Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial
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,
Evangelos J. Giamarellos-Bourboulis
Affiliations
Eleni Karakike
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Brendon P. Scicluna
Division of Infectious Diseases, Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam
Maria Roumpoutsou
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Ioannis Mitrou
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Niki Karampela
Intensive Care Unit, Korgialeneio Benakeio General Hospital
Athanasios Karageorgos
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Konstantinos Psaroulis
Intensive Care Unit, Aghios Dimitrios General Hospital
Eleni Massa
Intensive Care Unit, Hippokration General Hospital
Achillefs Pitsoulis
Intensive Care Unit, G. Gennimatas General Hospital
Panagiotis Chaloulis
Intensive Care Unit, Theageneion General Hospital
Evanthia Pappa
Intensive Care Unit, Laiko General Hospital
Irene T. Schrijver
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne
Frantzeska Frantzeskaki
2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens
Malvina Lada
2nd Department of Internal Medicine, Sismanogleion General Hospital
Nicolas Dauby
Department of Infectious Diseases, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB)
David De Bels
Department of Intensive Care, Centre Hospitalier Universitaire Brugmann
Ioannis Floros
Intensive Care Unit, Laiko General Hospital
Souzana Anisoglou
Intensive Care Unit, Theageneion General Hospital
Eleni Antoniadou
Intensive Care Unit, G. Gennimatas General Hospital
Maria Patrani
Intensive Care Unit, Korgialeneio Benakeio General Hospital
Glykeria Vlachogianni
Intensive Care Unit, Aghios Dimitrios General Hospital
Eleni Mouloudi
Intensive Care Unit, Hippokration General Hospital
Anastasia Antoniadou
4th Department of Internal Medicine, National and Kapodistrian University of Athens
David Grimaldi
Department of Intensive Care, CUB-Erasme, Université Libre de Bruxelles (ULB)
Thierry Roger
Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne
W. Joost Wiersinga
Division of Infectious Diseases, Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam
Iraklis Tsangaris
2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens
Evangelos J. Giamarellos-Bourboulis
4th Department of Internal Medicine, National and Kapodistrian University of Athens
Abstract Background Clarithromycin 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. Methods We 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. Results Fifty-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. Conclusions Clarithromycin 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.
