MRSA decolonisation: why/why not; who; when; how?
Transcript of MRSA decolonisation: why/why not; who; when; how?
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MRSA decolonisation:why/why not; who; when; how?
Andie LeeRoyal Prince Alfred Hospital
22 November 2013 1
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Terminology
• MRSA decolonisation or eradication
– Treatment to eradicate MRSA carriage– Treatment to eradicate MRSA carriage
– Treatment to suppress MRSA carriage
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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
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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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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
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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
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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
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• 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
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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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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
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7.7
10S
A in
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ion
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)All S.aureus NI Deep SSI
Large-scale S. aureus screening & decolonisation study
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Intervention Placebo
SA
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Bode et al. N Engl J Med 2010; 362: 9-17 15
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Multicentre study in surgery
Lee et al. BMJ Open 2013;3:e003126 16
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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
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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
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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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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
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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
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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
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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
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14
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20N
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150
200
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)
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1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
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Mu
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Mupirocin sensitive
Low-level mupirocin resistant
High-level mupirocin resistant
Mupirocin consumption
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Relationship between mupirocin consumption and mupirocin resistance
5060708090
100
Mu
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n r
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tan
ce (%
)
01020304050
80 100 120 140 160 180 200
Mupirocin consumption (g)
Mu
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)
r = 0.87, p= 0.002
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Genotypic chlorhexidine resistance in MRSA blood culturesHUG 1999 to 2008
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Year
Nu
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qacA-qacB absent
qacA-qacB present
qacA-qacB in 161/188 (86%) blood cultures
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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
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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
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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
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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
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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
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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
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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?
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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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