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Center For Drug Evaluation and Research, United States Food and Drug Administration, Rockville, MD
Correspondence to: John H. Powers, MD, HFD–104, 9201 Corporate Blvd, Rockville, MD 20850; e-mail: POWERSJOH{at}cder.fda.gov
To the Editor:
It is unclear whether the study by Brown et al (May 2003)1 either "confirms the value of dual therapy," or that previous investigations have "verified" the benefits of combination therapy in community-acquired pneumonia (CAP). While the accompanying editorial2 points out that many of the studies of combination therapy in CAP are retrospective, another issue complicating interpretation of these studies is their observational study design. Observational studies are, by their nature, not randomized. Clinicians’ decisions to administer combinations of antimicrobials are not random events, but based on factors relevant to the individual patient. Therefore, many factors other than antimicrobial therapy could have accounted for the results. Large numbers of patients do not mitigate the issues with lack of randomization, and increasing sample size does not strengthen the conclusions of the study. A trial3 on hormone replacement therapy (HRT) in women illustrates the issues with observational data. Numerous observational trials showed a benefit of HRT, but recent randomized placebo-controlled trials did not validate such benefits, and indeed, showed potential worse outcomes in women receiving HRT.
Administration of multiple antimicrobials for CAP also could result in potential worse outcomes in the form of increased drug-related adverse events. The study by Brown et al1 does not report on adverse events of combination compared to monotherapy. These data are necessary in order to balance the potential benefits with the potential for increased adverse events of combination therapy.
Several prospective trials4 5 have not shown a benefit of combination therapy in CAP. The use of combination therapy in these prospective trials has been discretionary, which results in the same biases due to lack of randomization. These results raise the question, however, of whether there is a true benefit of combination therapy in CAP. Observational, retrospective trials raise interesting hypotheses about the potential benefits of combination therapy in CAP, but do not provide us with definitive answers. We need randomized, prospective blinded trials comparing the safety and efficacy of monotherapy to combination therapy in CAP to answer these important questions. It is unclear whether the data at this time support recommendations of combination therapy for all patients with CAP.
Footnotes
The opinions expressed above represent those of the authors and not necessarily those of the United States Food and Drug Administration.
References
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