gram positives focus on mrsa from bench to bedside
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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
Gram-Positives: Focus on MRSA From Bench to Bedside

Andrew E. Simor, MD, FRCPC, FACP

Sunnybrook Health Sciences Centre

University of Toronto



  • I have received grants, or served as a consultant on Advisory Boards for:
    • Astellas Pharma
    • BD GeneOhm
    • Janssen-Ortho
    • Pfizer Canada
    • Sepracor Pharmaceuticals
staphylococcus aureus
Staphylococcus aureus
  • S. aureus is most common cause of healthcare-associated infections
  • MRSA is the major antibiotic-resistant organism in hospitals; CA-MRSA increasing
annual deaths in the u s for selected infectious diseases
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



mrsa in canada 1995 2009
MRSA in Canada, 1995-2009

Simor, Infect Control Hosp Epidemiol 2010; Canadian Nosocomial Infection Surveillance Program


MRSA in Canadian Hospitals

Simor, Infect Control Hosp Epidemiol 2010


MRSA Infections, 2008-09 (30%)


Canadian Nosocomial Infection Surveillance Program

mrsa in canadian hospitals
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

mrsa bloodstream infections
MRSABloodstream Infections

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

mrsa in canadian hospitals 2010
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


Molecular Epidemiology of CA-MRSA

Otter, Lancet ID, 2010

mrsa in canada evolving molecular epidemiology
MRSA in Canada:Evolving Molecular Epidemiology

Simor, Infect Control Hosp Epidemiol 2010;

Simor, IDSA 2010

ca mrsa epidemiology
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

livestock associated mrsa
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)
mrsa in domestic pets
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)

ca mrsa as a cause of healthcare associated infections
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)
ca mrsa in canadian hospitals
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

ca mrsa enhanced virulence
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
ca mrsa virulence
  • 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


MRSA USA300 Virulence Factors

David, Clin Microbiol Rev 2010

ca mrsa virulence1
  • 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)

PVL Gene and Survival

Gillet, Lancet 2002

pvl gene and virulence
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)
mrsa impact
  • 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)
impact of mrsa infections
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

why does antibiotic resistance affect outcome
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

mrsa bacteremia in canadian hospitals 2008 09
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

mrsa bacteremia in canadian hospitals 2008
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

mrsa infection
MRSA Infection

How does treatment affect outcome?


Predictors of Persistent MRSA

Bacteremia (multivariate analysis)

Yoon, J Antimicrob Chemother 2010

vancomycin mics and treatment outcome in mrsa bacteremia
Vancomycin MICs and Treatment Outcome in MRSA Bacteremia



1 Sakoulas, J Clin Microbiol 20042 Moise-Broder, Clin Infect Dis 2004

mrsa pneumonia outcome
MRSA PneumoniaOutcome
  • 158 cases MRSA pneumonia (HAP/VAP)
  • 28-day mortality: 32%
  • mortality increased with vancomycin MIC > 1.5 µg/ml

Haque, Chest 2010

what about hvisa
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)

Impact of hVISA: A Meta-Analysis

van Hal, Antimicrob Agents Chemother 2011


Canadian MRSA and Vancomycin

Adam, Antimicrob Agents Chemother 2010

vancomycin and treatment failure
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)

MRSA Treatment



Liu, Clin Infect Dis 2011

mrsa infection control strategies
MRSA Infection Control Strategies

contact precautions



evidence for effectiveness of active surveillance contact precautions
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)

pcr vs chromogenic media
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

mrsa decolonization
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)

mrsa the dutch experience
MRSA:The Dutch Experience

national “search and destroy policy”

screening patients, staff

strict isolation


environmental cleaning

outbreak control

Verhoef, EJCMID 1999; van Trijp, Infect Control Hosp Epidemiol 2007


MRSA Bacteremia - England

Pearson, J Antimicrob Chemother 2009

mrsa in canada 2011
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