MRSA

1
MRSA

• Mechanisms of resistance
• Lab detection
• Epidemiology
• Treatment
• Infection control What works?

2
MRSA

• mec determinant gt30 kb transposon
• mec gene approx 2.5 kb on transposon with
  regulatory genes and insertion sequences for
  other antibiotic resistance

3
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 popn 10-2-10-8)

4
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

5

• mecI mecR1 mecA
• repressor penicilin-binding structural genes
• proteins signal transducer mecA?PBP2a
• (senses presence of
• substrate to turn off
• mecI, and thereby
• activate mecA)

6
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

7
SCCmec
multiclonal model of evolution of MRSA
introduction of SCCmec into severalS. aureus
clones
SCCmec type locus size
I ccrAB1 34 kb
II ccrAB2 52 kb
III ccrAB3 66 kb
IV (4 subtypes) ccrAB4 lt30 kb
V ccrAB5
8
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 hrsox MIC ? 4 µg/ml)

9
MRSA Identification

• detection of mecA gene (PCR)
• detection of PBP2a(latex aggultination)

10
Prevalence of MRSA 2006
Grundmann, Lancet 2006
11
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
12
Antibiotic Resistant Pathogensin ICU Patients
(NNIS)

• 29

VRE
MRSA

• 59

MRSE
89

6
ESBL-E. coli
?

• 21

ESBL-Klebsiella
Quinolone-R P.aeruginosa

• 30

resistance
? 2003
1998-2002
13
MRSA in Canada, 1995-2008
Canadian Nosocomial Infection Surveillance Program
14
MRSA Infections (32)

Canadian Nosocomial Infection Surveillance Program
15
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
16
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

17
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
18
Molecular Epidemiology of CA-MRSA
Otter, Lancet ID, 2010
19
MRSA in CanadaEvolving Molecular Epidemiology
PFGE type 1995-1999 2004-2007 2008
CMRSA-2 (USA100) 14 58 49
CMRSA-10 (USA300) lt1 17 32
Simor, Infect Control Hosp Epidemiol 2010
Simor, IDSA 2010
20
Community-Associated MRSA

• no established health care-associated risk
  factors
• MRSA identified gt48 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
21
Canadian Nosocomial Infection Surveillance
Program
22
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

23
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)

24
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

25
CA-MRSAVirulence

• Enhanced virulence may be related to
• global gene regulators (agr, sarA) may upregulate
  expression of virulence genes
• acquisition of additional virulence genes

26
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)

27
Panton-Valentine Leukocidin

• Panton-Valentine Leukocidin (PVL)
• cytolytic, forms pores in human leukocytes
• lukSPV-lukFPV phage mediated
• common in CA-MRSA (up to gt 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
28
PVL and Survival, S. aureus Pneumonia
Gillet, Lancet 2002
29
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)

30
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
31
Standard Treatment of MRSA
Infections

• source control remove infected catheters,
  devices
• vancomycin
• other agents clindamycin, TMP-SMX,
  tetracyclines, rifampin, fusidic acid

32
Vancomycin

• less rapidly bactericidal
• less effective in clinical trials (Kim,
  Antimicrob Agents Chemother 2008)
• more toxic
• may induce resistance

33
Vancomycin SusceptibilityBreakpoints in
Staphylococci
MIC (µg/ml) Interpretation
?2 Susceptible
4-8 Intermediate
?16 Resistant
CLSI
34
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
35
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)

36
Vancomycin MICs and Treatment Outcome in MRSA
Bacteremia
p0.003
p0.01
1 Sakoulas, J Clin Microbiol 20042 Moise-Broder,
Clin Infect Dis 2004
37
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 medical device 10.4 (1.1-104.6) 0.05
MRSA infection at 2 sites 10.2 (1.7-61.0) 0.01
Yoon, J Antimicrob Chemother 2010
38
What about hVISA?

• hVISA (heteroresistant) MIC
  susceptible (lt 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)

39
Canadian MRSA and Vancomycin
Adam, Antimicrob Agents Chemother 2010
40
Newer Antimicrobial Agents for the
Treatment of MRSA

• Linezolid
• Daptomycin
• Tigecycline
• Dalbavancin, Telavancin, Oritavancin
• Ceftobiprole, Ceftaroline
• Iclaprim (a diaminopyramidine)

41
Contact Precautions Work to Decrease MRSA
Transmission
Source Source
Isolated Unisolated
Transmissions 5 10
Patient-days 558 72
Rates 0.009 0.140
RR15.6, 95 CI5.3-45.6, plt0.0001 RR15.6, 95 CI5.3-45.6, plt0.0001 RR15.6, 95 CI5.3-45.6, plt0.0001
Jernigan, Am J Epidemiol 1996
42
Active Surveillance to Control Spread of MRSA

• Active surveillance finding asymptomatic
  carriers
• Contact precautions for patients identified as
  colonized/infected

43
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)

44
Healthcare-Associated MRSA
Bacteremia Rates
Huang, Clin Infect Dis 2006
45
Controlling MRSA with Broad-Based Infection
Control Interventions
Edmond, Am J Infect Control 2008
46
MRSAThe 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
47
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)
48
MRSA Bacteremia - England
Pearson, J Antimicrob Chemother 2009