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The Management of Respiratory Tract Infections: A Focus on Appropriate Antibiotic Utilization
David P. Nicolau, PharmD, FCCP
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Clinical and Economic Outcomes in the Treatment of Lower Respiratory Tract Infections
Diana I. Brixner, RPh, PhD
The Evolution of Antimicrobial Agents Used for the Management of CARTIs: A Focus on a New Class of Antimicrobials"the Ketolides
John A. Sbarbaro, MD, MPH, FCCP
Treatment with Appropriate Antibiotic Therapy in Community-acquired Respiratory Tract Infections
David P. Nicolau, PharmD, FCCP

Clinical and Economic Outcomes in the Treatment of Lower Respiratory Tract Infections

Diana I. Brixner, RPh, PhD

The cost of healthcare in the United States continues to steadily increase, approaching a 10% annual increase in 2002.1 Despite representing only 10.5% of healthcare expenditures, many health plans have developed and implemented methods that seek to curtail spending on prescription drugs. Such methods include partnering with drug manufacturers for rebates and disease management programs,2 encouraging the use of generic medications,3 and cost shifting to patients by way of multitiered copayments and coinsurance.4 More than ever before, health plans are asking manufacturers to demonstrate the value of pharmaceuticals, as evidenced by the request for pharmacoeconomic analyses and economic modeling in the Academy of Managed Care Pharmacy's Format for Formulary Submissions.5

The true economic cost of pharmaceuticals includes more than the medication acquisition cost. In addition to the acquisition and preparation costs, health plans must factor in costs of medical care, adverse events, clinical monitoring, and treatment failures, all of which can be reduced by informed medical care and appropriate first-line drug selection. Selecting a medication with documented ability to improve the clinical course of a disease may significantly reduce overall healthcare costs. Health economic analyses and models can help health plans gauge the true cost of a product and estimate the impact of a formulary change.

The purpose of this article is to discuss the economic impact of community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB); to review outcomes studies examining current empiric treatment of these infections; to review current economic research on telithromycin, the first agent in the new ketolide class of antibiotics; and to determine the potential economic impact of the addition of this product to formulary.

Disease Burden and Economic Landscape

Community-acquired Pneumonia. CAP places an enormous clinical and financial burden on the healthcare system. In the United States, there are an estimated 5 million cases of CAP annually, accounting for more than 10 million physician visits, 10% of which require hospitalization.6,7 CAP is associated with significant mortality rates, and ranks high among the leading causes of death in the developed world. In the United States, CAP is the sixth leading cause of death (3.5% of all deaths) and the most frequent infectious cause of death among patients of all ages (46% of all infectious deaths).7,8

The sheer magnitude of CAP, with its associated morbidity and mortality rates, places a heavy economic burden on the healthcare system. A study examining the total overall costs of CAP (including indirect costs) determined that CAP generated $23 billion worth of costs in 1994. This figure includes direct costs of $14 billion and $9 billion in lost productivity.9,10

In a separate study by Colice and colleagues,11 patient-specific CAP costs were determined from the administrative claims database of a national employer from the years 1996 to 1998. Limited to the employed population and their dependents (<65 years of age), claims data for 100 000 patients were examined to determine treatment costs for managing both inpatient and outpatient cases of CAP. A total of 7249 episodes of CAP were identified; the hospitalization rate was 19.6%. Among hospitalized patients, the mortality rate was 9.1%. The mean (± standard deviation) treatment cost for an inpatient episode of CAP (including all inpatient and outpatient medical care) was $10 227 ± $15 342. The per-episode costs for inpatients that died during hospitalization were higher than for patients who were discharged from the hospital alive ($15 822 ± $26 541 vs $9595 ± $13 641). For outpatient treatment of CAP, the mean per-episode cost was $466 ± $1038.11

The results of the analysis by Colice and colleagues11 clearly demonstrate the high costs associated with inpatient treatment of CAP. Targeted, cost-effective treatments for CAP at the onset of disease can have a significant impact on the subsequent clinical and economic consequences. Therefore, continued efforts are being made to manage CAP patients more efficiently and effectively in the outpatient setting.7

Acute Exacerbations of Chronic Bronchitis. Over 11 million noninstitutionalized adult Americans were diagnosed with chronic bronchitis in 2001, approximately 5% of the population.12 Patients with chronic bronchitis typically experience 2 acute exacerbations per year, at which time antibiotic therapy is usually instituted.13 It is estimated the total treatment costs for patients with AECB is more than $1.6 billion, with $1.2 billion of these costs generated by patients ≥65 years old.14 Further, the majority of the treatment costs (93.7%) for AECB were because of hospital costs.14

An observational study conducted in Spain in 1996-1997 attempted to determine the total direct costs derived from the management of exacerbations of chronic bronchitis and chronic obstructive pulmonary disease (COPD) by primary care providers in an ambulatory setting. For 1 month, 2414 patients with exacerbated chronic bronchitis and COPD were followed. A total of 507 patients (21%) experienced a relapse; of these, 161 patients (31.7%) required attention in the emergency room and 84 patients (16.5%) required hospital admission. The total direct mean cost of all exacerbations was $159; hospitalized patients generated 58% of the total cost. The cost per treating patients who did not relapse was $58.70 compared with $477.50 in patients with initial treatment failure.15 This study demonstrates that the effective management of patients with AECB in the outpatient setting is likely to result in significant cost savings.

Hospitalization and Elderly Patients. Hospitalization as a complication of CAP and AECB continues to rise, and the elderly are the most vulnerable. Although the incidence of CAP requiring hospitalization is 258 per 100 000 people of all ages, it increases to 962 per 100 000 people aged ≥65 years.16 In 1997, Medicare patients hospitalized with CAP accounted for 6.2% of admissions (623 718), 6.3% of costs ($4.4 billion), 7% of hospital days (4.8 million), 7.4% of intensive care unit (ICU) days (633 232), and 12.3% of hospital deaths (66 044).17 In this group, 1 of 5 cases had a complex course of illness (admitted to the ICU or required mechanical ventilation), and nearly half of the hospital costs attributable to hospitalized CAP ($2.1 billion) were incurred by patients with these complex courses. For hospitalized CAP patients aged ≥65 years, the mean hospital length of stay (LOS) and costs per hospital admission were 7.6 days and $6949, respectively. The mean LOS and hospital costs increased for patients admitted to the ICU (22% of patients; LOS, 11.3 days; costs, $14 294) and those placed on mechanical ventilation (7.4% of patients; LOS, 15.7 days; costs, $23 961).17 These findings reinforce the notion that CAP is a major clinical and economic problem in the United States, particularly for the elderly, and the problem will continue to grow as the aging population rises.

Clinical and Economic Value of Current Treatments for Lower Respiratory Tract Infections

There are many advantages to determining a specific etiologic pathogen in patients with lower respiratory tract infections (LRTIs). However, this is not typically done in the outpatient setting, with the specific pathogen not identified in one third to one half of cases.18 Choosing an antimicrobial agent that is the most cost effective, safe, and specific to probable agents is encouraged. Current recommendations from the Infectious Diseases Society of America (IDSA) for empiric antibiotic selection in CAP are based on severity of illness, pathogen probabilities, resistance patterns of Streptococcus pneumoniae (the most commonly implicated pathogen in CAP), and comorbid conditions.19 Current outpatient CAP recommendations from the IDSA call for the administration of a macrolide, doxycycline, or fluoroquinolone with enhanced activity against S pneumoniae.20 For patients who are hospitalized, current IDSA and Canadian Infectious Diseases Society recommendations call for the administration of a fluoroquinolone alone or an extended-spectrum cephalosporin (cefotaxime or ceftriaxone) plus a macrolide.19,20 Economic analyses of randomized, clinical trials conducted utilizing the current treatments for LRTIs have demonstrated various results, sometimes supporting21 and at other times contradicting22 these recommendations.

Health and Economic Outcomes Trials for CAP. In a study by Brown and colleagues,21 investigators analyzed aggregate hospital claims data to assess the impact of initial antibiotic choice on 30-day mortality, total hospital costs, and hospital LOS for patients with CAP. In this study, 44 814 patients with CAP met the enrollment criteria and were divided into 5 monotherapy groups (ie, ceftriaxone, other cephalosporins, fluoroquinolones, macrolides, or penicillins) and 4 groups that received dual therapy (ie, one of the agents listed, except macrolides, plus a macrolide). It was determined that mortality was significantly decreased among all dual-therapy groups (range, 2.2%-2.9%) when compared with monotherapy groups (range, 4.9%-8.2%; all P <.05), and that patients receiving dual therapies generally experienced a shorter LOS compared with monotherapy. Among patients with dual therapy, ceftriaxone plus macrolide yielded the shortest LOS and least total hospital charges compared with monotherapy (P <.001). In addition, the use of fluoroquinolones or penicillins as monotherapy or as part of dual therapy with macrolides was associated with the highest total hospital charges and the longest LOSs. The study concluded that dual therapy, including macrolides as the second agent, provided statistically significant decreases in mortality from CAP, along with additional data supporting shorter LOSs and lower hospital charges.21 This study supports CAP guidelines for dual-therapy regimens.

In a study by Burgess and Lewis,22 a comparison was made between 213 hospitalized patients with CAP receiving a nonpseudomonal, third-generation cephalosporin with (n = 116) or without (n = 97) a macrolide. Macrolide use was primarily erythromycin (66%), whereas others received clarithromycin (19%), or oral azithromycin (15%). There were no statistical differences between patients who did and did not receive a macrolide in terms of comorbid illnesses, LOS (5.2 ± 2.8 vs 5.2 ± 3.4 days), length of intravenous (I.V.) antibiotic therapy (4.4 ± 2.5 vs 4.1 ± 2.3 days), or mortality (0.9% vs 3.1%; P = .333). The study authors concluded that the addition of a macrolide to a nonpseudomonal, third-generation cephalosporin as initial therapy for the treatment of hospitalized CAP patients may not be necessary and that the results of this trial did not support the use of dual therapy with a macrolide.

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