By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: Two hundred sixty non-neutropenic ICU patients with clinical evidence of sepsis receiving broad-spectrum antibiotics and known to be colonized by Candida species were randomized to micafungin for 14 days vs. placebo. Empirical micafungin therapy did not increase invasive fungal infection-free survival at 28 days.

SOURCE: Timsit JF, Azoulay E, Schwebel C, et al. Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure. The EMPIRICUS Randomized Clinical Trial. JAMA 2016;316:1555-1564.

Two hundred sixty critically ill adult patients with multisystem organ failure, with Candida colonization at peripheral sites, receiving broad-spectrum antibiotics with evidence of sepsis were randomized in a double-blind fashion to micafungin 100 mg IV daily vs. placebo. Two hundred fifty-one patients were included in the modified intent-to-treat analysis. The primary outcome was invasive fungal infection (IFI)-free survival at day 28. Median baseline sequential organ failure assessment (SOFA) score was 8, number of colonized sites was 3, and (1,3)-β-D-glucan was 99 pg/mL. At day 28, 68% of micafungin recipients and 60% of placebo recipients were alive and free of IFI. Subgroup analysis showed no difference in outcome between treatment groups in patients with elevated (1,3)-β-D-glucan at baseline, and no difference in outcome in patients with high (> 8) SOFA scores. Overall survival at day 28 was 90/128 in the micafungin group and 86/123 in the placebo group. Empirical micafungin reduced the rate of new IFI at day 28 (3%) vs. placebo (12%) with P = 0.008.

COMMENTARY

Invasive fungal infections are seen more commonly now than in years past in critically ill non-neutropenic patients treated in both medical and surgical intensive care units (ICUs). In critically ill patients in ICUs, antifungal agents are commonly administered to patients who are febrile despite broad-spectrum antibiotics, although there is a lack of solid evidence to support this practice. In fact, this study largely replicates the results of an earlier clinical trial using caspofungin.1 In this study, caspofungin was safe and tended to reduce the incidence of invasive candidiasis when used for prophylaxis, but the difference was not statistically significant.

Having started my training during the time when the only systemic antifungal agent was amphotericin B, I certainly have seen the field evolve. One common misperception many physicians have is that Candida is difficult to grow in blood cultures. This may be a holdover from the old pre-imidazole days when patients with acute myelogenous leukemia and profound neutropenia who remained febrile (with negative blood cultures) despite broad-spectrum antibiotics often were found to have hepatosplenic candidiasis at autopsy, and this, in many cases, was a cause of death. Hepatosplenic candidiasis is really a different clinical disease than either line-associated candidemia or invasive candidiasis seen in non-neutropenic ICU patients.

One interpretation of this current study is that invasive fungal infection rarely is the cause of death in non-neutropenic ICU patients and that empirical therapy with an echinocandin, while marginally reducing IFI incidence, has little, if any, effect on survival.

REFERENCE

  1. Ostrosky-Zeichner L, Shoham S, Vazquez J, et al. MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 2014;58:1219-1226.