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: 1-12 Hoge 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

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

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

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 bacteraemia rates in the SENTRY Antimicrobial Surveillance Program US Hospitals 2000–2010 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 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.

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%) 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

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 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

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

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

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 E. faecalis Daptomycin MIC = 0.5 mg/L Hall AD et al. Antimicrob Agents Chemother 2012; 56: 3174-80

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

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

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