovaginal candidiasis. Other molecules are yet in the preclinical development, e.g., a second generation echinocandin ASP9726 with enhanced activity against Aspergillus spp.

Maximum efforts should be made by industry, academia and government to avoid the gap in the clinical development of antifungals that is currently observed with antibacterial drugs.