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.
| Specialty Area | Score |
|---|---|
| Hospital Doctor/Hospitalists | |
| Internal Medicine | |
| Respirology/Pulmonology | |
| Infectious Disease |
Much has been made of the anti-inflammatory effects of macrolides, but enthusiasm and physiologic thinking has generally been stronger than the evidence in pneumonia. This is an important trial as the first RCT to demonstrate a benefit that seems to isolate the mechanism to something about macrolides other than simply their bacterial spectrum coverage. Also, the trial uses new regulatory endpoints that makes it even more relevant for front-line providers.
It is difficult to believe that in 2024 we are looking at studies randomizing patients to drugs developed in 1990. This paper looks at the benefits of clarithromycin as adjunctive therapy for community-acquired pneumonia. The results were astonishing to the point of credulity. In the US, it is very common to use azithromycin as part of the empiric therapy for CAP. The authors acknowledge this, but they feel clarithromycin could be superior (based on other papers). The difference in a variety of indirect measures is plausible, but the mortality benefit does strain credulity. The authors note that some of the mortality endpoints are not "significant," but "end of treatment" mortality was lower in a post hoc analysis. This is not ideal. The population in this study has a mean age of 81, and the most common pathogen was S aureus, which represents an unusual cross-section of patients. These issues do not invalidate the study, but the clinical implications seem less robust than suggested.
This trial provides the first RCT evidence to support the current guideline recommendations for using clarithromycin for immune modulation in community-acquired pneumonia.
Azithromycin is standard now and a beta lactam clarithromycin is not as generally well tolerated by patients.
If this really is the first RCT for a practice that we commonly follow, then this is a very important trial as the clinically important components of the composite are quite different between groups.
This RCT showed that adding clarithromycin to empiric beta-lactam antibiotic therapy for patients hospitalized for community-acquired pneumonia with evidence of systemic inflammatory response and organ dysfunction led to faster improvement in respiratory symptoms and systemic inflammation. This supports existing guideline recommendations that have until now been based on observational data suggesting a survival benefit (not definitively confirmed in this trial). However, this is likely the first randomized trial to confirm that a strategy of adding a macrolide routinely to patients hospitalized with CAP, regardless of considerations regarding the likelihood of atypical organisms, confers meaningful benefit.
One wonders whether this is a class effect of broad-spectrum macrolides. If so, this is a reassuring study. In the USA, azithromycin is frequently given along with a beta-lactam in hospitalized CAP patients. Clarithromycin has been relegated to a secondary role, including for treating certain non-TB mycobacterial infections.
Very well done prospective study that essentially "certifies" the guidelines for adding a macrolide antibiotic when treating patients with community-acquired pneumonia that requires hospitalization.
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