Transcript Strategies in the Selection of Antibiotic Therapy in the ICU

Strategies in the
Selection of Antibiotic
Therapy in the ICU
Mazen Kherallah, MD, FCCP
King Faisal Specialist Hospital &
Research Center
Scope of the Problem
Inadequate Initial
Antibiotic Therapy Bacterial Resistance
Infection Distribution in Adult
ICU’s
Major Types of Infection (NNIS data, 1992-1997)
4%
6%
4%
4%
32%
3%
19%
28%
UTI
Pneumonia
BSI
GI
LRT
EENT
CV
Others
Nosocomial Infection
35
30
25
20
Percent
15
10
5
0
UTI
Pneumonia
Bloodstream
Infection
Richards MJ et al, CCM. 1999;27:887-882
other
NNIS
40
35
Percent
30
CN staph
Enterococci
S. aureus
P. aeruginosa
Enterobacter
25
20
15
10
5
0
BSI
Pneumonia
Richards MJ et al, CCM. 1999;27:887-882
Pathogens Most Frequently associated
with Nosocomial Pneumonia in the ICU
2%
20%
35%
18%
5%
4% 4%
12%
S. aureus
P/ aeruginosa
Enterobacter spp
K. pneumoniae
H. influenzae
C. albicans
other pathogens
Enterococcus
Inadequate Initial Antibiotic
Therapy
Inadequate Initial
Antibiotic Therapy
Initial Inadequate Therapy
Kollef, 1998
Luna, 1997
Alvarez-lerma,
1996
Rello, 1997
0
10
20
30
40
50
60
70
% patients receiving inadequate initial therapy
80
Mortality Associated with Initial
Inadequate Therapy
Alvarez-lerma, 1996
Rello, 1997
Kollef, 1999
Kollef, 1998
Ibrahim, 2000
Luna, 1997
0
20
40
60
80
%Mortality
Initial Inadequate Therapy
Initial Adequate herapy
100
Resistant Pathogens, Inadequate
Treatment and Mortality (BSI)
MSSA
Enterococcus
P.aeruginosa
MRSA
VRE
0
20
40
60
80
100
%Mortality
Inadequate antibiotic therapy
Hospital mortality
Ibrahim EH, et al. Chest 2000;118:145-155
120
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
45
40
35
30
Inadequate 25
Therapy% 20
15
10
5
0
Nosocomial+Community
infection
Nosocomial Infection
Community Infection
Kollef MH, et al chest. February 1999;115(2):462-474
Cohort of Infected Patients and
Inadequate Therapy
1 .0 b1
Risk factor
Adjusted Odds
Prior ABs
3.39
BSI
1.88
APACHE II
1.04
Decreasing age
1.01
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
2.51.5
1.91.4
Hospital LOS
(days)
APACHE II
22.825.7
2025.8
10.210.2
7.18.5
Decreasing
age
11.110.6
7.69.2
1 .0 b1
Kollef MH, et al chest. February 1999;115(2):462-474
Hospital Mortality of Infected
Patients
60
P<0.001
50
40
Hospital
30
Mortality (%)
20
10
0
All Causes
Inadequate therapy
ID related
Adequate therapy
Kollef MH, et al chest. February 1999;115(2):462-474
Reduce Inappropriate Initial
Antimicrobial Therapy
► Guidelines
► Broad
spectrum and combination antibiotics
► ID consultation
► Automated antibiotic consultant
► More selective and sensitive diagnostic
methods
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 after24-48 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
Clinical Guidelines for the Treatment of
Ventilator Associated Pneumonia
35
30
25
Percent
20
Incidence of
Inadequate Antibiotic
Therapy
15
10
5
0
Befor
After
Ibrahim EH et al. Crit Care Med, 2001;29: 1109-1115
Automated Antibiotic Consultant
Inadequate therapy %
Inadequate Abx
100
90
80
70
60
50
40
30
20
10
0
AAC
Evans Arch Int Med 1994
MDs
Aztreonam+amikacin+vanco
mycin
Broad-Spectrum and
Combination Antibiotics
0
20
40
60
80
% Susceptibility
Trouillet et al. Am J Res Crit Care Med. 1998;157:531-539
100
ID Consultation
80
70
60
50
Frequency of
Inadequate Intitial
Therapy
% 40
30
20
10
0
ID
Byl B. Clin Inf Dis; 1989
Other MDs
Emergent Bacterial Resistance
Bacterial Resistance
Impact of Antibiotic Restriction on
Resistance
Neurosurgical Intensive Care Unit in London
60
All antibiotics stopped
50
40
30
20
10
0
1968
Total infections
1969
1970
Infections due to Klebseilla aerogenes
Price. Lancet. 1970
Decrease in Hospital-acquired ICU
Infection Rates, NNIS, 1990-1999
Type of ICU CR-BSI (%)
VAP (%)
CR-UTI (%)
Medical
44
56
46
Surgical
31
38
30
Pediatric
32
26
59
Possible Explanation for Decrease
in Infection Rate
► Efforts
to prevent infections: new
research findings, prevention guidelines
► Shift of health care from hospital-based
care
► True decrease secondary to adhesion to
infection control policies
Rates of Resistance Among Nosocomial Infections
Reported in Intensive Care Patients, Comparison of
1999 (January-July) with Historical Data
VRE
Methicillin/CNS
MRSA
3rd Ceph/E.coli
3rd Ceph/K.Pneum.
Imipenem/seud
Quinolone/Pseud.
3rd Ceph/Pseud.
3rd Ceph/Enterobacter
0
10
20
30
40
50
% Resistance
January-July 1999
1993-1998
60
70
80
90
Emerging Pathogens
► Methicillin-resistant
Staphylococcus
► Methicillin-resistant
Staphylococcus
aureus (MRSA)
epidermitis (MRSE)
► Vancomycin-resistant
enterococci (VRE)
► Vancomycin-intermediate
Staphylococcus aureus (VISA)
► Extended-spectrum beta-lactamase
(ESBL)-producing gram-negative
organisms
Antibacterial Resistance in Nosocomial Infections
Gram-Negative Pathogens
P. Aeruginosa
P. Aeruginosa
Resistance to quinolones
25
35
20
30
25
15
Rate%
Rate%
Resistance to imipenem
10
20
15
10
5
5
0
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
0
Klebsiella pneumoniae
Resistance to third-generation cephalosporins
14
12
Rate%
10
8
6
ICU
Non-ICU
4
2
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
0
Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315
Antibacterial Resistance in Nosocomial Infections
Gram-Positive Pathogens
Methicillin-resistant Coagulasenegative Staphylococcus
Vancomycin-resistant enterococci
35
30
Rate%
25
20
15
ICU
Non-ICU
10
5
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
0
Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315
2001
2000
1999
1998
1997
1996
1989
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
0
1995
10
1994
20
1993
30
100
90
80
70
60
50
40
30
20
10
0
1992
40
Rate%
Rate%
50
1991
60
1990
MRSA
% resistant
Methicillin Resistant Staphylococci
by setting
90
80
70
60
50
40
30
20
10
0
ICU
S.aureus
Non-ICU
Outpatient
Coagulase-negative Staphylococci
Fridkin. Clin Infect Dis.1999
Vancomycin-resistant Staphylococcus
aureus
► June
2202- First case of VRSA isolated from
a swab obtained from a catheter exit site
► The isolate was resistant to:
 Oxacillin (MIC >16 µg/ml)
 Vancomycin (MIC >128 µg/ml)
► The
isolate contained:
 The oxacillin-resistant gene mecA
 The vanA vancomycin resistant gene from
enterococci
CDC MMWR. 2002;51:565-567
Epidemiology of VRE
► Present
in all 50 states in the United States
► Number of isolated continues to grow
► Recognized in Europe, Japan, Central and
South America
► Resistance to alternate antibiotic therapy
continues to be a problem
Risk Factors for VRE
► Prior
broad spectrum antibiotics
(especially cephalosporins and
vancomycin)
► Prolonged hospitalization
► Immunocompromised host
► Neutropenia
► Admission to an intensive care unit
► Renal failure requiring dialysis
Noskin. J Lab Clin Med. 1997
Antibiotics and Colonization
with VRE
Antimicrobial
Penicillins
Odds Ration
2.2
P
0.10
2nd and 3rd
Cephalosporins
Metronidazole
9.4
<0,001
3.6
0.02
Quinolons
2.2
0.40
Vancomycin
3.6
0.007
Ostrowsky. Arch Intern Med. 1999
Use of Vancomycin in US and
Rate of VRE
Rate of VRE
120
20
18
16
14
12
10
8
6
4
2
0
100
80
60
40
20
0
% VRE
Kilogram of vanco (X100) purchased
Usage of Vancomycin
84 85 86 87 88 89 90 91 92 93 94 95 96 97
Kirsl et al. Historical usage of vancomycin. Antimicrob Agent Chemo 1998
National Nosocomial Infection Surveillance System (CDC)
Independent Predictors of VancomycinResistant Enterococci in Adult Intensive Care
Units
Change in Predictor
Estimated Change
in Rate of VRE
+++
P-value
Cephalosporin use (3rd)
++
0.0002
Vancomycin use
++
0.0001
Type of ICU
+
0.01
Non-ICU VRE rate
NNIS
0.0001
Enterococcal Resistance by
Species
90
80
70
60
50
Ampicillin resistant
Vancomycin resistant
40
30
20
10
0
E. faecium
E. fecalis
Jones. Diagn. Microbiol Infect Dis. 1998
Outcome of Enterococcus
faecium Bacteremia
Outcome Measure
VSE
(n=32)
13 (41)
VRE
(n=21)
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
Mortality
P
Stosor. Arch Intern Med. 1998
Extended Spectrum lactamases
ESBLs
► ESBL
inactivates oxyamino beta-lactams and
fourth-generation cephalosporins (to some
extent) and aztreonam
► Large plasmids encoding multiple antibiotic
resistance determinants including
aminoglycoside modifying enzymes
► Strains producing ESBL are typically sensitive
to cephamycins and carbapenems
► Common ESBL-producers: K. pneumoniae,
and less common other Enterobactericae
K. pneumoniae Resistant to ExtendedSpectrum -lactam (ESBL) at NNIS
Evidence of Inter-hospital Transmission
70
60
%ESBL
50
Hospital A
0-20 miles from A
>20 miles from A
40
30
20
10
0
86
87
88
89
90
91
92
93
Mannel DL, et al. Infect Control Hosp Epidemiolo 1997
Emergence of Carbapenemresistant Acinetobacter spp.
► Frequent
use of aminoglycosides,
fluroquinolones, ureidopenicillins and
third generation cephalosporins
► Reported from South America, Europe,
Far East, Middle East, and United States
► Numerous outbreaks (some strains
susceptible only to polymyxin B)
► High mortality rates
► Endemic in some hospitals
Endemic Carbapenem-Resistant
Acinetobacter spp. In Brooklyn, New York
15 hospitals
► November 1997, all aerobic bacteria collected
► Acinetobacter spp. (233) accounted for 10% of the gram
negative bacilli
► Carbapenem resistance ranged from 0-100%
► 10% of isolated were susceptible only to polymyxin
► Risk factors
 Use of third generation cephalosporins plus aztreonam
 Environment and healthcare worker hands
contamination documented
 PFGE documented inter- and intra-hospital spread
►
VM Manikal et al. CID. 2000
Antimicrobial Susceptibility of 233 Acinetobacter
spp., 15 Hospital, Brooklyn, New York
Polymixin B
Amikacin
Gentamicin
Ciprofloxacin
Imipenem
Ceftazidime
Ceftriaxone
Pip/tazobactam
Ampiillin/sulbactam
0
20
40
60
80
100
VM Manikal et al. CID. 2000
Efforts to Decrease the Rate of
Emergent Antimicrobial
Resistance
►CDC
guidelines and barrier
precautions
►Antibiotic restriction
►Selective bowel decontamination
►Rotation antibiotics
►Short course antibiotic course
Impact of CDC Guidelines on
Endemic VRE
Site
Barrier
Vancomycin
VRE
Precautions
Use
Colonization
Infection
NY
28% to 92%
-
MD
Initial 64%
59%
IN
22% to 88%
-
50%
35%
But not statistically
significant
0
80%
M. Montecalvo et al. Ann Int Med. 1999
J Morris et al. Ann Int Med. 1995
E Jochimsen et al. ICHE 1999
Impact of Formulary Change on VRE
Empiric therapy for febrile neutropenia
Factor
1998
1999
P
Cefepime
32
491
<0.0001
Piperacillin
755
71
<0.0001
Total cephalosporins
394
727
<0.0001
VRE colonization (per
1000 pt. Days)
VRE bacteremia
1.48
5.50
<0.0001
4
12
Antibiotic:
Lisgaris. IDSA (abstract). 2000
Prevention of GRE
Therapy 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
Bradley. JAC. 1999
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
► Reduce
No. of new cases per 1000
discharges
25
20
15
10
5
0
Baseline Intervention
MRSA
CRKP
usage of
cephalosporins,
imipenem,
clindamycin and
vancomycin
► Increased use of lactam/-lactamase
inhibitors
Landman. Clin. Infect Dis. 1999
Ceftazidime Resistant K.
35
Cleveland VA Medical Center
Resistance (%)
30
25
20
15
10
5
0
800
700
600
500
400
300
200
100
0
Antibiotic use (g)
pneumoniae
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Months
%ceftaz. Res.
Ceftaz Use (Gm)
P/T Use (Gm/10)
Impact of a Rotating Empiric Antibiotic
Schedule on Infectious Mortality in an
Intensive Care Unit
No rotation
Rotation
35
30
25
20
15
10
5
0
rGPC/1000 patient days
rGNR/1000 patient days
Raymond DP. Crit Care Med 01-Jun-2001, 29(6);1101-8
Impact of a Rotating Empiric Antibiotic
Schedule on Infectious Mortality in an
Intensive Care Unit
VAP Mortality%
35
30
25
20
15
10
5
0
No rotation
Rotation
Raymond DP. Crit Care Med 01-Jun-2001, 29(6);1101-8
Short Course Antibiotic
Therapy
Hospital Acquired Pneumonia
Clinical Pulmonary Infection Score (CPIS)
<6
>6
Antibiotics
10-21 days
Ciprofloxacin
3 days
Antibiotics
10-21 days
Reevaluate CPIS at 3 days
<6 D/C
>6 treat
as pneumonia
Singh N, et al. Am J Resp Crit Care Med. 2000;162:505-511
Short Course Antibiotic Therapy
Hospital Acquired Pneumonia
40
35
30
25
Percent 20
15
Superinfection Rate
10
5
0
Short
Standard
Singh N, et al. Am J Resp Crit Care Med. 2000;162:505-511
In Conclusion:
Reduce Inappropriate Initial
Antimicrobial Therapy
► Guidelines
and goal directed protocols
► 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 and appropriate utilization:
 Decrease cephalosporin use
 Increase extended-spectrum penicillin/betalactamase inhibitor use
 Limit carbapenem and vancomycin use to desired
therapy
Selective bowel decontamination
Rotation antibiotics
Short course antibiotic course: HAP
Conclusion
Judicious Use of Antimicrobial
► Decrease
cephalosporin use
► Increase extended-spectrum
penicillin/beta-lactamase inhibitor use
► Limit carbapenem and vancomycin use
to desired therapy
Handwashing compared to
Alcohol Hand
Time required
Efficacy
Acceptance by
personnel
Soap and Water
Handwashing
Alcohol Hand
Rub
30-120 seconds
10-30 seconds
Good to very
good
Excellent
Poor
Excellent