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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 orpoint mutations in mecI and mecR1 promoter regions, resulting in constitutive expression of mecA
mecI mecR1 mecA
repressor penicilin-binding structural genesproteins signal transducer mecAPBP2a
(senses presence ofsubstrate to turn offmecI, and therebyactivate mecA)
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 insertionof the gene complex)+ other transposons, plasmids
SCCmec
SCCmec type locus size
I ccrAB1 34 kb
II ccrAB2 52 kb
III ccrAB3 66 kb
IV (4 subtypes) ccrAB4 <30 kb
V ccrAB5
multiclonal model of evolution of MRSA: introduction of SCCmec into severalS. aureus clones
MRSALab 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 of mecA gene (PCR)
detection of PBP2a(latex aggultination)
Prevalence of MRSA 2006
Grundmann, Lancet 2006
Prevalence of S. aureusNasal 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 Pathogensin ICU Patients (NNIS)
0 10 20 30 40 50 60 70 80 90
29%
59%
89%
6%
21%
30%
VRE
MRSA
MRSE
ESBL-E. coli
ESBL-Klebsiella
Quinolone-R P.aeruginosa
% resistance: 2003 1998-2002;
MRSA in Canada, 1995-2008
0
2
4
6
8
10
12
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
MR
SA
per
1,0
00 a
dm
issi
ons
Overall Infection Colonization
Canadian Nosocomial Infection Surveillance Program
MRSA Infections (32%)
0
10
20
30
40
Skin/Softtissue
SSI Resp Blood Urine Other
%
Canadian Nosocomial Infection Surveillance Program
MRSABloodstream Infections
Location MRSA as a % of S. aureus bacteremias
U.K.* 36
Ontario† 18
Quebec§ 24
* Jeyaratnam, BMJ 2008; † QMPLS, 2009;§ Institut National de Santé Publique du Québec, 2008
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 CanadaAcquisition
Acquisition 1995-2002 2003-2007 2008
Healthcare-associated
92.8 79.5 67.1
Community-associated
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 1995-1999
2004-2007
2008
CMRSA-2(USA100)
14% 58% 49%
CMRSA-10(USA300)
<1% 17% 32%
Simor, Infect Control Hosp Epidemiol 2010; Simor, IDSA 2010
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 2003Fridkin, NEJM 2005
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-MRSAPatient 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% healthcare-associated bacteremias, 20% nosocomomial MRSA BSIs, Atlanta, GA (Seybold, CID 2006)
USA300 common cause of SSI, University of Alabama (Patel, J Clin Microbiol 2007)
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
CA-MRSAVirulence
Enhanced virulence may be related to: global gene regulators (agr, sarA)
may upregulate expression of virulence genes
acquisition of additional virulence genes
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)
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
Gillet, Lancet 2002
PVL and Survival, S. aureus Pneumonia
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)
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 SusceptibilityBreakpoints 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)
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
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
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)
Huang, Clin Infect Dis 2006
Healthcare-Associated MRSA Bacteremia Rates
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 controlVerhoef, EJCMID 1999; van Trijp, Infect Control Hosp Epidemiol 2007
MRSA in France – A Success Story
Year HA-MRSA Infection Rate per 1,000 patient-days
2005 0.55
2008 0.44
Coignard, 5th Decennial International Conference on Healthcare-Associated Infections 2010 (abstr. 410)
MRSA Bacteremia - England
Pearson, J Antimicrob Chemother 2009