Uncertainty about the evidence on untargeted antifungal treatment

We read with great interest the narrative review by Antinori et al. about candidaemia and invasive candidiasis in adults [ ]. We focused our attention on the description of main results from three recent studies investigating the effect of untargeted antifungal treatment, namely the administration of antifungal drugs before definitive microbiological evidence of fungal infection. The authors reported that these studies failed to demonstrate any outcome benefit. However, untargeted antifungal strategies have been widely investigated for 30 years and the evidence about its efficacy is complex. We recently published a Cochrane systematic review of randomized controlled trials (RCTs) comparing untargeted antifungal treatment to placebo or no intervention in non-neutropenic patients [ ]. Notably, the term ‘untargeted antifungal treatment’ encompasses three antifungal strategies: 1) prophylaxis: the administration of antifungal drugs in patients without proven or suspected fungal infection but with risk factors for its development 2) pre-emptive: treatment trigger by microbiological evidence of infection without definitive microbiological proof, e.g. positive surrogate marker [ , ] 3) empiric: treatment triggered by signs and symptoms of infection in patients at risk for invasive fungal infections [ ]. The Cochrane systematic review included 22 RCTs and 2761 patients. There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce total all-cause mortality (Relative Risk 0.93, 95% CI 0.79 to 1.09, P value = 0.36). However, there was a low grade evidence that these strategies significantly reduce by about 45% the incidence of proven invasive fungal infections, defined as clinical illness consistent with the diagnosis and either histopathological evidence of IFI or a positive fungal culture from sterile site specimens (Relative Risk 0.57, 95% CI 0.39 to 0.83. P value = 0.0001). Most of studies investigated antifungal prophylaxis and empiric treatment. Only one RCT investigated pre-emptive treatment driven by beta-d-glucan. Among included studies, there was a predominance of RCTs using azoles (14) rather than echinocandins (4) or other antifungals (4). From these global data, a paradox may arise from high crude mortality of invasive infections by Candida spp. and the absence of effects in terms of overall mortality by untargeted antifungal treatment, despite the reduction of invasive fungal infections rate [ , ]. ESCMID 2012 guideline supports the use of fluconazole prophylaxis in patients who recently underwent abdominal surgery and had reoperations for perforation or anastomotic leakage [ ]. On the contrary, empiric treatment and the use of beta-D-glucan to guide therapy are not supported. IDSA 2015 guideline describes antifungal prophylaxis with fluconazole or echinocandins as a therapeutic option in high-risk patients (weak recommendation) [ ]. A strong recommendation supports empiric treatment in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever. Notably, IDSA guideline described well the conflicting results of studies investigating this type of antifungal treatment, especially from RCTs. Moreover, it could not take into consideration the evidence from Knitsch et al. (last RCT to date on this topic) and the Cochrane systematic review [ ].