MRSA l l Mechanisms of resistance l l Lab detection l l Epidemiology l l Treatment l l Infection...

MRSA

Mechanisms of resistance Lab detection Epidemiology Treatment Infection control – What works?

MRSA

mec determinant >30 kb transposon

mec gene approx 2.5 kb on transposon with regulatory genes and insertion sequences for other antibiotic resistance

MRSA

mecA encodes a unique PBP (PBP2’ or PBP2a) with low affinity for ß-lactams, and able to fulfill functions of other PBPs

cross-resistance to all ß-lactams

heterogeneous resistance with variable expression of resistance (proportion of pop’n: 10-2-10-8)

MRSA regulatory genes:

mecI - inhibits mecA mecR1 – inducer of mecA

most MRSA have deletions orpoint mutations in mecI and mecR1 promoter regions, resulting in constitutive expression of mecA

mecI mecR1 mecA

repressor penicilin-binding structural genesproteins signal transducer mecAPBP2a

(senses presence ofsubstrate to turn offmecI, and therebyactivate mecA)

Staphylococcal Cassette Chromosome (SCC)mec

SCCmec= a mobile genetic element (22-100 kb)located on chromosome; contains mecA

and insertion sites (for multidrug resistance determinants)

SCCmec= mec gene complex (mecI, mecR1, mecA)+ ccr gene complex (ccrA, ccrB)(responsible for mobility and insertionof the gene complex)+ other transposons, plasmids

SCCmec

SCCmec type locus size

I ccrAB1 34 kb

II ccrAB2 52 kb

III ccrAB3 66 kb

IV (4 subtypes) ccrAB4 <30 kb

V ccrAB5

multiclonal model of evolution of MRSA: introduction of SCCmec into severalS. aureus clones

MRSALab Detection

disk diffusion: cefoxitin disk preferable to oxacillin because greater expression of mecA

oxacillin agar screen (MH agar with 4% NaCI, 6 µg/ml ox, 35ºC, 24 hrs)

broth microdilution (MH broth with 2% NaCI, 35ºC, 24 hrs;ox MIC 4 µg/ml)

MRSA Identification

detection of mecA gene (PCR)

detection of PBP2a(latex aggultination)

Prevalence of MRSA 2006

Grundmann, Lancet 2006

Prevalence of S. aureusNasal Colonization, 2003-04

S. aureus MRSA

Prevalence (%) 28.6 1.5

Estimated no. (in millions)

78.9 4.1

National Health and Nutrition Examination Survey(NHANES) 2001-2004. Gorwitz, J Infect Dis 2008

Antibiotic Resistant Pathogensin ICU Patients (NNIS)

0 10 20 30 40 50 60 70 80 90

29%

59%

89%

6%

21%

30%

VRE

MRSA

MRSE

ESBL-E. coli

ESBL-Klebsiella

Quinolone-R P.aeruginosa

% resistance: 2003 1998-2002;

MRSA in Canada, 1995-2008

0

2

4

6

8

10

12

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

MR

SA

per

1,0

00 a

dm

issi

ons

Overall Infection Colonization

Canadian Nosocomial Infection Surveillance Program

MRSA Infections (32%)

0

10

20

30

40

Skin/Softtissue

SSI Resp Blood Urine Other

%

Canadian Nosocomial Infection Surveillance Program

MRSABloodstream Infections

Location MRSA as a % of S. aureus bacteremias

U.K.* 36

Ontario† 18

Quebec§ 24

* Jeyaratnam, BMJ 2008; † QMPLS, 2009;§ Institut National de Santé Publique du Québec, 2008

MRSA in Canada, 2008

There were:

approx 32,000 new MRSA patients

13,000 new MRSA infections

2,400 MRSA-related deaths

at least $250 million excess costs attributable to MRSA

MRSA in CanadaAcquisition

Acquisition 1995-2002 2003-2007 2008

Healthcare-associated

92.8 79.5 67.1

Community-associated

7.2 20.5 32.9

Canadian Nosocomial Infection Surveillance Program

Molecular Epidemiology of CA-MRSA

Otter, Lancet ID, 2010

MRSA in Canada:Evolving Molecular Epidemiology

PFGE type 1995-1999

2004-2007

2008

CMRSA-2(USA100)

14% 58% 49%

CMRSA-10(USA300)

<1% 17% 32%

Simor, Infect Control Hosp Epidemiol 2010; Simor, IDSA 2010

Community-Associated MRSA no established health care-associated risk factors:

MRSA identified >48 h after hospital admission

history of hospitalization, surgery, or dialysis within 1 yr of MRSA culture

residence in a LTCF within 1 yr of MRSA culture

indwelling catheter or device (eg. Foley catheter, tracheostomy, gastrostomy) at time of culture

prior known MRSA Naimi, JAMA 2003Fridkin, NEJM 2005

CA-MRSA & HA-MRSA MRSA infections by age-groups 2008 surveillance

0.00%

5.00%

10.00%

15.00%

20.00%

25.00%

<10 [10-19] [20-29] [30-39] [40-49] [50-59] [60-69] [70-79] >80

Patients' age (years)

Perc

en

tag

e (

%)

CA-MRSA

HA-MRSA

Canadian Nosocomial Infection Surveillance Program

CA-MRSAPatient Profile

often younger IVDU, MSM incarcerated, homeless sports teams native aboriginals

Groom, JAMA 2001; Pan, CID 2003;

Naimi, JAMA 2003; Begier, CID 2004;

Kazakov, NEJM 2005

Emergence of CA-MRSA as a Cause of Healthcare-Associated Infections

USA400 post-partum infections, NY (mastitis, cellulitis, abscesses) (Saiman, CID 2003)

USA300 prosthetic joint infections, Atlanta, GA (Kourbatova, Am J Infect Control 2005)

USA300 accounted for 28% healthcare-associated bacteremias, 20% nosocomomial MRSA BSIs, Atlanta, GA (Seybold, CID 2006)

USA300 common cause of SSI, University of Alabama (Patel, J Clin Microbiol 2007)

CA-MRSAVirulence

USA 300/400 more virulent than other strains of S. aureus/MRSA in a mouse model of bacteremia

more resistant to killing by human PMNs

Voyich, J Immunol 2005

CA-MRSAVirulence

Enhanced virulence may be related to: global gene regulators (agr, sarA)

may upregulate expression of virulence genes

acquisition of additional virulence genes

CA-MRSAVirulence

Panton-Valentine Leukocidin (PVL) -hemolysin (increased expression in

CA-MRSA; -hemolysin antibody protective in mouse model) (Wardenburg, Nature Med 2007)

Argenine catabolic mobile element (ACME; unique to CA-MRSA, S. epidermidis; may help strain evade host response and facilitate colonization)

Panton-Valentine Leukocidin

Panton-Valentine Leukocidin (PVL) cytolytic, forms pores in human

leukocytes lukSPV-lukFPV: phage mediated common in CA-MRSA (up to > 95%) rare in HA-MRSA (0-1%), MSSA (5%) associated with necrotizing pneumonia

Dufour, Clin Infect Dis 2002; Diep, PLoS One 2008;Li, PNAS 2009

Gillet, Lancet 2002

PVL and Survival, S. aureus Pneumonia

MRSAImpact

• attributable mortality and morbidity (Whitby, Med J Austr 2001; Cosgrove, Clin Infect Dis 2003)

• prolonged hospital length of stay (Engemann, Clin Infect Dis 2003; Cosgrove, Infect Control Hosp Epidemiol 2005)

• excess/attributable costs, $14,360 (Kim, Infect Control Hosp Epidemiol 2001)

Why does antibiotic resistance affect outcome?

• Host factors• Organism virulence• Delay in instituting effective

therapy (or vancomycin less effective)

Bradley, Clin Infect Dis 2002; Paterson, Clin Infect Dis 2004; Kim, Antimicrob Agents Chemother 2008

Standard Treatment of MRSA Infections

source control; remove infected catheters, devices

vancomycin other agents: clindamycin,

TMP-SMX, tetracyclines, rifampin, fusidic acid

Vancomycin

• less rapidly bactericidal

• less effective in clinical trials (Kim, Antimicrob Agents Chemother 2008)

• more toxic

• may induce resistance

Vancomycin SusceptibilityBreakpoints in Staphylococci

MIC (µg/ml) Interpretation

2 Susceptible

4-8 Intermediate

16 Resistant

CLSI

Vancomycin-Resistant S. aureus

11 cases in US (2010); all MRSA, not epidemiologically linked (MI, PA, NY)

vancomycin MICs: 16 (µg/ml); vanA+

associated with prior vancomycin exposure and VRE colonization

Sievert, Clin Infect Dis 2008

VISA: Vancomycin-Intermediate

abnormal, thickened bacterial cell wall, not normally cross-linked, and with altered PBPs (no van genes)

strains appear to be clonally related (agr II group)

Vancomycin MICs and Treatment Outcome in MRSA Bacteremia

0

10

20

30

40

50

60

70

<0.5 1.0 - 2.0

Vancomycin MIC (mg/ml)1

Cli

nic

al

su

cc

es

s (

%)

0

10

20

30

40

50

60

70

0.5 1 2

Vancomycin MIC (mg/ml)2

Clin

ical

su

cces

s (%

)1 Sakoulas, J Clin Microbiol 20042 Moise-Broder, Clin Infect Dis 2004

p=0.01

p=0.003

Risk factors OR (95% CI) P value

Vancomycin MIC ≥ 2 µg/ml

6.3 (1.2-33.1) 0.03

Retained medical device

10.4 (1.1-104.6) 0.05

MRSA infection at ≥ 2 sites

10.2 (1.7-61.0) 0.01

Predictors of Persistent MRSA Bacteremia (multivariate analysis)

Yoon, J Antimicrob Chemother 2010

What about hVISA?

hVISA (heteroresistant): MIC susceptible (< 4 µg/ml), but with a resistant sub-population; detected by PAP-AUC

preliminary step towards development of VISA (Hiramatsu. Lancet ID, 2001)

may be associated with treatment failure (Sakoulas, Antimicrob Agents Chemother 2005)

Canadian MRSA and Vancomycin

Adam, Antimicrob Agents Chemother 2010

Newer Antimicrobial Agents for the Treatment of MRSA

• Linezolid• Daptomycin• Tigecycline• Dalbavancin, Telavancin, Oritavancin• Ceftobiprole, Ceftaroline• Iclaprim (a diaminopyramidine)

Contact Precautions Work to Decrease MRSA Transmission

Source

Isolated Unisolated Transmissions 5 10

Patient-days 558 72

Rates 0.009 0.140

RR=15.6, 95% CI=5.3-45.6, p<0.0001 Jernigan, Am J Epidemiol 1996

Active Surveillance to Control Spread of MRSA

• Active surveillance – finding asymptomatic carriers

• Contact precautions for patients identified as colonized/infected

Evidence for Effectiveness of Active Surveillance + Contact Precautions

• ecological studies (Verhoef, EJCMID 1999; Tiemersma, Emerg Infect Dis 2004)

• observational/quasi-experimental studies (Jernigan, Am J Epidemiol 1996; Chaix, JAMA 1999; Huang, Clin Infect Dis 2006; Robicsek, Ann Intern Med 2008)

• mathematical models (Bootsma, PNAS 2006)

Huang, Clin Infect Dis 2006

Healthcare-Associated MRSA Bacteremia Rates

Controlling MRSA with Broad-Based Infection Control Interventions

Edmond, Am J Infect Control 2008

MRSA:The Dutch Experience

• national “search and destroy policy”

screening patients, staff

strict isolation

decolonization

environmental cleaning

outbreak controlVerhoef, EJCMID 1999; van Trijp, Infect Control Hosp Epidemiol 2007

MRSA in France – A Success Story

Year HA-MRSA Infection Rate per 1,000 patient-days

2005 0.55

2008 0.44

Coignard, 5th Decennial International Conference on Healthcare-Associated Infections 2010 (abstr. 410)

MRSA Bacteremia - England

Pearson, J Antimicrob Chemother 2009