Respiratory Medicine (2010) 104, 1396e1403

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

REVIEW

Short-course fluoroquinolone therapy in

exacerbations of chronic bronchitis and COPD
Antonio Anzueto a,*, Marc Miravitlles b

a
Department of Medicine, Pulmonary Disease, 111E, 7400 Merton Minter Boulevard, The University of Texas Health
Science Center at San Antonio, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
b
Fudació Clı´nic. Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clı´nic, 08036 Barcelona,
Catalonia, Spain

Received 28 October 2009; accepted 26 May 2010

KEYWORDS Summary
Chronic bronchitis; Acute exacerbations of chronic bronchitis (AECB) and chronic obstructive pulmonary disease
COPD; (COPD) are associated with significant healthcare costs and contribute to the progress of the
AECB; disease. Although a number of factors may trigger these episodes, between 40% and 60% are
Fluoroquinolones; bacterial in nature. Antimicrobial therapy can be effective in treating exacerbations, leading
Duration of therapy; to improved peak expiratory flow rates, fewer hospitalizations, lower relapse rates, and
Short-course therapy greater clinical success. Evidence suggests that short-course antimicrobial therapy can be as
effective as standard duration therapy (>7 days) in treating exacerbations. Randomized trials
have shown that clinical and bacteriological success rates are comparable with both 5-day and
standard antibiotic courses. Furthermore, 5-day fluoroquinolone therapy is associated with
faster recovery, fewer relapses, prolonged duration between episodes, and less hospitalization
when compared with standard therapy. Both moxifloxacin and gemifloxacin have received
FDA-approval for 5-day therapy in AECB.
ª 2010 Elsevier Ltd. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397
Etiology of exacerbations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397
Antimicrobial therapy in the management of AECB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1397
Short-course therapy versus standard therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1399
Short-course therapy with cephalosporins, b-lactams, and macrolides . . . . . . . . . . . . . . . . . . . . . . . . . . 1399

* Corresponding author. Tel.: þ1 210 617 5256; fax: þ1 210 949 3006.
E-mail address: anzueto@uthscsa.edu (A. Anzueto).

0954-6111/$ - see front matter ª 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2010.05.018
Duration of fluoroquinolone therapy in AECB and COPD 1397

Short-course fluoroquinolone therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1399

Outcomes of antimicrobial therapy: speed of recovery and relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1400
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1401
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1402

Introduction causative pathogens. Further, multidrug-resistant bacteria

Approximately 13 million Americans suffer from chronic
bronchitis or chronic obstructive pulmonary disease
(COPD).1 Acute exacerbations of chronic bronchitis (AECB)
affect many of these individuals and account for an
estimated 12 million physician visits annually.1 Exacerba-
tions lead to declines in lung function, cause significant
morbidity and mortality, accelerate disease progression,1e3
and significantly lower the quality of life,4 including an
increase in the risk of being housebound.5,6
The cardinal symptoms of exacerbations are increased
cough, dyspnea, increased sputum volume, and increased
sputum purulence.7 COPD patients have between 1 and 3
exacerbation episodes per year,1 and the frequency may be
associated with disease severity.2,8
are common among patients with severe acute exacerba-
tions requiring intubation and mechanical ventilation.1
Likely causative pathogens vary according to the
severity of the underlying COPD and the degree to which
the lung function is impaired. In patients with mild-to-
moderate COPD, H. influenzae and S. pneumoniae are the
most common pathogens implicated in exacerbations.
Staphylococcus aureus and Gram-negative bacteria, such as
P. aeruginosa and Enterobacteriaceae species, predomi-
nate in patients who experience severe exacerbations and
have a forced expiratory volume in 1 s (FEV1)  35%.11,13
Approximately 30e50% of AECB are associated with a viral
infection.9,10 These infections may exacerbate existing
inflammation in patient airways and predispose individuals
to secondary bacterial infection.6,14,15

Etiology of exacerbations Antimicrobial therapy in the management of

Environmental factors such as air pollutants, allergens,
temperature changes, or irritants (i.e., dust and cigarette
smoke) can precipitate an exacerbation. Comorbid condi-
tions such as congestive heart failure or pulmonary embo-
lism may aggravate or mimic an exacerbation, while lack of
compliance with therapy has also been implicated in some
patients.1 However, infections are the most common
trigger, with bacterial or viral pathogens accounting for 80%
of AECB episodes.9,10
Bacterial pathogens occur in 40e60% of AECB sputum
samples,9 and require appropriate and timely antimicrobial
therapy. Patients who are elderly or with multiple comorbid
conditions, those who have more purulent sputum or
patients with worsening COPD, are more likely to have
bacterial infections.11,12 In many cases, bacterial exacer-
bations are secondary to viral infections, and 25% of
patients may have a viral/bacterial coinfection.1,10
Gram-negative bacteria are more likely to be involved in
AECB, with Haemophilus influenzae accounting for 50% of
all bacterial exacerbations.11,10,13 However, Moraxella
catarrhalis causes some AECBs, and Pseudomonas aerugi-
nosa and other Gram-negative bacilli, such as Enter-
obacteriaceae, are more prevalent in patients with severe
impairment of lung function.11,13 Among Gram-positive
bacteria, Streptococcus pneumoniae is the most common,
and S. pneumoniae and M. catarrhalis have been found in
approximately 30% of isolates obtained from patients with
exacerbations. Atypical respiratory pathogens, including
Chlamydophila pneumoniae, occur in 5e10% of AECB.9
Resistance is an important issue in AECB, with both
b-lactam and macrolide resistance occurring among
AECB
Successful management of AECB entails achievement of
four goals: rapidly resolving symptoms, preventing relapse,
prolonging the time between exacerbations, and inter-
rupting the vicious cycle of recurrent infection induced lung
damage.1 A number of guidelines have established treat-
ment recommendations for AECB. The American College of
Physicians and the American College of Chest Physicians
endorse the benefit of antibiotic therapy,16 especially for
patients with more severe exacerbations.16 Evidence indi-
cates that antimicrobial therapy can be effective in treat-
ing exacerbations, leading to improved peak expiratory
flow rates, fewer hospitalizations, lower relapse rates, and
greater clinical success.7,17,18 Current guidelines for anti-
microbial therapy in AECB include those from the Global
Initiative for Chronic Obstructive Lung Disease (GOLD), the
American Thoracic Society, the Canadian Thoracic Society
and the Canadian Infectious Disease Society, the European
Respiratory Society, and a consensus statement formulated
by a number of Spanish medical societies.1,19e21
Selection of effective antimicrobial therapy is critical.
Some evidence suggests that use of inappropriate antibi-
otics may result in poor outcomes and greater likelihood of
relapse.17 The Council for Appropriate and Rational Anti-
biotic Therapy (CARAT) criteria recommend that selection
of antibiotic treatment be supported with strong clinical
evidence, such as data from randomized, double-blind,
controlled multicenter trials.22 Table 1 presents Canadian
guidelines for first-line antimicrobial treatment and alter-
natives for treatment failure in AECB.1 These guidelines
represent a joint effort by the Canadian Thoracic Society
 1398
Table 1 Initial empiric therapy in outpatients with acute bacterial exacerbations of chronic bronchitis.
Risk group Basic clinical state Symptoms and risk factors Probable pathogens First choice Alternatives for treatment
failure
I Chronic bronchitis without Increased cough and sputum, Haemophilus influenzae, 2nd-generation macrolide, Fluoroquinolone, b-lactam/
risk factors (simple) sputum purulence, and Haemophilus spp. Moraxella 2nd- or 3rd-generation b-lactamase inhibitor
increased dyspnea catarrhalis, Streptococcus cephalosporin, amoxicilin,
pneumoniae doxycycline, TMP-SMX
II Chronic bronchitis with risk As in group I plus 1 of the As in group I plus Klebsiella Fluoroquinalone or b-lactam/ May require parenteral therapy
factors (complicated) following: spp. þ other Gram-negative b-lactamase inhibitor Consider referral to a specialist
 FEV1 < 50% predicted pathogens Increased or hospital
 >4 exacerbations/yr probability of b-lactam
 Cardiac disease resistance
 Use of home oxygen
 Chronic oral steroid use
 Antiobiotic use in the
past 3 mo
III Chronic suppurative As in group II with constant As in group II plus Pseudomonas Ambulatory patients: tailor e
bronchitis purulent sputum aeruginosa and multiresistant treatment to airway pathogen
 Some have bronchiectasis Enterobacteriaceae P aeruginosa common
 FEV1 < 35% predicted (ciprofloxacin)
 Use of home oxygen Hospitalized patients:
 Multiple risk factors (e.g., parenteral therapy usually
frequent exacerbations required
and FEV1 < 50% predicted)
FEV1: forced expiratory volume in 1 s; TMP-SMK: trimethoprim-sulfamethoxazole. Reproduced with permission from Balter MS, La Forge J, Low DE Mandell L, Grossman RF, and the Chronic
Bronchitis Working Group on behalf of the Canadian Thoracic Society and the Canadian Infectious Disease Society. Canadian guidelines for the management of acute exacerbations of

A. Anzueto, M. Miravitlles
chronic bronchitis: executive summary. Can Respir J 2003; 10:248e58.
Duration of fluoroquinolone therapy in AECB and COPD
and the Canadian Infectious Disease Society.1 Patients are
stratified according to risk factors, with antibiotic recom-
mendations for each group.1
P. aeruginosa and other Gram-negative bacilli are more
common in patients who have frequent exacerbations,
chronic use of oral steroids, or severe pulmonary disease
(GOLD IV),11,13,23 such as Group III patients with AECB
(Table 1) and patients with more-advanced exacerbations
of COPD.24 In a recent study of hospitalized patients with
exacerbations of COPD, Garcia-Vidal and colleagues iden-
tified the BODE (body mass index, airflow obstruction,
dyspnea, exercise capacity) index ([odds ratio] OR 2.18;
95% confidence interval [CI], 1.26e3.78; P Z 0.005),
admissions in the previous year (OR 1.65; 95% CI,
1.13e2.43; P Z 0.005), systemic steroid treatment (OR
14.7; 95% CI, 2.28e94.8; P Z 0.01), and previous isolation
of P. aeruginosa (OR 23.1; 95% CI, 5.7e94.3; P < 0.001) as
risk factors for P. aeruginosa infection.23 Many of these
organisms are resistant to traditional first-line agents, such
as amoxicillin, doxycycline, trimethoprim/sulfamethox-
azole, azalides, and macrolides.25 Fluoroquinolones
(ciprofloxacin, and high-dose levofloxacin 750 mg) have
been recommended as the agent of choice when these
pathogens are identified in patients with AECB.1
Short-course therapy versus standard therapy
Duration of antimicrobial treatment is a critical decision.
Short-course therapy (defined as 5 days) may have
a number of advantages over standard therapy (>7 days),
including improved speed of recovery, shortened time to
symptom improvement, decreased relapse rate, and pro-
longed intervals between recurrences. Additionally, short-
course therapy may reduce the risk of adverse events and
the pressure that drives bacterial resistance as a result of
shorter exposure to antibiotics.26,27 Reduced hospital
admission rates, hospital lengths of stay, and healthcare
costs have also been demonstrated with short-course
therapy.26,28e32 Further, there may also be an impact on
the long-term course of the disease.32 In patients with
pseudomonas infections, mainly nosocomial infections, the
current recommendations are to receive antibiotics for up
to 15 days. Longer duration of therapy is associated with
reduced failure rates.33
A meta-analysis of 7 randomized controlled trials, with
a total patient population of 3083, compared different
treatment durations of the same antibiotic regimen. The
short-duration treatment proved as effective as and safer
than long-duration antimicrobial therapy in patients with
AECB.26 Short-course therapy was associated with fewer
adverse events as compared with standard, longer duration
treatment.26 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 bacteri-
ological cure rates observed with short-course therapy
were comparable to those achieved with conventional
duration therapy in patients with mild-to-moderate exac-
erbations.34 Similar observations were found for early cure
when different treatment durations of the same antibiotic
were compared. The authors suggested that a shorter
course of antibiotic treatment may enhance compliance
1399
and reduce antibiotic costs, and further recommended that
antibiotic treatment duration be no longer than 5 days,
regardless of antibiotic class, in patient with mild-to-
moderate exacerbations of COPD or chronic bronchitis.34
Short-course therapy with cephalosporins,
b-lactams, and macrolides
A trial investigating the efficacy and safety of a 5-day
course of pharmacokinetically-enhanced amoxicilline
clavulanate (2000/125 mg bid) compared with a 7-day
course of conventional amoxicillineclavulanate (875/
125 mg bid) in AECB found that the shorter course was as
effective clinically in the per-protocol (PP) population as
the longer course regimen, with a clinical success rate of
93.0% and 91.2%, respectively.35 Further, bacteriological
success was achieved in 76.7% and 73.0%, respectively.35 A
once-daily, 5-day course of clarithromycin extended-
release (1000 mg) was compared to 7-day clarithromycin
regular-release taken twice daily (500 mg) for AECB. As
with the other trials, results were similar in both groups e
clinical cures among evaluable patients were 84% in both
extended- and regular-release groups. The bacteriological
cure rates were 87% and 89%, respectively, and overall
target pathogen eradication rates were 88% and 89%,
respectively.36 However, 5-day clarithromycin extended-
release was better tolerated and caused statistically
significantly fewer drug-related adverse events due to
abnormal taste than the regular-release formulation (3%
and 8%, respectively, P Z 0.012).36
Short-course fluoroquinolone therapy
The respiratory fluoroquinolones (levofloxacin, moxi-
floxacin, and gemifloxacin) exhibit a broadespectrum
activity against most pathogens associated with AECB.28
Fluoroquinolones have been recommended as first-line
treatment for AECB in patients with chronic bronchitis
complicated by comorbid illness, severe COPD with
a FEV1 < 50%, patients >65 years, or recurrent exacerba-
tions (Table 1).1
Clinical studies have demonstrated comparable, and in
some cases, superior efficacy for short-course, 5-day fluo-
roquinolone therapy to that of standard therapy in AECB, as
measured by both clinical and bacteriological outcomes. In
a randomized, double-blind study of a 5-day course of
500 mg levofloxacin qd compared with the 7-day, 500 mg qd
regimen in 532 patients with AECB, the clinical success rates
in the PP analysis were 82.8% for the 5-day regimen and
84.4% for the 7-day regimen. Bacteriological eradication
rates were also similar at 82.1% and 83.2%, respectively.37
In a randomized, noninferiority study, 369 patients with
severe AECB were randomized to receive either high-dose
levofloxacin therapy (750 mg qd) for 5 days or amoxicillin/
clavulanate (875/125 mg bid) for 10 days.30 Significantly
more patients in the 5-day levofloxacin group had resolu-
tion of purulent sputum production (57.5% vs 35.6%;
P < 0.006), sputum production (65.4% vs 45.3%; P < 0.013),
and cough (60.0% vs 44.0%; P < 0.045), compared with the
amoxicillin/clavulanate group in the intent-to-treat (ITT)
population.30
1400
Short-course levofloxacin therapy was also evaluated in
763 patients stratified by severity of illness, based on pre-
determined criteria and risk factors.38 In the uncompli-
cated group, patients were randomized to levofloxacin
(750 mg qd) for 3 days or azithromycin (500  1 d/250 mg
qd) for 5 days, while those in the complicated AECB group
received levofloxacin (750 mg qd) for 5 days or amoxicillin/
clavulanate (875/125 mg bid) for 10 days.38 In the uncom-
plicated group, Martinez and colleagues showed that both
clinical success and microbiological eradication rates in
microbiologically evaluable patients were superior for the
3-day levofloxacin regimen as compared with 5 days of
azithromycin (96.3% vs 87.4% and 93.8% vs 82.8%, respec-
tively). In the complicated cases, the clinical success and
microbiological eradication rates were similar for 5 days of
levofloxacin and 10 days of amoxicillin/clavulanate (81.4%
vs 80.9% and 81.4% vs 79.8%, respectively). The investiga-
tors concluded that short courses (3e5 days) of levofloxacin
750 mg are at least as effective as traditional courses of
azithromycin and amoxicillin/clavulanate for the spectrum
of patients with AECB.38
Short-course moxifloxacin therapy has also been inves-
tigated in AECB. A 5-day course of moxifloxacin was
explored in a randomized, multicenter study involving 936
patients with AECB that compared the efficacy of 5 days of
moxifloxacin (400 mg qd) to 10 days of moxifloxacin (400 mg
qd) or clarithromycin (500 mg bid). Overall, clinical reso-
lution was similar: 89% for 5-day moxifloxacin, 91% for 10-
day moxifloxacin, and 91% for 10-day clarithromycin.27
Bacteriological eradication rates at follow-up were also
comparable at 94%, 95%, and 91%, respectively. The 5-day
moxifloxacin therapy, however, has a favorable safety and
tolerability profile as compared to 10-day treatment with
moxifloxacin or clarithromycin; drug-related events were
reported for 26%, 30%, and 35%, respectively. The investi-
gators recommended that 5-day moxifloxacin is as effective
and furthermore, a more convenient treatment regimen
than a standard course of clarithromycin or a long duration
of moxifloxacin therapy for patients with AECB.27
Another clinical study of 563 patients compared 2
respiratory fluoroquinolones e levofloxacin and moxi-
floxacin e in the treatment of AECB. A 5-day, 400 mg qd
course of moxifloxacin was both clinically and microbio-
logically equivalent to a 7-day, 500 mg qd course of levo-
floxacin. Clinical success rates were achieved in 91.0% and
94.0% of patients in the moxifloxacin and levofloxacin
groups, respectively, while bacteriological eradication
rates were 92.8% and 93.8%, respectively.39
A randomized, nonblinded study including 162 patients
observed clinical success rates of 88.6% and 89.2% and
pathogen eradication rates at 14 days of 90.9% and 90.0% in
the 5-day moxifloxacin (400-mg tablet qd) and 7-day
amoxicillin/clavulanate (one, 625-mg tablet every 8 h)
groups, respectively.40 Similar results comparing a 5-day
course of moxifloxacin 400 mg qd to another short-course
therapy, 3-day azithromycin 500 mg qd, were reported by
Zervos et al.41 Of 342 patients randomized to either
treatment, clinical success rates for azithromycin and
moxifloxacin were comparable at days 10e12 (90% vs 90%)
and days 22e26 (81% vs 82%) in the ITT analysis. Further,
a similar safety and tolerability profile was observed in the
two short-course treatment groups.41
A. Anzueto, M. Miravitlles
MOSAIC was a large international study that compared
short- and long-term outcomes of antibiotic treatment of
AECB in patients with a history of heavy smoking and
significant COPD.32,42 Five-day moxifloxacin treatment was
compared with a 7e10-day course of amoxicillin, clari-
thromycin, or cefuroxime-axetil. The 5-day moxifloxacin
regimen demonstrated superior clinical cure rates and
higher bacteriological success rates than standard therapy
among the 730 patients enrolled.32,42 In the ITT population,
clinical cure was achieved in 70.9% of patients receiving
moxifloxacin compared with 62.8% given standard therapy
(95% CI, 1.4e14.9), while in the PP population those figures
were 69.7% and 62.1%, respectively (95% CI, 0.3e15.6).32
Higher bacteriologic eradication rates were observed in
the ITT population (76.8% vs 67.5%, respectively; 95% CI,
1.8e20.4) and in the microbiologically valid population
(91.5% vs 81.0%, respectively; 95% CI, 0.4e22.1).32 Multi-
variate analyses further confirmed the clinical cure benefit
(OR 1.49; 95% CI, 1.08e2.04) and clinical success (OR 1.57;
95% CI, 1.03e2.41) of short-course moxifloxacin compared
with standard therapy in patients with AECB.42
Short-course therapy with gemifloxacin has also been
investigated. A randomized, double-blind study was con-
ducted to compare 5-day oral gemifloxacin (320 mg qd)
with 7-day oral levofloxacin (500 mg qd) in 360 patients.
Gemifloxacin proved at least as effective as levofloxacin,
with clinical success rates at follow-up (days 14e21) in the
PP population of 88.2% for gemifloxacin and 85.1% for lev-
ofloxacin. Success rates at the long-term follow-up (days
28e35) were 83.7% and 78.4%, respectively.43
A 5-day course of gemifloxacin (320 mg qd) was compared
with 7 days of clarithromycin (500 mg bid) in a randomized,
double-blind study of 712 patients with AECB. Clinical
success rates were 85.4% and 84.6% for the gemifloxacin and
clarithromycin groups, respectively, and bacteriological
success rates were 86.7% and 73.1%, respectively.44 The
long-term health outcome of AECB recurrence also favored
short-course gemifloxacin. Significantly more patients
receiving gemifloxacin remained free of AECB recurrence
after 26 weeks compared with those receiving clari-
thromycin (71.0% vs 58.5%, respectively; P Z 0.016).44 File
et al. reported similar results comparing 5 days of gemi-
floxacin to 7 days of amoxicillin/clavulanate.45
Outcomes of antimicrobial therapy: speed of
recovery and relapse
Recovery after an exacerbation is influenced by the
severity of the exacerbation and the patient’s history of
exacerbations, including frequency of previous exacerba-
tions.6 Median recovery time after an episode is 6 days for
lung function and 7 days for symptoms.15 However,
recovery time may be considerably longer, as only 75% of
patients return to baseline peak flows 35 days after the
exacerbations have resolved.15 If the patient has not
improved after the first course of antibiotics, a second
course is indicated. Table 2 presents factors associated
with an increased risk of recurrence of AECB.1
When compared with standard therapy that involves
long-duration treatment (7 days) with non-fluo-
roquinolone regimens, 5-day fluoroquinolone therapy also
Duration of fluoroquinolone therapy in AECB and COPD 1401

Table 2 Risk factors associated with increased recurrence

of AECB.
 Frequent purulent exacerbations.
 Poor underlying lung function.
 Lengthy duration of chronic obstructive lung disease.
 Chronic corticosteroid administration.
 Use of supplemental oxygen.
 Significant cardiac disease.
 Malnutrition.

shows an association with more rapid symptom resolution,

faster rate of recovery, lower relapse rate, and prolonged
relapse time intervals.28,29
Clinical studies have demonstrated improvements in Figure 1 Life-table analysis of time to the first composite
speed of recovery and relapse rate in AECB with short- event (treatment failure, and/or new exacerbation, and/or
course fluoroquinolone therapy. In a study comparing 5-day any further antibiotic treatment) stratified according to the
moxifloxacin therapy with 7-day ceftriaxone in 476 time of the last exacerbation prior to randomization to moxi-
patients, moxifloxacin was associated with lower relapse floxacin or standard therapy.27 Reproduced with permission
rates (23.3% vs 28.3%; P > 0.05) and shorter hospitalization from Wilson R, Allegra L, Huchon G, et al. Short-term and long-
(137 days shorter than the control group treated with cef- term outcomes of moxifloxacin compared to standard antibi-
triaxone in inpatient plus day-hospital settings), resulting in otic treatment in acute exacerbations of chronic bronchitis.
greater cost savings.29 Chest 2004; 125:953e64.
The MOSAIC study also showed significantly improved
long-term outcomes in AECB with short-course fluo-
roquinolone therapy. Median times to new exacerbations in not differ significantly between the two treatment groups
patients who did not require further antibiotics were 131.0 at baseline. However, the difference widened progressively
days (mean Z 132.8 days) in the moxifloxacin group, and after treatment, and at 26 weeks, the SGRQ score was 4.6
103.5 days (mean Z 118.0 days) with standard therapy, the units (95% CI, 9.1e0.1) lower in the gemifloxacin group,
difference was statistically significant (P Z 0.03).32 Addi- suggesting that gemifloxacin may have a greater impact
tionally, a life-table analysis of time to the first composite than clarithromycin on the recovery of health status in
event (treatment failure, and/or new exacerbations, and/ patients with AECB.31
or further antibiotic treatment) demonstrated a significant
difference favoring moxifloxacin for up to 5 months of
follow-up (P Z 0.03) (Fig. 1).32 For the elderly and patients
with >3 exacerbations in the previous year, the difference
was significant for 9 months in favor of moxifloxacin.42
Evidence from previously conducted Spanish studies also
indicates that recovery from AECB is faster in patients
treated with 5-day fluoroquinolone therapy.46,47 Time to
recovery was 20% shorter in one study, suggesting that
return to work or other activities could be hastened with
such treatment.46 In another study, 70.3% of patients
treated with a 5-day course of moxifloxacin recovered
within 5 days or less, compared with 44.4% of those treated
with co-amoxiclav or 49.7% treated with clarithromycin
(P < 0.0001).47 Moxifloxacin appeared to provide a protec-
tive effect against slow recovery as compared with co-
amoxiclav (OR 0.34; 0.26e0.45) and clarithromycin (OR
0.41; 0.31e2.85).47 In trials which compared real-life
treatment of AECB with moxifloxacin tablets to oral mac-
rolides, azithromycin, clarithromycin or roxithromycin, 5- Figure 2 Improvement rate over the first 10 days of obser-
day moxifloxacin provides faster relief of symptoms and vation. Mean duration until improvement in moxifloxacin-
higher recovery rates with comparable safety and tolera- treated patients was 3.2 days compared with 4.5 days in
bility profiles (Fig. 2).48 macrolide-treated patients. The difference of 1.2 days was
The Gemifloxacin Long term Outcomes in Bronchitis statistically significant (P < 0.0001).44 Reproduced with
Exacerbations (GLOBE) study compared 5-day gemifloxacin permission from Schaberg T, Möller M, File T, Stauch K, Landen
(320 mg qd) and 7-day clarithromycin (500 mg bid) on the H. Real-life treatment of acute exacerbations of chronic
time for recovery of heath status, as measured by St. bronchitis with moxifloxacin or macrolides: a comparative
George’s Respiratory Questionnaire (SGRQ) scores, post-marketing surveillance study in general practice. Clin
following an AECB.31 In 438 patients, the SGRQ scores did Drug Investig 2006; 26:733e44.
1402
Conclusions
It is important to determine that an exacerbation is due to
bacterial infection before prescribing antibiotic therapy, as
40e60% of exacerbations are related to bacterial infec-
tions. The goals of therapy include rapidly resolving
patients’ symptoms, preventing relapse, prolonging the
time between exacerbations, interrupting the cycle of
recurrent infection, and reducing the extent of lung
damage. The most important decision is antibiotic choice.
Guidelines stratify patients by risk factor and disease
severity, and thus help improve selection of an appropriate
antibiotic and reduce treatment failures.
Studies of a variety of antimicrobial classes have
demonstrated that a shorter duration of therapy provides
comparable clinical outcomes to a standard, longer dosing
duration. In addition, short-course treatment regimens may
improve patient compliance, decrease the risk of adverse
events, lower costs, and possibly reduce the pressures that
drive antibiotic resistance.27 Research conducted on short-
course fluoroquinolone therapy supports its use. Further-
more, short-course, high-dose fluoroquinolone therapy also
demonstrates more rapid symptom resolution and faster
recovery rates than traditional therapy using non-fluo-
roquinolones for standard treatment durations. A 5-day
regimen for AECB has been approved by the US FDA for both
moxifloxacin (400 mg qd) and gemifloxacin (320 mg qd).
However, gemifloxacin 320 mg therapy has not been rec-
ommended by the Committee for Medicinal Products for
Human Use (CHMP) of EMEA.49
The demonstrations that 5-day fluoroquinolone therapy
is better than 7-day macrolide/b-lactam therapy, and that
5-day fluoroquinolone therapy is not worse than 7-day or
10-day fluoroquinolone (when stratified by severity),
support the recommendation of short-course, 5-day fluo-
roquinolone therapy as a treatment option for patients with
AECB.
Overall, short-course antibiotic therapy in exacerbations
of COPD and bronchitis is at least as effective as traditional
standard therapy in clinical success and microbiological
eradication rates. Additionally, short-course therapy is
associated with favorable safety and tolerability, and low-
ered risks of adverse events as compared with standard,
longer duration treatment. Moreover, in comparison with
long-duration non-fluoroquinolone treatment regiments,
short-course fluoroquinolone therapy also improved speed
of recovery, decreased relapse rate, prolonged recurrence
intervals, reduced hospitalization, shortened hospital stay,
and exhibited a beneficial impact on the long-term course
of the underlying chronic bronchitis or COPD. Short course
treatment is not recommended for patients with severe
lung disease that may have pseudomonas infection.
Conflict of interest
Antonio Anzueto has been consultant and speaker for
Bayer-Schering-Pharma, Schering-Plough, Pfizer, Boeh-
ringer Ingelheim, GlaxoSmithKline, Dey, Ortho-McNeil, and
AstraZeneca. Marc Miravitlles has been consultant and
speaker for Bayer-Schering-Pharma, Pfizer, Boehringer
Ingelheim, GlaxoSmithKline, and AstraZeneca.
A. Anzueto, M. Miravitlles
Acknowledgements
The authors would like to acknowledge the editorial assis-
tance of Dr. Ching-Ling Chen in the preparation of this
manuscript. Support for this assistance was provided by
Schering-Plough Corporation. The authors accept full
responsibility for the contents of this manuscript.
References
1. Balter MS, La Forge J, Low DE, Mandell L, Grossman RFthe
Chronic Bronchitis Working Group on behalf of the Canadian
Thoracic Society and the Canadian Infectious Disease Society.
Canadian guidelines for the management of acute exacerba-
tions of chronic bronchitis: executive summary. Can Respir J
2003;10:248e58.
2. Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA.
Relationship between exacerbation frequency and lung func-
tion decline in chronic obstructive pulmonary disease. Thorax
2002;57:847e52.
3. Soler-Cataluña JJ, Martinez-Gracı́a MA, Roman Sánchez P,
Salcedo E, Navarro M, Ochando R. Severe acute exacerbations
and mortality in patients with chronic obstructive pulmonary
disease. Thorax 2005;60:925e31.
4. Miravitlles M, Ferrer M, Pont A, Zalacain R, Alvarez-Sala JL,
Masa F, et al. Effect of exacerbations impair quality of life in
patients with chronic obstructive pulmonary disease: a 2 year
follow-up study. Thorax 2004;59:387e95.
5. Miravitlles M, Anzueto A, Legnani D, Forstmeier L, Fargel M.
Patient’s perception of exacerbations of COPDdthe PERCEIVE
study. Respir Med 2007;101:453e60.
6. Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic
obstructive pulmonary disease. Proc Am Thorac Soc 2007;4:
554e64.
7. Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES,
Harding GKM, Nelson NA. Antibiotic therapy in exacerbation of
chronic obstructive pulmonary disease. Ann Intern Med 1987;
106:196e204.
8. Miravitlles M, Murio C, Tirado-Conde G, Levy G, Muellerova H,
Soriano JB, et al. Geographic differences in clinical charac-
teristics and management of COPD: the EPOCA study. Int J
Chron Obstruc Pulmon Dis 2008;3:803e14.
9. Sethi S. Infectious etiology of acute exacerbations of chronic
bronchitis. Chest 2000;17:380Se5S.
10. Papi A, Bellettato CNM, Braccioni F, Romangoli 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.
11. Miravitlles M, Espinosa C, Fernandez-Laso E, Martos JA,
Maldonado JA, Gallego M. Relationship between bacterial flora
in sputum and functional impairment in patients with acute
exacerbations of COPD. Chest 1999;116:40e6.
12. Stockley RA, O’Brien C, Pye A, Hill SL. Relationship of sputum
color to nature and outpatient management of acute exacer-
bations of COPD. Chest 2000;117:1638e45.
13. Eller J, Ede A, Schaberg T, Niederman MS, Mauch H, Lode H.
Infective exacerbations of chronic bronchitis: relation between
bacteriologic etiology and lung function. Chest 1998;113:1542e8.
14. Seemungal TAR, Harpe-Owen R, Bhowmik A, Jeffries DJ,
Wedzicha JA. Detection of rhinovirus in induced sputum at
exacerbation of chronic obstructive pulmonary disease. Eur
Respir J 2000;16:677e83.
15. Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ,
Wedzicha JA. Time course and recovery of exacerbations in
patients with chronic obstructive pulmonary disease. Am J
Respir Crit Care Med 2000;161:1608e13.
Duration of fluoroquinolone therapy in AECB and COPD
16. Snow V, Lascher S, Mottur-Pilson Cfor the Joint Expert Panel on
Chronic Obstructive Pulmonary Disease of the American College
of Chest Physicians and the American College of Phys-
icianseAmerican Society of Internal Medicine. Evidence base
for management of acute exacerbations of chronic obstructive
pulmonary disease. Ann Intern Med 2001;134:595e9.
17. Adams SG, Melo J, Luther M, Anzueto A. Antibiotics are asso-
ciated with lower relapse rates in outpatients with acute
exacerbations of COPD. Chest 2000;117:1345e52.
18. Miravitlles M. Do we need new antibiotics for treating exac-
erbations of COPD? Ther Adv Respir Dis 2007;1:61e76.
19. O’Donnell DE, Aaron S, Bourbeau J, Hernandez P, Marciniuk DD,
Balter M, et al. Canadian Thoracic Society recommendations
for management of chronic obstructive pulmonary dis-
eased2007 update. Can Respir J 2007;14(Suppl. B):5Be32B.
20. Miravitlles M, Monso E, Mensa J, Aguarón Pérez J, Barberán J,
Bárcena Caamaño M, et al. Antimicrobial treatment of exac-
erbation in chronic obstructive pulmonary disease: 2007
consensus statement. Arch Bronconeumol 2008;44:100e8.
21. Woodhead M, Blasi F, Ewig S, Huchon G, Leven M, Ortqvist A,
et al. Guidelines for the management of adult lower respira-
tory tract infections. Eur Respir J 2005;26:1138e80.
22. Martinez FJ, Anzueto A. Appropriate outpatient treatment of
acute bacterial exacerbations of chronic bronchitis. Am J Med
2005;118(7A):39Se44S.
23. Garcia-Vidal C, Almagro P, Romani V, Rodriguez-Carballeira M,
Cuchi E, et al. Pseudomonas aeruginosa in patients hospitalised
for COPD exacerbation: a prospective study. Eur Respir J 2009;
34(5):1072e8.
24. Murphy TF, Brauer AL, Eschberger K, Lobbins P, Grove L, Cai X,
et al. Pseudomonas aeruginosa in chronic obstructive pulmo-
nary disease. Am J Respir Crit Care Med 2008;177:853e60.
25. Obaji A, Sethi S. Acute exacerbations of chronic bronchitis.
What role for the new fluoroquinolones? Drugs Aging 2001;18:
1e11.
26. Falagas ME, Avgeri SG, Matthaiou DK, Dimopoulos G. Siempos II.
Short- versus long-duration antimicrobial treatment for exac-
erbations of chronic bronchitis: a meta-analysis. J Antimicrob
Chemother 2008;62:442e50.
27. Chodosh S, Deabate CA, Haverstock D, Aneiro L, Church D. Short-
course moxifloxacin therapy for treatment of acute bacterial
exacerbations of chronic bronchitis. Respir Med 2000;94:18e27.
28. Miravitlles M, Anzueto A. Moxifloxacin: a respiratory fluo-
roquinolone. Expert Opin Pharmacother 2008;9:1755e72.
29. Grassi C, Casali L, Curti E, Tellarini M, Lazzaro C, Schito Gon
behalf of the SMART Study Group. Efficacy and safety of short
course (5-day) moxifloxacin vs 7-day ceftriaxone in the treat-
ment of acute exacerbations of chronic bronchitis (AECB).
J Chemother 2002;14:597e608.
30. Grossman RF, Ambrusz ME, Fisher AC, Khashab MM, Kahn JB.
Levofloxacin 750 mg QD for five days versus amox-
icillin/clavulanate 875 mg/125 mg BID for ten days for treat-
ment of acute bacterial exacerbation of chronic bronchitis:
a post hoc analysis of data from severely ill patients. Clin Ther
2006;28:1175e80.
31. Spencer S, Jones PW. Time course of recovery of health status
following an infective exacerbation of chronic bronchitis.
Thorax 2003;58:589e93.
32. Wilson R, Allegra L, Huchon G, Izquierdo J-L, Jones P,
Schaberg T, et al. Short-term and long-term outcomes of mox-
ifloxacin compared to standard antibiotic treatment in acute
exacerbations of chronic bronchitis. Chest 2004;125:953e64.
33. Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D,
et alfor the PneumA Trial Group. Comparison of 8 vs 15 days of
antibiotic therapy for ventilator-associated pneumonia in
adults: a randomized trial. JAMA 2003;290:2588e98.
34. El Moussaoui R, Roede BM, Speelman P, Bresser P, Prins JM,
Bossuyt PMM. Short-course antibiotic treatment in acute
1403
exacerbations of chronic bronchitis and COPD: a meta-analysis
of double-blind studies. Thorax 2008;63:415e22.
35. Sethi S, Breton J, Wynne B. Efficacy and safety of pharmaco-
kinetically enhanced amoxicillineclavulanate at
2000/125 milligrams twice daily for 5 days versus amox-
icillineclavulanate at 875/125 milligrams twice daily for 7 days
in the treatment of acute exacerbations of chronic bronchitis.
Antimicrobial Agents Chemother 2005;49:153e60.
36. Gotfried M, Notario G, Spiller J, Palmer R, Busman T.
Comparative efficacy of once daily, 5-day short-course therapy
with clarithromycin extended-release versus twice daily, 7-day
therapy with clarithromycin immediate-release in acute
bacterial exacerbation of chronic bronchitis. Curr Med Res
Opin 2005;21:245e54.
37. Masterton RG, Burley CJ. Randomized, double-blind study
comparing 5- and 7-day regimens of oral levofloxacin in
patients with acute exacerbation of chronic bronchitis. Int J
Antimicrob Agents 2001;18:503e12.
38. Martinez FJ, Grossman RF, Zadeikis N, Fisher AC, Walker K,
Ambruzs ME, et al. Patient stratification in the management of
acute bacterial exacerbation of chronic bronchitis: the role of
levofloxacin 750 mg. Eur Respir J 2005;25:1001e10.
39. Urueta-Robledo J, Ariza H, Jardim JR, Caballero A, Garcia-
Calderon A, Amabile-Cuevas CF, et althe MOX-CB Study Group.
Moxifloxacin versus levofloxacin against acute exacerbations of
chronic bronchitis: the Latin American Cohort. Respir Med
2006;100:1504e11.
40. Starakis I, Gogos CA, Bassaris H. Five-day moxifloxacin therapy
compared with 7-day co-amoxiclav therapy for the treatment
of acute exacerbation of chronic bronchitis. Int J Antimicrob
Agents 2004;23:129e37.
41. Zervos M, Martinez FJ, Amsden GW, Rothermel CD, Treadway G.
Efficacy and safety of 3-day azithromycin versus 5-day moxi-
floxacin for the treatment of acute bacterial exacerbations of
chronic bronchitis. Int J Antimicrob Agents 2007;29:56e61.
42. Wilson R, Jones P, Schaberg T, Arvis P, Duprat-Lomon I,
Sagnier PPfor the MOSAIC Study Group. Antibiotic treatment
and factors influencing short and long-term outcomes of acute
exacerbations of chronic bronchitis. Thorax 2006;61:337e42.
43. Sethi S, Fogarty C, Fulambarker A. A randomized, double-blind
study comparing 5 days oral gemifloxacin with 7 days oral
levofloxacin in patients with acute exacerbation of chronic
bronchitis. Respir Med 2004;98:697e707.
44. Wilson R, Schentag JJ, Ball P, Mandell Lfor the 068 Study
Group. A comparison of gemifloxacin and clarithromycin in
acute exacerbations of chronic bronchitis and long-term clin-
ical outcomes. Clin Ther 2002;24:639e52.
45. File T, Schlemmer B, Garau J, Lode H, Lynch S, Young Cthe 070
Clinical Study Group. Gemifloxacin versus amox-
icillin/clavulanate in the treatment of acute exacerbations of
chronic bronchitis. J Chemother 2000;12:314e25.
46. Miravitlles M, Zalacain R, Murio C, Ferrer M, Alvarez-Sala JL,
Masa JF, et al. Speed of recovery from acute exacerbations of
chronic obstructive pulmonary disease after treatment with
antimicrobials. Clin Drug Investig 2003;23:439e50.
47. Miravitlles M, Llor C, Naberan K, Cots JM, Molina Jfor the
EFEMAP Study Group. Variables associated with recovery from
acute exacerbations of chronic bronchitis and chronic
obstructive pulmonary disease. Respir Med 2005;99:955e65.
48. Schaberg T, Möller M, File T, Stauch K, Landen H. Real-life
treatment of acute exacerbations of chronic bronchitis with
moxifloxacin or macrolides. Clin Drug Investig 2006;26:
733e44.
49. Marketing authorization application withdrawn for Factive
(gemifloxacin), http://www.nelm.nhs.uk/en/NeLM-Area/
News/2009dJune/24/Marketing-authorisation-application-
withdrawn-for-Factive-gemifloxacin-/. Available at:Accessed
5.02.10.