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VRE - treatment options for severe infections

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

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VRE - treatment options for severe infections

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  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

  4. 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: 600-5.

  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.

  6. 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

  7. Mandatory surveillance of glycopeptide-resistant enterococcus bacteraemia, England 2003-2011 http://www.hpa.org.uk

  8. Mandatory surveillance of glycopeptide-resistant enterococcus bacteraemia, England 2003-2011 http://www.hpa.org.uk

  9. ~20% Vanc-R ~2% Vanc-R Voluntary surveillance of enterococcal bacteraemia, England, Wales & NI 2003-2010 http://www.hpa.org.uk

  10. 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

  11. Trends in vancomycin-resistant enterococcal bacteraemiarates in the SENTRY Antimicrobial Surveillance ProgramUS Hospitals 2000–2010 Arias CA et al. Clin Infect Dis 2012; 54(S3): S233–8

  12. 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 Treatment options for invasive infection due to VRE • Not quite here yet • Oritavancin • Dalbavancin • (new oxazolidonones) • (Cephalosporins with enhanced Gram positive activity) No specific recommendations in AHA, ESCMID or BSAC endocarditis guidelines

  13. 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…

  14. 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.

  15. Comparative data on treatment outcome • 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

  16. Comparative data on treatment outcome • 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

  17. Comparative data on treatment outcome • 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 Cheah ALY et al. Clin Microbiol Infect. 2013 Epub ahead of print

  18. Review of VRE endocarditis treatment • Retrospective review of 50 VRE endocarditis cases 2000-2008 • 26 E. faecium, 24 E. faecalis Forrest GN et al. J Infect 2011; 63: 420-8

  19. 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

  20. 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: 3174-80

  21. 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: 3174-80

  22. 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: 838-44

  23. 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

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