Antibiotics for AECOPD:

Making the Right Choice

Sanjay Sethi
USA
 An#bio#cs  for  AECOPD:  
Making  the  Right  Choice  

Sanjay Sethi MD
Assistant Vice-President for Health Sciences
Professor and Division Chief
Pulmonary, Critical Care and Sleep Medicine
University at Buffalo, SUNY
ssethi@buffalo.edu
 Interac#ve  Ques#on  #1   0:15
  exacerbation is based on:
The correct diagnosis of COPD

1.  A  change  in  pulmonary  

1   0%  
symptoms  more  than  day  
to  day  variation  
2.  Documented  drop  in  O2   2   0%  

saturation  
3.  New  =indings  on  physical   3   0%  
exam  
4.  Viral  prodrome  followed   4   0%  
by  increased  lung  
symptoms   1   2   3   4  

Voted: 0
2  
Interac#ve  Ques#on  #1  
 

The  correct  diagnosis  of  COPD  exacerbation  is  

based  on:  
1.  A  change  in  pulmonary  symptoms  more  
than  day  to  day  variation  
2.  Documented  drop  in  O2  saturation  

3.  New  =indings  on  physical  exam  

4.  Viral  prodrome  followed  by  increased  lung  

symptoms  
 What is acute exacerbation of
COPD (AECOPD)?
n  Acute change in patient’s
symptoms beyond daily
variations sufficient to
cause a change in therapy
n  Exclude other causes of
increased symptoms
n  Pneumonia
n  CHF
n  PE
n  Non-compliance

Rodriguez-Roisin, R. Chest 2000;117:398S-401S

ATS/ERS Statement ERJ 2004;23:932-946
Sethi S, et al. NEJM 2002;347:465
 Treating Infection in COPD

n  Do all patients with AECOPD need

antibiotics?

n  Do they all need the same antibiotic?

Rational Antibiotic Treatment of
AECOPD
n  What proportion of AECOPD are bacterial?
n  Which Bacteria and their antibiotic
susceptibility?
n  Do Antibiotics work?

n  Does Antibiotic selection matter?

n  How does one distinguish bacterial from

non-bacterial exacerbations?
Rational Antibiotic Treatment of
AECOPD
n  What proportion of AECOPD are bacterial?
n  Which Bacteria and their antibiotic
susceptibility?
n  Do Antibiotics work?

n  Does Antibiotic selection matter?

n  How does one distinguish bacterial from

non-bacterial exacerbations?
AECOPD: Mechanisms
Smoking/irritants
Impaired host defenses:
§  respiratory viruses
§  new strains of bacteria
§  environmental irritants

Acute Impaired lung defense

cycle

Acute on chronic
inflammation
(pathogen + host-
mediated inflammatory Progressive loss of lung
factors) function and deteriorating
quality of life
 Etiology of AECOPD

Non-infectious
Bacteria

Virus
Bacteria and Virus

Papi A, et al. AJRCCM 2006;173:1114-21

Etiology of AECOPD
Bacteria  

Bacteria  +  Virus  

Bacteria  +  Eosinophil  

Bacteria  +  Virus  +  
Eosinophil  
Virus  

Eosinophil  

Virus  +  Eosinophil  

None  

Bafadhel M, et al. AJRCCM 2011;184(6):662-71

 Interac#ve  Ques#on  #2   0:15
What is the most common bacterial pathogen implicated as a
cause of AECOPD?

1.  Streptococcus 1   0%  
pneumoniae
2.  Nontypeable 2   0%  
Haemophilus
influenzae 3   0%  
3.  Pseudomonas
aeruginosa 4   0%  

4.  Moraxella catarrhalis

1   2   3   4  

Voted: 0
 Interactive Question #2

n  What is the most common bacterial

pathogen implicated as a cause of
AECOPD?
1.  Streptococcus pneumoniae
2.  Nontypeable Haemophilus influenzae
3.  Pseudomonas aeruginosa
4.  Moraxella catarrhalis
 Etiology of AECOPD: Bacteria
Microbe Role in Exacerbations
Haemophilus influenzae 20-30%
Streptococcus pneumoniae 10-15%
Moraxella catarrhalis 10-15%
Pseudomonas aeruginosa 5-10%, more in advanced disease
Enterobacteriaceae Isolated in advanced disease, ? significance
Staphylococcus aureus Isolated infrequently, ? significance
Haemophilus haemolyticus Isolated frequently, unlikely cause
Haemophilus parainfluenzae Isolated frequently, unlikely cause

Sethi S, et al. N Engl J Med 2008;359:2355–2365

 Interac#ve  Ques#on  #3   0:15
What is the major reason for the poor clinical results with
Amoxicillin in AECOPD?

1.  Poor  oral  absorption  

1   0%  
2.  Inadequate  lung  
concentrations  
2   0%  
3.  β-­‐lactamase  mediated  
resistance  
3   0%  
4.  Resistance  due  to  
alteration  in   4   0%  
Penicillin  
1   2   3   4  

Voted: 0
 Interac#ve  Ques#on  #3  

n  What  is  the  major  reason  for  the  poor  

clinical  results  with  Amoxicillin  in  AECOPD?  
1.  Poor  oral  absorption  
2.  Inadequate  lung  concentrations  
3.  β-­‐lactamase  mediated  resistance  
4.  Resistance  due  to  alteration  in  Penicillin  
Binding  Proteins  
 An#microbial  Resistance  is  Prevalent    
in  the  Community  in  Adults  
100
Penicillin Macrolide
80 Tetracycline TMP-SMX
Percent

60

40

20

0
H. influenzae S. pneumoniae M. catarrhalis

Pfaller MA, et al. Am J Med 2001;111:4S-12S.

 Ra#onal  An#bio#c  Treatment  of  
AECOPD  
n  What  proportion  of  AECOPD  are  bacterial?  
n  Which  Bacteria  and  their  antibiotic  
susceptibility?  
n  Do  Antibiotics  work?  

n  Does  Antibiotic  selection  matter?    

n  How  does  one  distinguish  bacterial  from  

non-­‐bacterial  exacerbations?  
 Efficacy of Antibiotics and Steroids in
AECOPD: Systematic Analyses

Antibiotics (n=11) Steroids (n=10)

Outcome RR n NNT or RR n NNT or
NNH NNH
Mortality 0.23 (0.10-0.52) 4 8 0.85 (0.45-1.59) 9
Treatment 0.75 (0.63-0.90) 6 3 0.48 (0.34-0.68) 9 9
Failure
Adverse 2.91 (1.48-5.72) 2 7 2.28 (1.56-3.34) 7 6
Effects

n  Antibiotics
n  + Sputum purulence resolution
n  -- PEFR and gas exchange
n  Steroids Ram FSF, et al, Cochrane Lib Vol 2, 2006
n  + PEFR, FEV1 and gas exchange Wood-Baker RR, et al, Cochrane Lib Vol 2, 2006
 RDBPC Trial in moderate
AECOPD
p=0.02
n  Moderate 100
p=0.02
Exacerbations 90
80
(outpatient treatment 70
with antibiotics and 60
steroids) 50
40
n  158 patients received 30
Amox/Clav
Amox/Clav 20 Placebo
10
n  152 patients received 0
placebo Clinical Clinical
n  Oral Corticosteroids in Success Cure at
at Day Day 10
17% of patients 10

Llor C, et al. AJRCCM 2012;186:716-23

Antibiotics Prolong Time to Next
Exacerbation
Median time to next
exacerbation in
clinical successes at
Day 10

Amox/Clav: 233
days

Placebo:166 days

p=0.015

Llor C, et al. AJRCCM 2012;186:716-23

Antibiotics in Hospitalized AECOPD
An Observational Study

Rothberg MB, et al. JAMA 2010;303(20):2035-2042

Antibiotics in Outpatient AECOPD
An Observational Study
n  Observational study of
Oral steroids AECOPD
and Antibiotics
n  Mortality after
treatment with oral
steroids alone (OS) vs.
Oral Steroids
oral steroids and
alone antibiotics (OSA)
n  n = 842, 17% died in
the follow up period
n  OS 20%, OSA 14%
n  p = 0.02
n  HR 0.62 (0.45 – 0.87)

Roede BM, et al. ERJ 2009;33:282-8

 Doxycycline vs Placebo in AECOPD
CS = Clinical Success
CC = Clinical Cure
n  2 center study in
Netherlands Doxy   Placebo  
90  
n  Hospitalized Anthonisen
Type 1 or 2 80   * *
70  
exacerbation
60  

% of patients
n  265 exacerbations in 50  
233 patients 40  
n  Tapering systemic 30  
corticosteroids in all 20  
patients 10  
0  
CS  30  d   CC  30  d   CS  10  d   CC  10  d  
Daniels JMA, et al. AJRCCM 2010;181:150-7
 Ra#onal  An#bio#c  Treatment  of  
AECOPD  
n  What  proportion  of  AECOPD  are  bacterial?  
n  Which  Bacteria  and  their  antibiotic  
susceptibility?  
n  Do  Antibiotics  work?  

n  Does  Antibiotic  selection  matter?    

n  How  does  one  distinguish  bacterial  from  

non-­‐bacterial  exacerbations?  
 E#ology  of  AECOPD:  Bacteria  
Microbe Role in Exacerbations
Haemophilus influenzae 20-30%
Streptococcus pneumoniae 10-15%
Moraxella catarrhalis 10-15%
Pseudomonas aeruginosa 5-10%, more in advanced disease
Enterobacteriaceae Isolated in advanced disease, ? significance
Staphylococcus aureus Isolated infrequently, ? significance
Haemophilus haemolyticus Isolated frequently, unlikely cause
Haemophilus parainfluenzae Isolated frequently, unlikely cause

Sethi S, et al. N Engl J Med 2008;359:2355–2365

 An#microbial  Resistance  is  Prevalent    
in  the  Community  in  Adults  
100
Penicillin Macrolide
80 Tetracycline TMP-SMX
Percent

60

40

20

0
H. influenzae S. pneumoniae M. catarrhalis

Pfaller MA, et al. Am J Med 2001;111:4S-12S

Antibiotic comparison trials in
AECOPD

Obaji and Sethi, Drugs and Aging 2001;18:1-11

First Line vs. Second Line Antibiotics in
AECOPD: Meta-analysis
n  12 randomized controlled trials
n  9 Double Blind

n  3 Single Blind

n  2261 adult patients with AECB

n  First line antibiotics:
n  10: amoxicillin, ampicillin or pivampicillin

n  1: Doxycycline (n = 76)

n  1: TMP/SMX (n = 39)

n  Modified Jadad Quality Score (1-5): Mean was 3.3, 10
were ≥ 3

Dimopoulos G, et al. Chest 2007;132(2):447-55.

First Line vs. Second Line Antibiotics in
AECOPD: Clinical Success

n  Clinical Success Odds Ratio

(0.51, 95% CI 0.34 to
0.75)
n  Sensitivity Analyses:
n  Trials before 1991 (n=974)

n  OR (0.80, 95% CI 0.38

to 1.69)
n  Trials after 1991 (n=1287)

n  OR (0.46, 95% CI 0.29

to 0.73)
n  No difference in all-cause
mortality and adverse effects

Dimopoulos G, et al. Chest 2007;132(2):447-55.

 MOSAIC Study: Time to First
Occurence of Composite Event*
ITT population, N=730
*Failure, next AECB or need for further antimicrobial treatment
100
Moxifloxacin
Patients not experiencing

90 Comparator
composite event (%)

80 (Amoxicillin,
Cefuroxime,
70
Clarithromycin)
60

50

40

30
p=0.03
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

80 71.0
70
58.5
60
% patients

50
40
30
20
10
0
Gemifloxacin Clarithromycin

Wilson R, et al. Clin Ther 2002;24:639-52

 MAESTRAL Study: Moxifloxacin vs. Amoxicillin/
clavulanate in Complicated AECOPD
Characteristics Moxifloxacin Amoxicillin/ P-value
(N=677) clavulanic acid
(N=675)
Male sex, n (%) 534 (79) 585 (81) 0.471
Age (years), mean ± SD 69.6 ± 6.8 69.6 ± 6.6 0.982
Range 59 - 93 60 - 91
≥65 years, n (%) 486 (72) 492 (73) 0.631
Systemic corticosteroid use, n (%) 236 (35) 239 (35) -
FEV1 (mL), mean ± SD 982 ± 370 978 ± 360 0.971
FEV1 group
FEV1<30%, n (%) 174 (26) 165 (24) 0.80
FEV1≥30%, n (%) 501 (74) 507 (74)
All comorbidities 533 (79) 545 (81) 0.642
Exacerbations in previous year 0.512
Mean ± SD 2.5 ± 1.1 2.5 ± 1.1
Range 1–15 1–10
1Cochran-Mantel-Haenszel test stratified by region and stratum
2 Two-way ANOVA stratified by stratum and region Wilson R, et al. ERJ 2012;40:17-27
MAESTRAL Study: Bacteriological Response at EOT
Correlated with Clinical Cure at Week 8 post-
therapy (ITT with pathogens)
Confirmed eradication at EOT
Confirmed persistence/superinfection at EOT
100
P=0.0014 P=0.003
Clinical cure at 8 weeks post-therapy

P=0.150
80.4
80 76.8
72.4
62.1 61.1 63.0
60

40

20

149/194 123/198 86/107 55/90 63/87 68/108

0
Overall Moxifloxacin Amoxicillin/clavulanic acid

Wilson R, et al. ERJ 2012;40:17-27

 Doxycycline vs Placebo in AECOPD
CS = Clinical Success
CC = Clinical Cure
n  2 center study in Doxy   Placebo  
Netherlands 90  
n  Hospitalized Anthonisen 80   * *
Type 1 or 2 70  
exacerbation 60  
n  265 exacerbations in 50  
233 patients 40  
30  
n  Tapering systemic 20  
corticosteroids in all 10  
patients 0  
CS  30  d   CC  30  d   CS  10  d   CC  10  d  
Daniels JMA, et al. AJRCCM 2010;181:150-7
 Doxycycline vs Placebo in AECOPD
Bacteriological Results at 10 days

Doxy Placebo
90
80 * *
18/22

70 *
52/78 *
18/23
% Response

2/3
28/44
60
50
40 10/44

25/73 14/42 9/27

30
1/4
20
10
0
Overall NTHi SP MC PA

Daniels JMA, et al. AJRCCM 2010;181:150-7

 Bacterial Persistence and Airway
Inflammation following AECOPD
Bacteria Bacteria Bacteria Bacteria
eradicated persisting eradicated persisting
by day 10 at day 10 by day 10 at day 10
100 10

MPO (units/ml)
10
1
LTB4 (nM)

0.1
0.1

p<0.001 p<0.001
0.01 p<0.001 0.01 p<0.05

1 10 1 10 1 10 1 10
Day Day
White AJ, et al. Thorax 2003;58:680-685
Rational Antibiotic Treatment of
AECOPD
n  What proportion of AECOPD are bacterial?
n  Which Bacteria and their antibiotic
susceptibility?
n  Do Antibiotics work?

n  Does Antibiotic selection matter?

n  How does one distinguish bacterial from

non-bacterial exacerbations?
 Interactive Question #4   0:15

Which of these can reliably distinguish a bacterial from non-bacterial

exacerbation?

1.  Presence of fever

1   0%  
2.  Presence of purulent
sputum 2   0%  
3.  Sputum culture positive
for a pathogen 3   0%  
4.  Sputum Gram stain
showing neutrophils 4   0%  

1   2   3   4  

Voted: 0
 Interactive Question #4

n  Which of these can reliably distinguish a

bacterial from non-bacterial exacerbation?
1.  Presence of fever
2.  Presence of purulent sputum
3.  Sputum culture positive for a pathogen
4.  Sputum Gram stain showing neutrophils
 Antibiotics in AECOPD:
Clinical Resolution
80 p<0.01

70
60
% success

50
40
Placebo
30
Antibiotic
20
10

0
All Type 1 Type 2 Type 3

Type of Exacerbation

Anthonisen NR, et al. Ann Intern Med 1987:106:196-204

Bronchoscopic Validation of Sputum Purulence in
Severe AECOPD: Anthonisen criteria
n  Cardinal Symptoms 100
n  Increased Dyspnea 90
n  Increased Sputum volume

% Pathogen positive PSB culture

80
n  Increased Sputum 70
purulence 60
n  Type 1: All 3 cardinal symptoms 50
present 40
n  Type 2: 2 of the 3 present 30
n  Type 3: 1 of the 3 symptoms 20
plus URTI, fever, cough,
10
wheeze or a 20% increase HR
0
or RR
Type 1 Type 2 Type 3

Anthonisen NR, et al. Ann Intern Med 1987;106:196-204

Soler N, et al. Thorax 2007;62:29-35
 Purulent Sputum and Sputum
Bacteriology in Exacerbation
120
Purulent Mucoid
100
% of Samples

80

60

40

20

0
PMN Gram Stain Positive >107CFU/mL
Culture

Stockley RA, et al. Chest 2000;117:1638-1645

Approaching Antibiotic Therapy of
AECOPD
n  Resistance!
What resistance??!!
n  Outcome?
Who cares!!
n  All patients treated
with a conventional
agent or not at all
Approaching Antibiotic Therapy of
AECOPD
n  Hasta la vista Baby!

n  All patients treated

with the best
available agent
Approaching Antibiotic Therapy of
AECOPD
n  Stratification approach
n  Determinants of Success
n  Antimicrobial Efficacy
n  Host Characteristics
n  Age
n  Underlying disease
severity
n  Comorbid conditions
n  Frequency of
Exacerbations
n  Choose antibiotics based on
n  Severity of acute illness
n  Likelihood of bacterial
infection
n  Determinants of Outcome
n  Host
n  Bacterial resistance
 An#bio#cs  for  AECOPD:  Risk  Stra#fica#on    
MILD MODERATE OR SEVERE
Only 1 of the 3 cardinal symptoms: At least 2 of the 3 cardinal symptoms:
•  Increased dyspnea •  Increased dyspnea
•  Increased sputum volume •  Increased sputum volume
•  Increased sputum purulence •  Increased sputum purulence

•  No antibiotics Uncomplicated COPD Complicated COPD

•  Increased bronchodilator No risk factors:
•  Symptomatic therapy Age <65 years
•  Monitoring of symptoms FEV1 >50% predicted
<2 exacerbations/year
No cardiac disease
1 or More risk factors:
Age ≥65 years
FEV1 ≤50% predicted
>2 exacerbations/year
Cardiac disease

• Advanced macrolide •  Fluoroquinolone

(azithromycin, clarithromycin)
• Cephalosporin (cefuroxime,
cefpodoxime, cefdinir)
•  Doxycycline
•  Trimethoprim–sulfamethoxazole
•  If recent antibiotic exposure (<3
months), use alternative class
(moxi, gemi, levofloxacin)
•  Amoxicillin-clavulanate
•  If at risk for Pseudomonas,
consider ciprofloxacin and
obtain sputum culture
•  If recent antibiotic exposure (<3
months), use alternative class

Worsening clinical status or inadequate response in 72 hrs

Modified from: Sethi S, Murphy TF. NEJM Re-evaluate

2008;359:2355-65. Consider sputum culture
 Treating AECOPD: The Future

n  Rapid molecular diagnosis of infectious pathogens

n  Biomarker panels
n  Inhaled antibiotics
n  Specific anti-inflammatory drugs
Panel Discussion