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Inadequate Empiric Antibiotic Therapy. Mazen Kherallah, MD, FCCP King Faisal Specialist Hospital & Research Center. Terms. Infection SIRS Bacteremia and BSI Sepsis Severe sepsis. Sepsis Syndromes 1992: SCCM/ACCP. Parasite. Severe Sepsis. Virus. SIRS. Infection. Sepsis. Fungus. - PowerPoint PPT Presentation
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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