REVIEW

Moxifloxacin in the management of exacerbations

of chronic bronchitis and COPD

Marc Miravitlles Abstract: Bacteria are isolated in more than 50% of exacerbations of chronic bronchitis (CB)
Servei de Pneumologia, Institut Clínic and chronic obstructive pulmonary disease (COPD). The most prevalent respiratory pathogens
del Tòrax (IDIBAPS), Hospital Clínic, include Gram-positive (Streptococcus pneumoniae) and Gram-negative (Haemophilus influenzae,
Barcelona, Spain Moraxella catarrhalis) microorganims. Moxifloxacin is a fourth-generation fluoroquinolone
that has been shown to be effective against respiratory pathogens, including atypicals and those
resistant to most common antibiotics. The bioavailability and half-life of moxifloxacin provides
potent bactericidal effects at a dose of 400 mg once daily. Among the fluoroquinolones, the
ratio of the area under the concentration-time curve (AUC) to minimal inhibitory concentration
of moxifloxacin is the highest against S. pneumoniae. Moxifloxacin has demonstrated better
eradication in exacerbations of CB and COPD compared with standard therapy, in particular,
with macrolides. Patients treated with moxifloxacin showed a prolonged time to the next
exacerbation and observational studies suggest that moxifloxacin induces a faster release of
symptoms of exacerbation. Some guidelines recommend the use of moxifloxacin as first-line
therapy in bacterial exacerbations in patients with moderate to severe COPD and in patients with
mild COPD with risk factors. The current article reviews the use of moxifloxacin in bacterial
exacerbations of CB and COPD.
Keywords: moxifloxacin, antibiotics, exacerbations, chronic bronchitis, COPD

Introduction
After cardiovascular disease, respiratory diseases rank second in terms of mortality,
incidence, prevalence, and costs. The European prevalence of chronic obstructive pulmonary
disease (COPD) ranges from ⬍2% in France and the UK, to 9% in Spain (Sobradillo et al
2000), and ⬎10% in Germany and Italy (Loddenkemper 2003). Moreover, a European-
wide increase in the prevalence and mortality of COPD and other smoking-related diseases,
particularly in women, is projected for the coming decades (Peto et al 1992). Chronic
bronchitis (CB), a component of COPD, usually associated with frequent exacerbations,
is even more prevalent; as an example, 4.1% of the French population aged 25+ years
develop this disease (Huchon et al 2002). Nonetheless, the prevalence of CB differs between
countries. In a recent study of young European adults, the prevalence of CB in subjects aged
20–44 years ranged from 0.7% in the UK to 9.7% in Spain (De Marco et al 2004), with the
prevalence being directly associated with smoking prevalence (Cerveri et al 2001).
Due to the high prevalence and chronic course of these conditions, COPD and CB
represent a great burden to society. The mean annual direct medical costs of a COPD
patient are an estimated 1800, with 42% of the costs being due to hospitalisations,
Correspondence: Marc Miravitlles most because of exacerbations (Miravitlles et al 2003a). Each exacerbation treated
Servei de Pneumologia, Institut Clínic
del Tòrax, Hospital Clínic,Villarroel 170, in the community has a mean cost of 175, but costs are higher for complicated
08036, Barcelona, Spain exacerbations requiring hospital admission (Miravitlles et al 2002).
Tel +34 93 227 5549
Fax +34 93 227 5549
In addition, COPD and CB are debilitating conditions affecting fundamental aspects
Email [email protected] of everyday life including normal physical exertion, work, and social and family

International Journal of COPD 2007:2(3) 191–204 191

© 2007 Dove Medical Press Limited. All rights reserved
Miravitlles

activities (Murray and Lopez 1997). Chronic lung disease Topoisomerases are essential enzymes which play a
thus has substantial effects on health-related quality of life crucial part in the replication, transcription, and repair
(HRQoL), with increasing CB severity and factors such as of bacterial DNA. Topoisomerase IV is also known
frequency and nature of exacerbations being associated with to influence bacterial chromosome division. Kinetic
increasing symptoms and deteriorating HRQoL (Seemungal investigations have demonstrated that moxifloxacin
et al 1998; Miravitlles et al 2004a). HRQoL has been found to exhibits a concentration-dependent killing rate; minimum
be significantly adversely affected during exacerbations with bactericidal concentrations (MBC) were found to be within
increased anxiety about breathlessness and the coughing up the range of the minimum inhibitory concentrations (MIC)
of phlegm in public (Nicolson and Anderson 2000). (Stass 1999; Krasemann et al 2001).
Bacterial are isolated in 50%–75% of exacerbations
(Miravitlles 2002a; Papi et al 2006). Because of the difficulties Antimicrobial activity
in establishing a bacteriological diagnosis of respiratory tract Moxifloxacin demonstrates excellent in vitro activity (as
infections (RTIs) in ambulatory clinical practice, it is common assessed by MIC90 concentrations of 0.06 to 0.25 mg/L)
practice to commence antibiotic treatment empirically. In against all the predominant respiratory pathogens including
an analysis of initial antibiotic treatment in Europe for all Gram-positive (Streptococcus pneumoniae), Gram-negative
infections, including RTIs, 85% of these therapies were started (H. influenzae, M. catarrhalis), anaerobic (peptostreptococci
empirically (Halls 1993). In view of the limits of the spectrum or Prevotella spp.), and atypical strains (C. pneumoniae,
of activity of some antibiotics, as well as the increasing M. pneumoniae). Against both beta-lactamase positive
prevalence of bacterial resistance to older generation agents, and negative M. catarrhalis and H. influenzae, MIC90
multiple antibiotics are administered in some cases of RTIs or values to moxifloxacin were <0.06 μg/mL. Similarly,
when resistant or polymicrobial infection is suspected (Smith moxifloxacin MIC90 values ranged from 0.06 to 0.25 μg/mL
et al 1999). There is a continued need to find antibiotics that against clinical isolates of S. pneumoniae regardless of
can be used in empiric treatment regimens so that the patient penicillin susceptibility (Woodcock 1997; Blondeau 1999)
responds rapidly and the risk of development of resistance (Table 1).
is limited.
Moxifloxacin hydrochloride (Avelox ® , Bayer AG) Pharmacokinetics
is a fluoroquinolone that has been shown to be effective Following oral administration moxifloxacin is rapidly
against Moraxella catarrhalis, Haemophilus influenza, and and almost completely absorbed, with an absolute
multi-drug resistant pneumococcal strains (Blondeau 1999; bioavailability of approximately 91% (Stass et al 2001).
Saravolatz et al 2001; Miravitlles 2005). Moxifloxacin Its penetration into pulmonary tissues is excellent
is strongly targeted to alveolar tissue (Soman 1999 et al; and concentrates in alveolar macrophages (Table 2).
Miravitlles 2000), and has shown rapid initial killing and Following a 400 mg oral dose, peak concentrations of
eradication rates for pneumococcal bacteria (Lister and 3.1 mg/L are reached within 0.5–4 hours post admin-
Sanders 2001). istration. Peak and trough plasma concentrations at
This paper will focus on recent advances in the study steady-state (400 mg once daily) are 3.2 and 0.6 mg/L,
of antimicrobial treatment of exacerbations of CB and respectively. Moxifloxacin is rapidly distributed to extra-
COPD with moxifloxacin. In this respect, new trials vascular spaces; and an area under the concentration-time
have documented improved outcomes related to time to curve (AUC) of 35 mg·h L–1 is observed after a dose of
resolution of symptoms and extended time to the next 400 mg. Moxifloxacin is mainly bound to serum albumin.
exacerbation. These new outcomes derive from the better In vitro and ex vivo experiments have shown a protein
understanding of the natural history of CB and COPD binding of approximately 40%–42%, independently of
and their exacerbations. the concentration of the drug (Soman et al 1999; Sullivan
et al 1999).
Pharmacology Moxifloxacin is eliminated from plasma with a mean
Mechanism of action terminal half-life of approximately 12 hours (Stass 1999).
Moxifloxacin is a forth generation fluoroquinolone with After a 400 mg dose, recovery of parent compound and
bactericidal activity as a result of its interference with metabolites of moxifloxacin from urine and feces totals
topoisomerase II (DNA gyrase) and IV (Scheld 2003). approximately 96% (Table 3).

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 Moxifloxacin in exacerbations of COPD

Table 1 Minimum inhibitory concentrations (MIC) of moxifloxacin and other quinolones against common respiratory pathogens
MIC90 (mg/L)
Bacterium Moxifloxacin Ciprofloxacin Levofloxacin Trovafloxacin
S. pneumoniae
penicillin-sensitivea 0.06–0.25 1–2 1–2 0.12–0.25
penicillin-resistantb 0.12–0.25 1–2 1–2 0.12–0.25
S. aureus
methicillin-sensitive 0.12 0.5–1 0.25 0.06
methicillin-resistant 2 32–128 16 2
M. catarrhalis
beta-lactamase positive 0.012–0.06 0.015–0.06 0.06–0.094 0.03
beta lactamase negative 0.012–0.06 0.015–0.06 0.06 0.03
H. influenzae
beta-lactamase positive 0.03–0.06 0.015–0.03 0.03–0.47 0.015
beta lactamase negative 0.03–0.06 0.015–0.03 0.03–0.32 0.015

Adapted from Blondeau (1999).

a
penicillin sensitive indicates a penicillin MIC of <0.06 μg/mL.
b
penicillin resistant or non-susceptible indicates an MIC >0.1 μg/mL.

The pharmacokinetic and pharmacodynamic parameters (192–400 35 mg·h L–1) (Wise 1999) (Table 3). Despite
for antibacterial agents can be integrated into the ratio of the achieving good tissue penetration, levofloxacin is only
AUC to MIC90, or area under the inhibition curve (AUIC), moderately active against S. pneumoniae, whereas
ie, the AUC/MIC normalized for 24 hours (Schentag gatifloxacin is more bactericidal but only achieves modest
et al 1996). tissue levels. Levofloxacin does not have the chemi-
Agents with a low Cmax, short t1/2 and low in vitro activity cal structure of moxifloxacin to fight resistance, eg, a
against a specific pathogen (viz: higher MIC90 values) have a methoxy moiety at position C-8 – a substitution that has
lower AUIC than those with high Cmax, prolonged t1/2 and high been shown to select for mutants much less frequently
in vitro activity. Quinolones with AUIC values above 85–125 than a hydrogen moiety (Wise 1999). In addition, moxi-
and Cmax to MIC ratios of 8–10 have been associated with better floxacin has a 7-azabicyclo side chain that makes it more
clinical and bacteriological cure rates compared with agents difficult to efflux the antibiotic out of the bacterial cell
with lower AUIC values (Forrest et al 1993). High AUIC (Wise 1999).
values indicate rapid eradication of pathogens and a reduced The approved dose and regimen of oral moxifloxacin
likelihood of resistance development, as pathogens are killed for the indication of exacerbations of CB is: 400 mg orally
before they have time to mutate (Schentag et al 1996). once daily for 5–7 days.
Compared with other fluoroquinolones, moxifloxacin
has the highest AUIC ratio against S. pneumoniae
Efficacy of moxifloxacin in
exacerbations of chronic bronchitis
Table 2 Tissue concentrations by site 10 hours after oral ad-
and COPD
ministration of 400 mg of moxifloxacin Registration clinical trials
Site Tissue concentration Plasma ratio The clinical program for moxifloxacin included four studies
Plasma 3.1 mg/L n/a comparing the efficacy and safety of moxifloxacin (400 mg
Saliva 3.6 mg/L 0.75–1.3 once daily, 5 days) with either clarithromycin (500 mg
Blister fluid 1.61 mg/L 1.71 twice daily, 7–10 days) or cefuroxime-axetil (500 mg twice
Bronchial mucosa 5.4 mg/kg 1.7–2.1
Alveolar Macrophages 56.7 mg/kg 18.6–70.0
daily, 10 days) in 2381 patients with exacerbations of CB
Epithelial lining fluid 20.7 mg/L 5–7 (Miravitlles 2005).
Interstitial fluid 1.0a mg/L 0.8–1.4a, b The clinical and bacteriological success rates 7–14 days
Data from Stass (1999); Stass et al (2001); Sullivan et al (1999). post-treatment were comparable between the three treatment
a
unbound concentration.
b
from 3 hours up to 36 hours post dose.
groups. However, there was a trend towards improved
n/a, not applicable. bacteriological success after 5 days of moxifloxacin therapy

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Miravitlles

Table 3 Main pharmacokinetic/pharmacodynamic parameters of and FEV1⬍85% of predicted value. Patients with a severe
moxifloxacin after an oral dose of 400 mg exacerbation of CB within 12 months of enrolment were
Bioavailability 90% randomized to receive either oral moxifloxacin 400 mg
Cmax 3–4 mg/L
Tmax 1–2 h
once daily for 5 days or one of the comparators: amoxicillin
Mean half-life 13 h 500 mg tid for 7 days, clarithromycin 500 mg bid for 7 days
Binding to plasma proteins <40% or cefuroxime-axetil 250 mg bid for 7 days. Patients were
Steady state volume of distribution 2–3 L/kg
assessed at screening, end of treatment and 7–10 days after
Renal clearance 24–53 mL/min
Total body clearance 179–246 mL/min treatment, and were contacted by phone monthly until a new
AUC 35–45 mg.h L–1 exacerbation occurred or up to a maximum of 9 months.
Cmax/MIC90 (pneumococcus) 25–35 Clinical cure was defined as a return to pre-exacerbation
AUC24h/MIC90 or AUIC (pneumococcus) 192–400 mg.h L–1
status, and clinical success as cure and improvement
Data from Stass (1999); Stass et al (2001). combined, overall and by strata of steroid use and prognostic
Abbreviations: Cmax, maximal or peak plasma concentration; Tmax, time to Cmax;
AUC, area under the curve; AUIC, area under the inhibition curve; MIC, minimum factors. Other efficacy measures were needed for further
inhibitory concentration.
antimicrobials, time to next exacerbation, and bacteriological
treatment success. Of 1935 enrolled patients, 733 (37.9%)
had severe (Anthonisen type I) exacerbation within 12
compared with 7–10 days of clarithromycin treatment. The
months of screening and were randomized; 730 receiving
three treatment regimens were also similar with respect
either moxifloxacin (n = 354) or comparator (n = 376).
to eradication of S. pneumoniae and M. catarrhalis. In
Clinical success was seen in 83.0%–87.6% of patients across
contrast, moxifloxacin showed improved eradication rates
treatment arms and populations, with statistical equivalence
against H. influenzae (129/132, 97%) as compared with
in all populations except a significant difference in favor
clarithromycin (62/86, 72%) (Niederman et al 2006). Taken
of moxifloxacin patients not receiving steroids. However,
together, the studies of the clinical program demonstrated that
treatment with moxifloxacin 400 mg once daily for 5 days
achieves a clinical response rate of 89% and a bacteriological Table 4 Risk factors for relapse after ambulatory treatment of
exacerbations of chronic bronchitis and COPD
response rate of 87% (Miravitlles 2005).
1. Risk factors for frequent exacerbations (more than two
Clinical studies of antimicrobials in exacerbations of
per year)
CB such as those performed in the original clinical program
Increasing age
have been limited by factors such as inadequate information
Severity of FEV1 impairment
on patient condition prior to the exacerbation and lack of Chronic bronchial mucus hypersecretion
long-term follow-up, as well as a lack of prospective control Frequent past exacerbations
for steroid use, which can positively affect the outcome of the Daily cough and wheeze
Bronchitic symptoms
episode (Miravitlles and Torres 2004a), and for prognostic
factors that can have a negative impact (Dewan et al 2000; 2. Risk factors for relapse

Miravitlles 2001a) (Table 4). After the registration trials, Coexisting cardiopulmonary disease
new studies have been designed to evaluate the clinical Increasing number of previous visits to the GP for respiratory
problems
efficacy of moxifloxacin in different patient populations
Increasing number of previous exacerbations
with exacerbations of chronic bronchial disease. In parallel, Increasing baseline dyspnoea
new outcomes have been analyzed in this new generation Severity of FEV1 impairment
of clinical trials. Use of home oxygen

3. Risk factors for hospital admission

Clinical efficacy of moxifloxacin: Significant comorbidities

Severity of FEV1 impairment
short-term outcomes High admission rates for previous exacerbations
The MOSAIC study (Wilson et al 2004, 2006) was a Three or more admissions previous year
multicenter, multinational, randomized study of two Underprescription of LTOT
Lack or reduction in physical activity
parallel treatment arms including outpatients aged ⬎45
years with stable CB, history of smoking of ⱖ20 packs/ From Adams et al (2000); Dewan et al (2000); Miravitlles (2000b); Miravitlles et al
(2001a, b); Prescott et al (1995); Seemungal et al (1998).
year, ⱖ2 documented exacerbations in the previous year, Abbreviations: LTOT, long-term oxygen therapy.

194 International Journal of COPD 2007:2(3)

 Moxifloxacin in exacerbations of COPD

clinical cure rates were significantly higher with moxifloxacin with azithromycin (p = 0.019) and 90.1% with moxifloxacin
(70.9%) compared with the comparators (62.8%) (95% vs 64.3% with clarithromycin (p = 0.001) (Niederman et al
confidence interval (CI) of the difference = 0.3%–15.6%); 2006) (Figure 1).
the clinical cure rate was also significantly greater in the The results of the MOSAIC trial also showed that up to
moxifloxacin arm when analyzed by prognostic factors of 14.8% of patients treated with a comparator antibiotic required
age, airway obstruction, number of exacerbations of CB a second prescription of antibiotics to control symptoms of
in the previous year, duration of CB and cardiopulmonary exacerbation, compared with only 8.8% of patients randomized
comorbidity (Wilson et al 2004). to receive moxifloxacin (p = 0.03) (Wilson et al 2004).
Bacterial eradication with moxifloxacin in bacterio- Although initially designed to demonstrate non-inferiority
logically evaluable patients was significantly higher with of moxifloxacin over standard therapy, the MOSAIC study
moxifloxacin compared with the control antibiotics (91.5% was the first clinical trial to demonstrate the superiority of
vs 81%; 95% CI = 0.4%–22%) (Wilson et al 2004). Bacterial an antibitic, moxifloxacin, over the comparators in clinical
eradication with moxifloxacin has been demonstrated to be cure and bacteriological eradication rates.
superior compared with macrolides. In a pooled analysis of A recent publication has provided a systematic analysis and
moxifloxacin phase III trials compared with macrolide agents meta-analysis of published clinical trials with moxifloxacin in the
in eradication of H. influenzae, the results showed superiority treatment of exacerbations of CB up to June 2005 (Miravitlles
of moxifloxacin against both azithromycin and clarithro- et al 2007a) with the objective to determine the superiority of
mycin. Eradication of H. influenzae with moxifloxacin was moxifloxacin over standard therapy in this indication. A total
93% (133/143) compared with 73.2% (109/149) with mac- of 45 studies were identified, but only 9 fulfilled the inclusion
rolides, p = 0.001. Considering both macrolides separately, criteria in the meta-analysis. Of them, 5 were randomized and
eradication rates were 96.8% with moxifloxacin vs 84.6% double-blind and 4 were randomized and open labeled.

Moxifloxacin Azithromycin Clarithromycin

P = 0.019
P = 0.001

(60/62)
(73/81)
96.8 (55/65)
100 90.1
84.6
Bacterial eradication,

(54/84)
% patients (n/N)

80
64.3
60

40

20

0
Bacteriological eradication rate
Figure 1 Eradication rates for H. influenzae in exacerbations of CB treated with moxifloxacin or macrolides. Derived from Niederman et al (2006).

International Journal of COPD 2007:2(3) 195

Miravitlles

All studies concluded that the efficacy of treatment with In a secondary analysis, the authors attempted to identify
moxifloxacin was at least as good as treatment with the com- the variables independently and significantly associated
parator. One of the studies concluded that eradication and with a prolonged time to the next exacerbation. Treatment
cure rates were superior with moxifloxacin versus compara- with moxifloxacin was associated with a prolonged time to
tors, as highlighted above (Wilson et al 2004). recurrence (hazard ratio for recurrence with moxifloxacin
The global analysis included 3905 randomized patients versus comparators 0.82; 95% CI = 0.68–0.98) (Wilson
and showed an aggregated superior clinical success rate of et al 2006).
moxifloxacin of 1.5% (95% CI = –0.4%–3.4%) which did This effect of moxifloxacin on time to relapse has not been
not reach statistical significance, but showed a trend towards observed with other fluoroquinolones. In a recent study, levo-
a better clinical outcome with moxifloxacin (Figure 2). It is floxacin was compared with clarithromycin in a group of 434
of note that these results were obtained from a combined patients with exacerbations of CB. After a 1-year follow-up,
analysis of studies individually designed to show equivalence no differences in time free from exacerbation were observed
between both treatment arms and without enough statistical between patients treated with levofloxacin (mean of 100.5
power to demonstrate superiority. days) or clarithromycin (95 days), p = 0.32 (Lode et al 2004).
These results may be the consequence of a lower antibacterial
Long-term outcomes: prevention activity of levofloxacin compared to moxifloxacin or more
of exacerbations with moxifloxacin likely to the inclusion of a milder patient population in the
The most important unmet need in the treatment of latter study, making clinical differences against macrolides
exacerbations of COPD is the prevention of recurrence less likely (Miravitlles and Torres 2004b).
(Miravitlles et al 2007b). One of the characteristics of the The rationale for the prevention of exacerbations with
MOSAIC trial was the follow-up period of up to 9 months moxifloxacin derives from a combination of at least three
after recovery from the exacerbation. The hypothesis was that different factors: a) an immunomodulatory effect of the drug
a better eradication rate with moxifloxacin would translate (Dalhoff and Shalit 2003); b) the rapid and more complete
into a prolonged time to the next exacerbation. In 405 patients eradication prevents epithelial damage and restores the
with new exacerbations during the follow-up period, the local defence mechanisms of the bronchial mucosa (De
mean time to event was 10 days longer with moxifloxacin Benedetto and Sevieri 2006); c) as a consequence of the better
treatment (127.6 ± 68.1 days) than comparators (116.7 ± 68.8), eradication, fewer viable pathogens remain in the bronchial
with more patients receiving the comparator having new tissue after antimicrobial treatment, requiring longer for
exacerbations within 60 days of treatment (51/208, 24.5%) the bacterial population to increase sufficiently to induce
than moxifloxacin (31/197, 15.7%). The log rank test showed a new exacerbation (Chodosh 2005). This last hypothesis
a significant difference in favor of moxifloxacin for up to 5 is also known as the “fall and rise” hypothesis of bacterial
months of follow-up (p = 0.03) (Wilson et al 2004). exacerbation of CB (Miravitlles 2002b). In clinical trials with

Author Effect Min Max. Cases p −0,25 −0,13 0,00 0,13 0,25
Chodosh 2000 −0,016 −0,070 0,037 272 0,553
Hautamaki 2001 −0,011 −0,056 0,034 461 0,643
Starakis 2004 −0,006 −0,105 0,094 153 0,909
De Abate 2000 −0,003 −0,062 0,057 464 0,926
Wilson 1999 0,008 −0,041 0,056 649 0,762
Grassi 2002 0,016 −0,042 0,073 423 0,595
Kreis 2000 0,043 −0,031 0,116 399 0,257
Schaberg 2001 0,045 0,004 0,087 512 0,031
Wilson 2004 0,076 −0,001 0,154 572 0,055
Combined (Fixed effects) 0,015 −0,004 0,033 3905 0,120
Combined (random effects) 0,015 −0,004 0,034 3905 0,125

Heterogeneity: X2= 8.65 GL=8 p=0.37 Control superior Moxifloxacin superior

Figure 2 Results of the meta-analysis of clinical trials with moxifloxacin in exacerbations of CB and COPD. Data obtained from 9 studies including 3,905 patients. Repro-
duced with permission from Miravitlles M, Molina J, Brosa M. 2007a. Clinical efficacy of moxifloxacin in the treatment of exacerbations of chronic bronchitis: a systematic
review and meta-analysis. Arch Bronconeumol, 43:22–28. Copyright © 2007 Elsevier.

196 International Journal of COPD 2007:2(3)

 Moxifloxacin in exacerbations of COPD

antibiotics, a prolonged time to the next exacerbation has been patients with chronic bronchial colonisation and frequent
observed in patients who eradicate the bronchial pathogen exacerbations. In this group of patients, the change in the
after an exacerbation compared with those who cured the serotype of the colonising bacteria may act as a trigger
exacerbation but without effective eradication (Chodosh et al that initiates profileration of microorganisms in some
1998). According to the “fall and rise” hypothesis, patients cases. The “fall and rise” can also explain relapses when
who effectively eradicate bacteria would need a longer time bacteria have not been eradicated after antibiotic treatment
to achieve the threshold of bacterial counts compared with of the exacerbation. In contrast, the change of serotype of
patients who cured the exacerbation but in whom bacteria infective bacteria may be crucial in patients who do not
still persisted after antibiotic treatment (Miravitlles 2002b). suffer frequent exacerbations, ie, less than two in a year.
This hypothesis would also explain why patients with It is difficult to explain the appearance of an exacerbation
acute exacerbations may be clinically cured even without more than four months after a preceding episode based only
eradication of the bacterial pathogen (Wilson et al 1999). on bacterial growth in the airways without any precipitating
This is not proof that this particular bacterium is not the cause factor, such as change in serotype (Sethi et al 2002). New
of the exacerbation, but does demonstrate that the antibiotic evidence is required on the complex relationship between
only needs to reduce bacterial counts to below the threshold to microorganisms and the host, particularly considering that
eliminate symptoms. Nevertheless, if eradication also occurs, important therapeutic implications may be derived from
the time for a number of bacteria above the threshold to be these findings. In fact, if the new exacerbation is caused by
reached will be longer (Figure 3). the regrowth of the same bacteria that remained unkilled,
The quantitative or “fall and rise” hypothesis may the logical approach to treatment would be to use a different
explain the basic mechanism of bacterial exacerbations in antibiotic and rotation of antibiotics should be recommended

Modifying factors
Clinical
threshold
Bacterial load

AB1
(CFU/mL)

AB2
Time (days)
AE AB Cure Cure Stop AB

Time to relapse
Figure 3 The “fall and rise” hypothesis of bacterial exacerbations of COPD.
Note: Some patients with COPD have bacterial colonization of the lower airways. This colonisation is usually due to potentially pathogenic microorganisms (PPMs) in
low concentrations (low colony forming units [CFU]/mL). Under special circumstances, these PPMs may proliferate and produce increasing inflammatory reaction in the
host. When this proliferation exceeds a threshold, symptoms of acute exacerbation may appear. Under antimicrobial therapy, CFU/mL decrease, and when the threshold is
crossed, clinical symptoms will disappear. When the intensity and speed of bactericidal activity of the antimicrobial increases (AB2), recovery will be more rapid and time
to the next exacerbation will be prolonged. Antimicrobial activity will produce a “fall” in bacterial concentrations, which if not completely eradicated after the pressure of
antimicrobial disappears, will “rise” again. Some modifying factors (risk factors, see Table 4) may change the threshold of clinical symptoms.
Modified from Miravitlles (2002b).

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Miravitlles

to prevent bacteriological failure and the development of slow recovery (more than 5 days) were the use of long-term
resistance. In contrast, if new exacerbations are caused by oxygen therapy (odds ratio (OR) = 1.97; 95% CI = 1.35–2.85);
the acquisition of new strains, the same antibiotic can be used the increased use of rescue medication with short-acting
in repeated exacerbations without concern about increased beta-2 agonists (OR = 1.51; 95% CI = 1.17–1.92); and the
exposure to the same antibiotic. use of amoxicillin/clavulanate or clarithromycin compared
with moxifloxacin (OR = 2.94; 95% CI = 2.22–3.84 and
Speed of recovery after antibiotic OR = 2.43; 95% CI = 1.17–3.22, respectively) (Miravitlles
treatment of an exacerbation et al 2005). Although all studies consistently indicate a faster
Fast recovery of the symptoms of an exacerbation is highly resolution of symptoms of exacerbations with moxifloxacin
demanded by patients (Miravitlles et al 2007b). Antibiotics compared to other frequently used antibiotics, these results
that exhibit faster bacterial killing in vitro should provide must be interpreted with caution because they derive from
faster relief of symptoms in patients with exacerbations of observational studies and, as such, are subjected to possible
CB and COPD. sources of biases.
Observational studies and cross-sectional analyses in A economic analysis derived from the results of the
patients with CB and COPD have suggested that patients EFEMAP study has shown that exacerbations treated
recover from symptoms of exacerbations more rapìdly with with moxifloxacin generated a direct medical cost similar
moxifloxacin than with other commonly used treatments to those treated with amoxicillin/clavulanate ( 111.46;
(Kreis et al 2000; Miravitlles et al 2003b, 2004b). 95% CI = 73.4–149.5 compared with 109.45; 95% CI
One large, multicenter comparative study using a 2-year = 68.2–150.7, respectively); and lower, although not
protocol (IMPAC study) showed a significant reduction significantly, than those treated with clarithromycin (
in the time to recovery from exacerbations of moderate to 138.95; 95% CI = 89.4–188.5). These differences were
severe COPD (Miravitlles et al 2003b). In 441 patients with mainly due to the higher costs associated with relapse in
COPD, all with a FEV1 <50% predicted (mean FEV1 = 36% the group treated with clarithromycin (Llor et al 2004)
predicted), the investigators treated 614 exacerbations with (Figure 4).
moxifloxacin (exacerbations = 111) and 503 with either
amoxicillin/clavulanate, cefuroxime, or clarithromycin. Clinical efficacy of moxifloxacin
Moxifloxacin was available in the second study year only. in patients belonging to risk groups
In year 2, exacerbations treated with moxifloxacin resulted Failure rates after ambulatory treatment derive from
in complete recovery from symptoms in a mean of 4.6 days, clinical trials on antibiotics in CB and range from 7% to
compared with 5.8 days for the other treatments administered 12%. Nevertheless, these results cannot be extrapolated
(p = 0.02). In the longitudinal analysis of 27 patients treated to everyday practice, since patients included in clinical
with moxifloxacin who had received other treatments in trials consist of CB patients and include subjects with
year 1, the mean time to recovery from exacerbations was ages ranging from 18 to 90 years, a significant proportion
significantly reduced from a mean of 6.8–3.7 days (p = 0.02). of never smokers, and individuals without ventilatory
These results were confirmed in another study, the EFEMAP impairment (not COPD) (Miravitlles and Torres 2004b).
study (Estudio FarmacoEconómico de Moxifloxacino en las However, more recently, some studies have addressed
Agudizaciones de la EPOC), with mild to moderate COPD treatment failure in observational “real-life” studies and
patients in primary care centers (Miravitlles et al 2004b). showed a failure rate ranging from 12% to 26% (Dewan
A total of 1456 patients with COPD (mean FEV1 = 52% et al 2000; Adams et al 2000; Miravitlles 2000b; Miravitlles
predicted) received either moxifloxacin (n = 575), amoxicillin/ et al 2001a; Macfarlane et al 2001). Identification of risk
clavulate (n = 460), or clarithromycin (n = 421). Clinical factors for failure may permit the implementation of more
success was observed in 97.2%, 93.1%, and 94.4% of the aggressive broad spectrum treatment and closer follow-
cases, respectively, without significant differences among up. In a further step, risk factors associated with relapse
the groups. However, symptoms of purulence and the volume should be incorporated into management guidelines to
of expectoration resolved a mean of one day earlier with aid in identifying at-risk patients. Among the risk factors,
moxifloxacin compared with the other groups (Miravitlles severity of the underlying pulmonary disease is probably
et al 2004b). In a secondary analysis of the EFEMAP study, the most important. A summary of the main risk factors for
the factors associated significantly and independently with a relapse is presented in Table 4.

198 International Journal of COPD 2007:2(3)

 Moxifloxacin in exacerbations of COPD

54.76 57.82
60
47.01
Costs (Euro)
40

20

0
Moxifloxacin 400mg/day PO for Amoxicillin/clavulanate Clarithromycin 500mg/12h PO
5 days (n = 450) 500mg/8h PO for 7–10 days for 7–10 days (n = 309)
(n = 338)
Figure 4 Mean cost per patient incurred by treatment failures of exacerbations of CB and COPD in each group. Derived from Llor et al (2004).

Some of the studies included in the meta-analysis of mellitus, and there was no evidence of an increased risk
clinical trials evaluated the efficacy of moxifloxacin in of adverse cardiovascular events (Ball 2004).
patients belonging to different risk groups. In a study
comparing moxifloxacin and amoxicillin-clavulanate
Conclusions
(Schaberg et al 2001), individuals older than 60 years
The prevalence of chronic bronchial diseases caused by tobacco
showed a significantly better success rate with moxifloxacin
smoking, namely CB and COPD is great in developed and
(p = 0.048) and a tendency towards a better outcome with
developing countries. Exacerbations constitute the mean cause
moxifloxacin in patients with cardiopulmonary comorbidity
for medical consultation of patients with these diseases and
(p = 0.054). The MOSAIC study has also demonstrated
bacterial infection is involved in more than half of the cases. Most
the superiority of moxifloxacin over the comparators in
of the microorganisms involved in pathogenesis of exacerbations
elderly patients and those with a higher number of previous
of CB and COPD have developed diverse degrees of resistance
exacerbations (Wilson 2006). Table 5 presents the results
to the traditional antibiotics used as first-line treatment.
of moxifloxacin and comparators in patients belonging to
Development of resistance is caused by the increased volume
different risk groups.
of prescription, the inadequate indication of the antibiotic and/or
The main studies of moxifloxacin for the treatment
inadequate administration or treatment compliance by the patient.
of exacerbations of CB and COPD are summarized in
Patients with acute (viral) bronchitis and those with exacerbations
Table 6.
without changes in the volume or characteristics of sputum
should not be treated with antibiotics. When bacterial infection
Safety is suspected, there is a growing tendency to treat exacerbations
Adverse events more aggressively with shorter courses of antimicrobials to help
Moxifloxacin has shown a highly favorable safety and reduce antibiotic resistance (Perez-Gorricho and Ripoll 2003).
tolerability profile in clinical trials as well as in the This is possible with the new generation fluoroquinolones
clinical setting. In a meta-analysis of data from clinical such as moxifloxacin. Moxifloxacin is a fourth generation
trials and post-marketing surveillance comprising over fluoroquinolone that has an excellent in vitro activity against the
25 million patient treatments, the most frequent adverse most common respiratory pathogens and its rapid bactericidal
events reported in clinical trials were nausea (7.1%), action allows short-course 5-day therapy for exacerbations of CB
diarrhea (5.2%), and dizziness (2.6%) following the and COPD. In addition, its long half-life allows administration in
administration of a dosage of 400 mg, once daily (Ball single daily doses. The once-daily, short-course administration
et al 2004). In all cases the frequency of side-effects was guarantees better patient compliance and makes the development
not statistically different to that of the comparators. There of resistance less likely.
was no evidence that moxifloxacin caused disturbances in Moxifloxacin is 4- to 10-fold more active than levofloxacin
glucose metabolism in patients with or without diabetes against S. pneumoniae. A greater intrinsic activity is linked

International Journal of COPD 2007:2(3) 199

Miravitlles

Table 5 Clinical success rates with moxifloxacin and comparators in patients belonging to risk groups in clinical trials of exacerba-
tions of chronic bronchitis and COPD
Risk factor Moxifloxacin Comparator/s p value
Age >60 years 46/51 (90.1%) 47/52 (90.4%) 1.00a
167/184 (90.8%) 161/181 (89.0%) 0.081b
145/152 (95.4%) 122/137 (89.1%) 0.048c

More than 3 exacerbations 36/42 (85.7%) 30/35 (85.7%) 1.00a

previous year 138/160 (86.3%) 136/160 (85.0%) 0.043b
111/118 (84.1%) 103/110 (83.6%) NSc

Cardiopulmonary comorbidity 22/26 (84.6%) 15/19 (78.9%) 0.74a

21/25 (84.0%) 19/28 (67.9%) 0.010b
192/202 (95.0%) 166/185 (89.7%) 0.054c

Concomitant use of oral 33/38 (86.8%) 28/32 (87.5%) 1.00a

corticosteroids 140/160 (87.5%) 105/128 (82%) 0.027b
48/50 (96%) 37/44 (84.1%) NSc

FEV1 (%) < 50% 70/119 (58.0%) 69/130 (53.1%) 0.36d

66/69 (95.6%) 67/69 (97.1%) NSc

Adapted from Miravitlles et al 2007a.

a
Starakis et al (2004); bWilson et al (1999); cSchaberg et al (2001); dWilson et al (2004).
NS = nonsignificant differences; p value not reported in the original publication.

with faster eradication and reduced susceptibility of the devel- MOSAIC trial, patients treated with moxifloxacin showed
opment of resistance. In fact, some reports have described the a significantly better eradication, together with an extended
development of resistance of S. pneumoniae during treatment time to the next exacerbation compared with the standard
with levofloxacin (Davidson et al 2002), but no reports have treatments.
shown the same phenomenon in patients treated with more The results obtained in registration trials of patients with
active fluoroquinolones such as moxifloxacin or gatifloxacin. exacerbations of CB and COPD, together with the new trials
Therefore, these findings support the concept of “use the best performed after launching moxifloxacin have had an impact
first”. The most potent agent of the class should be used as on the development of guidelines of antibacterial treatment of
first line therapy to avoid the development of resistance to exacerbations. The Canadian guidelines indicate fluoroquino-
the entire class of antimicrobials, particularly in moderate lones as the first-line treatment for patients with exacerbated
to severe cases or those with risk factors for relapse or poor CB with risk factors (FEV1 <50% predicted, more than 4
compliance. exacerbations/year, cardiac disease, use of home oxygen,
Moxifloxacin has demonstrated better eradication in chronic steroid use or antibiotic use in the past 3 months) and
exacerbations of CB and COPD compared to standard second-line therapy in uncomplicated CB (Balter et al 2003).
therapy, in particular compared to macrolides. The complete The Latin American guidelines recommend moxifloxacin as
eradication of bacteria present in the airways is important first-line therapy in exacerbated COPD patients with FEV1
for the prevention of resistance development (Stratton 2003) between 35% to 50%, those with an FEV1 <35% without
and for clinical outcome. The persistence of bacteria after risk factors for Pseudomonas infection and those with FEV1
antibiotic treatment of an exacerbation has been associated >50% with risk factors (ALAT Work Group 2004). Recent
with increased inflammation, poorer evolution of the guidelines published in Spain by the Spanish Society of Pneu-
baseline disease and early recurrence of exacerbation. Fast mologists and Thoracic Surgeons and the Spanish Society of
and complete eradication of bacteria may induce a “virtuous Geriatrics recommend moxifloxacin as first-line therapy in
circle” preserving and/or restoring the integrity of the patients with suspected bacterial exacerbation of COPD with
bronchial mucosa and making it more resistant to further an FEV1 <50% predicted and without risk factors for Pseu-
bacterial colonization and the development of exacerbations. domonas infection and in patients with FEV1 >50% with risk
In addition, the reduction in the frequency of exacerbations factors (Miravitlles and Martín Graczyk 2006) (Figure 6).
will contribute to preserve pulmonary function and health The appropriate use of moxifloxacin in patients with
status (De Benedetto and Sevieri 2006) (Figure 5). In the exacerbated chronic bronchial disease and clear criteria of

200 International Journal of COPD 2007:2(3)

 Table 6 A summary of clinical trials with moxifloxacin (400 mg once daily) in E-CB and E-COPD
Outcomes by treatment group
Study Design Patients Test of cure Treatment group Clinical Bacteriological
response rate response rate
Chodosh et al 2000 Randomized, E-CB, N = 926 0–6 days post-treatment 5-day MOX (n = 312) 89% 94%
double-blind 10-day MOX (n = 302) 91% 95%
10-day CLR (n = 312) 91% 91%
Wilson 1999 Randomized, E-CB Type I/II, N = 649 7 days post-treatment 5-day MOX (n = 322) 89% 77%
double-blind 7-day CLR (n = 327) 88% 62%
DeAbate et al 2000 Randomized, E-CB, N = 567 14–21 days post-treatment 5-day MOX (n = 283) 88% 95%
double-blind 5-day AZM (n = 284) 88% 94%

International Journal of COPD 2007:2(3)

Wilson et al 2004 Randomized, E-CB Type I, N = 730 7–10 days post-treatment 5-day MOX (n = 354) 87% 91%
double-blind 7-day comparator
(n = 376)
(AMX, CLR or CFU) 84% 81%
Kreis et al 2000 Randomized, E-CB, N = 124 14–21 days post-treatment 5-day MOX (n = 62) 85% n/a
open-label 5-day AZM (n = 62) 88% n/a
Miravitlles et al 2003 Observational, E-COPD; FEV1 <50% 30 days post-treatment; 5-day MOX (111 AEs) 66% n/a
open-label N = 441 relapse-free period 7-day comparator (503 AEs) 65%
(AMX, CLR or CFU)
Grassi et al 2002 Randomized, E-CB, Types I and II; N = 423 10 days post-treatment 5-day MOX 91% 92%
open-label 7-day CRO 89% 91%
Schaberg et al 2001 Randomized, E-CB, N = 512 14 days post-treatment 5-day MOX 96% 88%
open-label 7-day AMX-CLA 92% 90%
Landen et al 2001 Observational, CA-RTIs 3–10 days post-treatment 5- to 10-day MOX 97% n/a
open-label E-CB; N = 7944
Lorenz et al 2001 Open-label E-CB Type I, N = 328 12 days from treatment onset 5-day MOX 91% n/a
Hautamaki et al 2001 Randomized, E-CB, N = 461 7–21 days post-treatment 5-day MOX 93% 96%
double-blind 7-day LEV 94% 96%
Miravitlles et al 2004b Observational, E-CB types I and II 10 days from treatment onset 5-day MOX 97% n/a
open-label N = 1456 7-day CLR 94%
7-day AMX-CLA 93%
Starakis et al 2004 Randomized, E-CB types I and II 14 days from treatment onset 5-day MOX 88% 91%
open-label N = 153 7-day AMX-CLA 89% 70%
Urueta-Robledo et al 2006 Randomized, E-CB; N = 437 7–14 days post-treatment 5-day MOX 91% 93%
double-blind 7-day LEV 94% 94%
Miravitlles et al 2001b Observational, E-CB, N = 5737 7 days post-treatment 5- to 10-day MOX 93% n/a
open-label

Updated from Miravitlles (2005).

Abbreviations: AMX, amoxicillin; AMX-CLA, amoxicillin-clavulanate; AZM, azithromycin; CA-RTIs, community-acquired respiratory tract infections; CFU, cefuroxime-axetil; E, exacerbation; CLR, clarithromycin; CRO, ceftriaxone; E-CB,
exacerbation of chronic bronchitis; E-COPD, exacerbation of chronic obstructive pulmonary disease; LEV, levofloxacin; MOX, moxifloxacin; n/a, not assessed.

201
Moxifloxacin in exacerbations of COPD
Miravitlles

Fast bacterial killing

MOXIFLOXACIN
Few days with bacteria
COPD

Complete eradication

Immunomodulatory activity Reduce inflammation

•Less frequent exacerbations

•Better preserved pulmonary function
•Improved HRQoL
•Less need for symptomatic treatment Reduce organ damage
•Fewer hospitalizations
•Reduction in healthcare costs
Figure 5 The “virtuous circle” of antibiotic treatment of exacerbations of CB and COPD. Derived from De Benedetto and Sevieri (2006).

Exacerbation
No
Change in sputum color
No bacterial infection
or purulence of sputum
Search for other causes
of exacerbation
Bacterial infection Yes

Specific treatment
Increase bronchodilator
treatment

FEV1 > 50% FEV1 < 50%

Risk factors:
- Cardiac comorbidity
Moxifloxacin/Levofloxacin*
- 3 or more exacerbations/year
-Previous antibiotic treatment
No Yes

Amoxicillin-clavulanate Moxifloxacin/Levofloxacin
or amoxicillin-clavulanate

Figure 6 Algorithm of antibiotic treatment of ambulatory patients with exacerbations of COPD from the Spanish Society of Pneumology and Thoracic Surgery (SEPAR)
and the Spanish Society of Geriatry and Gerontology (SEEG). Derived from Miravitlles and Martín Graczyk (2006).
Note: *Except in patients with risk factors for infection with P. aeruginosa, such as impaired lung function, bronchiectasis, and prior use of antibiotics (Eller et al 1998;
Miravitlles et al 1999; Monsó et al 2003).

202 International Journal of COPD 2007:2(3)

 Moxifloxacin in exacerbations of COPD

bacterial infection may improve the short- and long-term Eller J, Ede A, Schaberg T, et al. 1998. Infective exacerbations of chronic
bronchitis. Relation between bacteriologic etiology and lung function.
clinical outcome. Restriction of the use of fluoroquinolones, Chest, 113:1542–8.
such as moxifloxacin, in patients with acute bronchitis, Forrest A, Nix DE, Ballow CH, et al. 1993. Pharmacodynamics of intravenous
suspected viral infections or benign infections that can ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother,
37:1073–81.
be successfully treated with older antibiotics will help to Grassi C, Casali L, Curti E, et al. 2002. Efficacy and safety of short
preserve the antibacterial activity of the class. The use of course (5-day) moxifloxacin vs 7-day ceftriaxone in the treatment
of acute exacerbations of chronic bronchitis (AECB). J Chemother,
the most active fluoroquinolone first (“use the best first”) 14:597–608.
may also contribute to preserve the antibacterial activity Halls GA. 1993. The management of infections and antibiotic therapy: a
of all quinolones and allow its use in patients who really European survey. J Antimicrob Chemother, 31:985–1000.
Hautamaki D, Bruya T, Kureishi A, et al. 2001. Short-course (5-day)
benefit from the better outcome obtained with moxifloxacin. moxifloxacin versus 7-day levofloxacin therapy for treatment of acute
Physicians need to be familiar with criteria for suspecting exacerbations of chronic bronchitis. Today’s Therapeutic Trends,
19:117–36.
bacterial infection in exacerbated patients and identify risk Huchon GJ, Vergnenègre A, Neukirch F, et al. 2002. Chronic bronchitis
factors for relapse in order to indicate the use of moxifloxacin among French adults: high prevalence and underdiagnosis. Eur Respir
according to local and international guidelines. J, 20:806–12.
Krasemann C, Meyer J, Tillotson G. 2001. Evaluation of the clinical micro-
biology profile of moxifloxacin. Clin Infect Dis, 32(Suppl 1):S51–63.
References Kreis SR, Herrera N, Golzar N, et al. 2000. A comparison of moxifloxacin
Adams SG, Melo J, Luther M, et al. 2000 A. Antibiotics are associated with and azithromycin in the treatment of acute exacerbations of chronic
lower relapse rates in outpatients with acute exacerbations of COPD. bronchitis. J Clin Outcomes Manag, 7:33–7.
Chest, 117:1345–52. Landen H, Möller M, Tillotson GS, et al. 2001. Clinical experience in
ALAT Work Group. 2004. Update to the Latin American Thoracic Society Germany of treating community-acquired respiratory infections with
(ALAT) recommendations on infectious exacerbation of COPD. Arch the new 8-methoxyfluoroquinolone, moxifloxacin. J Int Med Res,
Bronconeumol, 40:315–25. 29:51–60.
Ball P, Stahlmann R, Kubin R, et al. 2004. Safety profile of oral and Lister PD, Sanders CC, 2001. Pharmacodynamics of moxifloxacin,
intravenous Moxifloxacin: Cumulative data from clinical trials and levofloxacin and sparfloxacin against Streptococcus pneumoniae.
postmarketing studies. Clin Ther, 26:940–50. J Antimicrob Chemother, 47:811–18.
Balter MS, La Forge J, Low DE, et al. 2003. Canadian guidelines for the Llor C, Naberan K, Cots JM, et al. 2004. Economic evaluation of the anti-
management of acute exacerbations of chronic bronchitis. Can Respir biotic treatment of exacerbations of chronic bronchitis and COPD in
J, 10 (Suppl B):3B–32B. Primary care centers. Int J Clin Pract, 58:937–44.
Blondeau J, 1999. A review of the comparative in vitro activities of 12 Loddenkemper R (Ed). 2003. The European Lung White Book. European
antimicrobial agents, with a focus on five new respiratory quinolones. Respiratory Society.
J Antimocrob Chemother, 43:1–11. Lode H, Eller J, Linnhoff A, et al. 2004. Levofloxacin versus
Cerveri I, Accordini S, Verlato G, et al. 2001. Variations in the prevalence clarithromycin in COPD exacerbation: focus on infection-free
across countries of chronic bronchitis and smoking habits in young interval. Eur Respir J, 24:947–53.
adults. Eur Respir J, 18:85–92. Lorenz J, Busch W, Thate-Waschke I-M, et al. 2001. Moxifloxacin in acute
Chodosh S, Deabate CA, Haverstock D, et al. 2000. Short-course moxifloxa- exacerbations of chronic bronchitis:clinical evaluation and assessment
cin therapy for treatment of acute bacterial exacerbations of chronic by patients. J Int Med Res, 29:61–73.
bronchitis. The Bronchitis Study Group. Respir Med, 94:18–27. Macfarlane J, Holmes W, Gard P, et al. 2001. Prospective study of the
Chodosh S, Schreurs A, Siami G, et al. 1998. The efficacy of oral ciprofloxa- incidence, aetiology and outcome of adult lower respiratory tract illness
cin vs. clarithromycin for the treatment of acute bacterial exacerbations in the community. Thorax, 56:109–14.
of chronic bronchitis. Clin Infect Dis, 27:730–8. Miravitlles M. 2000. Moxifloxacin: an antibiotic designed for use in the
Chodosh S. 2005. Clinical significance of the infection-free interval in the community. Eur Respir Rev, 10:161–9.
management of acute bacterial exacerbations of chronic bronchitis. Miravitlles M. 2002a. Epidemiology of chronic obstructive pulmonary
Chest, 127:2231–6. disease exacerbations. Clin Pulm Med, 9:191–197.
Davidson R, Cavalcanti R, Brunton Jl, et al. 2002. Resistance to levofloxacin Miravitlles M. 2002b. Exacerbations of chronic obstructive pulmonary disease:
and failure of treatment of pneumococcal penumonia. N Engl J Med, when are bacteria important?. Eur Respir J, 20 (Suppl 36):9s–19s.
346:747–50. Miravitlles M. 2005. Moxifloxacin in respiratory tract infections. Expert
Dalhoff A, Shalit I. 2003. Immunomodulaotry effects of quinolones. Lancet Opin Pharmacother, 6:283–293.
Infect Dis, 3:359–71. Miravitlles M, Anzueto A, Legnani D, et al. 2007b. Patient’s
Deabate CA, Mathew CP, Warner JH, et al. 2000. The safety and efficacy perception of exacerbations of COPD – the PERCEIVE study. Respir
of short course (5-day) moxifloxacin vs. azithromycin in the treatment Med, 101:453–60.
of patients with acute exacerbation of chronic bronchitis. Respir Med, Miravitlles M, Espinosa C, Fernández-Laso E, et al. 1999. Relationship
94:1029–37. between bacterial flora in sputum and functional impairment in patients
De Benedetto F, Sevieri G. 2006. Chronic obstructive pulmonary disease with acute exacerbations of COPD. Chest, 116:40–6.
(COPD) exacerbation and inflammation of the respiratory tract: clini- Miravitlles M, Ferrer M, Pont A, et al. 2004a. for the IMPAC study
cal implication, prognostic consequences, and therapeutic strategies. group:Exacerbations impair quality of life in patients with chronic
Multidisciplinary Respiratory Medicine, 1:36–48. obstructive pulmonary disease. A two-year follow-up study. Thorax,
De Marco R, Accordini S, Cerveri I, et al. 2004. An international survey 59:387–95.
of chronic obstructive pulmonary disease in young adults according to Miravitlles M, Guerrero T, Mayordomo C, et al. 2000. Factors associated
GOLD stages. Thorax, 59:120–5. with increased risk of exacerbation and hospital admission in a cohort
Dewan NA, Rafique S, Kanwar B, et al. 2000. Acute exacerbation of COPD. of ambulatory COPD patients: a multiple logistic regression analysis.
Factors associated with poor outcome. Chest, 117:662–71. Respiration, 67:495–501.

International Journal of COPD 2007:2(3) 203

Miravitlles

Miravitlles M, Llor C, Naberan K, et al. 2004b. The effect of various anti- Schaberg T, Ballin I, Huchon G, et al. 2001. A multinational, multicentre,
microbial regimens on the clinical course of exacerbations of chronic non-blinded, randomized study of moxifloxacin oral tablets compared
bronchitis and chronic obstructive pulmonary disease in Primary Care. with amoxicillin-clavulanate oral tablets in the treatment of acute
Clin Drug Invest, 24:63–72. exacerbation of chronic bronchitis. J Int Med Res, 29:314–28.
Miravitlles M, Llor C, Naberan K, et al. 2005. Variables associated with Scheld WM. 2003. Maintaining fluoroquinolone efficacy:review of
recovery from acute exacerbations of chronic bronchitis and chronic influencing factors. Emerg Infect Dis, 9:1–9.
obstructive pulmonary disease. Respir Med, 99:955–65. Schentag J, Nix DE, Forrest A, et al. 1996. AUIC – the universal parameter
Miravitlles M, Martín Graczyk A. 2006. Tratamiento del paciente con EPOC within the constraint of a reasonable dosing interval. Ann Pharmacother,
agudizada. Guía de buena práctica clínica en Geriatría “Enfermedad 30:1024–8.
Pulmonar Obstructiva Crónica”. Normativa conjunta SEPAR-SEGG Seemungal TA, Donaldson GC, Paul EA, et al. 1998. Effect of exacerba-
(Sociedad Española de Geriatría y Gerontología). Ed Elsevier Farma. tion on quality of life in patients with chronic obstructive pulmonary
75–88. disease. Am J Respir Crit Care Med, 157:1418–22.
Miravitlles M, Molina J, Brosa M. 2007a. Clinical efficacy of moxifloxacin Sethi S, Evans N, Grant BJ, et al. 2002. New strains of bacteria and
in the treatment of exacerbations of chronic bronchitis: a systematic exacerbations of chronic obstructive pulmonary disease. N Engl J
review and meta-analysis. Arch Bronconeumol, 43:16–21. Med, 347:465–71.
Miravitlles M, Murio C, Guerrero T. 2001a. Factors associated with re- Smith JA, Redman P, Woodhead MA. 1999. Antibiotic use in patients
lapse after ambulatory treatment of acute exacerbations of chronic admitted with acute exacerbations of chronic obstructive pulmonary
bronchitis. A prospective multicenter study in the community. Eur disease. Eur Respir J, 13:835–8.
Respir J, 17:928–33. Sobradillo Pena V, Miravitlles M, Gabriel R, et al. 2000. Geographical
Miravitlles M, Murio C, Guerrero T, et al. 2002. Pharmacoeconomic evalu- variations in prevalence and underdiagnosis of COPD. Results of the
ation of acute exacerbations of chronic bronchitis and COPD. Chest, IBERPOC multicentre epidemiological study. Chest, 118:981–9.
121:1449–55. Soman A, Honeybourne D, Andrews J, et al. 1999. Concentrations of
Miravitlles M, Murio C, Guerrero T, et al. 2003a. Costs of chronic bronchitis moxifloxacin in serum and pulmonary compartments following a single
and COPD. A one year follow-up study. Chest, 123:784–91. 400 mg oral dose in patients undergoing fibre-optic bronchoscopy.
Miravitlles M, Ros F, Cobos A, et al. 2001b. The efficacy of moxifloxacin J Antimicrob Chemother, 44:835–8.
in acute exacerbations of chronic bronchitis: a Spanish physician and Starakis I, Gogos CA, Bassaris H. 2004. Five-day moxifloxacin therapy
patient experience. Int J Clin Pract, 55:437–44. compared with 7-day co-amoxiclav therapy for the treatment
Miravitlles M, Torres A. 2004a. No more equivalence trials for antibiotics of acute exacerbation of chronic bronchitis. Int J Antimicrob Agents,
in exacerbations of COPD, please. Chest, 125:811–13. 23:129–37.
Miravitlles M, Torres A. 2004b. Antibiotics in exacerbations of COPD: Stass H, Kubitza D. 1999. Pharmacokinetics and elimination of moxi-
lessons from the past. Eur Respir J, 24:896–7. floxacin after oral and intravenous administration in man. J Antimicrob
Miravitlles M, Zalacain R, Murio C, et al. 2003b. Speed of recovery from Chemother, 43 (Suppl B):83–90.
acute exacerbations of COPD after treatment with antimicrobials: Stass H, Kubitza D, Schühly U. 2001. Pharmacokinetics, safety and
Results of a two-year study. Clin Drug Invest, 23:439–50. tolerability of moxifloxacin, a novel 8-methoxyfluoroquinolone,
Monsó E, García-Aymerich J, Soler N, et al. 2003. Bacterial infection in after repeated oral administration. Clin Pharmacokinet, 40
exacerbated COPD with changes in sputum characteristics. Epidemiol (Suppl 1):1–9.
Infect, 131:799–804. Stratton CW. 2003. Dead bugs don’t mutate: susceptibility issues in the
Murray CJL, Lopez AD. 1997.Alternative projections of mortality and dis- emergence of bacterial resistance. Emerg Infect Dis, 9:10–16.
ability by cause 1990-2020: Global Burden of Disease study. Lancet, Sullivan JT, Woodruff M, Lettieri J, et al. 1999. Pharmacokinetics of a
349:1498–504. once-daily oral dose of moxifloxacin (BAY 12-8039), a new enantio-
Nicolson P, Anderson P. 2000. The patient’s burden: physical and psycho- merically pure 8-methoxyquinolone. Antimicrob Agents Chemother,
logical effects of acute exacerbations of chronic bronchitis. J Antimicrob 43:2793–7.
Chemother, 45:25–32. Urueta-Robledo J, Ariza H, Jardim JR, et al. 2006. Moxifloxacin versus
Niederman MS, Anzueto A, Sethi S, et al. 2006. Eradication of H. influenzae levofloxacin against acute exacerbations of chronic bronchitis: the Latin
in AECB: A pooled analysis of moxifloxacin phase III trials compared American cohort. Respir Med, 100:1504–11.
with macrolide agents. Respir Med, 100:1781–90. Wilson R, Kubin R, Ballin I, et al. 1999. Five day moxifloxacin therapy
Papi A, Bellettato CM, Braccioni F, et al. 2006. Infections and airway inflam- compared with 7 day clarithromycin therapy for the treatment of
mation in chronic obstructive pulmonary disease severe exacerbations. acute exacerbations of chronic bronchitis. J Antimicrob Chemother,
Am J Respir Crit Care Med, 173:1114–21. 44:501–13.
Perez-Gorricho B, Ripoll M. For the PACE Study Group. 2003. Does Wilson R, Allegra L, Huchon G, et al. 2004. Short-term and long-term
short-course antibiotic therapy better meet patient expectations? Int J outcomes of moxifloxacin compared to standard antibiotic treatment
Antimicrob Agents, 21:222–8. in acute exacerbations of chronic bronchitis. Chest, 125:953–64.
Peto R, Lopez AD, Boreham J, et al. 1992. Mortality from tobacco in Wilson R, Jones P, Schaberg T, et al. 2006. Antibiotic treatment and fac-
developed countries: indirect estimation from vital statistics. Lancet, tors influencing short and long term outcomes of acute exacerbations
339:1268–78. of chronic bronchitis. Thorax, 61:337–42.
Prescott E, Lange P, Vestbo J. 1995. Chronic mucus hypersecretion Wise R. 1999. A review of the clinical pharmacology of moxifloxacin, a new
in COPD and death from pulmonary infection. Eur Respir J, 8-methoxyquinolone and its potential relation to therapeutic efficacy.
8:1333–8. Clin Drug Invest, 17:365–87.
Saravolatz L, Manzor O, Check C, et al. 2001. Antimicrobial activity of mox- Woodcock JM, Andrews JM, Boswell FJ, et al. 1997. In vitro activity of
ifloxacin, gatifloxacin and six fluoroquinolones against Streptococcus BAY 12-8039, a new fluoroquinolone. Antimicrob Agents Chemother,
pneumoniae. J Antimicrob Chemother, 47:875–7. 41:101–6.

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