Effect of erythromycin on mortality and the host response in critically ill patients with sepsis: a target trial emulation

Author:

Reijnders Tom D. Y.,Peters-Sengers Hessel,van Vught Lonneke A.,Uhel Fabrice,Bonten Marc J. M.,Cremer Olaf L.,Schultz Marcus J.,Stuiver Martijn M.,van der Poll Tom,de Beer Friso M.,Bos Lieuwe D. J.,Glas Gerie J.,van Hooijdonk Roosmarijn T. M.,Horn Janneke,Schouten Laura R. A.,Straat Marleen,Wieske Luuk,Witteveen Esther,Reijnders Tom D. Y.,Schuurman Alex R.,van Engelen Tjitske S. R.,Pereverzeva Liza,Hoogendijk Arie J.,Huson Mischa A.,Wiewel Maryse A.,Klouwenberg Peter M. C. Klein,Ong David S. Y.,Frencken Jos F.,Koster-Brouwer Maria E.,van de Groep Kirsten,Verboom Diana M.,

Abstract

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 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.

Funder

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Nierstichting

Center for Translational Molecular Medicine

Publisher

Springer Science and Business Media LLC

Subject

Critical Care and Intensive Care Medicine

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