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

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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


  • I have received grants, or served as a consultant on Advisory Boards for:

    • Astellas Pharma

    • BD GeneOhm

    • Janssen-Ortho

    • Pfizer Canada

    • Sepracor Pharmaceuticals

Resistant Gram-Positive Pathogens



C. difficile

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

DeLeo and Chambers JCI2009

adapted from Klevens JAMA2007

1.Boucher CID2008; 46(Suppl 5):S344-9



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

  • CANWARD: 10 hospitals, 2008

  • MRSA accounted for 5% of all clinical isolates (5% blood, 6% respiratory, 12% wound isolates)

Zhanel, Antimicrob Agents Chemother 2010

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

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

Simor, Infect Control Hosp Epidemiol 2010;

Simor, IDSA 2010

Canadian Nosocomial Infection Surveillance Program

Canadian Nosocomial Infection Surveillance Program

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

  • 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

  • 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

  • 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

  • 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?

  • 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


  • 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


  • 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

  • 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)


  • 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

* 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?

  • 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 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

  • 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

How does treatment affect outcome?

Vancomycin SusceptibilityBreakpoints in Staphylococci


Predictors of Persistent MRSA

Bacteremia (multivariate analysis)

Yoon, J Antimicrob Chemother 2010

Vancomycin MICs and Treatment Outcome in MRSA Bacteremia



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

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?

  • 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

  • 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)

Liu, Clin Infect Dis 2011

MRSA Treatment



Liu, Clin Infect Dis 2011

Can we do a better job of preventing MRSA infection?

MRSA Infection Control Strategies

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

  • 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

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

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

  • 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

The End

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