1. VRE - treatment options for severe infections
Dr Nick Brown
Addenbrooke’s Hospital, Cambridge
14 March 2013
Conflict of interest: None

2. Evidence biased medicine
Class 0 Things I believe
Class 0a Things I believe despite the available data
Class 1 Randomized controlled clinical trials that agree with what I believe
Class 2 Other prospectively collected data
Class 3 Expert opinion
Class 4 Randomized controlled clinical trials that don’t agree with what I believe
Class 5 What you believe that I don’t
Bleck TP. BMJ 2000; 321: 239

3. VRE - treatment options for severe infections
Context
Confounding factors
Treatment options
Studies of efficacy
Combination therapy

5. Characteristics of infection with enterococci
Rarely occur in the healthy host
Majority of infections are nosocomial
Bacteraemia is often polymicrobial
In-hospital crude mortality is high
Moellering R. J Antimicrob Chemother 1991; 28: 1-12
Hoge CW et al. Rev Infect Dis 1991; 13:

6. ‘Enterococcal bacteraemia – to treat or not to treat?’
81 enterococcal bacteraemias in US
50% considered clinically significant
Treatment assessed for appropriateness
Even non-significant bacteraemia mortality ~50%
Appropriateness of treatment made no difference
Overall 51% mortality if significant
Treated appropriately = 38%
Treated inappropriately = 83%
Hoge CW et al. Rev Infect Dis 1991; 13:

7. Identification of 222 enterococci submitted to ARMRL as part of the BSAC bacteraemia resistance surveillance programme.
National Glycopeptide-Resistant Enterococcal Bacteraemia Surveillance Working Group report to the Department of Health August J Hosp Infect. 2006; 62 Suppl 1: S1-27

8. Mandatory surveillance of glycopeptide-resistant enterococcus bacteraemia, England 2003-2011

9. Mandatory surveillance of glycopeptide-resistant enterococcus bacteraemia, England 2003-2011

10. Voluntary surveillance of enterococcal bacteraemia, England, Wales & NI 2003-2010
~20% Vanc-R
~2% Vanc-R

11. Enterococcus faecium: percentage (%) of invasive isolates resistant to vancomycin, by EU/EEA country, 2011
Antimicrobial resistance surveillance in Europe Annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2011

12. Trends in vancomycin-resistant enterococcal bacteraemia rates in the SENTRY Antimicrobial Surveillance Program US Hospitals 2000–2010
Arias CA et al. Clin Infect Dis 2012; 54(S3): S233–8

14. Treatment options for invasive infection due to VRE
The main contenders
Penicillin/amoxicillin
+/- aminoglycoside
Linezolid
Daptomycin
(Quinupristin-dalfopristin)
Tigecycline
Have been used at some point
(usually as part of combination)
Teicoplanin
Chloramphenicol
Tetracycline
Rifampicin
Fosfomycin
Quinolones
Not quite here yet
Oritavancin
Dalbavancin
(new oxazolidonones)
(Cephalosporins with enhanced Gram positive activity)
No specific recommendations in AHA, ESCMID or BSAC endocarditis guidelines

15. Combination therapy reported in the literature (note - data on efficacy are extremely limited and conflicting evidence of synergy or antagonism have been reported for some combinations)
ampicillin + quinupristin-dalfopristin
ampicillin + quinolone
quinupristin-dalfopristin + doxycycline + rifampicin
quinupristin-dalfopristin + minocycline
minocycline + chloramphenicol
daptomycin + ampicillin +/- gentamicin
daptomycin + gentamicin + rifampicin
daptomycin + tigecycline
ampicillin + ciprofloxacin + tetracycline
ciprofloxacin + gentamicin + rifampicin
ceftriaxone + vancomycin + gentamicin
fosfomycin + ceftriaxone
…and more…

16. Comparative data on treatment outcome
Retrospective review 113 VRE bacteraemia Nebraska, USA
112 E. faecium, 1 E. faecalis
All isolates ampicillin-resistant and HLGR
Overall mortality 37.2%
Univariate analysis significant advantage to linezolid
Advantage disappeared when underlying factors taken into account
QPD (n=20)
LZD (n=71)
OTHER (n=22)
Crude mortality
13 (65%)
18 (25%)
11 (50%)
P= 0.002
Directly due to VRE
5 (25%)
1 (1.4%)
5 (23%)
P=0.10
Erlandson KM et al. Clin Infect Dis 2008; 46: 30-6.

17. Comparative data on treatment outcome
Retrospective review 201 VRE bacteraemia treated with daptomycin or linezolid in larger cohort of 361 patients, US hospital
All E. faecium
63 daptomycin vs. 138 linezolid treatment
Daptomycin group more likely to have haematological malignancy (33% v 14%) or liver transplant (13% v 4%)
LZD (n=138)
DAPTO (n=63)
Clinical Cure
74%
75% NS
Microbiological Cure
94%
Recurrence 3%
12%
P= 0.03
Average LOS
37 days
40 days
All cause mortality
18%
24%
Twilla JD et al. J Hosp Med. 2012; 7: 243-8

18. Comparative data on treatment outcome
Retrospective review 96 VRE bacteraemia 2 US hospitals
92 E. faecium, 4 E. faecalis
30 daptomycin vs. 68 linezolid treatment
No significance difference in baseline demographics or clinical characteristics, although daptomycin group more often on ICU
LZD (n=68)
DAPTO (n=30)
Microbiological Cure
88.2%
90.0%
P= 0.80
Relapse
2.9%
6.7%
P= 0.41
All cause mortality
20.6%
26.7%
P= 0.51
Mave V et al. J Antimicrob Chemother 2009; 64: 175–180

19. Comparative data on treatment outcome
Retrospective review of 116 VRE in cohort of 724 enterococcal bacteraemias in Australia
All VRE were vanB genotype
107 E. faecium, 9 E. faecalis
54 teicoplanin 800mg once daily
22 linezolid 600 mg twice daily
14 no antibiotic treatment
Died (n=42)
Survived (n=74)
OR (95% CI)
teicoplanin
16 (30%) 38
Reference
linezolid
3 (14%) 19
0.13 ( )
other
12 (46%) 14
0.79 ( )
No antibiotic
11 (79%) 3
6.85 ( )
Cheah ALY et al. Clin Microbiol Infect Epub ahead of print

20. Review of VRE endocarditis treatment
Retrospective review of 50 VRE endocarditis cases
26 E. faecium, 24 E. faecalis
Forrest GN et al. J Infect 2011; 63: 420-8

21. Dose of daptomycin
Evaluation of 31 patients receiving daptomycin for VRE bacteraemia
Many had factors contra-indicating use of linezolid
2 cases of endocarditis
Factors associated with good outcome:
Older age
Disease other than haematological malignancy
Dose of daptomycin >6 mg/kg/day
Grim SA et al. J Antimicrob Chemother 2009; 63: 414-6

22. VRE in an in vitro model with simulated endocarditis vegetations
E. faecalis
Daptomycin MIC = 0.5 mg/L
Hall AD et al. Antimicrob Agents Chemother 2012; 56:

23. VRE in an in vitro model with simulated endocarditis vegetations
E. faecium
Daptomycin MIC = 4 mg/L
Hall AD et al. Antimicrob Agents Chemother 2012; 56:

24. Ampicillin plus daptomycin in VRE endocarditis
E. faecium
Amp-R, Vanc-R
Daptomycin MIC = 1 mg/L
Sakoulas G et al. Antimicrob Agents Chemother 2012; 56:

25. Summary
No good evidence to show which treatment option should be used for bacteraemia due to VRE
Beta-lactam plus aminoglycoside combinations are still considered optimal where susceptibility allows
Some evidence of efficacy of both linezolid and daptomycin as single agents
Higher doses of daptomycin may have better efficacy
Combination therapy may be better for severe infection, such as endocarditis, but further data needed