Journal of Antimicrobial Chemotherapy (1976) 2, 279-285
Bacampicillin in acute exacerbations of chronic bronchitis— a dose-range study
Departments of Pulmonary Diseases*, Microbiology^, Clinical Chemistryt, The "Wever" Hospital, Heerlen, The Netherlands and Medical Department, Astra Pharmaceuticals, Sodertalie, Sweden^
During the initial clinical evaluation of a new aminopenicillin, bacampicillin, 21 patients were treated for acute exacerbations of chronic bronchitis. The study was "single-blind" and comprised three dose-levels, which permitted a systematic study of dose-response relationships. Both the ampicillin levels in serum and sputum and the clinical outcome were dose-dependent. Sputum purulence and ampicillin levels were found to be a significant factor for predicting clinical outcome. With 400 to 800 mg bacampicillin t.i.d. mean ampicillin levels inhibitory for Haemophilus influenzae were maintained in sputum for at least 6 to 8 h and the clinical results were satisfactory, whereas this time was considerably shorter with the 200 mg t.i.d. dose, which also gave poorer clinical results. The ampicillin sputum to serum level ratio was 13 % at 1 h and 20 % at 3 h after a dose. No sideeffects were observed.
Introduction
Bacampicillin (1 '-ethoxycarbonyloxyethyl-6-(D-a-aminophenylacetamido penicillanate) is a new semi-synthetic penicillin, closely related to ampicillin. It differs from the latter in having an ethoxycarbonyloxyethyl group attached to the 3-carboxyl group on the penicillin nucleus, thus forming an ester (Bodin et ah, 1975). Bacampicillin is stable at normal gastric pH and undergoes very little hydrolysis to ampicillin at neutral pH values. The whole ester is almost completely absorbed from the intestinal tract but is soon broken down by non-specific esterases (Bodin et al., 1975). An absorption of 98% has been claimed (Klastersky, Rosencweig & Staquet, 1975). Thus absorption is much more complete than that obtained with ampicillin and the levels of free ampicillin in the serum have been shown to be 2 to 3 times higher than those attained after an equimolar dose of ampicillin (Magni, Sjoberg, Sjovall & Wessman, 1975). Ampicillin is widely used for the treatment of acute exacerbations of chronic bronchitis. In this condition the commonest pathogen is Haemophilus influenzae, which is present in at least 80% of patients with purulent sputum and which is more sensitive to ampicillin than to other penicillins (Williams & Andrews, 1974). The other common pathogen, Streptococcus pneumoniae, remains fully sensitive to ampicillin. 279
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F. P. V. Maesen*, H. Beeuwkesf, B. I. Daviesf, H. J. Buytendijk*, P. J. Brombacher} and J. Wessman§
280
F. P. V. Maesen et al.
It has been claimed that the dose of ampicilhn necessary to yield concentrations bactericidal to H. influenzae in the sputum is at least 1 g 6-hourly (May, 1972), but the drug is not completely absorbed from the bowel and urine recoveries of the order of 30 to 50% only have been reported (Rolinson & Sutherland, 1973). Incomplete intestinal absorption may also result in diarrhoea and in the development of ampicillin-resistant enterobacteriaceae. In view of the shortcomings of ampicillin, it seemed worthwhile to carry out a doserange study with bacampicillin in the treatment of acute exacerbations of chronic bronchitis in hospital patients. Material and methods
Laboratory methods Sputum samples were collected and were sent immediately to the laboratory where a special proforma was completed. The sputum was assessed macroscopically and selected quantities of pus were removed with a loop and washed in 3 changes of sterile normal saline by the method of Mulder (Mulder, Goslings, van der Plas & Lopes Cardozo, 1952). Smears for Gram staining were made and the material was cultured on blood agar, chocolate agar and on a heated blood agar medium containing 10 units/ml of bacitracin. Organisms were identified and sensitivity tests carried out by standard techniques. Blood samples for ampicillin estimation were drawn by venepuncture 1, 3, 5 and 7 h after administration of the first dose of bacampicillin. Sputum was collected over 2 h periods and representative portions of pus were chosen for determination of ampicillin content. These assays were carried out daily during weekdays, but specimens were kept frozen at —20°C over weekends. For both blood and sputum assays an agar-cup diffusion technique was used, the medium being 1% agarose in 0-8% Nutrient Broth (Difco), containing 3-5% bovine serum albumin. The final pH was 7-2. For the sputum determinations a sensitive Sarcina lutea strain was used, whereas for the higher levels in the serum a strain of Staphylococcus aureus was employed. All the standard ampicillin solutions were prepared in a mixture of equal parts of normal human serum and 3-5% bovine albumin solution. All determinations were duplicated. Sputum was cultured on entry to the trial and 7, 14 and 21 days after the start of treatment. At the same time total and differential leucocyte counts, platelet counts, ESR, haematocrit, and haemoglobin estimations were carried out, as well as urine microscopy and estimation of serum creatinine levels and liver function tests. Clinical methods Normal methods of clinical assessment were used to measure the progress of each patient daily during the treatment period and once weekly in the following 2 weeks.
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The patients Patients were admitted to the trial when they fulfilled the criteria for chronic bronchitis set out by the Medical Research Council (1965). Sputum from each patient with an acute exacerbation was examined before entry to the study, and only patients with Gram stained smears suggestive of the presence of H. influenzae or Strept. pneumoniae were included. Patients known to be allergic to penicillins or cephalosporins were excluded, as were those with malignancy, pulmonary tuberculosis and hepatic or renal dysfunction. Any patients who had received antibacterial drugs in the 7 days before admission to hospital were also excluded. We studied 16 males and 5 female patients, aged between 31 and 78 years (mean 57 years).
Bacampicillin in acute exacerbations
281
The temperature was recorded twice daily and the sputum was weighed every 24 h. Predefined rating scales were used for scoring cough frequency, sputum appearance, degree of dyspnoea, etc. Overall clinical efficacy was scored in the way described in Table III.
Statistical methods For the comparison between different groups regarding clinical efficacy, where an ordinal scale was appropriate, a two-sided Mann-Whitney U-test was employed. Clinical efficacy was assessed by observing if eradication of the initial pathogens was achieved, in which case a two-sided Fisher's exact test was used. In an attempt to trace the most important factors influencing the clinical outcome a step-wise multiple regression analysis was carried out. A significance level of 5% was considered as suitable for the purpose of this investigation. Results Haemophilus influenzae was cultured in all initial sputum specimens from the 21 patients in the study. In 16 it was the only respiratory pathogen found, but pneumococci were grown as well in 4 patients (Table I). One patient's sputum yielded mixed enterobacteria Table I. Bacteriology on admission No. of patients Organism isolated 200 mg
400 mg
800 mg
H. influenzae H. influenzae +pneumococci H. influenzae ( + Proteus+Klebsiella) {Proteus and Klebsiella species) as well as the H. influenzae. On day 7 of the trial the pathogens were eradicated only in 4 of the 7 patients who received the lowest dosage (200 mg 3 times daily) but they had disappeared in 13 of the 14 patients on 400 or 800 mg dose-schedules. By day 21, 2 weeks after the end of treatment, H. influenzae or Strept. pneumoniae were again found in sputum samples from two patients in each of the 3 treatment groups (Table II). The mixed enterobacteria, whose significance was in doubt, remained throughout in the 1 patient. After treatment only 1 patient in each of the 3 groups still had purulent sputum; half the patients were free from pus by day 4. However, reduction in daily sputum volume
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Treatment schedules Three different bacampicillin dosage schedules were employed, viz. 200, 400 or 800 mg 3 times daily. All patients were treated for 7 days and the doses were given independently of meals. Patients were randomly allocated to their respective treatment groups. The first dose served as a test-dose for the evaluation of serum and sputum concentrations and was always given at 8 a.m. on an empty stomach by the same nurse who collected all the serum and sputum samples. As this nurse was not involved in the clinical or laboratory evaluation of the drug, the investigation can be considered as "single-blind".
282
F. P. V. Maesen et at.
was slower than reduction of sputum purulence, and there was much more variation between patients. A dose-response effect was observed (Table IV), the sputum volume decreasing most with the highest dose of bacampicillin. Subjective clinical improvement was generally observed, with reduction of cough in all patients and lessening of dyspnoea in most. Table n . Eradication of initial pathogens* (7 patients on each dose-level) No. of patients 400 mg
800 mg
4 3 2
7f 0 2
6 1 2
Eradicated on day 7 Failed to eradicate Reisolated day 21
•Only H. influenzae and pneumococci considered. ^Proteus and Klebsiella remained in 1 patient. Table HI. Clinical assessment
Responset
No. of patients 800 mg* 400 mg 200 mg*
Excellent Good Poor Bad
4 3 0 0
1 5 1 0
0 5 2 0
•U = 7-5 (P
Bacampicillin in acute exacerbations of chronic bronchitis— a dose-range study
Departments of Pulmonary Diseases*, Microbiology^, Clinical Chemistryt, The "Wever" Hospital, Heerlen, The Netherlands and Medical Department, Astra Pharmaceuticals, Sodertalie, Sweden^
During the initial clinical evaluation of a new aminopenicillin, bacampicillin, 21 patients were treated for acute exacerbations of chronic bronchitis. The study was "single-blind" and comprised three dose-levels, which permitted a systematic study of dose-response relationships. Both the ampicillin levels in serum and sputum and the clinical outcome were dose-dependent. Sputum purulence and ampicillin levels were found to be a significant factor for predicting clinical outcome. With 400 to 800 mg bacampicillin t.i.d. mean ampicillin levels inhibitory for Haemophilus influenzae were maintained in sputum for at least 6 to 8 h and the clinical results were satisfactory, whereas this time was considerably shorter with the 200 mg t.i.d. dose, which also gave poorer clinical results. The ampicillin sputum to serum level ratio was 13 % at 1 h and 20 % at 3 h after a dose. No sideeffects were observed.
Introduction
Bacampicillin (1 '-ethoxycarbonyloxyethyl-6-(D-a-aminophenylacetamido penicillanate) is a new semi-synthetic penicillin, closely related to ampicillin. It differs from the latter in having an ethoxycarbonyloxyethyl group attached to the 3-carboxyl group on the penicillin nucleus, thus forming an ester (Bodin et ah, 1975). Bacampicillin is stable at normal gastric pH and undergoes very little hydrolysis to ampicillin at neutral pH values. The whole ester is almost completely absorbed from the intestinal tract but is soon broken down by non-specific esterases (Bodin et al., 1975). An absorption of 98% has been claimed (Klastersky, Rosencweig & Staquet, 1975). Thus absorption is much more complete than that obtained with ampicillin and the levels of free ampicillin in the serum have been shown to be 2 to 3 times higher than those attained after an equimolar dose of ampicillin (Magni, Sjoberg, Sjovall & Wessman, 1975). Ampicillin is widely used for the treatment of acute exacerbations of chronic bronchitis. In this condition the commonest pathogen is Haemophilus influenzae, which is present in at least 80% of patients with purulent sputum and which is more sensitive to ampicillin than to other penicillins (Williams & Andrews, 1974). The other common pathogen, Streptococcus pneumoniae, remains fully sensitive to ampicillin. 279
Downloaded from http://jac.oxfordjournals.org/ at Indiana University Library on May 11, 2015
F. P. V. Maesen*, H. Beeuwkesf, B. I. Daviesf, H. J. Buytendijk*, P. J. Brombacher} and J. Wessman§
280
F. P. V. Maesen et al.
It has been claimed that the dose of ampicilhn necessary to yield concentrations bactericidal to H. influenzae in the sputum is at least 1 g 6-hourly (May, 1972), but the drug is not completely absorbed from the bowel and urine recoveries of the order of 30 to 50% only have been reported (Rolinson & Sutherland, 1973). Incomplete intestinal absorption may also result in diarrhoea and in the development of ampicillin-resistant enterobacteriaceae. In view of the shortcomings of ampicillin, it seemed worthwhile to carry out a doserange study with bacampicillin in the treatment of acute exacerbations of chronic bronchitis in hospital patients. Material and methods
Laboratory methods Sputum samples were collected and were sent immediately to the laboratory where a special proforma was completed. The sputum was assessed macroscopically and selected quantities of pus were removed with a loop and washed in 3 changes of sterile normal saline by the method of Mulder (Mulder, Goslings, van der Plas & Lopes Cardozo, 1952). Smears for Gram staining were made and the material was cultured on blood agar, chocolate agar and on a heated blood agar medium containing 10 units/ml of bacitracin. Organisms were identified and sensitivity tests carried out by standard techniques. Blood samples for ampicillin estimation were drawn by venepuncture 1, 3, 5 and 7 h after administration of the first dose of bacampicillin. Sputum was collected over 2 h periods and representative portions of pus were chosen for determination of ampicillin content. These assays were carried out daily during weekdays, but specimens were kept frozen at —20°C over weekends. For both blood and sputum assays an agar-cup diffusion technique was used, the medium being 1% agarose in 0-8% Nutrient Broth (Difco), containing 3-5% bovine serum albumin. The final pH was 7-2. For the sputum determinations a sensitive Sarcina lutea strain was used, whereas for the higher levels in the serum a strain of Staphylococcus aureus was employed. All the standard ampicillin solutions were prepared in a mixture of equal parts of normal human serum and 3-5% bovine albumin solution. All determinations were duplicated. Sputum was cultured on entry to the trial and 7, 14 and 21 days after the start of treatment. At the same time total and differential leucocyte counts, platelet counts, ESR, haematocrit, and haemoglobin estimations were carried out, as well as urine microscopy and estimation of serum creatinine levels and liver function tests. Clinical methods Normal methods of clinical assessment were used to measure the progress of each patient daily during the treatment period and once weekly in the following 2 weeks.
Downloaded from http://jac.oxfordjournals.org/ at Indiana University Library on May 11, 2015
The patients Patients were admitted to the trial when they fulfilled the criteria for chronic bronchitis set out by the Medical Research Council (1965). Sputum from each patient with an acute exacerbation was examined before entry to the study, and only patients with Gram stained smears suggestive of the presence of H. influenzae or Strept. pneumoniae were included. Patients known to be allergic to penicillins or cephalosporins were excluded, as were those with malignancy, pulmonary tuberculosis and hepatic or renal dysfunction. Any patients who had received antibacterial drugs in the 7 days before admission to hospital were also excluded. We studied 16 males and 5 female patients, aged between 31 and 78 years (mean 57 years).
Bacampicillin in acute exacerbations
281
The temperature was recorded twice daily and the sputum was weighed every 24 h. Predefined rating scales were used for scoring cough frequency, sputum appearance, degree of dyspnoea, etc. Overall clinical efficacy was scored in the way described in Table III.
Statistical methods For the comparison between different groups regarding clinical efficacy, where an ordinal scale was appropriate, a two-sided Mann-Whitney U-test was employed. Clinical efficacy was assessed by observing if eradication of the initial pathogens was achieved, in which case a two-sided Fisher's exact test was used. In an attempt to trace the most important factors influencing the clinical outcome a step-wise multiple regression analysis was carried out. A significance level of 5% was considered as suitable for the purpose of this investigation. Results Haemophilus influenzae was cultured in all initial sputum specimens from the 21 patients in the study. In 16 it was the only respiratory pathogen found, but pneumococci were grown as well in 4 patients (Table I). One patient's sputum yielded mixed enterobacteria Table I. Bacteriology on admission No. of patients Organism isolated 200 mg
400 mg
800 mg
H. influenzae H. influenzae +pneumococci H. influenzae ( + Proteus+Klebsiella) {Proteus and Klebsiella species) as well as the H. influenzae. On day 7 of the trial the pathogens were eradicated only in 4 of the 7 patients who received the lowest dosage (200 mg 3 times daily) but they had disappeared in 13 of the 14 patients on 400 or 800 mg dose-schedules. By day 21, 2 weeks after the end of treatment, H. influenzae or Strept. pneumoniae were again found in sputum samples from two patients in each of the 3 treatment groups (Table II). The mixed enterobacteria, whose significance was in doubt, remained throughout in the 1 patient. After treatment only 1 patient in each of the 3 groups still had purulent sputum; half the patients were free from pus by day 4. However, reduction in daily sputum volume
Downloaded from http://jac.oxfordjournals.org/ at Indiana University Library on May 11, 2015
Treatment schedules Three different bacampicillin dosage schedules were employed, viz. 200, 400 or 800 mg 3 times daily. All patients were treated for 7 days and the doses were given independently of meals. Patients were randomly allocated to their respective treatment groups. The first dose served as a test-dose for the evaluation of serum and sputum concentrations and was always given at 8 a.m. on an empty stomach by the same nurse who collected all the serum and sputum samples. As this nurse was not involved in the clinical or laboratory evaluation of the drug, the investigation can be considered as "single-blind".
282
F. P. V. Maesen et at.
was slower than reduction of sputum purulence, and there was much more variation between patients. A dose-response effect was observed (Table IV), the sputum volume decreasing most with the highest dose of bacampicillin. Subjective clinical improvement was generally observed, with reduction of cough in all patients and lessening of dyspnoea in most. Table n . Eradication of initial pathogens* (7 patients on each dose-level) No. of patients 400 mg
800 mg
4 3 2
7f 0 2
6 1 2
Eradicated on day 7 Failed to eradicate Reisolated day 21
•Only H. influenzae and pneumococci considered. ^Proteus and Klebsiella remained in 1 patient. Table HI. Clinical assessment
Responset
No. of patients 800 mg* 400 mg 200 mg*
Excellent Good Poor Bad
4 3 0 0
1 5 1 0
0 5 2 0
•U = 7-5 (P
