Journal of Infection (2013) 67, 497e515

www.elsevierhealth.com/journals/jinf

REVIEW

Antibiotics for treatment and prevention

of exacerbations of chronic obstructive
pulmonary disease
Robert Wilson a,*, Sanjay Sethi b, Antonio Anzueto c,
Marc Miravitlles d

a
Host Defence Unit, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
b
Division of Pulmonary, Critical Care and Sleep Medicine, University at Buffalo, State University of
New York, Buffalo, NY, USA
c
University of Texas Health Science Center at San Antonio, South Texas Veterans Health Care System,
San Antonio, TX, USA
d
Pneumology Department, Hospital Universitari Vall d’Hebron, Ciber de Enfermedades Respiratorias
(CIBERES), Barcelona, Spain

Accepted 16 August 2013

Available online 22 August 2013

KEYWORDS
Acute bacterial
exacerbation of COPD;
Chronic inflammation;
Inhalation therapy;
Long-term outcome;
Antibiotics;
Fluoroquinolones;
Macrolides
Summary Acute exacerbations (AE) can be recurrent problems for patients with moderate-
to-severe chronic obstructive pulmonary disease (COPD) increasing morbidity and mortality.
Evidence suggests that
50% of acute exacerbations involve bacteria requiring treatment
with an antibiotic which should have high activity against the causative pathogens. However,
sputum analysis is not a pre-requisite for antibiotic prescription in outpatients as results are
delayed and patients are likely to be colonised with bacteria in the stable state. Clinicians
rely on the clinical symptoms, sputum appearance and the patient’s medical history to
decide if an AE-COPD should be treated with antibiotics. This article reviews the available
data of antibiotic trials in AE-COPD. Management of frequent exacerbators is particularly
challenging for physicians. This may include antibiotic prophylaxis, especially macrolides
because of anti-inflammatory properties; though successful in reducing exacerbations, con-
cerns about resistance development remain. Inhalation of antibiotics achieves high local con-
centrations and minimal systemic exposure; therefore, it may represent an attractive
alternative for antibiotic prophylaxis in certain COPD patients. Inhaled antibiotic prophylaxis

* Corresponding author. Tel.: þ44 207 351 8337; fax: þ44 207 351 8338.
E-mail address: r.wilson@rbht.nhs.uk (R. Wilson).

0163-4453 ª 2013 The Authors. Published by Elsevier Ltd on behalf of the The British Infection Association. Open access under
CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.jinf.2013.08.010
498 R. Wilson et al.

has been successfully used in other respiratory conditions such as non-cystic fibrosis bronchi-
ectasis which itself might be present in COPD patients who have chronic bacterial infection,
particularly with Pseudomonas aeruginosa.
ª 2013 The Authors. Published by Elsevier Ltd on behalf of the The British Infection Association.
All rights reserved.

Introduction important therapeutic goals for antimicrobial treatment

in COPD that may improve, in addition to other conven-
tional treatments (e.g. long-acting bronchodilators and
Chronic obstructive pulmonary disease (COPD) is a substan-
inhaled corticosteroids), the patients’ quality of life.
tial public health burden, associated with a high incidence
The rate at which exacerbations occur appears to reflect
of morbidity and mortality and affecting 24 million people
an independent susceptibility phenotype.5,29 Furthermore,
in the USA and approximately 7% of Europeans.1e3 The pre-
exacerbations appear to cluster together, with some pa-
dicted number of affected people in Asia Pacific region is
tients remaining at high risk for recurrent exacerbation
even higher (>55 million).4 The progressive course of
for some weeks after the initial exacerbation,5,9,30,31
COPD is accelerated by acute exacerbations (AE-COPD),
possibly due to ongoing lung and systemic inflammation.32
which are episodes of worsening of symptoms, which are
While acquisition of new strains of respiratory pathogens
the most frequent cause of hospitalisations and death
is an important mechanism underlying acute COPD exacer-
among COPD patients.5e8 Health status of hospitalised pa-
bations,33 chronic microbial colonisation of the lower respi-
tients with severe exacerbations declines more rapidly af-
ratory tract is also relevant.34e36 This colonisation is likely
ter the second admission with risk of mortality remaining
to contribute to chronic inflammation and progressive loss
high for approximately 90 days after every severe episode.7
of lung function in COPD due to increased rate of exacer-
Therefore, treatments that reduce exacerbation frequency
bations.33,35e39 Treatments aimed at reducing bacterial
will have a significant impact on health status, survival and
colonisation, which may be regarded as chronic infection
reduce the economic burden of COPD.9,10
in the presence of an inflammatory response,40 may, there-
Treatment with inhaled corticosteroids, long-acting
fore, help reduce the progression of the disease. It is also
anticholinergics or beta-agonists appears to have modest
likely that the chronic inflammation in COPD compromises
but significant effects on preventing or reducing subse-
innate lung defence, increasing susceptibility to acute
quent moderate and severe exacerbations in COPD pa-
infection and thus the risk of subsequent exacerbations.
tients.11e14 However, improvements in the treatment of
Identifying the sub-group of COPD patients who are subject
stable COPD are needed to further decrease exacerbations
to this vicious cycle of chronic inflammation and infection is
and improve outcomes. Evidence based on sputum culture
challenging, though infection is signalled by the presence of
results suggests that bacterial infection may be responsible
chronic purulent sputum production. High resolution CT
for around half of AE-COPD,15 with a clear relationship be-
scan may help identify bronchiectasis, particularly in the
ing demonstrated between sputum purulence and the pres-
presence of Pseudomonas aeruginosa.41e43 In the future,
ence of bacteria.16,17 For this reason, current guidelines
sputum biomarkers might help in management.44
recommend acute antibiotic therapy for patients with
Traditionally, most antibiotic clinical trials have focussed
more severe symptoms of AE-COPD, with treatment typi-
on short-term clinical efficacy in the treatment of AE-COPD.
cally lasting for 5e7 days.18e21 In particular, guidelines is-
Recently, information has emerged on the longer-term out-
sued by the Global Initiative for Chronic Obstructive Lung
comes of acute treatment for an exacerbation (i.e. several
Disease (GOLD) and the Joint Task Force of the European
weeks or months after initial antimicrobial treatment), and
Respiratory Society and the European Society for Clinical
on the possible value of long-term antibiotic therapy as a
Microbiology and Infectious Diseases advocate antibiotic
longer-term strategy to prevent future exacerbations.45,46
use for those with Anthonisen type I (worsening dyspnoea
This article reviews the current evidence on the impact of
with increased sputum volume and purulence) or type II
acute antibiotic treatment on the long-term outcomes in
(change in any two of these symptoms, particularly if one
COPD, explores the potential for the use of prophylactic an-
of these symptoms is increase in sputum purulence) epi-
tibiotics and discusses the possible role of inhaled antibiotics
sodes,18,20,21 while the Canadian Thoracic Society suggests
in patients with the condition.
that antibiotics are beneficial for severe purulent AE-
COPD (i.e. new increased expectoration of mucopurulent
sputum and dyspnoea).19 Nevertheless, while such treat-
Impact of acute antibiotic treatment on long-
ment has been shown to reduce the risk of subsequent ex- term outcome in AE-COPD
acerbations, relapse is common.22 Failure may be related
to inadequate antibiotic efficacy, which through incom- Clarifying the precise benefit of antibiotics in AE-COPD
plete resolution of the initial exacerbation and persistent patients is challenging since few placebo-controlled clinical
bacterial infection is likely to influence risk of relapse.23e27 trials have been conducted in this population. Older studies,
Indeed, confirmed bacterial eradication following antibi- however, show that patients with more symptomatic exacer-
otic therapy has been shown to be associated with higher bations, such as those with increased dyspnoea, sputum
clinical cure rates in patients with AE-COPD.28 Effective production and purulence [Anthonisen type 1 exacerbation],18
treatment of the acute exacerbation and reducing the frequent exacerbations or exacerbations requiring hospital-
risk of a subsequent bacterial exacerbation are thus isation26,47,48 derive benefit from antibiotic treatment. There
Antibiotics for treatment and prevention of AE-COPD
have been two recent placebo-controlled trials of antibiotics
in AE-COPD.26,27 In one study, addition of 7-day doxycycline
treatment to systemic corticosteroids in patients hospitalised
with AE-COPD, showed limited benefit from the antibiotic
treatment. The primary clinical endpoint of clinical success
on Day 30 was not met (61% vs 53%; odds ratio [OR] 1.3;
P Z 0.32), with the two arms also being equivalent for clinical
cure at Day 30.26 Although doxycycline was found to be supe-
rior to placebo in terms of clinical success (OR 1.9; P Z 0.03)
and clinical cure (OR 1.9; P Z 0.01) on Day 10 of the study,26
such treatment had no effect on lung function or systemic
inflammation (measured by change in FEV1 and serum C-reac-
tive protein, respectively, at Days 10 or 30). The authors
concluded that failure of the primary outcome may have
been due to the use of steroids, which may have limited the
benefit of antibiotics in this study. Alternatively, the lack of ef-
fect may have been due to insufficient antibacterial activity of
doxycycline; indeed, the rate of bacteriological eradication of
the offending pathogen in this study was only 67% with doxycy-
cline versus 34% with placebo, which could explain the lack of
durability of the clinical efficacy. Llor et al.27 in an outpatient
study of the efficacy of antibiotics in acute exacerbation of
mild-to-moderate COPD demonstrated that amoxicillin-
clavulanate is associated with greater clinical success
compared to placebo at the end-of-therapy visit (Days 9e11)
for those with Anthonisen type II criteria (74.1% vs 59.9%,
respectively; 95% CI of the difference in percentage of success
3.7e24.3%). This study showed that there are clear short-term
benefits from antibiotics in an outpatient setting in patients
without severe disease.27
Based on these and previous studies, the short-term
benefit in terms of clinical cure or success of about 13e15%
above placebo is seen with antibiotic use. Interestingly, this
magnitude of benefit is very similar to what is seen with
systemic steroid use at exacerbation. Few studies have
addressed whether antibiotic treatments have any enduring
effects. This is due to the fact that most antibiotic studies
only include follow up for up to 21 days after the end-of-
treatment.49e54 These follow-up periods are likely to be far
too short to identify all relapses, since risk of relapse is
highest in the 8-week period after the end-of-therapy.30
The effect of a single course of acute antibiotic treatment
on longer-term outcomes has been examined in some
studies, with patients being followed for between 8 weeks
and 1 year.27,28,31,55e61 Only one of these studies27 was pla-
cebo controlled, while the remainder were antibiotic com-
parison trials. In the placebo-controlled trial by Llor et al.
discussed above, amoxicillin/clavulanate was associated
with a significantly prolonged time to the next exacerbation
during the long-term follow-up period (233 days vs 160
days; P < 0.05).27 The antibiotic comparison trials are
important also, as they demonstrate that antibiotic choice
impacts on long-term outcomes in AE-COPD, specifically
reducing clinical relapses, the need for additional antibi-
otics and prolonging the time to the next exacerbation.
However, not all studies demonstrated differences in
long-term outcomes between antibiotic treatments. Antibi-
otic comparison trials where long-term outcomes of exacer-
bations were examined are summarised in Table 1.
Comparison between these trials is difficult due to the
fact that some enrolled patients with AE-COPD, while
others involved patients with exacerbations of chronic
499
bronchitis; patients included may, therefore, reflect
different inflammatory sub-phenotypes and varying
severity of airflow obstruction within COPD.62 The end-
points employed and the demographic characteristics of
the study populations also varied between studies. For
example, in the study reporting the longest follow-up
period of one year, patients receiving antibiotic treatment
with either levofloxacin or clarithromycin experienced a
mean exacerbation-free interval of more than 300 days.59
In a further study employing a 6-month follow-up, antibi-
otic treatment with levofloxacin or clarithromycin led to
an infection-free interval of 112 and 102 days, respec-
tively.58 The difference in exacerbation-free interval re-
sulting from levofloxacin treatment in these two studies
(300 days vs 112 days) is unclear, but may be due to the
fact that 82% of patients in the latter study had severe or
very severe COPD (forced expiratory volume in 1 s
[FEV1] < 50% predicted),58 in contrast to only 27% of severe
patients in the former study.59
The pioneering trial in this field by Chodosh et al.60
demonstrated that ciprofloxacin achieved higher bacterio-
logical eradication rates than clarithromycin, however,
with a non-significant increase in the infection-free interval
associated with ciprofloxacin (142 vs 51 days, P Z 0.15).
The MOSAIC trial, a large study enrolling patients with sta-
ble COPD prior to an acute exacerbation, showed significant
improvement in long-term outcomes with moxifloxacin dur-
ing a 9-month follow-up period versus standard antibiotics
(amoxicillin, clarithromycin or cefuroxime-axetil)55 report-
ing delayed onset of a composite failure event (treatment
failure and/or new exacerbation and/or any further antibi-
otic treatment). In two other studies, gemifloxacin was
associated with significantly lower relapse rates in 6
months, non-significant reduction in hospitalisations
(P Z 0.059) and better health status scores at 6 months
than clarithromycin.9,31 A smaller study, conducted by
Nouira et al., was not able to show any difference in
long-term outcomes in hospitalised patients between cipro-
floxacin and trimethoprim-sulfamethoxazole.61 In the
recently published MAESTRAL study, while moxifloxacin
treatment was comparable to amoxicillin/clavulanic acid
for the primary endpoint of clinical failure at 8-weeks
post-therapy, moxifloxacin resulted in significantly lower
clinical failure and higher bacteriological eradication in a
sub-population of patients with bacterial pathogens iso-
lated from sputum at the time of exacerbation.28
The exact mechanism(s) underlying the effects of acute
antibiotic treatment on long-term outcome is (are) uncer-
tain, though eradication of the infecting bacteria causing
the exacerbation is likely to play a key role. This was best
demonstrated in the MAESTRAL study, in which in the post-
hoc assessment of a sub-group of patients with bacterial
pathogens isolated from sputum at the time of exacerba-
tion, a significant relationship was observed between
bacterial eradication at end-of-treatment (EOT) and the
rate of clinical cure at 8 weeks. This relationship was seen
both in the overall population and in moxifloxacin-treated
patients, though the correlation was not present in those
treated with amoxicillin/clavulanic acid.28 Interestingly,
the studies that have shown significant differences
between the fluoroquinolones and the comparators in
long-term outcomes have been conducted with agents
Table 1 Studies reporting long-term effects of acute oral antibiotic therapy on AE-COPD or AECB.

500
Study (total Study Diagnosis/patient characteristics Treatment Endpoint Duration of Long-term
number of design at baseline (mean) follow-up outcome
patients)
Chodosh et al.60 Randomised, Diagnosis: AECB 14 Days Infection-free 36 Weeks  Non-significant trend towards
(n Z 491) double-blind, Mean age: ciprofloxacin ciprofloxacin interval between AECB longer infection-free interval
multicentre 59 yrs; clarithromycin 60 yrs 500 mg qd vs for ciprofloxacin (142 vs 51
Current smokers: ciprofloxacin 14 days days for clarithromycin;
P Z 0.15)
38%; clarithromycin 31% clarithromycin
 Bacteriological eradication was
Comorbidity: N/R 500 mg bid significantly higher for
FEV1 < 50% predicted: N/R ciprofloxacin (91% vs 77%;
Anthonisen type 2/3: P < 0.01)
ciprofloxacin 21%;
clarithromycin 26%
2 Exacerbations in
previous yr: ciprofloxacin 68%;
clarithromycin 70%
Grassi et al.56 Randomised, Diagnosis: AECB 5 Days Clinical response 6 Months  Comparable clinical success
(n Z 476) open-label, Mean age: moxifloxacin 70 yrs: moxifloxacin at TOC (10 d after at TOC (91% vs 89%)
multicentre ceftriaxone 69 yrs 400 mg PO qd vs end-of-therapy)  Lower relapse rate (23% vs 28%;
Current smokers: 22% 7 days ceftriaxone NS) greater cost savings (V1993
vs V2219) and lower
Comorbidity: N/Ra 1 g IM qd
hospitalisation rate (1864 vs
FEV1 < 50% predicted: N/R 2001) for moxifloxacin
Exacerbations in previous yr: 3.0
Wilson et al.31 Randomised, Diagnosis: AECB 5 Days gemifloxacin Long-term effect 26 Weeks  Similar clinical
(n Z 712) double-blind, Mean age: gemifloxacin: 58 yrs; 320 mg qd vs 7 days of therapy on AECB success rates between
multicentre clarithromycin 58 yrs clarithromycin recurrence requiring treatments after 2e3
Current smokers: gemifloxacin: 500 mg bid additional antibiotic weeks (85.4% vs 84.6%
 Significantly more
44%; clarithromycin 47% therapy after resolution
gemifloxacin patients
Mean duration of chronic of the initial episode remained free of
bronchitis: gemifloxacin: 13 yrs; AECB recurrence
clarithromycin 12 yrs (71% vs 59%; P Z 0.016)
Comorbidity: N/R  Fewer hospitalisations for

4 Exacerbations in previous yr: gemifloxacin vs clarithromycin
gemifloxacin: 10%; patients (2.3% vs 6.3%;
clarithromycin 11% P Z 0.059 [NS])
Lode et al.59 Randomised, Diagnosis: AE-COPD 7 Days levofloxacin Exacerbation-free 1 Year  Exacerbation-free interval
(n Z 511) double-blind, Mean age: levofloxacin 60 yrs; 500 mg qd vs 10 days interval at 1 year at 1 yr was similar in the two
multicentre clarithromycin 60 yrs clarithromycin groups (300 vs 350 days)
Current smokers: levofloxacin 250 mg bid  Significantly higher

R. Wilson et al.
bacteriological eradication
34%; clarithromycin 33%
rate for levofloxacin
CVD comorbidity: levofloxacin (96% vs 81.7%; P < 0.0001)
36%; clarithromycin 39%
FEV1 % predicted: levofloxacin
58%; clarithromycin 59%
Exacerbations in previous yr:
2/yr

Wilson et al.55 Randomised, Diagnosis: AECB
(n Z 1935) double-blind, Mean age: moxifloxacin 64 yrs;
multicentre comparator 63 yrs
Current smokers: moxifloxacin
41%; comparator 46%
Cardiopulmonary disease:
moxifloxacin 15%; comparator
14%
FEV1 < 50% predicted:
moxifloxacin 42%; comparator
42%

4 Exacerbations in previous yr:
moxifloxacin 27%;
comparator 28%
Ruiz-Gonzales Randomised, Diagnosis: AE-COPD
et al.58 open-label Mean age: levofloxacin 64 yrs;
(n Z 116) standard 62 yrs
Current smokers: N/R
Comorbidity: levofloxacin 58%;
standard 63%
Severe COPDb: levofloxacin
51%; standard 58%
Exacerbations in
previous yr: N/R
Petitpretz et al.57 Randomised, Diagnosis: AE-COPD
(n Z 585) open-label, Mean age: levofloxacin 64 yrs;
multicentre, cefuroxime 64 yrs
Current smokers: levofloxacin
40%; cefuroxime 41%
Comorbidity: levofloxacin 41%;
cefuroxime 36%
FEV1 % predicted: levofloxacin
51%; cefuroxime 53%
Exacerbations in previous yr:
levofloxacin 3.5; cefuroxime 3.6
Antibiotics for treatment and prevention of AE-COPD
5 Days moxifloxacin Primary: clinical 9 Months  Similar clinical success
400 mg qd vs 7 days success 7e10 d after therapy. rates between treatments
amoxicillin 500 mg tid, Secondary: clinical (88% vs 83%)
or clarithromycin cure (return to  Superior clinical cure (71% vs
63%), clinical success in pts
500 mg bid or pre-exacerbation
with bacteriologically confirmed
cefuroxime-axetil status), further AECB (88% vs 78%) and
250 mg bid antimicrobial use, bacteriological success (77% vs
time to next AECB, 68%) for moxifloxacin
and bacteriologic success  Longer mean time to
next exacerbation for
moxifloxacin
(132.8 vs 118 days;
P Z 0.03)
 Less frequent
occurrence of failure,
new exacerbation, or
need for antibiotics for
moxifloxacin for up to
5 months (P Z 0.03).
10 Days levofloxacin Long-term outcome 6 Months  Similar numbers of
500 mg qd vs 10 days (including mortality, exacerbations during
clarithromycin no. of exacerbations, follow-up (33 vs 41) and
500 mg bid, hospitalisation, infection-free interval
(112 vs 102 days)
cefuroxime- infection-free interval
 Reduced hospitalisation
axetil 500 mg bid or time) at 6 months at 6 months for levofloxacin
amoxicillin/clavulanate vs standard antibiotics
875/125 mg tid (33% vs 66%; P Z 0.02)
10 days levofloxacin Clinical cure 6 Months  Similar clinical cure
500 mg qd vs 10 days rate at TOC rates at TOC (95% vs 94%)
cefuroxime 250 mg bid (day 17e21)  Probability of relapse
during follow-up in 25%
of pts longer for levofloxacin
(93 vs 81 days; NS)
(continued on next page)
501
 502
Table 1 (continued )
Study (total Study Diagnosis/patient characteristics Treatment Endpoint Duration of Long-term
number of design at baseline (mean) follow-up outcome
patients)
Nouira et al.61 Randomised, Diagnosis: AE-COPD 10 days trimethoprim- Primary: hospital 6 Months  Combined hospital
(n Z 170) double-blind, Mean age: trimethoprim- sulfamethoxazole death and the death and additional
multicentre sulfamethoxazole 68 yrs; 160/800 mg bid vs 10 need for an additional antibiotic prescription
ciprofloxacin 67 yrs days ciprofloxacin course of antibiotics rates were similar for
trimethoprim-sulfamethoxazole
No. of pack-yrs smoking: 750 mg bid Secondary:
and cirprofloxacin
trimethoprim-sulfamethoxazole exacerbation-free (16.4% vs 15.3%; P Z 0.832).
61 yrs; ciprofloxacin 56 yrs interval  Mean exacerbation-free
Comorbidity: N/Ra interval was similar in
FEV1 ml/s: trimethoprim- both treatment groups
sulfamethoxazole 953; (83 vs 79 days; P Z 0.41).
ciprofloxacin 878
Exacerbations in previous yr:
trimethoprim-sulfamethoxazole
2.3; ciprofloxacin 2.3
Wilson et al.28 Randomised, Diagnosis: AE-COPD 5 Days moxifloxacin Clinical failure 8 Weeks  Similar clinical failure
(n Z 1492) double-blind, Mean age: moxifloxacin 70 yrs; 400 mg qd vs 7 days at 8-weeks post-therapy rates at 8 wks post-therapy
multicentre amoxicillin/clavulanic acid 69 yrs amoxicillin/ (21% vs 22%);
 Significantly lower clinical
Current smokers: moxifloxacin clavulanic acid
failure for moxifloxacin in
24%; amoxicillin/clavulanic 875/125 mg bid
pts with confirmed
acid 23% bacterial AE-COPD
Comorbidity: moxifloxacin 78%; (19% vs 25%; P Z 0.016)
amoxicillin/clavulanic acid 81%  Higher eradication rate
FEV1 % predicted: moxifloxacin for moxifloxacin in the
39%; amoxicillin/clavulanic sub-population of pts
acid 39% with confirmed pathogens
Exacerbations in previous yr: at baseline (66% vs 59%;
moxifloxacin 2.5; amoxicillin/ P Z 0.026).
clavulanic acid 2.5
TOC, test-of-cure; AECB, acute exacerbation of chronic bronchitis; AE-COPD, acute exacerbation of chronic obstructive pulmonary disease; SGRQ, St George’s Respiratory Questionnaire;
bid, twice daily; qd, once daily; tid, three times daily; NS, not significant; N/R, not reported; CVD, cardiovascular disease; FEV1, forced expiratory volume in 1 s, PO, per os, IM,
intramuscularly.
a
Patients with significant comorbid conditions were excluded.
b
30%  FEV1 < 50% predicted.

R. Wilson et al.
Antibiotics for treatment and prevention of AE-COPD
(moxifloxacin and gemifloxacin) that have better activity
against Gram-positive pathogens such as Streptococcus
pneumoniae. In contrast, initial studies with ciprofloxacin
and low-dose levofloxacin have not been able to
show improvement in long-term outcomes. While the
increased airway inflammation present during an acute
exacerbation is thought to be reduced following antibiotic
treatment,63e66 this improvement may be dependent on
bacterial eradication.25 Such incomplete resolution of
the initial exacerbation and persistent bacterial infection
appear to be important determinants of the risk of
relapse.23e26,37
Overview of clinical trials of prophylactic
antimicrobial use in AE-COPD
The concept of long-term antibiotic use comes from a
number of other chronic respiratory tract conditions in
which chronic bacterial infection occurs. The well-
established indication for the long-term use of inhaled
antibiotics is the prevention of exacerbations in cystic
fibrosis patients,67e71 and more recently in non-cystic
fibrosis bronchiectasis.72 Long-term macrolide therapy
was first shown to be of significant benefit in a predomi-
nantly Japanese respiratory disease, diffuse pan-bronchio-
litis.73 Though less well established long-term treatment
with low-dose erythromycin or clarithromycin has also
been shown to improve clinical outcome in patients with
intractable chronic sinusitis.74,75 In non-cystic fibrosis bron-
chiectasis, addition of twice-weekly azithromycin to pa-
tients’ usual medications for 6 months significantly
decreased the incidence of exacerbation and 24-h sputum
volume.76 Furthermore, long-term, low-dose erythromycin
has been shown to be effective in bronchiectasis subjects
with frequent infective exacerbations.77 More recently, 6-
month treatment with azithromycin reduced the frequency
of exacerbations in bronchiectasis patients with a history of
at least one exacerbation in the previous year, though no
improvement in quality of life was observed during the
treatment period.78
The potential role of long-term antibiotic therapy in the
management of COPD was first investigated in the 1950s
and 1960s. However, these studies were limited by small
patient numbers, use of low doses of narrow-spectrum
antibiotics and poor efficacy measurements. Concerns
regarding resistance also hindered further investigation
into the value of this approach.79 Nonetheless, new antibi-
otic formulations with improved antibacterial activity
coupled with better understanding of the pathogenesis of
COPD has led to renewed interest in the role of long-term
antibiotic use in COPD management,80 though no agents
are currently licensed for such therapy.
Review of more recent reports from the last decade
investigating the long-term use of antibiotic treatment in
COPD patients revealed a total of seven studies examining
continuous therapy45,81e86 and one employing an intermit-
tent/pulsed schedule (Table 2).46 Of the studies investi-
gating continuous therapy, all investigated long-term
macrolide therapy, with most examining treatment over a
12-month period.45,81,86 The rationale for the use of macro-
lides as maintenance therapy stems from the fact that these
503
agents hold immunomodulatory and anti-inflammatory ef-
fects in addition to their antibacterial properties.87 In the
first 12-month study, erythromycin therapy was found to
have beneficial effects on the prevention of exacerbations
in 55 COPD patients.81 The proportion of patients with one
or more episodes of exacerbation during the treatment
period was lower in patients treated with erythromycin
(11%) compared to the controls (56%), and significantly
more control patients than erythromycin patients were hos-
pitalised due to exacerbations (P Z 0.0007). It should be
noted, however, that this investigation was limited in that
it was an open-label study, not a randomised double-blind
placebo-controlled trial. Such a trial of erythromycin treat-
ment was subsequently shown to significantly reduce exac-
erbation frequency and median time to exacerbation in a
12-month study, though no differences between arms
were observed in FEV1 or inflammatory markers.86 In
contrast, no reduction of exacerbations, sputum neutrophil
numbers or cytokine levels were observed following 3-
month treatment with clarithromycin versus placebo,
possibly due to the small sample size (n Z 67) and shorter
study period.82 However, significant reductions in inflamma-
tory markers and neutrophil counts were reported following
6-month treatment with azithromycin in addition to stan-
dard care in severe COPD patients83 and with erythromycin
versus placebo, respectively.84
Recently, in a large definitive study, Albert et al.45 have
investigated the use of 12-month treatment with daily azi-
thromycin in COPD patients with an increased risk of exac-
erbations (mean age 65 years, FEV1 % predicted was 39%). In
this study, addition of azithromycin to standard therapy led
to a 27% decrease in the frequency of exacerbations, an in-
crease in the median time to exacerbations (266 days vs 174
days, respectively; P < 0.001) and significantly improved
disease specific health status (St George’s Respiratory
Questionnaire [SGRQ] 2.8 vs 0.6; P Z 0.004). However,
the improvement in the SGRQ did not reach the minimal
clinically important difference. Azithromycin was also
shown to reduce exacerbations, hospitalisations, and
length of hospital stay in patients with severe COPD
(mean age 71 years, FEV1 % predicted 32%, 7.0 exacerba-
tions in previous year) in a 12-month retrospective study.85
The effect of azithromycin in this study was particularly
marked in patients with common potentially pathogenic mi-
croorganisms isolated in sputum (i.e. Haemophilus influen-
zae, S. pneumoniae or Moraxella catarrhalis), reducing
exacerbations and hospitalisations by 70% and mean hospi-
tal stay by 25 days.
Intermittent, pulsed fluoroquinolone antibiotic therapy
in COPD patients has been investigated in a study conduct-
ed by Sethi et al.46 In this study, moxifloxacin was adminis-
tered once daily for 5 days, with treatment being repeated
every 8 weeks for a total of six courses.46 The rationale for
pulsed therapy was mainly driven by the concerns about
the emergence of resistance with long-term continuous
use of antibiotics. Pulsed therapy would allow time for
the normal flora to recover and therefore potentially pre-
vent or delay the emergence of resistant strains.33
Moxifloxacin was selected for the study based on its potent
in vitro activity against the major COPD pathogens,
excellent penetration into respiratory tissues, high oral
bioavailability and proven efficacy in increasing the

Table 2 Studies investigating use of prophylactic oral antibiotics in stable COPD patients.
Study Study design Patient characteristics
at baseline (mean)
Continuous therapy
Suzuki et al.81 Randomised, Mean age: erythromycin
un-blinded 69 yrs; no therapy 72 yrs
controlled trial Current smokers: N/R
Comorbidity: N/Ra
FEV1 L/s: erythromycin
1.3; no therapy 1.5
Exacerbations in
previous yr: N/R
Banerjee Randomised, Mean age: clarithromycin
et al.82 double-blind, 65 yrs; placebo 68 yrs
controlled trial Current smokers:
clarithromycin 45%;
placebo 64%
Comorbidity: N/Rb
FEV1 % predicted:
clarithromycin 43%;
placebo 44%
Exacerbations in
previous yr: N/Rc
Seemungal Randomised, Mean age: erythromycin
et al.86 double-blind, 67 yrs; placebo 68 yrs
controlled trial Current smokers:
erythromycin 51%;
placebo 45%
Comorbidity: N/Rb
FEV1 % predicted:
erythromycin 49%;
placebo 51%

3 exacerbations in
previous yr: erythromycin
36%; placebo 34%
Blasi et al.83 Randomised, Mean age: azithromycin
open label study 72 yrs; SC 73 yrs
Current smokers: 0%
Comorbid HTN:
azithromycin 36%; SC 46%
Comorbid CAD:
Treatment
Erythromycin 200e400
mg/day (n Z 55) vs no
therapy (n Z 54)
Clarithromycin
500 mg/day (n Z 31)
vs placebo n Z 36)
Erythromycin
250 mg bid (n Z 53)
vs placebo (n Z 56)
Azithromycin 500 mg
three times/week
(n Z 11) vs SC (n Z 11)
504
Duration of Outcome Side effects
antibiotic
treatment
12 months  Reduction in no. of Not reported
common colds in 1 yr
for erythromycin
(1.2 vs 4.5; P Z 0.0002)
 Fewer erythromycin
patients had
1
exacerbation (11% vs 56%)
 More control patients
were hospitalised for
exacerbations (P Z 0.0007)
3 months  No effect of clarithromycin GI symptoms in one
on sputum total cell or clarithromycin
neutrophil count or patient
cytokine levels
 Small reduction in the
neutrophil differential
(P Z 0.04) and neutrophil
chemotaxis
(P Z 0.058) vs placebo
12 months  Significant reduction No significant
in exacerbation differences between
frequency for erythromycin arms
vs placebo (P Z 0.006)
One case of
 Erythromycin reduced the
erythromycin
median time to exacerbation
(271 vs 89 days; P Z 0.02)
resistance
 No difference between
arms in FEV1 or inflammatory
markers (sputum IL-6, IL-8,
myeloperoxidase, serum
C-reactive protein
or serum IL-6)
6 months  Significant reduction No serious AEs
R. Wilson et al.
in exacerbations No resistance reported
(P Z 0.001) and
hospitalisations (P Z 0.02)
after 3 months
azithromycin vs. SC

azithromycin 27%; SC 36%
FEV1 % predicted: N/R
MRC: azithromycin 3.0; SC 2.6
Exacerbations in previous yr:
azithromycin 3.0; SC 3.1
He et al.84 Randomised, Mean age: erythromycin
double-blind, 69 yrs; placebo 69 yrs
controlled trial Smoking pack-yrs:
erythromycin 42; placebo 41
Comorbidity: N/Rb
FEV1 % predicted:
erythromycin 44%;
placebo 42%
Exacerbations in
previous yr: N/R
Albert et al.45 Randomised, Mean age: azithromycin
double-blind, 65 yrs; placebo 66 yrs
controlled trial Current smokers:
azithromycin 21%; placebo 23%
Comorbidity: N/Rb
FEV1: FVC %: azithromycin
42%; placebo 43%
Exacerbations in
previous yr: N/R
Pomares Retrospective, Mean age: 71 yrs
et al.85 uncontrolled Current smokers: 0%
study Chronic bronchitis: 24%
FEV1 % predicted: 32%
Exacerbations in
previous yr: 7.0
Antibiotics for treatment and prevention of AE-COPD
 Significant reduction
in no. of exacerbations
during 6-month azithromycin
treatment vs 6-month follow-up
(P Z 0.016); no
difference in the SC
group (P Z 0.56)
 Reduction if inflammatory
markers e TNFa and IL-6
during azithromycin treatment
 Significant improvement in
QoL after 3 (P Z 0.006) and 6
months (P Z 0.002) azithromycin
Erythromycin 125 mg 6 months  Significant reduction in Two erythromycin
three times/day neutrophil counts in sputum patients discontinued
(n Z 18) vs placebo for erythromycin vs (abdominal pain
placebo (P Z 0.05)
(n Z 18) and heart failure
 Reduction in exacerbation
complications)
rate for erythromycin vs placebo
(RR 0.554; P Z 0.042)
No resistance
 Erythromycin delayed the reported
time to first exacerbation vs
placebo (P Z 0.032)
Azithromycin 250 mg/day 12 months  Azithromycin reduced the Hearing decrements
(n Z 570) vs placebo median time to exacerbation more common in
(n Z 572) (266 vs 174 days; P < 0.001) azithromycin arm
 Reduced frequency of
(25% vs. 20%;
exacerbations for azithromycin
p Z 0.04).
(1.48 vs 1.83/pt yr; P Z 0.01)
 Significantly improved QoL
Increased resistance
for azithromycin patients to macrolides in
(P Z 0.004) the azithromycin
group (81% vs 41%;
p < 0.0001)
Azithromycin 500 mg 12 Months  Significant reduction No clinically
three times/week (n Z 24) in exacerbations for significant AEs
azithromycin vs baseline observed
(2.8 vs 6.8; P < 0.001),
One H. influenzae
hospitalisations (1.4 vs 3.6;
and four
P < 0.001), and days in
hospital (25 vs 44; P Z 0.01)
S. pneumoniae
 Exacerbations reduced isolates developed
by 43% and hospitalisations azithromycin
by 47% in pts colonised resistance
by P. aeruginosa.
(continued on next page)
505
 506
Table 2 (continued )
Study Study design Patient characteristics Treatment Duration of Outcome Side effects
at baseline (mean) antibiotic
treatment
Continuous therapy
Intermittent/pulsed therapy
Sethi et al.46 Randomised, Mean age: moxifloxacin Moxifloxacin 400 mg/day 6  5-day treatments  Odds of suffering an More
double-blind, 66 yrs; placebo 66 yrs (n Z 573) vs placebo every 8 weeks exacerbation at 48 weeks treatment-emergent,
controlled trial Current smokers: moxifloxacin (n Z 584) 48 week treatment; was reduced by 25% with drug related AEs
35%; placebo 31% 24 week follow-up moxifloxacin (PP population) with moxifloxacin
and 45% in pts with
Comorbidity: N/Rb vs placebo
purulent/mucopurulent
FEV1 % predicted: moxifloxacin sputum at baseline (p < 0.001), mainly
40%; placebo 41%  Significant difference due to GI events
Exacerbations in previous yr: in favour of moxifloxacin (4.7% vs 0.7%).
moxifloxacin 2.6; placebo 2.6 in the SGRQ symptom No evidence of
domain (8.8 vs 4.4; relevant resistance
P Z 0.006). development
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; GI, gastrointestinal; QoL, quality of life; AEs, adverse events; PP, per protocol; SGRQ, St George’s Respiratory Question-
naire; SC, standard care; CAD, coronary artery disease; HTN, hypertension; MRC, Medical Research Council Dyspnoea Scale; TNFa, tumour necrosis factor-a; IL-6, interleukin-6; RR, relative
risk; N/R, not reported.
a
Patients with bronchiectasis or diffuse pan-bronchiolitis were excluded.
b
Patients with comorbid asthma, bronchiectasis or uncontrolled cardiac disease were excluded.
c
Patients with an infective exacerbation with in the previous 6 weeks were excluded.

R. Wilson et al.
Antibiotics for treatment and prevention of AE-COPD
exacerbation-free interval.46,55,88 Pulsed therapy with
moxifloxacin was found to significantly reduce the risk of
an exacerbation by 25% (per protocol population) in pa-
tients with moderate-to-severe COPD, while in a post-hoc
analysis, this reduction was 45% in patients with puru-
lent/mucopurulent sputum at randomisation.46
These studies suggest that long-term antibiotic treat-
ment in COPD patients reduces exacerbation frequency,
though evidence for a reduction in inflammation is limited.
Long-term antibiotic therapy appears to be well tolerated,
though not all studies reported safety.81 Nevertheless,
gastrointestinal events were more common in patients
receiving pulsed moxifloxacin versus placebo (4.7% vs
0.7%, respectively)46 and 12-month azithromycin treatment
resulted in a higher incidence of hearing loss (25% of pa-
tients with azithromycin vs 20% of patients with placebo).45
Although long-term (daily) azithromycin treatment led to a
decrease in the incidence of colonisation by respiratory
pathogens, such treatment was also associated with an
increased prevalence of macrolide-resistant bacteria colo-
nising the airways, though there was no evidence that
this colonisation increased the number of exacerbations
or the incidence of pneumonia.45 No relevant resistance
was reported in the study with pulsed (with one cycle last-
ing for only 5 days in every 8 weeks) moxifloxacin treat-
ment,46 while in others resistance development was
minimal85,86 or not reported.81,82
Although the studies described above suggest that use of
prophylactic oral antibiotic therapy is well tolerated, some
macrolides are known to be proarrhythmic and even 5-day
treatment with azithromycin has been associated with a
small absolute increase in cardiovascular deaths.89 This
issue, coupled with concerns of increased antibiotic resis-
tance, indicates that such treatment should be reserved
for those with severe COPD who experience frequent exac-
erbations requiring multiple antibiotic treatments, in spite
of adequate management of their COPD with standard
treatments.90
Future directions: the role of inhaled
antibiotics in patients with COPD
Use of inhaled antibiotics is expected to have a future role
in the long-term management of patients with COPD since
this route of administration has the ability to target drug
delivery directly to respiratory tract. Such targeting reduces
systemic exposure and maximizes pharmacodynamic param-
eters, thereby also likely reducing the emergence of
antibiotic resistance and minimizing the development of
systemic adverse effects. Inhaled antibiotics have already
been used in the treatment of other respiratory tract
conditions, including cystic fibrosis (CF)67,68 and bronchiec-
tasis.91,92 Administration of aerosolised antibiotics plays a
particularly important role in CF, since patients with the
condition suffer from diminished mucociliary clearance,
increasing their susceptibility to colonisation and infection
by bacterial pathogens, including P. aeruginosa.93 In this
population, intermittent inhaled tobramycin has been
shown to improve pulmonary function and decrease
the density of P. aeruginosa in sputum, leading to significant
reductions in respiratory hospitalisations.67,68 Inhaled
507
gentamycin has recently been shown to have a beneficial ef-
fect on outcomes in bronchiectasis, reducing the number of
exacerbations and decreasing P. aeruginosa in the sputum.72
In addition, use of inhaled dry powder ciprofloxacin in bron-
chiectasis patients has been associated with improved qual-
ity of life, which is likely to be due to reductions in bacterial
load and improved eradication (of approximately 35%).91
Inhaled antibiotics appear to be well tolerated in most
of the above studies, reducing the risks of adverse effects
associated with systemic exposure. While wheezing and
localised irritation (e.g. cough, bronchospasm) have been
reported in some studies,92,94,95 most report minimal side
effects.67,68,91 Choice of antimicrobial is dependent on
pharmacokinetics/pharmacodynamics in the bronchopul-
monary tree, with the ability to achieve high Cmax values fa-
vouring concentration-killing drugs, while the applied
delivery system influences particle size distribution and
hence deposition and exposure.96,97 Although the optimal
dosing regimen (e.g. continuous or pulsed) for inhaled anti-
biotics in COPD has not been determined, their administra-
tion in aerosolised form has the ability to achieve high,
microbiologically relevant concentrations in respiratory se-
cretions in excess of the MIC of the infecting organism(s).98
In COPD patients with chronic bacterial infection, delivery
of a high concentration of antibiotic in the airway through
inhalation may lead to a reduction in chronic inflammation
via a reduction in bacterial load, potentially reducing the
frequency of exacerbations. Nevertheless, evidence for a
reduction in airway inflammation following the use of aero-
solised antibiotics is limited.
The pharmacodynamic/pharmacokinetic profile of
inhaled antibiotic therapy in the lower respiratory tract
are quite different from systemic antibiotic use. The
measured concentrations of various antibiotics (gentamy-
cin, sisomycin, amikacin, tobramycin) in various locations
in the respiratory tract following inhalation exceeded the
highest MICs of the prevalent pathogens by between 50 and
125 times.99e105 In the presence of such high concentration
of antibiotics the density of pathogens was reduced in the
sputum or the pathogens were completely eradicated
(Table 3).67,91,106e116 However, adequate delivery of antibi-
otic to the airways through inhalation is a complex method
influenced by several factors. Conditions that have to be
optimised include the choice of nebuliser (jet or ultrasonic,
vibrating mesh inhaler), the drug formulation (aerosolised
solution or dry powder), the particle size (must be between
1 mm and 5 mm for adequate deposition and delivery into
lower airways), the chemical properties of the molecule
(e.g. lipophilic or hydrophilic). Furthermore, patient char-
acteristics including age and lung function, the respiratory
cycle length and inspiratory/expiratory ratio, may also in-
fluence efficiency of inhaled antibiotic delivery.
As seen with long-term systemic antibiotic use, concern
exists too for inhaled antibiotics regarding the possibility of
resistance development during long-term treatment. As
shown in Table 3, there is inconsistent evidence for the
emergence of resistant pathogens during treatment with
aerosolised antibiotics in some respiratory conditions67,95
(Table 3). It is likely that risk of resistance development
may be lessened by use of shorter courses, intermittent
therapy (as currently practiced in cystic fibrosis) or alter-
nating different antibiotic classes.
 508
Table 3 Studies investigating resistance development during therapy with inhaled antibiotics.
Study Study design Indication Treatment Duration of therapy Secondary outcome on
resistance development
during or after therapy
and/or bacteriological outcome
Ramsey et al.67 Randomised, double-blind, CF Tobramycin 300 mg bid 28 days therapy with Decreased density of
placebo-controlled, (n Z 258, PARI LC 28 days run-off P. aeruginosa in sputum
multicentre trial Plus) vs placebo (n Z 262) period, 3 cycles and increased % of
P. aeruginosa isolates
with MIC
8 mg/L at the
end of the study (14.3%
of patients)
Lenoir et al.106 Randomised, double-blind, CF Tobramycin 300 mg bid 28 days with 28 days No changes in MIC90
placebo-controlled, (n Z 29, Pari LC follow-up period, 1 cycle were observed up to
multicentre trial Plus) vs placebo (n Z 30) EOT with sputum
concentration of
tobramycin remaining
above the MIC throughout
the treatment; twice as
many patients in the
tobramycin group as in
the placebo group achieved
bacterial eradication at EOT
Chuchalin et al.107 Randomised, double-blind, CF Tobramycin 300 mg bid 28 days on- and 28 MIC90 for mucoid strains of
placebo-controlled, (n Z 161, Pari LC days off-therapy, 3 cycles P. aeruginosa increased
multicentre trial Plus) vs placebo (n Z 84) from 6.6 mg/L to 18.2 mg/L
and the % of resistant
P. aeruginosa strains
increased from 9.7% to 23.6%
by the end of the study in the
tobramycin group; no MIC
changes were seen in placebo
group; bacteriological
eradication was achieved
by EOT in twice as many
tobramycin-treated patients
as in placebo-treated patients
McCoy et al.108 Randomised, double-blind, CF Aztreonam (AZLI) 75 mg bid 28 Days with 56 days MIC90 transiently increased
placebo-controlled, (n Z 69) vs placebo (n Z 66) follow-up, 1 cycle 4-fold in AZLI-treated patients

R. Wilson et al.
multicentre trial for P. aeruginosa and returned
after treatment has finished,
P. aeruginosa density
decreased in sputum
Palmer et a.109 Randomised, double-blind, Ventilator-associated Vancomycin, 120 mg, 14 Days treatment There was no resistance

Antibiotics for treatment and prevention of AE-COPD

placebo-controlled, tracheobronchitis in tid and/or Gentamycin, with 14 days follow-up development with aerosolised
single-centre trial hospitalised patients 80 mg, tid (n Z 19, period antibiotics (vancomycin or
pathogen-targeted therapy gentamycin) by EOT and
using AeroTech II nebuliser) vs bacterial growth was
placebo (n Z 24) reduced in purulent
tracheobronchial secretions
Hansen et al.110 Retrospective cohort CF Inhaled colistin (1 mio. or Since diagnosis 15 Longer interval without
observational study 2 mio, bid or tid) þ PO years follow up of P. aeruginosa in sputum
ciprofloxacin (10e20 mg/kg/day) patients compared with non-treated
CF patients
No colistin resistance was
found among all P. aeruginosa
isolates
Retsch-Bogart Randomised, double-blind, CF Aztreonam (AZLI) 75 mg 28 Days with 14 MIC90 transiently increased
et al.111 placebo-controlled, tid (n Z 80) vs placebo (n Z 84) days follow-up, 4-fold in AZLI-treated
multicentre trial 1 cycle patients for P. aeruginosa,
without increases in drug
concentration in sputum,
and returned by day 42;
P. aeruginosa density decreased
in sputum
Oermann et al.112 Open label, not CF Aztreonam (AZLI) 75 mg tid 18 Months of alternating P. aeruginosa MIC50 and MIC90
controlled study (n Z 189) or 75 mg bid 28 days on-therapy and transiently increased during
(n Z 85), PARI eFlow 28 days off-therapy the study
4-fold during bid
and tid administration in
20% and 30% of patients,
respectively
Konstan et al.113 Randomised, open-label, CF Tobramycin 112 mg bid 28 Days therapy with Decreased density of
placebo-controlled, (n Z 46 using T-326 28 days run-off, 3 cycles P. aeruginosa in sputum
multicentre study Inhaler) vs placebo (n Z 49), and increased % of patients
with MICs
8 mg/L for
P. aeruginosa by the end
of the study
Konstan et al.114 Randomised, open-label, CF Tobramycin 112 mg bid 28 Days therapy with Decreased density of
multicentre, two-arm study (n Z 308, via T-326 Inhaler) 28 days run-off period, P. aeruginosa in sputum,
or tobramycin 300 mg bid 3 cycles and increased % of patients
(n Z 209, via PARI LC Plus) with MICs
8 mg/L for P. aeruginosa
by the end of the study
Wainwright et al.115 Randomised, double-blind, CF Aztreonam (AZLI) 75 mg tid 28 Days with 14 Decreased density of
placebo-controlled, (n Z 76) vs placebo (n Z 81) days follow-up, P. aeruginosa in sputum,
multicentre trial 1 cycle increased MIC50 and MIC90
in AZLI-treated patients
and increased % of patients
with MICs
8 mg/L for

509
P. aeruginosa by the end of the study
(continued on next page)

Table 3 (continued )
Study Study design
Wilson et al.91 Randomised, double-blind,
placebo-controlled,
multicentre trial
Clancy et al.116 Randomised, double-blind,
placebo-controlled,
multicentre trial
CF, cystic fibrosis; NCFB, non-cystic fibrosis bronchiectasis; qd, once daily; bid, twice daily; tid, three times daily; MIC, minimum inhibitory concentration (mg/L); EOT, end-of-therapy;
PO, per os.
510
Indication Treatment Duration of therapy Secondary outcome on
resistance development
during or after therapy
and/or bacteriological outcome
NCFB Ciprofloxacin dry powder 28 Days with 56 Pseudomonas aeruginosa,
inhalation 32.5 mg bid days follow-up S. maltophilia, H. influenzae
(n Z 60) vs placebo (n Z 64) MICs transiently increased
in six subjects by EOT and
MIC decreased by day 56
in the ciprofloxacin dry powder
inhalation group, with a
decrease in density of pathogens
in sputum, in addition 35% of
patients in ciprofloxacin
dry powder inhalation
group vs 8% of patients in
placebo group achieved
bacterial eradication at EOT
CF Amikacin liposomal 28 Days with Decreased density of
aerosol, 70 mg, 28 days run-off, P. aeruginosa in sputum with
140 mg, 280 mg, up to 6 cycles highest dose and no significant
560 mg qd (n Z 69) changes in MIC50 and in MIC90
vs placebo (n Z 36) for P. aeruginosa during treatment
R. Wilson et al.
Antibiotics for treatment and prevention of AE-COPD
To date, there have been only two published reports
investigating the use of inhaled antibiotics in patients with
COPD. Dal Negro et al.117 examined the impacts of 14-day,
twice daily treatment with inhaled tobramycin nebuliser so-
lution on clinical outcome as well as inflammatory markers
in bronchial secretions from a small cohort (n Z 13) of mul-
tiresistant P. aeruginosa-colonised patients with severe
COPD (FEV1 < 50% predicted). P. aeruginosa infection is
associated with a severe degree of functional impairment
in COPD,118 and colonisation could well herald the presence
of bronchiectasis,41,119 suggesting a potential role for
inhaled antibiotics. Indeed, such treatment resulted in a
substantial reduction from baseline of pro-inflammatory
chemotactic mediators, including interleukin-1 beta
(P < 0.03), interleukin-8 (P < 0.02) and eosinophilic cationic
protein (P < 0.01). After the 6-month follow-up period, P.
aeruginosa was considered to be eradicated in two patients,
while P. aeruginosa density was reduced in a further four pa-
tients. Two-week treatment with inhaled tobramycin
decreased the frequency of exacerbations by 42%, when
compared with the 6-month period prior to initiating inhaled
tobramycin therapy.117 Although this study has many limita-
tions, including its open-label design and its small size, it
does suggest a therapeutic role for inhaled antibiotics in
COPD patients, particularly those colonised with multiresist-
ant P. aeruginosa. Nevertheless, a recent phase II study
investigating the efficacy of MP-376 (levofloxacin inhaled so-
lution) in COPD patients at high risk for exacerbations
(n Z 322) failed to demonstrate a significant reduction in
the exacerbation rate or an increase in the time to the
next exacerbation compared with placebo.120 However,
the treatment duration employed in this study (5 days every
28 days for 9e12 cycles) may have been suboptimal in a pop-
ulation of patients with chronic infection.121 Ongoing and
future trials will inform us if inhaled antibiotics are a useful
therapeutic option in the prevention of exacerbations of
COPD.
Conclusions
Acute, efficacious antibiotic treatment is the mainstay in
the management of patients with severe COPD and symp-
tomatic exacerbations that include at least 2 of the 3
cardinal symptoms (increased sputum purulence, volume
and increased dyspnoea; Anthonisen type I or II exacerba-
tions). Although such treatment is associated with clinical
benefit, treatment failure and relapse rates may be high in
patients with the frequent exacerbator phenotype. Failure
may be related to inadequate antibiotic efficacy through
incomplete resolution of the initial exacerbation and
persistent bacterial infection.23e26 These factors have led
to recommendations for a stratified approach to antibiotic
therapy based on patient risk factors.15 Patients at greatest
risk for poorer outcome (i.e. those with complicated COPD)
are likely to derive greatest benefit from early treatment
with the most potent antibiotic therapy, such as amoxi-
cillin/clavulanate and respiratory fluoroquinolones which
have a broad spectrum of activity against likely patho-
gens.28,122e124 The use of the most efficacious antibiotics
in patients with risk factors may be crucial in preventing re-
lapses or delaying subsequent exacerbations which appear
511
to cluster in time, and if the exacerbation is poorly
controlled there is a high risk of the next episode occurring
within a few weeks.30 A significant relationship exists be-
tween bacterial eradication at the end of antibiotic treat-
ment and no relapse in the following eight weeks.28
Studies conducted in the last 20 years suggest that long-
term or intermittent antibiotic therapy may have a bene-
ficial effect on the outcome of COPD patients and may
improve quality of life by reducing exacerbation frequency
and hospitalisations for exacerbations, or by extending
time to next exacerbation. The mechanisms underlying
such improvements are unclear. It is possible that the
benefit of long-term antibiotic treatment may be due to a
reduction in the frequency of exacerbations due to erad-
ication of colonising potentially pathogenic bacteria and/or
reduction in chronic airway inflammation,37 though the ev-
idence supporting such a hypothesis is limited. While mac-
rolides are known to have both antibacterial and anti-
inflammatory effects, it is unknown to what degree these
actions are responsible for their efficacy when used for
the treatment of chronic respiratory conditions. The
increased rate of nasopharyngeal colonisation by pathogens
resistant to macrolides seen following long-term azithromy-
cin therapy45 suggests that emergence of antibiotic resis-
tance is likely with this approach.
Although systemic antibiotics are likely to remain the
primary treatment option for patients with moderate-to-
severe COPD, inhaled antibiotics may provide a more
appropriate way for the treatment and prevention of
exacerbations in the future, particularly for the frequent
exacerbators with chronic bacterial infection and for those
with radiologically confirmed bronchiectasis. Regardless of
the route of administration, however, further studies are
required to estimate the potential risks of antibiotic pro-
phylaxis in terms of long-term adverse events and resis-
tance development and to assess whether benefit
outweighs the potential risks.
Conflicts of interest
Antonio Anzueto has participated as a speaker in scientific
meetings or courses organised and financed by various
pharmaceutical companies including: AstraZeneca, Boeh-
ringer Ingelheim, Bayer, Pfizer, GlaxoSmithKline, Sanofi-
Aventis. A. Anzueto has been a consultant for AstraZeneca,
Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Sanofi-
Aventis, Bayer. He has also been the principal investigator
for research grants for the University of Texas Health
Science Center (San Antonio, TX, USA) and was paid for
participating in a multicentre clinical trial sponsored by:
GlaxoSmithKline, Bayer, Lilly and National Institutes of
Health. Marc Miravitlles has received speaker fees from
Boehringer Ingelheim, Pfizer, AstraZeneca, Bayer Schering,
Novartis, Talecris-Grifols, Takeda-Nycomed, Merck, Sharp
& Dohme and Novartis, and consulting fees from Boehringer
Ingelheim, Pfizer, GSK, AstraZeneca, Bayer Schering, No-
vartis, Almirall, Merck, Sharp & Dohme, Talecris-Grifols and
Takeda-Nycomed. Sanjay Sethi has received institutional
research funds from AstraZeneca and GlaxoSmithKline.
He has received lecture and/or consulting fees from
AstraZeneca, Bayer, Boehringer Ingelheim, Forest, Pfizer,
512
GlaxoSmithKline, Mpex, and Novartis. Robert Wilson has
received honoraria for taking part in advisory boards and
presenting at meetings from Almirall, Aperion Advisors LLC,
AstraZeneca, Athena Medical PR, Bayer HealthCare, Forest
Laboratories (Bronchiectasis symposium), Genactis Ltd,
Opticom International, Penn Technology Partnership, Res-
olutions Group, Rivervest, Transave, VacZine Analytics and
Wyeth Pharmaceuticals.
Acknowledgements
Highfield Communication, Oxford, UK, provided editorial
assistance in the preparation of this manuscript.
References
1. Mannino DM, Buist AS. Global burden of COPD: risk factors,
prevalence, and future trends. Lancet 2007;370:765e73.
2. NHLBI. Chronic obstructive pulmonary disease data fact
sheet. 03-5229. NIH Publication; 2003.
3. Global surveillance, prevention and control of chronic respi-
ratory diseases. A comprehensive approach. WHO; 2007, ISBN
978 92 4 156346 8; 2007http://www.who.int/respiratory/
publications/global_surveillance/en/index.html.
4. Tan WC, Ng TP. COPD in Asia: where east meets west. Chest
2008;133:517e27.
5. Hurst JR, Vestbo J, Anzueto A, Locantore N, Mu €llerova H, Tal-
Singer R, et al. Susceptibility to exacerbation in chronic obstruc-
tive pulmonary disease. N Engl J Med 2010;16:1128e38.
6. Sialer S, Adamantia L, Guerrero M, Torres A. Relation between
chronic obstructive pulmonary disease and antibiotics. Curr
Infect Dis Rep 2012;14:300e7.
7. Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of
chronic obstructive pulmonary disease: severe exacerbations
and mortality. Thorax 2012;67:957e63.
8. Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P,
Salcedo E, Navarro M, Ochando R. Severe acute exacerbations
and mortality in patients with chronic obstructive pulmonary
disease. Thorax 2005;60:925e31.
9. Spencer S, Jones PW. GLOBE Study Group. Time course of re-
covery of health status following an infective exacerbation of
chronic bronchitis. Thorax 2003;58:589e93.
10. Miravitlles M, Murio C, Guerrero T, Gisbert R. Costs of chronic
bronchitis and COPD: a 1-year follow-up study. Chest 2003;
123:784e91.
11. Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA,
Maslen TK. Randomised, double blind, placebo controlled
study of fluticasone propionate in patients with moderate to
severe chronic obstructive pulmonary disease: the ISOLDE
trial. BMJ 2000;320(7245):1297e303.
12. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S,
Olsson H. Maintenance therapy with budesonide and formo-
terol in chronic obstructive pulmonary disease. Eur Respir J
2003;22:912e9.
13. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C,
Jones PW, et al. TORCH investigators. Salmeterol and flutica-
sone propionate and survival in chronic obstructive pulmonary
disease. N Engl J Med 2007;356:775e89.
14. Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S,
et al. UPLIFT Study Investigators. A 4-year trial of tiotropium
in chronic obstructive pulmonary disease. N Engl J Med 2008;
359:1543e54.
15. Sethi S, Murphy TF. Infection in the pathogenesis and course
of chronic obstructive pulmonary disease. N Engl J Med
2008;359:2355e65.
R. Wilson et al.
16. Wilson R. Treatment of COPD exacerbations: antibiotics. Eur
Respir Rev 2005;14:32e8.
17. Miravitlles M, Kruesmann F, Haverstock D, Perroncel R,
Choudhri SH, Arvis P. Sputum colour and bacteria in chronic
bronchitis exacerbations: a pooled analysis. Eur Resp J
2012;39:1354e60.
18. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES,
Harding GK, Nelson NA. Antibiotic therapy in exacerbations
of chronic obstructive pulmonary disease. Ann Intern Med
1987;106:196e204.
19. O’Donnell DE, Hernandez P, Kaplan A, Aaron S, Bourbeau J,
Marciniuk D, et al. Canadian Thoracic Society recommenda-
tions for management of chronic obstructive pulmonary dis-
ease - 2008 update - highlights for primary care. Can Respir
J 2008;15(Suppl. A):1Ae8A.
20. GOLD. Global strategy for the diagnosis, management and
prevention of COPD. Global Initiative for Chronic Obstructive
Lung Disease (GOLD); 2011. Available from: http://www.
goldcopd.org/uploads/users/files/GOLD_Report_2011_Feb21.
pdf.
21. Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M,
et al. Guidelines for the management of adult lower respira-
tory tract infections e full version. Clin Mirobiol Infect 2011;
17(Suppl. 6):E1e59.
22. Roede BM, Bresser P, Prins JM, Schellevis F, Verheij TJ,
Bindels PJ. Reduced risk of next exacerbation and mortality
associated with antibiotic use in COPD. Eur Respir J 2009;
33:282e8.
23. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are asso-
ciated with lower relapse rates in outpatients with acute ex-
acerbations of COPD. Chest 2000;117:1345e52.
24. Aaron SD, Vandemheen KL, Hebert P, Dales R, Stiell IG,
Ahuja J, et al. Outpatient oral prednisone after emergency
treatment of chronic obstructive pulmonary disease. N Engl
J Med 2003;348:2618e25.
25. White AJ, Gompertz S, Bayley DL, Hill SL, O’Brien C, Unsal I,
et al. Resolution of bronchial inflammation is related to bac-
terial eradication following treatment of exacerbations of
chronic bronchitis. Thorax 2003;58:680e5.
26. Daniels JMA, Snijders D, de Graaff CS, Vlaspolder F, Jansen HM,
Boersma WG. Antibiotics in addition to systemic corticosteroids
for acute exacerbations of chronic obstructive pulmonary dis-
ease. Am J Respir Crit Care Med 2010;181:150e7.
27. Llor C, Moragas A, Hema ndez S, Bayona C, Miravitlles M. Effi-
cacy of antibiotic therapy for acute exacerbations of mild to
moderate COPD. Am J Respir Crit Care Med 2012;186:
716e23.
28. Wilson R, Anzueto A, Miravitlles M, Arvis P, Alder J,
Haverstock D, et al. Moxifloxacin vs amoxicillin/clavulanic
acid in outpatient acute exacerbations of COPD: MAESTRAL
results. Eur Respir J 2012;40:17e27.
29. Wedzicha JA, Seemungal TA. COPD exacerbations: defining
their cause and prevention. Lancet 2007;370:786e96.
30. Hurst JR, Donaldson GC, Quint JK, Goldring JJ, Baghai-
Ravary R, Wedzicha JA. Temporal clustering of exacerbations
in chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2009;179:369e74.
31. Wilson R, Schentag JJ, Ball P, Mandell L. 068 Study Group. A
comparison of gemifloxacin and clarithromycin in acute exac-
erbations of chronic bronchitis and long-term clinical out-
comes. Clin Ther 2002;24:639e52.
32. Perera WR, Hurst JR, Wilkinson TMA, Sapsford RJ,
Mu€llerova H, Donaldson GC, et al. Inflammatory changes, re-
covery and recurrence at COPD exacerbation. Eur Respir J
2007;29:527e34.
33. Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria
and exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 2002;347:465e71.
Antibiotics for treatment and prevention of AE-COPD
34. Sethi S. Infection as a comorbidity of COPD. Eur Respir J 2010;
35:1209e15.
35. Patel IS, Seemungal TAR, Wilks M, Lloyd-Owen SJ,
Donaldson GC, Wedzicha JA. Relationship between bacterial
colonisation and the frequency, character, and severity of
COPD exacerbations. Thorax 2002;57:759e64.
36. Banerjee D, Khair OA, Honeybourne D. Impact of sputum bac-
teria on airway inflammation and health status in clinical sta-
ble COPD. Eur Respir J 2004;23:685e91.
37. Wilkinson TM, Patel IS, Wilks M, Donaldson GC, Wedzicha JA.
Airway bacterial load and FEV1 decline in patients with
chronic obstructive pulmonary disease. Am J Respir Crit
Care Med 2003;167:1090e5.
38. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway
inflammation and bronchial bacterial colonization in chronic
obstructive pulmonary disease. Am J Respir Crit Care Med
2006;173:991e8.
39. Marin A, Garcia-Aymerich J, Sauleda J, Belda J, Millares L,
Garcı́a-Nu ~ez M, et al. Effect of bronchial colonisation on
n
airway and systemic inflammation in stable COPD. COPD
2012;9:121e30.
40. Matkovic Z, Miravitlles M. Chronic bronchial infection in
COPD. Is there an infective phenotype? Resp Med 2013;107:
10e22.
 Soler-Catalun
41. Martı́nez-Garcı́a MA, ~a JJ, Donat Sanz Y, Catalan
Serra P, Agramunt Lerma M, Ballestı́n Vicente J, et al. Factors
associated with bronchiectasis in patients with COPD. Chest
2011;140:1130e7.
42. Remy-Jardin M, Amara A, Campistron P, Mastora I,
Delannoy V, Duhamel A, et al. Diagnosis of bronchiectasis
with multislice spiral CT: accuracy of 3-mm-thick structured
sections. Eur Radiol 2003;13:1165e71.
43. Miszkiel KA, Wells AU, Rubens MB, Cole PJ, Hansell DM. Ef-
fects of airway infection by Pseudomonas aeruginosa: a
computed tomographic study. Thorax 1997;52:260e4.
44. Paone G, Conti V, Vestri A, Leone A, Puglisi G, Benassi F, et al.
Analysis of sputum markers in the evaluation of lung inflam-
mation and functional impairment in symptomatic smokers
and COPD patients. Dis Markers 2011;31:91e100.
45. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper Jr JA,
Criner GJ, et al. Azithromycin for prevention of exacerbations
of COPD. N Engl J Med 2011;365:689e98.
46. Sethi S, Jones PW, Theron MS, Miravitlles M, Rubinstein E,
Wedzicha JA, et al. Pulsed moxifloxacin for the prevention
of exacerbations of chronic obstructive pulmonary disease:
a randomized controlled trial. Respir Res 2010;11:10.
47. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug F.
Once daily oral ofloxacin in chronic obstructive pulmonary
disease exacerbation requiring mechanical ventilation: a
randomised placebo-controlled trial. Lancet 2001;358:
2020e5.
48. Allegra L, Blasi F, de Bernardi B, Cosentini R, Tarsia P. Antibi-
otic treatment and baseline severity of disease in acute exac-
erbations of chronic bronchitis: a re-evaluation of previously
published data of a placebo-controlled randomized study.
Pulm Pharmacol Ther 2001;14:149e55.
49. Allegra L, Konietzko N, Leophonte P, Hosie J, Pauwels R,
Guyen JN, et al. Comparative safety and efficacy of sparflox-
acin in the treatment of acute exacerbations of chronic
obstructive pulmonary disease: a double-blind, randomised,
parallel, multicentre study. J Antimicrob Chemother 1996;
27(Suppl. A):93e104.
50. Bandak SI, Bolzon LD, Turnak MR, Johns D, Henle SK, Allen BS.
Cefaclor versus amoxicillin/clavulanate in acute bacterial ex-
acerbations of chronic bronchitis: a randomised multicentre
study. Int J Clin Pract 1999;53:578e83.
51. Chodosh S, DeAbate CA, Haverstock D, Aneiro L, Church D.
The Bronchitis Study Group. Short course moxifloxacin
513
therapy for treatment of acute bacterial exacerbations of
chronic bronchitis. Resp Med 2000;94:18e27.
52. DeAbate CA, Mathew CP, Warner JH, Heyd A, Church D. The
safety and efficacy of short course (5 day) moxifloxacin vs.
azithromycin in the treatment of patients with acute exacer-
bations of chronic bronchitis. Resp Med 2000;94:1029e37.
53. Weiss LR. Open-label, randomized comparison of clarithromy-
cin, levofloxacin and cefuroxime axetil in the treatment of
adults with acute bacterial exacerbations of chronic bron-
chitis. Clin Ther 2002;24:1414e24.
54. Urueta-Robledo J, Ariza H, Jardim JR, Caballero A, Garcı́a-
Caldero n A, Amabile-Cuevas CF, et al. Moxifloxacin versus lev-
ofloxacin against acute exacerbations of chronic bronchitis:
the Latine American cohort. Respir Med 2006;100:1504e11.
55. Wilson R, Allegra L, Huchon G, Izquierdo JL, Jones P,
Schaberg T, et al. Short and long-term outcomes of moxiflox-
acin compared to standard antibiotic treatment in acute ex-
acerbations of chronic bronchitis. Chest 2004;125:953e64.
56. Grassi C, Casali L, Curti E, Tellarini M, Lazzaro C, Schito G.
SMART Study Group. Studio Multicentrico con Moxifloxacina
nel Trattamento delle Riacutizzazioni de Bronchite Cronica. Ef-
ficacy and safety of short course (5-day) moxifloxacin vs 7-day
ceftriaxone in the treatment of acute exacerbations of chronic
bronchitis (AECB). J Chemother 2002;14:597e608.
57. Petitpretz P, Chone C, Tremolieres F. Investigator Study Group.
Levofloxacin 500 mg once daily versus cefuroxime 250 mg twice
daily in patients with acute exacerbations of chronic obstruc-
tive bronchitits: clinical efficacy and exacerbation-free inter-
val. Int J Antimicrob Agents 2007;30:52e9.
58. Ruiz-Gonzalez A, Gimenez A, Gomez-Arbones X, Soler-
Gonza lez J, Sa
nchez V, Falguera M, et al. Open-label, ran-
domized comparison trial of long-term outcomes of levoflox-
acin versus standard antibiotic therapy in acute
exacerbations of chronic obstructive pulmonary disease. Re-
spirology 2007;12:117e21.
59. Lode H, Eller J, Linnhoff A, Ioanas M. Evaluation of therapy-
free interval in COPD patients study group. Levofloxacin
versus clarithromycin in COPD exacerbation: focus on
exacerbation-free interval. Eur Respir J 2004;24:947e53.
60. Chodosh S, Schreurs A, Siami G, Barkman Jr HW, Anzueto A,
Shan M, et al. Efficacy of oral ciprofloxacin vs. clarithromycin
for treatment of acute bacterial exacerbations of chronic
bronchitis. Clin Infect Dis 1998;27:730e8.
61. Nouira S, Marghli S, Besbes L, Boukef R, Daami M, Nciri N,
et al. Standard versus newer antibacterial agents in the treat-
ment of severe acute exacerbation of chronic obstructive pul-
monary disease; a randomised trial of trimethoprim-
sulfamethoxazole versus ciprofloxacin. Clin Infect Dis 2010;
51:143e9.
62. Snoeck-Stroband JB, Lapperre TS, Gosman MME, Boezen HM,
Timens W, ten Hacken NH, et al. Chronic bronchitis sub-
phenotype within COPD: inflammation in sputum and bi-
opsies. Eur Respir J 2008;31:70e7.
63. Gompertz S, O’Brien C, Bayley DL, Hill SL, Stockley RA.
Changes in bronchial inflammation during acute exacerba-
tions of chronic bronchitis. Eur Respir J 2001;17:1112e9.
64. Zhu J, Qiu YS, Majumdar S, Gamble E, Matin D, Turato G,
et al. Exacerbations of bronchitis: bronchial eosinophilia
and gene expression for interleukin-4, interleukin-5, and
eosinophil chemoattractants. Am J Respir Crit Care Med
2001;164:109e16.
65. Sethi S. New developments in the pathogenesis of acute exac-
erbations of chronic obstructive pulmonary disease. Curr Opin
Infect Dis 2004;17:113e39.
66. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P,
Caramori G, et al. Infections and airway inflammation in
chronic obstructive pulmonary disease severe exacerbations.
Am J Respir Crit Care Med 2006;173:1114e21.
514
67. Ramsey B, Pepe MS, Quan JM, Otto KL, Montgomery AB,
Williams-Warren J, et al. Cystic Fibrosis Inhaled Tobramycin
Study Group. Intermittent administration of inhaled tobramy-
cin in patients with cystic fibrosis. N Engl J Med 1999;340:
23e30.
68. Murphy TD, Anbar RD, Lester LA, Nasr SZ, Nickerson B,
VanDevanter DR, et al. Treatment with tobramycin solution
for inhalation reduces hospitalizations in young CF subjects
with mild lung disease. Pediatr Pulmonol 2004;38:314e20.
69. Stead RJ, Hodson ME, Batten JC. Inhaled ceftazidime
compared with gentamicin and carbenicillin in older patients
with cystic fibrosis infected with Pseudomonas aeruginosa. Br
J Dis Chest 1987;81:272e9.
70. Jensen T, Pedersen SS, Garne S, Heilmann C, Høiby N, Koch C.
Colistin inhalation therapy in cystic fibrosis patients with
chronic Pseudomonas aeruginosa lung infection. J Antimicrob
Chemother 1987;19:831e8.
71. Schaad UB, Wedgwood J, Ruedeberg A, Kraemer R, Hampel B.
Ciprofloxacin as antipseudomonal treatment in patients with
cystic fibrosis. Pediatr Infect Dis J 1997;16:106e11.
72. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS,
Chalmers JD, et al. A randomized controlled trial of nebulized
gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir
Crit Care Med 2011;183:491e9.
73. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improve-
ment of survival in patients with diffuse panbronchiolitis
treated with low-dose erythromycin. Am J Respir Crit Care
Med 1998;157:1829e32.
74. Hashiba M, Baba S. Efficacy of long-term administration of
clarithromycin in the treatment of intractable chronic sinus-
itis. Acta Otolaryngol Suppl 1996;525:73e8.
75. Cervin A, Kalm O, Sandkull P, Lindberg S. One-year low-dose
erythromycin treatment of persistent chronic sinusitis after
sinus surgery: clinical outcome and effects on mucociliary pa-
rameters and nasal nitric oxide. Otolaryngol Head Neck Surg
2002;126:481e9.
76. Cymbala AA, Edmonds LC, Bauer MA, Jederlinic PJ, May JJ,
Victory JM, et al. The disease-modifying effects of twice-
weekly oral azithromycin in patients with bronchiectasis.
Treat Respir Med 2005;4:117e22.
77. Serisier DJ, Martin ML. Long-term, low-dose erythromycin in
bronchiectasis subjects with frequent infective exacerba-
tions. Respir Med 2011;105:946e9.
78. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H,
et al. Azithromycin for prevention of exacerbations in non-
cystic fibrosis bronchiectasis (EMBRACE): a randomised,
double-blind, placebo-controlled trial. Lancet 2012;380:
660e7.
79. Staykova T, Black P, Staykova T, Chacko E, Poole P. Prophylac-
tic antibiotic therapy for chronic bronchitis. Cochrane Data-
base Syst Rev 2003;(1):CD004105.
80. Milstone AP. Use of azithromycin in the treatment of acute ex-
acerbations of COPD. Int J COPD 2008;3:515e20.
81. Suzuki T, Yanai M, Yamaya M, Satoh-Nakagawa T, Sekizawa K,
Ishida S, et al. Erythromycin and common cold in COPD. Chest
2001;120:730e3.
82. Banerjee D, Honeybourne D, Khair OA. The effect of oral clar-
ithromycin on bronchial airway inflammation in moderate-to-
severe stable COPD: a randomized controlled trial. Treat Re-
spir Med 2004;3:59e65.
83. Blasi F, Bonardi D, Aliberti S, Tarsia P, Confalonieri M, Amir O,
et al. Long-term azithromycin use in patients with chronic
obstructive pulmonary disease and tracheostomy. Pulmon
Phamacol Ther 2010;23:200e7.
84. He Z-Y, Ou L-M, Zhang J-Q, Bai J, Liu GN, Li MH, et al. Effect
of 6 months of erythromycin treatment on inflammatory cells
in induced sputum and exacerbations in chronic obstructive
pulmonary disease. Respiration 2010;80:445e52.
R. Wilson et al.
85. Pomares X, Monto n C, Espasa M, Casabon J, Monso  E, Gallego M.
Long-term azithromycin therapy in patients with severe COPD
and repeated exacerbations. Int J COPD 2011;6:449e56.
86. Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ,
Wedzicha JA. Long-term erythromycin therapy is associated
with decreased chronic obstructive pulmonary disease exacer-
bations. Am J Respir Crit Care Med 2008;178:1139e47.
87. Crosbie PA, Woodhead MA. Long-term macrolide therapy in
chronic inflammatory airway diseases. Eur Respir J 2009;33:
171e81.
88. Miravitlles M, Marı́n A, Monso  E, Vila
 S, de la Roza C, Hervas R,
et al. Efficacy of moxifloxacin in the treatment of bronchial
colonisation in COPD. Eur Respir J 2009;34:1066e71.
89. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromy-
cin and the risk of cardiovascular death. N Engl J Med 2012;
366:1881e90.
90. Miravitlles M, Soler-Catalun ~ a JJ, Calle M, Molina J, Almagro P,
Quintano JA, et al. Spanish COPD Guidelines (GesEPOC): phar-
macological treatment of stable COPD. Arch Bronconeumol
2012;48:247e57.
91. Wilson R, Welte T, Polverino E, De Soyza A, Greville H,
O’Donnell A, et al. Ciprofloxacin DPI in non-cystic fibrosis
bronchiectasis: a phase II randomised study. Eur Resp J
2013;41:1107e15.
92. Drobnic ME, Sun ~é P, Montoro JB, Ferrer A, Orriols R. Inhaled
tobramycin in non-cystic fibrosis patients with bronchiectasis
and chronic bronchial infection with Pseudomonas aerugi-
nosa. Ann Pharmacother 2005;39:39e44.
93. Fiel S. Aerosolized antibiotics in cystic fibrosis: current and
future trends. Exp Rev Resp Med 2008;2:479e87.
94. Couch LA. Treatment with tobramycin solution for inhalation
in bronchiectasis patients with Pseudomonas aeruginosa.
Chest 2001;120(Suppl. 3):114Se7S.
95. Bilton D, Henig N, Morrissey B, Gotfried M. Addition of inhaled
tobramycin to ciprofloxacin for acute exacerbations of Pseu-
domonas aeruginosa infection in adult bronchiectasis. Chest
2006;130:1503e10.
96. Diot P, Dequin PF, Rivoire B, Gagnadoux F, Faurisson F, Diot E,
et al. Aerosols and anti-infectious agents. J Aerosol Med 2001;
14:55e64.
97. Kuhn R. Formulation of aerosolized therapeutics. Chest 2001;
120:945e85.
98. Hagerman JK, Hancock KE, Klepser ME. Aerosolised antibi-
otics: a critical appraisal of their use. Expert Opin Drug Deliv
2006;3:71e86.
99. Klastersky J, Huysmans E, Weerts D, Hensgens C, Daneau D.
Endotracheally administered gentamicin for the prevention
of infections of the respiratory tract in patients with trache-
ostomy: a double-blind study. Chest 1974;65:650e4.
100. Klastersky J, Carpentier-Meunier F, Kahan-Coppens L,
Thys JP. Endotracheally administered antibiotics for gram-
negative bronchopneumonia. Chest 1979;75:586e91.
101. Brown RB, Kruse JA, Counts GW, Russell JA, Christou NV,
Sands ML. The Endotracheal Tobramycin Study Group. Dou-
ble-blind study of endotracheal tobramycin in the treatment
of gram-negative bacterial pneumonia. Antimicrob Agents
Chemother 1990;34:269e72.
102. Palmer LB, Smaldone GC, Simon SR, O’Riordan TG, Cuccia A.
Aerosolized antibiotics in mechanically ventilated patients:
delivery and response. Crit Care Med 1998;26:31e9.
103. Elman M, Goldstein I, Marquette CH, Wallet F, Lenaour G,
Rouby JJ. Experimental ICU Study Group. Influence of lung
aeration on pulmonary concentrations of nebulized and intra-
venous amikacin in ventilated piglets with severe broncho-
pneumonia. Anesthesiology 2002;97:199e206.
104. Luyt CE, Clavel M, Guntupalli K, Johannigman J, Kennedy JI,
Wood C, et al. Pharmacokinetics and lung delivery of PDDS-
aerosolized amikacin (NKTR-061) in intubated and
Antibiotics for treatment and prevention of AE-COPD
mechanically ventilated patients with nosocomial pneu-
monia. Crit Care 2009;13:R200.
105. Griese M, Eismann C, Börner G, Denk O, Schierholz JM,
Keller M, et al. A pharmacokinetics and safety comparison
of a highly concentrated tobramycin solution with TOBI. J
Aerosol Med Pulm Drug Deliv 2013 Jun 22. http:
//dx.doi.org/10.1089/jamp.2012.1022 [Epub ahead of print].
106. Lenoir G, Antypkin YG, Miano A, Moretti P, Zanda M, Varoli G,
et al. Efficacy, safety, and local pharmacokinetics of highly
concentrated nebulized tobramycin in patients with cystic
fibrosis colonized with Pseudomonas aeruginosa. Paediatr
Drugs 2007;9(Suppl. 1):11e20.
107. Chuchalin A, Csiszér E, Gyurkovics K, Bartnicka MT, Sands D,
Kapranov N, et al. A formulation of aerosolized tobramycin
(Bramitob) in the treatment of patients with cystic fibrosis
and Pseudomonas aeruginosa infection: a double-blind, pla-
cebo-controlled, multicenter study. Paediatr Drugs 2007;
9(Suppl. 1):21e31.
108. McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-
Bogart GZ, Montgomery AB. Inhaled aztreonam lysine for
chronic airway Pseudomonas aeruginosa in cystic fibrosis.
Am J Respir Crit Care Med 2008;178:921e8.
109. Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T,
Monteforte M, et al. Aerosolized antibiotics and ventilator-
associated tracheobronchitis in the intensive care unit. Crit
Care Med 2008;36:2008e13.
110. Hansen CR, Pressler T, Høiby N. Early aggressive eradication
therapy for intermittent Pseudomonas aeruginosa airway
colonization in cystic fibrosis patients: 15 years experience.
J Cyst Fibros 2008;7:523e30.
111. Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM,
McCoy KS, Montgomery AB, et al. Efficacy and safety of
inhaled aztreonam lysine for airway pseudomonas in cystic
fibrosis. Chest 2009;135:1223e32.
112. Oermann CM, McCoy KS, Retsch-Bogart GZ, Gibson RL,
McKevitt M, Montgomery AB. Pseudomonas aeruginosa antibi-
otic susceptibility during long-term use of aztreonam for inha-
lation solution (AZLI). J Antimicrob Chemother 2011;66:
2398e404.
113. Konstan MW, Geller DE, Minic P, Brockhaus F, Zhang J,
Angyalosi G. Tobramycin inhalation powder for P. aeruginosa
infection in cystic fibrosis: the EVOLVE trial. Pediatr Pulmonol
2010;46:230e8.
515
114. Konstan MW, Flume PA, Kappler M, Chiron R, Higgins M,
Brockhaus F, et al. Safety, efficacy and convenience of tobra-
mycin inhalation powder in cystic fibrosis patients: the EAGER
trial. J Cyst Fibros 2011;10:54e61.
115. Wainwright CE, Quittner AL, Geller DE, Nakamura C,
Wooldridge JL, Gibson RL, et al. Aztreonam for inhalation so-
lution (AZLI) in patients with cystic fibrosis, mild lung impair-
ment, and P. aeruginosa. J Cyst Fibros 2011;10:234e42.
116. Clancy JP, Dupont L, Konstan MW, Billings J, Fustik S, Goss CH,
et al. Arikace Study Group. Phase II studies of nebulised Ari-
kace in CF patients with Pseudomonas aeruginosa infection.
Thorax 2013;68:818e25.
117. Dal Negro R, Micheletto C, Tognella S, Visconti M, Turati C. To-
bramycin nebulizer solution in severe COPD patients colo-
nized with Pseudomonas aeruginosa: effects on bronchial
inflammation. Adv Ther 2008;25:1019e30.
118. Garcia-Vidal C, Almagro P, Romanı́ V, Rodrı́guez-Carballeira M,
Cuchi E, Canales L, et al. Pseudomonas aeruginosa in patients
hospitalised for COPD exacerbation: a prospective study. Eur
Respir J 2009;34:1072e8.
119. Davies G, Wells AU, Doffman S, Watanabe S, Wilson R. The
effect of Pseudomonas aeruginosa on pulmonary function
in patients with bronchiectasis. Eur Respir J 2006;28:
974e9.
120. Sethi S, Rennard SI, Miravitlles M, Martinez FJ, Donohue JF,
Anzueto A, et al. A Phase 2 study to evaluate the safety, toler-
ability and efficacy of levofloxacin inhalation solution (MP-
376) administered for 5 days every 28 days to prevent acute
exacerbations in high risk COPD patients. Am J Respir Crit
Care Med 2012;185:A3037.
121. Azoicai D, Antoniu S. MP-376 (Aeroquin) for chronic Pseudo-
monas aeruginosa infections. Expert Opin Investig Drugs
2013;22:267e76.
122. Murphy TF, Sethi S. Chronic obstructive pulmonary dis-
ease. Role of bacteria and guide to antibacterial selection
in the older patient. Drugs Aging 2002;19:761e75.
123. Dever LL, Shashikumar K, Johanson WG. Antibiotics in the
treatment of acute exacerbations of chronic bronchitis.
Expert Opin Investig Drugs 2002;11:911e25.
124. Miravitlles M, Llor C. Determining factors in the prescrip-
tion of moxifloxacin in exacerbations of chronic bronchitis
in the primary-care setting. Clin Drug Invest 2007;27:
95e104.