A phase III trial has demonstrated that the addition of oral clarithromycin to beta-lactam antibiotic treatment effectively improves the clinical response of individuals with community-acquired pneumonia (CAP) and systemic inflammatory response syndrome (SIRS). According to the study published in Lancet Respiratory Medicine, patients who received clarithromycin in addition to standard care had a significantly higher proportion of meeting the primary composite endpoint after 72 hours of treatment compared to those who only received beta-lactam antibiotics. The primary endpoint included criteria for respiratory symptom improvement and early dampening of the inflammatory burden. Specifically, 68% of patients randomized to clarithromycin and 38% of patients receiving beta-lactam antibiotics alone met the criteria (OR 3.40, 95% CI 2.06-5.63).
In addition to improving clinical response, the combination of clarithromycin and antibiotics also resulted in other benefits. The study showed a significant reduction in the risk of subsequent organ dysfunction, prevention of new sepsis development, and shortened hospital discharge time in the group receiving the combination therapy. These findings suggest that the inclusion of clarithromycin in the management of hospitalized CAP patients can help alleviate the inflammatory burden and achieve early clinical benefits.
The occurrence of serious treatment-emergent adverse events (TEAEs) within 90 days did not differ significantly between the two groups. Both the clarithromycin group and the beta-lactam antibiotics alone group had similar numbers of TEAEs (43% vs 53%). The study’s time-to-event curves indicate that most of the benefit from clarithromycin was observed in the first 8 days of treatment. The researchers caution, however, that despite its positive effects on immune function, clarithromycin should still be used with caution to avoid the emergence of resistance.
An interesting aspect of the study was the investigation into how clarithromycin modifies the immune response. Analysis of immune function showed that patients in the clarithromycin group produced more tumor necrosis factor-alpha and less interleukin-10 in response to lipopolysaccharide stimulation compared to the placebo group. Grant Waterer, MD, PhD, of the University of Western Australia and Royal Perth Hospital, remarked that if impairment in early downregulation of pro-inflammatory responses is beneficial, it could have fundamental implications for our understanding of the pathobiology of severe sepsis. The study’s findings suggest that primary sepsis was likely driving mortality rather than a reduction in secondary infections.
The ACCESS trial addressed the need for a well-conducted randomized trial on the combination of beta-lactam antibiotics and macrolides for CAP. Currently, both American and European guidelines recommend this combination therapy. The trial took place at multiple public hospitals in Greece from 2021 to 2023. The inclusion criteria involved adults requiring hospital admission who exhibited two or more CAP-related symptoms and two or more criteria for systemic inflammatory response syndrome. Patients with recent contact with healthcare facilities were ineligible for the trial. A total of 278 patients were enrolled and randomized to either standard care or standard care with oral clarithromycin added.
Individual components of the primary endpoint favored the clarithromycin group over the control group. The clarithromycin group showed greater decreases in respiratory symptom severity scores (72% vs 48%), a decrease of 30% or more in Sequential Organ Failure Assessment (SOFA) score (68% vs 41%), and favorable changes in procalcitonin kinetics (69% vs 54%). None of the TEAEs were found to be related to the study treatments. The most common adverse events observed were septic shock, anemia, and SARS-CoV-2 infection, with slightly higher frequencies in the placebo group.
While the results of the ACCESS trial provide evidence for the efficacy of adding clarithromycin to beta-lactam antibiotic treatment in CAP patients with SIRS, further investigation is still required to fully understand the role of macrolides in the management of CAP. The study’s limitations include a high inflammatory burden among the enrolled patients and a significant pathogen presence, which sets ACCESS apart from previous studies. Nonetheless, the trial’s findings support current guidelines and demonstrate the potential benefits of combination therapy in CAP patients.
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