1. Community-Associated Methicillin-Resistant Staphylococcus aureus Ruth Lynfield, M.D. Minnesota Department of Health

2. Chambers, EID 7:178-182, 2001 Time required for prevalence rates of resistance to reach 25% in hospitals Drug Year Drug Introduced Years to Report of Resistance Years Until 25% Rate in Hospitals Years Until 25% Rate in Community Penicillin 19411-2615-20 Methicillin 1961<125-30 40-50 (projected) Emergence of Resistance in S. aureus

3. Methicillin Resistance in S. aureus mecA confers resistance to penicillins and cephalosporins mecA is part of the staphylococcal cassette chromosome mec (SCCmec), a mobile genetic element (21-67 kb in size) that may also contain genes that confer resistance to non-beta-lactam antimicrobials SCCmec has been classified into 5 main types based on polymorphisms in its conserved genes

4. Staphylococcal Cassette Chromosome mec Types Oliveira et al., Lancet ID, 2002 SCCmec type I - Archaic clone SCCmec type IV - Pediatric clone orfX RJ LJ  mecR1 HVR dcs ccrAB4 IS1272 SCCmec type II - NY/Japan clone SCCmec type IIIA - Brazilian clone SCCmec type III - Hungarian clone orfX RJ pls LJ  mecR1 HVR dcs ccrAB1 IS1272 orfX RJ pls LJ  mecR1  HVR dcs pUB110 ccrAB1 IS1272 SCCmec type IA - Iberian clone orfX pT181 pI258Tn554 LJ RJ ips  ccrAB  Tn554 ccrAB3 mecI mecR1 HVR pUB110 ccrAB2 kdp LJ RJ orfX HVR dcs mecI mecR1 Tn554 mecI mecR1 HVR pI258 Tn554 LJ RJ  ccrAB orfX  Tn554 ccrAB3 mecI mecR1 HVR 10 Kb mecA IS431 LJ - chromosomal left junction RJ - chromosomal right junction

5. Background: Healthcare-associated (HA) MRSA Leading cause of nosocomial pneumonia, surgical wound infection, and bloodstream infection Established risk factors include – Current or recent hospitalization – Residence in long-term care facilities – Dialysis Typical resistance profile – Resistant to many antimicrobials in addition to beta-lactams

6. Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) Reports began in 1980s of MRSA occurring in the community in patients without established risk factors –Younger patients –Indigenous peoples and racial minorities –Skin infections common –Outbreaks: Injection drug users Players of close-contact sports Prison/jail inmates Group Homes (developmentally disabled) Men who have sex with men

7. CA-MRSA Isolates typically susceptible to most antimicrobial classes other than beta-lactams Isolates differ by PFGE from HA-MRSA Isolates have different SCCmec types from HA- MRSA Isolates have been identified that are highly related to MSSA except for SCCmec element* Although most infections associated with CA-MRSA have been skin and soft tissue, some infections have been very severe including necrotizing pneumonia and other life-threatening infections *Fey. Antimic Agents Chem. 2003; 47: 196-203. Mongkolrattanothai. Clin Infec Dis. 2003: 37: 1050-8.

8. CA-MRSA in Minnesota 1997- Minnesota Department of Health (MDH) received reports of MRSA infections in young, previously healthy individuals Reported four pediatric deaths due to MRSA infection (MMWR, August 20, 1999)

9. Four Pediatric Deaths, CA-MRSA Minnesota and North Dakota, 1997-99 Clonal group A Clonal group A (MW2) Clonal group A PFGE T/S, tet, cip, gent, ery, clind, vanc Antimicrobial susceptibility Necrotizing pneumonia/ sepsis Sepsis Septic joint, pneumonia/ empyema Syndrome White American Indian African American Race MaleFemale Gender 12 months13 years16 months7 years Age Case 4Case 3Case 2Case 1

10. CA-MRSA in Minnesota Minnesota Communicable Disease Reporting rule amended in 1999: –All cases of serious illness or death due to CA- MRSA reportable –Sentinel sites were required to report all cases of MRSA

11. Minnesota Definition of CA-MRSA Used in Prospective Surveillance Positive culture for MRSA obtained within 48 hours of admission (if hospitalized) No history of hospitalization in past year No history of surgery in past year No history of long-term care in past year No history of dialysis in past year No permanent indwelling catheters or percutaneous medical devices No prior history of MRSA infection or colonization

12. MRSA patients Community-onset, no risk factors documented in medical record Healthcare- associated Hospital- acquired Community- onset with Risk factors Risk factors (-) Medical record review Risk factors (+) Risk factors (-) No interview Risk factors (+) Telephone interviewIndeterminate Community-associated Minnesota MRSA Surveillance

13. Prospective MRSA Surveillance: Methods, MN, 2000 12 sentinel hospitals selected to represent different geographic regions (6 metro area, 6 greater MN) reported all cases MRSA Patient information was collected and MRSA isolates were obtained for all cases (HA and CA- MRSA) Presumptive CA-MRSA patients were interviewed to verify that they met the CA-MRSA case definition

14. Minnesota MRSA Surveillance Methods: Laboratory MRSA isolates from sentinel sites sent to MDH Laboratory All CA-MRSA isolates tested 25% of HA-MRSA isolates from each site randomly selected for testing Isolates confirmed as S. aureus (tube coagulase) Antimicrobial susceptibility testing (including oxacillin) by broth micro-dilution PFGE subtyping 26 CA and 26 HA-MRSA isolates characterized for toxins

15. Minnesota MRSA Surveillance Results: 2000 4,612 patients with S. aureus identified at 10 sentinel sites in 2000 (total number S. aureus unavailable at two sites) 1100 (25%) were MRSA (range 10-49%) –937 (85%) were HA-MRSA –131 (12%) were CA-MRSA (range 4-50%) after patient interview* –32 (3%) not enough information to classify *13% of presumptive CA-MRSA cases were reclassified as HA-MRSA after interview

16. Age and Culture Sites of CA-MRSA Cases, MN, 2000 CA-MRSA (n = 131) HA-MRSA (n = 937)p-value Age (median)23 years68 years <0.05 Culture siteNo. (%) Skin 98 (75)343 (36)<0.05 Respiratory 8 ( 6)205 (22)<0.05 Blood 5 ( 4) 83 ( 9) NS Urine 1 ( 1)185 (20)<0.05 Other 10 (7)110 (12)NS

17. CA and HA-MRSA PFGE Subtype Patterns, Minnesota, 2000 Healthcare- associated (clonal group H) Community- associated (clonal group A)

18. PFGE Relatedness of CA and HA-MRSA Isolates to Reference Strain, MN, 2000 Number of Bands Different from MRSA Reference Strain Number of Isolates 0 10 20 30 40 50 60 70 80 90 100 110 120 130 0123456789101112131415 15%35%50%70%90%100% Clonal Group A Community-associated (n=106) Healthcare-associated (n=211) Relatedness to Reference Strain (MW2)

19. Initial Empiric Treatment of CA-MRSA Infections, MN, 2000 (n = 92)

20. Susceptibility of CA and HA- MRSA Isolates by Antimicrobial Agent, MN, 2000 p<0.001 p=0.001 79 16 83 21 44 9 94 80 95 90 92 96 94 100

21. Trends in Antimicrobial Susceptibility of CA-MRSA Isolates, MN, 1996-2001 No significant change in susceptibilities to tetracycline, TMP-SMX, gentamicin, or rifampin Susceptibility decreased over time: –Ciprofloxacin: 92% to 77%, x 2 trend=15.3, p<0.001 –Clindamycin: 90% to 80%, x 2 trend=4.1, p<0.05 –Erythromycin: 70% to 39%, x 2 trend=14.8, p<0.001

22. erm msrA Macrolides (e.g., erythromycin) Lincosamides (e.g., clindamycin) Streptogramin B Methylase Macrolides Lincosamides Streptogramin B Macrolides Efflux pump Macrolide Resistance Mechanisms in S. aureus Ribosome Protein synthesis