Transcript Acute Exacerbation of Chronic Bronchitis (AECB)

Indications for Antibiotics in
Exacerbations of COPD
Sanjay Sethi MD
Professor
Pulmonary, Critical Care and Sleep Medicine
University at Buffalo, SUNY
[email protected]
Myths in AECOPD





Exacerbations are harmless
Exacerbations resolve spontaneously
Exacerbations are not bacterial in origin
Benefits of antibiotics in AECOPD are unproven
Choice of antibiotics does not matter in AECOPD
COPD Exacerbations: Survival
Probability of surviving
1.0
0.8
No exacerbation
0.6
p<0.001
1–2 exacerbations
p<0.0001
0.4
p=0.07
3–4 exacerbations
0.2
0.0
0
10
20
30
40
50
60
Time (months)
Soler-Cataluña JJ et al. Thorax. 2005;64:925-31
Myths in AECOPD





Exacerbations are harmless
Exacerbations resolve spontaneously
Exacerbations are not bacterial in origin
Benefits of antibiotics in AECOPD are unproven
Choice of antibiotics does not matter in AECOPD
Outcome of Exacerbations

In ICU patients


Hospital mortality
6 - 8%
In ER patients


11-24 %
In hospitalized patients


In-Hospital mortality
Relapse (repeat ER visit)
19 - 32%
In outpatients


Treatment failure rate
13 - 32%
Hospitalization rate in treatment failures 16-52%
Connors AJRCCM 1996, Seneff JAMA 1995, Esteban JAMA 2002,
Groenewegen Chest 2003, Martin Chest 1992, Murata Ann Emerg Med 1991,
Aaron NEJM 2003, Adams Chest 2000, Miravittles ERJ 2001, Ball QJM 1995, Dewan Chest 2000
Antibiotics in AECOPD:
Clinical Resolution
% success
Spontaneous
Resolution at
3 weeks
80
p<0.01
70
60
50
40
Placebo
30
Antibiotic
20
10
0
All
Type 1
Type 2
Type 3
Type of Exacerbation
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Antibiotics in AECOPD
Clinical Deterioration
% deterioration
35
30
25
p<0.05
20
Placebo
15
Antibiotic
10
5
0
All
Type 1
Type 2
Type 3
Type of exacerbation
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Myths in AECOPD





Exacerbations are harmless
Exacerbations resolve spontaneously
Exacerbations are not bacterial in origin
Benefits of antibiotics in AECOPD are unproven
Choice of antibiotics does not matter in AECOPD
Evidence for Bacterial Etiology of
AECOPD


Bacteria can be cultured from the distal airways
in significant concentrations in >50% of
patients
Acquisition of strains of bacteria new to the
patient is associated with a greater than 2 fold
increase in the risk of exacerbation
Monso E, et al. AJRCCM. 1995;152:1316-20; Sethi S, et al. NEJM. 2002; 347;465-71. Sethi S, et al. AJRCCM.
2004;168:448-53; Sethi S, et al. Chest. 2000;118:1557-65.
Evidence for Bacterial Etiology of
AECOPD


Specific immune responses develop to infecting
bacterial strains following exacerbation
Neutrophilic airway inflammation is associated
with recovery of bacterial pathogens during an
exacerbation
Monso E, et al. AJRCCM. 1995;152:1316-20; Sethi S, et al. NEJM. 2002; 347;465-71. Sethi S, et al. AJRCCM.
2004;168:448-53; Sethi S, et al. Chest. 2000;118:1557-65.
Proof of Global Warming
Myths in AECOPD





Exacerbations are harmless
Exacerbations resolve spontaneously
Exacerbations are not bacterial in origin
Benefits of antibiotics in AECOPD are unproven
Choice of antibiotics does not matter in AECOPD
Efficacy of Antibiotics and Steroids in
AECOPD: Systematic Analyses
Antibiotics (n=11)

Outcome
RR
n
NNT or
NNH
RR
n
Mortality
0.23 (0.10-0.52)
4
8
0.85 (0.45-1.59)
9
Treatment
Failure
0.75 (0.63-0.90)
6
3
0.48 (0.34-0.68)
9
9
Adverse
Effects
2.91 (1.48-5.72)
2
7
2.28 (1.56-3.34)
7
6
NNT or
NNH
Antibiotics



Steroids (n=10)
+ Sputum purulence resolution
-- PEFR and gas exchange
Steroids

+ PEFR, FEV1 and gas exchange
Ram FSF et al, Cochrane Lib Vol 2, 2006
Wood-Baker RR et al Cochrane Lib Vol 2, 2006
AECOPD trials: effect of patient
selection
p = ns
100
% success
90
80
p<0.01
70
60
50
40
Placebo
Antibiotic
30
20
10
0
Sachs
Anthonisen
Success rate
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Sachs et al, Thorax 1995;50:758-63
AECB trials: effect of patient
selection
Characterisitic
Anthonisen
Sachs
n
362
71
Age (yrs)
67.3  9
51.7  16.3
Minimum Age
35
18
Smoking
39.9  28.9
16.5 (0.15 –77)
Smokers
93.6%
69.1%
Asthmatics
Excluded
Included
FEV1 (%predicted)
33.9  3.7
NA
PEF (L/min)
227.5  96.1
285.3  99.2
Anthonisen et al,
Ann Intern Med
1987;106:196-204
Sachs et al,
Thorax
1995;50:758-63
Myths in AECOPD






Exacerbations are harmless
Exacerbations resolve spontaneously
Exacerbations are not bacterial in origin
Exacerbation severity is easy to define
Benefits of antibiotics in AECOPD are unproven
Choice of antibiotics does not matter in AECOPD
Antibiotic comparison trials in
AECOPD
Obaji and Sethi, Drugs and Aging 2001; 18:1-11
Antibiotic trials in AECOPD: Pitfalls




Limitation
Small n
Mild underlying COPD
Non-bacterial
exacerbations included
End-points compared at
3 weeks after onset
Potential consequence
› Type 2 statistical error
› Diminished perceived
antibiotic efficacy
› Type 2 statistical error
›
›
Spontaneous resolution
mitigates differences
Clinically irrelevant
Sethi S. Proc Am Thorac Soc. 2004;1:109-14
Antibiotic trials in AECOPD: Pitfalls




Limitation
Speed of resolution not
measured
Lack of long-term follow
up
Antibiotic with limited in
vitro efficacy
Poor penetration in to
respiratory tissues
Potential consequence
› Clinically relevant endpoint not assessed
› Time to next exacerbation
not assessed
› Diminished perceived
efficacy of antibiotics
› Diminished perceived
efficacy of antibiotics
Sethi S. Proc Am Thorac Soc. 2004;1:109-14
Proposed Goals for Treatment of
Exacerbations
Clinical





Faster resolution of
symptoms
Clinical Resolution to Baseline
Prevention of Relapse
Increasing exacerbation-free
interval
Preservation of health related
quality of life
Biological





Bacterial eradication
Resolution of airway
inflammation
Resolution of systemic
inflammation
Restoration of lung function
to baseline
Preservation of lung function
Bacterial Persistence and Airway
Inflammation following AECOPD
Bacteria
eradicated
by day 10
Bacteria
persisting
at day 10
Bacteria
eradicated
by day 10
100
MPO (units/ml)
10
10
LTB4 (nM)
Bacteria
persisting
at day 10
1
0.1
1
0.1
p<0.001
p<0.001
p<0.001
0.01
1
10
1
Day
p<0.05
0.01
10
1
10
1
10
Day
White et al. Thorax 2003;58:680-685
MOSAIC Study: Time to First
Occurence of Composite Event*
Patients not experiencing
composite event (%)
ITT population, N=730
*Failure, next AECB or need for further antimicrobial treatment
100
Moxifloxacin
90
Comparator
80
70
60
50
40
30
p=0.032
20
0
1
2
3
4
5
6
7
8
9
10
Time since randomisation (months)
Wilson R et al., Chest 2004, 125: 953 - 964.
GLOBE : Percentage of Patients
with no Recurrences at 26 Weeks
P = 0.016
% patients
80
71.0
70
60
58.5
50
40
30
20
10
0
Gemifloxacin
Clarithromycin
Wilson et al., Clin Ther 2002, 24:639-52
Rate of Recovery
Antibiotic Choice
80
p<0.0001
% recovered
70
60
RR for Slow
Recovery
Moxifloxacin vs
Clarithromycin
0.41 (0.31-0.55)
 Moxifloxacin vs
Amox-clav
0.34 (0.26-0.45)

50
Moxifloxacin
Clarithromycin
Amox-clav
40
30
20
10
0

<5 days
>5 days
Miravittles et al, Resp Med 2005; 99:955-65
Antibiotic Therapy of AECOPD


Stratification approach
Choose antibiotics based
on

Severity of acute illness

Expected outcome

Expected resistance
Proposed Therapies for AECB According
to Patient Subsets
Simple, uncomplicated
AECB
Complicated
AECB
• <4 exacerbations/year
• >4 exacerbations/year
• No comorbid illness
• Serious comorbid illness
• FEV1 >50%
• FEV1 <50%
• Patients with chronic
bronchial sepsis
• Chronic oral steroids
• Need for chronic
corticosteroid therapy and
frequent (>4/year) courses of
antibiotics
• Recent antibiotic therapy
• FEV1 <35%
• Home oxygen
Advanced macrolide
Selected cephalosporins
Doxycycline
TMP/SMX
Complicated AECB
at risk for P. aeruginosa
New fluoroquinolones
Amoxicillin–clavulanate
Fluoroquinolone
with antipseudomonal
activity (e.g. ciprofloxacin)
O’Donnell DE, et al. Can Respir J 2003
Risk Stratification and Acute
Exacerbations of COPD
Exacerbations
MILD
Only 1 of the 3 cardinal symptoms:
• Increased dyspnea
• Increased sputum volume
• Increased sputum purulence
No antibiotics
Always ask
about
antibiotic use
in previous 3
months
MODERATE OR SEVERE
At least 2 of the 3 cardinal symptoms:
• Increased dyspnea
• Increased sputum volume
• Increased sputum purulence
Simple COPD
Complicated COPD
• Cephalosporin (cefuroxime,
cefpodoxime, cefdinir),
• Ketolide (telithromycin),
• Advanced macrolide
(azithromycin, clarithromycin),
• Doxycycline,
•TMP/SMX
• Fluoroquinolone
(moxifloxacin, gemifloxacin,
levofloxacin),
• Amoxicillin-clavulanate
• If at risk for Pseudomonas,
consider ciprofloxacin and
obtain sputum culture
Worsening clinical status or inadequate response in 72 hrs
Reevaluate
Consider sputum culture
Sethi S, Murphy TF. Infect Dis Clin N Am. 2004;18:861-82.
Pathogenesis of Exacerbations
Impaired host defenses:
respiratory virus
new strains of bacteria
environmental irritants
Acute
cycle
Antibiotics
Smoking/Irritants
Chronic bacterial
colonization
Damaged respiratory
epithelium
Acute on chronic
inflammation
(bacterial + host mediated
inflammatory factors)
Chronic
cycle
Chronic inflammation
Progressive loss of lung
function and deteriorating
quality of life
(bacterial + host
mediated inflammatory
factors)
Antibiotics: Antibacterial mechanisms
Impaired host defenses:
respiratory virus
new strains of bacteria
environmental irritants
Prevent
AECOPD
Acute on chronic
inflammation
(bacterial + host mediated
inflammatory factors)
Chronic bacterial
colonization
X
Damaged respiratory
epithelium
X
Suppressive
Abx therapy
Chronic inflammation
(bacterial + host
mediated inflammatory
factors)
X
Trial
Overview
Primary endpoint:
no. of exacerbations
Moxi 400mg
OD x 5 days
Secondary endpoints:
•no. of exacerbations
•diff in lung function
•HEOR
•QoL, etc.
Pulse
#2
Pulse
#6
ET
FU
#1
FU
#3
Pulse
#2
Pulse
#6
ET
FU
#1
FU
#3
N=1132
Mod-severe CB
stable phase
Placebo
OD x 5 days
Screened &
Randomized
8 wks
8 wks
48 week treatment period
8 wks
8 wks
8 wks
24 week follow-up period