Indications for Antibiotics in Exacerbations of COPD

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




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





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




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


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


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


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

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Indications for Antibiotics in Exacerbations of COPD