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:
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•
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Astellas Pharma
BD GeneOhm
Janssen-Ortho
Pfizer Canada
Sepracor Pharmaceuticals
Resistant Gram-Positive Pathogens
MRSA
VRE
C. difficile
Staphylococcus aureus
•
•
S. aureus is most common
cause of healthcare-associated
infections
MRSA is the major antibioticresistant organism in hospitals;
CA-MRSA increasing
Annual Deaths in the U.S.
for Selected Infectious Diseases
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):S344-9
2. http://www.cdc.gov/hiv/topics/surveillance/basic.htm#ddaids
3 http://www.cdc.gov/TB/publications/factsheets/statistics/TBTrends.htm
DeLeo and Chambers JCI 2009
adapted from Klevens JAMA 2007
MRSA in Canada, 1995-2009
Overall
Infection
Colonization
MRSA per 1,000 admissions
12
10
8
6
4
2
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
0
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%)
40
30
20
%
10
0
Skin/Soft
tissue
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
MRSA
Bloodstream Infections
Location
MRSA as a % of
S. aureus bacteremias
U.K.*
36
Ontario†
Quebec§
18
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
19951999
20042007
20082009
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)
90.0%
80.0%
Percent MRSA Isolates
70.0%
CMRSA1
CMRSA2
60.0%
CMRSA3/6
CMRSA4
50.0%
CMRSA5
CMRSA7
40.0%
CMRSA8
CMRSA9
30.0%
CMRSA10
Others (non-CMRSAs)
20.0%
10.0%
0.0%
BC n=219
AB n=399
SK/MB n=150
ON n=458
QC n=129
ATL n=267
Province
Canadian Nosocomial Infection Surveillance Program
CA-MRSA & HA-MRSA MRSA infections by age-groups
2008 surveillance
25.00%
Percentage (%)
20.00%
15.00%
CA-MRSA
HA-MRSA
10.00%
5.00%
0.00%
<10
[10-19]
[20-29]
[30-39]
[40-49]
[50-59]
[60-69]
[70-79]
>80
Patients' age (years)
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-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
Virulence
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)
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
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
1y bacteremia, CA-BSI
pneumonia

- 36%
- 24%
- 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 Susceptibility
Breakpoints in Staphylococci
MIC (µg/ml)
Interpretation
2
Susceptible
4-8
Intermediate
16
Resistant
CLSI
Predictors of Persistent MRSA
Bacteremia (multivariate analysis)
Risk factors
OR (95% CI)
P value
Vancomycin
MIC ≥ 2 µg/ml
6.3 (1.2-33.1)
0.03
Retained
10.4 (1.1-104.6)
medical device
0.05
MRSA infection
at ≥ 2 sites
0.01
10.2 (1.7-61.0)
Yoon, J Antimicrob Chemother 2010
70
Clinical success (%)
Clinical success (%)
Vancomycin MICs and Treatment
Outcome in MRSA Bacteremia
60
50
40
p=0.01
30
20
10
0
<0.5
1.0 - 2.0
Vancomycin MIC (mg/ml)1
1
Sakoulas, J Clin Microbiol 2004
2 Moise-Broder, Clin Infect Dis 2004
70
60
p=0.003
50
40
30
20
10
0
0.5
1
2
Vancomycin MIC (mg/ml)2
MRSA Pneumonia
Outcome
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
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•
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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
Guidelines:
Evidence-Based?
Liu, Clin Infect Dis 2011
Can we do a better job
of preventing MRSA
infection?
MRSA Infection Control Strategies
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contact precautions
screening
decolonization
Evidence for Effectiveness of Active
Surveillance + Contact Precautions
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ecological studies (Verhoef, EJCMID 1999;
Tiemersma, Emerg Infect Dis 2004)
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observational/quasi-experimental
studies (Jernigan, Am J Epidemiol 1996; Chaix,
JAMA 1999; Huang, Clin Infect Dis 2006; Robicsek,
Ann Intern Med 2008)
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mathematical models (Bootsma, PNAS 2006)
PCR vs. Chromogenic Media
prospective, crossover 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
decolonization
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
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Infectious morbidity of HA-MRSA
and CA-MRSA continues to increase
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Need to better understand variables
associated with treatment failure
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Need to better understand and
implement effective strategies for
MRSA infection prevention
The End