MRSA decolonisation: why/why not; who; when; how?

MRSA decolonisation:why/why not; who; when; how?

Andie LeeRoyal Prince Alfred Hospital

22 November 2013 1

2

3

Terminology

• MRSA decolonisation or eradication

– Treatment to eradicate MRSA carriage– Treatment to eradicate MRSA carriage

– Treatment to suppress MRSA carriage

4

S. aureus decolonisation agents

Topical•Mupirocin (Bactroban®)•Chlorhexidine Gluconate (Hibiclens®)•Bacitracin

Systemic• Rifampicin• Cotrimoxazole• Minocycline

•Bacitracin•Hexachlorophane (Phisohex®)•Neomycin / Triple Antibiotic Ointment (Neosporin®)•Pleuromutilin (Altabax®)•Triclosan (i.e., Dial Anti-bacterial soap)

Other• Bacterial interference

(S.aureus 502A)• Phage therapy• Lysostaphin• Tea tree oil• Honey 5

Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

6

Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

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Wertheim et al. LID 2005; 5: 751-628

MRSA carriage

• MRSA colonisation pressure• Major risk factor for subsequent infection

– 10-30%1

– Risk of infection with MRSA vs MSSA– Risk of infection with MRSA vs MSSA4-fold increased risk of infection2

(OR 4.08, 95% CI 2.10-7.44)– Most infection by endogenous strains3

80% of bacteraemic S. aureus isolates are endogenous4

1. Weber SG et al. AJIC 2007; 35: 73-852. Safdar N & Bradley ES. Am J Med 2008; 121: 310-153. Wertheim HF et al. Lancet Infect Dis 2005; 5: 751-624. von Eiff C et al. NEJM 2001; 344: 11-16 9

Potential benefits of decolonisation

• For the patient– Reduce risk of infection– No need for isolation or contact precautions– No need for isolation or contact precautions

• For others– Reduce risk of transmission– Reduce costs of MRSA infection

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Decolonisation - Is it effective?

Mody L et al. Clin Infect Dis, 2003; 37: 1467-7411

• Mupirocin– Mupirocin effective for MRSA eradication1

– Estimated success: - 90% one week after treatment

Decolonisation - Is it effective?

- 90% one week after treatment- 60% at longer follow-up

• Chlorhexidine– Routine bathing in ICU2

– MRSA acquisition decreased 32%

1. Ammerlaan et al. Clin Infect Dis 2009; 48: 922-302. Climo MW et al. Crit Care Med 2009; 37:1858-1865 12

Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

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Who should be treated?

• Reduction in S. aureus infection with mupirocin1

(RR 0.55, 95% CI 0.43 to 0.70)• Outbreaks2

• Surgical3• Surgical3

• Dialysis4

• General inpatients5

– Decreased colonisation NOT infection– May delay infection

1. van Rijen et al. Cochrane Sys Rev 2008, 2. Lally et al. AJIC 2004; 32: 44-7, 3. Perl et al. NEJM 2002; 346: 1871-7, 4. Tacconelli et al. CID 2003; 37: 1629-38, 5. Robicsek ICHE 2009 14

7.7

10S

A in

fect

ion

rat

e (%

)All S.aureus NI Deep SSI

Large-scale S. aureus screening & decolonisation study

3.4

1.1

4.9

0

5

Intervention Placebo

SA

infe

ctio

n r

ate

(%)

Bode et al. N Engl J Med 2010; 362: 9-17 15

Multicentre study in surgery

Lee et al. BMJ Open 2013;3:e003126 16

33 surgical wards10 hospitals9 countries

Serbia

Setting and Participants

SerbiaFranceSpainItalyGreeceScotlandIsraelGermanySwitzerland

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Study Design

Prospective, controlled, multicentre, intervention March 2008 to July 2010

Enhanced hand hygiene

BaselinePhase

WashoutPhase

Collection of data regarding MRSA rates and secondary outcomes

6-7 months 12 months 6 months

Combined

Screening & decolonisation

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Nosocomial MRSA Infection Rate

Intervention Intervention Intervention1

Enhanced hand hygiene Screening & decolonisation Combined

Rat

e pe

r 10

0 ad

mis

sion

s

0

.5

1 4 7 10 13 16 19 22 25 1 4 7 10 13 16 19 22 25 1 4 7 10 13 16 19 22 25

Predicted MRSA rateObserved MRSA rate

Rat

e pe

r 10

0 ad

mis

sion

s

Study month

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MRSA Infection Rate

Variable aIRR* 95% CI P ValueBaseline Phase

TrendIntervention Phase

Change in levelEnhanced hand hygieneScreening & decolonisation

1.00

1.280.97

0.90-1.11

0.79-2.060.49-1.92

0.98

0.310.94Screening & decolonisation

CombinedChange in trend

Enhanced hand hygieneScreening & decolonisationCombined

Washout PhaseChange in levelChange in trend

0.971.17

0.990.930.90

1.521.00

0.49-1.920.62-2.20

0.89-1.100.82-1.050.80-1.02

0.66-3.510.88-1.15

0.940.63

0.840.270.096

0.320.95

*aIRR = Adjusted incidence rate ratio20

MRSA Infection RateClean Surgery Wards

• Change in trend in MRSA rates– Screening and decolonisation arm

aIRR 0.83, 95% CI 0.69-0.99, p=0.04aIRR 0.83, 95% CI 0.69-0.99, p=0.04

– Combined armaIRR 0.84, 95% CI 0.70-1.00, p=0.06

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Nasal decolonisation

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Nasal decolonisation regardless of colonisation status

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Nasal decolonisation:S. aureus carriers only

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Who and when should patients be treated?

• Certain surgical procedures– Cardiac– Orthopaedic

• All patients or carriers only?– Cost– Mupirocin resistance– Ease of implementation

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Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

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US survey of S. aureus screening and decolonisation

Diekema et al. ICHE 2011; 32: 1042-1044 28

Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

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Mupirocin

• Pseudomonic Acid A – produced by Pseudomonas fluorescens

• Inhibits bacterial isoleucyl-tRNA-synthetase• Emergence of resistance with therapeutic use –

especially prolonged, repeated or widespread1

1. Patel et al. CID 2009; 49: 935-41 30

Chlorhexidine

• Cationic biocide antiseptic• Strong affinity for skin and mucous

membranes – binding electrostatically• Persistent effect for several hours

McConeghy et al. Pharmacotherapy 2009; 29: 263-8031

Resistance

Phenotype MIC(µg/mL) Molecular Mechanism

MupirocinSensitive < 4 Wild typeSensitive < 4 Wild type

Low-level R (L-MuR) 8 - 64 Native tRNA synthetase mutations1

High-level R (H-MuR) > 512 Plasmid-mediated mupA gene1

ChlorhexidineResistant 2 - 4 x Plasmid-mediated qacA/B genes2

1. Patel et al. Clin Infect Dis 2009; 49: 935-412. Batra et al. Clin Infect Dis 2010; 50: 210-17

*

*MBCs

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Resistance

• Clinical significance– Mupirocin

• High-level - decolonization failure1

• Low-level - unclear

– Chlorhexidine• qacA/B gene carriage – unclear2

1. Robicsek et al. Infect Control Hosp Epidemiol 2009; 30: 623-322. Vali L et al. J Antimicrob Chemother 2008; 61: 524-32

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Mupirocin Resistance in S. aureus in NZ after introduction of mupirocin in 1986

Upton, A., S. Lang, et al. J Antimicrob Chemother 2003, 51(3): 613-7 34

Significance of Chlorhexidine Resistance in MRSA

• EpidemiologyWorldwide in MRSA strains1

– 10%–20% UK– 63% European– 80% Brazilian– 55% Taiwanese

• Clinical Significance– MBC well below the treatment concentrations– the clinical significance of qacA/B carriage remains

unclear2

1. Batra R et al. CID 2010; 50: 210-72. Vali L et al. JAC 2008; 61: 524-32

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Mupirocin resistance in MRSA blood culturesHUG 1999 to 2008

8

10

12

14

16

18

20N

um

ber

of M

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Ab

loo

d c

ultu

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tes

100

150

200

250

Mu

pir

oci

n c

on

sum

ptio

n (g

)

0

2

4

6

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

Nu

mb

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SA

blo

od

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iso

late

s

0

50

Mu

pir

oci

n c

on

sum

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n (g

)

Mupirocin sensitive

Low-level mupirocin resistant

High-level mupirocin resistant

Mupirocin consumption

Lee et al. JHI 2011; 77: 360-2 36

Relationship between mupirocin consumption and mupirocin resistance

5060708090

100

Mu

pir

oci

n r

esis

tan

ce (%

)

01020304050

80 100 120 140 160 180 200

Mupirocin consumption (g)

Mu

pir

oci

n r

esis

tan

ce (%

)

r = 0.87, p= 0.002

Lee et al. JHI 2011; 77: 360-2 37

Genotypic chlorhexidine resistance in MRSA blood culturesHUG 1999 to 2008

8

10

12

14

16

18

20

Nu

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1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Year

Nu

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late

s

qacA-qacB absent

qacA-qacB present

qacA-qacB in 161/188 (86%) blood cultures

Lee et al. JHI 2011; 77: 360-2 38

What is the frequency of decolonisation failure at HUG?

MRSA screening

D5 D7 D8 D9

MRSA screening

Decolonisation Decolonisation

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Lee et al. CID 2011; 52: 1422-143040

Methods

Study design• Retrospective case-control study

Setting• The University of Geneva Hospitals

1901 beds, 47 706 admissions 2009• Targeted MRSA screening• Decolonization of carriers since 1994• MRSA storage policy

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Methods - Sample Selection

Inclusion criteria• MRSA carriers admitted 2001 to 2008• Decolonized > 3 days• MRSA stored < 1 month

before decolonization• > 1 screening swab or clinical sample

1-12 months after decolonization• Patients only included once

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Methods - Sample Selection

Exclusion criteria• High-level mupirocin resistance• Decolonization therapy last 6 months• Exogenous recolonization• Exogenous recolonization

documented by change in:– Antibiotic sensitivities– SCC-mec classification– MLVA pattern1

before and after decolonization1. Francois et al. J Clin Microbiol 2005; 43: 3346-55 43

Methods - Case Definitions

CASESPatients who failed decolonization

• Persistent carriage or relapse• Persistent carriage or relapse• > 1 positive MRSA culture

1-12 months after decolonization

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Methods - Case Definitions

CONTROLSPatients successfully decolonized

Defined by:Defined by:• Last follow-up sample < 2 years -

> 6 consecutive negative MRSA swabs• Last follow-up sample > 2 years -

All MRSA swabs negative45

Methods - Case Definitions

• Follow-up period 2 years

• Any positive MRSA culture within the follow-up period made the patient a follow-up period made the patient a potential Case

• Cases and Controls matched by year

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Methods - Laboratory procedures

• Screening for mupirocin resistance– 0.5 McF suspension on Mueller-Hinton agar– 5µg disk (Becton Dickinson) at 35oC for 18-24 hours1

– Zone of inhibition <14mm– Zone of inhibition <14mm

• Mupirocin MICs– Etests (AB Biodisk, Solna, Sweden)2:

MIC 8-256 µg/mL = L-MuR

MIC > 512 µg/mL = H-MuR

1. de Oliveira et al. J Med Microbiol 2007; 56: 937-9392. Finlay et al. Antimicrob Agents Chemother 1997; 41: 1137-1139 47

Methods - Laboratory procedures

• Genotypic resistance– Mupirocin resistance

• Allelic discrimination V588F point mutation1

• mupA PCR2

– Chlorhexidine resistance• qacA/B gene PCR3

• MLVA typing– Pre- and post-decolonization isolates4

1. Antonio et al. Antimicrob Agents Chemother 2002; 46: 438-4422. Zhang et al. J Clin Microbiol 2004; 42: 4947-49553. Mayer et al. J Antimicrob Chemother 2001; 47: 896-8974. Francois et al. J Clin Microbiol 2005; 43: 3346-55

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Methods – Decolonisation Data2ck BS Février 2004 1

1ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

1ck BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1 1 1

2ak BS Février 2004 1 1 1 1 1 1 1 1 1

2bk BS Février 2004 1 1

2bk BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2bk BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2bk BS Février 2004 1 1 1 1 1 1 1 1 1 1 1 1

2ck BS Février 2004 1 1 1 1

2ck BS Février 2004 1 1 1 1 1 1 1 1 1

2dk BS Février 2004 1 1 1 1 1 1 1 1 1 1 149

Results - Sample Selection

MRSA isolates stored 2001 to 2008

n = 13 556(n = 5094 patients)

Decolonized at least 3 days

SAMPLE POPULATION

n = 911

Exclusions (n= 1558)

Inadequate follow-up 1413 Decolonised last 6 mths 145

Decolonized at least 3 days

n = 2469

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Results - Sample Selection

Successfully decolonized ?

Potential Casesn = 824

Potential Controlsn = 87

SAMPLE POPULATIONn = 911

No Yes

Exclusions (n = 38)Nonviable/contaminated 2H-MuR 8Antibiogram change 2SCC-mec change 1MLVA type change 2Insufficient records 2Other 5Matching by year 16

Casesn = 75

Controlsn = 75

Exclusions (n = 12)Nonviable/contaminated 6H-MuR 6

Random sample of Casesn = 113

n = 824 n = 87

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Cases Controls Univariate analysis

Exposure n (%) n (%) OR (95% CI) p value

Mupirocin resistance

L-MuR 49 (64) 26 (35) 3.4 (1.7-7.1) 0.0003

V588F mutation 52 (69) 26/73 (36) 4.6 (2.1-9.9) <0.0001

Results - Resistance toMupirocin and Chlorhexidine

mupA gene 12/49 (24) 2/26 (8) 5.1 (1.0-25.8) 0.03

Chlorhexidine resistance

qacA/B gene 68 (91) 51 (68) 10.2 (2.6-40.7) <0.0001

Resistance combinations

Fully sensitive 6 (8) 24 (32) 0.1 (0.007-0.37) <0.0001

Mupirocin R only 1 (1) 0 (0) … 0.32

Chlorhexidine R only 21 (28) 25 (33) 0.7 (0.3-1.6) 0.44

Resistant to both 47 (63) 26 (35) 3.2 (1.6-6.5) 0.00152

Multivariate analysis

Risk factor OR (95% CI) p value

Mupirocin/chlorhexidine resistance 3.4 (1.5-7.8) 0.004

Independent risk factors associated withpersistent colonization

Age (per 1 year increment) 1.04 (1.02-1.1) 0.001

Prior hospitalisation (2 years) 2.4 (1.1-5.7) 0.04

Wound/pressure sore 5.7 (1.8-17.6) 0.003

MRSA-inactive antibiotics 3.1 (1.3-7.2) 0.01

Central venous catheter 5.7 (1.4-23.9) 0.02

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Conclusions

1. Low-level mupirocin and chlorhexidine resistance are strongly associated with failure of decolonization therapy

2. Emergence of resistance and its impact 2. Emergence of resistance and its impact should be monitored in institutions with widespread use of these agents

3. Alternative agents may be required to effectively control MRSA in settings with high prevalence of resistance

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Important questions to ask…

• Why? Is it effective?• Who should be treated?• When should patients be treated?• When should patients be treated?• How should they be treated?• Why not?

55

AcknowledgementsEve-Julie Bonetti, Genomic Research Laboratory

Fatiha Hassene, Bacteriology LaboratoryMOSAR WP4 Study Team

Staff of the Infection Control ProgramUniversity of Geneva Hospitals, Geneva, Switzerland

European CommissionEuropean Commission

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