Journal of Antimicrobial Chemotherapy (1991) 27, Suppl. A, 101-108
A comparison of clarithromycin with ampicillin in the treatment of
outpatients with acute bacterial exacerbation of chronic bronchitis
P. M. Aldons
Prince Charles Hospital, Rode Road, Chermside 4032, Queensland, Australia
Introduction
Ampicillin has been standard antibiotic therapy in acute bacterial exacerbations of
chronic bronchitis. However, many of the typical bronchial pathogens such as
Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, and
Branhamella catarrhalis include strains resistant to /Mactam antibiotics (Brook, 1986;
Davies & Maesen, 1986; Hager et al, 1987; Jansson & Kalin, 1987; Lafong et al.,
1988). Clarithromycin, a new broad spectrum macrolide antibiotic is not inactivated by
/Mactamases produced by these respiratory pathogens (Morimoto et al., 1984;
Fernandes et al, 1986; Benson et al, 1987; Fernandes, 1987; Jansson & Kalin, 1987;
Hardy et al, 1988; Fernandes et al, 1988). Clarithromycin has favourable pharmacokinetics with a long elimination half-life, high plasma concentrations, good lung tissue
penetration, and acid stability (Sennello et al, 1986; Suwa et al, 1986; Nilsen, 1987).
101
0305-7453/91/27AI01 +08 $02.00/0
© 1991 The British Society for Antimicrobial Chemotherapy
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One hundred and twenty-five outpatients with clinical symptoms of an acute
bacterial exacerbation of chronic bronchitis were enrolled in a multicentre, doubleblind, randomized clinical trial to compare the efficacy and safety of oral clarithromycin and ampicillin. Only those patients presenting with pathogens cultured from
pre-treatment specimens susceptible to both study drugs were included in the study;
/J-lactamase producing strains were excluded. Sixty patients received clarithromycin
250 mg 12-hourly and 65 had ampicillin 250 mg 6-hourly for 7-14 days. Clinical and
bacteriological evaluations were performed pre-treatment, during treatment, and
post-treatment within 48 h of cessation of therapy. All adverse events reported were
evaluated. Twenty patients from the clarithromycin group and 24 from the ampicillin group were withdrawn from the study when no pathogen was isolated from the
pre-treatment specimens. Twenty-eight patients who received clarithromycin and 23
who received ampicillin were evaluable for clinical and bacteriological efficacy. Both
treatment groups were similar with respect to clinical and bacteriological response
rates. The clinical cure rate for clarithromycin was 96% (27/28) compared with 91%
(21/23) for the ampicillin group. Clarithromycin achieved a bacteriological cure rate
of 96% (27/28) compared with 100% (23/23) for the ampicillin group. Adverse
events, which were generally mild and associated with the digestive system, were
reported by 11-7% of patients receiving clarithromycin and 1-5% of patients
receiving ampicillin. Adverse events caused two patients in each group to discontinue treatment. Laboratory profiles for both groups were unremarkable throughout
treatment. The results of this study indicate that the efficacy and safety of clarithromycin 250 mg 12-hourly is comparable with that of ampicillin 250 mg 6-hourly in
the treatment of acute exacerbations of chronic bronchitis.
102
P. M. Aldons
This study was designed to compare the efficacy and safety of clarithromycin with
ampicillin in the treatment of outpatients with acute bacterial exacerbations of chronic
bronchitis.
Patients and methods
Patients
Study design and procedure
This study was a double-blind, randomized, multicentre outpatient clinical trial.
The diagnosis of chronic bronchitis was based on a history of recurrent productive
cough which was present on most days during at least three consecutive months in
more than two successive years. The diagnosis of an acute bacterial exacerbation of
chronic bronchitis had to be supported by one or more of the following clinical signs
and symptoms: increased cough, increased sputum production, change in sputum
colour or consistency indicative of acute bacterial infection (e.g. change to yellow or
green with increased tenacity of sputum), increased chest discomfort and/or congestion,
and the development of, or increase in, dyspnoea, rales, rhonchi or cyanosis.
On day 1 of the study (visit 1) all patients were assessed by history, physical
examination and chest X-ray; a specimen of sputum was obtained for Gram stain and
culture to qualify for microbiological evaluation. A pathogen had to be cultured from
the pre-treatment specimen, and any pathogens cultured before treatment had to be
susceptible to both study antibiotics, for the patient to remain eligible to continue in the
study. Study day 1 was defined as the day the first dose of antibiotic was administered.
Standard haematological, biochemical and urinalysis tests were performed before
treatment. Patients already taking theophylline had a serum theophylline level
measured.
Clarithromycin and ampicillin were dispensed according to a 1:1 randomization
schedule. All patients received antibiotic doses 6-hourly. Patients received either
clarithromycin 250 mg 12-hourly (two 125 mg capsules 12-hourly with two placebo
capsules at the mid point of the intervening 12-h period) or ampicillin 250 mg 6-hourly
(one 250 mg capsule and one placebo capsule 6-hourly). Medications were administered
one hour before or at least two hours after a meal.
At each subsequent visit—days 3 to 5 (visit 2), 8 to 10 (visit 3—only if therapy was
continuing), and within 48 h of cessation of therapy (visit 4)—patients' clinical signs
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Males and females 18 years of age or older, and if female of non-child bearing
potential, presenting as outpatients with an acute exacerbation of chronic bronchitis
were considered for enrolment. The study had local ethics committee approval and
all patients provided informed consent. Those with a history of hypersensitivity to
macrolide or /Mactam antibiotics were not eligible. Patients with underlying medical
conditions which would interfere with assessment of clinical efficacy, such as those who
required a concomitant antibiotic, were excluded, as were those patients with radiographic evidence of pneumonia, active tuberculosis, and primary or metastatic carcinoma involving the lung, those patients concurrently being treated with warfarin,
ergotamine or carbamazepine, and those with significant hepatic, renal or haematological abnormalities or who had been treated with a systemic antibiotic within three days
of enrolment assessment.
Exacerbations of chronic bronchitis
103
and symptoms of infection and vital signs were assessed. Further specimens of sputum
for culture were obtained, if cultivable material was available, and laboratory tests were
repeated. Any adverse event or concomitant medication was recorded. If by visit 4
complete resolution of clinical signs and symptoms had not occurred further follow-up
visits were scheduled until complete resolution was achieved (visit 5, etc).
Assessment of clinical signs and symptoms
Clinical signs and symptoms assessed were sputum (according to the amount of pus),
severity of cough and dyspnoea, and the presence or absence of rales, rhonchi and
cyanosis.
Clinical responses were evaluated by comparing the clinical signs and symptoms
obtained at visits 1 and 4 (and at each additional follow-up visit). Patients were
considered clinically cured if the pre-treatment signs and symptoms of infection were
completely resolved; clinical improvement was considered as improvement without
complete resolution of pre-treatment signs and symptoms. Patients were considered
clinical failures when no improvement was observed, and not evaluable when no
pathogen was isolated within 48 h before treatment began, or if the pathogen isolated
was resistant. If a patient did not complete the minimum course of therapy, or if
concomitant antibiotics were administered during therapy or before the 48 h posttreatment visit, patients were not considered evaluable.
Assessment of bacteriological response
Eradication was defined as the absence of the pre-treatment pathogen within the 48 h
post-treatment period; persistence was defined as the presence of the infecting microorganism within 48 h post-treatment period.
Analysis of data
Statistical analysis was performed using appropriate methods to compare patient
characteristics and homogeneity of the treatment groups as well as bacteriological and
clinical responses.
The two treatment groups were compared with respect to sex, 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 previous respiratory infections using a
one-way analysis of variance. Efficacy assessments were compared using a Fisher's
Exact test (two-tailed) and 90% two-sided confidence intervals combined across
investigators. Investigator-bias was investigated using a logistic regression model for
binary data.
Adverse events, recorded using COSTART (1985), concomitant medication and
laboratory results were tabulated for comparison to baseline values. Incidences of
adverse events were compared using a Fisher's Exact test (two tailed) combined across
investigators.
Within-treatment group changes were tested using a one sample t test and the mean
square error from the analysis of variance comparison.
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Clinical response to treatment
104
P. M. Aldons
Table I. Evaluable patients
Clarithromycin
Ampicillin
60
28
29
60
65
23
24
65
Total entered
Clinically evaluable
Bacteriologically evaluable
Safety evaluation
Patients
One hundred and twenty-five patients (60 clarithromycin-treated patients and 65
ampicillin-treated patients) were enrolled in the study. Patients who received at least
one dose of antibiotic were included in the safety evaluation. Patients in the clarithromycin group (27 females, 33 males) ranged in age from 21 to 95 years (mean 60-3) and
in weight from 34 to 112 kg (mean 69-3). Patients in the ampicillin group (28 females,
37 males) ranged in age from 25 to 87 years (mean 580) and in weight from 45 to
107 kg (mean 67-3). The breakdown of evaluable and non-evaluable patients appears in
Tables I and II.
The demographic features for evaluable patients were not significantly different from
those of the initially enrolled group. There were no significant differences between the
evaluable patients in the two treatment groups with respect to age, sex, history of
infection, infection status, overall clinical condition before therapy, and duration of
therapy. Evaluable patients in the clarithromycin group weighed slightly more than
those in the ampicillin group (mean 71-2 vs 62-4 kg). Concomitant medication use was
Table II. Non-evaluable patients and reasons
Reasons
No pathogen in pre-treatment culture
No susceptible pathogen in pre-treatment culture
Adverse event
Clarithromycin
Ampicillin
Total
20
7
2
24
11
2
44
18
4
Table III. Changes in clinically evaluable patients
Incidence
(all patients)
Sign
Cough
Dyspnoea
Sputum appearance
Cyanosis
Rales
Rhonchi
87
95
91
25
88
40
Change
clarithromycin
28/28 (100)
24/26 (92)
28/28 (100)
1/2 ( - )
10/12 (83)
6/27 (22)
ampicillin
20/23 (87)
20/21 (95)
21/23 (91)
1/4 ( - )
7/8 (87)
8/20 (40)
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Results
105
Exacerbations of chronic bronchitis
(a)
00 - 96%
90
80
70
60
50
40
30
10
4%
° % 77777X
Cure
Improved
4%
4%
WKZZZZL
Foilure
Eradication
Figure 1. Clinical (a) and bacteriological (b) response, (a) • Clarithromycin (n
(n = 23). (b) | , Clarithromycin (n = 29); 0 , ampicillin (n = 24).
Persistence
28); 0 , ampicillin
reported by 96% of patients in both treatment groups and included inhaled adrenergic
agonists, topical nasal decongestants, and theophylline. Five patients in each group
required alterations in theophylline dose during the study in order to maintain a
therapeutic serum level.
Clinical and bacteriological response
Changes in clinical signs and symptoms (Table III) were comparable in both groups as
was clinical response (Figure 1). The clinical cure rate post-treatment was 96% for
clarithromycin (27/28) and 91% for ampicillin (21/23).
Eradication rates for individual pathogens in evaluable patients are shown in Table
FV. Both treatment groups were comparable in terms of bacteriological eradication rate
(Figure 1), clarithromycin achieving an eradication rate of 97% (28/29) and ampicillin
Table IV. Evaluable pathogen eradication rates within eight days
following the end of treatment with clarithromycin 250 mg 12-hourly,
or ampicillin 250 mg 6-hourly (mean duration 12-6 + 2 days)
Target pathogen,»•*
H. influenzae
Sir. pneumoniae
B. catarrhalis
Staph. aureus
Overall
Clarithromycin
19/20
2/2
6/6
1/1
28/29
95%
—
100%
—
97%
Ampicillin
17/17
6/6
1/1
0
24/24
100%
100%
—
—
100%
"All non-/)-lactamase producers.
'One patient in each treatment group had two evaluable pre-treatment
pathogens.
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20
106
P. M. Aldons
Table V. Adverse events following treatment with clarithromycin 250 mg 12-hourly or ampicillin
250 mg 6-hourly
Body system
6 (10%)
4 (6-6%)
2 (3-3%)
1 (1-7%)
1 (1-7%)
0
2 (3-3%)
7(11-7%)
1 (1-5%)
0
0
0
1 (1-5%)
1 (1-5%)
2(3-1%)
3 (4-6%)
Study drug related events
clarithromycin
ampicillin
(«= 60)
(n = 65)
6 (10%)"
4 (6-6%)
2 (3-3%)
1 (1-7%)
1 (1-7%)
0
1 (1-7%)
7(11-7%)"
0°
0
0
0
0
1 (1-5%)
0
1 (1-5%)°
'Significantly different from the corresponding study drug treatment at P ^ O05 using a Fisher's Exact test
(two-tailed).
a rate of 100% (24/24). One patient in each treatment group had two evaluable pretreatment pathogens.
Clinical response paralleled bacteriological response in both treatment groups except
for one ampicillin patient (pathogen eradicated, clinical failure). No investigator bias
was evident for either treatment group.
Adverse events and laboratory values
Adverse events were generally mild and predominantly associated with the digestive
system. More antibiotic related events were reported by patients receiving clarithromycin than by patients in the ampicillin group (Table V)—11-7% for the clarithromycin group and 1-5% for the ampicillin group. Two patients in each group
prematurely discontinued the study because of adverse events—one with nausea and
vomiting and one with a theophylline interaction from the clarithromycin group, and
one with severe back pain and one with a moderate rash from the ampicillin group.
Changes from baseline haematology, biochemistry, urinalysis and vital signs were
comparable in both groups and were unremarkable throughout the study.
Discussion
Many of the common respiratory pathogens, for example H. influenzae,
Str. pneumoniae and Staph. aureus, have strains resistant to /Mactam antibiotics. In
addition, /Mactamase producing B. catarrhalis has been shown to act both as a direct
and indirect pathogen, causing and exacerbating respiratory infections (Brook, 1986;
Da vies & Maesen, 1986). Interest in macrolide antibiotics for the treatment of
respiratory infections has increased because of their activity against previously
uncommon pathogens, such as Chlamydia pneumoniae (TWAR), and their resistance to
inactivation by /Mactamases (Brook, 1986; Da vies & Maesen, 1986; Malmborg, 1986;
Lafong et ai, 1988).
The MICJQ of clarithromycin for B. catarrhalis, Str. pneumoniae and Staph. aureus is
equal to or lower than that of erythromycin, and lower than those of josamycin,
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Gastrointestinal
nausea
vomiting
dyspepsia
abdominal pain
Skin and appendages
Other
Overall
All adverse events
clarithromycin
ampicillin
(n = 60)
(n = 65)
Exacerbations of chronic bronchitis
107
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