British Society for Antimicrobial Chemotherapy Symposium Resistance and treatment issues in

1. British Society for Antimicrobial Chemotherapy Symposium Resistance and treatment issues in Blood Stream Infection: S.aureus Alasdair MacGowan BCARE University of Bristol & North Bristol NHS Trust BRISTOL UK

2. 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%

3. Background (2): Trends in S.aureus bacteraemia susceptibility 2001-2011 (www.bsacsurv.org – accessed 16th November, 2012)

4. Background (2): Trends in S.aureus bacteraemia susceptibility 2001-2011 (www.bsacsurv.org – accessed 16th November, 2012)

5. 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:

6. 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

7. 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

8. 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.

9. 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%)

10. Predicting raised vancomycin MICs in MRSA Lubin et al 2011, CID 52, 997 Scoring System:

11. 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.

12. 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)

13. Empiric Antibiotic Therapy for S.aureus bacteraemia Background: Kim et al 2004; JAC 54, 489-497 MRSA BSI n=127 Delay 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=162 No difference in deaths in those receiving glycopeptides within 48 hrs compared to after 48hrs.

14. 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

15. 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

16. 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

17. 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.