COPD - gdi-mv.de · PDF fileCOPD - Aktuelle Leitlinien und der Einsatz von Antibiotika? COPD Aktuelle Leitlinien und der Einsatz von Antibiotika? Sven Gläser Universitätsklinikum

COPD - Aktuelle Leitlinien und der Einsatz von Antibiotika?

COPD

Aktuelle Leitlinien und der Einsatz von Antibiotika?

Sven Gläser

Universitätsklinikum GreifswaldZentrum für Innere Medizin

Klinik und Poliklinik für Innere Medizin B

Schwerpunkt Pneumologie und Infektiologie


COPD – eine unterdiagnostizierte Erkrankung?

Lancet 2007; 370: 741–50







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 SpiroergometrischeParameter besser geeignet zur Verlaufs-kontrolle bei COPDals 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



3497 smoker 5906 never smoker (NHANES III)





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.



Seemungal TAR et al. AJRCCM 1998/2000



• 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 + paCO2 ≥ 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]

Sethi S. Semin Respir Crit Care Med. 2005,26:192-203

25 – 50%


Exazerbation und Infektion

Sethi S, Sethi R et al. Airway Bacterial Concentrations and Exacerbations ofChronic Obstructive Pulmonary Disease. AJRCCM 2007

HH -Haemophilus haemolyticus; HI – nontypeable Haemophilus influenzae; HP - Haemophilus parainfluenzae; MC - Moraxella catarrhalis; SP - Streptococcus pneumoniae.

Gepaarter Vergleich gleicher Patient/gleicher StammBakterielle Konzentration

… over 81 months, 104 subjects completed 3,009 clinic visits, 560 (19.6%) during exacerbations and 2,449 (80.4%) during stable disease


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.“



1-2%Mycoplasma pneumoniae

3-5%Chlamydophila pneumoniae

Atypical Bacteria 3-5%Human metapneumovirus

3-5%Adenovirus

5-10%Coronavirus

5-10%Respiratory syncytial virus

5-10%Influenza

5-10%Parainfluenza

20-25%Rhinovirus

Viruses

Isolated infrequently, unlikely causeStaphylococcus aureus

Isolated frequently, unlikely causeHaemophilus parainfluenzae

Isolated frequently, unlikely causeHaemophilus haemolyticus

Isolated in advanced disease, pathogenic significance undefinedEnterobacteriaceae

5-10%, prevalent in advanced diseasePseudomonas aeruginosa

10-15%Moraxella catarrhalis

10-15%Streptococcus pneumoniae

15-25%Haemophilus influenzae

Bacteria

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?

Quon BS CHEST 2008

Antibiose und Therapieversagen



• Indikation für antibiotische Behandlung:– Mindestens 2/3 von 3 Kardinalsymptomen:

• Dyspnoezunahme• Zunahme in Sputumpurulenz• Zunahme in Sputummenge• Beatmungsindikation

– Evidenzgrad B: Beatmungsindikation; 3/3 Kardinalsymptomen– Evidenzgrad C: 2/3 Kardinalsymptomen, wenn Sputumpurulenz

enthalten [GOLD 2007]

Stockley RA et al. Chest 2000,117:1638-45.Soler N et al. Thorax. 2007,62:29-35.


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 intention-to-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?

Quon BS CHEST 2008

Steroide und Therapieversagen Steroide und Verweildauer


Exazerbation COPD – NIV?

Quon BS CHEST 2008

NIV und Risiko für Intubation NIV und In-Hospital-Mortalität


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 sub-group 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. 1St George's, University of London, London, United Kingdom; 2Bayer HealthCare AG, Global Health Economics and Reimbursement, Wuppertal, Germany; 3Bayer Pharmaceuticals Corporation, Global Biostatistics Department, Connecticut, United States of America; 4Division 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?

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COPD - gdi-mv.de · PDF fileCOPD - Aktuelle Leitlinien und der Einsatz von Antibiotika? COPD Aktuelle Leitlinien und der Einsatz von Antibiotika? Sven Gläser Universitätsklinikum