Combination antifungal therapy against Candida species: the new frontier--are we there yet?

In the past decade, we have seen a significant increase in the incidence of invasive fungal infections. In addition, opportunistic fungal infections resistant to antifungal agents have become increasingly common and their frequency will more than likely continue to increase. The antifungal armamentarium for the treatment of serious fungal infections remains limited. A possible approach to overcoming antifungal drug resistance and high mortality rates seen in severe fungal infections is to combine two or three classes of antifungals, especially if the drugs have different mechanisms of action. The unique properties of newer antifungals now provide us with the opportunity to investigate antifungal combinations that may become the standard of care for serious fungal infections. Combinations of new agents along with more traditional antifungals have now been shown to possess some synergistic or at least additive activity against Candida in clinical trials. On the other hand, caution is still needed since other antifungal combinations have demonstrated antagonistic activity in vitro. Well-controlled clinical trials are needed to define the most efficacious antifungal regimen. Furthermore, these trials should also evaluate the side effect potential of combination regimens and the pharmacoeconomic impact these regimens may have. Thus, while much optimism exists for combination therapy, there is much yet to be done.