septic shock: antibiotics, activated protein c, steroids, and source control david a. talan, md,...
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Septic Shock: Antibiotics, Activated Protein C, Steroids, and Source ControlSeptic Shock: Antibiotics, Activated
Protein C, Steroids, and Source Control
David A. Talan, MD, FACEP, FIDSADavid A. Talan, MD, FACEP, FIDSA
Professor and ChairProfessor and Chair
UCLA School of MedicineUCLA School of Medicine
Olive View-UCLA Dept. of Emergency Medicine Olive View-UCLA Dept. of Emergency Medicine
and Division of Infectious Diseasesand Division of Infectious Diseases
David A. Talan, MD, FACEP, FIDSADavid A. Talan, MD, FACEP, FIDSA
Professor and ChairProfessor and Chair
UCLA School of MedicineUCLA School of Medicine
Olive View-UCLA Dept. of Emergency Medicine Olive View-UCLA Dept. of Emergency Medicine
and Division of Infectious Diseasesand Division of Infectious Diseases
What's New and Effective in Septic Shock?
What's New and Effective in Septic Shock?
Early Goal-Directed Therapy
Antibiotics & new resistance patterns
Activated Protein C
CorticosteroidsCorticosteroids
IgG
Early Goal-Directed Therapy
Antibiotics & new resistance patterns
Activated Protein C
CorticosteroidsCorticosteroids
IgG 30-50%30-50%
35%35%
15%15%
20%20%
30%30%
50%50%
AntibioticsAntibiotics
Appropriate Antibiotics and Mortality from Bloodstream Infections
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. Leibovici L. J Intern MedJ Intern Med 1998;244:379.1998;244:379.Leibovici L. Leibovici L. J Intern MedJ 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
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
Time to Antibiotics & 30-Day Mortality for Community-Acquired Pneumonia
E. coli(FQREC)
E. coli(FQREC)
S. aureus(MRSA)
S. aureus(MRSA)
S. pneumoniae (DRSP)S. pneumoniae (DRSP)
Community-Acquired Septic ShockCommunity-Acquired Septic Shock
Spain ‘9617%
(AAC 1999)
Spain ‘9617%
(AAC 1999)
US & others30%
(Talan 2003)
US & others30%
(Talan 2003)
Hong Kong ‘0013%
(JAC 2001)
Hong Kong ‘0013%
(JAC 2001)
Empirical Antimicrobials for Community-Acquired
Septic Shock Unclear Source
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)Levo/Ciprofloxacin ( or Gentamicin)
VancomycinVancomycin
Siegman-Igra Y. Clin Infect Dis 2002;34:1431.Siegman-Igra Y. Clin Infect Dis 2002;34:1431.
Empirical Antimicrobials forSeptic Shock - Recently
Discharged/Nursing Home
Empirical Antimicrobials forSeptic Shock - Recently
Discharged/Nursing Home
Res. E. coli/Pseudomonas
Enterococcus S. pneumoniae S. aureus
Res. E. coli/Pseudomonas
Enterococcus S. pneumoniae S. aureus
VancomycinVancomycin
Gentamicin & CeftazidimeGentamicin & Ceftazidime
Siegman-Igra Y. Clin Infect Dis 2002;34:1431.Siegman-Igra Y. Clin Infect Dis 2002;34:1431.
Empirical Antimicrobialsfor Urosepsis
Empirical Antimicrobialsfor Urosepsis
E. coli
Enterococcus
S. aureus
Pseudomonas
E. coli
Enterococcus
S. aureus
Pseudomonas
Levo/Ciprofloxacin and/or gentamicinLevo/Ciprofloxacin and/or gentamicin
Pip-tazobactamPip-tazobactam
Nitrite +Nitrite +
Nitrite -Nitrite -
Empirical Antimicrobials for Community-Acquired Pneumonia
Empirical Antimicrobials for Community-Acquired Pneumonia
S. pneumoniae
Legionella/Mycoplasma
S. aureus
S. pneumoniae
Legionella/Mycoplasma
S. aureus
LevofloxacinLevofloxacin
Ceftriaxone (or Vancomycinif MRSA-CA, FQ-RSP)
Ceftriaxone (or Vancomycinif MRSA-CA, FQ-RSP)
ATS. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347.ATS. Am J Respir Crit Care Med 2001;163:1730. Bartlett JG. Clin Infect Dis 2000;31:347.
Empirical Antimicrobials for Bacterial Meningitis
Empirical Antimicrobials for Bacterial Meningitis
S. pneumoniae
N. meningitidis
Listeria monocytogenes(immunocompromised, elderly)
S. pneumoniae
N. meningitidis
Listeria monocytogenes(immunocompromised, elderly)
Vancomycin & CeftriaxoneVancomycin & Ceftriaxone
AmpicillinAmpicillin
Siegman-Igra Y. Clin Infect Dis 2002;34:1431.Siegman-Igra Y. Clin Infect Dis 2002;34:1431.
AftersteroidsAfter
steroids
Streptococcal Myositis - Clindamycin
Streptococcal Myositis - Clindamycin
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18Delay in Treatment (hrs)
% S
urv
ival
Clindamycin
Erythromycin
Untreated
Penicillin
Streptococcal Toxic Shock: Clindamycin vs. -lactams
Streptococcal Toxic Shock: Clindamycin vs. -lactams
Deep Superficial
Cell wall inhibitors 1/7 (14 %) 12/25 (48%)
Protein synthesis 10/12 (83%)* 10/12 (83%)* inhibitors (87% clindamycin)
Zimbelman J. Pediatr Infect Dis 1999;18:1096.
Deep Superficial
Cell wall inhibitors 1/7 (14 %) 12/25 (48%)
Protein synthesis 10/12 (83%)* 10/12 (83%)* inhibitors (87% clindamycin)
Zimbelman J. Pediatr Infect Dis 1999;18:1096.
Proportion with Favorable OutcomesProportion with Favorable OutcomesRetrospectiveNo progression after 24 hrs of Abx
RetrospectiveNo progression after 24 hrs of Abx
Empirical Antimicrobialsfor Severe Skin/Soft Tissue
Infection/Necrotizing Fasciitis
Empirical Antimicrobialsfor 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-tazobactamClindamycin & Pip-tazobactam
GentamicinGentamicin
Check rapidstrep test
Check rapidstrep test
Bernard GR. N Engl J Med 2001;344:699.Bernard GR. N Engl J Med 2001;344:699.
The Role of Protein C in SepsisThe 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
PROWESS Study of Protein C in SepsisPROWESS 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 <T > 38, P > 90, RR > 20, 4,000 < WBC > 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 <T > 38, P > 90, RR > 20, 4,000 < WBC > 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
Activated Protein C (Drotregcogin alfa, Xigris) vs. Placebo for Severe SepsisActivated 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 C24ug/kg/hr X 96 hours
Activated Protein C24ug/kg/hr X 96 hours PlaceboPlacebo
Bernard GR, Seigel JP. N Engl J Med 2001;344:699.Bernard GR, Seigel JP. N Engl J Med 2001;344:699.
19% decreased mortality
19% decreased mortality
~1/2 serious bleedingduring invasive procedure;
hold 2 hrs before/12 hrs after
~1/2 serious bleedingduring invasive procedure;
hold 2 hrs before/12 hrs after
Activated Protein C for Severe Sepsis:FDA Approved Indication
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, PaO2, 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, PaO2, Na, K, Cr, Hct, WBC, GCS plus age and chronic health points)
Activated Protein C (Drotregcogin alfa, Xigris) - Long-Term Survival
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 CActivated Protein C PlaceboPlacebo
Angus DC. Chest 2002;122(suppl4):51S.Angus DC. Chest 2002;122(suppl4):51S.
Follow-up 90%, median 43 mo.s Follow-up 90%, median 43 mo.s
SteroidsSteroids
Dexamethasone for Bacterial Meningitis in Adults
Dexamethasone for Bacterial Meningitis in Adults
Mortality (%) all pts 7 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 pts 7 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 hoursX 4 days(n=157)
DMS 10 mg Q 6 hoursX 4 days(n=157)
Placebo(n=144)
Placebo(n=144)
De Gans J. NEJM 2002;347:1549.De Gans J. NEJM 2002;347:1549.
Adults 45 + 20 yrsRandomized, double-blind
DMS before/during Abx
Adults 45 + 20 yrsRandomized, double-blind
DMS before/during Abx
53-58% decreased mortality
53-58% decreased mortality
Low-Dose MaintenanceCorticosteroids in Septic Shock
Low-Dose MaintenanceCorticosteroids 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 mgQ6hours/Flucortisone
50 g Q24 hours
Hydrocortisone 50 mgQ6hours/Flucortisone
50 g Q24 hoursPlaceboPlacebo
Annane D. JAMA 2002;288:862.Annane D. JAMA 2002;288:862.
Adults mean age 60 yrswith septic shock -
unresp. to fluid, on vent.Corticotropin test
Adults mean age 60 yrswith septic shock -
unresp. to fluid, on vent.Corticotropin test
16% decreased mortality
16% decreased mortality
Pain!!!Pain!!!
Flesh-Eating Bacteria Flesh-Eating Bacteria
AntibodiesAntibodies
Streptococcal Toxic Shock: IVIGStreptococcal Toxic Shock: IVIG
30 day survival (%) 67 34 (50%, p=.02)
30 day survival (%) 67 34 (50%, p=.02)
IVIG (2g/kg)n=21
IVIG (2g/kg)n=21
No IVIGn=32
No IVIGn=32
Kaul R. Clin Infect Dis 1999;28:800. The Cochrane Library, Issue 3, 2002.Kaul R. Clin Infect Dis 1999;28:800. The Cochrane Library, Issue 3, 2002.
Cochrane Review: Polyclonal IVIGReduces overall mortality by 1/3rd and
sepsis-related mortality by 2/3rds
Cochrane Review: Polyclonal IVIGReduces overall mortality by 1/3rd and
sepsis-related mortality by 2/3rds
50% decreased mortality
50% decreased mortality
Source ControlSource Control
Abdominal CT ScanAppendicitis & Diverticular Abscess
Abdominal CT ScanAppendicitis & Diverticular Abscess
Ultrasound - HydronephrosisUltrasound - Hydronephrosis
Take Home PointsTake 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