indications for antibiotics in exacerbations of copd
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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 - PowerPoint PPT PresentationTRANSCRIPT
Indications for Antibiotics inIndications for Antibiotics in Exacerbations of COPD Exacerbations of COPD
Sanjay Sethi MDSanjay Sethi MD
ProfessorProfessor
Pulmonary, Critical Care and Sleep Pulmonary, Critical Care and Sleep MedicineMedicine
University at Buffalo, SUNYUniversity at Buffalo, SUNY
[email protected]@buffalo.edu
Myths in AECOPDMyths in AECOPD
Exacerbations are harmlessExacerbations are harmless Exacerbations resolve spontaneouslyExacerbations resolve spontaneously Exacerbations are not bacterial in originExacerbations are not bacterial in origin Benefits of antibiotics in AECOPD are Benefits of antibiotics in AECOPD are
unprovenunproven Choice of antibiotics does not matter in Choice of antibiotics does not matter in
AECOPDAECOPD
Soler-Cataluña JJ et al. Thorax. 2005;64:925-31
COPD Exacerbations: SurvivalCOPD Exacerbations: Survival
0.0
0.2
0.4
0.6
0.8
1.0
0 10 20 30 40 50 60
Time (months)
Pro
bab
ility
of s
urvi
ving
p<0.0001
p<0.001
p=0.073–4 exacerbations
1–2 exacerbations
No exacerbation
Myths in AECOPDMyths in AECOPD
Exacerbations are harmlessExacerbations are harmless Exacerbations resolve spontaneouslyExacerbations resolve spontaneously Exacerbations are not bacterial in originExacerbations are not bacterial in origin Benefits of antibiotics in AECOPD are Benefits of antibiotics in AECOPD are
unprovenunproven Choice of antibiotics does not matter in Choice of antibiotics does not matter in
AECOPDAECOPD
Outcome of Exacerbations Outcome of Exacerbations In ICU patients In ICU patients
In-Hospital mortality 11-24 %In-Hospital mortality 11-24 % In hospitalized patientsIn hospitalized patients
Hospital mortality 6 - 8%Hospital mortality 6 - 8% In ER patientsIn ER patients
Relapse (repeat ER visit) 19 - 32%Relapse (repeat ER visit) 19 - 32% In outpatientsIn outpatients
Treatment failure rate 13 - 32%Treatment failure rate 13 - 32% Hospitalization rate in treatment failures 16-Hospitalization rate in treatment failures 16-
52%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: Antibiotics in AECOPD: Clinical ResolutionClinical Resolution
0
10
20
30
40
50
60
70
80
% s
uccess
All Type 1 Type 2 Type 3
Type of Exacerbation
Placebo
Antibiotic
p<0.01
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Spontaneous Resolution at 3 weeks
Antibiotics in AECOPDAntibiotics in AECOPDClinical DeteriorationClinical Deterioration
0
5
10
15
20
25
30
35%
dete
riora
tion
All Type 1 Type 2 Type 3
Type of exacerbation
Placebo
Antibiotic
p<0.05
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Myths in AECOPDMyths in AECOPD
Exacerbations are harmlessExacerbations are harmless Exacerbations resolve spontaneouslyExacerbations resolve spontaneously Exacerbations are not bacterial in originExacerbations are not bacterial in origin Benefits of antibiotics in AECOPD are Benefits of antibiotics in AECOPD are
unprovenunproven Choice of antibiotics does not matter in Choice of antibiotics does not matter in
AECOPDAECOPD
Evidence for Bacterial Etiology of Evidence for Bacterial Etiology of AECOPDAECOPD
Bacteria can be cultured from the distal Bacteria can be cultured from the distal airways in significant concentrations in airways in significant concentrations in >50% of patients>50% of patients
Acquisition of strains of bacteria new to Acquisition of strains of bacteria new to the patient is associated with a greater the patient is associated with a greater than 2 fold increase in the risk of than 2 fold increase in the risk of exacerbationexacerbation
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 Evidence for Bacterial Etiology of AECOPDAECOPD
Specific immune responses develop to Specific immune responses develop to infecting bacterial strains following infecting bacterial strains following exacerbationexacerbation
Neutrophilic airway inflammation is Neutrophilic airway inflammation is associated with recovery of bacterial associated with recovery of bacterial pathogens during an exacerbationpathogens 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 WarmingProof of Global Warming
Myths in AECOPDMyths in AECOPD
Exacerbations are harmlessExacerbations are harmless Exacerbations resolve spontaneouslyExacerbations resolve spontaneously Exacerbations are not bacterial in originExacerbations are not bacterial in origin Benefits of antibiotics in AECOPD are Benefits of antibiotics in AECOPD are
unprovenunproven Choice of antibiotics does not matter in Choice of antibiotics does not matter in
AECOPDAECOPD
Efficacy of Antibiotics and Steroids in Efficacy of Antibiotics and Steroids in AECOPD: Systematic Analyses AECOPD: Systematic Analyses
Antibiotics (n=11)Antibiotics (n=11) Steroids (n=10)Steroids (n=10)
OutcomeOutcome RRRR nn NNT NNT or or
NNHNNH
RRRR nn NNT or NNT or NNHNNH
MortalityMortality 0.23 (0.10-0.52)0.23 (0.10-0.52) 44 88 0.85 (0.45-0.85 (0.45-1.59)1.59)
99
Treatment Treatment FailureFailure
0.75 (0.63-0.90)0.75 (0.63-0.90) 66 33 0.48 (0.34-0.48 (0.34-0.68)0.68)
99 99
Adverse Adverse EffectsEffects
2.91 (1.48-5.72)2.91 (1.48-5.72) 22 77 2.28 (1.56-2.28 (1.56-3.34)3.34)
77 66 Antibiotics
+ 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
0
10
20
30
40
50
60
70
80
90
100
% s
uccess
Anthonisen Sachs
Success rate
Placebo
Antibiotic
p<0.01
Anthonisen et al, Ann Intern Med. 1987:106:196-204
Sachs et al, Thorax 1995;50:758-63
p = ns
AECOPD trials: effect of patient AECOPD trials: effect of patient selectionselection
AECB trials: effect of patient AECB trials: effect of patient selectionselection
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 AECOPDMyths in AECOPD
Exacerbations are harmlessExacerbations are harmless Exacerbations resolve spontaneouslyExacerbations resolve spontaneously Exacerbations are not bacterial in originExacerbations are not bacterial in origin Exacerbation severity is easy to defineExacerbation severity is easy to define Benefits of antibiotics in AECOPD are Benefits of antibiotics in AECOPD are
unprovenunproven Choice of antibiotics does not matter in Choice of antibiotics does not matter in
AECOPDAECOPD
Antibiotic comparison trials in Antibiotic comparison trials in AECOPDAECOPD
Obaji and Sethi, Drugs and Aging 2001; 18:1-11
Antibiotic trials in AECOPD: Antibiotic trials in AECOPD: PitfallsPitfalls
LimitationLimitation Small nSmall n Mild underlying COPDMild underlying COPD
Non-bacterial Non-bacterial exacerbations includedexacerbations included
End-points compared at End-points compared at 3 weeks after onset3 weeks after onset
Potential consequencePotential consequence› Type 2 statistical errorType 2 statistical error› Diminished perceived Diminished perceived
antibiotic efficacyantibiotic efficacy› Type 2 statistical errorType 2 statistical error
› Spontaneous resolution Spontaneous resolution mitigates differencesmitigates differences
› Clinically irrelevantClinically irrelevant
Sethi S. Proc Am Thorac Soc. 2004;1:109-14
Antibiotic trials in AECOPD: Antibiotic trials in AECOPD: PitfallsPitfalls
LimitationLimitation Speed of resolution not Speed of resolution not
measuredmeasured Lack of long-term follow Lack of long-term follow
upup Antibiotic with limited in Antibiotic with limited in
vitro efficacyvitro efficacy Poor penetration in to Poor penetration in to
respiratory tissuesrespiratory tissues
Potential consequencePotential consequence› Clinically relevant end-Clinically relevant end-
point not assessedpoint not assessed› Time to next exacerbation Time to next exacerbation
not assessednot assessed› Diminished perceived Diminished perceived
efficacy of antibioticsefficacy of antibiotics› Diminished perceived Diminished perceived
efficacy of antibioticsefficacy of antibiotics
Sethi S. Proc Am Thorac Soc. 2004;1:109-14
Proposed Goals for Treatment of Proposed Goals for Treatment of ExacerbationsExacerbations
ClinicalClinical Faster resolution of Faster resolution of
symptomssymptoms Clinical Resolution to Clinical Resolution to
BaselineBaseline Prevention of RelapsePrevention of Relapse Increasing exacerbation-Increasing exacerbation-
free intervalfree interval Preservation of health Preservation of health
related quality of liferelated quality of life
BiologicalBiological Bacterial eradicationBacterial eradication Resolution of airway Resolution of airway
inflammationinflammation Resolution of systemic Resolution of systemic
inflammationinflammation Restoration of lung Restoration of lung
function to baselinefunction to baseline Preservation of lung Preservation of lung
functionfunction
Bacterial Persistence and Airway Bacterial Persistence and Airway Inflammation following AECOPDInflammation following AECOPD
White et al. Thorax 2003;58:680-685
LT
B4
(nM
)
100
10
1
0.1
0.01
1 10 1 10
Bacteria eradicated by day 10
Bacteria persisting at day 10
p<0.001p<0.001
Day
MP
O (
un
its/
ml)
10
1
0.1
0.01
1 10 1 10
Bacteria eradicated by day 10
Bacteria persisting at day 10
p<0.05p<0.001
Day
MOSAIC Study: Time to First Occurence of Composite Event*
ITT population, N=730*Failure, next AECB or need for further antimicrobial treatment
Pat
ien
ts n
ot
exp
erie
nci
ng
co
mp
osi
te e
ven
t (%
)
20
40
60
80
100
30
50
70
90
Time since randomisation (months)0 1 2 3 4 5 6 7 8 9 10
p=0.032
Moxifloxacin
Comparator
Wilson R et al., Chest 2004, 125: 953 - 964.
58.5
71.0
0
10
20
30
40
50
60
70
80
Gemifloxacin Clarithromycin
% p
ati
ents
P = 0.016
GLOBE : Percentage of GLOBE : Percentage of Patients Patients with no Recurrences with no Recurrences at 26 Weeksat 26 Weeks
Wilson et al., Clin Ther 2002, 24:639-52
Rate of RecoveryRate of RecoveryAntibiotic ChoiceAntibiotic Choice
0
10
20
30
40
50
60
70
80
% re
cove
red
<5 days >5 days
MoxifloxacinClarithromycinAmox-clav
RR for Slow RR for Slow RecoveryRecovery Moxifloxacin vs Moxifloxacin vs
ClarithromycinClarithromycin
0.41 (0.31-0.55)0.41 (0.31-0.55) Moxifloxacin vs Moxifloxacin vs
Amox-clavAmox-clav
0.34 (0.26-0.45)0.34 (0.26-0.45)
p<0.0001
Miravittles et al, Resp Med 2005; 99:955-65
Antibiotic Therapy of AECOPDAntibiotic Therapy of AECOPD
Stratification Stratification
approachapproach Choose antibiotics Choose antibiotics
based onbased on Severity of acute Severity of acute
illnessillness Expected outcomeExpected outcome Expected resistanceExpected resistance
Proposed Therapies for AECB According to Patient Subsets
• <4 exacerbations/year
• No comorbid illness
• FEV1 >50%
• >4 exacerbations/year
• Serious comorbid illness
• FEV1 <50%
• Home oxygen
• Chronic oral steroids
• Recent antibiotic therapy
Advanced macrolide Selected cephalosporins DoxycyclineTMP/SMX
New fluoroquinolones Amoxicillin–clavulanate
Fluoroquinolone with antipseudomonal activity (e.g. ciprofloxacin)
Simple, uncomplicated AECB
Complicated AECB
Complicated AECB at risk for P. aeruginosa
O’Donnell DE, et al. Can Respir J 2003
• Patients with chronic bronchial sepsis
• Need for chronic corticosteroid therapy and frequent (>4/year) courses of antibiotics
• FEV1 <35%
Risk Stratification and Acute Risk Stratification and Acute Exacerbations of COPDExacerbations of COPD
Exacerbations
No antibiotics Simple COPD Complicated COPD
• Cephalosporin (cefuroxime,
cefpodoxime, cefdinir), • Ketolide (telithromycin),• Advanced macrolide (azithromycin, clarithromycin),• Doxycycline,•TMP/SMX
Worsening clinical status or inadequate response in 72 hrs
Reevaluate Consider sputum culture
MODERATE OR SEVEREAt least 2 of the 3 cardinal symptoms:
• Increased dyspnea• Increased sputum volume
• Increased sputum purulence
MILDOnly 1 of the 3 cardinal symptoms:
• Increased dyspnea• Increased sputum volume
• Increased sputum purulence
• Fluoroquinolone (moxifloxacin, gemifloxacin, levofloxacin),• Amoxicillin-clavulanate• If at risk for Pseudomonas, consider ciprofloxacin and obtain sputum culture
Sethi S, Murphy TF. Infect Dis Clin N Am. 2004;18:861-82.
Always ask about antibiotic use in previous 3 months
Pathogenesis of Exacerbations
Chronic bacterial colonization
Chronic inflammation
(bacterial + host mediated inflammatory
factors)
Damaged respiratory epithelium
Impaired host defenses:respiratory virusnew strains of bacteriaenvironmental irritants
Acute on chronic inflammation
(bacterial + host mediated inflammatory factors) Progressive loss of lung
function and deteriorating quality of life
Smoking/Irritants
Chronic cycle
Acute cycle Antibiotic
s
Antibiotics: Antibacterial mechanisms
Chronic bacterial colonization
Chronic inflammation
(bacterial + host mediated inflammatory
factors)
Damaged respiratory epithelium
Impaired host defenses:respiratory virusnew strains of bacteriaenvironmental irritants
Acute on chronic inflammation
(bacterial + host mediated inflammatory factors)
Suppressive Abx therapy
X
X
Prevent AECOPD
X
Trial Trial OverviewOverview
Mod-severe CBstable phase
Moxi 400mg OD x 5 days
Screened & Randomized
Primary endpoint:no. of exacerbations
Placebo OD x 5 days
Pulse#2
Pulse#2
8 wks
Pulse#6
Pulse#6
8 wks
ET
8 wks 8 wks
ET
FU#1
8 wks
FU#1
FU#3
FU#3
Secondary endpoints:•no. of exacerbations •diff in lung function•HEOR•QoL, etc.
48 week treatment period 24 week follow-up period
N=1132