Add-On Clarithromycin Pans Out in Community-Acquired Pneumonia Trial

In a phase III trial, the addition of oral clarithromycin to beta-lactam antibiotic treatment improved the clinical response of people with community-acquired pneumonia who had systemic inflammatory response syndrome, findings that support existing guidelines.

In the study, the proportion of patients meeting the primary composite endpoint after 72 hours of treatment — fulfilling criteria for both respiratory symptom improvement and an early dampening of the inflammatory burden — reached 68% of those randomized to clarithromycin atop standard care and 38% of those receiving beta-lactam antibiotics alone (OR 3.40, 95% CI 2.06-5.63), reported Evangelos Giamarellos-Bourboulis, MD, of the National and Kapodistrian University of Athens, Greece, and coauthors.

Additionally, the combination of antibiotics significantly reduced the risk for subsequent organ dysfunction, prevented development of new sepsis, and shortened the time to hospital discharge, according to the double-blind ACCESS trial published in Lancet Respiratory Medicine.

“Our results suggest that clarithromycin should be added to the management of hospitalized patients with community-acquired pneumonia to alleviate the inflammatory burden and to achieve early clinical benefit,” the group wrote.

Serious treatment-emergent adverse events (TEAEs) out to 90 days occurred in similar numbers between groups (43% vs 53%; OR 1.46, 95% CI 0.89-2.35).

Time-to-event curves suggested most of the benefit of the macrolide occurred in the first 8 days. The investigators added that they had indirect evidence of clarithromycin having a strong effect at the level of immune function — given that the clarithromycin group produced more tumour necrosis factor-α and less interleukin-10 in response to lipopolysaccharide stimulation than patients in the placebo group at day 4 — though cautioned that the antibiotic should still be used with caution to avoid emergence of resistance.

“Perhaps the most intriguing aspect of the study was the attempt to assess how clarithromycin modified immune response,” commented Grant Waterer, MD, PhD, of the University of Western Australia and Royal Perth Hospital.

“If impairment in early downregulation of pro-inflammatory responses is beneficial, this has fundamental implications for our understanding of the pathobiology of severe sepsis. Because most of the trend to benefit in mortality with clarithromycin was observed in the first 6-7 days, primary sepsis was probably driving mortality, not a reduction in secondary infections,” he wrote in an invited comment.

In any case, ACCESS filled the need for a good randomized trial on combining beta-lactam antibiotics and macrolides for community-acquired pneumonia, a practice that has already been recommended by American and European guidelines alike.

ACCESS was conducted at multiple public hospitals within Greece from 2021 to 2023.

Investigators sought adults requiring hospital admission who were experiencing two or more community-acquired pneumonia-related symptoms such as cough, dyspnoea, pleuritic chest pain, or purulent sputum expectoration. Participants were ineligible if they had any history of contact with the hospital environment or with healthcare facilities during the preceding 90 days.

Patients also needed to exhibit two or more criteria for systemic inflammatory response syndrome, have a total Sequential Organ Failure Assessment (SOFA) score of at least 2, and have a procalcitonin concentration of at least 0.25 ng/mL.

A total of 278 patients were enrolled in the trial and randomized to standard care with or without oral clarithromycin (500 mg tablets every 12 hours for a week). Over 60% of the patient population were men, and all of the patients were white.

Individual components of the primary endpoint all favored the clarithromycin group over controls:

• Decreases in respiratory symptom severity scores of at least 50% from baseline: 72% vs 48% (OR 2.83, 95% CI 1.70-4.70)
• Decrease of 30% or more in SOFA score: 68% vs 41% (OR 3.10, 95% CI 1.88-5.11)
• Favorable change in procalcitonin kinetics: 69% vs 54% (OR 1.86, 95% CI 1.12-3.06)

None of the TEAEs were found to be related to the study treatments. The most common events were septic shock, anemia, and SARS-CoV-2 infection, all of which were numerically more frequent among placebo patients.

As for the trial’s limitations, researchers noted that there was a heavy inflammatory burden among the patients enrolled and that the pathogen was ultimately found in 55% of the patient population, distinguishing ACCESS from other studies.

“Questions undoubtedly remain over the role of macrolides in community-acquired pneumonia,” Waterer wrote. “The threshold of severity for mandatory use is unclear and further studies are needed at lower thresholds, acknowledging that many patients with mild community-acquired pneumonia will have good outcomes regardless of the therapy chosen.”

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