Macrolide regimens for CAP may not offer survival benefit

Thomas File, MD

Macrolides are commonly recommended as part of combination empirical therapy for management of adults with community-acquired pneumonia (CAP). However, there remains debate as to the true benefit of macrolide-based regimens as empirical therapy for CAP. The meta-analysis by Asadi et al evaluated 23 randomized controlled trials (RCT) and observational studies, which included >130,000 patients, to examine the clinical impact of macrolide-based regimens in these patients. The primary endpoint assessed was 30-day mortality.

The authors reported a statistically significant 22% relative reduction in mortality associated with use of macrolide-based regimens compared with non-macrolide–based ones. However, there were high levels of heterogeneity in these studies and when the analysis was restricted to randomized controlled trials, this advantage disappeared.

If there is a true benefit associated with adding a macrolide to a beta-lactam agent for treatment, several potential mechanisms may explain this effect: antimicrobial synergism, differences in the kill rates of pathogens, antimicrobial tolerance, the effect of macrolides on cytokine production or adherence by pneumococci to respiratory epithelial cells, and the coexistence of atypical pathogens. Of these possibilities, the role of atypical pathogens and the immunomodulating effect of the macrolides are the most plausible. Asadi et al postulate the potential benefit of the macrolide to the immunomodulatory effect which has been well described mostly based on observational studies of bacteremic pneumococcal pneumonia.

Since the analysis restricted to RCTs showed no significant benefit of macrolides, the findings of Asadi et al further adds to a degree of controversy regarding the benefit of macrolide-based regimens; this may also apply to the debate as to whether or not empirical therapy of CAP should always include coverage for atypical pathogens. In this respect, Asadi et al acknowledge one limitation of the trials, which is that most did not provide detailed microbiological information regarding the etiology of CAP. I would like to add another limitation: mortality may not recognize a benefit of earlier resolution of illness, which may be a benefit of macrolide agents. Recent recommendations suggest that outcome assessment at an early time point (e.g. 3-5 days) may be better to identify differential effects of two treatments. [ Talbot et al. Clin Infect Dis. 2012 published online June 28, 2012). In a study presented at the most recent European Congress Clinical Microbiology and Infectious Diseases, we reported that patients with CAP caused by atypical pathogens showed a differential clinical benefit at day 4 when they received 1 day of treatment with a macrolide (no difference was seen at a later test-of-cure endpoint perhaps due to the self-limited course of many atypcial pneumonias). [File T. et al. Abstract #P721. 22^nd ECCMID March 31-April 3, 2012, London; this was reviewed in the May 2012 issue of Infectious Disease News, p32]

On the basis of their analysis, Asadi et al. concluded their findings “support current guideline recommendations for empiric treatment that covers both typical and atypical pathogens.” However, they also recognize the need to support an active-comparator clinical trial to determine the best treatment for this very common and significant infection. It will be helpful for future researchers to explore the significance of atypical pathogens by performing comprehensive microbiological studies and to further assess the immunomodulating effect of the macrolides with measurements of various proinflammatory markers during therapy.