• Eleni Karakike, Brendon P Scicluna, Maria Roumpoutsou, Ioannis Mitrou, Niki Karampela, Athanasios Karageorgos, Konstantinos Psaroulis, Eleni Massa, Achillefs Pitsoulis, Panagiotis Chaloulis, Evanthia Pappa, Irene T Schrijver, Frantzeska Frantzeskaki, Malvina Lada, Nicolas Dauby, David De Bels, Ioannis Floros, Souzana Anisoglou, Eleni Antoniadou, Maria Patrani, Glykeria Vlachogianni, Eleni Mouloudi, Anastasia Antoniadou, David Grimaldi, Thierry Roger, W Joost Wiersinga, Iraklis Tsangaris, and Evangelos J Giamarellos-Bourboulis.
• 4th Department of Internal Medicine, National and Kapodistrian University of Athens, 1 Rimini Street, 124 62, Athens, Greece.
• Crit Care. 2022 Jun 18; 26 (1): 183.

BackgroundClarithromycin may act as immune-regulating treatment in sepsis and acute respiratory dysfunction syndrome. However, clinical evidence remains inconclusive. We aimed to evaluate whether clarithromycin improves 28-day mortality among patients with sepsis, respiratory and multiple organ dysfunction syndrome.MethodsWe conducted a multicenter, randomized, clinical trial in patients with sepsis. Participants with ratio of partial oxygen pressure to fraction of inspired oxygen less than 200 and more than 3 SOFA points from systems other than the respiratory function were enrolled between December 2017 and September 2019. Patients were randomized to receive 1 gr of clarithromycin or placebo intravenously once daily for 4 consecutive days. The primary endpoint was 28-day all-cause mortality. Secondary outcomes were 90-day mortality; sepsis response (defined as at least 25% decrease in SOFA score by day 7); sepsis recurrence; and differences in peripheral blood cell populations and leukocyte transcriptomics.ResultsFifty-five patients were allocated to each arm. By day 28, 27 (49.1%) patients in the clarithromycin and 25 (45.5%) in the placebo group died (risk difference 3.6% [95% confidence interval (CI) - 15.7 to 22.7]; P = 0.703, adjusted OR 1.03 [95%CI 0.35-3.06]; P = 0.959). There were no statistical differences in 90-day mortality and sepsis response. Clarithromycin was associated with lower incidence of sepsis recurrence (OR 0.21 [95%CI 0.06-0.68]; P = 0.012); significant increase in monocyte HLA-DR expression; expansion of non-classical monocytes; and upregulation of genes involved in cholesterol homeostasis. Serious and non-serious adverse events were equally distributed.ConclusionsClarithromycin did not reduce mortality among patients with sepsis with respiratory and multiple organ dysfunction. Clarithromycin was associated with lower sepsis recurrence, possibly through a mechanism of immune restoration. Clinical trial registration clinicaltrials.gov identifier NCT03345992 registered 17 November 2017; EudraCT 2017-001056-55.© 2022. The Author(s).

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