COPD Aktuelle Leitlinien und der Einsatz von Antibiotika? Sven Gläser Universitätsklinikum Greifswald Zentrum für Innere Medizin Klinik und Poliklinik für Innere Medizin B Schwerpunkt Pneumologie und Infektiologie
COPD eine unterdiagnostizierte Erkrankung? Lancet 2007; 370: 741 50
COPD eine unterdiagnostizierte Erkrankung?
COPD eine unterdiagnostizierte Erkrankung?
COPD eine unterdiagnostizierte Erkrankung? Never smokers: male 3.1 [Cape Town] 9.4% [Manila] (Han 4.3%); female 3.2 [Vanc] 10.2% [Sydney] (Han 2.9%) Lancet 2007; 370: 741 50
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases. GOLD 2007
COPD eine Lungenerkrankung? Oga T et al. Exercise Capacity Deterioration in Patients With COPD*.Longitudinal Evaluation Over 5 Years. CHEST 2005; 128:62 69 Σ Spiroergometrische Parameter besser geeignet zur Verlaufskontrolle bei COPD als Spirometrie
COPD eine Lungenerkrankung? quartile 1 is a score of 0 to 2, quartile 2 is a score of 3 to 4, quartile 3 a score of 5 to 6, and quartile 4 a score of 7 to 10.
COPD eine Lungenerkrankung? COSYCO-NET German COPD and Systemic Consequences-Comorbidities Network Universität Marburg Helmholtz-Zentrum München Universität Greifswald Universität Heidelberg Medizinische Hochschule Hannover Universität Gießen MPI für Herz- und Lungenforschung, Bad Nauheim Charité, Berlin BMBF / DLR gefördertes Netzwerk, voraussichtlicher Förderbeginn 2/2009, Voraussichtliches Fördervolumen 3.4 Mio. / 3 Jahre
Pitfalls in diagnosing COPD
Pitfalls in diagnosing COPD 3497 smoker 5906 never smoker (NHANES III)
Pitfalls in diagnosing COPD
Pitfalls in diagnosing COPD SHIP I: 1809 volunteers, reference population 885 males, 924 females
Exazerbationen bei COPD Definition: Ereignis im natürlichen Krankheitsverlauf, der durch eine Veränderung der Baselinecharakteristika bzgl. Dyspnoe, Husten und/oder Sputumproduktion gekennzeichnet ist, der sich von der normalen Tag-zu-Tag-Variabilität unterscheidet und akut einsetzt.
Exazerbationen bei COPD Seemungal TAR et al. AJRCCM 1998/2000
Exazerbationen bei COPD Krankenhausmortalität ~ 11% [Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease: the SUPPORT investigators. Am J Respir Crit Care Med 1996; 154:959 967] Krankenhausmortalität/ICU ~ 25% [Seneff MG, Wagner DP, Wagner RP, et al. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA 1995; 274:1852 1857]
Exazerbation COPD SUPPORT trial (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments) 1016 Pat. mit Exazerbation einer COPD + Hospitalisierung + p a CO 2 50 mmhg Mortalität: in-hospital 11% 60-d 20% 180-d 33% 1-year 43% 2-year 49% 446 pts. re-admitted 754 times in the next 6 months AJRCCM 1996
Exazerbation und Infektion 70 80% der Exazerbation infektiös getriggert, 25 50% bakteriell [Sapey E, Stockley RA. Thorax. 2006,6:250-8] 25 50% Sethi S. Semin Respir Crit Care Med. 2005,26:192-203
Exazerbation und Infektion Bakterielle Konzentration Gepaarter Vergleich gleicher Patient/gleicher Stamm HH -Haemophilus haemolyticus; HI nontypeable Haemophilus influenzae; HP - Haemophilus parainfluenzae; MC - Moraxella catarrhalis; SP - Streptococcus pneumoniae. over 81 months, 104 subjects completed 3,009 clinic visits, 560 (19.6%) during exacerbations and 2,449 (80.4%) during stable disease Sethi S, Sethi R et al. Airway Bacterial Concentrations and Exacerbations of Chronic Obstructive Pulmonary Disease. AJRCCM 2007
Exazerbation und Infektion Sethi S et al. Am J Respir Crit Care Med. 2008,177:491-7 Clinical information, molecular typing of bacterial pathogens, sputum IL-8, tumor necrosis factor (TNF)- a and neutrophil elastase, and serum C-reactive protein. From 46 patients, 177 exacerbations were grouped as new strain, preexisting strain, other pathogen, and pathogen negative.
Exazerbation und Infektion Bacteria Haemophilus influenzae Streptococcus pneumoniae Moraxella catarrhalis Pseudomonas aeruginosa Enterobacteriaceae Haemophilus haemolyticus Haemophilus parainfluenzae Staphylococcus aureus Viruses Rhinovirus Parainfluenza Influenza Respiratory syncytial virus Coronavirus Adenovirus Human metapneumovirus Atypical Bacteria Chlamydophila pneumoniae Mycoplasma pneumoniae 15-25% 10-15% 10-15% 5-10%, prevalent in advanced disease Isolated in advanced disease, pathogenic significance undefined Isolated frequently, unlikely cause Isolated frequently, unlikely cause Isolated infrequently, unlikely cause 20-25% 5-10% 5-10% 5-10% 5-10% 3-5% 3-5% 3-5% 1-2% Sethi S, Murphy TF. Infect Dis Clin North Am. 2004,18:861-82
Exazerbation und Infektion - viral? Wilkinson TMA et al. CHEST 2006
Exazerbation und Infektion viral? Seemungal T et al. AJRCCM 2001
Exazerbation und Infektion Rationale für antibiotische Behandlung: Anthonisen NR et al. Ann Intern Med 1987,106:196-204. 3.5 y 173 pts, 362 exacerbations, 180 placebo vs. 182 antibiotic. Success rate 55% vs. 68%. rate of failure with deterioration 19% vs. 10%. Peak flow recovery +; no side effect increase. Nouira S et al. Lancet 2001, 15;358:2020-5. 93 pts. requiring mechanical ventilation due to COPD exacerbation. 400 mg Ofloxacin or placebo. Mortality 4% vs. 22% (absolute risk reduction 17.5%, 95% CI 4.3-30.7, p=0.01). Risk reduction additional courses of antibiotics (28.4%, 12.9-43.9, p=0.0006). Duration of mechanical ventilation and hospital stay: absolute difference 4.2 days, 95% CI 2.5-5.9; and 9.6 days, 3.4-12.8, respectively.
Exazerbation COPD Antibiose? Antibiose und Therapieversagen Quon BS CHEST 2008
Exazerbation und Infektion Indikation für antibiotische Behandlung: Mindestens 2/3 von 3 Kardinalsymptomen: Dyspnoezunahme Zunahme in Sputumpurulenz Zunahme in Sputummenge Beatmungsindikation Stockley RA et al. Chest 2000,117:1638-45. Soler N et al. Thorax. 2007,62:29-35. Evidenzgrad B: Beatmungsindikation; 3/3 Kardinalsymptomen Evidenzgrad C: 2/3 Kardinalsymptomen, wenn Sputumpurulenz enthalten [GOLD 2007]
Exazerbation und Infektion Indikation für antibiotische Behandlung PEG CAP S3-Leitlinie: Eine Antibiotika-Therapie wird empfohlen (Empfehlungsgrad B) bei: Patienten mit einer Typ I Exazerbation nach den Anthonisen-Kriterien und mittelschwerer oder schwerer COPD Patienten mit schwerer akuter Exazerbation, die eine respiratorische Unterstützung brauchen (nicht-invasive oder invasive maschinelle Beatmung) Eine Antibiotikatherapie kann erwogen werden (Empfehlungsgrad D) bei: Patienten aller Schweregrade mit häufig rezidivierenden akuten Exazerbationen (>4 /Jahr) Patienten aller Schweregrade mit relevanter kardialer Komorbidität
Welche Antibiose?? Risikostratifizierung GOLD 2007 Risikofaktoren: Co-Morbidität FEV1 <50% Exazerbationsfrequenz > 3 x Jahr Antibiotische Vorbehandlung innerhalb der letzten 3 Monate Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004;23:932-46. Miravitlles M et al. Relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of COPD. Study Group of Bacterial Infection in COPD. Chest 1999;116:40-6
Welche Antibiose?? Risiko für Pseudomonas-Infektionen (PEG CAP S3-LL) Pulmonale Komorbidität (strukturelle chronische Erkrankungen wie COPD im GOLD-Stadium IV, Bronchiektasen, Mukoviszidose) (OR 2.8) Stationärer Aufenthalt in den letzten 30 Tagen, länger als 2 Tage, allerdings nicht in den letzten 7 Tagen vor Beginn der akuten Pneumonieepisode (OR 3.5) Glukokortikoidtherapie (mindestens 10 mg Prednisonäquivalent über mindestens 4 Wochen) (OR 1.9) Aspiration (OR 2.3) Breitspektrum-Antibiotikatherapie über mehr als 7 Tage innerhalb des letzten Monats Malnutrition
Welche Antibiose?? PEG S3-LL 2005 Patienten mit einer leichten bis mittleren Einschränkung der Lungenfunktion (FEV1 zwischen 50% und 80% des Solls): Mittel der Wahl: Aminopenicillin ohne Betalaktamaseinhibitor (Amoxicillin) Alternativen: Makrolid (Azithromycin, Clarithromycin, Roxithromycin) oder Tetracyclin (Doxycyclin) Patienten mit schwerer Einschränkung der Lungenfunktion (FEV1 < 50% des Solls) ohne Risikofaktoren für eine Infektion durch P. aeruginosa: Aminopenicillin mit Betalaktamaseinhibitor (Amoxicillin + Clavulansäure oder Sultamicillin) Pneumokokkenwirksames Fluorchinolon (Levofloxacin, Moxifloxacin) Patienten mit Risikofaktoren für das Vorliegen einer Infektion durch P. aeruginosa oder für Patienten, die auf einer Intensivstation behandelt oder beatmet werden: Acylureidopenicillin + Betalaktamaseinhibitor (Piperacillin/Tazobactam) Pseudomonaswirksames Carbapenem (Imipenem, Meropenem) Pseudomonaswirksames Cephalosporin (Ceftazidim*, Cefepim) Pseudomonaswirksames Fluorchinolon (Ciprofloxacin*, Levofloxacin)
Welche Antibiose?? Metaanalyse von 19 RCT s, 7405 Pts.; 1999-2005: There was no difference regarding treatment success in intentionto-treat and clinically evaluable patients between macrolides and quinolones, A/C and quinolones or A/C and macrolides. The treatment success in microbiologically evaluable patients was lower for macrolides compared with quinolones (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.31 0.69). Fewer quinolonerecipients experienced a recurrence of ABECB after resolution of the initial episode compared with macrolide-recipients during the 26-week period following therapy. Adverse effects in general were similar between macrolides and quinolones. Administration of A/C was associated with more adverse effects (mainly diarrhoea) than quinolones (OR 1.36, 95% CI 1.01 1.85). Eur Respir J 2007; 29: 1127 1137
Exazerbation COPD Steroide? Steroide und Therapieversagen Steroide und Verweildauer Quon BS CHEST 2008
Exazerbation COPD NIV? NIV und Risiko für Intubation NIV und In-Hospital-Mortalität Quon BS CHEST 2008
Prävention? Black P; Staykova T; Chacko E; Ram FS; Poole P. Prophylactic antibiotic therapy for chronic bronchitis. Cochrane Database Syst Rev. 2003:CD004105. Metaanalyse 9 Studien, 1055 Pts. Conclusion: Prophylactic antibiotics in chronic bronchitis / COPD have a small but statistically significant effect in reducing the days of illness due to exacerbations of chronic bronchitis. They do not have a place in routine treatment because of concerns about the development of antibiotic resistance and the possibility of adverse effects. The available data are over 30 years old, so the pattern of antibiotic sensitivity may have changed and there is a wider range of antibiotics in use.
Prävention? Intermittent Moxifloxacin Therapy For The Prevention Of Acute Exacerbations In Patients With Chronic Bronchitis. RCT, Oct 2004 Apr 2008; 1402 Pts. Moxifloxacin alle 8 Wochen für 5 Tage vs. Placebo, follow-up 48 Wochen pep: exacerbations sep: Impact of treatment on the health related Quality of Life in St. George's Respiratory Questionaire (SGRQ) scores Deterioration in lung function test (PFEV1) Frequency of hospitalisation Mortality rates Time of first exacerbation Frequency of acute exacerbation of chronic bronchitis Time to next exacerbation from last pulsed dose Length of exacerbations Percentage of exacerbation free time
Prävention? Macrolide? Seemungal T et al. AJRRCM 2008 Statine? Blamoun AI et al. Int J Clin Pract 2008 Mucolytics? Zheng JP et al. Lancet 2008
Reduction in Number of Acute Exacerbations of COPD with Moxifloxacin in Patients with Mucopurulent/Purulent Sputum: A PULSE Study Sub-Analysis, [Publication Page: A962] S. Sethi, Buffalo, NY Background: The PULSE study demonstrates that intermittent pulsed antimicrobial therapy with moxifloxacin (MXF) decreases exacerbations of chronic obstructive pulmonary disease (COPD) when compared to placebo. The effectiveness of this pulsed MXF therapy was assessed in a patient subgroup enrolled in PULSE patients with mucopurulent (MP)/purulent (P) sputum at baseline. Methods: The PULSE study was a double-blind randomized clinical trial of intermittent MXF 400mg PO q.d. or placebo for 5 days every 8 weeks for 6 cycles. Post-hoc analysis was used to compare frequency of exacerbations between the two treatments in patients with MP/P sputum at baseline. Logistic regression analysis was performed and adjusted for region and pre-therapy % predicted FEV1. Results: In the end of treatment (EOT) per protocol (PP) population, 167/351 (47.6%) MXF- and 156/387 (40.3%) placebo-treated patients had MP/P sputum at their baseline, stable condition. For the primary outcome variable, the number of exacerbations during 48 weeks of therapy, was reduced from a mean (SD) of 1.0 (1.3) in the placebo group to 0.8 (1.3) in the MXF group. The adjusted odds ratio for exacerbation (95% CI) was 0.545 (95% confidence interval 0.355, 0.839; p=0.006) in the MXF arm compared to placebo arm. Conclusions: Among patients with COPD who produced mucopurulent or purulent sputum in their stable baseline state, intermittent pulsed therapy with MXF was associated with a relative 45.5% reduction in the odds of exacerbations in the PP (EOT) population, compared with placebo. This subgroup of patients therefore are good candidates for such therapy, when their standard therapy for COPD is inadequate in preventing exacerbations. Funding source: Bayer HealthCare.
Pulsed moxifloxacin therapy and health status in patients with acute exacerbations of chronic obstructive pulmonary disease (the PULSE study) Paul Jones, 1 Thomas Evers, 2 Daniel Haverstock, 3 Sanjay Sethi. 4. 1 St George's, University of London, London, United Kingdom; 2 Bayer HealthCare AG, Global Health Economics and Reimbursement, Wuppertal, Germany; 3 Bayer Pharmaceuticals Corporation, Global Biostatistics Department, Connecticut, United States of America; 4 Division of Pulmonary, Critical Care and Sleep Medicine, State University of New York, Western New York Healthcare System, State University of New York, and Department of Veterans Affairs, Western New York Healthcare System, Buffalo, NY, Unit. Background: The PULSE study showed that chronic intermittent pulsed therapy with moxifloxacin (MXF) reduced acute exacerbations of chronic obstructive pulmonary disease (AECOPD), versus placebo. Health status was a secondary endpoint. Methods: In the PULSE study, patients received MXF 400 mg PO q.d. or placebo for 5 days every 8 weeks for six cycles. Health status was measured by St George's Respiratory Questionnaire (SGRQ). Post hoc analyses were performed on mean change in SGRQ Symptom score (SGRQ-SDS), from baseline to week 48, with cut-off points for a clinically relevant response retrospectively defined as 4 or 8 units. Results: A total of 1,149 stable COPD patients received MXF (N=569) or placebo (N=580) of whom 1,008 (MXF, N=490; placebo, N=518) provided SGRQ data. Compared with placebo, significantly more MXF patients either improved, or had no change in SGRQ-SDS, and significantly fewer had deteriorations in SGRQ-SDS (Table 1).
Zusammenfassung COPD = Systemerkrankung Exazerbation von prognostischer und klinischer Relevanz 25 50% mit viraler Beteiligung mit hoher pathophysiologischer Bedeutung Therapie: Steroide Ggf. NIV bei 2/3 bzw. 3/3 Kardinalsymptomen Antibiose Impfungen! Prophylaxe?