EMPIRICUS

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

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 If blood cultures were subsequently positive for invasive candidiasis, the study drug was withdrawn and usual unit anti-fungal treatment was prescribed (patient still included in analysis)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

Metadata

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

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