Recent advances in the management of mucormycosis: from bench to bedside

Abstract

Recent therapeutic advances have the potential to improve outcomes of mucormycosis. Lipid formulations of amphotericin B (LFAB) have evolved as the cornerstone of primary therapy for mucormycosis. Posaconazole may be useful as salvage therapy, but it cannot be recommended as primary therapy for mucormycosis on the basis of available data. Preclinical and limited retrospective clinical data suggest that combination LFAB-echinocandin therapy may improve survival during mucormycosis. A definitive trial is needed to confirm these results. Combination therapy with LFAB and the iron chelator, deferasirox, also improved outcomes in animal models of mucormycosis. In contrast, combination polyene-posaconazole therapy was of no benefit in preclinical studies. Adjunctive therapy with recombinant cytokines, hyperbaric oxygen, and/or granulocyte transfusions can be considered for selected patients. Early initiation of therapy is critical to maximizing outcomes; recent developments in polymerase chain reaction technology are advancing early diagnostic strategies. Prospective, randomized clinical trials are needed to define optimal management strategies for mucormycosis.

Figure 1

Current targets of therapy for mucormycosis. As a result of recent translational research, strategies are available to attack 4 biochemical targets in Mucorales. These targets include (1) polyene binding to ergosterol in the cell membrane, resulting in creation of pores in the membrane; (2) posaconazole inhibition of cytochrome p450 14-α-demethylase, blocking synthesis of cell membrane-stabilizing ergosterol; (3) echinocandin inhibition of cross-linking of β-glucan in the fungal cell wall; and (4) deferasirox iron chelation therapy, blocking uptake of iron, which is essential for fungal growth. In addition, adjunctive therapy with host immune enhancing strategies, such as (5) granulocyte transfusions and (6) cytokine therapy, are possible. Granulocytes can damage the fungal cell and can be activated by recombinant cytokines, including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and interferon-γ (IFN-γ). Polymorphonuclear leukocytes also can be delivered to the site of infection in neutropenic hosts by granulocyte transfusions. Polymorphonuclear leukocytes and lipid formulations of amphotericin B act synergistically to damage hyphae of Rhizopus species.