The association between antibiotic use, increasing rates of resistance, and clinical treatment failure underlines the importance of optimizing antibiotic use in patients with communityacquired RTIs. Table 1 summarizes the key attributes to consider in selecting an antibiotic for empirical treatment; these include (1) the spectrum of activity, (2) the potential of the antibiotic to induce and select for resistance, (3) the tolerability and convenience of the regimen, and (4) the antibiotic’s impact on health outcomes.
Treatment Guidelines and Recommendations
Selecting the initial antibiotic therapy is generally considered central to achieving bacterial eradication and clinical success in patients with community-acquired RTIs. Treatment guidelines have been developed by a number of North American professional organizations aimed at promoting the use of appropriate antibiotic therapy1,4-6,37,38 while minimizing the development and spread of resistance.
Table 1 Ideal Characteristics of an Antibiotic Agent for the Treatment of Acute Community-Acquired Respiratory Tract Infections
|Antibacterial spectrum||Coverage against:|
|• Key common respiratory pathogens|
|• Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis|
|• Penicillin-resistant and macrolide-resistant strains of Streptococcus pneumoniae|
|• Atypical or intracellular pathogens|
|a Mycoplasma pneumoniae, Chlamydophila (Chlamydia) pneumoniae, Legionella pneumophila|
|Minimal impact on:|
|• Gram-negative nonrespiratory bacterial flora and pathogens|
|Tolerability and convenience||• Available as a short course of oral therapy|
|• Acceptable tolerability profile|
|Health outcome||• Favorable impact on additional utilization of health care resources|
|• Reduction in overall costs of care|
A number of guidelines recommend that patients be classified on the basis of the severity of disease and the presence or absence of risk factors for infection with drug-resistant bacteria prior to the selection of initial antibiotic therapy. Historically, guidelines have focused primarily on providing coverage against the key common respiratory tract pathogens: S. pneumoniae, H. influenzae, and M. catarrhalis. In the primary care setting, where causative pathogens are rarely identified before treatment, beta-lactams or macrolides are typically recommended as initial empirical therapy for AECB and ABS. Macrolides, unlike the beta-lactams, also cover atypical pathogens, including C. pneumoniae, M. pneumoniae, and L. pneumophila, and are therefore preferred for the empirical treatment of CAP.
More recently, the prevalence of in vitro resistance to beta-lactam and macrolide, in addition to concerns about the clinical and economic impact of treatment failure associated with such resistance, has led to the development of alternative oral antibiotics for community-acquired RTIs, including the fluoroquinolones and ketolides.
Second- and third-generation fluoroquinolones, such as levofloxacin (Ortho-McNeil), (Bristol-Myers Squibb), moxifloxacin (Avelox, Bayer), and gemi-floxacin mesylate (Factive, GeneSoft), provide coverage against all typical and atypical respiratory pathogens, and they display good tissue penetration, particularly in the respiratory tract. In clinical trials, these agents have been as effective as standard comparator antibiotics (including beta-lactams and macrolides) for patients with community-acquired RTIs.
However, because these agents also display in vitro activity against gram-negative bacteria, there is concern that their use may result in the development of resistance in important nonrespiratory bacterial flora and pathogens, a concept known as “collateral damage.” Indeed, reports have documented increased rates of fluoroquinolone resistance among gram-negative pathogens (including E. coli, Enterobacter spp., Pseudomonas spp., and Klebsiella spp.) linked to the increased prescription of these agents for a range of infections. Moreover, this is of increasing concern in the community-acquired RTI patient population, because it is clear that over the past several years, the use of both the macrolides and beta-lactams has declined in patients with CAP, whereas the use of fluoroquinolones continues to escalate. Given this potential for collateral damage, RTI treatment guidelines generally recommend that the fluoroquinolones be reserved for specific patient groups, including those who have not responded to treatment with other antibiotics and patients with severe disease or multiple risk factors for comorbidity.
Another option for outpatient treatment of community-acquired RTIs is the ketolide antibiotic telithromycin (Ketek, Aventis), which the U.S. Food and Drug Administration (FDA) approved in 2004 for clinical use in treating outpatients (18 years of age or older) with ABS, AECB, and CAP of mild-to-moderate severity.
Telithromycin provides a tailored spectrum of activity against key common and atypical pathogens. Unlike the fluoro-quinolones and beta-lactams, however, it displays minimal activity against gram-negative nonrespiratory pathogens and commensal bacteria. Furthermore, in vitro data indicate that this agent has a low potential to select for resistance among respiratory pathogens. These in vitro characteristics, combined with its high penetration into bronchopulmonary sites of infection and an efficacy profile equivalent to that of standard comparator agents (including macrolides, beta-lactams, and fluoroquinolones) in patients with community-acquired RTIs, suggest that telithromycin will become a useful therapeutic option. One study of patients with CAP found that telithromycin achieved significantly superior rates of clinical cure than rates achieved with other usual-care antibiotics (including beta-lactams, macrolides, and fluoroquinolones). canadian antibiotics
Tolerability and Convenience
Patients’ nonadherence to antibiotic regimens, resulting in subtherapeutic drug concentrations in target tissues, leads to an increased risk of treatment failure and may increase selection pressure for the development of antibiotic resistance among respiratory pathogens. Adherence to therapy is influenced by several factors, including drug tolerability and the convenience of the dosing regimen.
Differing tolerability profiles, both between and within antibiotic classes, may affect adherence to therapy, and clinicians should therefore consider this fact when selecting empirical antibiotic therapy. Compliance seems to be greatest with convenient, once-daily regimens of short duration. As a result, most of the newer-generation oral antibiotics introduced for the treatment of community-acquired RTIs have short, once-daily or twice-daily dosing regimens. For example, azithromycin and telithromycin offer once-daily dosing, but amoxicillin canadian and amoxicillin-clavulanate (Generic Augmentin, GlaxoSmithKline) must be administered twice and three times daily, respectively.
Until recently, most clinical studies focused primarily on the clinical and bacteriological efficacy of antibiotics in the treatment of RTIs; they were not designed to capture specific differences in outcomes between agents (e.g., speed of recovery or time to symptom resolution, utilization of health care resources, and quality-of-life measures). However, studies of the newer classes of antibiotic agents, including the fluoro-quinolones and the ketolides, have begun to address these issues, particularly in patients with infections of the lower respiratory tract (CAP and AECB).
Acute Exacerbations of Chronic Bronchitis
In a study of patients with AECB, Wilson and colleagues showed that significantly fewer patients receiving the fluoro-quinolone moxifloxacin (9.5%) required additional antibiotic treatment, compared with patients who received clarithromycin (15.1%). In addition, the time to the next exacerbation was longer with (median, 131 days) than with clarithromycin (median, 103.5 days).
Similar results were also noted in a study comparing gemi-floxacin and clarithromycin for AECB. Significantly more patients who had received gemifloxacin remained recurrence-free 26 weeks after treatment (71%) than those who were treated with clarithromycin (58.5%).
A trial designed to compare the efficacy and tolerability of telithromycin and clarithromycin in patients with AECB has also documented patients’ utilization of health care resources, including the following:
It is estimated that these differences in health care resource utilization contributed to a direct cost savings of approximately $146 per patient.
In another study, telithromycin therapy resulted in fewer hospitalizations and days spent in hospital than treatment with amoxicillin-clavulanate (when the dose was 500/125 mg three times daily for 10 days).
As in AECB, relatively few studies investigating the efficacy of oral antibiotic therapies for patients with mild-to-moderate CAP treated on an outpatient basis have included measures of health care resource utilization.
Among the fluoroquinolones, outcome differences between moxifloxacin and a standard oral therapy selected by the investigator (clarithromycin, either alone or in combination) were assessed as part of a study conducted by Torres et al. Analyses of data, including the use of additional antibiotics, hospitalizations, work status, and quality of life, indicated no significant differences between the two treatment arms. In contrast, an economic evaluation based on the use of resources concluded that canadian levofloxacin was less costly than cefuroxime axetil (GlaxoSmithKline) for outpatients with CAP; was associated with a total cost savings of $169 per patient.
CAP-associated data on health care resource utilization were collected in two studies involving patients receiving telithromycin or clarithromycin. Given that hospitalization is recognized as the major cost component in the treatment of patients with CAP, data from these two studies were pooled to allow further analysis of differences in hospital-associated costs between the treatment groups. Although the two treatments showed equivalent clinical efficacy, telithromycin (for five, seven, or 10 days) was associated with significantly fewer CAP-related hospitalizations (1.2 vs. 3.6 per 100 patients, respectively) and CAP-related days spent in hospital (8.8 vs. 33.8 days per 100 patients, respectively), resulting in an estimated cost savings of $302 per patient.
In summary, these investigations suggest that some of the newer antibiotic treatment options, including the fluoro-quinolones and telithromycin, may offer significant health care and economic benefits in patients with community-acquired RTIs.
Although antibiotic resistance represents a major challenge in the management of community-acquired RTIs and affects both clinical and economic outcomes, the appropriate use of antibiotics is considered essential to addressing this problem. Health care providers are now advised to consider several factors when they prescribe oral antibiotic therapy, including:
These considerations, which are aimed at minimizing both the risk of treatment failure and the development of future resistance, may also reduce patients’ utilization of health care resources and costs associated with the treatment of community-acquired RTIs.