British Society for Antimicrobial Chemotherapy Symposium

Resistance and treatment issues in Blood Stream Infection: S.aureus

Alasdair MacGowanBCAREUniversity of Bristol & North Bristol NHS TrustBRISTOLUK

Background (1)

MacGowan et al 2012, P1955 Monday this meeting

4 Centre English Prospective Study of Outcomes in Blood Stream Infection (BSI) (n=1113) - 2010-11.

MSSA BSI (n=105) 9.4% total

MRSA BSI (n=27) 2.4% total

30 Day Mortality:-

MRSA 38.5%P.aeruginosa 35.6%

E.coli 16.6%Candida 16.2%S.pneumoniae 15.7%MSSA 15.5%

% susceptible by year

2001 2003 2005 2007 2009 2011 Number of strains 218 215 225 225 430 460 Ciprofloxacin 56.9 46.0 60.0 61.8 73.3 79.8 Daptomycin ND 100 100 100 100 ND Erythromycin 58.7 59.1 67.6 65.3 75.1 77.6 Fusidic Acid ND 93.0 93.3 85.3 90.0 90.0 Gentamicin 96.3 92.1 98.7 95.6 97.7 97.6 Linezolid 100 100 100 100 100 100 Minocycline ND 98.1 100 98.2 99.3 99.1 Oxacillin 56.9 57.2 63.1 63.6 77.4 87.0 Rifampicin ND 98.1 99.6 99.6 99.8 98.7 Teicoplanin 99.5 98.1 99.6 99.6 99.3 100 Tygecycline ND 100 100 98.7 99.8 100 Vancomycin 100 100 100 100 100 100

Background (2):

Trends in S.aureus bacteraemia susceptibility 2001-2011(www.bsacsurv.org – accessed 16th November, 2012)

% susceptible by year

2001 2003 2005 2007 2009 2011 Number of strains 218 215 225 225 430 460 Ciprofloxacin 56.9 46.0 60.0 61.8 73.3 79.8 Daptomycin ND 100 100 100 100 ND Erythromycin 58.7 59.1 67.6 65.3 75.1 77.6 Fusidic Acid ND 93.0 93.3 85.3 90.0 90.0 Gentamicin 96.3 92.1 98.7 95.6 97.7 97.6 Linezolid 100 100 100 100 100 100 Minocycline ND 98.1 100 98.2 99.3 99.1 Oxacillin 56.9 57.2 63.1 63.6 77.4 87.0 Rifampicin ND 98.1 99.6 99.6 99.8 98.7 Teicoplanin 99.5 98.1 99.6 99.6 99.3 100 Tygecycline ND 100 100 98.7 99.8 100 Vancomycin 100 100 100 100 100 100

Background (2):

Trends in S.aureus bacteraemia susceptibility 2001-2011(www.bsacsurv.org – accessed 16th November, 2012)

Patient Group Guideline Recommendations

Had an ECHO 50% (46-54) Yes – especially if no focus Treated within 24h of positive culture 81% (77-84) ? >50% treatment oral 25% (21-30) No treated for <14d total 16% (13-20) No treated for ≥28d total 32% (27-37) ? combination therapy 48% (43-52) No

Background (3):

Management of S.aureus in the UK

Thwaites et al 2010, PLOS one, 5, e14170

8 UK Centres, prospective observational study (n=549, MRSA 24%)

Management Issues:

Topics:-

Vancomycin MIC and clinical outcomes in S.aureus bacteraemia (SAB)

Vancomycin creep in MRSA in UK

Initial appropriate chemotherapy for S.aureus bacteraemia (SAB)

European outcome data

Vancomycin MIC and S.aureus susceptibility: present status

BSAC/EUCAST clinical breakpoint for S.aureus is sensitive ≤2mg/L

However:-

“based primarily on clinical evidence, those strains of S.aureus with vancomycin MICs values of 2mg/L, which are on the border of the wild type MIC distribution, including hVISA phenotype are likely to have impaired clinical responses to vancomycin”

EUCAST vancomycin rationale document 2.1, 17th June, 2010

MICs and outcome – new data (1)

Systematic review and meta-analysis of vancomycin MICs and outcomes

Van Hal et al 2012, CID 54, 755

22 studies included: 2383 MRSA and 507 MSSA BSI

Conclusions:

Vancomycin MIC significantly associated with mortality in MRSA infection (OR 1.64, p <0.01)

E.test most common method of determining MIC

8 studies where E.test result stratified MIC as ≤1.0, ≥1.5 or ≥2mg/L. MIC ≥2mg/L associated with increased mortality in MRSA infection (OR 1.7 p<0.01). MIC ≥1.5mg/L not associated with increased mortality versus MIC ≤1.0mg/L.

MICs and outcome – new data (2)

Teicoplanin

Chang et al 2012; JAC 67, 736-41.

> MRSA bacteraemia, hospital based retrospective observational study (n=101)

> teicoplanin MIC>1.5mg/L associated with higher mortality (48.9% deaths vs 26%)

Score Age >50 years 3 Vancomycin for >48hr in last week 2 Chronic liver disease 2 History of MRSA bacteraemia 2 Non-tunneled central line 1 Score ≥4 - negative predictive rate 91% positive predictive value 30%

Predicting raised vancomycin MICs in MRSA

Lubin et al 2011, CID 52, 997

Scoring System:

Vancomycin MICs and MSSA outcomes

Holmes et al 2011, CID 204, 340

8 Australian hospitals 532 patients with S.aureus bacteraemia

Increasing vancomycin MIC associated with mortality in vancomycin treated patients

but

also MSSA patients treated with flucloxacillin (mortality 26.8% MIC >1.5mg/L, 12.2% <1.5mg/L: by E.test)

and also:-

Han et al 2012, AAC, 56, 5164-5170.

Glycopeptide MIC distributions

(n=271) MIC (mg/L)

Vancomycin Teicoplanin ≤0.25 1 4 0.35 0 23 0.5 27 104 0.71 169 78 1.0 61 34 1.41 12

_________ 19

_________ 2.0 1 4 >2.0 0 5

Vancomycin MIC creep in British Isles

Reynolds et al 2012, JAC doi 10.1093

- No evidence of upward creep of vancomycin MICs in MRSA 2001-07 (also no change in daptomycin or teicoplanin)

Empiric Antibiotic Therapy for S.aureus bacteraemia

Background:

Kim et al 2004; JAC 54, 489-497

MRSA BSI n=127Delay of 2 days in appropriate antibiotics especially glycopeptide may not effect patient outcome.

Lodise et al 2003, CID, 36, 1418

S.aureus bacteraemia (n=167)CART defined breakpoint for delayed therapy 44.75hr (mortality 20.2% before 44.75hr, 33.3% after)

Fang et al 2006, JAC 57, 511-519

MRSA BSI n=162No difference in deaths in those receiving glycopeptides within 48 hrs compared to after 48hrs.

Empiric Antibiotic Therapy of S.aureus bacteraemia: new data

Paul et al 2010, JAC, 65, 2658

Single Centre retrospective study of MRSA BSI - 510 episodes

Appropriate therapy was an antibiotic to which MRSA sensitive within 48h of blood culture being taken.

30 mortality -

inappropriate therapy (168/342) 49.1%

appropriate therapy (56/168) 33.3%

87% appropriate therapy was vancomycin

Schweizer et al 2010, PLUS one 5, e11432

Single centre retrospective study of SA BSI - 814 episodes

Appropriate therapy was not associated with decreased mortality

Empiric Antibiotic therapy of S.aureus bacteraemia:

Why the conflicting data?

> Difficult to show adverse outcomes of inappropriate therapy in MSSA as sensitive to most drug classes.

> Glycopeptide therapy may be only used in “at risk” patient – difficult to adjust for in observational studies

> Up to 10% S.aureus may be contaminants

> defining appropriate therapy may be difficult:

Co-trimoxazole for MRSA BSI

or

Vancomycin for MSSA BSI

> Vancomycin efficacy depends on MIC so clonally may be important

> Combination therapy is common and confounds analysis

Outcomes of MRSA BSI

Kraker et al 2011, AAC 55, 1598

Largest outcome study in S.aureus BSI to date: 13 European hospitals 2007-2008

Cohort 1 MRSA BSI n=248 n=453 controls

Cohort 2 MSSA BSI n=618 n=1170 controls

Compared to controls

MRSA BSI 30 day mortality, in hospital deaths, LOS 9.2d

MSSA BSI 30 day mortality, in hospital deaths, LOS 8.6d

MRSA compared to MSSA

MRSA BSI 30 day mortality, no in hospital death or LOS

Conclusions:-

poor outcomes in BSI due to S.aureus confirmed especially MRSA now including UK and European data.

highly variable management of S.aureus BSI across NHS in England.

Vancomycin MIC ≥2mg/L associated with impaired responses in S.aureus BSI (for MRSA and MSSA whether or not treated with vancomycin).

No evidence of vancomycin creep in UK MRSA BSI strains.

conflicting data on impact of empiric (48h) appropriate chemotherapy in S.aureus BSI, but most reported case series report no impact of delay

to 44h.