Is azithromycin the first-choice macrolide for treatment of community-acquired pneumonia?

Sir—The article by Sánchez et al. [1] in the 15 May 2003 issue of Clinical Infectious Diseases addressed an important issue: treatment choice for community-acquired pneumonia (CAP). The aim of this retrospective study was to compare outcomes, including mortality, for patients with CAP who were treated with either clarithromycin or azithromycin. However, there are a number of methodological problems with this study that may have biased the results, thus distorting the specified comparison. The main methodological problem involves the route of administration for the 2 study medications, clarithromycin and azithromycin. As indicated by Sánchez et al. [1], clarithromycin was administered either as an intravenous infusion or as an oral tablet. In contrast, azithromycin was available for administration only as an oral tablet. Although the Pneumonia Patient Outcomes Research Team (PORT) severity scores do not show significant differences between the 2 treatment groups (table 1 in [1]), it is possible that patients thought to have more severe CAP were treated with clarithromycin, because this would permit continuation of intravenous therapy (after the initial treatment with ceftriaxone for all patients). If physicians believed that patients had mild or moderate CAP, they may have been more likely to select azithromycin and discontinue intravenous therapy. Related to this, the duration of treatment for clarithromycin was specified as 10 days, whereas the duration of treatment for azithromycin was specified as 3 days. Among patients with equivalent CAP severity, the length of hospital stay reported for the azithromycin group may thus have been less than that for the clarithromycin group because of delays in switching from intravenous to oral therapy among patients who received clarithromycin, rather than because of morerapid symptom improvement due to azithromycin therapy. There are also a number of issues associated with the patient population included in this study. Patients with more severe CAP are likely to require intensive care unit (ICU) admission and may experience acute respiratory failure. Patients with acute respiratory failure requiring mechanical ventilation were excluded from this study; however, no information is provided on how many of these patients had been treated with azithromycin, compared with the number treated with clarithromycin. If the proportions of excluded patients in the 2 treatment arms were different, the patient populations included in the study would not represent equivalent groups; this could bias the overall mortality rate and length of stay. In addition, in the Results section, Sánchez et al. [1] indicate that, “[f]or hospitalized patients who no longer needed ICU admission, therapy with azithromycin plus a ceftriaxone remained a significant predictor of good outcome” (p. 1241). In the Discussion section, the authors also specify the “outcome of patients with CAP who do not require ICU admission” [1, p. 1243]. ICU admission is not listed as an exclusion criterion earlier in the article. Furthermore, no information is provided on the proportion of azithromycin versus clarithromycin patients requiring ICU admission, nor is there data on the outcomes for patients who did require ICU admission. Because the number of patients included in the multivariate analysis is not provided (table 3 in [1]), it is unclear how many patients were included in the study and whether the subgroups selected are representative of all patients with CAP treated with azithromycin or clarithromycin. Finally, there are a number of issues with regard to the study’s analysis that are problematic, particularly the selection of the reference group and the selection of variables in the multivariate analysis of mortality. Table 3 in their article [1] summarizes results of multivariate analysis of the impact of macrolide choice on the odds of having a length of stay 17 days. However, in controlling for CAP severity, the comparison group used in this analysis comprised patients with a PORT score 3. Because all patients with a PORT score of 1 or 2 were not hospitalized [2], including their length of stay (i.e., 0 days) in the analysis would bias the results if more of these patients with mild CAP were treated with azithromycin than with clarithromycin. The appropriate comparison group would be patients with a PORT score of 3, rather than those with a score of 3. In addition to controlling for CAP severity using PORT score, the multivariate analysis of mortality controlled for age (table 3 in [1]). Age, however, is a component of the PORT score. Because the azithromycin patient population was older than the clarithromycin population, including age twice in these regressions (as both an independent predictor variable and a component of the PORT score) may have biased the results. Furthermore, although age was included as an independent variable in the multivariate analysis of mortality, sex was not included in this analysis. In the multivariate analysis of length of stay, sex was included, whereas age is not. No explanation of the rationale