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Pittsburgh, PA
Dr. Milbrandt is Assistant Professor of Critical Care Medicine, University of Pittsburgh School of Medicine. Dr. Angus is Professor of Critical Care Medicine and Health Policy and Management, University of Pittsburgh School of Medicine.
Correspondence to: Eric B. Milbrandt, MD, MPH, 641 Scaife Hall, The CRISMA Laboratory, Department of Critical Care Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261; e-mail: milbeb{at}ccm.upmc.edu
Each year in the United States, there are as many as 5.6 million cases of community-acquired pneumonia (CAP), accounting for 600,000 to 1.1 million hospitalizations and $23 billion in health-care expenditures.1234 Among hospitalized patients, CAP mortality rates average from 11 to 14%,5 with each case costing between $5,000 and $7,500.12 Initial treatment is empiric, directed against commonly encountered pathogens, and guided by local susceptibility patterns. Current guidelines for patients hospitalized with CAP recommend either monotherapy with a fluoroquinolone, or combination therapy with a macrolide plus either a ß-lactam/ß-lactamase inhibitor or third-generation cephalosporin.234 While clinical outcomes appear to be equivalent for each strategy, concerns about emerging fluoroquinolone resistance have led the Centers for Disease Control and Prevention to recommend restricting the use of fluoroquinolones to specific CAP patient groups.6 Nevertheless, the perceived increase in costs associated with a combination of drugs might lead some to choose fluororquinolone monotherapy instead.
In this issue of CHEST (see page 3246), Samsa and colleagues7 present an article that essentially states that treating hospitalized CAP patients with combination therapy, although slightly more expensive from an antibiotic-related drug cost standpoint, is cost-saving overall as compared to fluoroquinolone monotherapy. As a clinician, you may ask yourself, why is this article about cost in CHEST, as opposed to a medical economics journal, and what are we meant to do about it? Ultimately, it is in CHEST because it offers an opportunity for clinicians to appraise not only the clinical benefits of a particular strategy, but the economic consequences as well. But why should clinicians learn about economic consequences of different antibiotic regimens when decisions about which antibiotics are available are typically made by hospital pharmacy and therapeutics committees? The reason is that the clinician, in the day-to-day care of patients, is the person who is best positioned to balance costs against clinical outcomes. If a study shows that a particular therapeutic regimen is less costly, yet produces equivalent or better outcomes without worrisome side effects,8 then it is the clinician’s responsibility to do something about it. In this instance, there is more than a day’s savings associated with combination therapy, which clearly drives the difference in cost. This leaves you to answer the question, "What’s in a day?" and, by extension, "Do I think I can get a day’s savings by applying the results of this study to my patients?" If you believe that you can, then you should go out and get that day. Because studies like this will continue to be published in clinical journals, it is essential for clinicians to read and understand them, working out if the study is not only internally valid but also externally valid and generalizeable to their situation, and whether the authors have addressed all other areas of concern.
Given this background, let us review the study by Samsa and colleagues.7 The authors compared estimated 30-day direct medical costs for a subgroup (n = 163) of patients in the CAP-IN trial, a randomized, open-label, industry-sponsored study that compared clinical outcomes for 212 hospitalized CAP patients treated with either IV levofloxacin followed by oral levofloxacin (the fluoroquinolone group) or IV azithromycin and ceftriaxone followed by oral azithromycin (the combination therapy group).9 Costs in each group were estimated using details about the hospitalization and information collected at a 30-day follow-up interview, including dosage of various drugs, hospital days and location, number of work days lost, home care, and postdischarge health-care resource utilization. Unit prices were assigned to each item to obtain estimated costs by category, which were then summed to estimate overall costs for each patient. Mean per-patient costs were then compared for the combination therapy (n = 81) and fluoroquinolone (n = 82) groups. The authors found that overall costs were significantly lower for the combination therapy group ($9,274 vs $11,755, p = 0.03), even though antibiotic-related drug costs, including preparation and administration, were slightly higher in the combination therapy group ($243 vs $189). Most of the difference in overall cost was attributed to a shorter mean hospital stay in the combination therapy group (7.0 days vs 8.8 days, p = 0.03).
The most striking finding in this economic study is the 1.8-day difference in hospital length of stay. Interestingly, the difference seen in the clinical outcomes study was smaller and not statistically significant (7.7 days vs 8.4 days, p = 0.46).10 Nevertheless, presuming the finding of reduced length of stay (approximately 1 day or so) is robust; the question is, why? The authors speculate the reduced length of stay may have been due to faster symptom resolution, pointing out that more patients in the combination therapy group were considered "cured" at 2 weeks and that macrolides may provide additional benefits due to their immune-modulating effects.10 It is important to keep in mind, however, that the study was not blinded, which could have affected the results. A certain amount of subjectivity exists in the decision to discharge patients, which was based on clinical judgment. Similarly, the timing of conversion from IV to oral medications, often the first step toward hospital discharge, may be somewhat subjective, although specific criteria were used to justify this decision. Physician perception and confidence in a particular regimen could have played a role in these length of stay and therefore cost-driving decisions. Teasing out these issues would require a blinded comparison.
Other limitations of this study deserve mention. The effectiveness of any antibiotic regimen depends heavily on local susceptibility patterns that are constantly changing. The prevalence of macrolide-resistant Streptococcus pneumoniae is increasing rapidly,11 and cephalosporin resistance is quite common in many areas. Were this study conducted in a setting with different susceptibility patterns, then perhaps the results would have been different. Preferential use of a particular antibiotic regimen over another will inevitably lead to greater resistance to the more frequently used regimen. While the short time horizon of this study did not permit addressing the costs associated with emergent resistance, it is possible that short-term length of stay and cost gains attributable to combination therapy might be offset by future resistance costs if the regimen were to become universally adopted.
Despite these limitations, the potential length of stay and cost savings are quite appealing. Yet, even if confirmed in a blinded randomized trial, length of stay reductions seen in select populations studied in clinical trials may not materialize in the more heterogeneous populations of clinical practice. Because increased antibiotic costs are certain yet length of stay reductions uncertain with the combination regimen, it will be important for clinicians to determine if the results apply to their patients by comparing the characteristics of the study population, organisms encountered, and susceptibility patterns with those of their own institutions. Otherwise, clinicians may be reluctant to speculate on the potential cost savings of combination therapy. This "bird in the hand vs two in the bush" philosophy is commonplace and not necessarily misplaced. However, if there really is a day to be saved, then it is worthwhile pushing for the combination therapy arm.
In summary, this is an interesting and provocative study, the findings of which should be confirmed in a blinded randomized controlled trial before being applied to routine patient care. We agree with the authors that the cost benefit, if any, attributable to combination therapy depends on its role in reducing length of stay and that cost is but one of many factors that should be considered by clinicians in decisions involving individual patients.
References
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