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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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Presentation on theme: "VRE - treatment options for severe infections Dr Nick Brown Addenbrookes Hospital, Cambridge 14 March 2013 Conflict of interest: None."— Presentation transcript:

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

2 Evidence biased medicine Class 0Things I believe Class 0aThings I believe despite the available data Class 1Randomized controlled clinical trials that agree with what I believe Class 2Other prospectively collected data Class 3Expert opinion Class 4Randomized controlled clinical trials that dont agree with what I believe Class 5What you believe that I dont Bleck TP. BMJ 2000; 321: 239

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

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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

9 Mandatory surveillance of glycopeptide-resistant enterococcus bacteraemia, England

10 Voluntary surveillance of enterococcal bacteraemia, England, Wales & NI ~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

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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 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: QPD (n=20)LZD (n=71)OTHER (n=22) Crude mortality13 (65%)18 (25%)11 (50%)P= Directly due to VRE5 (25%)1 (1.4%)5 (23%)P=0.10

17 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%) Twilla JD et al. J Hosp Med. 2012; 7: Comparative data on treatment outcome LZD (n=138)DAPTO (n=63) Clinical Cure74%75%NS Microbiological Cure94% NS Recurrence3%12%P= 0.03 Average LOS37 days40 daysNS All cause mortality18%24%NS

18 Retrospective review 96 VRE bacteraemia 2 US hospitals 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 Cure88.2%90.0%P= 0.80 Relapse2.9%6.7%P= 0.41 All cause mortality20.6%26.7%P= 0.51

19 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 Comparative data on treatment outcome Cheah ALY et al. Clin Microbiol Infect Epub ahead of print Died (n=42)Survived (n=74)OR (95% CI) teicoplanin16 (30%)38Reference linezolid3 (14%) ( ) other12 (46%) ( ) No antibiotic11 (79%)36.85 ( )

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

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

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

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

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


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