A randomized trial of Mycobacterium w in severe presumed Gram-negative sepsis (MIST).

Background Mycobacterium w (Mw), an immunomodulator, has been shown to resolve early organ failure in severe sepsis. Research question Does Mw improve survival in subjects with severe presumed Gram-negative sepsis? Study design and methods: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted in intensive care units (ICUs) of five tertiary care centers in India. We included consecutive subjects (aged ≥18 years) with presumed Gram-negative sepsis in the study within 48 hours of the first organ dysfunction. Subjects in the treatment arm received 0.3 mL/day of Mw intradermally for three consecutive days, while the control arm received matching placebo. The primary outcome was 28-day all-cause mortality. The secondary outcomes were ventilator-free days, days on vasopressor therapy, ICU-and hospital length of stay, nosocomial infection rate, antibiotic use duration, and delta SOFA. Results We included 202 subjects with severe sepsis (101 Mw, 101 placebo). The use of Mw significantly reduced the mortality (9/101 vs. 20/101, estimate difference [95% confidence interval], 0.11 [0.01 to 0.21], p value=0.04). We found no difference in ventilator-free days, days on vasopressor drugs, ICU, and the hospital length of stay. The time to mortality (median 13 vs. 8.5 days) was significantly longer in the Mw than in the placebo arm. The delta SOFA score, the rate of nosocomial infections, and the antibiotic use duration were similar in the two arms. We found Mw to significantly reduce the odds (odds ratio [95% confidence interval], 0.37 [0.15-0.9]) of mortality after adjusting for culture-positive sepsis, the baseline SOFA score, age, and sex. Interpretation The use of Mw was associated with a significant reduction in mortality in patients with severe presumed Gram-negative sepsis. Further studies are required to confirm our findings.