November 23, 2016


Invasive fungal infections (IFI) are characterised by high morbidity and mortality in non-neutropenic critically ill patients. Candida spp. is the most common fungal pathogen in ICU. Timely administration of appropriate antifungal treatment is an important part of IFI management. Moreover, the number of organ system failures and multi-site colonisation by Candida are established risk factors for IFI. The efficacy of empiric antifungal treatment, defined as the administration of antifungals to patients with signs and symptoms of infections without proven IFI diagnosis, is unclear.

In this multicentre randomised double-blind placebo-controlled trial authors investigated the effect of empiric antifungal treatment in non-neutropenic, non-transplanted, critically ill patients with ICU-acquired sepsis, multiple-site Candida colonisation, multiple organ failure, receiving broad-spectrum antibiotics. The study was performed between July 2012 and February 2015 in 19 ICU in France. Patients were randomised in two groups: micafungin 100 mg once daily or placebo. The primary outcome of the study was survival without proven invasive fungal infections (IFI) at 28 days from randomisation. Secondary outcomes included incidence of new proven IFI, survival at day 28 and day 90, incidence of ventilator-associated bacterial pneumonia. 

From 518 patients assessed for eligibility, 260 were randomised: 131 in the micafungin group and 129 in the placebo group. Patients enrolled were severely ill, with a mean SAPS II score of 48 and overall median SOFA score of 8. All patients had multiple risk factors for IFI and the median number of sites colonised at inclusion by fungi was 3. 

Regarding the primary outcome, no significant difference was found between groups: 87 patients in the micafungin group (68%) vs 74 patients in the placebo group (60.2%) were alive and free from IFI at 28 days from randomisation (hazard ratio 1.35, 95% CI 0.87-2.08). Moreover, no significant difference was detected in survival at day 28, survival at day 90 and incidence of ventilator-associated bacterial pneumonia. Notably, there was a significant difference in the number of patients developing new IFI between groups: 4 in the micafungin group and 15 in the placebo group (p= 0.008).

This study did not support the use of empiric antifungal treatment with micafungin in non-immunocompromised patients with ICU-acquired sepsis, multiple colonisation sites and multiple organ failure since it did not increase IFI-free survival at day 28 or mortality despite a reduced incidence of IFI.
It could be hypothesised that the lack of benefit in this study may be due to the late starting of the antifungal treatment during the clinical course. Further trials should evaluate different antifungal strategies in terms of timing of the intervention and patients’ selection.

Article review was submitted by NEXT Member Andrea Cortegiani.


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