MRSA
description
Transcript of MRSA
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MRSA
Mechanisms of resistance Lab detection Epidemiology Treatment Infection control – What works?
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MRSA
mec determinant >30 kb transposon
mec gene approx 2.5 kb on transposon with regulatory genes and insertion sequences for other antibiotic resistance
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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)
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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
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mecI mecR1 mecA
repressor penicilin-binding structural genesproteins signal transducer mecAPBP2a
(senses presence ofsubstrate to turn offmecI, and therebyactivate mecA)
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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
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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
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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)
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MRSA Identification
detection of mecA gene (PCR)
detection of PBP2a(latex aggultination)
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Prevalence of MRSA 2006
Grundmann, Lancet 2006
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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
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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;
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MRSA in Canada, 1995-2008
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1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
MR
SA
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1,0
00 a
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issi
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Overall Infection Colonization
Canadian Nosocomial Infection Surveillance Program
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MRSA Infections (32%)
0
10
20
30
40
Skin/Softtissue
SSI Resp Blood Urine Other
%
Canadian Nosocomial Infection Surveillance Program
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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
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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
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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
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Molecular Epidemiology of CA-MRSA
Otter, Lancet ID, 2010
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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
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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
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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
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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
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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)
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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
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CA-MRSAVirulence
Enhanced virulence may be related to: global gene regulators (agr, sarA)
may upregulate expression of virulence genes
acquisition of additional virulence genes
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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)
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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
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Gillet, Lancet 2002
PVL and Survival, S. aureus Pneumonia
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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)
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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
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Standard Treatment of MRSA Infections
source control; remove infected catheters, devices
vancomycin other agents: clindamycin,
TMP-SMX, tetracyclines, rifampin, fusidic acid
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Vancomycin
• less rapidly bactericidal
• less effective in clinical trials (Kim, Antimicrob Agents Chemother 2008)
• more toxic
• may induce resistance
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Vancomycin SusceptibilityBreakpoints in Staphylococci
MIC (µg/ml) Interpretation
2 Susceptible
4-8 Intermediate
16 Resistant
CLSI
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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
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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)
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Vancomycin MICs and Treatment Outcome in MRSA Bacteremia
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<0.5 1.0 - 2.0
Vancomycin MIC (mg/ml)1
Cli
nic
al
su
cc
es
s (
%)
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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
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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
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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)
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Canadian MRSA and Vancomycin
Adam, Antimicrob Agents Chemother 2010
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Newer Antimicrobial Agents for the Treatment of MRSA
• Linezolid• Daptomycin• Tigecycline• Dalbavancin, Telavancin, Oritavancin• Ceftobiprole, Ceftaroline• Iclaprim (a diaminopyramidine)
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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
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Active Surveillance to Control Spread of MRSA
• Active surveillance – finding asymptomatic carriers
• Contact precautions for patients identified as colonized/infected
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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)
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Huang, Clin Infect Dis 2006
Healthcare-Associated MRSA Bacteremia Rates
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Controlling MRSA with Broad-Based Infection Control Interventions
Edmond, Am J Infect Control 2008
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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
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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)
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MRSA Bacteremia - England
Pearson, J Antimicrob Chemother 2009