An Old Enemy with New Tricks Methicillin resistant Staphylococcus aureus

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An Old Enemy with New TricksMethicillin
resistant Staphylococcus aureus

• Wisconsin State Laboratory of Hygiene
  Teleconference
• September 2006

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Topics

• History
• Characteristics of staph
• Healthcare associated (HA) MRSA
• Community associated (CA) MRSA

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History

• 1928
• 
  Serendipitous discovery of penicillin

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Penicillium notatum
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History

• 1950s PRSA
• 1959 methicillin introduced
• 1961 MRSA appears in UK
• 1968 outbreaks of resistant staph in US
  nurseries

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Characteristics

• Gram positive cocci

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Characteristics

• Reservoirs
• Skin
• Nares
• Axilla
• Pharynx
• Perineum
• Contaminated surfaces, items

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Characteristics

• Causes minor infections such as pimples, boils,
  other skin conditions
• Impetigo
• Major infections include bacteremia, cellulitis,
  pneumonia, osteomylitis
• Scalded skin syndrome in newborns

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Characteristics

• Food poisoning
• Toxic shock syndrome
• Major cause of hospital acquired infections

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Characteristics

• Surface proteins promote biofilm
• Membrane-damaging toxins invasiveness
• Alpha hemolysin
• Beta toxin
• Leukocidin
• Staphylokinase

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Characteristics

• Polysaccharide capsule avoidance of host
  defenses
• Superantigens
• Enterotoxins food poisoning
• toxic shock syndrome toxin (TSST-1)
• Exfoliatin toxin (ET) scalded skin syndrome

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MRSA

• Acquisition of antibiotic resistance due to
  horizontal gene transfer
• MecA gene plasmid/transposons
• Staphylococcal chromosome cassette mec (SCCmec)

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HA MRSA

• Why focus on MRSA?
• Increased morbidity, mortality, cost
• More prevalent than other resistant organisms
• Threat of vancomycin resistance (VISA, VRSA)
• New community strains

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Antibiotic Resistant Pathogensin ICU Patients
(NNIS)

• 29

VRE

• 59

MRSA
89
MRSE
?6
ESBL-E. coli

• 21

ESBL-Klebsiella
Quinolone-R P.aeruginosa

• 30

Resistance
2003

- NNIS, AJIC 2004
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HA MRSA

• MRSA is spread by direct and indirect contact.
• Both colonized and infected persons are sources
  of transmission.
• Colonized persons are not always identified.

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HA MRSA

• Most common way HA MRSA is spread in health
  care facilities is from patient to patient via
  the hands of health care workers.

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HA MRSA

• MRSA colonization leads to infection
• Admission nares cultures on patients in five
  units
• 30/758 (3.96) colonized on admission
• 19 colonized on admission and 25 colonized
  during hospital stay developed MRSA infection
  compared to 1.5 with MSSA colonization and 2
  with no colonization

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HA MRSA

• Conclusion Patients colonized with MRSA were 9
  times more likely to develop infection than those
  colonized with MSSA and were 12 times more likely
  to develop infection than those not colonized.

Davis et al CID 200439776-782
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Reservoir for the Spread of Antibiotic Resistant
Pathogens
clinical infections
colonized (asymptomatic) patients
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Active Surveillancefor HA MRSA

• Screen high risk patients with culture of
  nares and any active infection sites at time of
  admission
• OR
• Place all high risk patients in contact
  precautions upon admission

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Active Surveillancefor HA MRSA

• Patients likely to have MRSA on admission
• History of health care contact
• 75 years old
• Indwelling devices
• Underlying illness
• Previous history of MRSA
• History of antibiotics in past 30 days
• Other categories defined by facility

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Active Surveillancefor HA MRSA

• Culture and isolate on admission
• ?
• Remove from isolation if negative
• ?
• Periodic re-culture (i.e. 5-7 days)

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Active Surveillancefor HA MRSA

• Culture on admission
• ?
• Isolate if positive
• ?
• Periodic re-culture (i.e. 5-7 days)

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CA MRSA

• Genetically distinct from HA-MRSA
• Emerged in 1990s
• Infections occur in persons with no history of
  health care, nursing home residency, dialysis,
  indwelling devices, antibiotic use

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Comparison of HA-MRSA and CA-MRSA
SCC Staphylococcal cassette chromosome PVL
Panton Valentine leukocidin
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Epidemiology of CA-MRSA

• Populations with high rates of cases
• Native Americans
• Pacific Islanders
• Alaskan Natives
• Children under 2 years of age
• Inmates of correctional facilities

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Epidemiology of CA-MRSA

• Prevalence colonized
• Outbreaks have occurred in
• Prisons
• Sports teams
• Military recruits
• MSM
• IV drug users

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Epidemiology of CA-MRSA

• Risk factors for community transmission
• Crowding
• Close contact
• Compromised skin
• Contaminated surfaces, items
• Cleanliness (lack of)

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Epidemiology of CA-MRSA

• Healthcare associated transmission
• Postpartum women at Columbia University Hospital
• Post-op infections in orthopedic patients at
  Grady Memorial, Atlanta
• Newborn nurseries in Chicago and Los Angeles

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Wisconsin Prevalence
MRSA Outpatient Clinical Isolates 2004
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EMERGEncy ID Net Study

• Bacterial isolates from purulent SST infections
  in 11 US emergency departments during August 2004
• S. aureus was isolated from 320/422 (76) of
  patients with SST infections
• 59 were MRSA
• 97 were USA300 strain
• NEJM 2006355666-74

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EMERGEncy ID Net Study

• SCCmec type IV and PVL toxin gene detected in 98
  of MRSA isolates
• Among MRSA isolates
• 95 susceptible to clindamycin
• 6 susceptible to erythromycin
• 60 susceptible to fluoroquinolones
• 100 susceptible to rifampin and TMP/SMX
• 92 susceptible to tetracycline

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EMERGEncy ID Net Study

• Antibiotic therapy was not concordant with
  results of susceptibility testing in 100 of 175
  patients who received antibiotics (57)
• Conclusions
• MRSA most common identifiable cause of SST
  infections
• When antibiotics indicated, clinicians should
  consider obtaining cultures and modifying empiric
  therapy to cover MRSA

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Management of CA-MRSA

• Place persons with spider bite lesions in
  contact isolation
• Culture when possible
• Incision and drainage of abcesses, boils, pimples
  is essential and often the only treatment
  necessary

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Management of CA-MRSA

• Localized infections TMP/SMX, clindamycin
• Some erythromycin resistant strains have
  inducible resistance to clindamycin D-test used
  to detect
• Serious, systemic infections vancomycin,
  linezolid

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Prevention of Transmission in Community Settings

• Hygiene
• Keep skin intact

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New Treatments

• Linezolid (Zyvox)
• Can be given orally
• Skin infections/nosocomial pneumonia
• Daptomycin (Cubicin)
• Skin/skin structure infections
• Administered IV
• Bactericidal

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New Treatments

• Lysostaphin
• Enzyme that attacks cell wall
• Phase I/II trials show nasal eradication
• StaphVAX
• Polysaccharide conjugate against most prevalent
  nosocomial staph strains
• Failed phase III trials

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MRSA

• Link to Guidelines for ARO and CA MRSA
• http//dhfs.wisconsin.gov/communicable/
• Communicable/HlthProvider.htm

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• At the dawn of a new millennium, humanity is
  faced with another crisis. Formerly curable
  diseases...are now arrayed in the increasingly
  impenetrable armor of antimicrobial resistance.
• --Director-General, World Health Organization
• 2000

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Gwen Borlaug, CIC, MPHDivision of Public
Health1 West Wilson Street Room 318Madison, WI
53701608-267-7711borlagm_at_dhfs.state.wi.us
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Those Smart, Nasty Staph

• 1941 penicillin introduced
• 3 years later----penicillinase-producing S.
  aureus
• 1960 methicillin (penicillinase stable)
  introduced
• MRSA isolated in 1961
• 1958 vancomycin introduced
• VISA 1996
• VRSA 2002
• 1999 quinupristin-dalfopristin introduced in USA
• Rare resistant strains found during clinical
  trials
• Additional resistant strains being reported

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Nasty Staph (Cont)

• 2000 linezolid introduced in USA
• 2001resistant S. aureus isolated
• 2003 daptomycin introduced in USA
• Several resistant S. aureus isolated

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Methicillin-resistant Staph

• MRSA, ORSA, MRSE, MR-CoNS
• mecA gene
• Codes for a supplemental penicillin-binding
  protein, PBP2a
• Homogeneous expression
• Easily detected with standard methods
• Heterogeneous expression
• More difficult to detect

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Penicillinase-Stable Penicillins

• Oxacillin----represents the group
• More stable than others
• Oxacillin results used to predict results of
  other antimicrobials in the group
• Methicillin
• Nafcillin
• Dicloxacillin
• Cloxacillin
• Flucloxacillin

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Methods of Detection

• Disk diffusion
• Broth dilution MIC
• Agar dilution MIC
• Etest
• Oxacillin agar screen
• Cefoxitin disk diffusion
• PBP 2a detection
• mecA gene detection

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Test Methods

• Must have CLSI references
• M2-A9 Disk Diffusion Standards
• M7-A7 MIC Standards
• M100-S16 Interpretative Tables
• M45 Fastidious and Infrequently Encountered
  Organisms

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Oxacillin Disk for mecA-mediated
Oxacillin-Resistance Staph. species

• Inoculum
• Prepare using direct colony suspension method
• NOT growth method
• Mueller-Hinton Agar
• Incubate at 33-35C for a FULL 24 hours
• Keep temperature below 35C
• Read the oxacillin zone with transmitted light
• Any discernable growth RESISTANCE

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Oxacillin Disk Interpretation

• Disk screening test for prediction of
  mecA-mediated oxacillin resistance
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  Oxacillin (mm)
• R I S
• S. aureus 13
• S. lugdunensis 13
• CoNS 18
• Report MRSA and MR-CoNS resistant to all other
  penicillins, carbapenems, cephems, and
  B-lactam-B-lactamase inhibitors, regardless of in
  vitro test results
• CLSI M100-S16, 2006

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Cefoxitin Disk for mecA-mediated
Oxacillin-Resistance Staph. species

• Cefoxitin current recommendation (CX,30)
• Replaces oxacillin disk to detect mecA-mediated
  resistance
• Cefoxitin easier to read better inducer
• Read with reflected light
• Report results as OXACILLIN, not cefoxitin
  resistant or susceptible

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Testing Cefoxitin to Predict the Presence of mecA

• Disk screening test for prediction of
  mecA-mediated oxacillin resistance
• Cefoxitin
  (mm)
• R S
• S. aureus 20
• S. lugdunensis 20
• CoNS 25
• CLSI M100-S16, 2006

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Performance of Cefoxitin and Oxacillin Disk Tests

• Sensitivity Specificity
• S. aureus
• fox 98 100
• ox 98 99
• CN-S
• fox 99 97
• ox 99 89
• from Swenson, JCM 433818-3823, 2005

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Oxacillin-salt agar Screen for S. aureus

• Medium
• Mueller Hinton Agar 4 NaCl 6 ug/ml Oxacillin
• Inoculum
• Direct Suspension 0.5 McFarland standard
• Use 1 ul loop or swab
• Incubation
• 35C for full 24 hours
• Examine carefully for small colonies (1) or
  light film of growth
• Presence of either interpreted as RESISTANT

NOT TO BE USED FOR CoNS
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MIC Tests for mecA-mediated Resistance in
Staphylococcus species

• Inoculum
• Prepare using direct suspension method
• Test Medium
• Mueller-Hinton Broth/Agar with 2 NaCl
• Incubation
• 35C for FULL 24 hours
• For commercial systems, follow manufacturers
  instructions.

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Oxacillin MIC Interpretation
S I R S. aureus 4 S. lugdunensis
4 CoNS 0.5
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Performance of Cefoxitin and Oxacillin MIC Tests
as Compared to mecA PCR

• Sensitivity Specificity
• S. aureus
• fox 99 99
• ox 98 100
• CN-S
• fox 98 97
• ox 98 91
• from Swenson, JCM 433818-3823, 2005
• Cefoxitin interpretation Susceptible 8 ug/ml, Resistant

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Gold Standards

• Detection of mecA gene by PCR
• Detection of PBP2a

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Screening and Surveillance for MRSA

• Anterior nares
• Culture
• mecA PCR

www.chromagar.com
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Culture for MRSA Screening

• Variety of Selective and differential media
• Mannitol salt agar with oxacillin
• Mannitol salt agar with cefoxitin
• MRSA chromagars
• Several commercial manufacturers
• Enrichment broth in combination with PCR or
  subculture to selective/differential agar

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Comparison of MRSA Screening Agar
Stokes, L. et al. J Clin Microbiol 44637-639,
2006
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Nastier than Nasty----VRSA

• 6 VRSA and 20 VISA in US
• Michigan (4)
• 2 foot ulcers and 2 wounds
• Pennsylvania
• Wound
• New York
• Wound
• VRSA MICs-----32-1024 ug/ml
• Van A resistance

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Algorithm for Testing S. aureus with Vancomycin
(VA)
Acceptable Primary Test Methods Include
MIC method plus VA screen plate1 (BHIA with 6
µg/ml of VA)
Disk diffusion plus VA screen plate2 (BHIA with 6
µg/ml of VA)
VA MIC VA MIC 4 µg/ml AND/OR GROWTH on VA screen plate
VA zone VA zone 15 mm AND GROWTH on VA screen plate
VA zone 15 mm AND NO growth on VA screen plate
Report Probable VSSA3
Possible VISA/VRSA
Possible VISA/VRSA
Report VSSA3
CHECK for purity
Clinical and Laboratory Standards Institute S.
aureus/Vancomycin Breakpoints (M100-S16 Jan.
2006) Susceptible 4-8 µg/ml (VISA) Resistant 16 µg/ml (VRSA)
CONFIRM isolate ID
Algorithm Revised March 31, 2006
RETEST using a validated MIC method4
SAVE ISOLATE
NOTIFY infection control, physician, local health
department and CDC5 of possible VISA/VRSA
SEND to reference laboratory for confirmation
Important Footnotes 1 Laboratories using
automated MIC methods that have not been
validated for VRSA detection should add a
commercial VA agar screen plate (6 µg/ml). 2 Disk
diffusion will not differentiate VISA (MICs 4-8)
from susceptible strains (MICs 0.5-2). VA screen
plate will not reliably detect strains for which
MIC4. 3 If concerned about a result based on a
patients history, send to a reference lab for
MIC testing. 4 Validated methods reference broth
microdilution, agar dilution, Etest (0.5
McFarland inoculum, Mueller-Hinton agar),
MicroScan overnight and Synergies plus BD
Phoenix system. For other automated methods,
check with the manufacturer about FDA-clearance
to detect MICs 4 (i.e., VISA/VRSA). 5 Report to
CDC by email SEARCH_at_cdc.gov
More VISA/VRSA info http//www.cdc.gov/ncidod/dhq
p/ar_visavrsa.html
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