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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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Lecture 3 MRSA Methicillin resistant S. aureus

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Lecture 3 mrsa methicillin resistant s aureus l.jpg

Lecture 3MRSAMethicillin resistant S. aureus

Tues – 1/15/2008


S aureus the pathogen l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

MRSA - mechanism of resistance

  • Modifying enzymes

  • Degrading enzymes

  • Target Change

  • Efflux pumps


Genetic mechanisms horizontal vs vertical transmission l.jpg

Mutation

Plasmid

transfer

Transformation

Genetic Mechanisms Horizontal vs. Vertical transmission

Large genetic mobile elements (cassettes)


Mrsa mechanism ii l.jpg

MRSA – mechanism-II

  • mecAis part of a large, mobile, genetic element –Staphylococcal cassette chromosome mec (SCCmec)


Scc mec cassette l.jpg

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 l.jpg

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


Genetic organization of sccmec type i vi de lencastre et al 2007 l.jpg

Genetic organization of SCCmec type I-VIde Lencastre et al. 2007


Origin of scc mec and the mec gene l.jpg

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


Prevalence of mrsa in usa cumulative data 1998 2005 shorr cid 2007 l.jpg

Prevalence of MRSA in USA(cumulative data 1998-2005)/ Shorr CID 2007


Mrsa among s aureus isolates in europe l.jpg

MRSA among S. aureus isolates in Europe


Mrsa a nosocomial pathogen until 1996 l.jpg

MRSA – a nosocomial pathogenUntil ~1996


Ca mrsa an emerging infection l.jpg

JAMA 1998

CID 2004

EID 2003

CA-MRSA – an emerging infection


Ca mrsa 1996 2008 changing definitions l.jpg

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…


Community acquired mrsa ca mrsa weber cid 2005 l.jpg

Community acquired MRSA (CA-MRSA)/ Weber. CID 2005


Risk factors for mrsa l.jpg

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 l.jpg

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:…


Antibiotic consumption and mrsa an ecologic study eid 2004 l.jpg

Antibiotic consumption and MRSA, an ecologic study (EID 2004)


Changing epidemiology of mrsa crum et al am j med 2006 l.jpg

Changing Epidemiology of MRSA / Crum et al. Am. J. Med 2006


Ca mrsa infections in texas 2002 2004 kaplan et al cid 2005 l.jpg

CA-MRSA infections in Texas (2002-2004) /Kaplan et al. CID 2005


Mrsa in the netherlands l.jpg

MRSA in the Netherlands


How did ca mrsa evolve l.jpg

How did CA-MRSA evolve?

  • Recent evolution of CA-MRSA from common MSSA?

  • “Hospital escape” of unsuccessful HA-MRSA


Sccmec type iv mobile mec l.jpg

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 l.jpg

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 l.jpg

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 l.jpg

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


Acme arginine catabolic mobile element arc gene cluster l.jpg

ACME (Arginine Catabolic Mobile Element) – arc gene cluster


Acme positive isolates in uk ellington et al jac 2008 l.jpg

ST8 (US300)

ACME positive isolates in UK / Ellington et al. JAC 2008

ST8

ACME neg

ST97


How do we control mrsa l.jpg

How do we control MRSA?

  • Hospitals:

    • Infection control!!!

    • Antibiotic control??

  • Community:

    • ?????


Treatment of mrsa l.jpg

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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