TY - JOUR
T1 - Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome
T2 - a randomized clinical trial
AU - Karakike, Eleni
AU - Scicluna, Brendon P.
AU - Roumpoutsou, Maria
AU - Mitrou, Ioannis
AU - Karampela, Niki
AU - Karageorgos, Athanasios
AU - Psaroulis, Konstantinos
AU - Massa, Eleni
AU - Pitsoulis, Achillefs
AU - Chaloulis, Panagiotis
AU - Pappa, Evanthia
AU - Schrijver, Irene T.
AU - Frantzeskaki, Frantzeska
AU - Lada, Malvina
AU - Dauby, Nicolas
AU - de Bels, David
AU - Floros, Ioannis
AU - Anisoglou, Souzana
AU - Antoniadou, Eleni
AU - Patrani, Maria
AU - Vlachogianni, Glykeria
AU - Mouloudi, Eleni
AU - Antoniadou, Anastasia
AU - Grimaldi, David
AU - Roger, Thierry
AU - Wiersinga, W. Joost
AU - Tsangaris, Iraklis
AU - Giamarellos-Bourboulis, Evangelos J.
N1 - Funding Information: The study was supported by the Hellenic Institute for the Study of Sepsis and by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129—granted to the National and Kapodistrian University of Athens). The funders had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. Funding Information: E. Karakike is supported by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129- granted to the National and Kapodistrian University of Athens). I.T. Schrijver is supported by the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (grant number 676129- granted to Lausanne University Hospital) and received a scholarship from the Société Académique Vaudoise (Lausanne, Switzerland). N. Dauby is a post-doctorate clinical master specialist of the Belgian F.R.S-FNRS and reports personal fees from Roche and Boehringer Ingelheim, and non-financial support from Pfizer, Janssen and Merck Sharp & Dohme, all outside the submitted work. T. Roger is funded by the European Union Horizon 2020 Marie Skłodowska-Curie Action Innovative Training Network European Sepsis Academy (ESA-ITN, grant number 676129) and by the European Union Horizon 2020 grant ImmunoSep (847422). W. J. Wiersinga is supported by the Netherlands Organization for Scientific Research (VIDI grant 91716475) and the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” and received consulting fee paid to the host institution from MDS, GSK and Swedish Orphan Biovitrum AB. A. Antoniadou has received honoraria from Gilead, Pfizer, MSD, ViiV, BMS, Astellas and independent educational grants from Gilead, GSK and Biotest. D. Grimaldi received consultation fees from Transgene SA Illkirch-Graffenstaden (France). E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, GSK, InflaRx GmbH, ThermoFisher Brahms GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, AxisShield, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie Skłodowska-Curie International Training Network “the European Sepsis Academy” (granted to the National and Kapodistrian University of Athens); the Horizon 2020 European Grants ImmunoSep and RISC in COVID (granted to the Hellenic Institute for the Study of Sepsis); and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). The other authors do not report any conflict of interest. Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - Cholesterol
KW - Clarithromycin
KW - Macrolides
KW - Multiple organ dysfunction
KW - Recurrence
KW - Sepsis
UR - http://www.scopus.com/inward/record.url?scp=85132196505&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13054-022-04055-4
DO - https://doi.org/10.1186/s13054-022-04055-4
M3 - Article
C2 - 35717241
SN - 1364-8535
VL - 26
JO - Critical Care
JF - Critical Care
IS - 1
M1 - 183
ER -