Loracarbef (LY163892) in the Treatment of Acute Exacerbations of Chronic Bronchitis: Results of U.S. and European Comparative Clinical Trials MICHAEL L.
ZECKEL, M.D., Indianapolis, Indiana
Two controlled clinical trials compared loracarbef (LY163892 with amoxicillin/clavulanate or amoxicillin in the treatment of acute exacerbations of chronic bronchitis. Collectively, of 1,057 patients enrolled, 390 qualified for analysis: group 1 comprised 200 patients treated with loracarbef (400 mg twice daily); group 2, 120 patients treated with amoxicillin/ clavulanate (500 mg three times daily); and group 3, 70 patients treated with amoxicillin (500 mg three times daily). Symptomatic and bacteriologic outcomes were assessed at posttherapy (within 72 hours of therapy completion), and at late-posttherapy (10-14 days after therapy completion). These evaluations were combined to provide an "overall" evaluation that accounted for all unfavorable outcomes occurring at either the posttherapy or lateposttherapy visit. At the posttherapy evaluation, 93.0% of group 1 patients, 95.0% of group 2 patients, and 88.6% of group 3 patients demonstrated favorable clinical outcomes (cure or improvement). "Overall" favorable clinical outcomes were achieved in 88.0% of group 1 patients, 90.0% of group 2 patients, and 81.4% of group 3 patients. Bacteriologic results from the two studies could not be merged due to marked differences in how posttherapy bacteriologic results were assessed. The clinical significance of positive posttherapy sputum cultures was doubtful: 90% of patients with a positive sputum culture at the posttherapy visit who returned for the late-posttherapy visit had successful clinical outcomes documented at the late-posttherapy evaluation. Loracarbef was associated with a lower incidence of diarrhea and a higher incidence of headache as compared with amoxicillin/clavulanate. These re-
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Requests for reprints should be addressed to Michael L. Zeckel, M.D., Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, 307 East McCarty, Indianapolis, Indiana 46285.
6A-58S
suits suggest that 400 mg loracarbef twice daily for 7 days is effective and safe in the treatment of acute exacerbations of chronic bronchitis.
hronic bronchitis and asthma affect more than 14 million people in the United States. EpideC miologic studies suggest that many more people have symptoms of chronic bronchitis but do not seek medical care [1]. In the 1980 National Ambulatory Medical Care Survey, bronchitis (unspecified) was the seventh most common condition diagnosed by general and family physicians, accounting for 1.9% of all office visits [2]. It is estimated that in North America, acute bronchitis accounts for approximately 12 million physician visits a year and more than $300 million in health-care expenditures annually [2]. Acute exacerbations of chronic bronchitis may be induced by environmental factors (e.g., air pollution, industrial fumes, smoking) and infectious agents (both bacterial and viral). The most common bacterial isolates associated with acute exacerbations of chronic bronchitis include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella (BranhameUa) catarrhalis. The pathogenic role for these organisms is confounded by their frequent presence in sputum of chronic bronchitis patients, even in the absence of acute exacerbations [3]. Increasing sputum purulence may be associated with a quantitative increase in the number of S. pneumoniae bacteria in the sputum [4]; however, this association has not been reported for
H. influenzae. The selection of an antibiotic for the treatment of presumed bacterial exacerbation of chronic bronchitis should be predicated upon (a) activity against organisms associated with disease exacerbation; (b) clinical effectiveness; (c) low incidence of adverse events; (d) dosing convenience; and (e) cost effectiveness. Loracarbef (LY163892), a fl-lactam compound with a carbacephem nucleus with improved chemical stability, provides good in vitro activity against the broad spectrum of bacteria associated with ex-
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY/ ZECKEL
acerbations of chronic bronchitis [5-15]. Pharmacokinetic studies of 400 mg capsules (administered twice daily) have demonstrated an 80-90% absorption rate, mean peak concentrations of 15.3 tLg/mL, and a half-life of 1.1 hours (Data on file; Eli Lilly and Company, Indianapolis, Indiana), suggesting potential benefits with minimal residual effect on bowel flora [16]. This article reviews the results of two recent multicenter controlled clinical trials comparing the efficacy and safety of toracarbef (LY163892) with either amoxicillin/clavulanate or amoxicillin in the treatment of acute exacerbations of chronic bronchitis. Study 1 compared loracarbef (400 mg twice daily) and amoxicillin/clavulanate (500 mg three times daily) in 579 patients enrolled from 67 sites throughout the United States. S t u d y 2 compared loracarbef (400 mg twice daily) and amoxicillin (500 mg three times daily) in 478 patients enrolled from 58 sites throughout Europe.
PATIENTS AND METHODS Patients weighing ->37.5 kg were candidates for the studies if they had a clinical diagnosis of acute exacerbation of chronic bronchitis defined by (a) cough productive of purulent sputum; (b) rapid onset of signs and symptoms of
ZECKEL, M.D., Indianapolis, Indiana
Two controlled clinical trials compared loracarbef (LY163892 with amoxicillin/clavulanate or amoxicillin in the treatment of acute exacerbations of chronic bronchitis. Collectively, of 1,057 patients enrolled, 390 qualified for analysis: group 1 comprised 200 patients treated with loracarbef (400 mg twice daily); group 2, 120 patients treated with amoxicillin/ clavulanate (500 mg three times daily); and group 3, 70 patients treated with amoxicillin (500 mg three times daily). Symptomatic and bacteriologic outcomes were assessed at posttherapy (within 72 hours of therapy completion), and at late-posttherapy (10-14 days after therapy completion). These evaluations were combined to provide an "overall" evaluation that accounted for all unfavorable outcomes occurring at either the posttherapy or lateposttherapy visit. At the posttherapy evaluation, 93.0% of group 1 patients, 95.0% of group 2 patients, and 88.6% of group 3 patients demonstrated favorable clinical outcomes (cure or improvement). "Overall" favorable clinical outcomes were achieved in 88.0% of group 1 patients, 90.0% of group 2 patients, and 81.4% of group 3 patients. Bacteriologic results from the two studies could not be merged due to marked differences in how posttherapy bacteriologic results were assessed. The clinical significance of positive posttherapy sputum cultures was doubtful: 90% of patients with a positive sputum culture at the posttherapy visit who returned for the late-posttherapy visit had successful clinical outcomes documented at the late-posttherapy evaluation. Loracarbef was associated with a lower incidence of diarrhea and a higher incidence of headache as compared with amoxicillin/clavulanate. These re-
From Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Requests for reprints should be addressed to Michael L. Zeckel, M.D., Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, 307 East McCarty, Indianapolis, Indiana 46285.
6A-58S
suits suggest that 400 mg loracarbef twice daily for 7 days is effective and safe in the treatment of acute exacerbations of chronic bronchitis.
hronic bronchitis and asthma affect more than 14 million people in the United States. EpideC miologic studies suggest that many more people have symptoms of chronic bronchitis but do not seek medical care [1]. In the 1980 National Ambulatory Medical Care Survey, bronchitis (unspecified) was the seventh most common condition diagnosed by general and family physicians, accounting for 1.9% of all office visits [2]. It is estimated that in North America, acute bronchitis accounts for approximately 12 million physician visits a year and more than $300 million in health-care expenditures annually [2]. Acute exacerbations of chronic bronchitis may be induced by environmental factors (e.g., air pollution, industrial fumes, smoking) and infectious agents (both bacterial and viral). The most common bacterial isolates associated with acute exacerbations of chronic bronchitis include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella (BranhameUa) catarrhalis. The pathogenic role for these organisms is confounded by their frequent presence in sputum of chronic bronchitis patients, even in the absence of acute exacerbations [3]. Increasing sputum purulence may be associated with a quantitative increase in the number of S. pneumoniae bacteria in the sputum [4]; however, this association has not been reported for
H. influenzae. The selection of an antibiotic for the treatment of presumed bacterial exacerbation of chronic bronchitis should be predicated upon (a) activity against organisms associated with disease exacerbation; (b) clinical effectiveness; (c) low incidence of adverse events; (d) dosing convenience; and (e) cost effectiveness. Loracarbef (LY163892), a fl-lactam compound with a carbacephem nucleus with improved chemical stability, provides good in vitro activity against the broad spectrum of bacteria associated with ex-
June 22, 1992 The American Journal of Medicine Volume 92 (suppl 6A)
SYMPOSIUM ON ANTIMICROBIALTHERAPY/ ZECKEL
acerbations of chronic bronchitis [5-15]. Pharmacokinetic studies of 400 mg capsules (administered twice daily) have demonstrated an 80-90% absorption rate, mean peak concentrations of 15.3 tLg/mL, and a half-life of 1.1 hours (Data on file; Eli Lilly and Company, Indianapolis, Indiana), suggesting potential benefits with minimal residual effect on bowel flora [16]. This article reviews the results of two recent multicenter controlled clinical trials comparing the efficacy and safety of toracarbef (LY163892) with either amoxicillin/clavulanate or amoxicillin in the treatment of acute exacerbations of chronic bronchitis. Study 1 compared loracarbef (400 mg twice daily) and amoxicillin/clavulanate (500 mg three times daily) in 579 patients enrolled from 67 sites throughout the United States. S t u d y 2 compared loracarbef (400 mg twice daily) and amoxicillin (500 mg three times daily) in 478 patients enrolled from 58 sites throughout Europe.
PATIENTS AND METHODS Patients weighing ->37.5 kg were candidates for the studies if they had a clinical diagnosis of acute exacerbation of chronic bronchitis defined by (a) cough productive of purulent sputum; (b) rapid onset of signs and symptoms of
