Egyptian Journal of Chest Diseases and Tuberculosis (2015) xxx, xxxxxx

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The Egyptian Society of Chest Diseases and Tuberculosis

Egyptian Journal of Chest Diseases and Tuberculosis

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ORIGINAL ARTICLE

Impact of antibiotics on acute exacerbations of

COPD
Wafaa Ali Hassan
a
b

a,*

, Ibraheem Shalan b, Mahmmoud Elsobhy

Chest Department, Assiut, Egypt

Al-Azhar Universities, Egypt

Received 17 February 2015; accepted 9 March 2015

KEYWORDS
Exacerbation;
COPD;
Antibiotics

Abstract Background: Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However the value of their use remains uncertain. Some
controlled trials of antibiotics have shown benet while others have not. This study was conducted
in order to help resolve the issues surrounding the value of antibiotic therapy for exacerbations of
COPD.
Patients and methods: One hundred subjects were recruited from patients with type 1 exacerbation of COPD referred to the outpatient clinics of Assiut and Al-Azhar University hospitals for
treatment of COPD exacerbation from April 2013 to October 2014. Patients were divided into
two groups, placebo and antibiotic group. Each group contain 50 patients, the placebo group
received (bronchodilators, corticosteroids), the treatment group received bronchodilators, corticosteroids, and 10 day course of antibiotics.
Results: The frequency of individual symptoms was signicantly different before and after treatment in antibiotic and placebo-treated groups. Lung function studies showed no signicant difference in both antibiotic-treated and placebo groups. Peak ow data increased in antibiotic treated
group and in placebo treated group without statistical signicance (p = 0.205, paired t-test).
However, this increase in PEFR occurs signicantly more rapid and in shorter duration in antibiotic-treated group than placebo group (15 3 days versus 18 5 days) p = 0.001. The success
rate was higher in antibiotic-treated exacerbations while failure with deterioration was higher in placebo-treated group. When exacerbations without deterioration were considered, antibiotic-treated
exacerbations showed more rapid improvement in symptoms than those with placebo treated group
(13 7 days versus 16 6 days) p = 0.02.
Conclusions: In conclusion, this study has clearly shown that in type 1 exacerbations of COPD,
antibiotic therapy, signicantly results in decrease in duration of treatment, success rate and more
rapid improvement in peak ow.
2015 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and
Tuberculosis. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

* Corresponding author.
Peer review under responsibility of The Egyptian Society of Chest
Diseases and Tuberculosis.
http://dx.doi.org/10.1016/j.ejcdt.2015.03.007
0422-7638 2015 Production and hosting by Elsevier B.V. on behalf of The Egyptian Society of Chest Diseases and Tuberculosis.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
10.1016/j.ejcdt.2015.03.007

2
Background
Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However
the value of their use remains uncertain. Some controlled trials
of antibiotics have shown benet while others have not [1].
Exacerbations of COPD are often bacterial in origin and
antibiotic therapy seems appropriate for suspected bacterial
exacerbations [2]. It is increasingly recognized that exacerbations are also caused by viral infections of the upper respiratory tract, or even by no infection, when antibiotic
treatment does not seem warranted [3]. In addition, there is
a growing incidence of resistance to common antibiotics. We
therefore decided to do this study in order to help resolve
the issues surrounding the value of antibiotic therapy for
exacerbations of COPD and its impact on pulmonary function
tests.
Patients and methods
Subjects were recruited from consecutive patients referred to
the outpatient clinics of Assiut and Al-Azhar University hospitals for treatment of COPD exacerbation from April 2013 to
October 2014. We included all Patients with type 1 exacerbation of COPD (dened as an increase in dyspnea, sputum
purulence and increased sputum volume) [4,5]. Patients were
excluded if they had received antibiotic treatment during the
last 2 weeks or had another disease such as left ventricular failure, stroke, pneumonia, pneumothorax, cancer, coma, allergy
to quinolone derivatives, or concomitant infection requiring
systemic antibacterial therapy were also excluded [6].
Type of study
Randomized controlled trials (RCTs) using an antibiotic in the
treatment group and placebo in the control group.
Study protocol
One hundred patients with exacerbations of COPD were
included. Patients were divided into two groups, placebo and
antibiotic group. Each group contains 50 patients, the placebo
group received (bronchodilators, corticosteroids), the treatment group received bronchodilators, corticosteroids, and
10 day course of antibiotics in the form of quinolone in a dose
of 500 mg/twice daily or amoxicillin 500 mg/8 h. All patients
received inhaled albuterol by metered dose inhaler, oral long
acting theophyllines, oral prednisolone 40 mg/day for three
days followed by 510 mg for 12 days in steroid responsive
cases. Diuretics were given when needed and patients who fullled criteria for oxygen therapy received such therapy for
18 h/day. All 100 subjects had detailed clinical assessment performed to record ndings at the time of diagnosis. The outpatient hospital visit was repeated at 3 days interval until day 15
and the day 21. The data as follows were recorded for each
patient: anthropometric parameters (including age, gender
and residence), smoking history, if there was former or current
smoking practice; the number of cigarette packs/year was calculated as the product of the period of tobacco use (in years)
and the average number of cigarettes smoked per day.

W.A. Hassan et al.

Patients were asked about the presence and frequency of productive cough, sputum volume (sputum volume was estimated
by comparison with a teacup (150 ml)) [7]. And the degree of
dyspnea was determined using the Medical Research Council
(MRC) dyspnea grade. [8]. Clinical assessment also included
measurement of heart rate, respiratory rate, temperature and
presence or absence of crepitations.
Main outcome measures
Lung function measured at the beginning and end of the
study period (forced expiratory volume in one second
(FEV1), forced vital capacity (FVC), FEV1/FVC and peak
expiratory ow rate (PEFR).
Failure rate (no resolution or deterioration of symptoms
after trial of medication at the end of the study period, or
death).
Success rate (reduction in sputum volume and purulence
measured at the end of the study period).
Additional course of antibiotics (other than the antibiotics
given).
Improvement in dyspnea measured at the end of the study
period.
Change in vital signs measured at the end of the study
period.
Observation of side effects of treatment in both groups at
the end of the study period.
All patients gave a written consent for participation in this
study. The study followed the ethical instructions of the ethics
committee of Assiut and Al-Azhar Universities.
Pulmonary function tests
Forced Spirometry was obtained with pulmonary function
units (Smart, Germany). The forced vital capacity (FVC)
was expressed as a percentage of predicted value based on
height, age, gender and ethnic origin. Measurement of forced
vital capacity (FVC), forced vital capacity in 1 s (FEV1; best
results of 3 successful attempts) and peak expiratory ow rate
(PEFR) were done for all patients.
Statistical analysis
Statistical analysis of the data was performed by using
SPSS_16 software package under Windows_7 operating system. Categorical data parameters were presented in the form
of frequency and percent. Comparison was performed by
Chi-square test for categorical data. Quantitative data were
expressed in the form of mean, SD. Independent and paired
sample t-test were used to test the signicance between groups
and time of test for quantitative data. Probability level (Pvalue) was assumed signicant if less than 0.05 and highly signicant if P-value was less than 0.01. P-value was considered
non-signicant if greater than or equal to 0.05.
Results
Between April 2013 to October 2014, 83 males and 17 females
with mean age 61.8 6.5 (age range from 39 to 77) with type 1

Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
10.1016/j.ejcdt.2015.03.007

Impact of antibiotics on acute exacerbations of COPD

acute exacerbation of COPD were enrolled in this study.

Nearly all patients were smokers with average 25 packs/year,
although 48 were former smokers at the time of the study.
Other demographic characteristics are summarized in
Table 1. The frequency of individual symptoms was signicantly different before and after treatment in antibiotic and
placebo-treated groups (Table 2). Lung function studies
showed no signicant difference in both antibiotic-treated
and placebo groups (Table 3). Peak ow data increased from
a mean of 200 L/m at the onset of exacerbation to 215 L/m
in antibiotic treated group whereas it increased from a mean
of 190200 L/m in placebo treated group without statistical
signicance. (p = 0.205, paired t-test). However, this increase
in PEFR occurs signicantly more rapid and in shorter duration in antibiotic-treated group than placebo group
(15 3 days versus 18 5 days), p = 0.001 (Table 4).
Systemic steroid therapy was used in 48% of antibiotictreated exacerbations and in 45% of placebo-treated ones.
The success rate was higher in antibiotic-treated exacerbations
while failure with deterioration was higher in placebo-treated
group (Table 5). No signicant differences were seen in success
rates that depend on individual antibiotic used. About 60% of
patients were treated with ciprooxacin or its placebo whereas
40% were treated with amoxicillin or its placebo. The choice of
antibiotic was random and not related to the baseline lung
function or number of exacerbations. At the onset of exacerbations, no signicant difference was obtained in improvement of
symptoms in both groups but the success rates were higher in
all antibiotic treatment groups than placebo treated group. In
cases of treatment with antibiotics and steroids the success rate
was higher, though not signicant, than those treated with
steroids and placebo.

Table 1 Demographic parameters between antibiotic and

placebo groups.
Parameter

Treatment groups

P
value

Sig.

Placebo
(n = 50)

Antibiotic
(n = 50)

63.0 6.1

60.6 6.8

0.072

NS

Male
Female

42 (84.0%)
8 (16.0%)

41 (82.0%)
9 (18.0%)

0.790

NS

Rural
Urban

33 (66.0%)
17 (34.0%)

21 (42.0%)
24 (58.0%)

0.016

Ex-smoker
Mild
Smoker
Moderate
smoker
Heavy
smoker

19 (46.3%)
7 (17.1%)

19 (47.5%)
4 (10.0%)

0.768

NS

5 (12.2%)

7 (17.5%)

10 (24.4%)

10 (25.0%)

Age mean
(yr)
Gender

Residence

Smoking

Chi square and one way ANOVA are used to test the signicance
among groups.
NS not signicant.
*
Signicant (p < 0.05).

When exacerbations without deterioration were considered,

antibiotic-treated exacerbations showed more rapid improvement in symptoms than those with placebo treated group
(13 7 days versus 16 6 days) p = 0.02 (Table 5).
The incidence of side effects was low and not signicantly
different between antibiotic and placebo treated group.
Although gastrointestinal side effects were higher in antibiotic
treated group, other side effects were not different between the
two groups. Side effects considered as serious enough to withdraw therapy did not occur in any of the treatment groups
(Table 6).
Discussion
Exacerbations of COPD are often bacterial in origin and
antibiotic therapy seems appropriate for suspected bacterial
exacerbations. It is increasingly recognized that exacerbations
are also caused by viral infections of the upper respiratory
tract, or even by no infection, when antibiotic treatment does
not seem warranted [9]. In addition, there is a growing incidence of resistance to common antibiotics [10]. Therefore, limiting unnecessary use of antibiotics in exacerbations of COPD
is important to help control the incidence of antibiotic resistance [11]. This study compared antibiotics versus placebo in
treatment of type 1 exacerbations of COPD. It was found that,
antibiotics produced signicantly earlier resolution of symptoms than placebo treated group. The study was conducted
in double-blinded fashion in which placebo medications were
indistinguishable from antibiotics and neither the patient nor
the study team knew which tablets was the active medication.
Aside from the use of either the antibiotics or the placebo,
treatment regimens were not different between groups.
Steroid therapy was used in either antibiotic or placebo group
but the success rate was higher in antibiotic treated group.
Symptoms and pulmonary function tests did not differ in
antibiotic or placebo treated group, however deterioration of
symptoms (treatment failure) occurred more signicantly in
placebo group. Some might argue that the criteria used for
determination of the onset and the resolution of symptoms
were soft and subjective because they depend on the patient
reports of symptoms. We deliberately used symptoms to dene
exacerbations because there are strong criteria applied in clinical practice. Once onset was dened in these criteria, resolution
had to be dened in similar ones. There was no signicant difference in resolution of symptoms in antibiotic and placebo
treated group. However, the resolution of symptoms was faster
and occurred in shorter duration in antibiotic-treated than placebo group. Also the improvement in FEV1 occurred more
rapid than placebo group.
Due to the limited number of included studies and incomplete data reporting in published studies, it was not possible
to investigate a relationship between antibiotic efcacy and
severity of illness or on bacterial cultures. An analysis was
stratied by location of care (community or in-patients).
Two of the included trials did analyze the efcacy of antibiotics according to subgroups that were dened either by evidence of bacterial infection or severity of illness [12]. One
trial found that a priori criteria that were purported to select
patients with signs of infection (using the Winnipeg criteria,
1) showed better outcomes with antibiotic versus placebo treatment [1]. Patients with type-1 exacerbations (who met all the

Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
10.1016/j.ejcdt.2015.03.007

W.A. Hassan et al.

Table 2

Change in symptoms between placebo and antibiotic groups.

Parameter

Treatment groups
Placebo (n = 50)

Antibiotic (n = 50)

Before

After

Sig.

Before

After

Sig.

(1)
(2)
(3)
(4)

5 (10.0%)
12 (24.0%)
27 (54.0%)
6 (12.0%)

1
1
2
1

(2.0%)
(2.0%)
(4.0%)
(2.0%)

4 (8.0%)
10 (40.0%)
31 (62.0%)
5 (10.0%)

0
2 (4.0%)
3 (6.0%)
1 (2.0%)

Scanty
One cup
Two cups

5 (10.0%)
33 (66.0%)
12 (24.0%)

0
3 (6.0%)
2 (4.0%)

3 (6.0%)
40 (80.0%)
7 (14.0%)

0 (0.0%)
4 (8.0%)
2 (4.0%)

Yellowish
Grayish
Whitish

23 (46.0%)
20 (40.0%)
7 (14.0%)

2 (4.0%)
3 (6.0%)
0

**

24 (48.0%)
21 (42.0%)
5 (10.0%)

2 (4.0%)
3 (6.0%)
1 (2.0%)

**

24.7 2.3
94.3 8
50(100%)

20.7 3.2
84.6 11
5 (10%)

**

25.7 2.8
95.8 8
50(100%)

21.0 3.7
85.6 10
6 (12%)

**

Degree of dyspnea
Grade
Grade
Grade
Grade

**
**
*

**
**
*

Sputum volume
**
**

**
*

Sputum colors

RR (M SD)
Heart rate (M SD)
Crepitations

Table 3 Pulmonary function parameters before and after

treatment in placebo and antibiotic groups.
Parameter

Treatments
Placebo

P value

Sig.

Antibiotic

FEV1 (M SD)
Before
54.5 17.6
After
58.4 13.9

56.7 14.0
59.7 12.2

0.508

NS

FVC (M SD)
Before
112.1 33
After
116.9 35

105.6 25
109.5 23

0.259

NS

FEV1/FVC% (M SD)
Before
42.5 0.09
After
43.1 0.10

44.0 0.09
45.7 0.08

0.444

NS

following three criteria: increases in amount of sputum, purulence of sputum, and dyspnea) beneted the most, with resolution of symptoms in 63% of the antibiotic-treated
exacerbations and 43% of the placebo-treated exacerbations

Table 4 Duration of PEFR improvement in placebo and

antibiotic treated groups.
Parameter

Treatments
Placebo

PEFR
(M SD)
P value
Improvement
duration
(days)

**
**

**
**

Before

After

Before

After

190.5 9.5

200 8.5

200 8.9

215 10.3

0.205
18 5

15 3

**
**

Table 5 Comparison in success, failure rates and duration of

treatment between antibiotic and placebo groups.

0.326

t test was used to test the signicance between time and groups.

[13,14]. Those with type-2 exacerbations (who met two of the

above three criteria) showed an intermediate (not statistically
signicant) benet, with 70% resolving on antibiotics and
60% resolving on placebo. Patients with type-3 exacerbations
(who met one of the above three criteria) did not show any
benet, with 74% of exacerbations resolving on antibiotics
and 70% resolving on placebo [15,16].
Another trial matched patients based on severity of illness,
which was dened by two or more of the following: fever
higher than 37.5 C, pulmonary consolidation, or purulent
sputum [2]. The trial was terminated prematurely for reasons
unrelated to its results and before a signicant effect of antibiotic treatment was found. However, this analysis was based on
an assessment that was not blinded to bacteriologic results
and, thus, may have been biased. A later independent, blinded
assessment failed to nd a signicant difference between
antibiotic and placebo-treated patients [17]. Patients in the placebo group with greater severity of illness had more relapses in
hospital than did less severely ill patients; however, this
relationship was not found in the antibiotic group. It should
be noted that the criteria for severely ill (met by 19 of the
74 patients in the trial) would have resulted in exclusion from

Parameter

Antibiotic

**

Duration
(days)

Treatments

Success
rate
Failure
rate
16 6

Placebo

Antibiotic

35
(70.0%)
15
(30.0%)
13 7

44
(88.0%)
6 (12.0%)

P
value

Sig.

0.006

**

0.001

0.02

Chi square was used to test the signicance between groups.

Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
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Impact of antibiotics on acute exacerbations of COPD

Table 6
groups.

Side effects of treatment in placebo and antibiotic

Parameter

Nausea
Vomiting
Abdominal
cramps
Diarrhea
Skin rash
Others

Treatments

P
value

Sig.

5 (10%)
2 (4.0%)
1 (2.0%)

0.726
0.555
0.555

NS
NS
NS

3 (6.0%)
2 (4.0%)
2 (4.0%)

0.645
1
0.645

NS
NS
NS

Placebo
(n = 50)

Antibiotic
(n = 50)

4 (8.0%)
1 (2.0%)
2 (4.0%)
2 (4.0%)
2 (4.0%)
3 (6.0%)

other included studies of exacerbation of COPD, because of

either fever or pulmonary consolidation [18].
Studies varied with regard to whether corticosteroid treatment was permitted [19,7]. Only one study provided any information on the association of corticosteroid treatment with
antibiotic efcacy [1]. Corticosteroids were used in approximately 42% of the 362 exacerbations. The success rate was
reported to be better for antibiotic than placebo-treated
patients both in patients who were on corticosteroids and
those who were not.
The different study populations appear to have clinically
important differences in severity of illness, in terms of source
of patients, lung function, sputum purulence and level of care
[20,21]. When outcome data were reanalyzed with or without
the two studies conducted in the community [1,12] the results
did not differ. In addition, outcomes did not differ when
results were reanalyzed with or without the one trial conducted
in an ICU [14,22].
Nicotra and coworkers [4] completed a study on 40 patients
with COPD comparing tetracycline treatment with placebo.
Their assessment was based on lung function tests and blood
gases and after 7 days there was no difference between treatment groups. However, both arterial Po2 and peak ow
increased more in the tetracycline group. This was in agreement with our study in which more rapid improvement in peak
ow rate was observed among antibiotic group.
One trial [3] described a pilot trial comparing penicillin and
streptomycin with placebo in 30 patients hospitalized with
exacerbation of chronic bronchitis. All patients had purulent
sputum and half were described as severely ill. The study population had a mean age of 67.5 years, a mean PaCO2 of
70 mmHg, a mean PEFR of 88 L/min, a mean leukocyte count
of 12 109/L, and a fever of 37.3 C. Patients were examined
daily by a clinical assessor who was blinded to treatment
assignment and their clinical status was graded based on
obvious changes in their degree of well-being, color and dyspnea but not on the state of the sputum; the results were not
stratied according to severity of illness. In the antibiotic treated group, ten patients improved, three remained in an
unchanged condition, two deteriorated and one died. In the
placebo group, three patients improved, three remained
unchanged, nine deteriorated and three died. As the difference
in deterioration was statistically signicant the trial was halted
early. The investigators concluded that it was unethical to
include a placebo group in the subsequent larger trial.

The difference in success rate between antibiotic and treatment group in our study (88% versus 70%) and in failure with
deterioration (12% versus 30%) is of clinical signicance
because such patients were thought to be in need of additional
treatment, which certainly resulted in much costs and likely
was associated with increased morbidity and probably afford
the best argument for antibiotic therapy.
Argument against the use of antibiotic therapy would be
cost and side effects [23,24]. The cost of broad spectrum antibiotics like that we used during this study is relatively small and
should not deter their use. Side effects were not severe and
occurred no more often than with placebo. Most, if not all,
of our patients had had courses of broad-spectrum antibiotics
before they entered this trial, and presumably their physicians
specied a particular antibiotic in light of their past experience.
A drug was avoided if a patient was thought to be sensitive to
it, thereby decreasing the side effects seen in this study. It
would appear that, however, those side effects are likely to
be very uncommon and of little signicance in patients with
established COPD [25,26].
Antibiotic therapy would be more attractive if we were able
to identify kinds of exacerbation that are associated with the
greatest difference between antibiotics and placebo therapy.
Furthermore, these exacerbations could be identied at their
onset; the expense of close follow up in all patients could be
avoided [27,28]. As we included only type one exacerbations
with increased dyspnea, sputum amount and purulence, they
should benet from antibiotics. Comparison with other types
of exacerbations in which one or two symptoms are present
may not show such benets from antibiotic usage.
Limitations of the study
Since the denition of COPD has changed over the years, our
approach was to accept the inclusion of patients with a spirometric denition of COPD, COPD-like symptoms, or both
[29,30]. Nevertheless, differences in disease denition may bias
our results and this cannot be avoided as it reects the history
of research in COPD [29].
Another limitation is publication bias. Studies demonstrating a positive effect for antibiotic use are more likely to be published than negative studies. In order to minimize missing
studies we used extensive trial search criteria with no language
restrictions and made every effort to detect any unpublished or
ongoing studies [1,14].
When the results from included studies were combined
using meta-analytical techniques, antibiotics were clinically
superior to placebo in the management of exacerbations of
COPD. Since the earlier included trials were conducted before
the emergence of multi-drug-resistant organisms (in particular
to b-lactams and macrolides) and new antibiotics, they showed
only minimal benet with antibiotic treatment in the more severe exacerbations. Therefore, it is likely that the newer antibiotic therapies available now may lead to improved outcomes in
patients with exacerbations [31].
In conclusion, this study has clearly shown that in exacerbations of COPD associated with increased cough and sputum
purulence, antibiotic therapy, regardless of choice, signicantly
results in decrease in duration of treatment and more rapid
improvement in peak ow. These results should be interpreted
with caution as the differences in selection of patients, severity

Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
10.1016/j.ejcdt.2015.03.007

6
of illness and choice of antibiotic may alter treatment results.
Nevertheless, this study supports the use of antibiotics for
most patients with increased cough and sputum purulence with
type 1 exacerbations of COPD.
This study of antibiotic treatment for exacerbations with
COPD has shown evidence of clinical benet. This is most evident in those patients who are treated as outpatients. We do
not believe that it would be appropriate or ethical to conduct
further studies using placebo in patients admitted to hospital.
However, further research is needed on those patients with
non-purulent exacerbations looking at the effect of severity
of disease on treatment; what effect concomitant treatment
may have, particularly corticosteroid; which is the best antibiotic for treating exacerbations of COPD; and what is the ideal
duration of treatment. The priority for research should be to
look at patients with denite COPD who do not fulll the
three criteria set for an exacerbation; and longitudinal studies
looking at exacerbation in participants for whom all three criteria are fullled. Furthermore, an exact denition of what disease the individuals have should be a priority for any research.
Given the differences between hospital and community-based
studies, and the lack of studies in the community, some
research should be devoted to this large subset of people with
exacerbations.
Conict of interest
No conict of interest.
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Please cite this article in press as: W.A. Hassan et al., Impact of antibiotics on acute exacerbations of COPD, Egypt. J. Chest Dis. Tuberc. (2015), http://dx.doi.org/
10.1016/j.ejcdt.2015.03.007