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
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
P.aeruginosa
38.5%
35.6%
E.coli
Candida
S.pneumoniae
MSSA
16.6%
16.2%
15.7%
15.5%
Background (2):
Trends in S.aureus bacteraemia susceptibility 2001-2011
(www.bsacsurv.org – accessed 16th November, 2012)
Number of strains
2001
218
2003
215
% susceptible by year
2005
2007
225
225
Ciprofloxacin
Daptomycin
Erythromycin
Fusidic Acid
Gentamicin
Linezolid
Minocycline
Oxacillin
Rifampicin
Teicoplanin
Tygecycline
Vancomycin
56.9
ND
58.7
ND
96.3
100
ND
56.9
ND
99.5
ND
100
46.0
100
59.1
93.0
92.1
100
98.1
57.2
98.1
98.1
100
100
60.0
100
67.6
93.3
98.7
100
100
63.1
99.6
99.6
100
100
61.8
100
65.3
85.3
95.6
100
98.2
63.6
99.6
99.6
98.7
100
2009
430
2011
460
73.3
100
75.1
90.0
97.7
100
99.3
77.4
99.8
99.3
99.8
100
79.8
ND
77.6
90.0
97.6
100
99.1
87.0
98.7
100
100
100
Background (2):
Trends in S.aureus bacteraemia susceptibility 2001-2011
(www.bsacsurv.org – accessed 16th November, 2012)
Number of strains
2001
218
2003
215
% susceptible by year
2005
2007
225
225
Ciprofloxacin
Daptomycin
Erythromycin
Fusidic Acid
Gentamicin
Linezolid
Minocycline
Oxacillin
Rifampicin
Teicoplanin
Tygecycline
Vancomycin
56.9
ND
58.7
ND
96.3
100
ND
56.9
ND
99.5
ND
100
46.0
100
59.1
93.0
92.1
100
98.1
57.2
98.1
98.1
100
100
60.0
100
67.6
93.3
98.7
100
100
63.1
99.6
99.6
100
100
61.8
100
65.3
85.3
95.6
100
98.2
63.6
99.6
99.6
98.7
100
2009
430
2011
460
73.3
100
75.1
90.0
97.7
100
99.3
77.4
99.8
99.3
99.8
100
79.8
ND
77.6
90.0
97.6
100
99.1
87.0
98.7
100
100
100
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:
Had an ECHO
Treated within 24h of positive culture
>50% treatment oral
treated for <14d total
treated for ≥28d total
combination therapy
Patient Group
Guideline Recommendations
50% (46-54)
81% (77-84)
25% (21-30)
16% (13-20)
32% (27-37)
48% (43-52)
Yes – especially if no focus
?
No
No
?
No
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
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
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.
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%)
Predicting raised vancomycin MICs in MRSA
Lubin et al 2011, CID 52, 997
Scoring System:
Age >50 years
Vancomycin for >48hr in last week
Chronic liver disease
History of MRSA bacteraemia
Non-tunneled central line
Score ≥4
-
negative predictive rate 91%
positive predictive value 30%
Score
3
2
2
2
1
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.
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)
MIC
(mg/L)
≤0.25
0.35
0.5
0.71
1.0
1.41
2.0
>2.0
Glycopeptide MIC distributions
(n=271)
Vancomycin
Teicoplanin
1
4
0
23
27
104
169
78
61
34
12
19
_________
_________
1
4
0
5
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.
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
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
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
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.