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Abstract and Introduction
Abstract
Chronic bronchitis (CB) is a critical component of chronic obstructive pulmonary disease (COPD). Emphysema, reversible
airway disease and bronchiectasis also contribute to COPD. Elderly patients are at increased risk for COPD and its
components emphysema, CB and bronchiectasis. In addition, older patients are at increased risk for resistant organisms
during episodes of acute exacerbation of CB (AECB). These organisms include the more common bacteria implicated in
AECB, such as Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae, and less common
nonenteric, Gram-negative organisms such as Pseudomonas aeruginosa. Risk-stratified antibiotic treatment guidelines for
AECB appear to be useful, although they have not been prospectively validated for the general CB population, and
especially not in the elderly CB population. Many of the AECB treatment guidelines that are stratified based on risk factors
have recommended that the oral respiratory fluoroquinolone antibiotics (gemifloxacin, levofloxacin and moxifloxacin) play a
second-line but pivotal role, particularly in patients who have failed initial antibiotic treatment for simple CB or as initial
treatment for complicated CB.
Introduction
The relationship between chronic obstructive pulmonary disease (COPD) and chronic bronchitis (CB) is important, significant
and overlapping in nature. This review will analyze the relationship between these two syndromes and will discuss the
epidemiology, pathophysiology, etiology and clinical features of each, including diagnostic criteria and management of acute
exacerbation of CB (AECB) in the elderly patient.
Figure 1 offers a visual representation of the overlap of the syndromes that are responsible for COPD in the elderly. These
include inflammatory CB, bronchiectasis (as a subset of CB), reversible airway disease (asthma) with small-airway
obstruction and emphysema (i.e., the result of lung tissue destruction and loss of lung recoil).
[1,2]
The figure demonstrates
that individual elderly patients may have unique contributions to their chronic pathological lung state from the various
syndromes that are the foundation of COPD. Exacerbations of COPD are thought to have a bacterial, viral or mixed etiology
in 70% of cases.
[3]
It is also possible that CB can occur without obstructive airway disease, although when it does, coexisting
small-airway obstructive features are present.
[1,2]
Antibiotic Therapy in Elderly Patients with Acute
Exacerbation of Chronic Bronchitis
Timothy E Albertson, Andrew L Chan
Expert Rev Resp Med. 2009;3(5):539-548.
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Figure 1.
The syndromes that compose chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD)
is defined as a chronic syndrome or disease state characterized by airflow obstruction due to chronic bronchitis or
emphysema that may be augmented by partially reversible airway hyper-reactivity and small-airway obstruction.
[1]
This
figure demonstrates that COPD in the elderly is comprised of the syndromes of emphysema, small-airway obstruction or
reversible airways (asthma), chronic bronchitis and, to a lesser extent, bronchiectasis.
[6]
The complex process of aging appears to contribute to the increased risk of respiratory infections in the elderly.
[4]
These
include age-related changes in nutrition, increased risk for aspiration, structural lung processes, decline in innate and
acquired cell- and humoral-mediated immunity, as well as reduced local pulmonary immunity. As a result, respiratory tract
infections are a leading cause of morbidity and mortality in elderly patients.
[2,5]
Defining Respiratory Syndromes
Chronic bronchitis is a progressive disease characterized by the chronic production of mucous. It is defined as the presence
of a chronic cough with sputum production for at least 3 months in each of 2 consecutive years after other causes of cough,
such as TB and lung cancer, have been eliminated.
[6,7]
Acute exacerbations of CB are defined as recurrent attacks of
worsening bronchial inflammation that occur an average of 1.53-times a year, and are superimposed on baseline CB.
[6]
These exacerbations are marked by an increase in the volume of daily sputum produced, a change in color of the
expectorated sputum (i.e., darker, more yellow, more green) and worsening dyspnea. CB is reported in approximately 85%
of patients with COPD.
[7]
In a cohort of 433 COPD subjects (65 11 years), those with chronic cough and sputum production had more frequent
COPD exacerbations that required hospitalization.
[8]
Recent estimates in the USA suggest that 46% of the adult population
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have CB.
[9]
Over 90% of these patients seek healthcare treatment for CB, resulting in an estimated yearly cost of US$1.6
billion.
[10,11]
In Canada, AECB accounts for more than 1.5 million annual physician visits.
[7]
Following AECB, significant
declines are seen in both lung function and quality of life, including patients becoming housebound. Impaired health status
and resultant increased mortality also occur.
[3,5]
The reduction in lung function may be secondary to the strong association
of AECB with COPD exacerbations.
[1,3]
Acute exacerbation of CB is often the prodrome to hospitalization secondary to a COPD exacerbation. COPD is the fourth
leading cause of death in the USA, and was associated with an estimated direct medical cost of US$14.3 billion in
1993.
[12,13]
Increasing age is a prognostic marker for an increase in the frequency of COPD exacerbations and may explain the
worldwide rise in COPD-associated hospitalizations.
[12]
Elderly patients with COPD exacerbations who are admitted to
hospital have a threefold increase in risk of 90-day mortality compared with younger patients.
[13]
In addition, the relative risk
of death during and immediately after an exacerbation is 3.0 for those greater than 80 years of age compared with those
under 65 years of age.
[14]
In the UK, the prevalence of CB increases dramatically with age; increasing from 7.5 out of 10,000
in those between 25 and 44 years of age, to 65 out of 10,000 in those aged 4464 years, and to over 200 out of 10,000 in
people 7584 years of age.
[15]
The risk of an AECB increases markedly in elderly individuals, particularly in patients with
comorbidities, including advanced COPD, malnutrition, cardiac disease, active smoking, other pre-existing lung conditions,
recent viral infections, alcoholism, those with a decline in immune function and those who live in a long-term care facility.
[4,5,16]
Bronchiectasis is defined as the remodeling or distortion of the conducting airways by repeated pulmonary infections or
inflammatory reactions, resulting in dilation and scarring of the bronchi and bronchioles.
[17]
It is often associated with a
chronic productive cough and recurrent or persistent infections. There are several causes of bronchiectasis, including a
postinfectious state, idiopathic genetic disorders (e.g., primary ciliary dysfunction, cystic fibrosis and
1
-antitrypsin
deficiency), recurrent aspiration, immune deficiency, rheumatoid arthritis, ulcerative colitis and allergic bronchopulmonary
aspergillosis. Bronchiectasis has been increasingly associated with COPD. One study reported that 50% of COPD patients
with a mean forced expiratory volume in 1 s (FEV
1
) of 0.96 l demonstrated high-resolution chest computed tomography
evidence of bronchiectasis, and that these patients had more severe COPD exacerbations.
[18]
It is estimated that at least
110,000 individuals have significant noncystic fibrosis bronchiectasis in the USA, with a prevalence of 4.2 out of 100,000
population in the 1834 age group, and 272 out of 100,000 among those greater than 75 years of age.
[17]
Much higher
estimates for the prevalence of bronchiectasis exist outside the USA.
Acute Exacerbation of Chronic Bronchitis
Several potential triggers for AECB have been identified, including bacterial, viral and atypical pathogens, environmental
conditions (e.g., air pollution and tobacco smoke), lack of compliance with COPD therapies, and worsening congestive heat
failure or pulmonary embolism.
[7,18,19]
However, infections are likely to cause more than 80% of AECBs. Respiratory viruses
are associated with 30% of cases, atypical bacterial (mostly Chlamydophila pneumoniae) infections are implicated in less
than 10%, and bacterial pathogens in approximately 4050% of exacerbations.
[20]
Viral pathogens associated with AECB include influenza, parainfluenza, rhinovirus, coronavirus, adenovirus and respiratory
syncytial virus.
[20]
The three major bacterial causes of AECB in mild COPD exacerbations include nontypeable Haemophilus
influenzae, Moraxella catarrhalis and Streptococcus pneumoniae.
[5,18]
In one study, patients undergoing mechanical
ventilation for their AECB/COPD exacerbations were frequently found to have Pseudomonas aeruginosa and
Stenotrophomonas spp.
[5]
Investigators reported that the severity of COPD and baseline airway obstruction predicted the
identity of the bacterial organisms that would be isolated during an exacerbation. Patients who were less severely ill tended
to have S. pneumoniae and other Gram-positive cocci isolated from sputum, while more severe baseline airway obstruction
was associated with H. influenzae and M. catarrhalis. The most severely obstructed AECB/COPD patients tended to have
Pseudomonas and Enterobacterace spp. cultured from sputum.
[5]
Mycoplasma pneumoniae is thought to be a rare cause of
AECB, while C. pneumoniae may be isolated in as many as 510% of cases.
[20]
Bronchiectasis patients also frequently have nonenteric Gram-negative bacteria isolated from sputum during exacerbations.
H. influenzae has been isolated in 3047% of cases, P. aeruginosa (including mucoid species) in 1231%, M. catarrhalis in
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2.420%, S. pneumoniae in 710%, Staphylococcus aureus in 414%, Mycobacterium (primarily Mycobacterium avian
intracellular complex) in 217%, and no organisms in 2123% of sputum cultures obtained during exacerbations.
[17]
Unfortunately, many of the pathogens associated with AECB or exacerbation of bronchiectasis have developed significant
antibiotic resistance patterns to penicillin, -lactams/macrolides and trimethoprim/sulfamethoxazole. When compared with
younger patients, drug-resistant pathogens, such as drug-resistant S. pneumoniae, are more frequently isolated in elderly
patients with CB/COPD exacerbations.
[18]
They are also more likely to have H. influenzae and P. aeruginosa cultured from
their sputum during an exacerbation.
[16]
Diagnostic Criteria & Severity of AECB
The clinical severity of AECB is defined by the cardinal symptoms: increased sputum volume, increased sputum purulence
and worsening dyspnea. Anthonisen et al. provide definitions for severity of AECB.
[21]
The most severe, Type I AECB,
exhibits all three of the cardinal or major symptoms, while Type II AECB only demonstrates two of the major symptoms.
[21]
The least severe, Type III AECB, includes only one major symptom plus at least one of the minor symptoms (upper
respiratory tract infection within 5 days, increased wheezing, cough, fever or a 20% increase in respiratory or heart rate).
[7,21]
The frequency of AECB increases both with age and with the severity of the disease.
[101]
Management of AECB in the Elderly Patient
Hayes and Meyers
[5]
have noted that few studies or guidelines specifically address the treatment of AECB in the elderly.
Many, if not most, of the antibiotic trials include elderly patients, but few have independently reported the trial results as a
function of age. The main treatment goal for an elderly patient with AECB is rapid and complete relief of symptoms, clearing
of the causative pathogens, prevention of further loss of lung function and remodeling, and decreasing future recurrence, as
measured by the interval of time to the next exacerbation. Similar goals exist for the treatment for bronchiectasis and include
reducing the number of exacerbations, improving the quality of life, and identifying and addressing any treatable underlying
cause (e.g., IgG replacement for a deficiency state and steroid therapy for allergic bronchopulmonary aspergillosis).
Concurrent treatment of COPD with bronchodilators and steroids may also be needed in these patients, particularly during
exacerbations. Comorbidities such as congestive heat failure may require specific therapies.
Risk Stratification of Patients with AECB
Although strong evidence exists for the use of antibiotics in Type I and II AECB patients,
[7]
current guidelines for the use of
antibiotics in the treatment of AECB have utilized further risk stratification.
[57]
Guidelines that look primarily at AECB
[7,8,19]
and those that look at AECB in the context of COPD exacerbation
[22]
make antibiotic recommendations based on risk factor
analysis.
One guideline that utilizes risk-stratification systems creates three categories for the assessment and treatment of patients
with AECB.
[5,19,23]
The first category includes CB patients of any age who demonstrate the three cardinal clinical signs of
severity, have fewer than four exacerbations per year, with a FEV
1
of 50% or more of predicted value for the patients age
and height, and who have no history of cardiac disease. These patients are considered Group I, or Simple CB,
[5]
while
Group II, or Complicated CB, patients are those that meet simple CB criteria plus have one or more of the following risk
factors: an FEV
1
of less than 50% of predicted value, more than four exacerbations per year, a history of cardiac disease,
supplemental oxygen use, long-term oral corticosteroid use, or who have been on antibiotics within the last 3 months. The
final category is Group III, or chronic suppurative bronchitis.
[8]
These patients have the symptoms of Group II plus chronic
purulent sputum production, frequent exacerbations (more than four per year), require antibiotic treatment more than four
times a year (often requiring antibiotic use within the last 3 months) and have a baseline FEV
1
of less than 35% of predicted
value. They may have the same multiple risk factors as in Group II.
[8]
Blasi and colleagues have published an excellent review of the various international guidelines for antibacterial treatment of
AECB that are based on risk stratification and concluded that most guidelines are very similar.
[23]
offers a summary of the
Canadian risk-stratification schemes for AECB patients.
[7]
Martinez and colleagues also used patient stratification to define
the treatment of AECB.
[24]
In a prospective study, they demonstrated that patients with complicated CB exacerbations had
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lower clinical and microbiological success rates compared with patients with simple or uncomplicated CB exacerbations.
[24]
Table 1. Canadian Thoracic Society and Canadian Infectious Disease Society Chronic Bronchitis Stratification System.
Category Category definition
Group 0 (acute
tracheobronchitis)
Cough and sputum without previous pulmonary disease (patients do not meet
definition of CB)
Group I (simple CB) < 4 exacerbations/year (meets definition of CB)
FEV
1
> 50% predicted
Group II (complicated CB)
FEV
1
< 50% predicted
FEV
1
between 50 and 65% predicted and significant comorbidity: CHF, CAD and/or >
4 exacerbations/year
Group III (suppurative CB) As in Group II, but with constant purulent sputum
Frequent exacerbation (> 4/year), may have bronchiectasis
FEV
1
< 50% predicted (usually < 35% predicted)
CAD: Coronary artery disease; CB: Chronic bronchitis; CHF: Congestive heart failure; FEV
1
: Forced expiratory volume in 1
s.
Data taken from [7].
Nonantibiotic Therapy for Elderly Patients with AECB
A number of supportive care approaches exist for a patient with an AECB. These include therapies associated with
exacerbations of COPD such as supplemental oxygen, bronchodilators, and the use of topical and systemic
corticosteroids.
[101]
Optimizing nutrition, and ensuring adequate (but not excessive) hydration, rest and appropriate physical
activity are important adjunctive approaches. Maintaining current pneumococcal and influenza vaccinations are key
preventive measures in elderly patients with CB.
[25]
Smoking cessation should be attempted at any age. Pulmonary
rehabilitation programs are generally useful for the elderly CB/COPD patient.
[26]
Antibiotic Treatment in Elderly Patients with AECB
Elderly patients have alterations in pharmacokinetics and pharmacodynamics as a result of drug interactions, and decreases
in renal and metabolic clearances of drugs are seen with many drugs used in CB. Specific attention to potential drugdrug
interactions is required by prescribers to avoid adverse reactions. Owing to the potential complexity in elderly patients, it is
important to carefully evaluate drug selection, monitoring and dosing.
[27]
Empirical antibiotic treatment is almost always
required, as the pathologic organisms are not rapidly and reliably identified in routine clinical practice. When antibiotics are
started before hospitalization, significant decreases in the short-term mortality in the elderly patients with AECB have been
reported.
[28]
Antibiotics appear to be effective in treating AECB in elderly patients when they are selected based on a
risk-stratification approach that involves comorbidity evaluation, including recent exposure to antibiotics.
[5]
The general approach of most risk-stratification-based guidelines for the treatment of AECB is to treat lower-risk patients
with an antibiotic that has a more limited spectrum of antibacterial coverage. Several useful, but not prospectively validated,
guidelines have been published for the treatment of AECB.
[5,7,23]
outlines the risk-stratification system and summarizes the
antibiotic recommendations of the Canadian guidelines for treating AECB.
[7]
A recent meta-analysis of 21 double-blind
randomized, controlled studies demonstrated that antibiotic treatment lasting 5 days or less was as effective as longer
duration therapy in patients with AECB associated with COPD.
[29]
Excellent response rates to even 3-day courses of
azithromycin compared with amoxicillin and amoxicillin/clavulanate in the treatment of AECB have been reported.
[30]
A
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recent meta-analysis of seven, randomized controlled trials meeting strict criteria compared short- (5 days) versus
long-duration (7 or 10 days) antibiotic therapy in AECB. Short-duration antibiotic therapy was as effective and had fewer
adverse events (relative risk: 0.84; 95% CI: 0.720.97).
[31]
Table 1. Canadian Thoracic Society and Canadian Infectious Disease Society Chronic Bronchitis Stratification System.
Category Category definition
Group 0 (acute
tracheobronchitis)
Cough and sputum without previous pulmonary disease (patients do not meet
definition of CB)
Group I (simple CB) < 4 exacerbations/year (meets definition of CB)
FEV
1
> 50% predicted
Group II (complicated CB)
FEV
1
< 50% predicted
FEV
1
between 50 and 65% predicted and significant comorbidity: CHF, CAD and/or >
4 exacerbations/year
Group III (suppurative CB) As in Group II, but with constant purulent sputum
Frequent exacerbation (> 4/year), may have bronchiectasis
FEV
1
< 50% predicted (usually < 35% predicted)
CAD: Coronary artery disease; CB: Chronic bronchitis; CHF: Congestive heart failure; FEV
1
: Forced expiratory volume in 1
s.
Data taken from [7].
Table 2. Antibiotic recommendations for acute exacerbation of chronic bronchitis based on a Canadian Risk Stratification
System.
Category Antibiotic recommendation
Group 0 (acute
tracheobronchitis)
First-line oral antibacterial therapy: none unless symptoms persist for more than 1014
days
Alternative for treatment failure: macrolide or tetracycline
Group I (simple CB)
First-line oral antibacterial therapy: second-generation macrolide, second- or third-
generation cephalosporin, amoxicillin and doxycycline
Alternative for treatment failures: respiratory fluoroquinolone or BLBLi
Group II (complicated
CB)
First-line oral antibiotic therapy: respiratory fluoroquinolone or BLBLi
Alternative for treatment failure: parenteral therapy (home or hospital); sputum
culture-based or adjusted therapy; consider referral to specialist
Group III (suppurative
CB)
First-line oral antibacterial therapy: tailor ambulatory treatment based on sputum cultures,
treat P. aeruginosa oral ciprofloxacin if sensitive; parenteral therapy (hospital or home
based) adjusted by culture results
Respiratory fluoroquinolone: gemifloxacin, levofloxacin, or moxifloxacin.
BLBLi: -lactam/-lactamase inhibitor; CB: Chronic bronchitis.
Data taken from [7].
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Antibiotic treatment for elderly patients with bronchiectasis closely follows the suppurative CB guidelines. The selection of
oral or parental antibiotics is often based on previous or current sputum culture results. Frequent P. aeruginosa infections
can result in the common use of ciprofloxacin (orally or intravenously) together with other anti-pseudomonal agents.
Although not approved by the US FDA, inhaled tobramycin has been used in these patients, with limited proven efficacy.
[22,32]
Non-TB mycobacteria are frequently isolated in these patients and may require treatment by a specialist.
[17]
Macrolide antibiotics have been used in cystic fibrosis for their anti-inflammatory characteristics. A recent randomized,
controlled trial of long-term erythromycin use demonstrated a reduction in frequency and duration of exacerbations of CB
and COPD.
[28]
Despite significant data on treating cystic fibrosis with azithromycin, data on AECB are limited, with one study
showing benefit to using three doses of azithromycin every 3 weeks in COPD patients.
[26,33]
In addition to antimicrobial therapy, anti-inflammatory therapy (inhaled corticosteroids and chronic oral macrolides) should be
considered in patients with bronchiectasis. Replacement therapy (e.g., IgG or
1
-antitrypsin infusion) is used in the
appropriately deficient patients. Mechanical and pharmacologic techniques for the mobilization of secretions are often
important adjunctive treatments in these patients.
[17,33]
Use of Fluoroquinolones in AECB in the Elderly
The fluoroquinolone class of antibiotics plays a pivotal role in the treatment of AECB in all published guidelines. Oral and
parenteral ciprofloxacin is used in the treatment of Gram-negative infections, such as P. aeruginosa. In addition, the
respiratory fluoroquinolones, gemifloxacin, levofloxacin and moxifloxacin, are important second-line treatment alternatives in
AECB patients with simple CB. These agents are also a potential first-line therapy for AECB patients with complicated
CB.
[5,7,8]
summarizes recent trials evaluating fluoroquinolones in AECB.
Table 3. Recent respiratory fluoroquinolone trials in acute exacerbation of chronic bronchitis.
Study
Mean ages
(years)
Fluoroquinolone Comparative agent Outcome Ref.
Petitpretz et
al.
64.3, 64.2
L (500 q.d. 10
d)
Cef (250 b.i.d. 10 d)
CC: 94.6 vs 93.3% (NS)
No difference in RRR
[41]
Amsden et
al.
58.359.0,
59.154.0
L (500 q.d. 7 d)
Az (500 mg q.d. 1 d, 250 q.d.
4 d)
CC: 70.3 vs 67.6% (NS) [55]
Grossman et
al.
58.7 (37% >
65)
L (750 q.d. 5 d) A/C (875/125 b.i.d. 10 d)
Earlier clinical resolution with
L vs A/C
CC: no difference
AE: no difference
[40]
Martinez et
al.
UC: 50.7,
51.0
CB: 59.0,
59.3
UC: L (750 q.d.
3 d)
CB: L (750 q.d.
5 d)
AZ (500 q.d. 1 d, 250 q.d. 4
d)
A/C (875/125 b.i.d. 10 d)
UC: CC 93.0 vs 90.1%
(NS)
CB: CC 79.2 vs 81.7%
(NS)
L superior to Az in
microbiological eradication
[24]
Urueta-
Robledo et
al.
59.0, 61.0 M (400 q.d. 5 d) L (500 q.d. 7 d)
CC: 91.0 vs 94.0% (NS)
Equal microbiological
eradication
[49]
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Starakis et
al.
54.0, 49.0 M (400 q.d. 5 d) A/C (625 t.i.d. 7 d)
CC: 90.0 vs 89.4% (NS)
Equal microbiological
eradication
[47]
Wilson et al. 63.8, 62.6 M (400 q.d. 5 d)
A (500 t.i.d. 7 d) or CL (500
b.i.d. 7 d) or Cef (750 b.i.d.
7 d)
CC: 70.9 vs 62.8% (p < 0.05)
Fewer follow-up antibiotics
required with M
Mean time to next
exacerbation longer with M
(132.8 vs 118.0 d, p = 0.03)
[43]
Zervos et al. 55.5, 56.4 M (400 q.d. 5 d) Az (500 q.d. 3 d)
CC: 82 vs 81% (NS)
Equal microbiological
eradication
[45]
Grassi et al. 69.6, 69.1 M (400 q.d. 5 d) Ceft (1000 q.d. 7 d)
CC: 90.6 vs 89.0% (NS)
Equal microbiological
eradication
Cost savings with M vs Ceft
[46]
Schaberg et
al.
61.3, 59.3 M (400 q.d. 5 d) A/C (625 t.i.d. 7 d)
CC: 96.2 vs 91.6% (NS)
Equal microbiological
eradication
[48]
Wilson et al. 68.1, 67.1 G (320 q.d. 5 d)
Ceft (1000 q.d. 13 d)
followed by Cef (500 b.i.d. 46
d), maximum 7 d total
treatment
CC: 82.6 vs 72.1% (p < 0.05)
G 9 d vs Ceft/Cef 11 d to
hospital discharge (p = 0.04)
Equal microbiological
eradication
[42]
All doses in milligrams.
A: Amoxicillin; A/C: Amoxicillin/clavulanate; AE: Adverse events; Az: Azithromycin; b.i.d.: Twice daily; CB: Complicated
chronic bronchitis; CC: Clinical cure per protocol; Cef: Cefuroxime; Ceft: Ceftriaxone; CL: Clarithromycin; d: Day; G:
Gemifloxacin; L: Levofloxacin; M: Moxifloxacin; NS: Not significant; q.d.: Daily; RRR: Relapse response rate; t.i.d.: Three
times daily; UC: Uncomplicated chronic bronchitis.
Studies that have evaluated the pharmacokinetics of moxifloxacin in the elderly have shown no age- or gender-dependent
differences.
[33,34]
Elderly patients on dialysis or those with significantly reduced creatinine clearance (< 50 ml/h) require
dose reductions of gemifloxacin and levofloxacin, but not moxifloxacin.
[32,33,35]
With appropriate dose reductions for renal
disease, gemifloxacin had a safety profile that was similar in elderly patients and younger patients.
[36]
Studies evaluating the use of fluoroquinolones in the treatment of AECB often include elderly patients, but they are seldom
in the majority. For example, a large study of 2512 patients evaluating gatifloxacin (removed from the US market) in AECB
included 40% of the patients over 65 years of age, with a mean age of 59.1 years (SD 15.9 years). All acute symptoms
improved or returned to baseline level with no new symptoms presenting and no additional antibiotic courses being required
in 91.9% (95% CI: 90.893.0) of the gatifloxacin-treated cases.
[37]
Specific information on the patients older than 65 years of
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age was not reported in this study.
A recent meta-analysis of the treatment of AECB noted that second-line antibiotics (amoxicillin/clavulanic acid, second- or
third-generation cephalosporins, and fluoroquinolones) were more effective and just as safe as first-line antibiotics
(amoxicillin, ampicillin, pivamicillin, trimethoprim/sulfamethoxazole and doxycycline).
[38]
Furthermore, stratified analyses of
the antibiotic effectiveness by risk factors for poor outcomes, such as increased age, could not be performed owing to the
lack of data in the reports. The same investigators also performed a meta-analysis on the effectiveness and safety of
macrolides, fluoroquinolones and amoxicillin/clavulanate for the treatment of AECB.
[39]
They reported that the three
treatments were equivalent in short-term effectiveness. Fluoroquinolone antibiotics were associated with better
microbiological success and fewer recurrences of AECB than macrolides, while the use of amoxicillin/clavulanate was
associated with more adverse effects.
[39]
Again, a lack of data prevented risk stratification of factors for poor outcome, such
as an age of more than 65 years.
Martinez and colleagues randomized uncomplicated CB patients to levofloxacin (750 mg once daily for 3 days) or
azithromycin (500 mg/day for 5 days). This study also randomized complicated CB patients with AECB to levofloxacin (750
mg/day for 5 days) or amoxicillin/clavulanate (875/125 mg twice daily for 10 days).
[24]
The mean age of the uncomplicated
CB patients was 51 years, and the mean age for complicated CB patients was 59 years (p = 0.85).
[24]
In the uncomplicated
patients, levofloxacin was comparable to azithromycin in the treatment of AECB episodes. Similarly, in the complicated CB
patients, the longer exposure to levofloxacin was comparable to amoxicillin/clavulanate in treating patients with episodes of
AECB.
[24]
In a post hoc analysis of the complicated CB patients, the levofloxacin-treated group resolved purulent sputum
production (57.5 vs 35.6%; p 0.006) and cough (60.0 vs 44.0%; p < 0.045) more frequently when compared with the
amoxicillin/clavulanate-treated group at the on-treatment visit.
[40]
A study of 689 subjects with AECB randomly assigned to receive either levofloxacin (500 mg daily) or cefuroxime axetil (250
mg tablet twice daily) for 10 days demonstrated similar efficacy for levofloxacin (94.6%) and cefuroxime (93.8%).
[41]
When
per-protocol patients were evaluated, the time when 25% of the population would relapse with another AECB event was 93
days for levofloxacin-treated patients and 81 days for cefuroxime-treated patients (p = 0.756).
[41]
Subgroup analysis of
clinical cure demonstrated no significant difference in efficacy between levofloxacin or cefuroxime for those older than 65
years of age (93.7 vs 92%, respectively) or for those 65 years of age or less (95.7 vs 92.6%, respectively).
[41]
An open-label, randomized, controlled, multicentered trial compared gemifloxacin (320 mg/day for 5 days) with sequential
therapy of parenteral ceftriaxone (1000 mg intravenously daily for 3 days) followed by oral treatment with cefuroxime (500
mg/day for up to 7 more days) in hospitalized complicated CB patients with exacerbations.
[42]
Although age-specific
subgroup analysis was not provided, patients with complicated CB who required hospitalization tended to be older (68.1
9.8 years for gemifloxacin vs 67.1 10.28 years for ceftriaxone). The overall clinical success rates at follow-up for the intent-
to-treat patients were significantly higher in patients treated with gemifloxacin than those treated with ceftriaxone/cefuroxime
(82.6 vs 72.1%; 95% CI: 0.720.4).
[42]
The MOSAIC trial was a multicenter, multinational, randomized, double-blind study of two parallel treatment arms of patients
(n = 733) with Anthonisen Type I AECB.
[43]
The treatment arms consisted of dosing with moxifloxacin (400 mg/day for 5
days) compared with standard therapy with amoxicillin (500 mg/three times a day), clarithromycin (500 mg/twice a day) or
cefuroxime axetil (250 mg/twice a day for 7 days). The average age for the moxifloxacin-treated group was 63.8 9.7 years
and 62.6 9.9 for the comparator group (p = 0.08).
[43]
When intent-to-treat patients were evaluated, moxifloxacin-treated
patients had significantly lower failure rates (patients who required additional antibiotics) than the comparator group (7.6 vs
14.1%; 95% CI: 2.311.6).
[43]
Furthermore, the mean time to the next AECB was 132.8 67.5 days for moxifloxacin-treated
patients and 118.0 67.9 days for the comparator treatment (p = 0.03).
[43]
When investigators applied a multivariate
analysis to examine a composite end point comprised of treatment failure, a new exacerbation, or the need for further
antibiotic treatment for lower respiratory tract illness, moxifloxacin was shown to be significantly superior to comparator
treatment for up to 5 months.
[44]
Other parameters were also statistically significant predictors of the composite event,
including FEV
1
less than 50% of predicted, four or more AECB events in the last year, and the need for acute bronchodilator
use.
[44]
Comparable clinical and bacteriological efficacy and safety were demonstrated for azithromycin (500 mg/day for 3 days)
compared with moxifloxacin (400 mg/day for 5 days) in patients with AECB and an average age of less than 60 years.
[45]
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Similarly, comparable outcomes were seen when oral moxifloxacin (400 mg/day for 5 days) was compared with
intramuscular ceftriaxone (1000 mg a day for 7 days) in the treatment of AECB.
[46]
The average age in this study was 69.6
8.7 years in the moxifloxacin group and 69.1 8.0 years in the ceftriaxone group. Relapse rates were lower during a
6-month follow-up period in the moxifloxacin-treated group compared with ceftriaxone (23.3 vs 28.3%; p > 0.05), and overall
healthcare costs were also less.
[46]
Two trials have shown a 5-day course of oral moxifloxacin (400 mg/day) to be clinically equal to a 7-day course of oral
amoxicillin/clavulanate (625 mg three times/day) in patients with AECB.
[47,48]
A study that compared moxifloxacin (400
mg/day for 5 days) to levofloxacin (500 mg/day for 7 days) in a cohort from Latin America with AECB reported equivalent
efficacy for both therapies (clinical success 91 vs 94%, respectively).
[49]
In this study, the average age was 59 15 years for
the moxifloxacin group and 61 15 years for the levofloxacin group. Niederman and colleagues evaluated pooled data from
four double-blind, multicenter, randomized trials, and found that bacterial eradication of H. influenzae was significantly higher
after moxifloxacin treatment compared with macrolide treatment in AECB patients (93.0 vs 73.2%, p = 0.001).
[11]
Using an open community-based approach, 5737 patients with AECB and a mean age of 68.7 9.4 years were treated with
moxifloxacin (400 mg/day for 5 days) and were followed over a 45-day period in Spain.
[50]
Using daily diary cards and
physician evaluation, 93.0% of the treated patients were cured by day 7, with two-thirds feeling better by day 3 or 4.
[50]
Expanding on these results, patients aged 40 years or older with AECB were studied in Spain in an observational,
nonrandomized trial of risk factors.
[51]
Factors associated with therapeutic failure included previous hospitalization and two
or more exacerbations in the previous year. The use of moxifloxacin (400 mg/day for 5 days) had a protective effect against
late relapse (> 5 days) when compared with amoxicillin/clavulanate (625 mg/three times a day for 10 days; odds ratio [OR]:
0.34; 95% CI: 0.260.45), and when compared with clarithromycin (500 mg/twice a day for 10 days; OR: 0.41; 95% CI:
0.310.55).
[51]
In a prospective, noninterventional, multicentered study in Germany of patients with AECB whose last exacerbation had
been treated with a macrolide, Schaberg and colleagues
[52]
reported that the mean duration until improvement and clinical
cure was 3.2 1.5 days and 6.2 2.6 days for moxifloxacin-treated patients (average age 57.4 15.3 years) compared with
4.5 1.8 days and 7.5 3.0 days for the macrolide-treated group (average age 56.4 15.6 years). The mean durations until
improvement and clinical cure were both statistically significant (p < 0.0001), in favor of moxifloxacin.
[52]
Several limitations exist in the available trials evaluating the newer antibiotics, such as the respiratory fluoroquinolones,
compared with the older antibiotics. The studies often do not provide detailed information about risk stratification and do not
include a significant number of elderly patients. Most of the trials were equivalence trials, and were not designed to show
superiority of the newer agents compared with older antibiotics. The superiority of fluoroquinolones in the treatment of AECB
has really only been demonstrated in the previously mentioned meta-analysis.
[39]
Widespread use of fluoroquinolones has
resulted in emerging Gram-negative and Gram-positive fluoroquinolone resistance, which must be considered when
contemplating their use in AECB.
[53,54]
Conclusion
Chronic bronchitis is a critical component in the syndrome of COPD. Elderly patients are at increased risk for both
exacerbations of CB and AECB. Viral, bacterial and atypical organisms, along with environmental factors, are implicated as
triggers in AECB and COPD. Furthermore, elderly patients have an increased risk for resistant organisms, including
multidrug-resistant S. pneumoniae and nonenteric Gram-negative organisms such as H. influenzae and P. aeruginosa.
Although not prospectively validated, risk-stratification-based guidelines for the treatment of AECB appear to be helpful. The
fluoroquinolone antibiotics in general and the respiratory fluoroquinolones (gemifloxacin, levofloxacin and moxifloxacin) in
particular are important therapeutic options in the treatment of AECB in the elderly patient. Treatment guidelines suggest
that they should be used for the more complex and complicated CB patients.
Expert Commentary
Elderly patients are at increased risk for CB and COPD. Careful use of antibiotics plays an important role in the treatment of
AECB. The use of stratified antibiotic guidelines appears to be a rational approach. Further outcome studies of elderly
patients with AECB are needed to confirm the utility of current antibiotic guidelines.
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Five-year View
Progressive aging of the worlds population and the persistent emergence of resistant organisms will further challenge the
clinician in the treatment of elderly patients with AECB.
Sidebar
Key Issues
Chronic bronchitis is a common disease in elderly patients.
Acute exacerbation of chronic bronchitis (AECB) is a common feature of chronic obstructive pulmonary disease.
Antibiotic therapy based on risk-stratified guidelines are recommended.
Specific data on the treatment of AECB in the elderly patient is lacking.
Respiratory fluoroquinolone antibiotics play an important role in the current AECB treatment guidelines.
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Financial & competing interests disclosure
The authors accept full responsibility for the contents of this manuscript. Timothy E Albertson is on the Speakers Bureaus for
BI and GSK (COPD), Schering Plough (AECB) and has funded research from Pfizer (hospital pneumonia). Andrew L Chan
is on the Speakers Bureau for the France Foundation (Intermune IPF). The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
The authors would like to acknowledge the editorial assistance of Ching-Ling Chen, PhD, in the preparation of this
manuscript. Support for this assistance was provided by Schering-Plough Corporation.
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Papers of special note have been highlighted as:
of interest
of considerable interest
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No other writing assistance was utilized in the production of this manuscript.
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