BSAC ANTIMICROBIAL SUSCEPTIBILITY TESTING & RESISTANCE MEETING CARDIFF – 13 TH MAY, 2010
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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
0.69
0
20
40
60
80
100
≤0.25 0.5 1 2 4 8 >8.0
MIC, μg/ml
Pro
po
rtio
n o
f is
ola
tes
, %
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.