Effect of intravenous clarithromycin in patients with sepsis, respiratory and multiple organ dysfunction syndrome: a randomized clinical trial

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.

Keywords: Cholesterol; Clarithromycin; Macrolides; Multiple organ dysfunction; Recurrence; Sepsis.

Conflict of interest statement

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.

© 2022. The Author(s).

Figures

Fig. 1

CONSORT Flow Diagram in INCLASS trial. SOFA, Sequential Organ Failure Assessment

Fig. 2

Twenty-eight-day survival among trial participants (A) 28-day survival analysis by Kaplan–Meier curves among patients with sepsis and multiple organ dysfunction syndrome, treated with clarithromycin or placebo. Hazard ratio is provided by Cox-regression analysis. (B) Risk of death within 28-days in pre-specified subgroups among patients treated with clarithromycin or placebo. P values for interactions between treatment arm and subgroup are provided by the Breslow–Day test. *Calculated using the Firth correction. ARDS, acute respiratory distress syndrome; CI, confidence intervals; ICU, intensive care unit; SOFA, Sequential Organ Failure Assessment