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VRE - treatment options for severe

infections

Dr Nick Brown

Addenbrookes Hospital, Cambridge

14 March 2013

Conflict of interest: None

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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 dont

agree with what I believe

Class 5 What you believe that I dont

Bleck TP. BMJ2000; 321: 239

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VRE - treatment options for severe

infections

Context

Confounding factors

Treatment options

Studies of efficacy

Combination therapy

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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 Chemother1991; 28: 1-12

Hoge CW et al. Rev Infect Dis 1991; 13: 600-5.

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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 2004. J Hosp Infect. 2006; 62 Suppl 1: S1-27

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Mandatory surveillance of glycopeptide-resistant

enterococcus bacteraemia, England 2003-2011

http://www.hpa.org.uk

0

100

200

300

400

500

600

700

800

900

1,000

2003/4 2004/5 2005/6 2006/7 2007/8 2008/9 2009/10 2010/11

Totalno.ofbacteraemiaepisodesreported

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Mandatory surveillance of glycopeptide-resistant

enterococcus bacteraemia, England 2003-2011

0 50 100 150 200 250 300 350 400 450

Cambridge University Hospitals

King's College Hospital

Imperial College Healthcare

Barts & the London

University Hospital Birmingham

Oxford Radcliffe Hospitals

Central Manchester University Hospitals

Royal Free Hampstead

University Hospitals of Leicester

University Hospitals Bristol

Nottingham University Hospitals

No. of bacteraemia episodes

http://www.hpa.org.uk

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Voluntary surveillance of enterococcal bacteraemia,

England, Wales & NI 2003-2010

http://www.hpa.org.uk

0

1,000

2,000

3,000

4,000

5,000

6,000

7,000

8,000

9,000

2003 2004 2005 2006 2007 2008 2009 2010

Numberofreport

s

Enterococcus unspeciated

Enterococcus spp. Other named

E. faecium

E. faecalis

~20% Vanc-R~20% Vanc-R

~2% Vanc-R~2% Vanc-R

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Enterococcus faecium: percentage (%) of invasive isolates resistant to

vancomycin, by EU/EEA country, 2011

Antimicrobial resistance surveillance in EuropeAnnual report of the European Antimicrobial

Resistance Surveillance Network (EARS-Net) 2011

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Trends in vancomycin-resistant enterococcal bacteraemia

rates in the SENTRY Antimicrobial Surveillance Program

US Hospitals 20002010

0

10

20

30

40

50

60

70

80

90

100

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

P

ercentageresistancetovancomycin

E faecium

E faecalis

Arias CA et al. Clin Infect Dis 2012; 54(S3): S2338

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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

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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

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Retrospective review 201 VRE bacteraemia treated with daptomycinor linezolid in larger cohort of 361 patients, US hospital 2004-2009

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%)

Twilla JD et al. J Hosp Med. 2012; 7: 243-8

Comparative data on treatment outcome

LZD (n=138) DAPTO (n=63)

Clinical Cure 74% 75% NS

Microbiological Cure 94% 94% NS

Recurrence 3% 12% P= 0.03

Average LOS 37 days 40 days NS

All cause mortality 18% 24% NS

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Retrospective review 96 VRE bacteraemia 2 US hospitals 2003-2007

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

Mave V et al. J Antimicrob Chemother2009; 64: 175180

Comparative data on treatment outcome

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

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Review of VRE endocarditis treatment

Forrest GN et al.J Infect2011; 63: 420-8

Retrospective review of 50 VRE endocarditis cases 2000-2008 26 E. faecium, 24 E. faecalis

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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 Chemother2009; 63:414-6

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VRE in an in vitro model with simulated

endocarditis vegetations

Hall AD et al.Antimicrob Agents Chemother2012; 56:3174-80

E. faecalis

Daptomycin MIC = 0.5 mg/L

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VRE in an in vitro model with simulated

endocarditis vegetations

Hall AD et al.Antimicrob Agents Chemother2012; 56:3174-80

E. faecium

Daptomycin MIC = 4 mg/L

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Ampicillin plus daptomycin in VRE endocarditis

Sakoulas G et al.Antimicrob Agents Chemother2012; 56:838-44

E. faecium

Amp-R, Vanc-R

Daptomycin MIC = 1 mg/L

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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