Evidence for the use of new and old agents for MRSA infection. Dr Charis Marwick Ninewells Hospital & Medical School Dundee

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1 Evidence for the use of new and old agents for MRSA infection Dr Charis Marwick Ninewells Hospital & Medical School Dundee

2 32 year old man Admitted unwell for few days Cough, fever, short of breath, pleuritic pain Drowsy, cachectic, febrile Elevated JVP, systolic murmur, crepitations Intravenous drug user, HCV and HIV Recent admission to vascular ward MRSA positive on discharge screening MRSA in blood cultures this admission

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4 MRSA tricuspid endocarditis Vancomycin + rifampicin plus supportive mx Not for emergency surgery Two weeks with therapeutic vancomycin levels Intermittent fever and still bacteraemia Switched to daptomycin Better response over six weeks Refused further intravenous treatment Switched to linezolid

5 VANCOMYCIN DAPTOMYCIN LINEZOLID Glycopeptide Lipopeptide Oxazolidinone First line in BSAC endocarditis guideline Extensive experience Lack of response despite adequate levels Unlicensed indications in UK at the time Rapidly bactericidal, FDA approved indications Intravenous only Licensed for bacteraemia but not endocarditis Oral route Duration dependent toxicity

6 What is (was) the evidence for treatment of MRSA? BMJ Clinical Evidence systematic review Medline, Embase, Cochrane, FDA, MHRA to November 2009 Systematic reviews of RCTs, RCTs, cohorts Blinded, >20 patients, >80% follow up Eleven publications met criteria MRSA: treating people with infection. Nathwani D, Davey PG and Marwick CA. Clin Evid (Online) 2010 Oct 28. doi: pii:0922

7 INFECTION SITE Any HAP/VAP SSTI BSI Linezolid versus vancomycin OUTCOME LINEZ VANC COMPARISON (95% CI) Clinical cure 1 301/ /377 OR 2.48 ( ) Effective Rx 72h 2 53/61 37/70 23% difference (10-40%) Clinical cure 1 NA NA OR 3.45 ( ) Effective Rx 72h 2 22/28 18/34 26% difference (3-48%) Clinical cure 1 NA NA OR 2.84 ( ) Effective Rx 72h 2 31/33 19/26 21% difference (2-40%) Survival 3 24/36 24/37 OR 1.08 ( ) Clinical cure 4 65/92 41/68 RR 1.22 ( ) 1. Meta analysis: Xiao Lzhu. Chin J Antibiot 2008;33: RCT: Lin D, Sheng R. Int J Antimicrob Agents 2008;32: Meta analysis: Shorr AF et al. J Antimicrob Chemother 2005;56: Systematic review: Yue J-Rfang. Chin J Evid-Based Med 2009;9:646-51

8 INFECTION SITE Any HAP/VAP SSTI BSI Linezolid versus vancomycin OUTCOME LINEZ VANC COMPARISON (95% CI) Clinical cure 1 301/ /377 OR 2.48 ( ) Effective Rx 72h 2 53/61 37/70 23% difference (10-40%) Clinical cure 1 NA NA OR 3.45 ( ) Effective Rx 72h 2 22/28 18/34 26% difference (3-48%) Clinical cure 1 NA NA OR 2.84 ( ) ALL EVIDENCE LOW OR Effective Rx 72h 2 31/33 19/26 21% difference (2-40%) VERY LOW QUALITY BY Survival 3 24/36 24/37 OR 1.08 ( ) Clinical cure 4 65/92 41/68 RR 1.22 ( ) GRADE CRITERIA 1. Meta analysis: Xiao Lzhu. Chin J Antibiot 2008;33: RCT: Lin D, Sheng R. Int J Antimicrob Agents 2008;32: Meta analysis: Shorr AF et al. J Antimicrob Chemother 2005;56: Systematic review: Yue J-Rfang. Chin J Evid-Based Med 2009;9:646-51

9 Other RCT comparisons in review Similar rates of cure and adverse events: Linezolid vs. teicoplanin 1 Quinupristin-dalfopristin vs. vancomycin 2 Trimethoprim-sulfamethoxazole vs. vancomycin 3 Tigecycline vs. vancomycin 4 No RCTs meeting review criteria: macrolides, quinolones, clindamycin, daptomycin, tetracyclines, fusidic acid, rifampicin, trimethoprim, pristinamycin 1.Capeda JA et al. J Antimicrob Chemother 2004;53: Fagon J et al. Am J Resp Crit Care Med 2000;161: Markowitz N et al. Ann Intern Med 1992;117: Florescu I et al. J Antimicrob Chemother 2008;62:i17-28

10 Other RCT comparisons in review Similar rates of cure and adverse events: Linezolid vs. teicoplanin 1 Quinupristin-dalfopristin vs. vancomycin 2 Trimethoprim-sulfamethoxazole vs. vancomycin 3 Tigecycline vs. vancomycin 4 No RCTs meeting ALL EVIDENCE review criteria: LOW OR macrolides, quinolones, clindamycin, daptomycin, tetracyclines, VERY fusidic LOW acid, QUALITY rifampicin, trimethoprim, BY pristinamycin GRADE CRITERIA 1.Capeda JA et al. J Antimicrob Chemother 2004;53: Fagon J et al. Am J Resp Crit Care Med 2000;161: Markowitz N et al. Ann Intern Med 1992;117: Florescu I et al. J Antimicrob Chemother 2008;62:i17-28

11 Limitations of the evidence Incomplete reporting/sparse data Lack of adequate blinding Poorly defined subjective outcomes Retrospective subgroup analysis Inclusion other organisms and/or other treatments Not generalisable Low power due to study size

12 Conclusions and limitation of review Glycopeptides and linezolid seem to have similar efficacy at curing MRSA and have similar rates of adverse effects Linezolid may be better for SSTI and pneumonia Limited evidence that tigecycline may have similar cure rates as vancomycin Trimethoprim-sulfamethoxazole may be as effective as vancomycin in specific patients RESTRICTIVE INCLUSION CRITERIA AND LOW QUALITY OF EVIDENCE

13 Newer drugs and the evidence Double-blind RCT ceftaroline vs. vancomycin plus aztreonam for cssti Corey GR et al. Clin Infect Dis 2010;51(6): Double-blind RCTs telavancin vs. vancomycin for SSTI and HAP Stryjewski ME et al. Clin Infect Dis 2008;46: Rubinstein E et al. Clin Infect Dis 2011;52(1):31 40 Open label RCT of daptomycin vs. vancomycin or flucloxacillin in RIE and SAB Fowler VG et al. N Engl J Med 2006; 355: Pristinamycin for osteoarticular infection Observational data only: Ng J 2005 & Reid AB 2010

14 What about in clinical practice? Lack of high quality RCT evidence Clinical guidelines, treatment registries, observational data valuable BSAC guidelines Gould FK et al. JAC 2009;63: Legislation and approval (FDA, EMA, MHRA, SMC) and cost Antimicrobial management team & local policy Increasing experience with daptomycin and pristinamycin

15 thank you