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Indications for Antibiotics in Exacerbations of COPD

Indications for Antibiotics in Exacerbations of COPD. Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY ssethi@buffalo.edu. Myths in AECOPD. Exacerbations are harmless Exacerbations resolve spontaneously

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Indications for Antibiotics in Exacerbations of COPD

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  1. Indications for Antibiotics in Exacerbations of COPD Sanjay Sethi MD Professor Pulmonary, Critical Care and Sleep Medicine University at Buffalo, SUNY ssethi@buffalo.edu

  2. 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

  3. COPD Exacerbations: Survival 1.0 0.8 No exacerbation 0.6 p<0.001 Probability of surviving 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

  4. 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

  5. Outcome of Exacerbations • In ICU patients • In-Hospital mortality 11-24 % • In hospitalized patients • Hospital mortality 6 - 8% • In ER patients • 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

  6. Antibiotics in AECOPD: Clinical Resolution Spontaneous Resolution at 3 weeks Anthonisen et al, Ann Intern Med. 1987:106:196-204

  7. Antibiotics in AECOPDClinical Deterioration Anthonisen et al, Ann Intern Med. 1987:106:196-204

  8. 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

  9. 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.

  10. 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.

  11. Proof of Global Warming

  12. 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

  13. Efficacy of Antibiotics and Steroids in AECOPD: Systematic Analyses • 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

  14. AECOPD trials: effect of patient selection p = ns Anthonisen et al, Ann Intern Med. 1987:106:196-204 Sachs et al, Thorax 1995;50:758-63

  15. AECB trials: effect of patient selection Anthonisen et al, Ann Intern Med 1987;106:196-204 Sachs et al, Thorax 1995;50:758-63

  16. 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

  17. Antibiotic comparison trials in AECOPD Obaji and Sethi, Drugs and Aging 2001; 18:1-11

  18. 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 Antibiotic trials in AECOPD: Pitfalls Sethi S. Proc Am Thorac Soc. 2004;1:109-14

  19. 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 end-point not assessed Time to next exacerbation not assessed Diminished perceived efficacy of antibiotics Diminished perceived efficacy of antibiotics Antibiotic trials in AECOPD: Pitfalls Sethi S. Proc Am Thorac Soc. 2004;1:109-14

  20. 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 Proposed Goals for Treatment of Exacerbations

  21. Bacterial Persistence and Airway Inflammation following AECOPD Bacteria eradicated by day 10 Bacteria persisting at day 10 Bacteria eradicated by day 10 Bacteria persisting at day 10 100 10 10 1 MPO (units/ml) LTB4 (nM) 1 0.1 0.1 p<0.001 p<0.001 p<0.001 p<0.05 0.01 0.01 1 10 1 10 1 10 1 10 Day Day White et al. Thorax 2003;58:680-685

  22. ITT population, N=730 *Failure, next AECB or need for further antimicrobial treatment Moxifloxacin Comparator 100 90 80 70 Patients not experiencing composite event (%) 60 50 40 30 p=0.032 20 0 1 2 3 4 5 6 7 8 9 10 Time since randomisation (months) MOSAIC Study: Time to First Occurence of Composite Event* Wilson R et al., Chest 2004, 125: 953 - 964.

  23. P = 0.016 80 71.0 70 58.5 60 50 % patients 40 30 20 10 0 Gemifloxacin Clarithromycin GLOBE : Percentage of Patients with no Recurrences at 26 Weeks Wilson et al., Clin Ther 2002, 24:639-52

  24. Rate of RecoveryAntibiotic Choice • RR for Slow Recovery • Moxifloxacin vs Clarithromycin 0.41 (0.31-0.55) • Moxifloxacin vs Amox-clav 0.34 (0.26-0.45) p<0.0001 Miravittles et al, Resp Med 2005; 99:955-65

  25. Antibiotic Therapy of AECOPD • Stratification approach • Choose antibiotics based on • Severity of acute illness • Expected outcome • Expected resistance

  26. Proposed Therapies for AECB According to Patient Subsets Complicated AECB at risk for P. aeruginosa Complicated AECB Simple, uncomplicated AECB • <4 exacerbations/year • No comorbid illness • FEV1 >50% • >4 exacerbations/year • Serious comorbid illness • FEV1 <50% • Home oxygen • Chronic oral steroids • Recent antibiotic therapy • Patients with chronic bronchial sepsis • Need for chronic corticosteroid therapy and frequent (>4/year) courses of antibiotics • FEV1 <35% Advanced macrolide Selected cephalosporins Doxycycline TMP/SMX New fluoroquinolones Amoxicillin–clavulanate Fluoroquinolone with antipseudomonal activity (e.g. ciprofloxacin) O’Donnell DE, et al. Can Respir J 2003

  27. Risk Stratification and Acute Exacerbations of COPD Always ask about antibiotic use in previous 3 months Exacerbations • MILD • Only 1 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence • MODERATE OR SEVERE • At least 2 of the 3 cardinal symptoms: • Increased dyspnea • Increased sputum volume • Increased sputum purulence Simple COPD No antibiotics 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.

  28. Chronic cycle Acute cycle Pathogenesis of Exacerbations Smoking/Irritants • Impaired host defenses: • respiratory virus • new strains of bacteria • environmental irritants Chronic bacterial colonization Damaged respiratory epithelium Antibiotics Acute on chronic inflammation (bacterial + host mediated inflammatory factors) Chronic inflammation (bacterial + host mediated inflammatory factors) Progressive loss of lung function and deteriorating quality of life

  29. Antibiotics: Antibacterial mechanisms • Impaired host defenses: • respiratory virus • new strains of bacteria • environmental irritants Chronic bacterial colonization X Suppressive Abx therapy X Damaged respiratory epithelium Prevent AECOPD Acute on chronic inflammation (bacterial + host mediated inflammatory factors) Chronic inflammation (bacterial + host mediated inflammatory factors) X

  30. Secondary endpoints: • no. of exacerbations • diff in lung function • HEOR • QoL, etc. Primary endpoint: no. of exacerbations Trial Overview Moxi 400mg OD x 5 days Pulse #2 Pulse #6 ET FU #1 FU #3 N=1132 Mod-severe CB stable phase Pulse #2 Pulse #6 ET FU #1 FU #3 Placebo OD x 5 days Screened & Randomized 8 wks 8 wks 8 wks 8 wks 8 wks 48 week treatment period 24 week follow-up period

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