COPD Aktuelle Leitlinien und der Einsatz von Antibiotika?

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 - Aktuelle Leitlinien und der Einsatz von Antibiotika?

COPD – eine unterdiagnostizierte 

Erkrankung? 

Lancet 2007; 370: 741–50 


COPD – eine unterdiagnostizierte Erkrankung? 



Erkrankung? 



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 



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 + 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 



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 



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.“ 



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 



- viral? 

Wilkinson TMA et al. CHEST 2006 


Exazerbation und Infektion – 

viral? 

Seemungal T et al. AJRCCM 2001 



• 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 



• 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] 



• 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 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 



• 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 



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) 



• 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 



Exazerbation COPD – NIV? 

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 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?

COPD Aktuelle Leitlinien und der Einsatz von Antibiotika?

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