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Antimicrobial consumption and impact on resistance

Antimicrobial consumption and impact on resistance. 5th ESCMID School of Clinical Microbiology and Infectious Diseases Santander, Spain 10-16 June, 2006. Dr. Rafael Cantón Servicio de Microbiología. Hospital Universitario Ramón y Cajal

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Antimicrobial consumption and impact on resistance

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  1. Antimicrobial consumption and impact on resistance 5th ESCMID School of Clinical Microbiology and Infectious Diseases Santander, Spain 10-16 June, 2006 Dr. Rafael Cantón Servicio de Microbiología. Hospital Universitario Ramón y Cajal Associated Professor. Facultad de Farmacia. Universidad Complutense Madrid, Spain

  2. Antibiotic resistance • “Antibiotic resistance continues to plague antimicrobial chemotherapy of infectious diseases” Keith. Poole. J Antimicrob Chemother 2005; 56: 20-51 • “Evolution of bacteria towards resistance… …is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable” Patrice Courvalin. Emerg Infect Dis 2005; 11: 1507-6 • “Antibiotic resistance has resulted in a continuous need for new therapeutic alternatives” Carl Erik Nord. Clin Microbiol Infect 2004;10 (Supp 4) • “There is a need to re-invigorate antimicrobial development, which has been downgraded by major pharmaceutical houses” David Livermore. Lancet Infect Dis 2005; 5:450-59

  3. ertapenem tigecyclin daptomicin linezolid telithromicin quinup./dalfop. cefepime ciprofloxacin aztreonam norfloxacin imipenem cefotaxime clavulanic ac. cefuroxime gentamicin cefalotina nalidíxico ac. ampicillin methicilin vancomicin rifampin chlortetracyclin streptomycin pencillin G prontosil Development of anti-infectives The development of anti-infectives …

  4. ertapenem Development of anti-infectives Factors fuelling the development of anti-infectives … • Enhancement of spectrum activity • Avoidance of resistance mechanisms • Improvement of pharmacology (PK/PD)

  5. new resistance mechanisms new resistance mechanisms new antimicrobial agent new resistance mechanisms new antimicrobial agent new resistance mechanisms new antimicrobial agent Antibiotic resistance & development of anti-infectives The action and reaction principle …

  6. Transference of vanA gene from E. faecalis to S. aureus

  7. Antibiotic resistance: the action and reaction response

  8. Drugs developed to counteract resistance mechanisms

  9. Antibiotic resistance Antibiotics Bacteria

  10. Antibiotic resistance How did antibiotic resistance occur? • Genetic events - mutations and resistance gene acquisition • Selection (antibiotic density) - eradication of susceptible populations and dominance of natural resistant (sub)populations - co-selection processes (multiresistance) • Dispersion - spread of resistant isolates (clones) or even resistant genes Lipsitch & Samore. Emerg Infect Dis 2002; 8:347-354 Baquero, Coque, Cantón. ASM News 2003; 69; 547-52 Matlay et al. Emerg Infect Dis 2006; 12:183-190

  11. Resistant bacteria Mutations XX Gene transfer Resistant bacteria Antibiotic resistance: genetic events Susceptible bacteria

  12. Antibiotic resistance: mutational events • A natural resistant population (resistant mutants) is always present (frequency of mutation) in all bacterial populations • The number of resistant mutants increases with the inoculum • Under antibiotic pressure the susceptible subpopulation is inhibited and the resistant mutants can survive and become dominant within the population (selection) susceptible bacteria bacterias sensibles bacterias resistentes resistant bacteria

  13. Antibiotic resistance: acquisition • The acquisition of resistance genes in bacteria depends on: - capacity for sharing ecological niches with other bacteria - association of the resistant genes with gene capture units (plasmids, transposons, integrons, …) - integration capacity of resistant genes (recombination) • Under antibiotic pressure susceptible bacteria are eliminated but not those carrying resistant genes (selection)

  14. mutation well-adapted clones selection spread A A = antibiotic pressure lateral transfer A epidemic & endemic fixation of resistant genes and resistant bacteria in bacterial populations allodemic Dispersion of resistant bacteria

  15. amount of antibiotic per individual per geographic area Levy SB. Antibiotic resistance: an ecological imbalance Ciba Found Symp. 1997;207:1-9 antibiotic use (consumption) Antibiotic resistance • The use of antibiotics fuels antibiotic resistance - emergence (mutation and recombination) - dispersion - maintenance (fitness) selection density

  16. Antibiotic use (consumption) • Do we use a lot of antibiotics? How do we use antibiotics? • Is there any influence of antibiotic use on antimicrobial resistance trends?

  17. Antimicrobial resistance and consumption: the evidence • There is a direct correlation between specific antimicrobial use and antimicrobial resistance (resistant organisms) • - the increase in antimicrobial use increases antibiotic R (but not • - the decrease in antimicrobial use decreases antibiotic R always!) • Higher resistance levels in bacteria belonging to scenarios with high antibiotic density (nosocomial organisms) • Patients with infections due to (multi)resistant organisms have been treated with more antimicrobials • Those areas with higher antibiotic consumption present higher antimicrobial resistance • Prolonged antimicrobial use increases the risk for an infection due to a (multi)resistance organisms

  18. Antimicrobial resistance and consumption: the data • Patient level Antibiotic exposure: prescriptions, patient charts, local/national databases (e.g. pharmacy information system, insurance system) Resistance: patient charts, microbiology laboratory information system • Collective level (aggregated data) Antibiotic consumption: wholesalers, pharmacy purchases, dispensations to wards Resistance: microbiology laboratory information system

  19. Antimicrobial resistance and consumption: the data • Organisms - Infecting organisms (sentinel organisms) - Colonizing organisms - Epidemic clones • Resistance phenotypes • Resistance genes • Antibiotics - packages sold - defined daily dose per 1000 population per day (DDD/1000/day) - defined daily dose per 100 bed-days(DDD/100 bed-days)

  20. Antimicrobial resistance and consumption: the evidence Goossens et al. Lancet 2005; 365: 579-87

  21. Antimicrobial use in the community (Europe) EARS and IMS databases Cars et al. Lancet 2001; 357:1851-1853

  22. Antimicrobial use in the community (Europe) • (excluding over-the-counter sales) Goossens et al. Lancet 2005; 365: 579-87

  23. Antimicrobial use in the community (Europe) • (Seasonal variation) Goossens et al. Lancet 2005; 365: 579-87

  24. Streptococcus pneumoniae Global resistance trends (42 countries, 5 continents) PROTEKT Database (1999-2004) Farrell, Cantón, Hryniewicz. 16th ECCMID, 2006 Farrell, Felmingham. J Antimicrob Chemother 2005; 56: 795-7 Reinert. J Chemother 2004;16 (Suppl 6):35-48

  25. Low Intermediate High S. pneumoniae - penicillin resistance ( I+R ) Germany 4.7/1.3 0.3 Rep. of Ireland 2.6/19.7 3.4 Poland 8.3/9.3 1.9 Czech Rep. 1.2/4.4 0.6 UK 4.8/1.0 1.0 Slovak Rep. 20.4/28.6 0.0 The Netherlands 3.4/0.0 0.0 Hungary 11.3/26.8 1.4 Belgium 5.1/5.1 2.2 Austria 2.5/0.6 0.0 Portugal 3.5/12.9 4.7 France 16.7/47.7 10.2 Spain 13.4/34.9 17.2 Italy9.8/5.6 0.8 Switzerland 14.4/8.7 2.0 Greece 8.3/1.7 7.0 PROTEKT Database (2002-2003) Intermediate / high penicillin resistanceamoxicillin resistance

  26. Antimicrobial use in the community (Europe) • Penicillin I+R S. pneumoniae and antibiotic consumption EARS and IMS databases Pen I+R S. pneumoniae Bronzwaer et al. Emerg Infect Dis 2002; 8:278-282

  27. Antimicrobial use in the community (Europe) • Penicillin I+R S. pneumoniae and antibiotic consumption Goossens et al. Lancet 2005; 365: 579-87

  28. Low Intermediate High S. pneumoniae – erythromycin resistance Rep. of Ireland 17.9 Germany 15.4 Poland 14.5 UK 20.2 Czech Rep. 3.8 Slovak Rep. 34.7 The Netherlands 11.9 Belgium 32.1 Hungary 35.2 Austria 11.0 Portugal 12.9 Spain 33.8 France 60.6 Italy35.6 Switzerland 17.3 Greece 48.6 PROTEKT Database (2002-2003)

  29. Antibiotic consumption and resistance Erythromycin resistance in S. pneumoniae in Spain Macrolide comsumption total comsumption twice a day* three times per day once a day *r=0,886 p<0.01 Granizo et al. J Antimicrob Chemother 2000; 46:767-73

  30. Antibiotic consumption and resistance Escherichia coli from UTI in Europe (14 couuntries) Kahlmeter et al. J Antimicrob Chemother 2003; 52:1005-10

  31. Antibiotic consumption and resistance Escherichia coli from UTI in Europe (14 couuntries) Kahlmeter et al. J Antimicrob Chemother 2003; 52:1005-10

  32. Antimicrobial use in the hospitals • Higher selection density than in the community • Fewer antimicrobials in the formulary than in the community • Lower diversification • Cycling strategies • Circulation of multi-drug resistant clones • Maintenance of resistance genes

  33. Antimicrobial use in the hospitals (Europe) http://www.abdn.ac.uk/arpac/

  34. Antimicrobial use in the hospitals (Europe) http://www.abdn.ac.uk/arpac/

  35. Antimicrobial use in the hospitals (Europe) http://www.abdn.ac.uk/arpac/

  36. Antimicrobial use in the hospitals (Europe) http://www.abdn.ac.uk/arpac/

  37. Antibiotic use and resistance in hospitals as a risk factor Hospital Ramón y Cajal (Madrid, Spain) • Outbreak (11 patients, 97-98) TEM-4 K. pneumoniae clone - case control study at Ramón y Cajal University Hospital Asensio et al. Clin Infect Dis 2000; 30:55-60

  38. Antibiotic use and resistance in the hospital Squeezing the resistance balloon Meyer et al, Ann Intern Med, 1993; Rahal et al, J Am Med Assoc, 1998 Urban et al. MDR, 2000; Rahaal et al. Clin Infect Dis 2002

  39. Antibiotic use and resistance in the hospital MRSA: temporal series Aberdeen, 1996-2000 A) penicillins + β-lac inhibitors B) macrolides, C) 3rd gen. cephalosporins D) fluoroquinolones E) tetracyclines F) aminoglycosides Monnet et al. Emerg Infect Dis 2004; 10:1432-41

  40. Antibiotic use and resistance in the hospital MRSA: temporal series (Aberdeen, 1996-2000) Monnet et al. Emerg Infect Dis 2004; 10:1432-41

  41. Antibiotic use and resistance in the hospital P. aeuginosa and fluoroquinolones (USA, 199-2001) Polk et al. Clin Infect Dis 2004; 39:497-503

  42. Antimicrobial resistance and consumption The expected results • If an antibiotic use causes antibiotic resistance … … the decrease in antibiotic use should produce a decrease in the resistance levels! - macrolide resistance and S. pyogenes Seppälä et al. N Eng J Med 199; 337:441-6

  43. Macrolides and Streptococcus pyogenes (Finland) DDD/1000 inhabitants/year % of resistant isolates Seppälä et al. N Eng J Med 199; 337:441-6 Bergman et al. Clin Infect Dis 2004; 38:1251-6

  44. Antimicrobial resistance and consumption Decrease of 3rd-g ceph. use and decrease of ESBL- K. pneumoniae Lee et al. et al. Infect Control Hosp Epidemiol 2004; 25:832-7

  45. Antimicrobial resistance and consumption The unexpected results • The increase in antibiotic use does not always produce an increment in antibiotic resistance • - fluoroquinolone resistance and S. pneumoniae García-Rey et al. Clin Microbiol Infect 2006; 12 (Suppl 3):55-66 • The decrease in antibiotic use may not produce a decrease in the resistance levels - ESBLs and 3rd gen. cephalosporins Cobo, Cantón, Soler ICAAC, 2003 - sulphonamide resistance and E. coli Enne et al. Lancet 2001; 28: 357:1325-8

  46. Low Intermediate High S. pneumoniae – levofloxacin resistance Germany Poland 0.0 Rep. of Ireland 1.7 UK 1.0 Czech Rep. 0.0 Slovak Rep. 0.0 The Netherlands 0.0 Belgium 0.7 Hungría 0.0 Portugal 1.2 Austria 0.0 France 1.4 Spain 2.1 Italy1.5 Switzerland 0,9 Greece 0.0 PROTEKT Database (2002-2003)

  47. Antimicrobial resistance and consumption S. pneumoniae and fluorquinolones in Spain Ciprofloxacin resistance in S. pneumoniae R >= 2 µg/ml I + R >= 4 µg/ml Total fluorquinolones consumption in Spain Garcia-Rey et al. Clin Microbiol Infect 2006; (Suppl 3): 55-66

  48. Inverse correlation between quinolone consumption and resistance to ciprofloxacin in S. pneumoniae by province in Spain Garcia-Rey et al. Clin Microbiol Infect 2006; (Suppl 3): 55-66

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