Effect of erythromycin on mortality and the host response in critically ill patients with sepsis: a target trial emulation
MARS Consortium
(2022) Critical care (London, England), volume 26, issue 1
(Article)
Abstract
BACKGROUND: Immunomodulatory therapies that improve the outcome of sepsis are not available. We sought to determine whether treatment of critically ill patients with sepsis with low-dose erythromycin-a macrolide antibiotic with broad immunomodulatory effects-decreased mortality and ameliorated underlying disease pathophysiology. METHODS: We conducted a target trial emulation, comparing patients with sepsis
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admitted to two intensive care units (ICU) in the Netherlands for at least 72 h, who were either exposed or not exposed during this period to treatment with low-dose erythromycin (up to 600 mg per day, administered as a prokinetic agent) but no other macrolides. We used two common propensity score methods (matching and inverse probability of treatment weighting) to deal with confounding by indication and subsequently used Cox regression models to estimate the treatment effect on the primary outcome of mortality rate up to day 90. Secondary clinical outcomes included change in SOFA, duration of mechanical ventilation and the incidence of ICU-acquired infections. We used linear mixed models to assess differences in 15 host response biomarkers reflective of key pathophysiological processes from admission to day 4. RESULTS: In total, 235 patients started low-dose erythromycin treatment, 470 patients served as controls. Treatment started at a median of 38 [IQR 25-52] hours after ICU admission for a median of 5 [IQR 3-8] total doses in the first course. Matching and weighting resulted in populations well balanced for proposed confounders. We found no differences between patients treated with low-dose erythromycin and control subjects in mortality rate up to day 90: matching HR 0.89 (95% CI 0.64-1.24), weighting HR 0.95 (95% CI 0.66-1.36). There were no differences in secondary clinical outcomes. The change in host response biomarker levels from admission to day 4 was similar between erythromycin-treated and control subjects. CONCLUSION: In this target trial emulation in critically ill patients with sepsis, we could not demonstrate an effect of treatment with low-dose erythromycin on mortality, secondary clinical outcomes or host response biomarkers.
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Keywords: Critically ill, Erythromycin, Immunomodulation, Macrolides, Mortality, Propensity score, Sepsis, Target trial, Critical Care and Intensive Care Medicine
ISSN: 1466-609X
Publisher: Springer Science + Business Media
Note: Funding Information: Members of MARS consortium are: Departments of Intensive Care Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands: Friso M. de Beer, MD, Lieuwe D. J. Bos, PhD, Gerie J. Glas, MD, Roosmarijn T. M. van Hooijdonk, MD, Janneke Horn, MD, Laura R. A. Schouten, MD, Marleen Straat, MD, Luuk Wieske, MD, Esther Witteveen, MD. Center for Experimental and Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands, and Center of Infection and Immunity Amsterdam (CINIMA), Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Tom D.Y. Reijnders, MD, Alex R. Schuurman, MD, Tjitske S.R. van Engelen, MD, Liza Pereverzeva, MD, Arie J. Hoogendijk, PhD, Mischa A. Huson, MD, Maryse A. Wiewel, MD; Department of Medical Microbiology, Department of Intensive Care Medicine, and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Peter M.C. Klein Klouwenberg, MD, David S.Y. Ong, MD; Department of Intensive Care Medicine and Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands; Jos F. Frencken, MD, Maria E. Koster-Brouwer, MSc, Kirsten van de Groep, MD, Diana M. Verboom, MD. Funding Information: The MARS project was performed within the framework of the Center for Translational Molecular Medicine (CTMM; www.ctmm.nl ; grant 04I-201). TDYR is supported by research program “NACTAR,” project “MDR-phage” (grant number 16447) which is financed by the Dutch research council (NWO). HPS is supported by the Dutch Kidney Foundation (Kolff Grant 19OK009). LAvV is supported by the Netherlands Organisation for Health Research and Development ZonMW (NWO) VENI grant 09150161910033 and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Research Grant. The funders had no role in the data analysis or the decision to publish. Publisher Copyright: © 2022, The Author(s).
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