The Role of Prophylactic Antibiotics in COPD

The Role of Prophylactic
Antibiotics in COPD: Does It Have
a PULSE Or Should We TORCH
the Evidence?
Courtney Waye, Pharm.D.
PGY2 Internal Medicine Pharmacy Resident
Department of Pharmacy, South Texas Veterans Health Care System, San Antonio, TX
Division of Pharmacotherapy, the University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center,
University of Texas Health Science Center at San Antonio
September 27, 2013
Learning Objectives 1. Discuss the impact of COPD exacerbation on health status and progression of
the disease
2. Explain the potential role of prophylactic antimicrobials in COPD exacerbation
3. Evaluate the literature concerning the efficacy of long-term antibiotics for the
prevention of COPD exacerbation
4. Recognize the potential long-term and serious adverse side effects of long-term
antimicrobial therapy
Chronic Obstructive Pulmonary Disease (COPD) Background
1. Prevalence1
a. 14.8 million estimated individuals with COPD in 2010 in the United States
b. Undiagnosed in 12 million people
2. Morbidity and Mortality1-2
a. Chronic lower respiratory disease (CLRD) was the third leading cause of
death in 2008 in the United States
i. 135,000 deaths in 2010
ii. Under recorded on death certificates
Death by Major Causes, U.S.,
2010!
Lung- Blood8.9%! 0.4%!
Neonatal
Pulmonary
Disorders1.8%!
Cardio- Deaths from Lung Diseases, U.S., 2008!
pulmonary
Disease- Other-4.3%!
5.3%!
External
Agents-7.3%!
CVD31.9%!
Other58.8%!
Influenza
and
Pneumonia23.2%!
COPD56.7%!
Asthma1.4%!
Figure 1: Death by major cause and Deaths from Lung Diseases (adapted from reference 1)
b. COPD accounts for more than half of all deaths from lung disease
c. Deaths from COPD continue to rise
i. Notably in women and the older population >75 years old
ii. Other leading causes of death stable and/or declining
1
Figure 2: Death rates for medical causes (bottom line indicating COPD)
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1 3. Economic Burden1-2
a. Second most number of days of inpatient hospital care after
cardiovascular disease
Figure 3: Number of Days of Inpatient Hospital Care
1
b. Annual cost of CLRD in the United States estimations
i. Indirect cost: $68 billion
ii. Direct cost: $54 billion
c. Annual cost of COPD estimated at $30 billion in the United States
Pathophysiology of COPD
1. Definition2-3
a. Persistent airflow limitation
b. Progressive, preventable, and treatable, but not reversible
c. Enhanced chronic inflammatory response in lungs and airways
2. Causes2-4
a. Inflammation and narrowing of peripheral airways ⇓ forced expiratory
volume in 1 second (FEV1)
b. Parenchymal destruction due to emphysema and restrictive diseases
c. Peripheral airway obstruction
Peripheral Airway obstruction Air trapping during expiration Hyper-­‐
in;lation Reduced inspiratory capacity Increased dyspnea/ Limitation of exercise capacity d. Gas exchange abnormalities: hypoxemia/hypercapnia
e. Mucous hyper-secretion: results in chronic productive cough
f. Genetic
3. Risk Factors2-4
a. Tobacco smoking
b. Outdoor and indoor air pollution
c. Occupational dusts and chemicals
d. Frequent lower respiratory infections during childhood
e. Age
f. Asthma (not conclusive)
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2 Diagnosis and Staging
2-3
1. Symptoms
a. Dyspnea: heaviness, air hunger, gasping
b. Chronic Cough: productive or unproductive, usually present every day
c. Sputum production: 3 or more months in 2 consecutive years
d. History of exposure to risk factors including family history
2. Assessment (see appendix 1)5-6
a. COPD Assessment Test (CAT)
b. Modified British Medical Research Council Questionnaire (mMRC)
3. Spirometry2
a. Reproducible and objective measurement
b. Measurements: forced vital capacity (FVC) and FEV1
c. Diagnosis when post-bronchodilator FEV1/FVC <0.70
4. Classification: Global Initiative for Chronic Obstructive Lung Disease (GOLD)
Guidelies2
Table 1: Classification of Severity of Airflow Limitation in COPD
(Based on Post-Bronchodilator FEV1)
GOLD 1
Mild
FEV1 > 80% predicted
GOLD 2
Moderate
50% < FEV1 < 80% predicted
GOLD 3
Severe
30% < FEV1 < 50% predicted
GOLD 4
Very Severe
FEV1 < 30% predicted
5. Risk Assessment according to GOLD Guidelines2
2
Figure 4: Risk assessment (see Appendix 1 for symptom assessment scales)
Table 2: Risk assessment categories
Patient
Characteristics
Spirometric
Category
Classification
A
Low Risk, Less
GOLD 1-2
Symptoms
B
Low Risk, More
GOLD 1-2
Symptoms
C
High Risk, Less
GOLD 3-4
Symptoms
D
High Risk, More
GOLD 3-4
Symptoms
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Exacerbations
Per Year
1
mMRC
CAT
0-1
<10
1
2
10
2
0-1
<10
2
2
10
3 Treatment of Stable COPD Disease
2-3
1. Goals of Therapy
a. Reduce symptoms: relieve symptoms, improve exercise tolerance, improve
health status
b. Reduce risk: prevent disease progression, prevent and treat exacerbation,
reduce mortality
2. Non-pharmacologic2-3
a. Smoking cessation
b. Pulmonary rehabilitation: reduce symptoms, improve quality of life, increase
physical and emotional participation
c. Oxygen
3. Pharmacologic2-3 (See Prevention and Appendix 2)
a. Bronchodilators
i. Beta2- agonists
1. Short acting beta2-agonists (SABA)
2. Long acting beta2-agonists (LABA)
ii. Anticholinergics
iii. Methylxanthines
iv. Combination bronchodilator therapy
b. Corticosteroids
i. Inhaled (ICS)
ii. Combination ICS with bronchodilator
iii. Oral
c. Phosphodiesterase-4 (PDE-4) Inhibitors:
i. Roflumilast
d. Other
i. Vaccines: influenza and pneumococcal
ii. Alpha-1 antitrypsin augmentation therapy
iii. Antibiotics
2
Patient Group
Table 3: Initial Pharmacologic Management of COPD
Recommended First Choice
Alternative Choice
A
SAMA prn OR SABA prn
LAMA OR LABA OR
SABA + SAMA
B
LAMA OR LABA
LAMA + LABA
C
ICS + LABA OR LAMA
LAMA + LABA OR LAMA + PDE-4
OR LABA + PDE-4
D
ICS + LABA AND/OR LAMA
ICS + LABA + LAMA OR
ICS + LABA + PDE-4 OR
LABA + LAMA OR
LAMA + PDE-4
SAMA= short acting muscarinic antagonists, SABA = short acting beta2-agonist, LAMA= long acting antimuscarinic
antagonists, LABA= long acting beta2-agonist, ICS= inhaled corticosteroid, PDE-4 = Phosphodiesterase-4 inhibitor
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4 Acute Exacerbation of COPD (AECOPD)
2,7
1. Diagnosis
a. Variable definitions
b. Worsening or new onset of symptoms compared to stable state for at least
24-48 hours
c. Increase in cough, dyspnea, or sputum production/purulence
d. Anthonisen classification
Table 4: Anthonisen classification of COPD exacerbation based on cardinal symptoms
Severity
Characteristics
Severe
3 cardinal symptoms
•
Increased dyspnea
•
Sputum volume
•
Sputum purulence
Moderate
Any 2 of the above 3 cardinal symptoms
Mild
1 or more of the following minor symptoms or signs:
•
Cough
•
Wheezing
•
Fever without obvious source
•
Upper respiratory tract infection
•
Respiratory rate increase >20%
•
Heart rate increase >20%
2. Extent of problem2,8-11
a. Major contributor to morbidity and mortality
i. AECOPD resulting in hospitalization increases 30-day rate of death
from 4-30% from any cause
b. 69% of patients with COPD will have at least one exacerbation per year
i. Average patient with COPD has 1-2 exacerbations per year
ii. 726,000 hospitalizations for COPD in 2000
iii. Mean hospital stay of 9 days
c. ≥3 exacerbations per year requiring hospitalization have significantly reduced
5-year survival
d. Contribute up to ½ of the health economic burden of COPD
e. Negative effect on quality of life
Poor Quality
of life
Higher
mortality
Greater
airway
inflammation
Frequent Exacerbations
Faster decline
in lung
function
Figure 5: Effect of COPD exacerbation (adapted from reference 11)
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5 3. Complications10-12
a. Decline and incomplete recovery of lung function
0.95!
Infrequent exacerbators!
FEV1 (L)!
0.9!
0.85!
Frequent exacerbators!
0.8!
0.75!
0!
1!
2!
3!
4!
Years!
Figure 6: Rate of decline in FEV1 and lung function (adapted from reference 12)
i. Increases rate of FEV1 decline by 2 mL per year per exacerbation
ii. Cough and dyspnea present 30 days after the start of an exacerbation
in 75% of patients
b. Increased risk of cardiovascular events
c. Increased symptoms and longer recovery time over time
Etiology
1. Viral Infection11-12
a. Detected in up to 50% of exacerbations
b. Associated with longer and more severe AECOPD
c. Majority associated with rhinovirus (up to 64%)
d. Increased prevalence in winter: respiratory synctial virus (RSV)
e. Twice the hospitalization rate for AECOPD in influenza season
2. Bacterial Infection11,14
a. Lower airway colonization by bacteria in 25-50% of COPD patients
i. Most common
1. Haemophilus influenzae
2. Streptococcus pneumoniae
3. Moraxella catarrhalis
ii. Others
1. Chlamydia pneumoniae
2. Pseudomonas aeruginosa
3. Gram-negative Enterobacteriacea
4. Staphylococcus aureus
5. Haemophilus parainfluenzae
iii. Complexity increases with prior antibiotic therapy, treatment with oral
corticosteroids, > 4 exacerbations per year and FEV1 <40%13
b. Greater sputum purulence
i. Positive bacterial cultures in 84% of patients with purulent sputum
c. Isolation of a new bacterial strains = significant increase in AECOPD13
3. Environmental Factors11,14
a. 15-20% of exacerbations
b. Air pollution
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6 Management of AECOPD
1. General overview
Increase in Dose/ Frequency of Inhaled Bronchodilators
Systemic Corticosteroids
Oxygen +/Ventilatory
Support
Antibiotics (if change in sputum)
Other interventions
(Theophylline)
Increasing
Severity
AND Management of co-morbidities
THEN Consideration of exacerbation prevention strategies
Figure 7: General management of AECOPD (adapted from reference 11)
2. Management of AECOPD2,11
a. Maximize therapy
b. Short-acting bronchodilators
i. Short-acting inhaled beta2-antagonists with or without short-acting
anticholinergics preferred (limited evidence)
ii. No difference between metered dose inhalers or nebulizers
c. Systemic corticosteroids
i. Shorten recovery time, improve lung function, reduce risk of early
relapse, treatment failure, and length of hospital stay
ii. Dose of 30-40 mg prednisone per day for 7-14 days (limited evidence
on duration)
iii. Tapering not required
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7 d. Antibiotics2,7,14-15
i. Reduce short-term mortality, treatment failure, and sputum purulence
ii. Use in patients with moderate or severe exacerbation using
Anthonisen classification
1. Three cardinal symptoms
2. Two of the cardinal symptoms if increased purulence is one
iii. Use if patient requires mechanical ventilation
iv. Procalcitonin and C-reactive protein may assist in selection
1. Controversial
2. Limited evidence
v. Benefit seen when started earlier in AECOPD
vi. Continue for 5-10 days
vii. Antibiotic selection
1. Local resistance pattern
2. Degree of complication (Age >65, FEV1<50%,
>3 exacerbations per year, cardiac disease present, risk for
pseudomonas, recent antibiotic exposure)
Exacerbation Moderate or Severe Uncomplicated (No risk factors) Complicated (>1 risk factor) Azithromycin Cephalosporin Doxycycline Trim/sulfa Fluoroquinolone OR Amoxicillin/
clavulanate Mild No antibiotics Increase bronchodilators Figure 8: Directed selection of antibiotics in AECOPD (adapted from reference 15)
e. Other pharmacologic
i. Mucolytics: not currently recommended
ii. PDE-4 inhibitors: if unable to use inhaled therapy
iii. Methylxanthines: only if inadequate response to all other therapies
f. Respiratory support
i. Oxygen therapy
ii. Ventilatory support
1. Noninvasive mechanical ventilation (NIV)
2. Invasive ventilation if unable to tolerate NIV
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8 1.
2.
3.
4.
5.
Effectiveness of Therapy in the Prevention of AECOPD16-17
Smoking cessation18-19
a. No studies directly addressing effect on exacerbations
b. Likely correlation between decreased cough, sputum purulence, and
exacerbation
c. Enhances survival: in study of >5000 patients with COPD evaluated over 14.5
years, all-cause mortality significantly lower in group participating in smoking
cessation compared to no intervention (8.83 deaths per 1000 person-years
versus 10.38 deaths per 1000 person-years; p=0.03)
Influenza/pneumococcal vaccinations2,18,20
a. Reduction of COPD exacerbations by 50% over winter months
b. Hospitalizations for pneumonia and influenza twice as high in unvaccinated
elderly patients with COPD as compared to vaccinated patients
c. Associated with lower risk of death (OR 0.3, 95% CI, 0.21-0.43)
d. Associated with fewer outpatient visits for all respiratory conditions
Pulmonary rehabilitation21
a. Reduces number of hospitalizations and days in hospital (10.9 versus 21)
b. Improves survival (lower evidence, 67% versus 56%)
c. Enhances the effect of long-acting bronchodilators
Oxygen22
a. Long-term administration (>15 hours per day) increases survival
(55% vs 33%, p<0.05)
b. Continuous use compared to night time use increased survival (p<0.01, RR of
death 1.94, 95% CI, 1.17-3.24)
c. Indicated in resting PaO2 <55 mmHg or desaturation <88%
Maximized pharmacologic therapy
2
SABA
FEV1
Lung
Function
Symptoms
Quality of
Life/Health
status
Exacerbation
rate
Mortality
+
+
Table 5: Outcomes of selected therapy in COPD
LABA
LAMA
Combined lCS ICS/Bronchodilator
Broncho(compared to
dilators
agents alone)
+
+
+
+
+
+
+
+
+
+
+
+
+
-
+
+
+
+
+
+
+
Theophylline
PDE4
+/-
+
+ (*)
+
+
+ (#)
+/-
SABA = short acting beta2 agonist, LAMA= long acting antimuscarinic antagonists, LABA= long acting beta2 agonist, ICS=
inhaled corticosteroid, PDE-4 = Phosphodiesterase-4 inhibitor, (+)improvement, (*)with corticosteroids in patients with
very severe COPD, (#) added to LABA
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9 6. Comparison of therapies and effect on exacerbations
Trial
Burge et al.
23
ISOLDE 2000
Calverley et al.
24
2003
Calverley et al.
25
TORCH 2007
Kardos et al.
26
2007
Tashkin et al.
27
UPLIFT 2009
Wedzicha et al.
28
2008
Vogelmeier et al.
29
2011
Aaron et al.
30
2007
Zhou et al. 2006
31
Table 6: Effect of treatment on COPD exacerbations
Medication
Outcomes
Outcome Results (treatment vs control)
Fluticasone vs
Frequency of
0.99 vs 1.32 (p=0.026, 25% reduction)
placebo
exac
st
Budesonide vs
Days to 1 exac
178 vs 96 (p=0.51)
placebo
% change FEV1
2% (p=0.15)
Budesonide/formoterol
254 vs 154 (p<0.01)
vs formoterol
5% (p<0.01)
Fluticasone vs
All-cause
16% vs 15.2% (p=0.53)
placebo
mortality
0.93 vs 0.85 (p<0.001)
Fluticasone/salmeterol # exac
12.6% vs 13.5% (p=0.48)
vs placebo
1.13 vs 0.85 (p<0.001, 25% reduction)
(combined agents significantly better
than each agent alone or placebo)
Fluticasone/salmeterol # moderate and
334 vs 464 (p<0.001)
vs salmeterol
severe exac
st
Tiotropium vs placebo Months to 1
16.7 vs 12.5
in addition to freely
exac
prescribed respiratory
medications
Reduction in
14% (p<0.001)
exac
0.73 vs 0.85 (RR 0.86; 95% CI 0.81-0.91)
Exac per pt-year
Fluticasone/salmeterol Exac rate
1.28 vs 1.32 (p=0.66)
vs tiotropium
st
Tiotropium vs
Days to 1 exac
187 vs 145 (HR 0.72; 95% CI 0.61-0.85)
salmeterol
0.64 vs 0.72 (RR 0.89; 95% CI .83-0.96)
Annual # exac
Tiotropium plus
Pts with >1 exac
64.8% vs 62.8% (NS)
salmeterol vs
tiotropium
Mean exac per
1.75 vs 1.61 (NS)
pt-year
Tiotropium vs
60% vs 62.8% (NS)
tiotropium plus
fluticasone/salmeterol
1.37 vs 1.61 (NS)
Theophylline vs
Acute exac
0.79 vs 1.7 (p=0.047)
placebo
(per yr)
Days of exac
4.58 vs 12.47 (p=0.045)
Moderate or
1.14 vs 1.37 (17% reduction, p<0.003)
severe exac per
pt-year
*exac=exacerbation, pt= patient, ARR= absolute risk reduction, HR=hazard ration, RR= relative risk,
NS= not significant
Calverley et al.
32
2009
Roflumilast vs placebo
7. Long term antibiotics
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10 Rationale for long-term antimicrobial use in COPD
1. Bacterial association8,15
a. Increase in bacterial concentration in the airway
b. Acquisition of new bacterial strains
c. Disruption of innate defense mechanisms permitting bacterial pathogens
2. Role of long-term antimicrobials8,15
a. Prevention of new strain establishment in the airway
b. Decrease effect of bacterial colonization driven inflammation
c. Make the airway less hospitable to new bacterial strains
Figure 9: Conceptual benefits of long-term antibiotics in COPD
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8
11 3. Other chronic lung diseases using long-term macrolide therapy
a. Cystic fibrosis33-34
i. Autosomal recessive genetic disorder leading to frequent lung
infections
ii. Lead to improvement in FEV1 (3-11%) and FVC
iii. Comparing macrolide therapy to placebo:
1. Reduction in number of exacerbations (1.6 versus 3.3)
2. Reduction in days IV antibiotic use (7 versus 2)
3. Delayed time to first exacerbation in months (8.7 versus 2.9)
4. Decreased need for additional antibiotic courses
(2.1 courses versus 3.8 courses)
b. Diffuse panbronchiolitis35
i. Severe, progressive inflammatory disorder of airways found in East
Asia (Japan and Korea)
1. Lack of immune system resistance to viruses and bacteria
2. Genetic link
ii. Increased 5 year survival rates from 63% to 92%
iii. Significant symptom reduction and improved pulmonary function
c. Both involve chronic bacterial colonization and airway inflammation
d. Effect of macrolides is thought to be due to anti-inflammatory properties as
compared to antimicrobial activity
Literature Evaluation
1. Early studies (most prior to 1970)8
a. Showed minimal benefit with antibiotic use and reduction in AECOPD
b. Small and poorly defined patient populations
c. Little to no interest for almost 3 decades with a paucity of evidence
d. Use of penicillins, older antibiotics, and tetracyclines limits application today
2. Recent studies for analysis (2004-present)
a. Macrolides
i. Banerjee et al. 2005 (clarithromycin)36
ii. Seemungal et al. 2008 (erythromycin)37
iii. Albert et al. 2011 (azithromycin)38
b. Fluoroquoinolones
i. Sethi et al. 2010 (moxifloxacin)39
c. Meta-analysis
i. Lee et al. 201240
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12 Table 7: The effect of oral clarithromycin on health status and sputum bacteriology in
36
stable COPD
Prospective, double-blind, randomized, placebo-controlled trial
Study Design
One hospital group in the United Kingdom
Setting
To determine whether three months of oral clarithromycin
Objective
• Improves health status
• Diminishes sputum bacterial numbers
• Reduces exacerbation rates as compared to placebo
• Diagnosis of moderate to severe COPD
Inclusion
• Taking inhaled corticosteroids
• Allergy to macrolide antibiotics
Exclusion
• Recent infective exacerbation <6 weeks
• Clinical history of asthma, uncontrolled heart disease, or diabetes mellitus
• Clarithromycin 500 mg daily (n=31) for 3 months
Treatment
• Placebo (n=36) for 3 months
Primary
Outcomes
• Health status utilizing validated questionnaires
o St. George respiratory questionnaire (SGRQ scale of 0-100
with higher scores= more limitations)
o Short-form 36-item (SF-36 scale of 0-100 with
higher scores = less limitations)
Secondary
• Sputum bacterial quantitative load
• Infective exacerbation rate
• Shuttle walk test
• CRP levels
Statistics
Results
Authorsʼ
Conclusion
Comments
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Assessed at day 1 (after 2 week run-in), and at 3 months
Intention to treat
25 patients in each group required to meet power of 0.8 with two-sided
alpha of 0.05 and 95% confidence intervals (CI)
Baseline Characteristics
• More smokers in placebo group (45% vs 64%, NS)
• Worse functional status in treatment group
• Similar in age, BMI, cigarette pack-years, COPD stage and medications
Primary Outcome
No advantageous trends overall in SGRQ or SF-36 scores
Secondary Outcomes
No significant differences
Three months of oral clarithromycin in patients with moderate to severe COPD
did not significantly change health status, sputum bacteriology or exacerbation
rate
Side Effects
• One patient in clarithromycin group had GI upset and withdrew
Strengths
• Measured qualitative and quantitative data
• Varied patient population typically seen in COPD patients
Weaknesses
• Relied on patient reporting (subjective primary endpoint)
• Differences in baseline characteristics (worse baseline health status in
clarithromycin group)
• Relatively short duration (leads to low overall rate of exacerbations)
•
•
•
13 Table 8: Long-term Erythromycin Therapy is Associated with Decreased Chronic
37
Obstructive Pulmonary Disease Exacerbations
Study Design
Randomized, double-blind, placebo-controlled trial
Setting
Single Center in the United Kingdom
Objective
Test the hypothesis that regular therapy with macrolides reduces exacerbation
frequency
Inclusion
• Moderate to severe COPD
• Past or present cigarette smokers
• No acute exacerbation in month prior to study start
Exclusion
• History of asthma or other significant respiratory disease
• Unstable cardiac status (prolonged QTc, arrhythmia, cardiac failure)
• History of macrolide allergy or concomitant drugs with interactions
• History of hepatic impairment (abnormal LFTs)
Treatment
• Erythromycin 250 mg twice daily (n=53)
• Placebo (n=56)
• 1 month run-in period with 1 year treatment period, and 3 month follow-up
Outcomes
Primary
• Exacerbation frequency
Secondary
• Exacerbation duration
• Stable spirometry and inflammatory markers over 1 year
• Bacteriology
Statistics
• Intention-to-treat analysis
• 58 patients per group needed to detect decrease in 1.5 exacerbations per
year with 90% power and two-sided alpha of 0.05
Results
Baseline Characteristics
• More patients taking acting anticholinergic or theophylline in placebo group
Primary Outcome
• Median exacerbation frequency of 2 per patient in placebo group and 1 per
patient in macrolide group (p=0.0006)
• Exacerbation frequency significantly reduced in the macrolide arm (rate
ratio of 0.648 compared with placebo, p=0.003)
Secondary Outcomes
• Median duration 13 days in placebo arms compared to 9 days in placebo
group (p=0.036)
• No significant changes in spirometry or inflammatory markers
• No difference in detection rate for any organism between the two arms
Authorsʼ
• Macrolide therapy at 250 mg twice daily is associated with a significant
Conclusion
reduction in moderate to severe exacerbations and exacerbation duration
in patients with moderate to severe COPD
• No corresponding effect on FEV1 or on airway or systemic inflammatory
markers
Comments
Side Effects
• No significant difference between patients
Strengths
• Length of study
• Study design
• Assessed patient adherence
Weaknesses
• Limited analysis of effect of resistance and outcomes
• Quality of life not assessed
• Small study population
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14 Table 9: Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive
39
pulmonary disease: a randomized controlled trial (PULSE)
Study Design
Randomized, double-blind, placebo-controlled, parallel group trial
Setting
76 centers in 15 countries
Objective
To determine whether intermittent pulsed therapy with the respiratory
fluoroquinolone, moxifloxacin, is more efficacious than placebo in the reduction
of exacerbations of COPD
Inclusion
• 45 years of age
• 20 pack-year smoking history
• Diagnosis of COPD and chronic bronchitis
• >2 exacerbations requiring treatment with antibiotics and/or oral steroids in
the 12 months prior to enrollment
Exclusion
• Colonization of moxifloxacin-resistant P. aeruginosa
• Hypersensitivity to moxifloxacin
Treatment
• 400 mg moxifloxacin once daily for 5 days (n=569 ITT, 351 PP)
• Placebo once daily for 5 days (n=580 ITT, 387 PP)
• Treatment repeated every 8 weeks for a total of 6 courses and end of
treatment (EOT) at 48 weeks
Outcomes
Primary
• Frequency of exacerbation during 48 week treatment period
Secondary
• Hospitalization and mortality
• Changes in SGRQ
• Changes in lung function measured by FEV1
Statistics
• Intention to treat (ITT) and per-protocol (PP) populations
• Significance set at alpha of 0.05
Results
Baseline Characteristics
No significant differences
Primary Outcome*
Study
Treatment
Mean
OR (CI)
NNT
Population
exacerbation
PP
Moxifloxacin
0.75
0.75 (95%;
19
0.57-0.99)
Placebo
0.88
ITT
Moxifloxacin
0.88
0.81 (95%;
28
0.65-1.01)
Placebo
0.94
*Results of first definition of exacerbation: included unconfirmed pneumonia
and lower respiratory tract infections. With secondary definition (excluded
factors listed above) significant difference in ITT group with NNT of 21
Post-hoc analysis showed significantly less exacerbations in patients with
mucopurulent sputum treated with moxifloxacin in the PP population only:
(OR 0.55; 95% CI 0.36-0.84, p=0.006)
Secondary Outcomes
• Similar rates of hospitalization (14-23%) and mortality (low overall)
• No significant difference
o Total SGRQ score improvement
 Significant difference favoring moxifloxacin in symptom
portion of questionnaire
o Lung function (declined slightly in both groups)
• Trend towards reduction in total number of patients with pathogens
o One S. pneumoniae isolate resistant to moxifloxacin
o Transient increase in MIC in three isolates of S. aureus
•
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15 Authorsʼ
Conclusion
Comments
Treatment with intermittent, pulsed moxifloxacin should be considered in
patients with baseline purulent/mucopurulent sputum who have an
unacceptable frequency of exacerbations despite maximal therapy with inhaled
agents for COPD
Side Effects
• Higher in moxifloxacin group compared to placebo: nausea, vomiting,
diarrhea, dyspnea, urticaria, and hypersensitivity (14 versus 1)
Strengths
• Study design
• Evaluated resistance rates
• Primary endpoint looked at exacerbation
Weaknesses
• Low rate of exacerbation
• No standardization of COPD treatments (although no difference in
exacerbation seen in subgroup analysis)
• Funding by manufacturer of moxifloxacin
• Patient reported symptoms/exacerbations
38
Table 10: Azithromycin for Prevention of Exacerbations of COPD
Study Design
Prospective, parallel-group, placebo-controlled design
Setting
Academic health centers in the United States
Objective
To test the hypothesis that azithromycin decreases the frequency of acute
exacerbations of COPD when added to usual care
Inclusion
• > 40 years old
• 10 pack-year history
• Were either:
o Using continuous supplemental oxygen
• Or had
o Received systemic glucocorticoids within the previous year
o Gone to the ED or been hospitalized for an acute exacerbation of
COPD within previous year (but not in last 4 weeks)
Exclusion
• Asthma
• Resting heart rate >100 beats per minute
• Prolonged QTc >450 msec
• Use of medications that prolong the QTc or are associated with torsades
de pointes (with exception of amiodarone)
• Hearing impairment
Treatment
• Azithromycin 250 mg orally once daily (n=558)
• Placebo once daily (n=559)
• Treated for one year with three month follow-up
Outcomes
Primary
• Time to the first acute exacerbation of COPD
Secondary
• Quality of life by SGRQ and SF-36
• Nasopharyngeal colonization with S. aureus, S. pneumo, haemophilus spp,
and moraxella spp.)
• Adherence to medication
Statistics
• Intention-to-treat analysis
• 1130 subjects needed for 90% power to show a significant difference in
primary endpoint with two-sided alpha of 0.05
Waye
16 Results
Baseline Characteristics
• No significant differences in age, sex, lung function, smoking history, or
COPD medications used
Results (cont.)
Primary Outcome
st
Time to 1
exacerbation
Azithromycin
Placebo
226 days*
174 days
*HR
0.73
p<0.001
Exacerbations
per patientyear
1.48
1.83
#
#
NNT
P<0.001
2.86
Secondary Outcomes
• Significant improvement in SGRQ score (p<0.006) although less than
expected improvement of at least 4 points
• No significant difference in SF-36 score
• No significant difference in adherence (67.3% in azithromycin group and
66.9% in the placebo group)
Colonization and Resistance
Colonization
Colonization
at time of
at end of
enrollment
study
Azithromycin
14%
12%*
Placebo
15%
31%
*p<0.001 as compared to rates at enrollment
Macrolide
Resistance
(enrollment)
52%
57%
Macrolide
Resistance
(study end)
81%*
41%
No difference seen between nasopharyngeal colonization at any time and
rate of COPD exacerbation
• Azithromycin at 250 mg daily for 1 year decreased the frequency of
exacerbations in patients at increased risk for AECOPD with no hearing
impairment, resting tachycardia, or risk of QTc prolongation
• More patients receiving azithromycin met criteria for development of
hearing decrement
• Patients receiving azithromycin were less likely to become colonized with
respiratory pathogens but more likely to become colonized with macrolideresistant organisms; no evidence suggested this led to an increased risk of
AECOPD
Side Effects
• Hearing decrement in 25% of azithromycin patients compared to 20% of
placebo group (p<0.04)
o Hearing improved in 25-38% of patients upon repeat testing
Strengths
• Selection of patients at increased risk for COPD exacerbation
• Length of follow-up
• Large enough number of exacerbations to be measured
• Population size
• High number of patients taking glucocorticoids or maximized therapy
Weaknesses
• Clinical consequence of resistant colonization unable to be assessed
• Picked daily dose for adherence purposes only
• Self-reporting of exacerbations by patients
•
Authorsʼ
Conclusion
Comments
Waye
17 Table 11: Systematic review and meta-analysis of prophylactic antibiotics in COPD and/or
40
chronic bronchitis
Objective
Meta-analysis to assess whether prophylactic antibiotic treatment reduces the
frequency of exacerbations in patients with COPD and/or chronic bronchitis
Studies
• Banerjee et al. 2005 (clarithromycin, n=67)
Included for
• Seemungul et al. 2008 (erythromycin, n=109)
COPD
• He et al. 2010 (erythromycin, 36)
• Albert et al. 2011 (azithromycin, n=1142)
• Sethi et al. 2010 (moxifloxacin, n=1157)
• Inclusion Criteria:
o Prospective, randomized, placebo-controlled, parallel group designs
o Compared prophylactic antibiotics to placebo for at least 3 months
Outcomes
Co-primary
• Frequency of COPD exacerbations
o # exacerbations per patient per study
o # exacerbations per patient per year
• Adverse events of treatment
o # patients with adverse events per study
Statistics
Analyzed the five trials with COPD and 14 trials with chronic bronchitis separately
for frequency of exacerbation
Results
Heterogeneity
2
• Not statistically significant (I =26%, P=0.25)
COPD exacerbation
• Significantly reduced by prophylactic antibiotics (RR 0.73, 95% CI 0.66-0.82)
• No difference in rate of severe exacerbation requiring hospitalization (RR 0.89,
95% CI 0.76-1.04)
• Macrolides significantly reduced exacerbations (RR 0.71, 95% CI 0.62-0.81)
• Quinolones did not significantly reduce exacerbations (RR 0.81, 95% CI 0.651.02)
Adverse Effects
• No significant adverse events between antibiotics and placebo (RR 0.99, 95%
CI 0.9-1.08)
• 1-year macrolide treatment resulted in more significant hearing decrements
than placebo (25% versus 20%, p=0.04)
• Emergence of antibiotic-resistant bacteria significantly increased (RR 1.54,
95% CI 1.23-1.94)
Authorsʼ
• Prophylactic antibiotic treatment reduced the rate of exacerbations by 27%
Conclusion
• Macrolides had the most pronounced effect in reducing exacerbations in COPD
patients (29%)
• Prophylactic antibiotics treatment should be considered with caution for
patients with COPD who have experienced frequent exacerbation despite
optimal treatment
• Selected antibiotic dose, regimen, schedule, patient subgroups, and clinical
relevance of antibiotic resistance needs to be answered before routine use
Comments
Strengths
• Similar patient populations (non-significant heterogeneity)
• Separated COPD and bronchitis studies for analysis of COPD exacerbations
• Included relatively recent studies for evaluation of antibiotics in COPD
Weaknesses
• Subgroups comparing antibiotic groups uneven (4 studies with macrolides, 1
study with flouroquinolones)
• Adverse effects included 14 bronchitis studies (older, unreliable reporting)
Waye
18 Comparison of Antibiotic Classes for Prophylaxis
41
1. Macrolides
a. Immunomodulatory effects
i. Affects host-pathogen interactions
ii. Inhibition of proinflammatory cytokines in bronchial epithelium
iii. Down-regulation of innate immunity
iv. Direct modulation of adaptive immunity
b. Post-antibiotic effect
c. Anti-viral activity (erythromycin and rhinovirus)39
2. Respiratory fluoroquinolones36
a. In-vitro antimicrobial activity against major pathogens in COPD
b. Penetration into respiratory tissues
c. High oral bioavailability
d. Efficacy in the acute treatment of exacerbations
Long-term antimicrobial safety
1. Azithromycin
a. Cardiovascular Risk42
i. Patients taking 5 days of azithromycin as compared to no antibiotics
had increased risk of cardiovascular death
ii. As compared to 5 days of amoxicillin, 5 days of azithromycin resulted
in significant increases in the risk of cardiovascular death
Figure 10: Number of cardiovascular deaths per 1 million prescriptions
42
iii. Azithromycin had significantly greater risk of cardiovascular death as
compared with ciprofloxacin
iv. No significant difference in death rates seen between 5-day courses
of azithromycin versus levofloxacin
b. Ototoxicity
i. Higher rate (5%) of hearing decrements in study by Albert et al.38
Waye
19 2. Erythromycin43
a. Patients receiving erythromycin shown to be twice as likely to experience
sudden death due to cardiac causes than patients not taking either
erythromycin or amoxicillin
b. Concurrent erythromycin and CYP3A4 inhibitors has resulted in a 5-fold
greater risk of sudden cardiac death than patients not on any CYP3A4
inhibitor or other antibiotics
3. Clarithromycin44
a. Case reports of torsades de pointe with concurrent administration of
clarithromycin and strong CYP3A4 inhibitors
4. Fluoroquinolones44-45
a. Associated with QTc prolongation and increased risk of sudden cardiac death
b. Peripheral neuropathy: may occur at any time medication is taken and may
persist for unknown time
Recommendations
1. Overview:
a. Long-term antibiotics for the prevention of COPD exacerbation is associated
with up to a 27% reduction in occurrence of exacerbation
i. Evidence to show delayed rate of exacerbations
ii. No significant difference in rate of hospitalizations or mortality
b. Known reduction in exacerbation (25-40%) with available combination
pharmacologic therapy when maximized and used correctly
c. Known risks of long-term antibiotics include ototoxicity, torsades de pointe,
and sudden cardiac death
2. Consideration for selecting patients
a. Must first be on maximized therapy with a long-acting anticholinergic, LABA,
plus an inhaled corticosteroid
b. Must have received vaccinations
c. Should be on oxygen therapy for mortality benefit
d. Ensure the following
i. History of moderate to severe COPD with >4 exacerbations per year
combined or >2 AECOPD resulting in hospitalization
ii. QTc <450 msec
iii. Low baseline risk of cardiovascular disease
iv. Known compliance
3. Consideration of antibiotic selection and dosing
a. Would choose a macrolide as initial therapy
i. Importance of fluoroquinolones in other infectious disease states
ii. More evidence for macrolide therapy vs fluoroquinolones
4. Close follow-up especially after 1 year due to minimal data
5. Risk/benefit should be discussed with patient
6. Not currently recommended in the GOLD guidelines due to “unfavorable balance
between benefits and side effects”2
Waye
20 References
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Siddiqi A, Sethi S. Optimizing antibiotic selection in treating COPD exacerbations. International Journal of COPD
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Calverley P, Boonsawat W, Cseke Z, Zhong N, et al. Maintenance therapy with budesonide and formoterol in chronic
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Kardos P, Wencker M, Glaab T, et al. Impact of salmeterol/fluticasone propionate versus salmeterol on
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Waye
21 31. Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group,
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diseases. Am J Med 2004;117(Suppl 9):125-195.
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stable COPD. Respiratory Medicine 2005;99:208-215.
37. Seemungal TAR, Wilkinson TMA, Hurst JR, et al. Long-term Erythromycin Therapy Is Associated with Decreased
Chronic Obstructive Pulmonary Disease Exacerbations. Am J Respir Crit Care 2008;178:1139-1147.
38. Sethi S, Jones PW, Theron MS, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive
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40. Lee JS, Park DA, Hong Y, et al. Systematic review and meta-analysis of prophylactic antibiotics in COPD and/or
chronic bronchitis. Int J Tuberc Lung Dis 2012;17(2):153-162.
41. Altenburg J, de Graaff CS, van der Werf TS, et al. Immunomodulatory Effects of Macrolide Antibiotics- Part 1:
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Waye
22 Appendix 1: Assessment tools for symptoms (CAT and mMRC)
Image accessed from: http://www.catestonline.org/images/pdfs/CATest.pdf
Image accessed from Bestall JC, Paul EA, Garrod R, et al. Thorax 1999;54 (7):581-586.
Waye
23 Appendix 2: Formulations/ Doses/Adverse effects of COPD medications
Drug
Therapeutic Options in COPD
Formulations
Duration
(hours)
Beta2-agonists
Short-acting
Levalbuterol
MDI, nebulizer
6-8
Albuterol
MDI, nebulizer, oral
4-6
Long-acting
Formoterol
MDI, DPI, nebulizer
12
Arformoterol
Nebulizer
12
Indacaterol
Nebulizer
24
Salmeterol
MDI, DPI
12
Anticholinergics
Short-acting
Ipratropium
MDI, nebulizer
6-8
Long-acting
Aclidinium
DPI
12
Tiotropium
DPI, SMI
24
Combinations short-acting beta2-agonists plus anticholinergic
Albuterol/ipratropium
MDI, nebulizer
6-8
Methylxanthines
Theophylline
Oral
Up to 24
Adverse Effects
•
•
Tachycardia
Precipitate cardiac rhythm
disturbances
Tremor
Hypokalemia
•
•
•
Dryness of mouth
Urinary hesitancy
Cardiovascualr events?
•
•
See above
•
•
•
•
•
•
Inhaled corticosteroids
Budesonide
Fluticasone
DPI, nebulizer
MDI, DPI
•
•
•
•
Combination long-acting beta2-agonists plus corticoisteroids
Formoterol/budesonide
MDI, DPI
Formoterol/ mometasone MDI
Salmeterol/fluticasone
MDI, DPI
Systemic corticosteroids
Prednisone
Oral
Methylprednisolone
Oral, IV
Phosphodiesterase-4 inhibitors
Roflumilast
Oral
Atrial and ventricular
arrhythmias
Grand mal convulsions
Headaches
Insomnia
Nausea
Level dependent
Oral candidiasis
Hoarse voice
Skin brusing
Increased risk of
pneumonia
See above
•
Steroid myopathy (muscle
weakness, decreased
functionality, respiratory
failure)
•
Nausea
•
Reduced appetite
•
Abdominal pain
•
Diarrhea
•
Sleep disturbances
•
Headache
MDI= metered dose inhaler, DPI=dry powder inhaler, SMI=soft mist inhaler, IV- intravenous
Waye
24
24