In another neutropenic murine model of disseminated mucormycosis due to R. microsporus, mice were treated with posaconazole (PSC) (40 mg/kg/day) or G-CSF (300 μg/kg/day) or with the combination of PSC and G-CSF.[32] Treatment with G-CSF alone had no significant effect on survival or fungal burden in brain, liver, kidneys and lung. In addition, combination therapy was not superior to PSC monotherapy in terms of survival or reduction in fungal burden in various organs. The use of the above cytokines as adjunctive therapy for treatment of mucormycosis in clinical practice has not been systematically studied; Aloxistatin there are no randomised controlled

trials investigating possible benefits associated with cytokine administration. In the comprehensive review of 929 reported cases of patients with mucormycosis, MLN0128 Roden et al.

found a survival rate of 83% in 18 patients who received G-CSF as adjunctive treatment, as compared to 70% in 470 patients, who were treated with surgery plus antifungal therapy, and 69% in 116 patients who were treated with amphotericin B (AmB) lipid formulations[20]; these findings, however, need to be interpreted with caution as differences in outcome may be due to a number of confounding factors. A number of case reports and small series have also been published on the use of G-CSF, GM-CSF and IFN-γ in neutropenic and non-neutropenic patients with mucormycosis.[34-39] Based on the review of published evidence, guidelines from the 3rd European Conference on Infections in leukaemia (ECIL 3) state that hematopoietic growth factors (G-CSF, GM-CSF) should be used in patients with neutropenia and mucormycosis to Farnesyltransferase reverse the underlying risk factor (strength of recommendation and quality of evidence: BIII); however, the use of these cytokines in non-neutropenic patients cannot be recommended at this point.[40] Similar recommendation is given by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) joint guidelines.[41] Appropriately

designed clinical trials are needed to investigate the role of adjunctive cytokine therapy, particularly in non-neutropenic patients with mucormycosis. Mucorales show a resistant phenotype to most existing azoles and echinocandins with high MIC values and generally decreased susceptibility as compared to AmB formulations.[42, 43] Among the azoles, the fact that PSC and/or itraconazole are most active against different Mucorales has been attributed to their ability to accumulate within the fungal organism and stably bind to CYP51 target protein by means of their long side chain, absent from VRC or fluconazole.[42] Current in vitro and animal data show that Mucorales, being a heterogeneous group of organisms, display variable susceptibility profiles to azoles.