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Gram-Positives: Focus on MRSA From Bench to Bedside

Gram-Positives: Focus on MRSA From Bench to Bedside . Andrew E. Simor, MD, FRCPC, FACP Sunnybrook Health Sciences Centre University of Toronto. Disclosures. I have received grants, or served as a consultant on Advisory Boards for: Astellas Pharma BD GeneOhm Janssen-Ortho

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Gram-Positives: Focus on MRSA From Bench to Bedside

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  1. Gram-Positives: Focus on MRSA From Bench to Bedside Andrew E. Simor, MD, FRCPC, FACP Sunnybrook Health Sciences Centre University of Toronto

  2. Disclosures • I have received grants, or served as a consultant on Advisory Boards for: • Astellas Pharma • BD GeneOhm • Janssen-Ortho • Pfizer Canada • Sepracor Pharmaceuticals

  3. Resistant Gram-Positive Pathogens MRSA VRE C. difficile

  4. Staphylococcus aureus • S. aureus is most common cause of healthcare-associated infections • MRSA is the major antibiotic-resistant organism in hospitals; CA-MRSA increasing

  5. Annual Deaths in the U.S. for Selected Infectious Diseases DeLeo and Chambers JCI2009 adapted from Klevens JAMA2007 1.Boucher CID2008; 46(Suppl 5):S344-9 2. http://www.cdc.gov/hiv/topics/surveillance/basic.htm#ddaids 3 http://www.cdc.gov/TB/publications/factsheets/statistics/TBTrends.htm

  6. MRSA in Canada, 1995-2009 Simor, Infect Control Hosp Epidemiol 2010; Canadian Nosocomial Infection Surveillance Program

  7. MRSA in Canadian Hospitals Simor, Infect Control Hosp Epidemiol 2010

  8. MRSA Infections, 2008-09 (30%) % Canadian Nosocomial Infection Surveillance Program

  9. MRSA in Canadian Hospitals • CANWARD: 10 hospitals, 2008 • MRSA accounted for 5% of all clinical isolates (5% blood, 6% respiratory, 12% wound isolates) Zhanel, Antimicrob Agents Chemother 2010

  10. MRSABloodstream Infections *Jeyaratnam, BMJ 2008; †QMPLS, 2009; §Institut National de Santé Publique du Québec, 2008; **Adam, Diagn Microbiol Infect Dis 2011

  11. MRSA in Canadian Hospitals, 2010 There were: approx 36,000 new MRSA patients 11,000 new MRSA infections 2,200 MRSA-related deaths $250 million excess costs attributable to MRSA

  12. Molecular Epidemiology of CA-MRSA Otter, Lancet ID, 2010

  13. MRSA in Canada:Evolving Molecular Epidemiology Simor, Infect Control Hosp Epidemiol 2010; Simor, IDSA 2010

  14. Canadian Nosocomial Infection Surveillance Program

  15. Canadian Nosocomial Infection Surveillance Program

  16. CA-MRSA Epidemiology • neonates, children • homeless, incarcerated, IVDU • MSM, HIV-infected • military personnel • athletes (contact sports) • native aboriginals • household contacts • veterinarians, livestock handlers David, Clin Microbiol Rev 2010

  17. Livestock-Associated MRSA • SCCmec IV, PVL-neg • Pigs: ST398 (not typeable by PFGE SmaI)(Voss, Emerg Infect Dis 2005; Khanna, Vet Microbiol 2008; Golding, Emerg Infect Dis 2010) • Horses: CMRSA-5 (USA500; t007) (Weese, Emerg Infect Dis 2005)

  18. MRSA in Domestic Pets • reported in cats, dogs, guinea pigs, parrots • a variety of clones, often HA-MRSA (Weese, Vet Microbiol 2006; David, Clin Microbiol Rev 2010)

  19. CA-MRSA as a Cause of Healthcare-Associated Infections • USA400 post-partum infections, NY mastitis, cellulitis, abscesses(Saiman, CID 2003) • USA300 prosthetic joint infections, SSIs (Kourbatova, Am J Infect Control 2005; Patel, J Clin Microbiol 2007) • USA300 accounted for 28% healthcare-associated bacteremias, 20% nosocomomial MRSA BSIs, Atlanta, GA(Seybold, CID 2006) • USA300 transmission in a Canadian Burn unit(McGuire, SHEA 2007)

  20. CA-MRSA in Canadian Hospitals • predominantly SSTI, in younger adults, Western Canada • 60% community-associated; 40% healthcare-associated • 94% PVL-positive (predominantly CMRSA-10; SCCmec type IV) Simor, Infect Control Hosp Epidemiol 2010

  21. CA-MRSA: Enhanced Virulence? • associated with severe and recurrent SSTI, often in individuals without predisposing risk factors • associated with necrotizing pneumonia • appears to be easily transmitted in hospitals, households, and the community

  22. CA-MRSAVirulence • USA 300/400 more virulent than other strains of S. aureus/MRSA in a mouse model of bacteremia • more resistant to killing by human PMNs Voyich, J Immunol 2005; Li, PNAS 2009

  23. MRSA USA300 Virulence Factors David, Clin Microbiol Rev 2010

  24. CA-MRSAVirulence • Panton-Valentine Leukocidin (PVL) • -hemolysin (increased expression in CA-MRSA; -hemolysin antibody protective in mouse model) (Wardenburg, Nature Med 2007) • Argenine catabolic mobile element (ACME;unique to CA-MRSA, S. epidermidis; may help strain evade host response and facilitate colonization) (Goering, J Clin Microbiol 2007)

  25. PVL Gene and Survival Gillet, Lancet 2002

  26. PVL Gene and Virulence • using isogenic PVL knockout mutants in murine models (subcut abscess, pneumonia) has given conflicting results (Voyich, J Infect Dis 2006; Labandeira-Rey, Science 2007) • PVL does appear to contribute to virulence in a rabbit bacteremia model (An Diep, PLoS ONE 2008)

  27. MRSAImpact • attributable mortality and morbidity(Whitby, Med J Austr 2001; Cosgrove, Clin Infect Dis 2003) • prolonged hospital length of stay(Engemann, Clin Infect Dis 2003; Cosgrove, Infect Control Hosp Epidemiol 2005) • excess/attributable costs, $14,360(Kim, Infect Control Hosp Epidemiol 2001)

  28. Impact of MRSA Infections * Cosgrove, Clin Infect Dis 2003; Melzer, Clin Infect Dis 2003; Wyllie, BMJ 2006 † Combes, AJRCCM 2004; DeRyke, Chest 2005; Zahar, Clin Infect Dis 2005

  29. Why does antibiotic resistance affect outcome? • Host factors • Organism virulence • Delay in instituting effective therapy (or vancomycin less effective) Bradley, Clin Infect Dis 2002; Paterson, Clin Infect Dis 2004; Kim, Antimicrob Agents Chemother 2008

  30. MRSA Bacteremia in Canadian Hospitals, 2008-09 • MRSA bacteremia rates:0.50 per 1,000 admissions 0.61 per 10,000 patient-days • source of bacteremia:skin, soft tissue, SSI - 36% 1y bacteremia, CA-BSI - 24% pneumonia - 16% • healthcare-associated, 72% community-associated, 28%(CMRSA-2, 49%; CMRSA-10, 32%) Simor, IDSA 2010

  31. MRSA Bacteremia in Canadian Hospitals, 2008 • 30-day all-cause mortality: 23% • variables associated with mortality: age > 65 yrs (OR 2.3, 95% CI 1.3-3.9) pneumonia (OR 4.0, 95% CI 2.0-7.8) HA-MRSA (OR 2.3, 95% CI 1.1-4.8) • mortality not associated with PFGE type, PVL gene, or reduced susceptibility to vancomycin (3 isolates with MIC = 2) Simor, IDSA 2010

  32. MRSA Infection How does treatment affect outcome?

  33. Vancomycin SusceptibilityBreakpoints in Staphylococci CLSI

  34. Predictors of Persistent MRSA Bacteremia (multivariate analysis) Yoon, J Antimicrob Chemother 2010

  35. Vancomycin MICs and Treatment Outcome in MRSA Bacteremia p=0.003 p=0.01 1 Sakoulas, J Clin Microbiol 20042 Moise-Broder, Clin Infect Dis 2004

  36. MRSA PneumoniaOutcome • 158 cases MRSA pneumonia (HAP/VAP) • 28-day mortality: 32% • mortality increased with vancomycin MIC > 1.5 µg/ml Haque, Chest 2010

  37. What about hVISA? • hVISA (heteroresistant): MIC susceptible (< 4 µg/ml), but with a resistant sub-population; detected by PAP-AUC • preliminary step towards development of VISA (Hiramatsu, Lancet ID 2001) • may be associated with treatment failure (Sakoulas, Antimicrob Agents Chemother 2005)

  38. Impact of hVISA: A Meta-Analysis van Hal, Antimicrob Agents Chemother 2011

  39. Canadian MRSA and Vancomycin Adam, Antimicrob Agents Chemother 2010

  40. Vancomycin and Treatment Failure • higher vancomycin MICs associated with worse outcome • thus: recommendations to use higher vancomycin doses (target trough: 15-20 µg/ml) (Liu, Clin Infect Dis 2011) • but, higher troughs not associated with better outcome; associated with increased nephrotoxicity (Hidayat, Arch Intern Med 2006)

  41. Liu, Clin Infect Dis 2011

  42. MRSA Treatment Guidelines: Evidence-Based? Liu, Clin Infect Dis 2011

  43. Can we do a better job of preventing MRSA infection?

  44. MRSA Infection Control Strategies contact precautions screening decolonization

  45. Evidence for Effectiveness of Active Surveillance + Contact Precautions ecological studies (Verhoef, EJCMID 1999; Tiemersma, Emerg Infect Dis 2004) observational/quasi-experimental studies (Jernigan, Am J Epidemiol 1996; Chaix, JAMA 1999; Huang, Clin Infect Dis 2006; Robicsek, Ann Intern Med 2008) mathematical models (Bootsma, PNAS 2006)

  46. PCR vs. Chromogenic Media • prospective, cross-over study, 2 hospital wards, UK • median time to report MRSA: 47 hrs vs. 21 hrs (culture vs. PCR; p<0.001) • no reduction in MRSA transmission Aldeyab, J Hosp Infect 2009

  47. MRSA Decolonization decolonization to prevent staphylococcal SSI (Bode, N Engl J Med 2010) observational studies with mupirocin or other agents as part of infection control measures (Hill, J Antimicrob Chemother 1998; Strausbaugh, ICHE 1992; Sandri, ICHE 2006; Ridenour, ICHE 2007; Bowler, ICHE 2010) interrupted time-series analysis in 2 UK ICUs: chlorhexidine gluconate baths reduced MRSA transmission, but emergence of strains with reduced susceptibility to CHG (Batra, Clin Infect Dis 2010)

  48. MRSA:The Dutch Experience national “search and destroy policy” screening patients, staff strict isolation decolonization environmental cleaning outbreak control Verhoef, EJCMID 1999; van Trijp, Infect Control Hosp Epidemiol 2007

  49. MRSA Bacteremia - England Pearson, J Antimicrob Chemother 2009

  50. MRSA in Canada - 2011 • Infectious morbidity of HA-MRSA and CA-MRSA continues to increase • Need to better understand variables associated with treatment failure • Need to better understand and implement effective strategies for MRSA infection prevention

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