BSAC ANTIMICROBIAL SUSCEPTIBILITY TESTING & RESISTANCE MEETING

CARDIFF – 13TH MAY, 2010

Vancomycin Susceptibility Testing in Staphylococcus aureus:

Clinical Issues

Alasdair MacGowanBristol Centre for Antimicrobial Research & Evaluation (BCARE)Department of Medical MicrobiologySouthmead HospitalBRISTOL

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

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.

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

Indications

Trial Design

Findings

Reference

Pneumonia Single centre prospective observational (n=25)

8/17 receiving Vancomycin died 0/10 receiving Dicloxacillin (p<0.01)

Gonzalez et al,1999

Bacteraemia Multi-centre prospective observational (n=505)

Vancomycin vs Nafcillin significantly related to relapse

Chang et al, 2003

Oesteomyelitis Prospective observational study in a OPAT service (n=454)

2% of infections due to MRSA. Therapy of S.aureus (n=248) with Vancomycin double risk of recurrence vs B.lactams

Tice et al, 2003

Infective endocarditis in IVDU

Retrospective cohort (n=72)

Mortality related to infection 11/28 with Vancomycin, 5/44 with B.lactam

Lodise et al, 2007

Bacteraemia Retrospective cohort (n=294) Case matched (1/2) (n=81)

In cohort study mortality 10/27 vs B.lactam 47/267 (p0.02). In case control mortality Vancomycin 10/27 controls 6/54 (p<0.01)

Kim et al, 2008

Recurrent MSSA bacteraemia

Retrospective case control (n=33)

Glycopeptide therapy more likely to be associated with relapse than B.lactam (p=0.015)

Walker et al, 2009

Vancomycin in the treatment of MSSA infection

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

Vancomycin MIC distributions for S. aureus

0.0030.0030.259.5

74.2

15.4

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0

20

40

60

80

100

≤0.25 0.5 1 2 4 8 >8.0

MIC, μg/ml

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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)

The problem with definitions/MICs

Wootton M. Antimicrob Agents Chemother 2005;49:3982–3983

Vancomycinstatus byPAP–AUC

Vancomycin MIC, µg/ml

≤0.5 1 2 4 816

Susceptible(n=106)

11 91 4 0 0 0

hVISA(n=157)

0 3 126 28 0 0

VISA(n=20)

0 0 0 11 9 0

______________________________________________________________

Vancomycin in the treatment of infection due to MRSA with hVISA, VISA phenotype

Ref Clinical study design Findings

1 • Single-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

2 • Single-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

3 • Single-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;38:448–4512. Neoh H et al. Ann Clin Microbiol Antimicrobiol 2007;6:13–193. Maor Y et al. J Infect Dis 2009;199:619–624

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.

Indication

Trial Design

Findings

Reference

Any infection with MRSA Vancomycin MIC 4mg/L

Multi-centre case control study

Mainly bacteraemia patients with strains MIC 4mg/L (n=19) more likely to die than controls MIC 2mg/L (n=20) 63% vs 12%

Fridkin et al, 2003

Bacteraemia Retrospective cohort of selected patients from PKII/III studies who had, in many cases, failed Vancomycin

Clinical determined success 55.6% (n=9) Vancomycin MIC 0.5mg/L, 9.5% (n=21) MIC 1.0-2mg/L.

Sakoulas et al, 2004

Bacteraemia Single centre retrospective cohort study

5 patients with hVISA phenotype MIC 2-4mg/L 48 patients with VSSA phenotype MIC 0.5-2mg/L, higher MICs associated with longer bacteraemia, more fever days equivalent mortality

Charles et al, 2004

Vancomycin for the treatment of Vancomycin susceptible (MIC2, 4mg/L) MRSA (1)

Indication

Trial Design

Findings

Reference

All MRSA infections (77% pneumonia)

Single centre, prospective cohort study (n=95)

Patients with MIC2mg/L had lower end of treatment responses and higher mortality vs patients with MIC <2mg/L

Hidayat et al, 2006

Bacteraemia Single centre retrospective cohort study (n=414)

Vancomycin MIC 1µg/ml (n=92), MIC 1.5mg/L (n=213), MIC 2.0mg/L (n=92). No difference in overall mortality. Shock related to lower MIC. In multi-variant model receiving Vancomycin if MIC 2mg/L or inappropriate therapy associated with mortality

Soriano et al, 2008

Bacteraemia Single centre retrospective cohort study (n=92)

Vancomycin MIC1.5µg/L 24/66 failed, MIC <1.5ug/ml 4/26 failed. Failure composite endpoint of death, MRSA in blood 10 days after start Vancomycin, repeat bacteraemia in 60 days (no significant differences individually)

Lodise et al, 2008

Vancomycin for the treatment of Vancomycin susceptible (MIC2mg/L) MRSA (2)

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 all1.5mg/L) (n=38).

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)

Vancomycin MIC creep reported from several centres in the US: examples

Year (n)Geometric MIC, µg/ml

Modal MIC, µg/ml

MIC50,µg/ml

MIC90,µg/ml

2001 (108) 0.62 0.75 0.75 1

2002 (126) 0.7 0.75 0.75 1

2003 (143) 0.86 1 1 1

2004 (154) 0.92 1 1 1

2005 (131) 0.94 1 1 1

Wilmington, North Carolina2

Year (n)

% of strains with MIC of:

≤0.5 µg/ml 1 µg/ml 2 µg/ml

2000 (945) 79.9 19.9 0.2

2001 (1026) 80.9 18.9 0.2

2002 (1317) 64.6 35.1 0.3

2003 (1297) 60.1 39.7 0.2

2004 (1418) 28.8 70.4 0.8

UCLA Medical Centre1

1. Wang G et al. J Clin Microbiol 2006;44:3883–38862. Steinkraus G et al. J Antimicrob Chemother 2007;60:788–794

MRSA isolates from the SENTRY programme in the US (1997–2006)1

Year (n)

Vancomycin MIC, %

MIC50, µg/ml

MIC90,µg/ml

1 µg/m

l

2 µg/m

l

4 µg/m

l

1998–1999 (1864)

75 9 0 1 1

2000–2001 (2385)

81 11 0 1 2

2002–2003 (2174)

86 7 <0.1 1 1

2004–2005 (3347)

84 3 0.1 1 1

2006 (3214) 86 4 0.1 1 11. Jones RN. ICAAC 2007; Presentation 19822. 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 US2

Evidence for S. aureus MIC creep in the EU

SourceStudy, scope and

locationMIC creep identified

Robert et al., 20061

Single French centre (n=1075)

Yes (gentamicin-resistant strains

only)

Alos et al., 20082 Single Spanish centre (n=3141)

No

Bowker et al., 20083

Single English centre (n=396)

No

Hope et al., 20084

BSAC resistance surveillance 2001–2006:

25 British and Irish centres (n=1448)

No

1. Robert J et al. Antimicrob Agents Chemother 2006;57:4506–45102. Alos J et al. J Antimicrob Chemother 2008;62:773–7753. Bowker K et al. ECCMID 2008; Poster P17404. Hope R et al. Antimicrob Chemother 2008;62 (Suppl 2):ii65–ii74

Local investigation of vancomycin MIC creep in MRSA

MIC, µg/ml 1999–2000 2006–2007

≤0.25 2 1

0.5 49 51

1 144 144

1.5 2 1

2 0 0

4 0 0

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

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

No change in vancomycin MICs 

Vancomycin geometric mean MIC, µg/ml

Year Historical Re-test

2001 0.79 0.82

2002 1.07 0.79

2003 1.02 0.73

2004 1.73 0.73

2005 1.24 0.75

2006 1.35 0.73

2007 1.02 0.73

Trend 0.078 –0.027

95% CI (0.038, 0.118) (–0.047, 0.008)

Years 13 (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

EUCAST/BSAC definitions of vancomycin susceptibility for S. aureus

MIC breakpoint, μg/ml

Susceptible Resistant

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]

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.

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 AUC24).

Jeffries et al, 2006

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 <10µg/ml, 21% if 10-15µg/ml, 20% if 15-20µg/ml and 33% if >20µg/ml. Nephrotoxicity related to trough and AUC (Lodise et al, 2009).

Nephrotoxicity also related to duration of therapy, ICU stay and use of othernephrotoxic agents (Hidayat et al, Lodise et al, 2009).

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.

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.