Levofloxacin and Macrolides for Treatment of Legionnaires Disease: Multiple Comparisons Give Few Answers

Sir—Blázquez Garrido et al. [1] claim that treatment of legionnaires disease with levofloxacin is superior to treatment with macrolides, because levofloxacin is associated with fewer complications and shorter hospital stays for patients with severe disease. However, these conclusions are based on subgroup analyses from among at least 15 comparisons presented in table 1 of the article [1]. With 15 independent comparisons, the probability of finding at least 1 statistically significant result by chance alone (i.e., the type 1 error rate) increases from 5% (with a single primary end point) to 53% [2]. Blásquez Garrido et al. [1] do not specify a primary end point among the 5 different outcomes measured. P values should be adjusted when making multiple comparisons, and should not be considered statisP p . 05 tically significant [3]. In addition, the appropriate method for test comparison of treatment effects among subgroups is to compare the treatment difference between subgroups, called the “test for interaction,” rather than to compare the different effects of the test and control treatments within the individual subgroups [4]. Analysis of subgroups continues to be an important issue in the analysis and interpretation of trial results [5]. In observational studies, large sample sizes do not minimize potential confounders, such as unmeasured patient differences at baseline [6, 7]. Blásquez Garrido et al. [1] allude to this when they state that they do not find the differences in outcomes, which favor levofloxacin therapy alone compared with levofloxacin plus rifampin therapy, to be convincing, because the differences may be “a consequence of differences in the severity of illness.despite the fact that both groups had similar prognostic scores” [1, p. 804]. This same reasoning applies to the comparison of levofloxacin with macrolides as treatment for legionnaires disease: unmeasured differences are potential issues for all observational studies. It is unfortunate when clinicians conclude that randomized trials are unlikely to be performed. Outbreak situations provide an excellent opportunity to perform such trials. Blásquez Garrido et al. [1] began collecting information within 1 day after the start of the outbreak. For future outbreaks, it may be possible for investigators to randomize patients. Drafting informed consent forms and obtaining institutional review board approval should not be insurmountable hurdles in such a situation, because the drugs being studied are already licensed therapies. If the difference of 23.8% in favor of levofloxacin therapy in preventing complications of legionnaries disease were true, this difference could be detected in a randomized trial with 42 patients per arm with a 5% type 1 error rate and 80% power. The acceptance of preliminary results as conclusive can have profound implications for clinical practice. Although the study by Blásquez Garrido et al. [1] provides useful data, it would be unfortunate and misleading should authors of future reviews conclude that therapy with levofloxacin is superior to therapy with macrolides on the basis of these data alone. Blásquez Garrido et al. [1] mention supportive animal studies, which are useful in forming hypotheses but need confirmation from appropriately designed human trials. Investigators can best answer the question of what is optimal therapy by using appropriately designed randomized trials that include a primary end point and that control for type 1 error. Ensuring appropriate data analysis is an important consideration when evaluating the validity of conclusions from any study. We do not serve our patients well by allowing the challenges of performing and analyzing trials to be reasons for basing conclusions on less-than-optimal data.