Untargeted Antifungal Treatment in the ICU: Changing Definitions and Labels Do Not Change the Evidence

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We read with interest the systematic review by Dupont et al (1), in a recent issue of Critical Care Medicine, about antifungal prevention of systemic candidiasis (SC) in immunocompetent ICU adults. This review is the most up-to-date, since it includes the recent trial on this topic by Timsit et al (2). However, some points of the discussion and methods sections need clarifications.
The authors claimed novelty of their analysis in comparison of our recently published Cochrane review (3, 4) describing limitations of our review design. The authors stated that we based our analysis on a too large not homogenous population including pulmonary colonization, cancer patients, and nonabsorbable treatment. First, we included trials involving patients classified as critically ill such as those admitted to an ICU or having recently undergone major surgery, excluding trials involving neutropenic or cancer patients. We included trials enrolling non-neutropenic critically ill participants along with other groups if the proportion of these patients was less than 25% or if data on non-neutropenic patients were separately provided. Notably, Dupont et al (1) included the study by Slotman et al (5), enrolling also cancer and immunosuppressed patients, and the trial by Ostrosky-Zeichner et al (6), which had immunosuppressive therapy as potential inclusion criteria. This seems to be a violation of their criteria. Second, nonabsorbable antifungal treatment was part of the intervention studied in our review, and we provided separate analysis for systemic and nonabsorbable treatment (4). Third, Dupont et al (1) stated that one of the novelties of their analysis is that it concerns ICU patients only. However, they included, as we did, the study by He et al (7) which was also performed in surgical ward (ICU admission was only one of the potential inclusion criteria), and the study by Sandven et al (8) in which the study intervention was performed in operating room (3). So, their population seems to be quite similar to ours. We believe that inclusion criteria based on patients characteristics rather than admission department are more relevant for the review question. Furthermore, we do not understand how the exclusion of patients with lung colonization may improve the extrapolation of results in the general ICU population, since it is a common condition in ICU patients. We also believe that the inclusion of a mixed population is a positive aspect in terms of “real world” application of results. Fourth, they wrote that there is no specific analysis of each antifungal strategy in our Cochrane review, but, again, we have concerns on this point. We classified studies according to antifungal strategies (prophylaxis, preemptive treatment, and empiric treatment), based on European Society of Clinical Microbiology and Infectious Disease 2012 guidelines, and reported subgroup analyses accordingly (3, 9). Concerning the definitions of antifungal strategies reported by the authors, it should be noted that the difference between the definition of prophylaxis (antifungal used in patients at risk without individual risk factors) and preemptive treatment (patients with individual risk factors but no signs of infection) is not clear indeed since it is not easy to understand what an “individual risk factor” really is. We may speculate that these criteria, and the consequent classification, are subjective because the reference provided by the authors does not support these definitions (10). In the end, we are glad to see that, even changing definitions and labels, the results from the body of evidence remain quite similar.
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