MRSA





Mechanisms of resistance
Lab detection
Epidemiology
Treatment
Infection control – What works?
MRSA

mec determinant >30 kb
transposon

mec gene approx 2.5 kb on
transposon with regulatory genes
and insertion sequences for other
antibiotic resistance
MRSA

mecA encodes a unique PBP
(PBP2’ or PBP2a) with low
affinity for ß-lactams, and able to
fulfill functions of other PBPs

cross-resistance to all ß-lactams

heterogeneous resistance with
variable expression of resistance
(proportion of pop’n: 10-2-10-8)
MRSA

regulatory genes:
mecI - inhibits mecA
mecR1 – inducer of mecA

most MRSA have deletions or
point mutations in mecI and mecR1
promoter regions, resulting in
constitutive expression of mecA
mecI
mecR1
repressor penicilin-binding
proteins
signal transducer
(senses presence of
substrate to turn off
mecI, and thereby
activate mecA)
mecA
structural genes
mecAPBP2a
Staphylococcal Cassette
Chromosome (SCC)mec
SCCmec=
a mobile genetic element (22-100 kb)
located on chromosome; contains mecA
and insertion sites (for multidrug
resistance determinants)
SCCmec=
mec gene complex (mecI, mecR1, mecA)
+ ccr gene complex (ccrA, ccrB)
(responsible for mobility and insertion
of the gene complex)
+ other transposons, plasmids
SCCmec
multiclonal model of evolution of MRSA:
introduction of SCCmec into several
S. aureus clones
SCCmec type
locus
size
I
ccrAB1
34 kb
II
ccrAB2
52 kb
III
ccrAB3
66 kb
IV (4 subtypes)
V
ccrAB4
ccrAB5
<30 kb
MRSA
Lab Detection



disk diffusion:
cefoxitin disk preferable to oxacillin
because greater expression of mecA
oxacillin agar screen
(MH agar with 4% NaCI,
6 µg/ml ox, 35ºC, 24 hrs)
broth microdilution
(MH broth with 2% NaCI,
35ºC, 24 hrs;ox MIC  4 µg/ml)
MRSA Identification
 detection
 detection
of mecA gene (PCR)
of PBP2a
(latex aggultination)
Prevalence of MRSA 2006
Grundmann, Lancet 2006
Prevalence of S. aureus
Nasal Colonization, 2003-04
S. aureus
MRSA
Prevalence (%)
28.6
1.5
Estimated no.
(in millions)
78.9
4.1
National Health and Nutrition Examination Survey
(NHANES) 2001-2004. Gorwitz, J Infect Dis 2008
Antibiotic Resistant Pathogens
in ICU Patients (NNIS)
 29%
VRE
MRSA
 59%
MRSE
89%
ESBL-E. coli


6%
 21%
ESBL-Klebsiella
Quinolone-R
P.aeruginosa

0
10
20
30%
30
% resistance:
40
50
60
1998-2002;
70
80
 2003
90
MRSA in Canada, 1995-2008
Overall
Infection
Colonization
MRSA per 1,000 admissions
12
10
8
6
4
2
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Canadian Nosocomial Infection Surveillance Program
MRSA Infections (32%)
40
30
20
%
10
0
Skin/Soft
tissue
SSI
Resp
Blood
Urine
Other
Canadian Nosocomial Infection Surveillance Program
MRSA
Bloodstream Infections
Location
MRSA as a % of
S. aureus bacteremias
U.K.*
36
Ontario†
Quebec§
18
24
BMJ 2008; † QMPLS, 2009;
§ Institut National de Santé Publique du Québec, 2008
* Jeyaratnam,
MRSA in Canada, 2008
There were:
approx 32,000 new MRSA patients
13,000 new MRSA infections
2,400 MRSA-related deaths
at least $250 million excess costs
attributable to MRSA
MRSA in Canada
Acquisition
Acquisition
1995-2002
2003-2007
2008
Healthcareassociated
92.8
79.5
67.1
Communityassociated
7.2
20.5
32.9
Canadian Nosocomial Infection Surveillance Program
Molecular Epidemiology of CA-MRSA
Otter, Lancet ID, 2010
MRSA in Canada:
Evolving Molecular Epidemiology
PFGE type
CMRSA-2
(USA100)
CMRSA-10
(USA300)
19951999
14%
20042007
58%
2008
<1%
17%
32%
Simor, Infect Control Hosp Epidemiol 2010;
Simor, IDSA 2010
49%
Community-Associated MRSA

no established health care-associated risk factors:

MRSA identified >48 h after hospital admission

history of hospitalization, surgery, or dialysis
within 1 yr of MRSA culture

residence in a LTCF within 1 yr of MRSA culture

indwelling catheter or device (eg. Foley catheter,
tracheostomy, gastrostomy) at time of culture

prior known MRSA
Naimi, JAMA 2003
Fridkin, NEJM 2005
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
Patient Profile
often younger
 IVDU, MSM
 incarcerated, homeless
 sports teams
 native aboriginals

Groom, JAMA 2001; Pan, CID 2003;
Naimi, JAMA 2003; Begier, CID 2004;
Kazakov, NEJM 2005
Emergence of CA-MRSA as a Cause
of Healthcare-Associated Infections

USA400 post-partum infections, NY
(mastitis, cellulitis, abscesses) (Saiman, CID 2003)

USA300 prosthetic joint infections,
Atlanta, GA (Kourbatova, Am J Infect Control 2005)

USA300 accounted for 28% healthcareassociated bacteremias, 20% nosocomomial
MRSA BSIs, Atlanta, GA (Seybold, CID 2006)

USA300 common cause of SSI, University of
Alabama (Patel, J Clin Microbiol 2007)
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
CA-MRSA
Virulence
Enhanced virulence may be related to:
 global gene regulators (agr, sarA)
may upregulate expression of
virulence genes
 acquisition of additional virulence
genes
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)
Panton-Valentine Leukocidin






Panton-Valentine Leukocidin (PVL)
cytolytic, forms pores in human
leukocytes
lukSPV-lukFPV: phage mediated
common in CA-MRSA (up to > 95%)
rare in HA-MRSA (0-1%), MSSA (5%)
associated with necrotizing pneumonia
Dufour, Clin Infect Dis 2002;
Diep, PLoS One 2008;
Li, PNAS 2009
PVL and Survival, S. aureus Pneumonia
Gillet, Lancet 2002
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)
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
Standard Treatment
of MRSA Infections
source control; remove infected
catheters, devices
 vancomycin
 other agents: clindamycin,
TMP-SMX, tetracyclines,
rifampin, fusidic acid

Vancomycin
•
less rapidly bactericidal
•
less effective in clinical trials
(Kim, Antimicrob Agents Chemother 2008)
•
more toxic
•
may induce resistance
Vancomycin Susceptibility
Breakpoints in Staphylococci
MIC (µg/ml)
Interpretation
2
Susceptible
4-8
Intermediate
16
Resistant
CLSI
Vancomycin-Resistant S. aureus



11 cases in US (2010); all MRSA, not
epidemiologically linked (MI, PA, NY)
vancomycin MICs: 16 (µg/ml); vanA+
associated with prior vancomycin
exposure and VRE colonization
Sievert, Clin Infect Dis 2008
VISA: Vancomycin-Intermediate

abnormal, thickened bacterial cell
wall, not normally cross-linked, and
with altered PBPs (no van genes)

strains appear to be clonally related
(agr II group)
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
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
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)

Canadian MRSA and Vancomycin
Adam, Antimicrob Agents Chemother 2010
Newer Antimicrobial Agents
for the Treatment of MRSA
•
•
•
•
•
•
Linezolid
Daptomycin
Tigecycline
Dalbavancin, Telavancin, Oritavancin
Ceftobiprole, Ceftaroline
Iclaprim (a diaminopyramidine)
Contact Precautions Work to
Decrease MRSA Transmission
Source
Isolated
Unisolated
Transmissions
5
10
Patient-days
558
72
Rates
0.009
0.140
RR=15.6, 95% CI=5.3-45.6, p<0.0001
Jernigan, Am J Epidemiol 1996
Active Surveillance to
Control Spread of MRSA
•
Active surveillance –
finding asymptomatic
carriers
•
Contact precautions for
patients identified as
colonized/infected
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)
Healthcare-Associated
MRSA Bacteremia Rates
Huang, Clin Infect Dis 2006
Controlling MRSA with Broad-Based
Infection Control Interventions
Edmond, Am J Infect Control 2008
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 in France –
A Success Story
2005
HA-MRSA Infection Rate
per 1,000 patient-days
0.55
2008
0.44
Year
Coignard, 5th Decennial International Conference on
Healthcare-Associated Infections 2010 (abstr. 410)
MRSA Bacteremia - England
Pearson, J Antimicrob Chemother 2009