BSAC ANTIMICROBIAL SUSCEPTIBILITY
TESTING & RESISTANCE MEETING
CARDIFF – 13TH 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
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
Vancomycin in the treatment of MSSA infection
Indications
Trial Design
Findings
Reference
Pneumonia
Single centre
prospective
observational
(n=25)
Multi-centre
prospective
observational
(n=505)
Prospective
observational study
in a OPAT service
(n=454)
Retrospective
cohort
(n=72)
Retrospective
cohort (n=294)
Case matched (1/2)
(n=81)
Retrospective case
control
(n=33)
8/17 receiving Vancomycin died
Gonzalez et al,1999
Bacteraemia
Oesteomyelitis
Infective
endocarditis in
IVDU
Bacteraemia
Recurrent MSSA
bacteraemia
0/10 receiving Dicloxacillin (p<0.01)
Vancomycin vs Nafcillin significantly related
to relapse
Chang et al, 2003
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
Mortality related to infection 11/28 with
Vancomycin, 5/44 with B.lactam
Lodise et al, 2007
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)
Glycopeptide therapy more likely to be
associated with relapse than B.lactam
(p=0.015)
Kim et al, 2008
Walker et al, 2009
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
Vancomycin MIC distribution for wild-type S. aureus
in Europe (N=87,764)
Proportion of isolates, %
100
74.2
80
60
40
15.4
20
9.5
0.69
0.25
0.003
0.003
4
8
>8.0
0
≤0.25
0.5
1
2
MIC, μg/ml
EUCAST. 2009. http://217.70.33.99/Eucast2/SearchController/index.jsp?action=initAdvanced [accessed Feb 2010]
The problem with
definitions/MICs
______________________________________________________________
Vancomycin
status by
PAP–AUC
Susceptible
(n=106)
hVISA
(n=157)
VISA
(n=20)
Vancomycin MIC, µg/ml
16
≤0.5
1
2
4
8
11
91
4
0
0
0
0
3
126
28
0
0
0
0
0
11
9
0
Wootton M. Antimicrob Agents Chemother 2005;49:3982–3983
Vancomycin in the treatment of infection due to MRSA with hVISA,
VISA phenotype
Ref
Clinical study design
Findings
1
• Single-centre,
• Pts with hVISA phenotype more likely to
retrospective study of
have high bacterial load infections
MRSA bacteraemia
(undrained collections, infected prosthetic
(n=53)
material, persistent bacteraemia and fever
>7 days) initially low vancomycin serum
concentrations, and longer inpatient stay
2
• Single-centre,
• Vancomycin population analysis was
retrospective study of
related to clinical response in terms of days
MRSA bacteraemia
until afebrile and days until CRP ≤30%
(n=20)
maximum value
3
• Single-centre,
• hVISA phenotype associated with longer
retrospective study of
period of bacteraemia, greater prevalence
MRSA bacteraemia
of complications such as IE or
(n=250)
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
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.
Vancomycin for the treatment of Vancomycin susceptible (MIC2, 4mg/L) MRSA (1)
Indication
Trial Design
Findings
Reference
Any infection
with MRSA
Vancomycin
MIC 4mg/L
Multi-centre
case control
study
Fridkin et al, 2003
Bacteraemia
Retrospective
cohort of
selected
patients from
PKII/III studies
who had, in
many cases,
failed
Vancomycin
Single centre
retrospective
cohort 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%
Clinical determined
success 55.6% (n=9)
Vancomycin
MIC 0.5mg/L,
9.5% (n=21)
MIC 1.0-2mg/L.
5 patients with hVISA
phenotype MIC 2-4mg/L
Charles et al, 2004
Bacteraemia
48 patients with VSSA
phenotype
MIC 0.5-2mg/L, higher
MICs associated with
longer bacteraemia,
more fever days
equivalent mortality
Sakoulas et al, 2004
Vancomycin for the treatment of Vancomycin susceptible
(MIC2mg/L) MRSA (2)
Indication
Trial Design
All MRSA infections
(77% pneumonia)
Single centre,
Patients with MIC2mg/L Hidayat et al, 2006
prospective cohort had lower end of
study (n=95)
treatment responses and
higher mortality vs
patients with MIC
<2mg/L
Single centre
Vancomycin MIC 1µg/ml Soriano et al,
retrospective
(n=92),
2008
cohort study
MIC 1.5mg/L (n=213),
(n=414)
MIC 2.0mg/L (n=92).
Bacteraemia
Bacteraemia
Single centre
retrospective
cohort study
(n=92)
Findings
Reference
No difference in overall
mortality. Shock related
to lower MIC. In multivariant model receiving
Vancomycin if MIC
2mg/L or inappropriate
therapy associated with
mortality
Vancomycin
Lodise et al, 2008
MIC1.5µg/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)
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).
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
UCLA Medical Centre1
Year (n)
2000 (945)
2001 (1026)
2002 (1317)
2003 (1297)
2004 (1418)
Year (n)
2001 (108)
2002 (126)
2003 (143)
2004 (154)
2005 (131)
% of strains with MIC of:
≤0.5 µg/ml
1 µg/ml
79.9
19.9
80.9
18.9
64.6
35.1
60.1
39.7
28.8
70.4 2
Wilmington,
North Carolina
Geometric
MIC, µg/ml
0.62
0.7
0.86
0.92
0.94
Modal MIC,
µg/ml
0.75
0.75
1
1
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
MIC50,
µg/ml
0.75
0.75
1
1
1
2 µg/ml
0.2
0.2
0.3
0.2
0.8
MIC90,
µg/ml
1
1
1
1
1
MRSA isolates from the SENTRY
programme in the US (1997–2006)1
Vancomycin MIC, %
1
2
4
µg/ml µg/ml µg/ml
Year (n)
MIC50,
µg/ml
MIC90,
µg/ml
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
1
‘No evidence of creep across all US sites’
Also refer to Sader et al. 2009 – a nine-centre study across the US2
1. Jones RN. ICAAC 2007; Presentation 1982
2. Sader HS et al. Antimicrob Agents Chemother 2009;53:4127–4132
Evidence for S. aureus MIC creep in the EU
Source
Robert et al., 2006
Alos et al., 2008
2
Bowker et al.,
3
2008
Hope et al., 2008
1.
2.
3.
4.
4
1
Study, scope and location
MIC creep identified
Single French centre
(n=1075)
Yes (gentamicinresistant strains
only)
Single Spanish centre
(n=3141)
No
Single English centre
(n=396)
No
BSAC resistance
surveillance 2001–2006:
25 British and Irish
centres (n=1448)
No
Robert J et al. Antimicrob Agents Chemother 2006;57:4506–4510
Alos J et al. J Antimicrob Chemother 2008;62:773–775
Bowker K et al. ECCMID 2008; Poster P1740
Hope R et al. Antimicrob Chemother 2008;62 (Suppl 2):ii65–ii74
Local investigation of vancomycin MIC
creep in MRSA
Vancomycin MIC distribution in MRSA from a UK hospital
from 1999–2000 to 2006–2007 (n=394)*
MIC, µg/ml
≤0.25
1999–2000
2
2006–2007
1
49
144
2
0
51
144
1
0
0
0
0.5
1
1.5
2
4
*MICs determined according to modified CLSI agar dilution methodology using Mueller–Hinton agar
Bowker K et al. ECCMID 2008; Poster P1740
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
2001
2002
2003
2004
2005
2006
2007
Trend
95% CI
Years
Historical
Re-test
0.79
1.07
1.02
1.73
1.24
1.35
1.02
0.078
(0.038, 0.118)
13 (8–27)
0.82
0.79
0.73
0.73
0.75
0.73
0.73
–0.027
(–0.047, 0.008)
37 (21–131)
 In addition, no significant change in daptomycin or teicoplanin
MICs was observed
Reynolds R et al. ICAAC 2009; Abstract C2-145
EUCAST/BSAC definitions of vancomycin
susceptibility for S. aureus
MIC breakpoint, μg/ml
Vancomycin
Susceptible
Resistant
≤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 other
nephrotoxic 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.