Gram-Positives: Focus on MRSA From Bench to Bedside

Andrew E. Simor, MD, FRCPC, FACPSunnybrook 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• Pfizer Canada• Sepracor Pharmaceuticals

Resistant Gram-Positive Pathogens

MRSAVRE

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 JCI 2009 adapted from Klevens JAMA 2007

Infectious disease

No. of deaths Year

MRSA 19,000 20051

AIDS 14,561 20072

TB 644 20063

Viral hepatitis

5793 20021

1.Boucher CID 2008; 46(Suppl 5):S344-92. http://www.cdc.gov/hiv/topics/surveillance/basic.htm#ddaids3 http://www.cdc.gov/TB/publications/factsheets/statistics/TBTrends.htm

MRSA in Canada, 1995-2009

0

2

4

6

8

10

12

MR

SA

per

1,0

00 a

dm

issi

ons

Overall Infection Colonization

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%)

0

10

20

30

40

Skin/Softtissue

SSI Resp Blood Urine Other

%

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

Location MRSA as a % of S. aureus

bacteremias

U.K.* 36

Ontario† 18

Quebec§ 21

Canada (CANWARD)** 24**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

PFGE type 1995-1999

2004-2007

2008- 2009

CMRSA-2(USA100)

14% 58% 49%

CMRSA-10(USA300)

<1% 17% 32%

Simor, Infect Control Hosp Epidemiol 2010; Simor, IDSA 2010

Provincial Distribution of MRSA Strains (2008-2010)

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

90.0%

BC n=219 AB n=399 SK/MB n=150 ON n=458 QC n=129 ATL n=267

Province

Per

cent

MR

SA

Isol

ates

CMRSA1

CMRSA2

CMRSA3/6

CMRSA4

CMRSA5

CMRSA7

CMRSA8

CMRSA9

CMRSA10

Others (non-CMRSAs)

Canadian Nosocomial Infection Surveillance Program

CA-MRSA & HA-MRSA MRSA infections by age-groups 2008 surveillance

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

<10 [10-19] [20-29] [30-39] [40-49] [50-59] [60-69] [70-79] >80

Patients' age (years)

Perc

en

tag

e (

%)

CA-MRSA

HA-MRSA

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

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

MRSA USA300 Virulence Factors

David, Clin Microbiol Rev 2010

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)

Gillet, Lancet 2002

PVL Gene and Survival

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)

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)

Impact of MRSA Infections

Infection Mortality (%)

MRSA Bacteremia* 20-35

MRSA Pneumonia† 25-60

* 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

MIC (µg/ml) Interpretation

2 Susceptible

4-8 Intermediate

16 Resistant

CLSI

Risk factors OR (95% CI) P value

Vancomycin MIC ≥ 2 µg/ml

6.3 (1.2-33.1) 0.03

Retained medical device

10.4 (1.1-104.6) 0.05

MRSA infection at ≥ 2 sites

10.2 (1.7-61.0) 0.01

Predictors of Persistent MRSA Bacteremia (multivariate analysis)

Yoon, J Antimicrob Chemother 2010

Vancomycin MICs and Treatment Outcome in MRSA Bacteremia

0

10

20

30

40

50

60

70

<0.5 1.0 - 2.0

Vancomycin MIC (mg/ml)1

Cli

nic

al

su

cc

es

s (

%)

0

10

20

30

40

50

60

70

0.5 1 2

Vancomycin MIC (mg/ml)2

Clin

ical

su

cces

s (%

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

p=0.01

p=0.003

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)

van Hal, Antimicrob Agents Chemother 2011

Impact of hVISA: A Meta-Analysis

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

Liu, Clin Infect Dis 2011

MRSA Treatment Guidelines:

Evidence-Based?

Can we do a better job of preventing MRSA

infection?

MRSA Infection Control Strategies

• contact precautions• screening• decolonization

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 transmissionAldeyab, 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

decolonization

environmental cleaning

outbreak controlVerhoef, 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