Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Critical Analysis of the Risk/Benefit Ratio Related to the Use of Guidelines for the Treatment of Community-Acquired Pneumonia P375 Mailing address: P.M. Tulkens UCL 73.70 av. Mounier 73, 1200 Brussels – Belgium, [email protected] Sylviane Carbonnelle MD, PhD, Ann Lismond MSc, Françoise Van Bambeke PharmD, PhD, Paul M. Tulkens MD, PhD Unité de pharmacologie cellulaire et moléculaire & Centre de Pharmacie clinique, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium. Background Objective Resistance of the target organism(s) is a collateral effect of antibiotics that can lead to treatment failure. It should therefore be included, together with conventional adverse drug reactions (ADRs), in the analysis of the risk/benefit ratio of anti-infective drugs [1]. Although this is implicitly taken into account in the setting of national or regional guidelines, the ever changing pattern of resistance may make them rapidly less effective than expected. To assess to what extent most recent guidelines for the treatment of communityacquired pneumonia (CAP) in Europe and North America are safe and well-balanced with respect to the risk of bacterial resistance and to ADRs. Methods Multi-step approach examining the following items: Treatment guidelines: identified from (i) the US National Guideline Clearinghouse (NGC; www.guideline.gov), (ii) systematic search through SCIRUS and search engines; (iii) direct contact with key persons in specific countries. Only guidelines published or updated after 2003 from European, national and North American organizations were selected. Safety of recommended antimicrobials: compiled from the corresponding official labeling (EU SmPC if available; if not, Belgian and US labeling). Susceptibility patterns. Resistance data concerning S. pneumoniae (most critical organism in CAP) as obtained from (i) systematic literature analysis (PubMed [2007-2008], (ii) abstracts of main congresses in 2008-2009 [ECCMID, ICAAC]); (iii) main antimicrobial resistance surveillance programmes/system (TRUST [Tracking Resistance in the United States Today], GLOBAL [Global Landscape On the Bactericidal Activity of Levofloxacin], PROTEKT [Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin], EARSS [European Antimicrobial Surveillance System]). Results 1. Treatment guidelines 3. Susceptibilities % of S. pneumoniae isolates resistant to first-line antibiotics per country or region UK NL AT DE SE EARSS penicillin - I CH BE IT TRUST ZA 0 BE EUR-3 EUR-2 EUR-1 5 10 SE DK DE 0 GR 15 20 25 30 35 5 40 45 EARSS other -lactam CH SE IT PT UK BE FR AT SI NL ES UK EUR-5 SI 10 ES EUR 15 20 IT SK TR GR EUR-6 25 FR 30 35 40 45 50 50 TRUST amoxi/clav SI TR alternative amoxicillin DE NL UK ECCMID 08-09 EUR-6 DE tetracycline - R US Riedel US LAm Asia EUR ECCMID 08-09 1st line TRUST US GLOBAL EUR FR SI ES TR penicillin - R TR GLOBAL levofloxacin - R US US EUR LAm ZA Asia DE macrolide TRUST US ECCMID 08-09 ketolide clindamycin EUR LAm ZA GLOBAL EUR-1 TR BE BE EUR-3 GR EUR-2 DE EUR-5 EUR-4 0 1 2 EUR-6 3 4 5 6 7 8 9 10 Asia US pristinamycin fluoroquinolone ECCMID 08-09 EUR-3 EUR-1 TR EUR-2 EUR-6 EUR-5 10 15 BE DE tetracycline 0 cotrimoxazole 5 20 GR 25 30 35 40 45 50 -lactam + macrolide DE EARSS Map concerning adult outpatients only 12 guidelines for adults (from EUR, DE, FR, GB, ES, NL, BE, SE, AU, CH, NO and the US) and 6 for children (from the WHO, FR, BE, AU, NZ and the US) were reviewed. Most European guidelines for patients without comorbidities recommended beta-lactams or macrolides as first-line therapy (tetracyclines in some countries), with fluoroquinolones as alternatives (except in ES). CH SE AT NL UK PROTEKT SE NL -lactams Populations at high risk / main contra-indications amoxicillin anaphylactic reactions allergic patients clavulanic acid hepatic toxicity macrolides drug interactions (CYP450) hepatic toxicity cardiac toxicity (arrythmias, Torsades de Pointes) AU UK BE US DE CH ES LAm ZA NL Riedel Most frequent or serious side effects • France [recommending beta-lactams or macrolides], where reduced susceptibility to penicillins [requiring high doses] is > 25 % and full resistance to macrolides is > 30 %; erythromycin - R FR IT GR FR ZA JP CN TW US 2. Adverse drug effects Drugs within the class AT TR TRUST GLOBAL Class BE IT TR ES SI Current resistance of S. pneumoniae to lactams and macrolides is often high with typical examples being SE SE ECCMID 08-09 NL 0 UK DE SI DE UK DE AT UK 10 20 US EUR Asia In contrast, resistance of S. pneumoniae to "respiratory" fluoroquinolones (example: levofloxacin; when available, data are similar for moxifloxacin) remains low in all countries. FR IT EUR ES EUR-5 EUR-2 GR ES TR BE BE FR EUR-6 EUR-4 30 • North America [recommending macrolides] where full resistance is > 30 %. 40 IT 50 60 70 80 90 100 hepatic dysfunction patients taking drugs metabolized by CYP450 patients with antiarrythmics fluoroquinolones musculoskeletal (tendinopathies) elderly patients, or taking corticoids, and cartilage toxicity or with kidney, heart or lung prolongation of the QTc interval transplants and isolated cases of Torsades patients taking other drugs with de pointes effects on QTc, or antiarrythmics, or patients with hypokaliemia pregnancy, lactation, infants tetracyclines esophagitis and esophagal ulcerations hepatotoxicity photosensitivity pregnancy, lactation, infants sulfamides agranulocytosis, anemia, thrombocytopenia, leukopenia, neutropenia, hypoprothrombinemia, methemoglobinemia, eosinophilia metabolic and nutritional: hyperkalemia elderly patients or patients with preexisting folic acid deficiency or kidney failure pregnancy Most frequent conventional ADRs are (i) allergy for beta-lactams (with hepatotoxicity if combined with clavulanic acid), (ii) impairment of hepatic metabolism of co-administered drugs for macrolides (with cardiac toxicity for IV forms); (iii) tendonitis (especially in elderly patients and those receiving corticoids) for fluoroquinolones (not registered for children; (iv) hepatotoxicity and photosensitivity for tetracyclines, and (v) hematologic disturbances for sulfamides . Conclusions Antibiotic classes commonly recommended (-lactams, macrolides, and, in some countries, tetracyclines) • may constitute rational choices for CAP in regions with low resistance rates but carry significant risks of conventional ADRs; • expose patients to the risk of treatment failure in many other regions. While antibiotics considered as alternatives have also their own conventional ADRs, integration of resistance pattern data, and continuous readjustment of guidelines based on a more global assessment of risk/benefit ratio may be necessary. Reference 1. Aronson JK. Drug therapy. In: Haslett C, Chilvers ER, Boon NA, Colledge NR, Hunter JAA, eds. Davidson's principles and practice of medicine 19th ed. Edinburgh: Elsevier Science, 2002: 147-63. Acknowledgements S.C. is supported by the Belgian Fonds de la Recherche Scientifique Médicale (FRSM), A.L. by grants-in-aid from Sanofi-Aventis, Wyeth, and Bayer-Schering Pharma. F.V.B. is Maître de Recherches of the Belgian Fonds de la Recherche Scientifique (FNRS – FRS). This work was undertaken without specific commitment to these financing organizations. This poster will be made available for download after the meeting at http://www.facm.ucl.ac.be/posters.htm