Abstract
Infections of Exophiala spp. and Fusarium spp. are often chronic and recalcitrant. Systemic disseminations, which mostly occur in immunocompromised patients, are often refractory to available antifungal therapies. The conserved target of rapamycin (TOR) orchestrates cell growth and proliferation in response to nutrients and growth factors, which are important for pathogenicity and virulence. INK128 is a second-generation ATP-competitive TOR inhibitor, which binds the TOR catalytic domain and selectively inhibits TOR. In the present study, we investigated the in vitro activities of INK128 alone and the interactions of INK128 with conventional antifungal drugs including itraconazole, voriconazole, posaconazole, and amphotericin B against 18 strains of Exophiala spp. and 10 strains of Fusarium spp. via broth microdilution checkerboard technique system adapted from Clinical and Laboratory Standards Institute broth microdilution method M38-A2. INK128 alone was inactive against all isolates tested. However, favorable synergistic effects between INK128 and voriconazole were observed in 61% Exophiala strains and 60% Fusarium strains, despite Fusarium strains exhibited high MIC values (4–8 μg/ml) against voriconazole. In addition, synergistic effects of INK128/itraconazole were shown in 33% Exophiala strains and 30% Fusarium strains, while synergy of INK128/posaconazole were observed in 28% Exophiala strains and 30% Fusarium strains. The effective working ranges of INK128 were 0.125–2 μg/ml and 1–4 μg/ml against Exophiala isolates and Fusarium isolates, respectively. No synergistic effect was observed when INK128 was combined with amphotericin B. No antagonism was observed in all combinations. In conclusion, INK128 could enhance the in vitro antifungal activity of voriconazole, itraconazole and posaconazole against Exophiala spp. and Fusarium spp., suggesting that azoles, especially voriconazole, combined with TOR kinase inhibitor might provide a potential strategy to the treatment of Exophiala and Fusarium infections. However, further investigations are warranted to elucidate the underlying mechanism and to determine possible reliable and safe application in clinical practice.
Highlights
Exophiala spp. and Fusarium spp. are both increasingly recognized opportunistic pathogen causing cutaneous, subcutaneous and serious invasive infections, especially in immunocompromised and debilitated individuals (Li et al, 2011; Guarro, 2013)
The minimal inhibitory concentrations (MICs) ranges against Fusarium spp. are >16 μg/ml for INK128 and ITC, 4–8 μg/ml for VRC and POS, and 2–4 μg/ml for amphotericin B (AMB), respectively (Table 2)
When INK128 was combined with VRC, the MICs of INK128 and VRC against Exophiala spp. decreased to 0.125–2 μg/ml and 0.03–0.25 μg/ml, respectively, demonstrating favorable synergistic effects against 11 (61%) strains of E. dermatitidis (Table 1)
Summary
Exophiala spp. and Fusarium spp. are both increasingly recognized opportunistic pathogen causing cutaneous, subcutaneous and serious invasive infections, especially in immunocompromised and debilitated individuals (Li et al, 2011; Guarro, 2013). E. dermatitidis is one of the most common cause of chromoblastomycosis (Li et al, 2011), while Fusarium spp. causes keratitis and onychomycosis, or locally invasive infections (Guarro, 2013). Fusariosis is mostly refractory to available treatment, with a high mortality rate for systemic disseminations, which is in accordance with the poor in vitro activities of available antifungal drugs against Fusarium spp. Success rate for Exophiala spp. infection was only 40–70% despite most antifungal drugs showed favorable in vitro activities (Revankar and Sutton, 2010; Kondori et al, 2011; Patel et al, 2013).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
