Clarithromycin for Early Anti-Inflammatory Responses in Community-Acquired Pneumonia: The ACCESS Randomized Trial

Background: Although published guidelines favour the addition of macrolides to β-lactams for the treatment of hospitalized patients with community-acquired pneumonia (CAP), that opinion is based on observational studies and meta-analyses indicating survival benefit rather than results of prospective randomized clinical trials (RCT). We investigated if addition of clarithromycin to β-lactams could improve early clinical response, the new regulatory endpoint for CAP, and explored the possible contribution of modulation of the inflammatory host response to that outcome.Methods: The ACCESS trial, a prospective, double-blind RCT, recruited hospitalized adults with CAP who had systemic inflammatory response syndrome, SOFA (sequential organ failure assessment) score 2 or more and procalcitonin (PCT) 0∙25 ng/ml or more. Patients were 1:1 randomised to standard of care medication plus either oral placebo or oral clarithromycin 500mg twice daily for seven days. The primary endpoint required meeting two conditions during the first 72 hours; ≥50% decrease of the respiratory symptom score and ≥30% decrease of SOFA score and/or favorable PCT kinetics (defined as 80% decrease from baseline or PCT <0∙25 ng/ml). This was analyzed in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044).Findings: Patients were enrolled between 25 January 2021 and 11 April 2023; 133 patients in the placebo arm and 134 patients in the clarithromycin arm were the ITT population. The primary endpoint was met in 38∙3% (95% confidence interval 30∙5-46∙8%) of placebo-treated and in 67∙9% (59∙6-75∙2%) of clarithromycin-treated patients (p<0∙0001). Main secondary endpoints showed superiority of clarithromycin treatment towards favorable PCT kinetics at the end-of-treatment (EOT) (77∙6% [69∙8-83∙8%] vs 66∙2% [57∙8-73∙7%]), decrease of SOFA score at EOT (62∙7% [54∙3-70∙4%] vs 49∙6% [41∙3-58∙0%]), clinical success at the test-of-cure (68∙7% [60∙4-75∙9%] vs 53∙4% [44∙9-61∙6%]), lower incidence of organ dysfunction (6∙0% [3∙1-11∙3%] vs 17∙3% [11∙8-24∙6%]) or development of new sepsis (14∙4% [8∙7-20∙2%] vs 24∙1% [17∙6-31∙9%]) and greater likelihood of alive discharge by Day 28 (78∙4% [70∙7-84∙5%] vs 65∙4% [57∙0-72∙9%]). After 72 hours the production of tumour necrosis factor-alpha from circulating mononuclear cells was increased and circulating interleukin-10 was decreased.Interpretation: Adding clarithromycin enhances early clinical responses and attenuates the inflammatory burden of CAP. The mode of action is linked to the reversal of the immune dysregulation caused by CAP.Trial Registration: This trial is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044).Funding: This study was sponsored by the Hellenic Institute for the Study of Sepsis and funded by Abbott Products Operation AG.Declaration of Interest: E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and Xbiotech Inc; independent educational grants from Abbott CH, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Sobi and Xbiotech Inc.; and funding from the Horizon 2020 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 RISCinCOVID and the Horizon Health grant EPIC-CROWN-2 (granted to the Hellenic Institute for the Study of Sepsis). G. Poulakou has received honoraria and/or consulting fees by Astra-Zeneca, Gilead, GSK, Menarini, MSD, Norma, Pfizer and SOBI and research grants by the University of Minnesota/University College London, the Hellenic Institute for the Study of Sepsis, Bausch, Roche, Xenothera, FabNTech and Pfizer. I. Papanikolaou has received honoraria or served as PI for studies from Boehringer- ingelheim, GlaxoSmithKline and AstraZeneca. H. Milionis reports receiving honoraria, consulting fees and non-financial support from healthcare companies, including Amgen, Angelini, Bayer, Mylan, MSD, Pfizer, and Servier. G. Dalekos is an advisor or lecturer for Pfizer, Roche, Sanofi and Sobi, and received research grants from Gilead and has served as PI in studies for Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc., Sobi and Intercept Pharmaceuticals. K.Akinosoglou reports receiving honoraria & consulting fees from healthcare companies, including Angelini, MSD, Pfizer, Swedish Orphan Biotrivum AB, 3M hellas, GSK/ViiV and Gilead. The other authors do not declare any conflict of interest.Ethical Approval: The protocol was licensed by the National Ethics Committee of Greece (approval 122/20) and the National Organization for Medicines of Greece (approval IS113/20). Written informed consent was provided by the patients or their legal representative.