Mazen Kherallah, MD, FCCP

King Faisal Specialist Hospital & Research Center

Terms

Infection SIRS Bacteremia and BSI Sepsis Severe sepsis

Sepsis Syndromes1992: SCCM/ACCP

Parasite

Virus

Fungus

Bacteria

BSI

SevereSepsis

Shock

Burns

Trauma

SevereSIRS

Infection SIRSSepsis

The Sepsis Continuum

SIRS = systemic inflammatory response syndrome.

Bone et al. Chest. 1992;101:1644.

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

•A clinical response arising from a nonspecific insult, including 2 of the following:

•Temperature 38oC or 36oC•HR 90 beats/min•Respirations 20/min•WBC count 12,000/mm3 or 4,000/mm3 or >10% immature neutrophils

SIRS due to Infection

The Sepsis Continuum

SIRS = systemic inflammatory response syndrome.

Bone et al. Chest. 1992;101:1644.

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

Sepsis with 1 sign of organ dysfunction

*Cardiovascular (refractory hypotension)

*Renal*Respiratory*Hepatic*Hematologic*CNS*Unexplained metabolic acidosis

Shock

Sepsis: A Complex ClinicalChallenge

SepsisSepsisSIRSSIRSInfection/Infection/TraumaTrauma Severe SepsisSevere Sepsis

• High mortality rate (35%-45%)• Heterogeneous patient population• Unpredictable disease progression• Unclear etiology and pathogenesis

Wheeler and Bernard. N Engl J Med. 1999;340:207.

Sepsis: A Deadly Healthcare Challenge

Brun-Buisson, 1995*

Abraham, 1997†

Natanson, 1998‡

Friedman, 1998§

Severe sepsis

Severe sepsis

Septic shock

Severe sepsis/septic shock

Septic shock

56%-60% (1052)

36% (78)

42% (62)

38% (4356)

49.7% (10,694)

StudyStudy ConditionCondition Mortality Rate (N)Mortality Rate (N)

Brun-Buisson et al. JAMA. 1995;274:968; Abraham et al. JAMA. 1997;277:1531; Natanson et al. Crit Care Med. 1998:26:1927; Friedman et al. Crit Care Med. 1998;26:2078.

*Prospective survey, 28-day mortality; †Randomized placebo-controlled trial, 28-day mortality; ‡Analysis of placebo arms in 21 recent clinical trials; §Analysis of 131 studies.

Severe Sepsis: A Significant Healthcare Challenge

†Angus DC et al. Crit Care Med. 2001 .‡Sands KE et al. JAMA. 1997;278:234-40.§Zeni F et al. Crit Care Med. 1997;1095-100.

28%† 34%‡50%§

0

20

40

60

Mo

rtal

ity

(%)

Reduction of Mortality

Infection specific treatment Appropriate antimicrobials

Sepsis specific treatment Drotrecogin alpha: activated protein C

Supportive treatment Early goal directed therapy Intensive insulin therapy Low tidal volume ventilation Low dose steroids

Empiric Antimicrobial Regimen

Initial antibiotic regimen chosen for suspected infection based on clinical presentation and local epidemiological data, pending the results of obtained cultures.

When culture results are obtained: Appropriate initial regimen is the regimen which included

antibiotics turned out to be covering the isolated organism(s)

Inappropriate initial regimen is the regimen which did not include antibiotic(s) covering the isolated organism(s), and change of antibiotic is necessary to cover those organisms

Inappropriate Initial Antimicrobial Therapy

34

73

52

27

0

10

20

30

40

50

60

70

80

Alvarez-Lerma, 1996 Kollef, 1998 Luna, 1997 Rello, 1997

Inci

denc

e (%

)

430 60 65 100

Mortality Associated with Initial Inadequate Therapy

0 20 40 60 80 100

Luna, 1997

Ibrahim, 2000

Kollef, 1998

Kollef, 1999

Rello, 1997

Alvarez-lerma, 1996

%Mortality

Initial Inadequate Therapy Initial Adequate herapy

Inadequate Treatment and Mortality: (BSI) Resistant Pathogens

0 10 20 30 40 50 60 70 80 90 100

VRE

Candida spp

MRSA

CNS

P.aeruginosa

Klebsiella

Enterococcus

E.coli

MSSA

%Inadequate antibiotic therapy Hospital mortality

Ibrahim EH, et al. Chest 2000;118:145-155

Inadequate Antimicrobial Therapy

2000 consecutive MICU/SICU patients 655 (25.8%) with infections 169 (8.5%) with inadequate therapy

Kollef MH, et al chest. February 1999;115(2):462-474

Infection Classification

0

5

10

15

20

2530

35

40

45

Inadequate Therapy%

Nosocomial+Communityinfection

Nosocomial Infection Community Infection

Kollef MH, et al chest. February 1999;115(2):462-474

Cohort of Infected Patients and Inadequate Therapy

Risk factor Adjusted Odds

Prior ABs 3.39

BSI 1.88

APACHE II 1.04

Decreasing age 1.01

1 .0 b1

Kollef MH, et al chest. February 1999;115(2):462-474

Most Common Pathogens Inadequate therapy (n=169)

P. aeruginosa: 53 MRSA: 45 VRE: 13

Adequate therapy (n=486) Escherchia coli: 76 MSSA: 88

Kollef MH, et al chest. February 1999;115(2):462-474

Clinical Outcomes

Variable Inadequate Rx (n=169)

Adequate Rx (n=486)

Organ failure 2.51.5 1.91.4

Hospital LOS (days)

22.825.7 2025.8

APACHE II 10.210.2 7.18.5

Kollef MH, et al chest. February 1999;115(2):462-474

Hospital Mortality of Infected Patients

0

10

20

30

40

50

60

Hospital Mortality (%)

All Causes ID related

Inadequate therapy Adequate therapy

Kollef MH, et al chest. February 1999;115(2):462-474

P<0.001

Inappropriate Empiric Antibiotic Therapy: KFSHRC-Jeddah

4543%

6057%

Inappropriate Appropriate

Total of 105 patients with clinically significant, microbiologically documented infection

Inappropriate Initial Antimicrobial Therapy

34

73

52

27

43

0

10

20

30

40

50

60

70

80

Alvarez-Lerma,1996

Kollef, 1998 Luna, 1997 Rello, 1997 KFSH, 2002

Inci

denc

e (%

)

430 60 65 100 105

Inappropriateness based on Infection Setting: KFSHRC-Jeddah

9

35

26

34

0%10%20%30%40%50%60%70%80%90%

100%

Community-acquired Hospital acquired

Inappropriate Appropriate

KFSHRC-Jeddah, QM data 2002

Inappropriateness as per Site of Infection

1614 8

1523 11

0%10%20%30%40%50%60%70%80%90%

100%

Blood-stream Respiratory Urinary

Inappropriate Appropriate

KFSHRC-Jeddah, TQM data 2002

Based on Previous Antibiotic Use

27

18

50

10

0%10%20%30%40%50%60%70%80%90%

100%

No previous antibiotics Previous antibiotics

Inappropriate Appropriate

KFSHRC-Jeddah, TQM data 2002

Inappropriate Empiric Antibiotic Therapy: KFSHRC-Jeddah

1867%

933%

Inappropriate Appropriate

Total of 27 patients with hospital acquired infections and previously on antibiotics

KFSHRC-Jeddah, TQM data 2002

Inappropriate Coverage as per Organism

0 10 20 30 40 50 60 70 80 90 100

Pseudomonas

Klebsiella

E. coli

MSSA

CNS

Stenotrophomonas

Yeast

23

18

11

3

3

10

KFSHRC-Jeddah, TQM data 2002

6

Reasons for Inappropriateness

13

7

24

11

5

22

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

UnusualCandidaImp. Resist. GNB3rd ceph. resist. GNBResitant GPBIdentifed organismSensitive GNBNo antibiotics

b

KFSHRC-Jeddah, TQM data 2002

Reasons for Inappropriateness

28%44%

20%4%

4%

No coverageResistant organismsSensitive organismsCandidaUnusual

b

KFSHRC-Jeddah, 2002

Bacterial Resistance

Rates of Resistance Among Nosocomial Infections Reported in Intensive Care Patients, Comparison of 1999 (January-July) with Historical Data

0 10 20 30 40 50 60 70 80 90

% Resistance

3rd Ceph/Enterobacter

3rd Ceph/Pseud.

Quinolone/Pseud.

Imipenem/seud

3rd Ceph/K.Pneum.

3rd Ceph/E.coli

MRSA

Methicillin/CNS

VRE

January-July 1999

1993-1998

Antibacterial Resistance in Nosocomial InfectionsGram-Negative Pathogens

P. Aeruginosa Resistance to imipenem

0

5

10

15

20

25

Rat

e%

P. Aeruginosa Resistance to quinolones

0

5

10

15

20

25

30

35

Rat

e%

Klebsiella pneumoniaeResistance to third-generation cephalosporins

0

2

4

6

8

10

12

14

Rat

e%

ICUNon-ICU

Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315

Antibacterial Resistance in Nosocomial InfectionsGram-Positive Pathogens

MRSA

0

10

20

30

40

50

60

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

Rat

e%

Methicillin-resistant Coagulase-negative Staphylococcus

0102030405060708090

100

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

Rat

e%

Vancomycin-resistant enterococci

0

5

10

15

20

25

30

35

Rat

e% ICUNon-ICU

Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315

Methicillin Resistant Staphylococci by setting

0102030405060708090

ICU Non-ICU Outpatient

% r

esis

tant

S.aureus Coagulase-negative Staphylococci

Fridkin. Clin Infect Dis.1999

Use of Vancomycin in US and Rate of VRE

0

20

40

60

80

100

120

84 85 86 87 88 89 90 91 92 93 94 95 96 97

Kilo

gra

m o

f van

co (X

100)

pu

rch

ased

02468101214161820

% V

RE

Usage of Vancomycin Rate of VRE

Kirsl et al. Historical usage of vancomycin. Antimicrob Agent Chemo 1998National Nosocomial Infection Surveillance System (CDC)

Enterococcal Resistance by Species

0

10

20

30

40

50

60

70

80

90

E. faecium E. fecalis

Ampicillin resistantVancomycin resistant

Jones. Diagn. Microbiol Infect Dis. 1998

Independent Predictors of Vancomycin-Resistant Enterococci in Adult Intensive Care Units

Change in Predictor Estimated Change in Rate of VRE

P-value

Non-ICU VRE rate +++ 0.0001

Cephalosporin use (3rd) ++ 0.0002

Vancomycin use ++ 0.0001

Type of ICU + 0.01

NNIS

Outcome of Enterococcus faecium Bacteremia

Outcome Measure VSE (n=32)

VRE (n=21)

P

Mortality 13 (41) 16 (76) 0.009

Directly related 3 (9) 8 (38) 0.01

Indirectly related 6 (19) 5 (24) 0.24

Unrelated 4 (13) 3 (14) 0.31

Survival 19 (59) 5 (24) 0.009

Total hospital costs $56,507 $83,897 0.04

Stosor. Arch Intern Med. 1998

Reduce Inappropriate Initial Antimicrobial Therapy

Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

Efforts to Decrease the Rate of Emergent Antimicrobial Resistance

CDC guidelines and barrier precautions

Antibiotic restriction Selective bowel decontaminationRotation antibioticsShort course antibiotic course

Impact of CDC Guidelines on Endemic VRE

VRE Site Barrier Precautions

Vancomycin Use Colonization Infection

NY 28% to 92% - 50% 35%

MD Initial 64% 59% But not statistically significant

IN 22% to 88% - 80% 0

M. Montecalvo et al. Ann Int Med. 1999J Morris et al. Ann Int Med. 1995E Jochimsen et al. ICHE 1999

Impact of Formulary Change on VREEmpiric therapy for febrile neutropenia

Factor 1998 1999 P

Antibiotic:

Cefepime 32 491 <0.0001

Piperacillin 755 71 <0.0001

Total cephalosporins 394 727 <0.0001

VRE colonization (per 1000 pt. Days)

1.48 5.50 <0.0001

VRE bacteremia 4 12

Lisgaris. IDSA (abstract). 2000

Bradley. JAC. 1999

Prevention of GRETherapy for Febrile Neutropenia

Purpose: reduce glycopeptide resistant enterococci (GRE)

Situation: 50% colonization rate in oncology units

Methods: Phase 1: no intervention (ceftazidime) Phase 2a and 2b: replace ceftazidime with

piperacillin/tazobactam Phase 3: return to ceftazidime

Results

Phase Colonization Infection

1 57% 5

2a 29% 0

2b 8% 0

3 36% 3

Phase 1 vs 2b (P<0.001)

Bradley. JAC. 1999

Antimicrobial Utilization and Resistance

Interdisciplinary team in Indianapolis to control resistant organisms

Interventions: Reduce third generation cephalosporin use Reduce imipenem use Encourage use of ampicillin/sulbactam and

piperacillin/tazobactam Enhance compliance with infection control Education regarding antimicrobial resistance

Antimicrobial Utilization and Resistance

Rate of Resistance (%)

Bacteria 1994 1998

VRE 16 6

E. cloacae 61 28

E. Aerogenes 63 11

Acinetobacter 17 9

MRSA 34 23

Piperacillin/tazobactam resistant

Smith. Pharmacotherapy 1999

Impact of Formulary Changes on MRSA and Ceftazidime Resistant K. Pneumoniae

0

5

10

15

20

25

No.

of

new

cas

es p

er 1

000

dis

char

ges

Baseline Intervention

MRSA CRKP

Reduce usage of cephalosporins, imipenem, clindamycin and vancomycin

Increased use of -lactam/-lactamase inhibitors

Landman. Clin. Infect Dis. 1999

Ceftazidime Resistant K. pneumoniaeCleveland VA Medical Center

0

5

10

15

20

25

30

35

3 6 9 12 1518 21242730 333639 42 4548Months

Res

ista

nce

(%

)

0100

200300400

500600

700800

An

tib

ioti

c u

se (

g)

%ceftaz. Res. Ceftaz Use (Gm) P/T Use (Gm/10)

Reduce Inappropriate Initial Antimicrobial Therapy

Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

Blood Stream Infections

33%

21%10%

5%

24%

7%

CNS Staph aureus Pseudomonas Klebsiella GNR Yeast

b

0%10%20%30%40%50%60%70%80%90%

100%

Staph. Aureus

MRSA

MSSA

0%

10%20%

30%

40%50%

60%

70%

80%90%

100%

Pip Ceftaz Cipro Imipenem

Resistant

Sensitive

KFSHRC-Jeddah: Infection Control Data 2002

Nosocomial Pneumonia

28%

22%

11%

6%

8%8% 17%

Pseudomonas Klebsiella MRSA E. Coli Serratia Stenotrophomonas GNR

b

KFSHRC-Jeddah: Infection Control Data 2002

Urinary Tract Infection

47%

17%

13%

10%

3%10%

E. Coli Klebsiella Pseudomonas Enterococcus Yeast GNR

b

KFSHRC-Jeddah: Infection Control Data 2002

Clinical Guidelines for the Treatment of Ventilator Associated Pneumonia

Prospective study: 50 patients were evaluated in the before group and 52 in the after group

Administration of vancomycin/imipenem/ciprofloxacin within 12 hours of clinical diagnosis

Antibiotic modification after 24-48 hrs Seven-day course of therapy (>7 days if

symptoms and signs are persisted)

Ibrahim EH et al. Crit Care Med, 2001;29: 1109-1115

Inadequate Antibiotics for VAP

32

14.8

24

5.8

8.4 7.7

0

5

10

15

20

25

30

35

Inadeqaute (% ) Duration (days) Superinfection (% )

Perc

ent

(%)

Before intervention After Intervention

Ibrahim EH et al. Crit Care Med, 2001;29: 1109-1115

Reduce Inappropriate Initial Antimicrobial Therapy

Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

De-escalation Therapy: Broad Spectrum Initial Regimen: VAP

88

7683

68

0102030405060708090

100

Imipenem Ceftazidime Pip/ Taz Aztreonam

Appro

pri

ate

(%

)

Trouillet. Am J Resp Crit Care Med. 1998

Plus vancomycin and amikacin

Reduce Inappropriate Initial Antimicrobial Therapy

Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

ID Consultation

0

10

20

30

40

50

60

70

80

%

ID Other MDs

Frequency ofInadequate IntitialTherapy

Byl B. Clin Inf Dis; 1989

Reduce Inappropriate Initial Antimicrobial Therapy

Efforts to reduce rate of resistance Guidelines Broad spectrum and combination antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

Automated Antibiotic Consultant

05

101520253035404550

AAC MDs

Inad

equa

te t

hera

py %

Inadequate Abx

Evans Arch Int Med 1994

In Conclusion:

Rate of inappropriate initial antimicrobial regimen is high

Reduce Inappropriate Initial Antimicrobial Therapy

Guidelines Broad spectrum and combination

antibiotics ID consultation Automated antibiotic consultant More selective and sensitive diagnostic

methods

Thank You