1. Clinical Case Study 1: How to deal with an MRSA Benoit GUERY-Infectious Diseases- CHRU Lille-FRANCE

2. Michel R…, 43 years old Admitted on December 16 rd 2003 in the ER for acute respiratory distress

3. M. R… / Previous history Non hodgkin Lymphoma (Burkitt), EBV +. Chemotherapy from November 2000 to November 2001. Complete remission Zona in 1975 and 1998, Syphilis treated in 1992 B hepatitis infection HIV negative (last serology performed one month ago) … but otherwise… in very good shape!!

4. M. R… / Recent history December 11: fever 39°C associated with shivers, resistant to paracetamol. Did not call his MD. December 14: cough, dyspnea, still a fever (39°C). December 16: calls 911 and admitted in the ER: Vital parameters Arterial pressure: 120-80 mmHg ; Respiratory frequency : 40/min ; SPO 2 : 90 %, Cardiac frequency: 130b/min Temperature : 40,1 °C Glasgow coma score : 15 Crackles all over the right lung, cyanosis No other clinical abnormalities

5. M. R… / First biological data Blood gas analysis (O 2 : 6 l/min) : pH : 7,49 ; PCO 2 : 34 mmHg ; PaO 2 : 56 mmHg ; HCO 3 - : 24 mmol/l Urea : 4 mmol/l (0.24 mg/L) ; creatinin : 75 µmol/l (8mg/L) Ionogramm (mmol/l) : Na : 120 ; K : 3,5 ; Cl : 84 ; proteins (g/l) : 61; ASAT-ALATx2/normal Blood count: Hb : 8 g/dl ; WBC : 3,9 G/l (85 % PMN), platelets : 130 G/l Lactate : 3,4 mmol/l ; No coagulation abnormalities EKG : tachycardia

7. 7 Question n°1 First line treatment ?

8. M. R… / First line treatment Failure of the non invasive ventilation  Mechanical ventilation 17/12 : PaO 2 = 96 mmHg with an FiO2 : 0,6 Initial antibiotics: ceftriaxon (2g IV) + ofloxacin (200 mg IV x 2) Legionella pneumophila urine antigen : positive BAL : IF positive (BCYE culture positive on the 4th day)

9. 9 Do you change the antibiotics?

10. M. R… / Evolution December 18: Change for levofloxacin (500 mg IV x 2) + rifampin (600 mg IV x 2) Hemodynamic and respiratory stability until the 21 st December 21 st : worsening of the respiratory status: PaO 2 /FiO 2 = 97 with an FiO 2 = 1 Associated to septic shock (norepinephrin) Endotracheal aspiration: direct examination

11. 21 décembre 2002

12. 12 Question n°2 Do you change your prescription ? I guess yes…

13. M. R… /New molecules prescribed Vancomycin : bolus 15 mg/kg followed by 30 mg/kg continuous perfusion Imipenem : 50mg/kg IV Levofloxacine : no change Rifampin : no change

14. M. R… / Evolution December 22 : 10 7 CFU S aureus, 1 positive blood culture with a Gram positive cocci December 23 : Identification of MRSA also resistant to rifampin, gentamicin and quinolones Treament not changed but imipenem was stopped Within the next few days, the patient remained critical with an hemodynamical instability, requirement for high oxygen fractions, and persistant fever (40°C). Positive blood cultures to S. aureus on days 2, 3, 4 after vancomycin initiation

15. 15 Question n°3 And then ?

16. M. R… / Failure analysis Endovascular explanation Catheters changed (cultures negative) Transoesophageal echocardiography normal Pharmacodynamic failure MIC: vancomycin : 2 mg/l, teicoplanin : 6 mg/l Blood concentrations (mg/l) D2 : 20 D3 : 20 D4 : 42 D5 : 50

17. M. R… / End the case… Vancomycine + quinupristin/dalfopristin (7,5 mg/kg x 3) between day 4 and 9 On day 9 : quantitative endotracheal aspiration: 10 4 MRSA… Linezolid IV (600 mg x 2) (MIC = 0,5 mg/l) between day 9 and 11 Day 11 : MRSA positive blood culture Multiple organ failure and death on day 11 Autopsia : bilateral pneumonia with multiple abcess, no vascular or abdominal localisation.

18. M. R… / 30 décembre 2002

20. Map of Brooklyn indicating regions with low prevalence (white area) and high prevalence (gray area) for S. aureus USA300 strain

21. 21 MRSA, the therapeutics options

22. Linezolide Zyvoxid  Oxazolidinone fonction Semi-synthetic agent

23. Nosocomial pneumonia

24. * mITT : en intention de traiter modifiée. 1) Rubinstein E et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 32(3): 402-12. Vancomycine + aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté ZYVOXID ®  aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté Clinical response

25. * mITT : en intention de traiter modifiée. 1) Wunderink RG et al. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther 2003; 25(3): 980-92 Vancomycine + aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté ZYVOXID ®  aztréonam 1-2 g/8 h si bacille à Gram - prouvé ou suspecté Clinical response

26. * + aztréonam (ou autre) si infection concomitante à gram- documentée ou suspectée.** En intention de traiter. Weigelt J et al. Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005 Jun; 49(6): 2260-6. International multicentric study Open, randomized Compare the clinical efficacy of 2 protocols for complicated skin and soft tissue infections with suspected or documented Gram positive bacteria Complicated skin and soft tissue infections

27. Weigelt J et al. Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005 Jun; 49(6): 2260-6. Vancomycine***, **** ZYVOXID ® *** Clinical response

28. TYGECYCLINE

29. Tigecycline Inhibition of protein synthesis Through ribosome 30S fixation Inhibits the link with tRNA

31. Activity preservation Ribosomal protection Efflux pump protection

33. Tigecycline: bolus 100 mg and 50mg X 2 /day, 566 patients Vanco/aztreonam 1g/2g /12h, 550 patient E.J. Ellis-Grosse et coll. C.I.D. 2005

34. Clinical response

35. Bacteriological response

36. MRSA (n = 37) MIC (mg/l) MIC 90 (range)MBC 90 (range) Ceftobiprole1(< 0,125-2)2(0,25-2) Daptomycine1(< 0,125-1)2(0,25-4) Linézolide2(0,25-4)128(4-> 128) Vancomycine2(0,5-2)4(1-8) CNS (n = 51) MIC (mg/l) MIC 90 (range)MBC 90 (range) Ceftobiprole1(< 0,125-4*)1(< 0,125-8*) Daptomycine0,25(< 0,125-1)1(< 0,125-4) Linézolide2(0,25-2)64(4-> 128) Vancomycine2(0,25-2)4(0,5-8) Ceftobiprole: endocarditis strain ICAAC 2006 - M.S. Rouse et al., abstract E-118

37. MRSA Vancomycin-teicoplanin: still… Linezolid: the use is increasing Tigecycline: should be restricted? Ceftobiprole, new quinolones, …