Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure

Timsit J-F. JAMA 2016; 316(5): 1555-1564. doi:10.1001/jama.2016.14655

Clinical Question

• In critically ill patients with non-neutropenic sepsis, multiple Candida colonisation and multi organ failure, does empirical micafungin therapy increase invasive fungal infection-free survival at day 28 compared with placebo?

Background

• Although frequently used in treating intensive care unit patients with sepsis, empirical antifungal therapy, initiated for suspected fungal infection, has not been shown to improve outcome
• Two previous multicenter randomized clinical trials evaluated empirical antifungal therapy for fungal infection suspicion in patients with a central catheter and persistent fever despite treatment with broad-spectrum antibacterial agents
  • Schuster et al. Ann Intern Med 2008 – Empirical fluconazole did not improve composite clinical outcomes vs placebo in patients at high risk for invasive candidiasis
  • Ostrosky-Zeichner et al. Clin Infect Dis 2014 – Empirical caspofungin in ICU patients, with at least 2 risk factors for candidaemia, reduced incidence of invasive candidiasis (but no statistical difference)

Design

• Multicentre, randomised, double-blind, parallel group study
• Permuted-block randomisation using varying block size
• Modified intention to treat analysis, including all patients who received at least one dose of treatment
• Blood cultures drawn at inclusion. If blood cultures were subsequently positive for invasive candidiasis, the study drug was withdrawn and usual unit anti-fungal treatment was prescribed (patient still included in analysis)
• 235 patients were required to detect an absolute difference of 18% in the primary endpoint with an 80% power at a 0.05 significance level. It was decided that 260 patients were needed to account for attrition

Setting

• 19 ICUs in France
• July 2012 – Feb 2015

Population

• Inclusion: Adult ICU patients who were mechanically ventilated for at least 5 days with one or more other organ failure and new ICU-acquired sepsis of unknown origin AND
  • Presence of a central vein catheter and/or an arterial line
  • Use of broad spectrum antibacterial agent ≥ 4 days during the last seven days
  • At least one colonisation site (other than rectal swab or stool) positive for Candida species
•  Exclusion:
  • Proven invasive infection requiring antifungal treatment at the time of randomisation
  • Antifungal treatment with an echinocandin > 1 day or with any other antifungal agent > 72 hours the week preceding the inclusion
  • Neutropenia (neutrophils count < 500/mm3)
  • Previous bone marrow or solid organ transplantation
  • Recent chemotherapy (< 6 months) or receiving systemic immunosuppressants

• 518 patients screened, 260 randomised, 251 included in final analysis (the 9 missing withdrew consent)
• There were some differences in baseline characteristics:
  • Intervention group had higher BMI (over 30- 41% vs 30%), and greater incidence of chronic renal disease (12% vs 6%), and diabetes (34% vs 20%)
  • Control group had a greater incidence of chronic respiratory disease (33% vs 20%), immunosuppressed patients (8% vs 4%) and septic shock (37% vs 31%)
  • Other characteristics (age, illness severity, gender) were similar between both groups

Intervention

• 100mg micafungin/day as a 1 hour infusion for 14 days

Control

• 100mls of 0.9% NaCl as a 1 hour infusion for 14 days

Outcome

• Primary outcome:
  • No statistical difference in patients alive and free from invasive fungal infection at day 28
    • Eighty-seven (68%) patients in the micafungin group vs 74 (60.2%) patients in the placebo group
    • HR, 1.35; 95% CI, 0.87-2.08; P= 0.18
    • Hazard ratios in modified ITT analysis and predefined subgroups did not reach statistical significant between the groups
• Secondary outcomes:
  • micafungin group had a significantly lower incidence of new proven invasive fungal infections during follow up:
    • 4 (3%) in the micafungin group vs 15 (12%) of the placebo group developed at least one new proven fungal infection (P= 0.008)
    • Fragility index = 3
  • No statistical difference in
    • Survival at day 28: 70% placebo vs 70% micafungin P=0.95
    • Survival at day 90: 55% placebo vs 56% micafungin; P=0.90
    • Antifungal-free survival at day 28
    • Incidence of ventilator-associated bacterial pneumonia
    • Evolution of the SOFA score over the 28 day study period
    • Evolution of serum level of (1-3)-β-D-glucan over 28 days
  • Adverse events: Micafungin was well tolerated with minimal adverse effects in comparison to the placebo
    • 3 patients in the micafungin group had serious adverse events related to the drug (one cholestasis, one toxidermal reaction, one delirium; all resolved)

Authors’ Conclusions

• Among non-neutropenic critically ill patients with ICU acquired sepsis, Candida species colonisation at multiple sites, and multiple organ failure, empirical treatment with micafungin compared with placebo did not increase fungal infection-free survival at day 28

Strengths

• Large study investigating the effect of empirical anti-fungal treatment
• Multicentre performed across university-affiliated and non-university hospitals, adding to it’s external validity
• Appropriately powered
• Allocation concealment
• Blinding achieved by pharmacy producing opaque bags containing micafungin or placebo
• Statistical analyses used on secondary end points were predefined
• No patients lost to follow up
• Registered on clinicaltrials.gov
• An homogenous group of patients were selected, which improves the internal validity of the trial

Weaknesses

• Such an homogenous group of patients is highly selective and fairly uncommon; demonstrated by the fact it took 19 ICUs 3 years to recruit 260 patients – which averages at 4 patients per site per year
• General ICU management (such as lung protective ventilation) was not standardised between groups or between units – affecting the internal and external validity of the trial

The Bottom Line

• This study does not support empirical anti-fungal therapy with micafungin in a select group of intensive care patients at high risk of invasive candidiasis

External Links

• [article] 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
• [Editorial] Empirical Antifungal Therapy in Critically Ill Patients With Sepsis
• [Video] ICTV Hot topics- the EMPIRICUS trial
• [Article review] ESICM The EMPIRICUS trial
• [Further reading] Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group

Metadata

Summary author: Segun Olusanya
Summary date: 19th May 2017
Peer-review editor: Adrian Wong