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Old and new antibiotics for S. aureus bacteraemia

Old and new antibiotics for S. aureus bacteraemia. Guy Thwaites Reader in Infectious Diseases/Honorary Consultant in Infectious Diseases and Microbiology Centre for Diagnostics and Clinical Infection Research Kings College London/Guy’s and St. Thomas’ Hospital.

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Old and new antibiotics for S. aureus bacteraemia

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  1. Old and new antibiotics for S. aureus bacteraemia Guy Thwaites Reader in Infectious Diseases/Honorary Consultant in Infectious Diseases and Microbiology Centre for Diagnostics and Clinical Infection Research Kings College London/Guy’s and St. Thomas’ Hospital

  2. “My delight may be conceived when there were revealed to me beautiful tangles, tufts and chains of round organisms in great numbers, which stood out clear and distinct among the pus cells and debris...” • ‘Once established the micrococci are hard to kill • the only thing I found effective was cauterisation with a strong solution of chloride of zinc’ • Alexander Ogston.1844-1929

  3. Treatment of staphylococcal septicemia with sulfamethylthiazole and sulfathiazole. A report of 12 cases. Hamburger and Ruegsegger Ann Int Med. 14:1137. 1941

  4. Reserve Constable Albert Alexander John Radcliffe Hospital. Dec 1940. First recipient of IV penicillin for purulent staphylcoccal infection of head and neck; one eye enucleated. Produced by Florey, Chain and Heatley in Oxford

  5. PENICILLIN: ITS ANTIBACTERIAL EFFECT IN WHOLE BLOOD AND SERUM FOR THE HEMOLYTIC STREPTOCOCCUS AND STAPHYLOCOCCUS AUREUS CHARLES H. RAMMELKAMP AND CHESTER S. KEEFER ‘In patients with staphylococcal bacteremia or localized infections caused by Staphylococcus aureus, the blood or local lesion may not be sterilized for several days after the institution of penicillin therapy…’ J Clin Invest.22(5):649–657. 1943 California and Western Medicine. 63 (5); 1945

  6. 55 cases (64% endocarditis) • Mortality 71% • ‘No single drug regimen can be confidently recommended….but various combinations, in pairs, of penicillin, tetracycline, chloramphenicol and erythromycin are suggested…. and should be administered for at least 6 weeks.’ Wilson and Hamburger. Am J Med. 22 (3); 437. 1957

  7. What more do we know now?

  8. The management of S. aureus bacteraemia in 2009/10 The Management of Staphylococcus aureus Bacteremia in the United Kingdom and Vietnam: A Multi-Centre Evaluation.UKCIRG.PLOS One Dec 2010

  9. What does the current literature tell us? • Mortality 25% • 12,000 cases. UK • 16 RCT anti-microbial therapy • <1500 patients enrolled • Majority of evidence from uncontrolled observational studies March 2011

  10. What do we know in 2012? • Rapid identification and removal of the focus (pus) improves outcome • Prolonged antimicrobial treatment is required for cure • Glycopeptides aren’t as good as beta-lactams

  11. What don’t we know? • Are some beta-lactams better than others? • Best dose? • Best mode of delivery? • Optimal duration of therapy? • Are combinations better than single agents? • What role should the new agents – linezolid, daptomycin, tigecycline – play?

  12. Rapid identification and removal of the focus (pus) improves outcome Copenhagen, Denmark Duke Medical Centre, USA 244 patients with SAB 13% relapsed; 16% died Death 6.5X more likely if IV catheter not removed Persistent focus associated with death: OR 6.7 (2.1-21.0) Fowler V, CID. 27;478:1998 Detroit, USA 284 adults with SAB 33% died; 8% relapse 16X more likely to relapse or die If focus not removed Jensen A. Arch Int Med. 162;25:2002 Johnson L, Scand J ID. 35;782. 2003

  13. In-hospital outcome in 630 adults with SAB: 549 UK, 80 Vietnam UKCIRG. PLOS One. Dec 2010

  14. Prolonged antimicrobial treatment is required for cure 1 RCT. 11 adults with SAB. 2 vs 4 weeks • Rest of evidence is observational (>20 studies) Thomas and Morris, Int Med J. 2005. • Prospective study of 276 cases of catheter-associated SAB • 9% mortality; 4% metastatic disease • 33% given <10 days of antibiotics • No relationship between duration and outcome 235 patients: 46 IV catheter related Fowler and Cosgrove. Clin Infect Dis. 46: S386-S393. 2008

  15. Glycopeptides aren’t as good as beta-lactams • RCT evidence: Beta-lactam vs GP • 2 trials: 47 IVDU with Right sided S. aureus endocarditis • 68% failed in GP arm vs 5% in Beta-Lactam arm 123 haemodialysis patients with MSSA bacteraemia Treated with cefazolin (46) or vancomycin (77) Stryjiewski M, CID 2007.

  16. What is the role of new antibiotics?LinezolidDaptomycinTigecycline

  17. Linezolid ‘Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study ‘ ‘Linezolid versus vancomycin for the treatment of infections caused by methicillin-resistant Staphylococcus aureus in Japan.’ J Antimicrob Chemother. 2007 Dec;60(6):1361-9 J Antimicrob Chemother. 2004 Feb;53(2):345-55

  18. cSSTI Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): a meta-analysis. Curr Med Res Opin. 2010 Feb; 26(2):407-21

  19. Linezolid versus vancomycin for Staphylococcus aureus bacteraemia: pooled analysis of randomized studies • N= 99 • ‘Cure’ in 28 (55%) of 51 linezolid recipients and 25 (52%) of 48 vancomycin recipients • Odds ratio for cure with linezolid versus vancomycin = 1.12 (95% CI, 0.51-2.47) J Antimicrob Chemother. 2005 Nov;56(5):923-9

  20. Linezolid for HAP? Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a meta-analysis of randomized controlled trials. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med. 2010 Sep;38(9):1802-8. Chest. 2011 May;139(5):1148-55

  21. Daptomycin ‘Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus’ 246 patients with S. aureus bacteremia with or without endocarditis 6 mg/Kg of Daptomycin vs initial low-dose gentamicin + antistaphylococcal penicillin or vancomycin. 42 days later: modified ITT, successful outcome: Daptomycin: 53/120 (44.2%) Standard: 48/115 (41.7%) Absolute difference: 2.4 percent; 95 percent confidence interval, -10.2 to 15.1 percent). Note: Clinically significant renal dysfunction occurred in 11.0% who received daptomycin and in 26.3% who received standard therapy (P=0.004). N Engl J Med. 2006 Aug 17;355(7):653-65

  22. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis. 2010 Jun 15;50(12):1568-74.

  23. Tigecycline Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. Cure for MRSA disease: Tigecycline: 70/86 81.4% (71.6–89.0) Vancomycin: 26/31 83.9 (66.3–94.5) J Antimicrob Chemother. 2008 Sep;62 Suppl 1:i17-28 Clin Infect Dis. 2010 Jan 15;50(2):229-38 Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III clinical trials 170 patients with cSSI, cIAI, or CAP Cure rates for bacteraemia: MSSA/MRSA – 16/20 (80%) MRSA – 5/6 (83%)

  24. Why is S. aureus bacteraemia so difficult to treat?

  25. Persistent bacteraemia is an independent predictor of metastatic spread of S. aureus Detroit, USA • Prospective study of 245 adults with SAB • BC + >3 days in 38% (MRSA=MSSA) • Rapid extinction: complications in 5% • Persistent bactereamia (>3 days): complications in 40% Fowler V et al.Arch Int Med. 163(7):2066: 2003 Khatib Scand J ID. 38;7:2006

  26. Why does S. aureus persist in the bloodstream despite ‘active’ antibiotics?

  27. Rogers D, J Exp Med. 103 (6):713. 1957

  28. Neutropenia and invasive human S. aureus disease ‘Comparative study of clinical characteristics of neutropenic and non-neutropenic adult cancer patients with bloodstream infections’ 399 consecutive blood-stream infections S. aureus 12% in neutropenic vs 35% if non-neutropenic (p=0.02) ‘S. aureus bacteraemia in patients With haematological malignancies’ Velasco. J Clin Micro Infect Dis. 25. 1. 2006 • Neutropenia associated with: • Less severe signs of sepsis • Shorter duration of bacteraemia • Less metastatic complications Venditti. Haematologica. 88.923. 2003

  29. Survival of S. aureus within neutrophils is well documented Gresham. J Immunol. 164. 3713. 2000 Thwaites and Gant. Nat Rev Micro. 9. 215. 2011

  30. S. aureus persists in the bloodstream within neutrophils • Antibiotics with enhanced intracellular activity may terminate the bacteraemia • faster and improve patient outcome

  31. Combination therapy for SAB?

  32. Adjunctive gentamicin for SAB/endocarditis Ceftriaxone + gentamicin Cloxacillin + gentamicin Antimicrob Agents Chemother. 2002 Feb;46(2):378-84.

  33. ‘Initial Low-Dose Gentamicin for Staphylococcus aureus Bacteremia and Endocarditis Is Nephrotoxic’ Clin Infect Dis. 2009 Mar 15;48(6):713-21. Potential individual predictors of clinically significant decrease in creatinine clearance ‘Conclusions: Initial low-dose gentamicin as part of therapy for S. aureus bacteremia and native valve infective endocarditis is nephrotoxic and should not be used routinely, given the minimal existing data supporting its benefit.’

  34. Other possible agents • Fusidic acid: anecdotal evidence only; hepatic toxicity • Fluoroquinolones: 1 RCT (n=380) of adjunctive levofloxacin; no effect except if rifampicin used. • Tetracyclines: attractive pharmacological properties. No clinical data.

  35. Rifampicin: pros and cons Pros: pharmacology Cons: resistance and toxicity Serious hepatic toxicity <1% Drug interactions Incidence of rifampicin resistance: 0-25% Excellent oral bioavailability Concentrated within cells Active within biofilms Cheap: 73p daily oral dose

  36. Clinical evidence: 4 RCT (n=246 patients)

  37. Rifampicin: meta-analysis of RCT data (246 patients in total)

  38. Estimated effect sizes All patients with severe S. aureus infection (n=246) Bacteraemic patients only (n=98) Rifampicin reduced infection related death by 54% (p=0.22) Rifampicin reduced bacteriological failure by 77% (p=0.17) • Rifampicin reduced infection related death by 55% (p=0.02) • Rifampicin reduced bacteriolgical failure by 58% (p=0.004)

  39. AdjunctiveRifampicintoReduceEarlymortality from Staphylococcus aureusbacteraemia: a multi-centre, randomised, double blind placebo controlled trial (the ARREST trial) Proposal submitted to NIHR/HTA October 2010 Funded: November 2011 REC and MHRA approval May 2012 Start randomising patients in October 2012

  40. The UK Clinical Infection Research Group (UKCIRG): the ARREST Trialists Middlesbrough Hull Liverpool Sheffield Cambridge Birmingham Royal Free Bath UCLH Exeter Guy’s and STH Plymouth Kings St. Georges Oxford Brighton Portsmouth

  41. Blood taken for culture in adult with signs of infection S. aureus grown Physician decides and initiates standard antibiotic therapy empirically <96hrs antibiotics received, no contraindications to rifampicin and rifampicin not mandated in guidelines RANDOMISE 940CONSENTINGPATIENTS TO Co-primary endpoint: All-cause mortality through 14 days, bacteriological failure/death through 12 weeks 14 days blinded rifampicin 14 days matched placebo Follow-up: day 3, 7, 14 then weekly whilst in hospital, and at discharge. Final follow-up at 12 weeks.

  42. Summary • S. aureus bacteraemia is difficult to treat • Evidence-base for defining optimal therapy is woeful • Identify and remove the focus (pus) • Beta-lactams more effective than glycopeptides for MSSA • Newer agents as effective as vancomycin • Long antibiotic courses required if deep undrainable foci • Combination therapy? Rifampicin?

  43. Acknowledgements • All members of the UKCIRG • Special Trustees for the Hospital for Tropical Diseases • Wellcome Trust UK • And NIHR HTA for agreeing to fund the trial

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