lecture 3 mrsa methicillin resistant s aureus
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Lecture 3 MRSA Methicillin resistant S. aureus. Tues – 1/15/2008. S. aureus – the pathogen. Microbiology – Gr+ cocci with many virulent factors (toxins and enzymes) Frequent nosocomial- and community-acquired pathogen Mode of transmission – contact Clinical manifestations:

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s aureus the pathogen
S. aureus – the pathogen
  • Microbiology – Gr+ cocci with many virulent factors (toxins and enzymes)
  • Frequent nosocomial- and community-acquired pathogen
  • Mode of transmission – contact
  • Clinical manifestations:
    • Skin and soft tissue infections
    • Pneumonia
    • Osteomyelitis / Arthritis
    • Bacteremia / Sepsis
    • Endocarditis
    • Toxin-mediated disease: TSS, Food poisining
s aureus epidemiology
S. aureus - Epidemiology
  • Epidemiologic niche:
    • Nasal carriage (anterior nares)
    • GI tract (rectal)
    • Perineal
    • Throat
  • Nasal carriage – 30% of adults
    • 20% Persistant carriers
    • 60% Transient carriers
    • 20% Never carriers
  • Nosocomial transmission – transient hand carriage
risk groups with high carriage rates
Risk groups with high carriage rates
  • Diabetes Mellitus
  • Dialysis patients
  • HIV
  • Chronic skin diseases
  • IV Drug abusers
  • Health care workers (?)
antimicrobial resistance of s aureus history

1st MRSA isolate ‘61

Antimicrobial resistance ofS. aureus - history

SA genome sequence, Kuroda ‘01

CA-MRSA sequence, Baba ‘02

Cloning of mecA

Matsuhashi ‘86

SCCmec sequenced Ito ‘99

MRSA single clone theory Lacey & Grinsted, ‘73

1960

1970

1980

1990

2000

2003

Epidemic spread of MRSA, Europe, India, Australia, USA

2nd wave of epidemic MRSA (MDR), USA, Australia, Ireland

Increasing reports - CA-MRSA

Worldwide dissemination

CA-MRSA in Australia

Introduction of Methicillin – ‘59

1st VISA, Japan ‘97

1st VRSA, USA ‘02

mrsa mechanism i
MRSA – mechanism – I
  • Horizontally transferred DNA element -SCCmec.
  • Site specific recombination.
  • mecA gene encodes PBP2a.
  • PBP2a = 78 KDa PBP - capable of cell wall synthesis.
  • PBP2a has low affinity for all -lactams.
mrsa mechanism of resistance
MRSA - mechanism of resistance
  • Modifying enzymes
  • Degrading enzymes
  • Target Change
  • Efflux pumps
genetic mechanisms horizontal vs vertical transmission

Mutation

Plasmid

transfer

Transformation

Genetic Mechanisms Horizontal vs. Vertical transmission

Large genetic mobile elements (cassettes)

mrsa mechanism ii
MRSA – mechanism-II
  • mecAis part of a large, mobile, genetic element –Staphylococcal cassette chromosome mec (SCCmec)
scc mec cassette

Mec complex (class B)

ccr complex (type2)

orfX

mecA

IS431mec

IS 1272

mecR1

SCCmec cassette
  • A unique class of mobile genetic element (21-67kb)
  • Resembles a pathogenicity island, but with no virulence genes.
  • Ccr complex: ccrA & ccrB encode recombinase A & B enable SCCmec to integrate into the chromosome in correct orientation.
  • Mec complex: encodes β-lactam resistance and its inducible regulation + transposons + integrated copies of plasmids that carry various resistance genes (non-b-lactam)
slide11

ccr complex(type 1)

mec complex (class B)

Mec complex (class B)

Type IV SCCmec (24kb)

ccr complex (type2)

orfX

mecA

IS431mec

IS 1272

mecR1

orfX

TypeI SCCmec (34kb)

mecR1

R-I

ccrA1

ccrB1

mecA

IS1272

IS431mec

mec complex (class A)

TypeII SCCmec (53kb)

ccr complex(type 2)

orfX

pUB110

Tn554

ccrB2

ccrA2

IS431mec

mecI

mecR1

IS431mec

mecA

Type III SCCmec (67kb)

mec complex (class A)

ccr complex

ccr complex (type3)

orfX

pT181

mer

Tn554

ccrA3

mecI

mecA

Tn554

mecR1

ccrB3

IS431mec

IS431

IS431

origin of scc mec and the mec gene
Origin of SCCmec and the mec gene
  • Single clonal origin theory
  • Hiramatsu et al. 1996: Clonal diversity: different strains developed independently
  • Origin of mecA gene - horizontal transfer from:
    • SCN
    • S. scuiri
    • Enterococcus hiriae
ca mrsa 1996 2008 changing definitions

X

X

CA-MRSA: 1996-2008Changing definitions
  • No contact with health-care facilities in prior 6-12 m.
    • Maybe more than 1y.
  • Resistant only to b-lactams, but not to other classes.
    • Resistant to quinolones, macrolides and others
  • SCCmec IV
    • and V … and VI…
risk factors for mrsa
CA-MRSA

Skin, soft tissue infection

???

HA-MRSA

Previous contact with health care system

Longer hospitalization

ICU admission or invasive procedures

Ab Rx.

Risk factors for MRSA
clonal spread of mrsa
Clonal spread of MRSA
  • Spread is mainly clonal. Only few clones are the cause of most infections.
  • Major cause for clonal spread: lapses in IC
  • Yet - role of Ab pressure:…
how did ca mrsa evolve
How did CA-MRSA evolve?
  • Recent evolution of CA-MRSA from common MSSA?
  • “Hospital escape” of unsuccessful HA-MRSA
sccmec type iv mobile mec

Mec complex (class B)

ccr complex (type2)

orfX

  • Small Size

mecA

IS431mec

24kb

IS 1272

mecR1

SCCmec Type IV = “Mobile mec”
  • Novel SCCmec type
  • Smaller – more efficient horizontal transfer
resistance and virulence us300
Resistance and virulenceUS300
  • Major CA-MRSA clones in US: US300 & US400
  • US300 – the most common single clone of CA-MRSA
  • SCCmec IV
  • Resistant to ciprofloxacin (mutation in gyrA)
  • Many strains acquired MDR by plasmides (tetK, erm )
  • Several mobile genetic elements
  • Several Toxins
resistance and virulence panton valentine leukocidine
Resistance and virulencePanton Valentine leukocidine
  • A pore forming cytotoxin
  • Strains containing pvl genes were associated with severe SST – infections
  • Direct role of pvl – still controversial
acme arc gene cluster complete genome sequence of us300 diep et al lancet 2006
ACME – arc gene clusterComplete genome sequence of US300 /Diep et al. Lancet 2006
  • Arginine Catabolic Mobile Element: virulence/strain survival factor
  • Different from native arc gene carried by all S. aureus
  • Highly similar to ACME from S. epidermidis
  • Arginine deiminase pathway
    • Inhibits the nitric oxide production
    • Allows survival in low ph, anaerobic conditions
  • Enhances fitness: enhances potential to grow and survive within a host
how do we control mrsa
How do we control MRSA?
  • Hospitals:
    • Infection control!!!
    • Antibiotic control??
  • Community:
    • ?????
treatment of mrsa
CA-MRSA

Clindamycin ??

(high ery-R suggests inducible clinda-R)

TMP-SMX?

Rifampin?

Vancomycin

HA-MRSA

Vancomycin

Linezolid

Daptomycin

Treatment of MRSA
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