Pulmonary Perspective
Antibiotics for Acute and Chronic Respiratory Infection
in Patients with Chronic Obstructive Pulmonary Disease
Marc Miravitlles1 and Antonio Anzueto2
1
Pneumology Department, Hospital Universitari Vall d’Hebron, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES),
Barcelona, Spain; and 2Division of Pulmonary Diseases/Critical Care Medicine, Department of Medicine, University of Texas Health Science Center
at San Antonio and Audie L. Murphy Memorial Veterans Hospital Division, South Texas Veterans Health Care System, San Antonio, Texas
Prevention and effective treatment of exacerbations are major
objectives in the management of patients with chronic obstructive
pulmonary disease (COPD). Antibiotics are mainstay treatment for
patients with severe COPD with an acute exacerbation that includes
increased sputum purulence and worsening shortness of breath.
Although such treatment is associated with clinical benefit, treat-
ment failure and relapse rates may be high, particularly in cases of
inadequate antibiotic therapy through incomplete resolution of the
initial exacerbation and persistent bacterial infection. These aspects
have led to recommendations for a stratified approach to antibiotic
therapy based on patient characteristics associated with increased
risk factors for failure. Patients at greatest risk for poor outcome
(i.e., those with severe COPD) are likely to derive greatest benefit
from early treatment with antibiotics. Long-term or intermittent
antibiotic treatment has been shown to prevent COPD exacerba-
tions and hospitalizations. These effects may be achieved by reduc-
ing bacterial load in the airways in stable state and/or bronchial
inflammation. Although systemic antibiotics are likely to remain the
core treatment for patients with moderate to severe exacerbated
COPD, inhaled antibiotics may represent a more optimal approach
for the treatment and prevention of COPD exacerbations in the
future. Regardless of the route of administration, further studies are
required to evaluate the potential long-term adverse events of
antibiotics and the development of bacterial resistance.
Keywords: exacerbations of chronic obstructive pulmonary disease;
antibiotics; bacteria; prevention; colonization
Approximately 70% of exacerbations in chronic obstructive pul-
monary disease (ECOPD) are caused by respiratory infections
including bacteria (40–60%), viruses (about 30%), and atypical
bacteria (5–10%) (1, 2). For the last 25 years, the clinical criteria
described by Anthonisen and colleagues (3) have been incorpo-
rated in clinical guidelines to help in selecting patients who
require empiric antibiotic therapy (4). More recent studies have
identified a change in sputum color or an increase in purulence
as a good surrogate marker for the presence of bacterial infec-
tion (5–7). Furthermore, only the change in sputum color was
identified as a predictor of good response with antibiotics in
a placebo-controlled clinical trial in patients with mild to
(Received in original form March 4, 2013; accepted in final form July 15, 2013)
Correspondence and requests for reprints should be addressed to Antonio
Anzueto, M.D., Audie L. Murphy Memorial Veterans Hospital, Pulmonary Diseases
Section (111E), 7400 Merton Minter Boulevard, San Antonio, TX 78284. E-mail:
anzueto@uthscsa.edu
This article has an online supplement, which is available from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 188, Iss. 9, pp 1052–1057, Nov 1, 2013
Copyright ª 2013 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201302-0289PP on August 7, 2013
Internet address: www.atsjournals.org
moderate COPD (8). Therefore, change in sputum color and in-
creased purulence are the only clinical features that help clinicians
to decide whether to use an antibiotic in ambulatory ECOPD.
Understanding of the role of bacteria during stable COPD is still
incomplete. In patients with stable COPD, the isolation of potentially
pathogenic microorganisms (PPMs) in respiratory samples ranges be-
tween 20% and 60% of cases (9–11). Some studies have suggested
that these bacteria contribute to chronic airway inflammation lead-
ing to COPD progression (9, 10, 12). Therefore, it has been sug-
gested that the term chronic bronchial infection would be more
appropriate when addressing the presence of significant concentra-
tions of PPMs in the lower airways of patients with stable COPD
(10, 13). Patients with chronic bronchial infection may constitute an
infective phenotype (10). Finally, the relevance of the described
microbiota in lung health must be established. Molecular culture–
independent techniques have identified bacteria previously not ame-
nable to culture. Analysis of the highly conserved 16S ribosomal
RNA gene has been used to assign phylogeny and allowed a picture
of the complete microbial community in an environment (i.e., upper
airway, sinus, bronchial tree, etc.) to be constructed, offering a more
comprehensive analysis than classical culture-based techniques (14).
The number of studies examining the lower airway microbiome is
limited and there is some overlap between bacteria seen in COPD
and healthy individuals (15); however, one study has reported a sig-
nificantly different bacterial community in patients with very severe
COPD compared with nonsmokers, smokers, and patients with cys-
tic fibrosis (16). Studies are clearly needed to understand the role of
these microbiomes in healthy individuals and patients with COPD,
and furthermore, we need to understand the impact of antibiotics,
given for either acute exacerbation or chronic disease, on these
bacterial communities.
In chronically infected patients it is possible that reduction of
airway bacterial load and/or prevention of new strain acquisition
by the use of antibiotics may reduce the frequency and severity of
exacerbations. The potential role of long-term antibiotic therapy
in the management of COPD was first investigated in trials con-
ducted during the 1950s and 1960s. However, these studies were
limited by small patient numbers, use of low doses of narrow-
spectrum antibiotics, and inadequate efficacy measurements.
Concerns over the potential for developing bacterial resistance
further hampered investigation into the value of this treatment
(17). Nevertheless, emergence of new antibiotic formulations
with improved sensitivities coupled with increased understanding
of the pathogenesis of COPD has led to renewed interest in the
role of long-term antibiotic use in the management of the condition,
although no agents are currently licensed for such therapy in COPD.
MECHANISMS OF ACTION
Compared with stable COPD, during ECOPD a much larger
percentage of patients have PPMs in addition to significantly
Pulmonary Perspective
higher concentrations of bacteria in the airways (18).Treatment
with appropriate antibiotics significantly decreases the bacterial
burden (and frequently eradicates the organisms that are sensi-
tive) and reduces clinical failure and the risk of progression to
more severe infections, such as pneumonia (19).
Although the increased airway inflammation present during
ECOPD is reduced after antibiotic treatment, this resolution
has been shown to be dependent on bacterial eradication (20).
The incomplete resolution of the initial exacerbation and per-
sistent bacterial infection appear to be important determinants
of the risk of relapse and need for rehospitalization.
Among the major goals of COPD treatment in the current
guidelines is the prevention of acute exacerbations (21). Clinical
studies have shown that long-term continuous or intermittent
use of antibiotics has a beneficial effect of reducing exacerba-
tion frequency and extending the time to the next exacerbation
(22, 23). The mechanism underlying this improvement is un-
clear. It is possible that the benefit of long-term antibiotic treat-
ment may be due to eradication of colonizing bacteria and/or
a reduction in chronic airway inflammation, although evidence
supporting this hypothesis is limited. While macrolides are
known to have not only antibacterial, but also antiinflammatory,
immunomodulatory, and antiviral effects, in addition to a possi-
ble effect against biofilm formation, it is not known which of
these actions is responsible for their efficacy when used for the
treatment of long-term respiratory conditions.
USE OF ANTIBIOTICS TO TREAT COPD
EXACERBATIONS
In 1987 Anthonisen and colleagues (3) reported the results of
a large-scale placebo-controlled trial designed to determine the
efficacy of antibiotics in ECOPD. In this study, 173 patients
with COPD [mean FEV1(%), 33%] were monitored for
3.5 years. Patients classified as type 1 ECOPD (with increased
shortness of breath, increased sputum production, and change in
sputum purulence) and using antibiotics (amoxicillin, trimethoprim-
sulfamethoxazole, co-trimoxazole, or doxycycline) showed signifi-
cant clinical benefits as compared with placebo, whereas there was
no significant difference in the success rates between antibiotic and
placebo in patients with only one of these symptoms (type 3).
Overall, the antibiotic-treated patients showed more rapid improve-
ment in peak flow and a greater percentage of clinical success. In
addition, the length of illness was 2 days shorter for the antibiotic-
treated group. The major limitations of this study were the lack of
microbiology data and the assumption that all antibiotics were
equivalent. We also must take into consideration that this study
was done more than 25 years ago, and there has been a significant
change in the patterns of bacterial resistance, and in the patient
characteristics and patterns of treatment.
In another clinical study, Allegra and colleagues (24) found
a significant benefit with the use of amoxicillin–clavulanate
therapy compared with placebo in patients with moderate to
severe disease. Patients receiving this antibiotic exhibited a
higher success rate on Day 5 (86.4 vs. 50.3% in the placebo
group; P , 0.01) and lower frequency of recurrent exacerba-
tions. A double-blind, placebo-controlled study investigated the
efficacy of amoxicillin–clavulanate in patients with exacerbated
mild to moderate COPD (FEV1 . 50% predicted) treated in
primary care confirmed these findings. This study demonstrated
significant superiority for the antibiotic-treated group in clinical
cure rates (74.1 vs. 59.9%; difference, 14.2%; 95% confidence
interval, 3.7 to 24.3%). Furthermore, the median time to the
next exacerbation was also significantly prolonged in patients
receiving antibiotic compared with placebo (233 d compared
with 160 d; P , 0.05). Interestingly, this study demonstrated
1053
that sputum purulence was the most reliable marker of clinical
failure in the placebo group (8). Another randomized, placebo-
controlled trial investigated the efficacy of doxycycline in addi-
tion to systemic corticosteroids in the treatment of hospitalized
patients with ECOPD. Doxycycline was equivalent to placebo
in the primary end-point clinical success on Day 30; however, it
was superior to placebo in other secondary end points such as
clinical success and clinical cure on Day 10, microbiological
success, use of open label antibiotics, and symptom resolution.
The antibiotic was superior in patients with higher plasma levels
of C-reactive protein (25). The poor results observed with doxy-
cycline on Day 30 could be explained by the antibiotic bacteri-
ological spectrum and local bacterial resistance patterns.
During an ECOPD, antibiotics can reduce the burden of bac-
teria in the airway, thus having an impact on the risk of progression
to more severe infections, such as pneumonia. A prospective, ran-
domized, double-blind, placebo-controlled trial, evaluating the
use of ofloxacin in 90 consecutive patients with ECOPD who re-
quired mechanical ventilation showed that the antibiotic-treated
group had a significantly lower in-hospital mortality rate (4 vs.
22%; P ¼ 0.01) and reduced length of hospital stay (14.9 vs.
24.5 d; P ¼ 0.01) compared with the placebo group. In addition,
the ofloxacin-treated patients were less likely to develop pneu-
monia, especially during the first week of mechanical ventilation
(19). A summary of the placebo-controlled trials compared with
antibiotics in ECOPD is presented in Table E1 in the online
supplement.
Antibiotic resistance is a major public health problem world-
wide, and international efforts are needed to counteract its emer-
gence. Antibiotic consumption is increasingly being recognized
as the main cause of this emerging resistance (26). Therefore, the
recognition of clinical characteristics that identify patients with
ECOPD that can be safely treated without antibiotics is ex-
tremely important. In the case of ambulatory patients with mild
to moderate disease, the absence of sputum purulence and low
values of C-reactive protein test are associated with high rates
of clinical cure without antibiotics (27). Similarly, a small study
in admitted patients with ECOPD observed similar short- and
long-term outcomes in patients with purulent sputum treated
with antibiotics compared with patients with nonpurulent spu-
tum not treated with antibiotics, suggesting that use of antibi-
otics could be avoided in this last group (28).
After the decision of initiating empirical antibiotic therapy,
the choice of antibiotic must be considered. The reported relapse
rates for patients with ECOPD range from 17 to 32%, and differ
according to the antibiotics prescribed (29, 30). In one study,
moxifloxacin treatment was compared with amoxicillin–clavulanate
for the primary end point of clinical failure at 8 weeks posttherapy
in patients with moderate to severe COPD [mean FEV1(%) ¼
39%] and risk factors for failure. There were no significant
differences in the primary end point of the study; however,
moxifloxacin resulted in significantly lower clinical failure and
higher bacteriological eradication in the subpopulation of
patients with bacterial pathogens isolated from sputum at inclu-
sion (31). These results suggest that in confirmed bacterial
ECOPD the choice of antibiotic, particularly in patients with
severe disease, may result in different outcomes and justifies
antibiotic selection based on patterns of antimicrobial resistance
and the clinical characteristics of the patients.
USE OF ANTIBIOTICS TO PREVENT
COPD EXACERBATIONS
One of the unmet needs in the treatment of COPD is the pre-
vention of exacerbations in patients with severe disease. There-
fore, additional use of long-term antibiotics has been advocated
1054 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
in these patients. In the last decade, six studies have been published
showing the use of continuous long-term antibiotics in patients with
COPD (22, 32–35), and one employing intermittent/pulsed treat-
ment has been published (23) (Table E2). In the first open-label,
12-month study, erythromycin therapy was found to have benefi-
cial effects on the prevention of ECOPD (32). The proportion of
patients experiencing one or more exacerbations during the
treatment period was lower in the erythromycin group (11%)
compared with the control group (56%), and significantly more
control patients were hospitalized because of exacerbations
(P ¼ 0.0007). A subsequent trial of erythromycin showed a sig-
nificant reduction in ECOPD and the median time to exacer-
bation over a 12-month follow-up with no differences in lung
function or inflammatory markers (33). However, other studies
showed significant reductions in inflammatory markers and neu-
trophil counts after 6 months of treatment with azithromycin
(36) and erythromycin (35). In a large pivotal study, Albert and
colleagues (22) reported the use of 12-month treatment with
daily azithromycin in the prevention of ECOPD. In this study,
the addition of azithromycin to standard therapy was associated
with a 27% decrease in the frequency of exacerbations and an
increase in the median time to exacerbation (266 vs. 174 d,
respectively; P , 0.001). In another 12-month retrospective
study, azithromycin was also shown to reduce exacerbations,
hospitalizations, and length of hospital stay (34). The risk of
increasing bacterial resistance with long-term use of macrolides
is a concern. In view of the large patient population affected by
COPD, widespread use of macrolides, particularly azithromy-
cin, has the potential to substantially influence antimicrobial
resistance rates of a range of respiratory microbes (37). In the
study by Albert and colleagues (22), the incidence of resistance
to macrolides in respiratory pathogens isolated from nasopha-
ryngeal swabs was significantly increased in the group of
patients receiving azithromycin compared with the placebo arm.
Intermittent, pulsed fluoroquinolone antibiotic therapy in
patients with COPD was reported by Sethi and colleagues
(23) In this study, moxifloxacin was given once daily for 5 days,
and the treatment was repeated every 8 weeks for a total of six
courses. Pulsed therapy with moxifloxacin reduced the odds of
an exacerbation by 25% in the primary population for efficacy
analysis (per protocol population as prespecified in the proto-
col) in patients with moderate to severe COPD, whereas in
a post hoc analysis, this reduction was 45% in patients with
purulent or mucopurulent sputum at baseline. No relevant bac-
terial resistance was reported in the study with pulsed moxiflox-
acin treatment (23). However, it cannot be ruled out that more
prolonged courses of intermittent treatment with this or other
drugs might result in increases in resistance and, therefore, clear
stratification of patients is needed before this therapy can be
recommended.
DOSING STRATEGIES FOR ANTIBIOTICS
The standard duration of antibiotic administration in ECOPD
used to be 10 days. However, short-course therapy may reduce
the risk of adverse events and the development of bacterial re-
sistance as a result of shorter exposure to antibiotics. A meta-
analysis of 7 randomized controlled trials, with a total patient
population of 3,083, compared different treatment durations
of the same antibiotic regimen. The short-duration treatment
proved as effective and safer than long-duration antimicrobial
therapy in patients with ECOPD (38). Short-course therapy
was associated with fewer adverse events as compared with
standard, longer duration treatment. A second meta-analysis
involving 21 double-blind studies and 10,698 patients also found
that clinical cure rates, at both early and late follow-up, and
VOL 188 2013
bacteriological cure rates observed with short-course therapy
were comparable to those achieved with conventional duration
therapy in patients with mild to moderate exacerbations (39).
Thus, a shorter course of antibiotic treatment may enhance
compliance and reduce antibiotic costs.
Clinical studies have demonstrated comparable, and in some
cases, superior efficacy for short-course, 5-day fluoroquinolone
therapy compared with that of standard therapy in ECOPD,
as measured by both clinical and bacteriological outcomes (40).
Furthermore, short-course, high-dose fluoroquinolone therapy
also demonstrates more rapid symptom resolution and faster re-
covery rates than traditional therapy using nonfluoroquinolones
for standard treatment durations (41).
COMBINATION OF ANTIBIOTICS AND
SYSTEMIC CORTICOSTEROIDS
It is unclear whether antibiotics have additional benefits when
applied in patients with severe exacerbations that have already
been treated with systemic corticosteroids. Sachs and colleagues
(42) suggested that antibiotics did not provide additional clinical
benefit when corticosteroids were given, irrespective of sputum
color or bacterial involvement. However, this study had several
limitations including a small sample size (n ¼ 71), a population
with mild disease, and enrolled patients with COPD and patients
with asthma. In the study by Daniels and colleagues (25), the lack
of an effect with doxycycline on top of systemic corticosteroids
as the primary end point (clinical success on Day 30) may be
related to the scarce antibacterial activity of doxycycline against
pathogens such as Streptococcus pneumoniae and Haemophilus
influenzae.
More recent studies suggest that there are different pheno-
types of COPD exacerbations, and systemic corticosteroids
may be beneficial in those with predominant eosinophilic inflam-
mation (43). The different inflammatory profile of COPD exac-
erbations will need to be taken into consideration in the design
of clinical trials examining the efficacy of antibiotics and/or
corticosteroids in this disease.
MEASURING EFFECTS AND OUTCOMES
Clinical and microbiological end points in trials of antibiotic
treatment of ECOPD are not well defined. Microbiological
results depend on the production of a good-quality sputum sam-
ple, which results in a positive sputum culture in only 20–50% of
the patients. Clinical results are still based on the definition
of Chow and colleagues (44): End points are defined as cure
(a complete resolution of signs and symptoms associated with
the exacerbation) or improvement (a resolution or reduction of
the symptoms and signs without new symptoms and signs asso-
ciated with the exacerbation). Clinical success is considered
when either cure or improvement is observed. Failure is defined
as incomplete resolution, persistence, or worsening of symp-
toms that require a new course of antibiotics and/or oral cortico-
steroids or hospitalization. Evaluation is usually performed at
the end-of-therapy visit (Days 9–14). This short time frame may
not allow the identification of clinical relapses if they occur after
initial improvement. Some antibiotics may decrease bacterial
load sufficiently to produce an improvement in symptoms that
can be perceived as a clinical success at the end of treatment,
but when treatment is discontinued, the remaining microorgan-
isms will increase in numbers and produce recurrent symptoms
of exacerbation (45).
Because of the limitations of the clinical outcomes, there has
been a growing interest in the use of diary cards and standardized
questionnaires to evaluate ECOPD. The use of symptom-based
Pulmonary Perspective
diary cards may allow the quantification of the intensity and du-
ration of patient symptoms and comparison of different treat-
ment outcomes (46–48). More recently, the Exacerbations of
Chronic Pulmonary Disease Tool (EXACT), a new patient-
reported outcome diary, has been developed (49). The EXACT
is a validated instrument for quantifying the frequency, severity,
and duration of exacerbations. It consists of 14 items that can be
incorporated in the form of an e-diary, with scores ranges from
0 to 100 and higher scores indicating a more severe exacerba-
tion. Some standardized quality of life questionnaires have been
demonstrated to be responsive to changes in health status dur-
ing or after an exacerbation. The Saint George’s Respiratory
Questionnaire has been shown to be useful in monitoring re-
covery from ECOPD (50). The COPD Assessment Test is
a short (eight-item) questionnaire that has been demonstrated
to provide a reliable score of exacerbation severity (51). The
generic European Quality of Life Scale has been demonstrated
to be responsive to recovery from ECOPD (52, 53) and is a good
predictor of treatment failure (53). The COPD Severity Score is
a severity scale developed by Eisner and colleagues (54) that is
responsive to recovery from exacerbations and provides better
predictive value for clinical success than the usual physiologic
and clinical variables (53). However, these quality of life or
disease severity questionnaires have not been adequately tested
in comparative clinical trials of therapies for ECOPD.
ADVERSE EFFECTS OF ANTIBIOTICS
The adverse effects of antibiotics are variable and depend on the
type of drug used and concomitant comorbid conditions. Regard-
ing long-term use, treatment with erythromycin often results in
significant gastrointestinal symptoms including nausea, vomiting,
abdominal cramps, and diarrhea. This drug also has significant
interaction with drugs that are metabolized in the liver via the
P-450 enzyme system. The newer generation macrolides are bet-
ter tolerated, have minimal gastrointestinal symptoms, and fewer
drug interactions. However, clarithromycin has a distinctive taste
perversion that is less common with the extended release prep-
aration. Macrolides and quinolones have also been associated
with a prolonged QTc interval; thus, the U.S. Food and Drug
Administration recommends that these antibiotics not be given
to patients receiving class IA or class III antiarrhythmic agents or
to patients with known prolongation of the QTc interval. Even 5-
day treatment with azithromycin has been associated with a small
absolute increase in cardiovascular deaths (55).
Long-term azithromycin treatment led to changes in nasal
bacteria flora, increasing the prevalence of macrolide-resistant
bacteria (22). There are some concerns about the possibility
of hearing loss associated with long-term use of macrolides
(22). These issues, coupled with concerns of increased antibiotic
resistance, indicate that until further well-controlled studies are
conducted, such treatment should be reserved for patients with
severe COPD who experience frequent exacerbations requiring
multiple antibiotic treatments despite optimal bronchodilator
and antiinflammatory therapy (56).
In general, quinolones are well tolerated and have an adverse
event rate of approximately 4–5%. These adverse effects, which
are generally mild and transient, include rash, dizziness, head-
ache, gastrointestinal disturbances (usually nausea, vomiting,
dyspepsia, diarrhea, abdominal pain, etc.), and minor hemato-
logical abnormalities. The gastrointestinal side effects of quino-
lones are usually as severe and frequent as those associated with
macrolides or with amoxicillin–clavulanate (57). Despite the
potential for cardiac side effects, clinical trials have demon-
strated the cardiac safety of fluoroquinolones even in elderly
hospitalized patients (58). Some of the quinolone preparations
1055
can interact with medications that are metabolized by the he-
patic cytochrome P-450 system.
CLINICAL GUIDELINES
The current clinical guidelines of antibiotic treatment in ECOPD
are based on the Anthonisen criteria (3) and recommend anti-
biotic treatment when the three key symptoms are present. In
addition, antibiotics are also recommended in severe ECOPD
or in hospitalized patients with only two of the symptoms when
increased purulence of sputum is one of them and/or in patients
who require invasive or noninvasive ventilation (4). The Cana-
dian Thoracic Society guidelines were the first to adopt an ap-
proach to antibiotic choice based on risk factors for poor
outcome and the most likely pathogens involved (Table 1) (59).
In general, COPD guidelines do not recommend the use of
long-term antibiotics for the prevention of exacerbations. How-
ever, evidence of the efficacy of macrolides and, to a lesser ex-
tent, quinolones has been accumulating. More recent guidelines
have included, for the first time, a recommendation related to the
use of long-term antibiotics in a specific subgroup of patients with
severe COPD (56, 60). This treatment must be monitored closely
for the possible development of side effects and/or changes in the
patterns of bacterial resistance.
FUTURE DEVELOPMENTS OF ANTIBIOTICS FOR COPD
Inhaled antibiotics are likely to have a future role in the long-
term management of patients with COPD, because this route
of administration has the ability to target drug delivery directly
to the respiratory tract, reducing systemic exposure and maxi-
mizing pharmacodynamic parameters. Inhaled antibiotics have
already been used in the treatment of a number of respiratory
tract infections, including cystic fibrosis (61) and bronchiectasis
(62, 63).
To date, there has been only one report investigating the use
of inhaled antibiotics in patients with COPD. The study, con-
ducted by Dal Negro and colleagues (64), examined the effects
of 14-day, twice daily treatment with inhaled tobramycin ne-
bulizer solution (TNS) on clinical outcome and inflammatory
markers in bronchial secretions in a small cohort (n ¼ 13) of
TABLE 1. RISK CLASSIFICATION AND MOST FREQUENT
MICROORGANISMS
FEV1 Most Frequent
(% Predicted) Microorganisms
Mild to moderate COPD without .50% Haemophilus influenzae
risk factors Moraxella catarrhalis
Streptococcus pneumoniae
Chlamydia pneumoniae
Mycoplasma pneumoniae
Mild to moderate COPD with risk .50% Haemophilus influenzae
factors* Moraxella catarrhalis
PRSP
Severe COPD 30–50% Haemophilus influenzae
Moraxella catarrhalis
PRSP
Enteric gram negatives
Very severe COPD ,30% Haemophilus influenzae
PRSP
Enteric gram negatives
P. aeruginosa
Definition of abbreviations: COPD ¼ chronic obstructive pulmonary disease;
PRSP ¼ penicillin-resistant S. pneumoniae.
Data from References 59 and 63.
* Risk factors are as follows: age older than 65, cardiac comorbidity, and fre-
quent exacerbations in the previous year.
1056 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
multiresistant P. aeruginosa–colonized patients with severe
COPD. Two-week treatment with TNS resulted in a substantial
reduction from baseline of proinflammatory chemotactic medi-
ators and also led to a 42% decrease in the incidence of exac-
erbations, when compared with the 6-month period before
initiating TNS therapy. Ongoing and future trials using inhaled
powder formulation of antibiotics (quinolones) will provide in-
formation as to whether inhaled antibiotics are a useful thera-
peutic option in the prevention of ECOPD.
CONCLUSIONS
Antibiotics are the mainstay of treatment for patients with mod-
erate to severe COPD with exacerbations that include increased
purulence sputum. Antibiotics are associated with clinical ben-
efit, but in high-risk patients treatment failure and relapse rates
may be high in cases of inadequate antibiotic efficacy because of
incomplete resolution of the initial exacerbation and persistent
bacterial infection. Therefore, it is important to identify patients
at greatest risk for poor outcomes, because they are the patients
who will likely derive the greatest benefits from early treatment
with the most potent antibiotic therapy.
Studies conducted over the last decade have indicated that
treatment with long-term or intermittent antibiotics may have
a beneficial effect by reducing the frequency of exacerbations
and hospitalizations or by extending time to next exacerbation.
Although systemic antibiotics are likely to remain the core treat-
ment for patients with moderate to severe exacerbated COPD,
inhaled antibiotics may represent a more optimal approach for
the treatment and prevention of exacerbations in the future. Re-
gardless of the route of administration, further studies are required
to estimate the potential risks of antibiotic prophylaxis in terms of
long-term adverse events and the development of resistance, and
to assess whether the benefits outweigh the potential risks.
Author disclosures are available with the text of this article at www.atsjournals.org.
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