Combination antifungal therapy: what can and should we expect?

Invasive fungal infections are associated with significant morbidity and mortality among immunocompromised patients. Recent advances in antifungal development have afforded us more pharmacologic compounds to choose from when managing these fungal infections. The role of combination antifungal therapy has been well established for fungal infections such as cryptococcal meningitis. The availability of new antifungals, increased incidence of mould infections and high mortality among certain affected populations, such as hematopoietic stem cell transplant recipients, has stimulated interest in the clinical use of combination antifungal therapy. In this paper, we review supporting evidence for the use of combination antifungals in the treatment of cryptococcal meningitis, invasive candidiasis, invasive aspergillosis and zygomycosis. Several controlled clinical trials have demonstrated benefits of combination antifungal approaches for patients with cryptococcal meningitis and invasive candidiasis, but variable effects when using different agents in combination have been reported. Randomized prospective studies of combination antifungal therapy in mould infections are lacking but some series provide supportive evidence for this approach. We also describe limitations of the data and these study designs, including the fact that we still need randomized controlled multicenter studies of combination antifungal therapy for mould infections. Trials in this area should be performed with efficiency and economics in mind, and could potentially use surrogate markers as end points. Therefore, we suggest future investigations of combination antifungal therapy should include a randomized, comparative trial of primary therapy for invasive aspergillosis.