Community-Associated Methicillin-Resistant Staphylococcus aureus

Ruth Lynfield, M.D.

Minnesota Department of Health

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 1941 1-2 6 15-20

Methicillin1961 <1 25-30

40-50 (projected)

Emergence of Resistance in S. aureus

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

Staphylococcal Cassette Staphylococcal Cassette Chromosome Chromosome mec mec TypesTypes

Oliveira et al., Lancet ID, 2002

SCCmec type I - Archaic clone

SCCmec type IV - Pediatric clone

orfXRJLJ

mecR1HVR

dcsccrAB4 IS1272

SCCmec type II - NY/Japan clone

SCCmec type IIIA - Brazilian clone

SCCmec type III - Hungarian clone

orfXRJ

pls

LJmecR1

HVRdcs

ccrAB1 IS1272

orfXRJ

pls

LJmecR1 HVR dcs

pUB110ccrAB1 IS1272

SCCmec type IA - Iberian clone

orfXpT181 pI258 Tn554

LJ RJipsccrAB

Tn554ccrAB3 mecImecR1 HVR

pUB110ccrAB2kdp

LJ RJorfX

HVRdcsmecI

mecR1Tn554 mecImecR1 HVR

pI258 Tn554

LJ RJccrAB orfX

Tn554ccrAB3 mecImecR1 HVR

10 Kb

mecA

IS431

LJ - chromosomal left junctionRJ - chromosomal right junction

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

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

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.

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)

Four Pediatric Deaths, CA-MRSA Minnesota and North Dakota, 1997-99

Clonal group A

Clonal group A

Clonal group A (MW2)

Clonal group APFGE

T/S, tet, cip, gent, ery,

clind, vanc

T/S, tet, cip, gent, ery,

clind, vanc

T/S, tet, cip, gent, ery,

clind, vanc

T/S, tet, cip, gent, ery,

clind, vanc

Antimicrobial

susceptibility

Necrotizing pneumonia/

sepsis

Necrotizing pneumonia/

sepsisSepsis

Septic joint, pneumonia/ empyema Syndrome

WhiteWhiteAmerican

IndianAfrican

AmericanRace

MaleFemaleFemaleFemaleGender

12 months13 years16 months7 yearsAge

Case 4Case 3Case 2Case 1

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

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

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 interviewRisk factors (+)

Telephone interview Indeterminate

Community-associated

Minnesota MRSA SurveillanceMinnesota MRSA Surveillance

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

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

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

Age and Culture Sites of CA-MRSA Cases, MN, 2000

CA-MRSA

(n = 131)

HA-MRSA

(n = 937) p-value

Age (median) 23 years 68 years <0.05

Culture site No. (%) No. (%)

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

CA and HA-MRSA PFGE Subtype Patterns, Minnesota, 2000

Healthcare-associated (clonal group H)

Community-associated (clonal group A)

PFGE Relatedness of CA and HA-MRSA Isolates to Reference Strain, MN, 2000

Number of Bands Different from MRSA Reference Strain

Nu

mb

er o

f Is

ola

tes

0

10

20

30

40

50

60

70

80

90

100

110

120

130

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

15%35%50%70%90%100%

Clonal Group A

Community-associated (n=106)

Healthcare-associated (n=211)

Relatedness to Reference Strain

(MW2)

30%

70%

Beta-lactamOther

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

Susceptibility of CA and HA-MRSA Isolates by Antimicrobial

Agent, MN, 2000

0%

20%

40%

60%

80%

100%

CIP CLI ERY GENT TMP/SMX TET RIF VAN

Antimicrobial

% S

us

ce

pti

ble

CA-MRSA (n=106)

HA-MRSA (n=211)

p<0.001 p<0.001 p<0.001

p=0.001

79

16

83

21

44

9

94

80

9590 92 92

96 94100100

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%, x2 trend=15.3, p<0.001

– Clindamycin: 90% to 80%, x2 trend=4.1, p<0.05

– Erythromycin: 70% to 39%, x2 trend=14.8, p<0.001

erm msrA

Macrolides (e.g., erythromycin) Lincosamides (e.g., clindamycin) Streptogramin B

Methylase

MacrolidesLincosamidesStreptogramin B

Macrolides

Efflux pump

Macrolide Resistance Mechanisms in S. aureus

Ribosome

Proteinsynthesis