Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Addition of macrolide antibiotics to ß-lactam antibiotics for the treatment of patients in hospital with community-acquired pneumonia is based on results from observational studies and meta-analyses rather than randomised clinical trials. We investigated if addition of the macrolide clarithromycin to treatment with a ß-lactam antibiotic in this population could improve early clinical response-the new regulatory endpoint for community-acquired pneumonia-and explored the possible contribution of modulation of the inflammatory host response to that outcome. METHODS: The ACCESS trial was a phase 3 prospective, double-blind, randomised controlled trial, in which adults in hospital with community-acquired pneumonia who had systemic inflammatory response syndrome, Sequential Organ Failure Assessment (SOFA) score of 2 or more, and procalcitonin 0·25 ng/mL or more were enrolled in 18 internal medicine departments of public Greek hospitals. Patients were randomly assigned (1:1) by computer-generated block randomisation to standard of care medication (including intravenous administration of a third-generation cephalosporin or intravenous administration of ß-lactam plus ß-lactamase inhibitor combination) plus either oral placebo or oral clarithromycin 500 mg twice daily for 7 days. Investigators, staff, and patients were masked to group allocation. The primary composite endpoint required that patients fulfilled both of the following conditions after 72 hours (ie, day 4 of treatment): (1) decrease in respiratory symptom severity score of 50% or more as an indicator of early clinical response and (2) decrease in SOFA score of at least 30% or favourable procalcitonin kinetics (defined as ≥80% decrease from baseline or procalcitonin <0·25 ng/mL), or both, as an indicator of early inflammatory response. Participants who were randomly assigned and received allocated treatment were included in the primary analysis population. This trial is complete and is registered with the EU Clinical Trials Register (2020-004452-15) and ClinicalTrials.gov (NCT04724044). FINDINGS: Patients were enrolled between Jan 25, 2021, and April 11, 2023, and 278 individuals were randomly allocated to receive standard of care in combination with either clarithromycin (n=139) or placebo (n=139). 134 patients in the clarithromycin group (five withdrew consent) and 133 patients in the placebo group (six withdrew consent) were included in the analysis of the primary endpoint. The primary endpoint was met in 91 (68%) patients in the clarithromycin group and 51 (38%) patients in the placebo group (difference 29·6% [95% CI 17·7-40·3]; odds ratio [OR] 3·40 [95% CI 2·06-5·63]; p<0·0001). Serious treatment-emergent adverse events (TEAEs) occurred in 58 (43%) patients in the clarithromycin group and 70 (53%) patients in the placebo group (difference 9·4% [95% CI -2·6 to 20·9]; OR 0·67 [95% CI 0·42 to 1·11]; p=0·14). None of the serious TEAEs was judged to be related to treatment assignment. INTERPRETATION: Addition of clarithromycin to standard of care enhances early clinical response and attenuates the inflammatory burden of community-acquired pneumonia. The mechanism of benefit is associated with changes in the immune response. These findings suggest the importance of adding clarithromycin to ß-lactams for treatment of patients in hospital with community-acquired pneumonia to achieve early clinical response and early decrease of the inflammatory burden. FUNDING: Hellenic Institute for the Study of Sepsis and Abbott Products Operations.

Calprotectin and Imbalances between Acute-Phase Mediators Are Associated with Critical Illness in COVID-19.

The trajectory from moderate and severe COVID-19 into acute respiratory distress syndrome (ARDS) necessitating mechanical ventilation (MV) is a field of active research. We determined serum levels within 24 h of presentation of 20 different sets of mediators (calprotectin, pro- and anti-inflammatory cytokines, interferons) of patients with COVID-19 at different stages of severity (asymptomatic, moderate, severe and ARDS/MV). The primary endpoint was to define associations with critical illness, and the secondary endpoint was to identify the pathways associated with mortality. Results were validated in serial measurements of mediators among participants of the SAVE-MORE trial. Levels of the proinflammatory interleukin (IL)-8, IL-18, matrix metalloproteinase-9, platelet-derived growth factor (PDGF)-B and calprotectin (S100A8/A9) were significantly higher in patients with ARDS and MV. Levels of the anti-inflammatory IL-1ra and IL-33r were also increased; IL-38 was increased only in asymptomatic patients but significantly decreased in the more severe cases. Multivariate ordinal regression showed that pathways of IL-6, IL-33 and calprotectin were associated with significant probability for worse outcome. Calprotectin was serially increased from baseline among patients who progressed to ARDS and MV. Further research is needed to decipher the significance of these findings compared to other acute-phase reactants, such as C-reactive protein (CRP) or ferritin, for the prognosis and development of effective treatments.