VRE - treatment options for severe infections

Dr Nick Brown

Addenbrooke’s Hospital, Cambridge

14 March 2013

Conflict of interest: None

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

VRE - treatment options for severe infections

• Context• Confounding factors• Treatment options• Studies of efficacy• Combination therapy

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: 1-12Hoge CW et al. Rev Infect Dis 1991; 13: 600-5.

‘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: 600-5.

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

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

http://www.hpa.org.uk

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

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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

Voluntary surveillance of enterococcal bacteraemia, England, Wales & NI 2003-2010

http://www.hpa.org.uk

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Enterococcus unspeciated

Enterococcus spp. Other named

E. faecium

E. faecalis

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

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

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

Trends in vancomycin-resistant enterococcal bacteraemiarates in the SENTRY Antimicrobial Surveillance Program

US Hospitals 2000–2010

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Arias CA et al. Clin Infect Dis 2012; 54(S3): S233–8

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

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…

Comparative data on treatment outcome

• Retrospective review 113 VRE bacteraemia Nebraska, USA 1993-2005• 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

Erlandson KM et al. Clin Infect Dis 2008; 46: 30-6.

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

• Retrospective review 201 VRE bacteraemia treated with daptomycin or 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

• 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 Chemother 2009; 64: 175–180

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

• Retrospective review of 116 VRE in cohort of 724 enterococcal bacteraemias in Australia 2002-2010

• 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

Comparative data on treatment outcome

Cheah ALY et al. Clin Microbiol Infect. 2013 Epub ahead of print

Died (n=42) Survived (n=74) OR (95% CI)

teicoplanin 16 (30%) 38 Reference

linezolid 3 (14%) 19 0.13 (0.03-0.58)

other 12 (46%) 14 0.79 (0.21-3.04)

No antibiotic 11 (79%) 3 6.85 (1.42-33.1)

Review of VRE endocarditis treatment

Forrest GN et al. J Infect 2011; 63: 420-8

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

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

VRE in an in vitro model with simulated endocarditis vegetations

Hall AD et al. Antimicrob Agents Chemother 2012; 56: 3174-80

E. faecalisDaptomycin MIC = 0.5 mg/L

VRE in an in vitro model with simulated endocarditis vegetations

Hall AD et al. Antimicrob Agents Chemother 2012; 56: 3174-80

E. faeciumDaptomycin MIC = 4 mg/L

Ampicillin plus daptomycin in VRE endocarditis

Sakoulas G et al. Antimicrob Agents Chemother 2012; 56: 838-44

E. faeciumAmp-R, Vanc-R

Daptomycin MIC = 1 mg/L

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