© 2005 American Thoracic Society
Is Combination the Only Issue?From the Authors:We offer the following responses to the letters commenting on our article (1). All patients received antibiotic therapy on Day 1, although we do not have data on the precise timing of antibiotic administration. A huge sample size would be required to demonstrate that timing would be a statistically significant factor. In fact, the study by Houck and coworkers was a retrospective chart review of over 18,000 patients (2). In patients with bacteremic pneumococcal pneumonia, other bacteria isolated from sputum are likely to be colonizers. Although 78.7% of patients ultimately received mechanical ventilation, the overwhelming majority of ventilated patients (93%) had community-acquired infection. The issue of coinfection is unsettled. In two studies in which serologic conversion for Chlamydia pneumoniae and Mycoplasma pneumoniae was the basis for the diagnosis of coinfection, the mortality of pneumococcal pneumonia patients was not affected when these atypical pathogens were not treated with active antibiotics (3, 4). The mortality for all critically ill patients was 54.6%, and included nonevaluable patients (early deaths, inconsistent regimen, etc.). For the 94 evaluable patients, the mortality was 39.6%: 55.3% for combination and 23.4% for monotherapy (p = 0.0015). It should be noted that this study was prospective, not retrospective. The data supporting the superiority of combination is statistically significant by both univariate and multivariate analyses. Boussekey and colleagues accepted our recommendation for limiting the combination therapy to 3 d. Although supporting data was absent for this recommendation, we are also concerned about antibiotic overuse. Depuydt and coworkers commented that treatment guidelines were not consistently followed. This is incorrect. In many patients, combination therapy was appropriately administered on Day 1 as recommended in the guidelines; however, monotherapy was likewise instituted on Day 2 given the results of microbiologic testing. These patients were excluded since they did not fulfill our 2-d definition of either combination or monotherapy. We suggest an intuitively more simple explanation than that given by Depudyt and coworkers for the superiority of combination therapy for pneumococcal bacteremia. In particular, pneumococcal pneumonia responds readily to many antibiotics which have a wide range of potency. So, if a particular antibiotic regimen has any advantage, it might be manifest in only the sickest patients who otherwise would be expected to die. While it is desirable to know the mechanism of the survival advantage posed by the combination, many empiric observations of effective therapy that have passed the test of time were widely applied before the mechanism of action was fully understood (quinine for malaria, isoniazid for tuberculosis, and penicillins for pneumococci!). Depuydt and coworkers apparently overlooked our discussion in the RESULTS section concerning multivariate analyses. Combination therapy was consistently a significant factor in outcome in all logistic regression models even when controlling for chronic underlying disease or immunosuppression. Using the variables given by Depuydt and coworkers, severity of illness and immunosuppression were significant factors, as would be expected; however, combination antibiotic therapy was also significant. Community-acquired versus nosocomial and chronic underlying disease were not significant factors. Both Boussekey and colleagues Depuydt and colleagues restate our comment that a randomized control trial would be a more rigorous approach, although such a study has not yet been performed. Based on our large-scale study and several retrospective analyses, we conclude that combination antibiotic therapy may benefit severely ill patients with pneumococcal bacteremia. Dr. Schwartz presents an insightful analysis and suggests that the pharmacodynamics of ceftriaxone monotherapy every 24 h may lead to poorer outcome. Although we did find that monotherapy with ceftriaxone was indeed inferior to monotherapy with other antibiotics, the fact that patients suspected of having meningitis tended to receive ceftriaxone proved to be a confounding factor. Thus, we were unable to clarify the issue raised by Dr. Schwartz with our data. Given the logic of his point, however, we do believe that the issue of more frequent dosing of ceftriaxone should be strongly considered by clinicians when treating life-threatening infections; further studies of this issue are clearly warranted.
VA Medical Center, Pittsburgh, Pennsylvania
Emory University, Atlanta, Georgia
VA Medical Center, Pittsburgh, Pennsylvania
National Institutes of Health, Bethesda, Maryland
Mayo Clinic, Rochester, Minnesota FOOTNOTES Conflict of Interest Statement: V.L.Y. declares that Roche is providing funding for a study of bacterial meningitis which is distinct from this study and that the submitted study was unfunded; K.P.K. has served as a consultant, member of Advisory Board, and/or lectured in symposia sponsored by Abbott Laboratories, Bayer Corporation, Bristol-Myers Squibb Company, GlaxoSmithKline Pharmaceuticals, Aventis, and Wyeth Ayerst Laboratories, and his research unit currently receives research funding from Roche, Bayer, Aventis and Oscient Pharmaceuticals, and he has served as an expert witness for GSK and GENESOFT. M.M.W. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. C.C.C. does not have a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. L.M.B. received $10,660 from Bristol-Myers Squibb for 2001 and $5,000 for 2002 for speaking at conferences and received $6,500 in 2001 and $7,000 in 2002 from Schering for speaking at conferences. REFERENCES
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