Strategies in the Selection of

Antibiotic Therapy in the ICU

Dr. Abdullah Alshimemeri
Consultant Pulmonary and Critical care Medicine,
Associate Professor, College of Medicine, King Saud
Bin Abdulaziz University for Health Sciences
Riyadh, Saudi Arabia.
Scope of the Problem
Inadequate Initial
Antibiotic Therapy Bacterial Resistance
What Is Initial
Inadequate Therapy?
Myth
There is time to start with one therapy and then
escalate later, if needed.
Fact
Inadequate initial antimicrobial therapy increases mortality.
Changing from inadequate to appropriate therapy may not
decrease mortality.
Initially delayed appropriate antibiotic therapy (IDAAT) is
inadequate therapy.
Kollef MH et al. Chest 1999;115:462-474.
Ibrahim EH et al. Chest 2000;118:146-155.
Iregui M et al. Chest 2002;122:262-268.
Initial Inadequate Therapy In
Critically Ill Patients with Serious
Infections
Defining Initial Inadequate
Therapy
The antibiotic did not cover the infecting
pathogen(s)
The pathogen was resistant to the antibiotic
Dosing was not adequate
Combination therapy was not used, if indicated.
1
Kollef MH et al. Chest 1999;115:462-474.
2
Ibrahim EH et al. Chest 2000;118:146-155.
Initial therapy is considered to be inadequate if:
Initial Appropriate Therapy
Empiric broad-spectrum therapy initiated at the first suspicion of
serious infection.
Selection of antibiotic to ensure adequate coverage of all likely
pathogens.
Factors to consider when defining appropriate therapy:
Microbiologic data
Monotherapy vs. combination therapy
Dose and dosing frequency
Penetration
Timing
Toxicity
Risk of influencing resistance
Prior antibiotic use
Kollef MH et al. Chest 1999;115:462-474.
Factors in Selecting Initial
Appropriate Therapy
Patient features: Choose empiric therapy based on site and
severity of infection, and physician assessment of the likelihood
for deterioration and mortality.
Local susceptibility and epidemiology: Choose empiric therapy
to cover the likely infecting pathogens based on patterns while
considering prior antibiotic therapy.
Initial antibiotic therapy dosing and duration: Choose initial
empiric therapy that will deliver enough antibiotic to the site of
infection and be well-tolerated (consider antibiotic penetration).
Combination vs. monotherapy: Initial antibiotic choice should
give broad enough coverage, avoid emergence of resistance, and
have the potential for synergy if necessary.
Nosocomial Infection
0
5
10
15
20
25
30
35
Percent
UTI Pneumonia Bloodstream
Infection
other
Richards MJ et al, CCM. 1999;27:887-882
NNIS
Nationa Nosocomial Infections ecnallievruS
0
5
10
15
20
25
30
35
40
P
e
r
c
e
n
t
BSI Pneumonia
CN staph
Enterococci
S. aureus
P. aeruginosa
Enterobacter
Richards MJ et al, CCM. 1999;27:887-882
Pathogens Most Frequently
associated with Nosocomial
Pneumonia in the ICU
20%
18%
12%
4%
4%
5%
35%
2%
S. aureus
P/ aeruginosa
Enterobacter spp
K. pneumoniae
H. influenzae
C. albicans
other pathogens
Enterococcus
Inadequate Initial
Antibiotic Therapy
0 10 20 30 40 50 60 70 80
Rello, 1997
Alvarez-lerma,
1996
Luna, 1997
Kollef, 1998
% patients receiving inadequate initial therapy
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 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
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
1.0b1

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
Decreasing
age
11.110.6 7.69.2
1.0b1

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
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
Ibrahim EH et al. Crit Care Med, 2001;29: 1109-1115
0
5
10
15
20
25
30
35
Percent
Befor After
Incidence of
Inadequate Antibiotic
Therapy
Clinical Guidelines for the Treatment
of Ventilator Associated Pneumonia
Automated Antibiotic
Consultant
0
10
20
30
40
50
60
70
80
90
100
AAC MDs
I
n
a
d
e
q
u
a
t
e

t
h
e
r
a
p
y

%
Inadequate Abx
Evans Arch I nt Med1994
ID Consultation
0
10
20
30
40
50
60
70
80
%
ID Other MDs
Frequency of
Inadequate Intitial
Therapy
Byl B. Clin I nf Dis; 1989
Emergent Bacterial
Resistance
Bacterial Resistance
Impact of Antibiotic Restriction on
Resistance
Neurosurgical ICU in London
0
10
20
30
40
50
60
Total infections Infections due to Klebseilla aerogenes
1968 1969 1970
All antibiotics stopped
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
True decrease secondary to adhesion to
infection control policies
Emerging Pathogens
Methicillin-resistant Staphylococcus aureus
(MRSA)
Methicillin-resistant Staphylococcus epidermitis
(MRSE)
Vancomycin-resistant enterococci (VRE)
Vancomycin-intermediate Staphylococcus aureus
(VISA)
Extended-spectrum beta-lactamase (ESBL)-
producing gram-negative organisms
Multidrug-resistant Acinetobacter spp.
Antibacterial Resistance in
Nosocomial Infections
Gram-Negative Pathogens
P. Aeruginosa
Resistance to imipenem
0
5
10
15
20
25
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
R
a
t
e
%
P. Aeruginosa
Resistance to quinolones
0
5
10
15
20
25
30
35
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
R
a
t
e
%
Klebsiella pneumoniae
Resistance to third-generation cephalosporins
0
2
4
6
8
10
12
14
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
R
a
t
e
%
ICU
Non-ICU
Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315
Antibacterial Resistance in
Nosocomial Infections
Gram-Positive Pathogens
MRSA
0
10
20
30
40
50
60
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
R
a
t
e
%
Methicillin-resistant Coagulase-
negative Staphylococcus
0
10
20
30
40
50
60
70
80
90
100
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
R
a
t
e
%
Vancomycin-resistant enterococci
0
5
10
15
20
25
30
35
1
9
8
9
1
9
9
0
1
9
9
1
1
9
9
2
1
9
9
3
1
9
9
4
1
9
9
5
1
9
9
6
1
9
9
7
1
9
9
8
1
9
9
9
2
0
0
0
2
0
0
1
R
a
t
e
%
ICU
Non-ICU
Fridkin and Gaynes. Clin Chest Med. 1999:20:302-315
Methicillin Resistant
Staphylococci by setting
0
10
20
30
40
50
60
70
80
90
ICU Non-ICU Outpatient
%

r
e
s
i
s
t
a
n
t
S.aureus Coagulase-negative Staphylococci
Fridkin. Clin I nfect 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 g/ml)
Vancomycin (MIC >128 g/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 Odds Ration P
Penicillins 2.2 0.10
2
nd
and 3
rd

Cephalosporins
9.4 <0,001
Metronidazole 3.6 0.02
Quinolons 2.2 0.40
Vancomycin 3.6 0.007


Ostrowsky. Arch I ntern Med. 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
K
i
l
o
g
r
a
m

o
f

v
a
n
c
o

(
X
1
0
0
)

p
u
r
c
h
a
s
e
d
0
2
4
6
8
10
12
14
16
18
20
%

V
R
E
Usage of Vancomycin Rate of VRE
Kirsl et al. Historical usage of vancomycin. Antimicrob Agent Chemo1998
National Nosocomial Infection Surveillance System (CDC)
Enterococcal Resistance by
Species
0
10
20
30
40
50
60
70
80
90
E. faecium E. fecalis
Ampicillin resistant
Vancomycin resistant
Jones. Diagn. Microbiol I nfect Dis. 1998
Outcome of Enterococcus
faeciumBacteremia
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 I ntern 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
Emergence of Carbapenem-
resistant 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
Carbapenemresistance 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 (pulsed-field gel electrophoresis ) documented inter- and
intra-hospital spread
VM Manikal et al. CI D. 2000
Antimicrobial Susceptibility of 233
Acinetobacter spp., 15 Hospital,
Brooklyn, New York
VM Manikal et al. CI D. 2000
Efforts to Decrease the Rate of
Emergent Antimicrobial
Resistance
CDC guidelines and barrier
precautions
Antibiotic restriction
Selective bowel decontamination
Rotation antibiotics
Short antibiotic course
Antimicrobial Utilization and
Resistance
Interdisciplinary team in Indianapolis to
control resistant organisms
Interventions:
Reduce third generation cephalosporin use
Reduce imipenemuse
Encourage use of ampicillin/sulbactamand
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. Pharmacotherapy1999
Impact of a Rotating Empiric Antibiotic
Schedule on Infectious Mortality in an
Intensive Care Unit
0
5
10
15
20
25
30
35
No rotation Rotation
VAP Mortality%
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
<6 D/C
>6 treat
as pneumonia
Reevaluate CPIS at 3 days
Singh N, et al. Am J Resp Crit Care Med. 2000;162:505-511
Short Course Antibiotic
Therapy
Hospital Acquired Pneumonia
0
5
10
15
20
25
30
35
40
Percent
Short Standard
Superinfection Rate
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/beta-
lactamase inhibitor use
Limit carbapenem and vancomycin use to
desired therapy
Rotation antibiotics
Short course antibiotic course: HAP
Conclusion
Wise Use of Antimicrobial
Decrease cephalosporin use
Increase extended-spectrum
penicillin/beta-lactamase inhibitor use
Limit carbapenem and vancomycin use to
desired therapy
Importance of Timing of Antibiotic
Administration
107 patients with VAP in a medical ICU
All patients received an antibiotic shown to be active
in vitro against the bacteria
33 patients received treatment that was delayed for 24
hours (28.6 5.8 hours) (classified as receiving IDAAT)
74 patients received treatment timely within 24 hours
(12.5 4.2 hours)
Risk factors for hospital mortality
Iregui et al. Chest 2002;122:262268
IDAAT
31%
Timely
<24 h
69%
Appropriate Early Antibiotic Therapy
Reduces Mortality Rates In Patients With
Suspected VAP
Iregui et al. Chest 2002;122:262268
Mortality (%)
Hospital mortality Mortality attributed
to VAP
0
60
80
20
40
p<0.01
p<0.001
Initially delayed
antibiotic treatment
Early appropriate
antibiotic treatment
Summary
Initial inadequate therapy:
Inadequate initial empiric therapy leads to increased mortality
in patients with serious infection.
Initial appropriate therapy:
Means starting with a broad-spectrum antibiotic and then focusing
based on clinical and microbiological data. Broad-spectrum
antibiotics should not be held in reserve.
Should be based on patient stratification, and local epidemiology
and susceptibility patterns.
Includes use of appropriate drug, dose, and duration.
An Art in Medicine
Balance
An Evidence-Based Problem:
Mortality with
Inadequate Therapy
A Theoretical Dilemma:
Concern of Resistance with
Broad-Spectrum Therapy
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