1. Septic Shock: Antibiotics, Activated Protein C, Steroids, and Source Control David A. Talan, MD, FACEP, FIDSA Professor and Chair UCLA School of Medicine Olive View-UCLA Dept. of Emergency Medicine and Division of Infectious Diseases David A. Talan, MD, FACEP, FIDSA Professor and Chair UCLA School of Medicine Olive View-UCLA Dept. of Emergency Medicine and Division of Infectious Diseases

2. What's New and Effective in Septic Shock?  Early Goal-Directed Therapy  Antibiotics & new resistance patterns  Activated Protein C  Corticosteroids  IgG  Early Goal-Directed Therapy  Antibiotics & new resistance patterns  Activated Protein C  Corticosteroids  IgG 30-50% 35% 15% 20% 30% 50%

3. Antibiotics

4. Appropriate Antibiotics and Mortality from Bloodstream Infections Overall (n=3,413) 20% 34% 2.1* Septic shock (n=353) 74% 83% 2.1* Neutropenia (n= 293) 33% 42% 2.1* Comm.-acq. (n=2,077) 18% 29% 1.9* Overall (n=3,413) 20% 34% 2.1* Septic shock (n=353) 74% 83% 2.1* Neutropenia (n= 293) 33% 42% 2.1* Comm.-acq. (n=2,077) 18% 29% 1.9* Leibovici L. J Intern Med 1998;244:379. 1998;244:379. Inappropriate (n=1555/27%) Inappropriate (n=1555/27%) Appropriate (n=2158/63%) Appropriate (n=2158/63%) OR *p < 0.05 “Appropriate” if bacteria susceptible, abx IV < 48 hrs *p < 0.05 “Appropriate” if bacteria susceptible, abx IV < 48 hrs

5. Adjusted Mortality Odds Ratio Initial abx < 8 hrs 0.85 (0.75-0.96) p <0.001 (75.5%) Meehan TP. JAMA 1997;278:2080. Adjusted Mortality Odds Ratio Initial abx < 8 hrs 0.85 (0.75-0.96) p <0.001 (75.5%) Meehan TP. JAMA 1997;278:2080. Time to Antibiotics & 30-Day Mortality for Community-Acquired Pneumonia

6. E. coli (FQREC) E. coli (FQREC) S. aureus (MRSA) S. aureus (MRSA) S. pneumoniae (DRSP) Community-Acquired Septic Shock Spain ‘96 17% (AAC 1999) Spain ‘96 17% (AAC 1999) US & others 30% (Talan 2003) US & others 30% (Talan 2003) Hong Kong ‘00 13% (JAC 2001) Hong Kong ‘00 13% (JAC 2001)

7. Empirical Antimicrobials for Community-Acquired Septic Shock Unclear Source  E. coli  S. aureus  S. pneumoniae  E. coli  S. aureus  S. pneumoniae Levo/Ciprofloxacin ( or Gentamicin) Vancomycin Siegman-Igra Y. Clin Infect Dis 2002;34:1431.

8. Empirical Antimicrobials for Septic Shock - Recently Discharged/Nursing Home  Res. E. coli/ Pseudomonas  Enterococcus  S. pneumoniae  S. aureus  Res. E. coli/ Pseudomonas  Enterococcus  S. pneumoniae  S. aureus Vancomycin Gentamicin & Ceftazidime Siegman-Igra Y. Clin Infect Dis 2002;34:1431.

9. Empirical Antimicrobials for Urosepsis  E. coli  Enterococcus  S. aureus  Pseudomonas  E. coli  Enterococcus  S. aureus  Pseudomonas Levo/Ciprofloxacin and/or gentamicin Pip-tazobactam Nitrite + Nitrite -

10. Empirical Antimicrobials for Community-Acquired Pneumonia  S. pneumoniae  Legionella/Mycoplasma  S. aureus  S. pneumoniae  Legionella/Mycoplasma  S. aureus Levofloxacin Ceftriaxone (or Vancomycin if MRSA-CA, FQ-RSP) Ceftriaxone (or Vancomycin if MRSA-CA, FQ-RSP) ATS. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347.

11. Empirical Antimicrobials for Bacterial Meningitis  S. pneumoniae  N. meningitidis  Listeria monocytogenes (immunocompromised, elderly)  S. pneumoniae  N. meningitidis  Listeria monocytogenes (immunocompromised, elderly) Vancomycin & Ceftriaxone Ampicillin Siegman-Igra Y. Clin Infect Dis 2002;34:1431. After steroids After steroids

12. Streptococcal Myositis - Clindamycin

13. Streptococcal Toxic Shock: Clindamycin vs.  -lactams Deep Superficial Cell wall inhibitors1/7 (14 %) 12/25 (48%) Protein synthesis10/12 (83%)* 10/12 (83%)* inhibitors (87% clindamycin) Zimbelman J. Pediatr Infect Dis 1999;18:1096. Deep Superficial Cell wall inhibitors1/7 (14 %) 12/25 (48%) Protein synthesis10/12 (83%)* 10/12 (83%)* inhibitors (87% clindamycin) Zimbelman J. Pediatr Infect Dis 1999;18:1096. Proportion with Favorable Outcomes  Retrospective  No progression after 24 hrs of Abx  Retrospective  No progression after 24 hrs of Abx

14. Empirical Antimicrobials for Severe Skin/Soft Tissue Infection/Necrotizing Fasciitis  Group A strep  Clostridium/anaerobes  S. aureus  E. coli  Group A strep  Clostridium/anaerobes  S. aureus  E. coli Clindamycin & Pip-tazobactam Gentamicin Check rapid strep test Check rapid strep test

16. Bernard GR. N Engl J Med 2001;344:699.

17. The Role of Protein C in Sepsis  Inflammatory mediators (TNF, IL-1 & 6) promote thrombin release & coagulation  Protein C promotes fibrinolysis & inhibits thrombosis (decreases factor generated thrombin production) & decreases cytokine production  Cytokines in sepsis downregulate thrombin-thrombomodulin activation of protein C  Activated protein C levels in sepsis are low and predict mortality  Inflammatory mediators (TNF, IL-1 & 6) promote thrombin release & coagulation  Protein C promotes fibrinolysis & inhibits thrombosis (decreases factor generated thrombin production) & decreases cytokine production  Cytokines in sepsis downregulate thrombin-thrombomodulin activation of protein C  Activated protein C levels in sepsis are low and predict mortality

18. PROWESS Study of Protein C in Sepsis  Randomized, double-blinded, placebo-controlled  Adults (61 + 17 yrs) with severe sepsis =  presumed or known infection,  3 of 4 (36 38, P > 90, RR > 20, 4,000 12,000) and,  sepsis-induced organ dysfunction < 24 hours  1,690 patients  Exclusion: plts < 30,000, surgery < 12 hrs, head trauma/CVA < 3 mos, GI bleeding < 6 wks, bleeding/clotting disorder, organ transplant, end-stage renal/hepatic disease  Randomized, double-blinded, placebo-controlled  Adults (61 + 17 yrs) with severe sepsis =  presumed or known infection,  3 of 4 (36 38, P > 90, RR > 20, 4,000 12,000) and,  sepsis-induced organ dysfunction < 24 hours  1,690 patients  Exclusion: plts < 30,000, surgery < 12 hrs, head trauma/CVA < 3 mos, GI bleeding < 6 wks, bleeding/clotting disorder, organ transplant, end-stage renal/hepatic disease

19. Activated Protein C (Drotregcogin alfa, Xigris  ) vs. Placebo for Severe Sepsis 28 day all cause 24.7% 30.8% mortality Relative risk reduction 19.4 % (6.6% - 30.5%) Serious bleeding (#fatal) 3.5% (2)2.0% (1) [p=.06] Intracranial 0.2%0.1% 28 day all cause 24.7% 30.8% mortality Relative risk reduction 19.4 % (6.6% - 30.5%) Serious bleeding (#fatal) 3.5% (2)2.0% (1) [p=.06] Intracranial 0.2%0.1% Activated Protein C 24ug/kg/hr X 96 hours Activated Protein C 24ug/kg/hr X 96 hours Placebo Bernard GR, Seigel JP. N Engl J Med 2001;344:699. 19% decreased mortality ~1/2 serious bleeding during invasive procedure; hold 2 hrs before/12 hrs after ~1/2 serious bleeding during invasive procedure; hold 2 hrs before/12 hrs after

20. Activated Protein C for Severe Sepsis: FDA Approved Indication  Suspected or documented infection  Sepsis criteria  Sepsis-induced organ dysfunction (i.e., shock, ARDS, ARF, DIC, acidosis)  APACHE II >25 (31% vs. 44% 28-day mortality) (T, MAP, RR, PaO 2, Na, K, Cr, Hct, WBC, GCS plus age and chronic health points)  Suspected or documented infection  Sepsis criteria  Sepsis-induced organ dysfunction (i.e., shock, ARDS, ARF, DIC, acidosis)  APACHE II >25 (31% vs. 44% 28-day mortality) (T, MAP, RR, PaO 2, Na, K, Cr, Hct, WBC, GCS plus age and chronic health points)

21. Activated Protein C (Drotregcogin alfa, Xigris  ) - Long-Term Survival Median survival 1113 846 (days) Persons > 60 years 252 130 APACHE II > 25 450 71 Median survival 1113 846 (days) Persons > 60 years 252 130 APACHE II > 25 450 71 Activated Protein C Placebo Angus DC. Chest 2002;122(suppl4):51S. Follow-up 90%, median 43 mo.s Follow-up 90%, median 43 mo.s

22. Steroids

23. Dexamethasone for Bacterial Meningitis in Adults Mortality (%) all pts7 15 (53%,p=0.04) S. pneumoniae (%) 14 34 (58%p=.002) Glascow Outcome Score all pts 15 25 (p=0.03) 0-5, 0-4* unfavorable - %) S. pneumoniae, n=108 (%) 26 52 (p=.006) *4= unable to return to work/school Mortality (%) all pts7 15 (53%,p=0.04) S. pneumoniae (%) 14 34 (58%p=.002) Glascow Outcome Score all pts 15 25 (p=0.03) 0-5, 0-4* unfavorable - %) S. pneumoniae, n=108 (%) 26 52 (p=.006) *4= unable to return to work/school DMS 10 mg Q 6 hours X 4 days (n=157) DMS 10 mg Q 6 hours X 4 days (n=157) Placebo (n=144) Placebo (n=144) De Gans J. NEJM 2002;347:1549. Adults 45 + 20 yrs Randomized, double-blind DMS before/during Abx Adults 45 + 20 yrs Randomized, double-blind DMS before/during Abx 53-58% decreased mortality

24. Low-Dose Maintenance Corticosteroids in Septic Shock 28-day mortality Non-responders (n,%) 60/114 (53) 73/115 (63) (16%, p=.02) Responders (n,%) 22/36 (61) 18/34 (53) All patients (n,%) 82/150 (55) 91/149 (61) 28-day mortality Non-responders (n,%) 60/114 (53) 73/115 (63) (16%, p=.02) Responders (n,%) 22/36 (61) 18/34 (53) All patients (n,%) 82/150 (55) 91/149 (61) Hydrocortisone 50 mg Q6hours/Flucortisone 50  g Q24 hours Hydrocortisone 50 mg Q6hours/Flucortisone 50  g Q24 hours Placebo Annane D. JAMA 2002;288:862. Adults mean age 60 yrs with septic shock - unresp. to fluid, on vent. Corticotropin test Adults mean age 60 yrs with septic shock - unresp. to fluid, on vent. Corticotropin test 16% decreased mortality

25. Pain!!!

26. Flesh-Eating Bacteria

29. Antibodies

30. Streptococcal Toxic Shock: IVIG 30 day survival (%) 67 34 (50%, p=.02) IVIG (2g/kg) n=21 IVIG (2g/kg) n=21 No IVIG n=32 No IVIG n=32 Kaul R. Clin Infect Dis 1999;28:800. The Cochrane Library, Issue 3, 2002. Cochrane Review: Polyclonal IVIG Reduces overall mortality by 1/3rd and sepsis-related mortality by 2/3rds Cochrane Review: Polyclonal IVIG Reduces overall mortality by 1/3rd and sepsis-related mortality by 2/3rds 50% decreased mortality

31. Source Control

32. Abdominal CT Scan Appendicitis & Diverticular Abscess Abdominal CT Scan Appendicitis & Diverticular Abscess

33. Ultrasound - Hydronephrosis

36. Take Home Points  Use the right antibiotics, and soon  Consider activated protein C and IVIG if no response to EGDT  Steroids - septic shock - low-dose meningitis - high-dose  Simultaneous imaging and source control  Use the right antibiotics, and soon  Consider activated protein C and IVIG if no response to EGDT  Steroids - septic shock - low-dose meningitis - high-dose  Simultaneous imaging and source control