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Lecture 3 MRSA Methicillin resistant S. aureus

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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  1. Lecture 3MRSAMethicillin resistant S. aureus Tues – 1/15/2008

  2. 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

  3. 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

  4. Risk groups with high carriage rates • Diabetes Mellitus • Dialysis patients • HIV • Chronic skin diseases • IV Drug abusers • Health care workers (?)

  5. 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

  6. 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.

  7. MRSA - mechanism of resistance • Modifying enzymes • Degrading enzymes • Target Change • Efflux pumps

  8. Mutation Plasmid transfer Transformation Genetic Mechanisms Horizontal vs. Vertical transmission Large genetic mobile elements (cassettes)

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

  10. 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)

  11. 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  

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

  13. 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

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

  15. MRSA among S. aureus isolates in Europe

  16. MRSA – a nosocomial pathogenUntil ~1996

  17. JAMA 1998 CID 2004 EID 2003 CA-MRSA – an emerging infection

  18. 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…

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

  20. 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

  21. 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:…

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

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

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

  25. MRSA in the Netherlands

  26. How did CA-MRSA evolve? • Recent evolution of CA-MRSA from common MSSA? • “Hospital escape” of unsuccessful HA-MRSA

  27. 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

  28. 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

  29. 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

  30. 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

  31. ACME (Arginine Catabolic Mobile Element) – arc gene cluster

  32. ST8 (US300) ACME positive isolates in UK / Ellington et al. JAC 2008 ST8 ACME neg ST97

  33. How do we control MRSA? • Hospitals: • Infection control!!! • Antibiotic control?? • Community: • ?????

  34. 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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