`Anand Kumar MD, FRCPC, FCCP, FCCMProfessor of Medicine

University of Manitoba

Health Sciences Centre

St. Boniface Hospital

Winnipeg, Manitoba

For available slides: search “anand kumar” “medicine” “manitoba”

Email: akumar61@yahoo.com

Early Antibiotics for Sepsis and Septic Shock: A Gold Standard

Surviving Sepsis Bundle 2012

Severe Sepsis 3-Hour Resuscitation Bundle

• administer broad spectrum antimicrobials (1 hr)

• lactate level

• blood cultures prior to administration of antimicrobials

• 30 ml/kg crystalloid for hypotension or lactate ≥4

mmol/l

The Gold Standard for Evidence

in Medical Science

• RCT?

– Generalizability

– Reproducibility!

• Glycemic control

• Physiologic corticosteroid therapy

• Activated protein C (drotrecogin-alfa)

• Goal-directed resuscitation

3

The Gold Standard for Evidence

in Biological Science

• Biologic rationale…a reasonable hypothesis

• Reproducibility across a wide range of study

designs including observational studies; in the

case of early antimicrobials

– Experimental animal studies

– Direct observational human data

– Indirect but related observational data

– Bundle analysis

4

5

Speed is Life

• The speed of clearance of the microbial

pathogen is the critical determinant of

outcome in septic shock (and other

conditions where there is a time-

dependent risk of irreversible and

irreplaceable organ failure)

6

Time

Antiinflammatory

(endogenous)

CARS

SIRS RECOVERY

OrganInjury

van der Poll T, van Deventer SJH. Infect Dis Clin N Am

Infection

Antimicrobials

Sepsis and Septic Shock: An

Intensivist’s Immunologic View

7

Microbial load

Inflammatory response

Toxic burden

Cellular dysfunction/tissue injury

TIME

Shock

Threshold

DEATH

An Injury Paradigm of Septic

Shock: The Golden HoursA Kumar, Virulence 2014;5:80–97

8

An Injury Paradigm of Sepsis

and Septic Shock

Microbial load

Inflammatory response

Toxic burden

Cellular dysfunction/tissue injury

TIME

earlier

antimicrobial

therapy

Shock

Threshold

A Kumar, Virulence 2014;5:80–97

9

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

hrs post-implant

% s

urv

ival

sham (n=20)

no Rx (n=20)

saline (n=10)

Ab Rx 0h (n=10)

Ab Rx 6h (n=10)Ab Rx 12h (n=10)

Ab Rx 15h (n=10)

Ab Rx 18h (n=10)time response p<.0001

1500 cfu

E. coli murine peritonitis/septic shock

mortality vs time of antibiotic initiation

Kumar et al, JID 2006

10

Mean Arterial Pressure in Murine

Septic Shock

＊

††

†††

†P < 0.0001

Time (hr)

0 12 24 36 48 60 72 84 96

MA

P (

mm

Hg

)

20

40

60

80

100

120

Kumar et al, JID 2006

11Kumar et al. CCM. 2006:34:1589-96.

Cumulative Initiation of Effective

Antimicrobial Therapy and Survival in

Septic Shock

time from hypotension onset (hrs)

fraction o

f to

tal patients

0.0

0.2

0.4

0.6

0.8

1.0 survival fraction

cumulative antibioticinitiation

12Kumar et al, CCM. 2006:34:1589-96.

Mortality Risk with Increasing Delays in

Initiation of Effective Antimicrobial Therapy

Time (hrs)

Odds R

atio o

f D

eath

(95%

Confidence I

nte

rval)

1

10

100

Time to Antimicrobial: Severe Sepsis

Ferrer et al, Crit Care Med 2014;42:1749-1755

Hospital M

ort

alit

y

Benefit of Early versus Late Antibiotics

Odds Ratio of Survival (95% CI)

0.01 0.1 1 10 100

BenefitHarm

* courtesy, C Natanson

Author Year N Diagnosis

Miner 2001 171 Meningitis

Larche 2002 88 Bact/pneumonia*

Houck 2004 13,771 Pneumonia

Proulx 2005 118 Meningitis

Meehan 1997 14,069 Pneumonia

Gacouin 2002 213 Legionella

Iregui 2006 107 VAP

Lodise 2003 167 S. aureus

Kang 2003 123 P. aeruginosa

15

Impact of Appropriateness of Initial Antimicrobial

Therapy on Survival from Septic Shock

percent (%)

0 20 40 60 80 100

lcbi

cri

uti

sst

IAI

pneu

nosocomial

community

bacteremia -

bacteremia +

culture -

culture +

all

%survival

% appropriate

survival (%)

0 10 20 30 40 50 60 70 80

lcbi

cri

uti

sst

IAI

pneu

nosocomial

community

bacteremia -

bacteremia +

culture -

culture +

all

inappropriate

appropriate

Kumar et al, Chest 2009; 136:1237–1248

Meta-

analysis:

IAA in

severe

infection

16OR Death

Paul AAC

2010;54:

4851–4863

17

CAP Septic Shock: Finnsepsis

Varpula et al, Acta Anesthesiol Scand 2007

18

Impact of Bundle Elements on

Mortality of Septic Shock

Hazard Ratio

1

p value

0-1 hr .008

1-3 hr .127

3-6 hr .419

prev AbRx .383

fluid challenge .966

low dose steroid .688

aPC .004

4.25

Ferrer et al, AJRCCM 2009;180:861-6

Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2

0.01 0.1 1 10 100

Favors Control Favors Bundle

p < 0.0001

Heterogeneity

I2 = 0%, p = 0.97

Overall Odds Ratio

of Survival (95% CI)

Trzeciak '06

Kortgen '06

Shapiro '06

Micek '06

Nguyen '07

Jones '07

Author/Yr

Studies of Severe Sepsis

Bundles Survival

El Solh ‘08

Rivers ‘01

-3-2-10123

p < 0.0001

Favors Control Favors Bundle

Weighted Mean Difference (± 95% CI)

Heterogeneity

I2 = 0%, p = 0.89

Studies of Severe Sepsis Bundles

(what changes?): Hours to Antibiotics

Barochia, et al. Crit Care Med. 2010 Vol. 38, No. 2

Trzeciak '06

Kortgen '06

Shapiro '06

Micek '06

Nguyen '07

Jones '07

Author/Yr

El Solh ‘08

Rivers ‘01

p = 0.0005

Studies of Severe Sepsis Bundles Resuscitation

Components (what changes?)

I2 = 89%

p < 0.0001

Author / Year

Trzeciak '06Kortgen '06Shapiro '06Micek '06Nguyen '07Jones '07

Overall not reportable

Crystalloid Usage (L)

-4 -2 0 2 4

El Solh ‘08

Rivers ‘01

Vasopressor Usage

0.0

001

0.0

01

0.0

1

0.1 1 10

10

0

10

00

10

000

I2 = 84%

p < 0.0001

Overall not reportable

I2 = 0%

p = 0.57

Barochia, et al. Crit Care Med.

2010 Vol. 38, No. 2

Inotropes

Favors Control Favors Bundle0.001 0.01 0.1 1 10 100 1000

Trzeciak '06Kortgen '06Shapiro '06Micek '06Nguyen '07Jones '07El Solh ‘08

Rivers ‘01

RBC

Favors Control Favors Bundle0.001 0.01 0.1 1 10 100 1000

I2 = 89%

p < .0001

Overall not reportable

22

Time to Antimicrobial in Sepsis/Septic

Shock: Sterling Meta-analysis

Sterling et al, Crit Care Med, 2015:43:1907-1915

23

the “purgamentum init, exit

purgamentum” problem

Sterling et al, Crit Care Med, 2015:43:1907-1915

Requirements for an appropriate

time to antimicrobial study

1. Plausible biologic rationale

2. Index to appropriate antimicrobial

– Systematic bias to null

3. Index to an appropriate clinical start-point

– Physiologic parameter vs administrative

– Inclusion of patients with unclear start-point

(systematic bias to null)

24

25

Time to Antimicrobial: Severe

Sepsis

0%

25%

50%

75%

100%

0-1 1.1-2 2.1-6 6.1-12

12.1-24

24.1-48

48.1-72

25%

19%

70%

81%86%

100% 100%

Timing with respect to dose of 1st appropriate antibiotic (hours)

Mortality and Timing of Appropriate Antibiotic Therapy

Kumar et al. July 2003 Septic Shock data set

Early Antimicrobials in Sepsis

and Septic Shock: The Gold

Standard

26