DIAGN MICROBIOL INFECT DIS 1992;15:123S-127S
123S
Roxithromycin versus Doxycycline in the Treatment of Acute Exacerbations of Chronic Bronchitis Andre De Vlieger, Michel Druart, and Marc Puttemans
The efficacy and safety of roxithromycin (300 mg once daily) and doxycycline (200 mg once daily) in the treatment of acute exacerbations of chronic bronchitis in general practice were compared in a multicenter, double-blind, double-dummy trial. The data wesented .~ereare the results of an interim analysis of 76 patients. A satisfactory clinical resFonse was obtained in 81% of patients treated with roxithromycin and 80% of those treated with doxycycline. Among patients receiving roxithro-
mycin, 12.2% volunteered adverse events, compared with 33% of those receiving doxycycline; the test treatments were considered possibly or probably responsible for the adverse events in 9.8% and 21.2% of cases, respectively. Though patient numbers are too small for statistically significant differences to be detected, we conclude that the results to date suggest that roxithromycin and doxycyline are equivalent in terms of ef~aTcy, but that roxithromycin is better tolerated.
INTRODUCTION
against a wide range of respiratory pathogens and for the high concentrations reached at the site of infection. Roxithromycin is a macrolide with a spectrum comparable to that of erythromycin, but improved pharmacokinetic characteristics, for example, greater gastrointestinal absorption and a longer half-life (Tremblay et al., 1985; Nilsen, 1987; Puri and Lassman, 1987), thus enabling it to be given on a once-daily basis (Nilsen, 1987; Puri and Lassman, 1987). Roxithromycin readily penetrates into bronchial secretions, reaching effective concentrations in sputum. It has been shown to be safe and effective in the treatment of lower respiratory tract infections (Bertrand et al., 1989; Grassi et al., 1989; Hubrechts et al., 1989; Marsac et al., 1989; Steiner et al., 1989). The present study was designed to evaluate oncedaily roxithromycin in the treatment of acute exacerbation of chronic bronchitis compared with doxycycline.
Chronic purulent bronchitis consists of excess tracheobronchial mucus production and the expectoration of persistently or recurrently purulent sputum. Some 20% of men may have chronic bronchitis, the most important single cause being smoking. Since bronchitis and emphysema usually occur as a mixed disease and emphysema is irreversible, prevention of prog:'ession and rapid cure of acute bacterial exacerbate.on is strongly indicated. Exacerbation is understood as a short history of increased cough and/or dyspnea (for no more than 3 days), increased production of mucopurulent sputum, and the general signs and symptoms of acute infection. Any increase in the purulence, viscosity, or volume of secretion signals the onset of an acute exacerbation, which should be treated promptly (Ingram, 1987), and preferably with antibiotics (Bates, 1982). MacTolides are a class of antibiotic frequently used in resp:ratory tract infections, both for their activity From Koekelaere(A.D.V), Lier (M.D.), and Roussel Beb gium (M.P.), Brussels, Belgium. Addition~Jlcopiesof this supplement are availablefrom Roussel UCLAF,DomaineTh~rapeutiqueAnfibioth6rapie,35 Boulevarddes Invalides, 75007Paris, France. Received IODecember 1991;revisedand accepted 16 December 1991. © 1992ElsevierSciencePublishingCo., Inc. 655 Avenueof the Americas, New York, NY 10010 0732-8893/92/$5.00
MATERIALS AND METHODS
Test Drugs The study drugs were roxithromycin tablets (300 mg) 300 mg once daily (Roussel UCLAF, Romainville, France) or matching placebo; and doxycycline tablets
124S
(I00 mg) 200 mg once daily (Pfizer, Brussels, Belgium) or matching placebo. Treatments were to be taken 30 rain before breakfast.
Study D ~ i ~ This was a mul~-enter, double-blind, double-dummy study in randomized parallel groups. Treatment duration was 7-14 days.
A. De Vlieger et al.
blood cell count, hemoglobin, hematocrit, sedimentation rate, white blood cell count with differential, platelets, urea, creatinine, SGOT, SGPT, gGT, alkaline phosphatase, and total bilirubin and fibrinogen. At visit 2, the clinician assessed the clinical response as "cure," "failure," or "not ascertained." Bacteriologic response was similarly classified. Evaluable Cases
Patients Subjects over 18 years of age with signs of acute exacerbation of chronic bronchitis for no more than 3 days before the start of treatment were enroned. The noninclusion criteria were pregnancy/breastfeeding, pneumonia, cystic fibrosis, asthma, known hypersensitivity to macrolides or tetracycline, known severe hepatic or renal insufficiency, concomitant methylprednisolone consumption of >8 mg daily, or treatment with a contraindicated drug within the previous 7 days or with another investigational drug within the previous 2 weeks.
Assessments Full clinical examination was perfl~rmed at the beginning (visit 1) and end of the study (visit 2), comprising height, weight, axlllary b(gly temperature, pulse rate, and blood pressure. The following respiratory signs and symptoms--dyspnea, purulent sputum production, and complaints of chest pain-were assessed as severe, moderate, mild, or absent. The history of chronic bronchitis was recorded, and the severity of the present infection assessed as severe, moderate, or mild. A chest radiograph was taken at visit 1. Examination also covered the cardiovascular, endocrine, gastrointestinal, genitourinary, hematopoietic, and nervous and skeletal systems. A medication history was taken, listing all medication taken within the 2 weeks preceding the study as well as during the study. A sputum specimen was obtained for bacteriology at the start and end of treatment. Organisms were identified by standard techniques and susceptibility to roxithromycin and doxycycline tested by the disk diffusion method. Isolates were described as susceptible or resistant. Treatment was discontinued in patients who did not improve during therapy (these patients were classified as treatment failures if they received a minimum of 4 days' treatment) or if severe adverse events occurred that were probably or possibly related to the test medication. Adverse events during the trial, including laboratory results, were recorded. The following laboratory parameters were measured: red
Results from both visits were required for evaluation of clinical efficacy, and treatment had to have been taken daily for a minimum of 4 days. Patients who received antibiotics other than the test drugs were nonevaluable. For the evaluation of bacteriologic efficacy, the following criteria had to be met: (a) bacteriologic results had to be available from visit 1, (lo) potential pethogens had to have been identified in this specimen. (c) the isolate had to be sensitive to both test antibiotics, and (d) bacteriologic results had to be available from visit 2, unless collection was impossible due to lack of sputum and clinical cure. The study protocol was approved by the Medical Ethics Committee of the Free University of Brussels (VUB). Patients gave informed consent. Statistics All statistical tests were carried ou~ two-tailed at the 5% level of significance. The statistical calculations were performed using the SPSS/PC + program, version 3.0, run on an IBM-compatible PC. The following were analyzed:
Group Comparability The validity of randomization procedure was tested by comparing the two treatment groups on the basis of the variables recorded at the start of the trial. The t-test and Mann-Whitney U tests were used for continuous variables, and the chi-squared or Fisher's exact test (for sman expected frequencies) for discrete variables. For 2 x 2 tables, the chi-squared test was used with Yates' correction.
Evaluation of Efficacy Discrete clinical and bacteriologic response variables were compared between groups using the chi-squared test or Fisher's exact test. Pre- and posttreatment differences in discrete variables were evaluated in each treatment group by calculating the number of patients whose scores improved, remained the same, and worsened, and compared between groups by using McNemar's test.
Evaluation of Safe~ The incidence of adverse events was compared between groups by using the chi-squared test or Fisher's exact test.
Roxithromycin versus Doxycycline in Bronchitis
125S
RESULTS
Patients At the start of the study, there were no significant differences between: the groups in sex, age, weight, height, ethnic gror, p, radiographic results, or risk factors, or in their ~espiratory disease characteristics (Table 1).
The reasons for exclusion from the efficacy analysis are summarized in Table 2. Patient recruitment to the study continued while the analysis was undertaken.
Treatment Duration Mean treatment duration (and range) was 11.4 (818) and 11.6 (7-16) days in the roxithromycin and doxycycline groups, respectively.
Eligibility At the end of March 1991, data from 76 patients were available and were subiected to an interim analysis. Only patients meeting all selection criteria were included in efficacy and safety analyses: 62 and 74 patients, respectively.
Roxithromycin Group Six patients were excluded, two from both analyses because no posttreatment data were available (in one patient the diagnosis was pneumonia, and one patient defaulted) and four from the analysis of efficacy (one received diuretics concurrently, one received cotrin~oxazole, infection in one had been present for 6 days before the start of treatment, and in one the diagnosis was pnet,~nonia).
Doxycyclin~ Group Eight patients were excluded from the analysis of efficacy. One received an ergot alkaloid, two stopped treatme~ y after 3 days because of adverse events, one was z,ot compliant, ~:.re was treated for 31 days and another for 25 days, and in the final two patients infection had been present for 4 and 5 days before treatment, respectively.
Clinical Results Clinical cure was achieved in 30 evaluable patients (81%) in the roxithromycin group and 20 patients (80%) in the doxycycline group (NS, chi-squared test). The pre- and posttreatment differences in respiratory signs and symptoms, classified on a 4-point scale (none, mild, moderate, or severe) are shown as percentages per group in Table 3, and on a 3point scale (improved, no change, or worse) as the number of patients concerned in Table 4. Comparison between the groups after pooling the "no change" and "worse" categories showed no significant differences. Within each group and for each of the five variables, however, the number of patients who improved was significantly different (and always greater) than the number who deteriorated (McNemar test, p 0.05 for ~11parameters.
A. De Vlieger et al.
126S
TABLE 4 Assessment of Treatment Effect on Respiratory Signs and Symptoms on a 3-Point Scale: Improved, No Change, or Worse
TABLE 2 Reasons for Exclusion from the Analysis of Efficacy and Safety (N umber of Patients) Reason for Exclusion
Roxithromycin Doxycycline Variable
Diagnosis of pneumonia Infection >3 days Contraindicated medication Treatment taken
123S
Roxithromycin versus Doxycycline in the Treatment of Acute Exacerbations of Chronic Bronchitis Andre De Vlieger, Michel Druart, and Marc Puttemans
The efficacy and safety of roxithromycin (300 mg once daily) and doxycycline (200 mg once daily) in the treatment of acute exacerbations of chronic bronchitis in general practice were compared in a multicenter, double-blind, double-dummy trial. The data wesented .~ereare the results of an interim analysis of 76 patients. A satisfactory clinical resFonse was obtained in 81% of patients treated with roxithromycin and 80% of those treated with doxycycline. Among patients receiving roxithro-
mycin, 12.2% volunteered adverse events, compared with 33% of those receiving doxycycline; the test treatments were considered possibly or probably responsible for the adverse events in 9.8% and 21.2% of cases, respectively. Though patient numbers are too small for statistically significant differences to be detected, we conclude that the results to date suggest that roxithromycin and doxycyline are equivalent in terms of ef~aTcy, but that roxithromycin is better tolerated.
INTRODUCTION
against a wide range of respiratory pathogens and for the high concentrations reached at the site of infection. Roxithromycin is a macrolide with a spectrum comparable to that of erythromycin, but improved pharmacokinetic characteristics, for example, greater gastrointestinal absorption and a longer half-life (Tremblay et al., 1985; Nilsen, 1987; Puri and Lassman, 1987), thus enabling it to be given on a once-daily basis (Nilsen, 1987; Puri and Lassman, 1987). Roxithromycin readily penetrates into bronchial secretions, reaching effective concentrations in sputum. It has been shown to be safe and effective in the treatment of lower respiratory tract infections (Bertrand et al., 1989; Grassi et al., 1989; Hubrechts et al., 1989; Marsac et al., 1989; Steiner et al., 1989). The present study was designed to evaluate oncedaily roxithromycin in the treatment of acute exacerbation of chronic bronchitis compared with doxycycline.
Chronic purulent bronchitis consists of excess tracheobronchial mucus production and the expectoration of persistently or recurrently purulent sputum. Some 20% of men may have chronic bronchitis, the most important single cause being smoking. Since bronchitis and emphysema usually occur as a mixed disease and emphysema is irreversible, prevention of prog:'ession and rapid cure of acute bacterial exacerbate.on is strongly indicated. Exacerbation is understood as a short history of increased cough and/or dyspnea (for no more than 3 days), increased production of mucopurulent sputum, and the general signs and symptoms of acute infection. Any increase in the purulence, viscosity, or volume of secretion signals the onset of an acute exacerbation, which should be treated promptly (Ingram, 1987), and preferably with antibiotics (Bates, 1982). MacTolides are a class of antibiotic frequently used in resp:ratory tract infections, both for their activity From Koekelaere(A.D.V), Lier (M.D.), and Roussel Beb gium (M.P.), Brussels, Belgium. Addition~Jlcopiesof this supplement are availablefrom Roussel UCLAF,DomaineTh~rapeutiqueAnfibioth6rapie,35 Boulevarddes Invalides, 75007Paris, France. Received IODecember 1991;revisedand accepted 16 December 1991. © 1992ElsevierSciencePublishingCo., Inc. 655 Avenueof the Americas, New York, NY 10010 0732-8893/92/$5.00
MATERIALS AND METHODS
Test Drugs The study drugs were roxithromycin tablets (300 mg) 300 mg once daily (Roussel UCLAF, Romainville, France) or matching placebo; and doxycycline tablets
124S
(I00 mg) 200 mg once daily (Pfizer, Brussels, Belgium) or matching placebo. Treatments were to be taken 30 rain before breakfast.
Study D ~ i ~ This was a mul~-enter, double-blind, double-dummy study in randomized parallel groups. Treatment duration was 7-14 days.
A. De Vlieger et al.
blood cell count, hemoglobin, hematocrit, sedimentation rate, white blood cell count with differential, platelets, urea, creatinine, SGOT, SGPT, gGT, alkaline phosphatase, and total bilirubin and fibrinogen. At visit 2, the clinician assessed the clinical response as "cure," "failure," or "not ascertained." Bacteriologic response was similarly classified. Evaluable Cases
Patients Subjects over 18 years of age with signs of acute exacerbation of chronic bronchitis for no more than 3 days before the start of treatment were enroned. The noninclusion criteria were pregnancy/breastfeeding, pneumonia, cystic fibrosis, asthma, known hypersensitivity to macrolides or tetracycline, known severe hepatic or renal insufficiency, concomitant methylprednisolone consumption of >8 mg daily, or treatment with a contraindicated drug within the previous 7 days or with another investigational drug within the previous 2 weeks.
Assessments Full clinical examination was perfl~rmed at the beginning (visit 1) and end of the study (visit 2), comprising height, weight, axlllary b(gly temperature, pulse rate, and blood pressure. The following respiratory signs and symptoms--dyspnea, purulent sputum production, and complaints of chest pain-were assessed as severe, moderate, mild, or absent. The history of chronic bronchitis was recorded, and the severity of the present infection assessed as severe, moderate, or mild. A chest radiograph was taken at visit 1. Examination also covered the cardiovascular, endocrine, gastrointestinal, genitourinary, hematopoietic, and nervous and skeletal systems. A medication history was taken, listing all medication taken within the 2 weeks preceding the study as well as during the study. A sputum specimen was obtained for bacteriology at the start and end of treatment. Organisms were identified by standard techniques and susceptibility to roxithromycin and doxycycline tested by the disk diffusion method. Isolates were described as susceptible or resistant. Treatment was discontinued in patients who did not improve during therapy (these patients were classified as treatment failures if they received a minimum of 4 days' treatment) or if severe adverse events occurred that were probably or possibly related to the test medication. Adverse events during the trial, including laboratory results, were recorded. The following laboratory parameters were measured: red
Results from both visits were required for evaluation of clinical efficacy, and treatment had to have been taken daily for a minimum of 4 days. Patients who received antibiotics other than the test drugs were nonevaluable. For the evaluation of bacteriologic efficacy, the following criteria had to be met: (a) bacteriologic results had to be available from visit 1, (lo) potential pethogens had to have been identified in this specimen. (c) the isolate had to be sensitive to both test antibiotics, and (d) bacteriologic results had to be available from visit 2, unless collection was impossible due to lack of sputum and clinical cure. The study protocol was approved by the Medical Ethics Committee of the Free University of Brussels (VUB). Patients gave informed consent. Statistics All statistical tests were carried ou~ two-tailed at the 5% level of significance. The statistical calculations were performed using the SPSS/PC + program, version 3.0, run on an IBM-compatible PC. The following were analyzed:
Group Comparability The validity of randomization procedure was tested by comparing the two treatment groups on the basis of the variables recorded at the start of the trial. The t-test and Mann-Whitney U tests were used for continuous variables, and the chi-squared or Fisher's exact test (for sman expected frequencies) for discrete variables. For 2 x 2 tables, the chi-squared test was used with Yates' correction.
Evaluation of Efficacy Discrete clinical and bacteriologic response variables were compared between groups using the chi-squared test or Fisher's exact test. Pre- and posttreatment differences in discrete variables were evaluated in each treatment group by calculating the number of patients whose scores improved, remained the same, and worsened, and compared between groups by using McNemar's test.
Evaluation of Safe~ The incidence of adverse events was compared between groups by using the chi-squared test or Fisher's exact test.
Roxithromycin versus Doxycycline in Bronchitis
125S
RESULTS
Patients At the start of the study, there were no significant differences between: the groups in sex, age, weight, height, ethnic gror, p, radiographic results, or risk factors, or in their ~espiratory disease characteristics (Table 1).
The reasons for exclusion from the efficacy analysis are summarized in Table 2. Patient recruitment to the study continued while the analysis was undertaken.
Treatment Duration Mean treatment duration (and range) was 11.4 (818) and 11.6 (7-16) days in the roxithromycin and doxycycline groups, respectively.
Eligibility At the end of March 1991, data from 76 patients were available and were subiected to an interim analysis. Only patients meeting all selection criteria were included in efficacy and safety analyses: 62 and 74 patients, respectively.
Roxithromycin Group Six patients were excluded, two from both analyses because no posttreatment data were available (in one patient the diagnosis was pneumonia, and one patient defaulted) and four from the analysis of efficacy (one received diuretics concurrently, one received cotrin~oxazole, infection in one had been present for 6 days before the start of treatment, and in one the diagnosis was pnet,~nonia).
Doxycyclin~ Group Eight patients were excluded from the analysis of efficacy. One received an ergot alkaloid, two stopped treatme~ y after 3 days because of adverse events, one was z,ot compliant, ~:.re was treated for 31 days and another for 25 days, and in the final two patients infection had been present for 4 and 5 days before treatment, respectively.
Clinical Results Clinical cure was achieved in 30 evaluable patients (81%) in the roxithromycin group and 20 patients (80%) in the doxycycline group (NS, chi-squared test). The pre- and posttreatment differences in respiratory signs and symptoms, classified on a 4-point scale (none, mild, moderate, or severe) are shown as percentages per group in Table 3, and on a 3point scale (improved, no change, or worse) as the number of patients concerned in Table 4. Comparison between the groups after pooling the "no change" and "worse" categories showed no significant differences. Within each group and for each of the five variables, however, the number of patients who improved was significantly different (and always greater) than the number who deteriorated (McNemar test, p 0.05 for ~11parameters.
A. De Vlieger et al.
126S
TABLE 4 Assessment of Treatment Effect on Respiratory Signs and Symptoms on a 3-Point Scale: Improved, No Change, or Worse
TABLE 2 Reasons for Exclusion from the Analysis of Efficacy and Safety (N umber of Patients) Reason for Exclusion
Roxithromycin Doxycycline Variable
Diagnosis of pneumonia Infection >3 days Contraindicated medication Treatment taken
