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

SPS commentary:

In the trial patients were randomised to standard of care (including IV third-generation cephalosporin or IV β-lactam plus β-lactamase inhibitor) plus either placebo or oral clarithromycin 500 mg twice daily for 7 days. The primary composite endpoint required that patients fulfilled both of following conditions after 72 hours: decrease in respiratory symptom severity score of ≥50% as an indicator of early clinical response and decrease in Sequential Organ Failure Assessment (SOFA) score of ≥30% or favourable procalcitonin kinetics (≥80% decrease from baseline or procalcitonin <0.25 ng/mL), or both, as an indicator of early inflammatory response.

According to a commentary, the most recent American Thoracic Society and Infectious Diseases Society of America guidelines for community-acquired pneumonia (CAP) recommend combination antibiotic therapy with a macrolide for all in-patients with severe disease because of overwhelming data accumulated in past 20 years suggesting better outcomes than monotherapy. It notes however that the obligatory use of a macrolide has remained contested by some experts because of absence of high quality, prospective trials. It points out that questions remain over role of macrolides in CAP and threshold of severity for mandatory use is unclear and further studies are needed at lower thresholds, acknowledging that many patients with mild infection will have good outcomes regardless of therapy chosen. It discusses the procalcitonin threshold used in the trial which leaves the question open of whether the benefit of macrolides is only in bacterial disease. It adds that since macrolide therapy has been associated with improved longer term outcomes, studies with much longer follow-up are needed to determine the optimal treatment population. It concludes that for CAP with features of clinically significant sepsis, combination therapy with a β-lactam and a macrolide (not including erythromycin) should now be mandatory. It supports this with observation that:

• compared with most interventions, macrolides are not expensive
• patients in hospital with radiologically proven pneumonia contribute a trivial amount towards total community macrolide consumption
• benefits of macrolide combination therapy are now supported by a high-quality prospective trial