1. MRSA Mechanisms of resistance Lab detection Epidemiology Treatment
Infection control – What works?

2. MRSA mec determinant >30 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 pop’n: )

4. 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

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 ( 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 several S. aureus clones
SCCmec type
locus
size I
ccrAB1
34 kb II
ccrAB2
52 kb
III
ccrAB3
66 kb
IV (4 subtypes)
ccrAB4
<30 kb V
ccrAB5

8. MRSA Lab Detection
disk diffusion: cefoxitin disk preferable to oxacillin because greater expression of mecA
oxacillin agar screen (MH agar with 4% NaCI, µg/ml ox, 35ºC, 24 hrs)
broth microdilution (MH broth with 2% NaCI, ºC, 24 hrs;ox 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. aureus Nasal Colonization, 2003-04
MRSA
Prevalence (%)
28.6
1.5
Estimated no. (in millions)
78.9
4.1
National Health and Nutrition Examination Survey (NHANES) Gorwitz, J Infect Dis 2008

12. Antibiotic Resistant Pathogens in ICU Patients (NNIS)
VRE
29%
MRSA
59%
MRSE
89%
ESBL-E. coli 6% 
ESBL-Klebsiella
21%
Quinolone-R P.aeruginosa
30%
% resistance: ;
 2003

13. MRSA in Canada,
Overall
Infection
Colonization
Canadian Nosocomial Infection Surveillance Program

14. MRSA Infections (32%) %
Canadian Nosocomial Infection Surveillance Program

15. MRSA Bloodstream 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 approx 32,000 new MRSA patients
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 Canada Acquisition
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 Canada: Evolving Molecular Epidemiology
PFGE type
2008
CMRSA-2
(USA100)
14%
58%
49%
CMRSA-10
(USA300)
<1%
17%
32%
Simor, Infect Control Hosp Epidemiol 2010;
Simor, IDSA 2010

20. 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

21. Canadian Nosocomial Infection Surveillance Program

22. 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

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-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

25. 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

26. 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)

27. 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

28. PVL and Survival, S. aureus Pneumonia
Gillet, Lancet 2002

29. 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, (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 Susceptibility Breakpoints 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
p=0.003
p=0.01
1 Sakoulas, J Clin Microbiol 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 ( )
0.03
Retained medical device
10.4 ( )
0.05
MRSA infection at ≥ 2 sites
10.2 ( )
0.01
Yoon, J Antimicrob Chemother 2010

38. 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)

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
Isolated
Unisolated
Transmissions 5 10
Patient-days
558 72
Rates
0.009
0.140
RR=15.6, 95% CI= , p<0.0001
In another NICU active surveillance was used to control an outbreak of MRSA – 16 neonates were involved and 4 became infected. Transmission was documented in each case and it was found that neonates in isolation were 16 fold less likely to serve as a source of spread.
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. 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

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