Assessing micafungin/triazole combinations for the treatment of invasive scedosporiosis due to Scedosporium apiospermum and Scedosporium boydii

Scedosporium infections are associated with high therapeutic failure rates. Combination therapy may be an alternative approach to improve outcome. The in vitro and in vivo efficacy of micafungin plus posaconazole or plus voriconazole was investigated herein. Scedosporium boydii (naEuroS=aEuroS17) and Scedosporium apiospermum (naEuroS=aEuroS26) were tested using the chequerboard method according to CLSI M38-A2 guidelines and the fractional inhibitory concentration index (FICI) was evaluated. In vivo outcome of micafungin plus posaconazole or micafungin plus voriconazole against two isolates of each of the mentioned species was evaluated in a well-established, immunocompromised, haematogenous murine model of systemic scedosporiosis. Survival and tissue burden in kidneys and brain were investigated. The FICI category of 'no interaction' was most frequent, while 'synergism' or 'antagonism' was rarely observed. FICI failed to predict the in vivo outcome of both combinatorial treatment strategies. In vivo outcome was strain-dependent rather than species-dependent, even though effects on fungal tissue burden were more pronounced for S. boydii. Both combinations improved survival significantly when compared with untreated controls and micafungin monotherapy. Voriconazole and posaconazole did not differ in their efficacy and micafungin failed to be effective. Combinations were by trend better than voriconazole and posaconazole as single therapy, but statistically significant differences were lacking. No benefit of the azole/echinocandin combination was found when compared with voriconazole and posaconazole monotherapies. FICI failed to predict the outcome of in vivo drug combinations in the murine study.