Journal of Antimicrobial Chemotherapy (1991) 27, Suppl. A, 91-100
Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis Romeo T. Bachand Jr
This double-blind, randomized (1:1), 33 centre clinical trial compared the safety and efficacy of 250 mg clarithromycin (2xl25mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis. Clinical and bacteriological evaluations were performed during treatment (study days 3-5, 8-10) and within 48 h following the end of therapy. Two hundred and twenty-five patients were included in the safety analysis. Both clarithromycin and ampicillin were effective with clinical success rates of 97% (28/29) and 91% (31/34), respectively. Pathogen eradication rates were 86% (36/42) for clarithromycin and 88% (37/42) for ampicillin. No significant difference in the number of patients reporting one or more adverse events was observed between treatment groups. Eleven clarithromycin and six ampicillin patients prematurely discontinued the study owing to adverse events. Clarithromycin 12-hourly was as safe and effective as ampicillin 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis.
Introduction
Ampicillin has been a major therapeutic agent in the treatment of acute bacterial exacerbation of chronic bronchitis. However, the nature of respiratory pathogens is changing with increase in previously rare or unrecognized pathogens and the development of strains resistant to /Mactams (Brook, 1986; Da vies & Maessen, 1986; Hager et al., 1987; Lafong et al., 1988). Resistance to /Mactams has been shown in isolates of Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, and Staphylococcus aureus (Brook, 1986; Davies & Maessen, 1986; Malmborg, 1986; Fernandes, 1987; Hager et al., 1987; Lafong et al., 1988). Therefore, interest in macrolide antibiotics, which are not inactivated by /Mactamases, has been renewed (Malmborg, 1986; Fernandes, 1987). Efforts to improve upon the prototype macrolide, erythromycin, have resulted in a new generation of broad spectrum antibiotics. Clarithromycin, a new generation 14-membered lactone ring macrolide, has improved physical and chemical properties when compared with erythromycin (Mizushima & Hiratsuka, 1986; Sennello et al., 1986; Suwa et al., 1986; Fernandes, 1987). Unlike the metabolites of other macrolides, the 14-hydroxy metabolite of clarithromycin is microbiologically active and may act additively and synergistically with clarithromycin itself (Fernandes & Freiberg, 1986; Fernandes, 1987; Hardy et al., 1988). The combination of clarithromycin and 14-hydroxy clarithromycin is more active against H. influenzae than erythromycin, josamycin, miocamycin, roxithromycin, 91 0305-7453/91/27A091 + 10 $02.00/0
© 1991 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Abbott International Ltd Abbott Park, Illinois 60064-3500, USA
92
R. T. Bachand
Materials and methods
This study was conducted as a double-blind, 33-centre, clinical trial. Patients gave informed consent to participation and the protocol was approved by local ethics committees. Patients were excluded from the study if they were lactating or at risk for pregnancy, did not have a confirmed diagnosis of chronic bronchitis, did not have a diagnosis of acute bacterial exacerbation of chronic bronchitis supported by one or more clinical signs and symptoms, did not have a pretreatment Gram-stain performed within 48 h of study initiation, did not have pathogens susceptible to both clarithromycin and ampicillin, had radiographic evidence of active tuberculosis or lung tumour within the previous 12 months, had a history of hypersensitivity to macrolide or j?-lactam antibiotics, had an active eye inflammation, had been treated with an investigational drug within four weeks, a long acting injectable antibiotic within six weeks, or a systemic antibiotic within three days prior to study initiation, had renal or hepatic impairment or abnormal creatinine, SGOT, or SGPT values or had a concurrent condition that would interfere with study completion or which required concomitant antibiotic medication. Patients were randomized 1:1 by each investigator to receive either 250 mg clarithromycin (2 x 125 mg capsules) 12-hourly or 250 mg ampicillin (one capsule, Totacillin Beecham) 6-hourly under fasting conditions. To preserve the double-blind nature of the study, placebos were used so that the same number of capsules were administered 6hourly to all patients. Patients presented their medical histories and on visits 1 (study day 1), 4 (post-treatment, within 48 h following the end of therapy), and 5 (late followup, 14 + 4 days following the end of treatment) underwent physical and ophthalmic examinations; and were evaluated as to clinical laboratory profile (haematology and coagulation, blood chemistry, urinalysis), signs and symptoms, vital signs, and sputum culture (Gram-stain grading, culture results, susceptibility). In addition, visit 1 patients had a chest X-ray taken if pneumonia was suspected or if no X-ray had been performed within 12 months and provided blood and serum samples for determination of concurrent drug levels if they were receiving theophylline, digitalis glycosides, warfarin, ergotamine, and/or carbamazepine. At visits 2 (study day 3 to 5) and 3 (study day 8 to 10, if therapy was ongoing) patients were evaluated as to signs and symptoms, vital signs, sputum culture (Gram-stain grading, culture results, susceptibility) and clinical laboratory profile, and provided blood and serum samples, if necessary. Patients who
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
or cefaclor (Fernandes & Frieberg, 1986; Fernandes, 1987; Jansson & Kalin, 1987; Hardy et al., 1988). This is especially important since cefaclor is more stable than penicillin or ampicillin to the /Mactamases elaborated by H. influenzae (Jansson & Kalin, 1987). Clarithromycin is more potent than erythromycin in mouse protection tests against common respiratory pathogens, despite the fact that 14-hydroxy clarithromycin is not a rodent metabolite (Fernandes et al., 1986; Fernandes et al., 1988). Clarithromycin has been shown to be safe and effective in the treatment of patients with communityacquired pneumonia, legionella pneumonia, sinusitis, and pharyngitis. The present study has compared the safety and efficacy of 250 mg clarithromycin (2 x 125 mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of hospitalized patients and outpatients with acute bacterial exacerbations of chronic bronchitis.
Exacerbations of chronic bronchitis
93
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
prematurely withdrew from the study were required to complete a visit 4 evaluation within 48 h of the last dose of study drug. Bronchopulmonary secretion specimens were obtained by expectoration of sputum. The specimen was examined for saliva contamination (leucocytes, squamous epithelial cells). Poor or unsatisfactory specimens were not accepted for culture and additional sputum specimens were obtained. A sputum Gram-stain was reviewed by the investigator and then forwarded to an independent reviewed for evaluation. Target pathogens were identified as: B. catarrhalis, H. influenzae, H. parainfluenzae, Staph. aureus, Str. pyogenes, or Str. pneumoniae. Culture and susceptibility testing were primarily performed at SciCor Laboratories, Indianapolis, IN. MIC and disc zone size were both used to determine susceptibilities with disc zone size taking precedence. The disc zone diameters (mm) used were as follows: clarithromycin-//ae/no/7/n7M5 spp. > 23 susceptible, < 11 resistant; all others > 15 susceptible, < 11 resistant; ampid\]in-Haemophilus spp. ^ 20 susceptible, ^ 19 resistant; Staphylococcus and Branhamella spp. > 29 susceptible, < 28 resistant; Streptococcus spp. > 30 susceptible, < 21 resistant. Clinical signs and symptoms were assessed as follows: sputum- absent/present, mucoid (egg white appearance with traces of pus), mucopurulent ( 1/2 pus); cough, dyspnoea- absent/present, mild (does not interfere with activities), moderate (interferes with activities or sleep), severe (causes chest pain); rales, rhonchi, cyanosis- absent/present. Visit 4 responses were assessed as follows: cure- pretreatment signs and symptoms resolved/absence of evaluable pretreatment pathogens; improved/ mixed- pretreatment signs and symptoms improved but did not resolve/some pretreatment target pathogens eradicated, some persisted; failure- pretreatment signs and symptoms did not improve/pretreatment pathogen persisted; indeterminate- response to therapy could not be determined. The two treatment groups were compared at baseline with respect to sex, race, infection status, and overall clinical condition using a Fisher's Exact Test (two-tailed) and with respect to age, weight, treatment duration, and number of lower respiratory tract infections with the last 24 months using a one-way analysis of variance. Clinical and bacteriological responses were summarized by treatment groups and compared by a Fisher's Exact Test (two-tailed) combined across investigators. Confidence intervals (90%) were calculated for all efficacy endpoints based on asymptomatic distribiution using a separate estimate for each treatment group variance. The presence of investigator bias was investigated by a logistic regression model for binary data. All interaction analysis included data only from investigators who had at least two patients for each treatment. Changes from pretreatment to post-treatment in each clinical sign and symptom were summarized by treatment group and compared using a Fisher's Exact Test (two-tailed). Any adverse event was reported using COSTART (COSTART, 1985). Patients reporting one or more adverse events for a particular COSTART term were counted only once. If more than one type of event occurred within a body system, each type of event was counted. Incidence of adverse events were compared for each body system and overall using a Fisher's Exact Test (two-tailed) combined across investigators. The two treatment groups were compared with respect to baseline values and the changes from baseline values for haematology, serum chemistry, and vital signs data using a one-way analysis of variance. Within treatment group changes were tested equal to zero using a one sample /-test and the mean square error from the analysis of variance comparison. The clinical laboratory data were also summarized, and the treatment
94
R. T. Bachand
groups compared, with respect to the percentage of patients whose laboratory values increased, normalized, decreased, or remained the same, using a x1 analysis. Laboratory and vital sign data were reviewed by a medical monitor for clinically significant changes. Statistical analyses were obtained from SAS Version 5.18 (SAS, 1985). Fisher's Exact Test and other x2 tests were obtained from PROC FREQ, analysis of variance from PROC GLM, and linear models for categorical data from PROC CATMOD. Each treatment group comparison was two-sided with P
Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis Romeo T. Bachand Jr
This double-blind, randomized (1:1), 33 centre clinical trial compared the safety and efficacy of 250 mg clarithromycin (2xl25mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis. Clinical and bacteriological evaluations were performed during treatment (study days 3-5, 8-10) and within 48 h following the end of therapy. Two hundred and twenty-five patients were included in the safety analysis. Both clarithromycin and ampicillin were effective with clinical success rates of 97% (28/29) and 91% (31/34), respectively. Pathogen eradication rates were 86% (36/42) for clarithromycin and 88% (37/42) for ampicillin. No significant difference in the number of patients reporting one or more adverse events was observed between treatment groups. Eleven clarithromycin and six ampicillin patients prematurely discontinued the study owing to adverse events. Clarithromycin 12-hourly was as safe and effective as ampicillin 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis.
Introduction
Ampicillin has been a major therapeutic agent in the treatment of acute bacterial exacerbation of chronic bronchitis. However, the nature of respiratory pathogens is changing with increase in previously rare or unrecognized pathogens and the development of strains resistant to /Mactams (Brook, 1986; Da vies & Maessen, 1986; Hager et al., 1987; Lafong et al., 1988). Resistance to /Mactams has been shown in isolates of Streptococcus pneumoniae, Haemophilus influenzae, Branhamella catarrhalis, and Staphylococcus aureus (Brook, 1986; Davies & Maessen, 1986; Malmborg, 1986; Fernandes, 1987; Hager et al., 1987; Lafong et al., 1988). Therefore, interest in macrolide antibiotics, which are not inactivated by /Mactamases, has been renewed (Malmborg, 1986; Fernandes, 1987). Efforts to improve upon the prototype macrolide, erythromycin, have resulted in a new generation of broad spectrum antibiotics. Clarithromycin, a new generation 14-membered lactone ring macrolide, has improved physical and chemical properties when compared with erythromycin (Mizushima & Hiratsuka, 1986; Sennello et al., 1986; Suwa et al., 1986; Fernandes, 1987). Unlike the metabolites of other macrolides, the 14-hydroxy metabolite of clarithromycin is microbiologically active and may act additively and synergistically with clarithromycin itself (Fernandes & Freiberg, 1986; Fernandes, 1987; Hardy et al., 1988). The combination of clarithromycin and 14-hydroxy clarithromycin is more active against H. influenzae than erythromycin, josamycin, miocamycin, roxithromycin, 91 0305-7453/91/27A091 + 10 $02.00/0
© 1991 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
Abbott International Ltd Abbott Park, Illinois 60064-3500, USA
92
R. T. Bachand
Materials and methods
This study was conducted as a double-blind, 33-centre, clinical trial. Patients gave informed consent to participation and the protocol was approved by local ethics committees. Patients were excluded from the study if they were lactating or at risk for pregnancy, did not have a confirmed diagnosis of chronic bronchitis, did not have a diagnosis of acute bacterial exacerbation of chronic bronchitis supported by one or more clinical signs and symptoms, did not have a pretreatment Gram-stain performed within 48 h of study initiation, did not have pathogens susceptible to both clarithromycin and ampicillin, had radiographic evidence of active tuberculosis or lung tumour within the previous 12 months, had a history of hypersensitivity to macrolide or j?-lactam antibiotics, had an active eye inflammation, had been treated with an investigational drug within four weeks, a long acting injectable antibiotic within six weeks, or a systemic antibiotic within three days prior to study initiation, had renal or hepatic impairment or abnormal creatinine, SGOT, or SGPT values or had a concurrent condition that would interfere with study completion or which required concomitant antibiotic medication. Patients were randomized 1:1 by each investigator to receive either 250 mg clarithromycin (2 x 125 mg capsules) 12-hourly or 250 mg ampicillin (one capsule, Totacillin Beecham) 6-hourly under fasting conditions. To preserve the double-blind nature of the study, placebos were used so that the same number of capsules were administered 6hourly to all patients. Patients presented their medical histories and on visits 1 (study day 1), 4 (post-treatment, within 48 h following the end of therapy), and 5 (late followup, 14 + 4 days following the end of treatment) underwent physical and ophthalmic examinations; and were evaluated as to clinical laboratory profile (haematology and coagulation, blood chemistry, urinalysis), signs and symptoms, vital signs, and sputum culture (Gram-stain grading, culture results, susceptibility). In addition, visit 1 patients had a chest X-ray taken if pneumonia was suspected or if no X-ray had been performed within 12 months and provided blood and serum samples for determination of concurrent drug levels if they were receiving theophylline, digitalis glycosides, warfarin, ergotamine, and/or carbamazepine. At visits 2 (study day 3 to 5) and 3 (study day 8 to 10, if therapy was ongoing) patients were evaluated as to signs and symptoms, vital signs, sputum culture (Gram-stain grading, culture results, susceptibility) and clinical laboratory profile, and provided blood and serum samples, if necessary. Patients who
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
or cefaclor (Fernandes & Frieberg, 1986; Fernandes, 1987; Jansson & Kalin, 1987; Hardy et al., 1988). This is especially important since cefaclor is more stable than penicillin or ampicillin to the /Mactamases elaborated by H. influenzae (Jansson & Kalin, 1987). Clarithromycin is more potent than erythromycin in mouse protection tests against common respiratory pathogens, despite the fact that 14-hydroxy clarithromycin is not a rodent metabolite (Fernandes et al., 1986; Fernandes et al., 1988). Clarithromycin has been shown to be safe and effective in the treatment of patients with communityacquired pneumonia, legionella pneumonia, sinusitis, and pharyngitis. The present study has compared the safety and efficacy of 250 mg clarithromycin (2 x 125 mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of hospitalized patients and outpatients with acute bacterial exacerbations of chronic bronchitis.
Exacerbations of chronic bronchitis
93
Downloaded from http://jac.oxfordjournals.org/ at Laurentian University on November 25, 2014
prematurely withdrew from the study were required to complete a visit 4 evaluation within 48 h of the last dose of study drug. Bronchopulmonary secretion specimens were obtained by expectoration of sputum. The specimen was examined for saliva contamination (leucocytes, squamous epithelial cells). Poor or unsatisfactory specimens were not accepted for culture and additional sputum specimens were obtained. A sputum Gram-stain was reviewed by the investigator and then forwarded to an independent reviewed for evaluation. Target pathogens were identified as: B. catarrhalis, H. influenzae, H. parainfluenzae, Staph. aureus, Str. pyogenes, or Str. pneumoniae. Culture and susceptibility testing were primarily performed at SciCor Laboratories, Indianapolis, IN. MIC and disc zone size were both used to determine susceptibilities with disc zone size taking precedence. The disc zone diameters (mm) used were as follows: clarithromycin-//ae/no/7/n7M5 spp. > 23 susceptible, < 11 resistant; all others > 15 susceptible, < 11 resistant; ampid\]in-Haemophilus spp. ^ 20 susceptible, ^ 19 resistant; Staphylococcus and Branhamella spp. > 29 susceptible, < 28 resistant; Streptococcus spp. > 30 susceptible, < 21 resistant. Clinical signs and symptoms were assessed as follows: sputum- absent/present, mucoid (egg white appearance with traces of pus), mucopurulent ( 1/2 pus); cough, dyspnoea- absent/present, mild (does not interfere with activities), moderate (interferes with activities or sleep), severe (causes chest pain); rales, rhonchi, cyanosis- absent/present. Visit 4 responses were assessed as follows: cure- pretreatment signs and symptoms resolved/absence of evaluable pretreatment pathogens; improved/ mixed- pretreatment signs and symptoms improved but did not resolve/some pretreatment target pathogens eradicated, some persisted; failure- pretreatment signs and symptoms did not improve/pretreatment pathogen persisted; indeterminate- response to therapy could not be determined. The two treatment groups were compared at baseline with respect to sex, race, infection status, and overall clinical condition using a Fisher's Exact Test (two-tailed) and with respect to age, weight, treatment duration, and number of lower respiratory tract infections with the last 24 months using a one-way analysis of variance. Clinical and bacteriological responses were summarized by treatment groups and compared by a Fisher's Exact Test (two-tailed) combined across investigators. Confidence intervals (90%) were calculated for all efficacy endpoints based on asymptomatic distribiution using a separate estimate for each treatment group variance. The presence of investigator bias was investigated by a logistic regression model for binary data. All interaction analysis included data only from investigators who had at least two patients for each treatment. Changes from pretreatment to post-treatment in each clinical sign and symptom were summarized by treatment group and compared using a Fisher's Exact Test (two-tailed). Any adverse event was reported using COSTART (COSTART, 1985). Patients reporting one or more adverse events for a particular COSTART term were counted only once. If more than one type of event occurred within a body system, each type of event was counted. Incidence of adverse events were compared for each body system and overall using a Fisher's Exact Test (two-tailed) combined across investigators. The two treatment groups were compared with respect to baseline values and the changes from baseline values for haematology, serum chemistry, and vital signs data using a one-way analysis of variance. Within treatment group changes were tested equal to zero using a one sample /-test and the mean square error from the analysis of variance comparison. The clinical laboratory data were also summarized, and the treatment
94
R. T. Bachand
groups compared, with respect to the percentage of patients whose laboratory values increased, normalized, decreased, or remained the same, using a x1 analysis. Laboratory and vital sign data were reviewed by a medical monitor for clinically significant changes. Statistical analyses were obtained from SAS Version 5.18 (SAS, 1985). Fisher's Exact Test and other x2 tests were obtained from PROC FREQ, analysis of variance from PROC GLM, and linear models for categorical data from PROC CATMOD. Each treatment group comparison was two-sided with P
