1. BSAC ANTIMICROBIAL SUSCEPTIBILITY TESTING & RESISTANCE MEETING CARDIFF – 13 TH MAY, 2010 Vancomycin Susceptibility Testing in Staphylococcus aureus: Clinical Issues Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation (BCARE) Department of Medical Microbiology Southmead Hospital BRISTOL

2. Topics:-  Nomenclature: “resistance”, tolerance, VISA, hVISA, VRSA, MIC creep, changes in definitions, USA and Europe.  Vancomycin and treatment of MSSA  Vancomycin and treatment of hVISA/VISA  Vancomycin and treatment of Vancomycin susceptible MRSA  Vancomycin MIC creep  Potential clinical approaches  Summary

3. Issues about Vancomycin susceptibility and S.aureus (1) Vancomycin “resistance”  Vancomycin tolerance (MIC/MBC ratio >32, time kill cure).  Vancomycin intermediate S.aureus (VISA) MIC 4-8µg/mL, described by Hiramatsu in 1996, best defined by population analysis profiles (PAP), Mu50 archetypal strain  Hetero Vancomycin intermediate S.aureus (hVISA) MIC 2-4µg/ml, described by Hiramatsu in 1996, best defined by PAP, Mu3 archetypal strain  Vancomycin resistant S.aureus MIC  16µg/ml containing Van A genetic elements.

4. Issues about Vancomycin susceptibility in S.aureus (2)  Vancomycin MIC creep Change in Vancomycin MIC distributions over time so that strains with higher MICs become more common (especially MIC 2µg/ml).  Definitions of Vancomycin susceptibility in S.aureus have changed: Susceptibility defined as MIC  4µg/ml by CLSI and all European Committees until 2006 Now CLSI and EUCAST define susceptibility as  2µg/ml CLSI defines resistant as >8µg/ml EUCAST >2µg/ml In Europe, resistance now includes:- Some hVISA VISA Van A + MRSA

5. Vancomycin in the treatment of MSSA infection

6. Vancomycin in the treatment of MSSA Infection Use of Vancomycin to treat MSSA compared to B.lactams (penicillin or cephalosporins) is associated with:-  Higher death rates in pneumonia, infective endocarditis, bacteraemia  Higher risk of relapse in bacteraemia, oesteomyelitis, “ample clinical evidence that MSSA infections respond more poorly to Vancomycin than B.lactams” EUCAST rationale document on Vancomycin

7. Vancomycin MIC distributions for S. aureus EUCAST. 2009. http://217.70.33.99/Eucast2/SearchController/index.jsp?action=initAdvanced [accessed Feb 2010] Vancomycin MIC distribution for wild-type S. aureus in Europe (N=87,764)

8. The problem with definitions/MICs Wootton M. Antimicrob Agents Chemother 2005;49:3982–3983 Vancomycin status by PAP–AUC Vancomycin MIC, µg/ml ≤0.51248 16 Susceptible (n=106) 11914000 hVISA (n=157) 031262800 VISA (n=20) 0001190 ______________________________________________________________

9. Vancomycin in the treatment of infection due to MRSA with hVISA, VISA phenotype RefClinical study designFindings 1Single-centre, retrospective study of MRSA bacteraemia (n=53) Pts with hVISA phenotype more likely to have high bacterial load infections (undrained collections, infected prosthetic material, persistent bacteraemia and fever >7 days) initially low vancomycin serum concentrations, and longer inpatient stay 2Single-centre, retrospective study of MRSA bacteraemia (n=20) Vancomycin population analysis was related to clinical response in terms of days until afebrile and days until CRP ≤30% maximum value 3Single-centre, retrospective study of MRSA bacteraemia (n=250) hVISA phenotype associated with longer period of bacteraemia, greater prevalence of complications such as IE or osteomyelitis 1.Charles PGP et al. Clin Infect Dis 2004;38:448–451 2.Neoh H et al. Ann Clin Microbiol Antimicrobiol 2007;6:13–19 3.Maor Y et al. J Infect Dis 2009;199:619–624

10. Clinical Studies on hVISA, VISA phenotype  hVISA, VISA phenotype bacteraemia does not appear to increase mortality (Charles et al 2004, Maor et al 2009).  hVISA, VISA bacteraemia appears to adversely impact on outcome by prolonging hospital stay, delayed response to therapy (fever, CRP, days to sterile blood cultures), higher rates of complications (IE, Oesteomyelitis) and emergence of Rifampicin resistance.

11. Vancomycin for the treatment of Vancomycin susceptible (MIC  2,  4mg/L) MRSA (1)

12. Vancomycin for the treatment of Vancomycin susceptible (MIC  2mg/L) MRSA (2)

13. Vancomycin for the treatment of Vancomycin susceptible (MIC  2mg/L) MRSA (3) Price et al, 2009 Strains with lower Vancomycin MICs had a worse outcome (n=100) but mixed analysis of MSSA and MRSA Albur et al, 2009 No relation of MIC to 30 day mortality in MRSA bacteraemia (MICs all  1.5mg/L) (n=38).

14. Outcomes of Vancomycin therapy for MRSA strains related to MIC  MRSA strains with MIC  4mg/L associated with higher mortality than MIC  2mg/L – mainly bacteraemia  MRSA strain with MIC of 2mg/L or  2mg/L had worse mortality in pneumonia and bacteraemia.  MRSA strains with MIC  1.5mg/L had worse outcomes in bacteraemia using a composite endpoint, not mortality alone.  MRSA strains with MIC  1.0mg/L had worse outcomes in terms of clinician judged success in a highly selected group of patients.  At least 2 studies show no relation of MIC to outcome (?Publication bias)

15. Vancomycin MIC creep reported from several centres in the US: examples Year (n) Geometric MIC, µg/ml Modal MIC, µg/ml MIC 50, µg/ml MIC 90, µg/ml 2001 (108)0.620.75 1 2002 (126)0.70.75 1 2003 (143)0.86111 2004 (154)0.92111 2005 (131)0.94111 Wilmington, North Carolina 2 Year (n) % of strains with MIC of: ≤0.5 µg/ml1 µg/ml2 µg/ml 2000 (945)79.919.90.2 2001 (1026)80.918.90.2 2002 (1317)64.635.10.3 2003 (1297)60.139.70.2 2004 (1418)28.870.40.8 UCLA Medical Centre 1 1.Wang G et al. J Clin Microbiol 2006;44:3883–3886 2.Steinkraus G et al. J Antimicrob Chemother 2007;60:788–794

16. MRSA isolates from the SENTRY programme in the US (1997–2006) 1 Year (n) Vancomycin MIC, % MIC 50, µg/ml MIC 90, µg/ml 1 µg/ml 2 µg/ml 4 µg/ml 1998–1999 (1864)759011 2000–2001 (2385)8111012 2002–2003 (2174)867<0.111 2004–2005 (3347)8430.111 2006 (3214)8640.111 1.Jones RN. ICAAC 2007; Presentation 1982 2.Sader HS et al. Antimicrob Agents Chemother 2009;53:4127–4132 ‘No evidence of creep across all US sites’ Also refer to Sader et al. 2009 – a nine-centre study across the US 2

17. Evidence for S. aureus MIC creep in the EU SourceStudy, scope and locationMIC creep identified Robert et al., 2006 1 Single French centre (n=1075) Yes (gentamicin- resistant strains only) Alos et al., 2008 2 Single Spanish centre (n=3141) No Bowker et al., 2008 3 Single English centre (n=396) No Hope et al., 2008 4 BSAC resistance surveillance 2001–2006: 25 British and Irish centres (n=1448) No 1.Robert J et al. Antimicrob Agents Chemother 2006;57:4506–4510 2.Alos J et al. J Antimicrob Chemother 2008;62:773–775 3.Bowker K et al. ECCMID 2008; Poster P1740 4.Hope R et al. Antimicrob Chemother 2008;62 (Suppl 2):ii65–ii74

18. Local investigation of vancomycin MIC creep in MRSA MIC, µg/ml1999–20002006–2007 ≤0.2521 0.54951 1144 1.521 200 400 Bowker K et al. ECCMID 2008; Poster P1740 Vancomycin MIC distribution in MRSA from a UK hospital from 1999–2000 to 2006–2007 (n=394)* *MICs determined according to modified CLSI agar dilution methodology using Mueller–Hinton agar

19. MIC creep: caution! Reynolds R et al. ICAAC 2009; Abstract C2-145 MRSA bloodstream isolates were collected from a multicentre study (www.bsacsurv.org) in the UK & Ireland since 2001 –Initial testing using doubling dilutions –Repeat batch testing using 1.4-fold dilutions across MIC distribution –Daptomycin included as a control Reynolds R et al. ICAAC 2009; Abstract C2-145

20. No change in vancomycin MICs Vancomycin geometric mean MIC, µg/ml YearHistoricalRe-test 20010.790.82 20021.070.79 20031.020.73 20041.730.73 20051.240.75 20061.350.73 20071.020.73 Trend0.078–0.027 95% CI(0.038, 0.118)(–0.047, 0.008) Years13 (8–27)37 (21–131) Reynolds R et al. ICAAC 2009; Abstract C2-145  In addition, no significant change in daptomycin or teicoplanin MICs was observed

21. EUCAST/BSAC definitions of vancomycin susceptibility for S. aureus MIC breakpoint, μg/ml SusceptibleResistant Vancomycin≤2>2 1.S. aureus with vancomycin MIC values of 2 μg/ml are on the border of the wild-type MIC distribution, and there may be an impaired clinical response –The I/R breakpoint was reduced to 2 μg/ml (from 4 μg/ml) to avoid reporting ‘GISA’ isolates as intermediate, because serious infections with ‘GISA’ isolates are not treatable with increased doses of vancomycin –MICs are method dependent and should be delivered by broth microdilution (reference ISO 20776) EUCAST. http://www.srga.org/eucastwt/mictab/MICglycopeptides_v2.html [accessed Mar 2010]

22. Potential clinical approaches High dose Vancomycin therapy American Thoracic Society 2005 Trough Vancomycin serum concentrations in range 15-20µg/ml for HPA, VAP and HCAP based on:- Increasing strains with MIC 2µg/ml Pharmacokinetics especially poor lung penetration Pharmacodynamic target AUC/MIC of 400 All three arguments are open to question.

23. Clinical effectiveness of high dose regimens Limited clinical data  High dose regimens used to treat MRSA infection (various types) with MIC 2µg/ml, no improvement in outcomes. Hidayat et al, 2006  Vancomycin to treat HCAP, statification by trough concentration <10,10-15, 15-20, 20µg/ml, not associated with mortality (or AUC 24 ). Jeffries et al, 2006

24. Nephrotoxicity of high dose regimens Nephrotoxicity only occurred with trough Vancomycin concentration >15µg/ml in patients treated for a mixture of MRSA infections (Hidayat et al, 2006). Nephrotoxicity 34.6% (n=26) if receiving >4g/day, 10.9% (n=220) if receiving <4g/day, 6.7% (n=45) if receiving Linezolid. Initial trough 18.4  7.9µg/ml high dose, 9.1  4.5µg/ml, standard dose (Lodise et al, 2008). Nephrotoxicity associated with a steady state concentration of  28µg/ml in continuous infusion Vancomycin in an OPAT service, majority of patients had bone and joint infection (Ingram et al, 2008). Rate of nephrotoxicity 5% if initial trough 20µg/ml. Nephrotoxicity related to trough and AUC (Lodise et al, 2009). Nephrotoxicity also related to duration of therapy, ICU stay and use of other nephrotoxic agents (Hidayat et al, Lodise et al, 2009).

25. Potential clinical approaches – when to test Vancomycin susceptibility (MIC and/or PAP)  Perform MIC on all MRSA from serious infection (blood, respiratory, IE, bone & joint) assess therapy on basis of result.  Perform MIC on all MRSA isolates: the clinical significance is not always obvious.  Perform occasional surveys of Vancomycin susceptibility on local MRSA isolates.  Perform MIC testing on patients responding poorly to Vancomycin for MRSA infections i.e. persistently positive blood cultures after >5days Vancomycin.  Use other agents to Vancomycin for severe infections, use combination therapy with Vancomycin for severe infections.

26. Conclusions: Clinical Issues  Avoid use of Vancomycin to treat MSSA infection especially bacteraemia, IE, pneumonia and bone & joint.  VISA/hVISA phenotype associated with delayed therapeutic response to Vancomycin and increased risk of complications: alternative therapies probably best.  Vancomycin susceptible MRSA with MICs of 2mg/L may have a poorer clinical response and higher infection related death: alternative therapies probably best.  Vancomycin MIC creep is not a major problem in Europe and the UK (does not exclude importance in single centres),  High dose Vancomycin therapy (trough >15µg/ml, dose >4g/day; steady state >28µg/ml) may not be necessary, does not improve outcomes and is clearly more nephrotoxic than standard therapies.  Need to know local MRSA Vancomycin MIC distribution to determine best clinico-pathological approach to use of Vancomycin to treat MRSA infection.