Empirical Antifungal Therapy in Critically Ill Patients With Sepsis: Another Case of Less Is More in the ICU.
Candida species are the most common cause of invasive fungal infections, accounting for 70% to 90% of hospital cases.1,2 Although the overall US incidence of candidemia is low among nonneutropenic, critically ill adults (approximately 2/1000 intensive care unit [ICU] admissions) candidemia results in a longer length of stay =1 month) costs in excess of $40 000 per case, and a 30 day mortality greater than 50%.1 3 Moreover, mortality from invasive fungal infection has been increasing over the past decade, suggesting that advances in the management for invasive fungal infection have lagged behind those for bacterial septic shock.4 In light of the high mortality associated with invasive fungal infection, particularly among critically ill patients, a number of guidelines have focused on empirical treatment with antifungal echinocandins and surveillance for Candida either through culture or diagnostic biomarkers.5,6 Accordingly, the use of echinocandins has increased from 4.6% to 48.5% in some settings.7 Yet little was previously known about mortality benefits from prophylactic antifungal therapy. A series of recent studies have examined empirical antifungal therapy among nonneutropenic patients with septic shock but have had mixed results concerning invasive fungal infection. In a placebo controlled trial of empirical fluconazole treatment among critically ill surgical patients, Pelz et al demonstrated a 55% decrease in the rate of invasive fungal infection.8 Schuster et al conducted a similar study using fluconazole among critically ill ICU patients at high risk for invasive candidiasis, but did not find a decrease in the rate of invasive fungal infection.9 Ostrosky Zeichner et al found a nonsignificant reduction in invasive fungal infection using capsofungin as antifungal prophylaxis among ICU patients with at least 2 risk factors for candidemia.10 However, none of these trials took into account Candida colonization as an inclusion criterion. In this issue of JAMA, Timsit and colleagues11 report findings of a multicenter, randomized, placebo controlled trial (EMPIRICUS) to determine if a 14 day empirical course of micafungin led to a higher 28 day survival without proven invasive fungal infection relative to placebo in 260 nonneutropenic, nontransplanted, critically ill adult patients with at least 1 colonization site positive for Candida species. In this trial, the authors did not find a difference in the proportion of participants who were alive and without invasive fungal infection at 28 days when compared between the micafungin (68% and placebo groups (60.2% Moreover, even though there was a decrease in incident invasive fungal infection among patients who received micafungin (12% when compared with placebo (3% there was no difference in associated mortality at 28 days (30% mortality for the micafungin group vs 29.7% for placebo) Although the rates of invasive fungal infection may decrease with targeted administration of empirical therapy, the results of the EMPIRICUS trial together with previous randomized trials demonstrate substantial evidence that empirical antifungal therapy does not confer a mortality benefit. These findings highlight 2 emerging themes in critical care medicine, which are that less is more and the importance of targeted therapies in treating invasive fungal infection. The EMPIRICUS trial was conducted in 19 ICUs in France. The study was well powered to assess difference in mortality between groups and the results are largely generalizable to critically ill patients with characteristics similar to the study inclusion criteria. Nonsignificant improvement in survival was noted among patients with high Sequential Organ Failure Assessment scores, which may suggest that certain critically ill subgroups may benefit from empirical therapy. Additionally, there was low participation among patients with postoperative gastrointestinal leakage and acute necrotizing pancreatitis, among which there is a high risk of invasive fungal infection. Previous studies have shown surgical patients may benefit from empirical therapy.8 Following the development of dedicated critical care units in the 1950s, critical care medicine was characterized as aggressive with maximum interventions for life saving therapy. If some care is good, then more care was thought to be better.12 The near ubiquitous use of pulmonary artery catheters for invasive monitoring exemplified this approach until a number of studies demonstrated lack of clinical benefit to continuous monitoring and potential iatrogenic risk.12 Over the past 20 years, aggressive goals for many of the most relevant treatment options for critical illness have been revisited and modified or abandoned. Key examples include changes in the following treatment options: (1) the shift from high to low tidal volume for respiratory support; (2) from liberal to conservative strategies for fluid management and blood transfusion therapy; (3) from routine to more selective invasive hemodynamic monitoring; (4) from strict to more liberal glucose control; (5) from high dose common use to selective use of corticosteroids; and (6) from use of continuous sedation to daily Related article page 1555 Opinion
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