Optimal Antibiotic Strategies in ICU

Optimal Antibiotic Strategies in the ICU
“Can we do more with less …”

50% of 14,114 patients in
1,265 ICUs in 75 countries
were infected
Infected patients had twice
the chance of dying in the
hospital than uninfected
patients
•Inadequate coverage
•Treatment duration is too excessive
•Treatment of noninfectious entities
(colonization, pulmonary edema, etc…)
Nearly 1/3 of antimicrobial
use was inappropriate!!
“In an ICU setting…”
Vincent 2009 JAMA 302:2323-9

Are you prepared to face the Horror?
Now showing at a hospital near you!
MDR

Bad Bugs: No ESKAPE
Enterococcus
S. aureus
Klebsiella spp.
Acinetobacter
P. aeruginosa
Enterobacter spp.
Boucher H, et al, Clin Infect Dis 2009;48:1-12

Egypt
ESBL E. coli 60%
Enterobacteriacae 38.5%
MRSA 45%
Saudi Arabia
MRSA 12-49%
All ESBL 40%
E. coli 15-20%
Klebsiella 50+%
Jordan
ESBL Klebsiella spp. 60%
E. coli 30%
MRSA 60%
Iran
MRSA 54%
VRE 10%
Lebanon
ESBL E. coli & Klebsiella spp 30%
MRSA 10%
Antibiotic resistance is a significant problem

Source: Kollef M, et al: Chest 1999;115:462-74
17.10%
34.30%
45.20%
0%
10%
20%
30%
40%
50%
Community-onset
Hospital-onset
Community-onset, then
Hospital-onset
Inappropriate
Antimicrobial Therapy
(n = 655 ICU patients with infection)
Patient Groups
Inappropriate Antimicrobial Therapy:
Prevalence Among ICU Patients

Does Inadequate Therapy Result from Antibiotic
Resistance?
Inadequate therapy is more likely if antibiotic resistance is present, and antibiotic resistant organisms
are more commonly associated with inadequate therapy (adapted from Kollef).
0
5
10
15
20
25
30
35
40
Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.
% Inadequate Treatment of VAP

Mortality Associated With Initial Inadequate Therapy In
Critically Ill Patients With Serious Infections in the ICU
0% 20% 40% 60% 80% 100%
Luna, 1997
Ibrahim, 2000
Kollef, 1998
Kollef, 1999
Rello, 1997
Alvarez-Lerma,1996 Initial appropriate
therapy
Initial inadequate
therapy
*Mortality refers to crude or infection-related mortality
Mortality*
ICU
VAP
Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
Ibrahim EH et al. Chest 2000;118L146-155.
Kollef MH et al. Chest 1999; 115:462-474
Kollef MH et al. Chest 1998;113:412-420.
Luna CM et al. Chest 1997;111:676-685.
Rello J et al. Am J Resp Crit Care Med 1997;156:196-200.

Approprate
Antibiotic
Therapy
Antibiotic
Resistance

ICU Antibiotic Use: A Balancing Act
Early, broad, appropriate, and adequate..
Appropriate Initial
Antimicrobial Treatment
Avoid Unnecessary
Antimicrobial Use

Optimal Antibiotic Strategies
• Avoid repeated use of the same class of ATBs
• Avoid use of quinolones as first agent
• Broad spectrum
• Combination Therapy
Increase Appropriateness
• Combination therapy
• Clinical Guidelines
• De-escalation
• Duration of antibiotics
• Stewardship program
Decrease Resistance

The Impact of Recent Antibiotic Therapy
Trouillet JL et al. Clin Infect Dis. 2002;34:1047-1054.
Resistance of P aeruginosa strains To Imipenem, Ceftazidime, or Ciprofloxacin,
According to Previous Therapy With same drugs
16.7
8.2
26
52.4
29
57.1
0
10
20
30
40
50
60
70
80
Imipenem Ceftazidime Cipro
No
Yes
P< 0.001

 Fluoroquinolone use 
N= 239 patients hospitalized for >48 h who did not receive
antibiotics before ICU admission
To determine whether FQ use is associated with subsequent
emergence of MDR
Saad Nseir et al Crit Care Med 2007; 35:1888

 Fluoroquinolone use 
Saad Nseir et al Crit Care Med 2007; 35:1888
35
98
5
33
60
9
23
1
7
53
0
10
20
30
40
50
60
70
80
90
100
MRSA GNR FQ-r GNR Imip-r GNR Pip/Taz-r GNR CFTZ-r
FQ + FQ -

Patients(%)
27.8
22.2
5.5
44.4
14
36.7
34.2
10.1
0
10
20
30
40
50
Non-survivors
p=0.40
p=0.24
p=0.01
p<0.001
Aminoglycosides
(n=20)
β-lactam/
β-lactamase inhibitors
(n=33)
Carbapenems
(n=28)
Ciprofloxacin
(n=16)
n=97
Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987–1994
‘Seemingly’ adequate initial therapy
21-day mortality rates: Broad Spectrum

Combination Therapy?
Achieve synergy,
improve clinical and
microbiological
successes
Prevent
emergence of
resistance
Better chance to
initial
appropriate
therapy
Paul M et al. BMJ 2004

Beta lactam monotherapy versus beta lactam-aminoglycoside
combination therapy for sepsis in immunocompetent patients:
Systematic review and meta-analysis of randomized trials
All cause Fatality

Beta lactam monotherapy versus beta lactam-aminoglycoside
combination therapy for sepsis in immunocompetent patients:
Systematic review and meta-analysis of randomized trials
All cause Fatality
All cause fatality—Forty three
trials including 5527 patients
reported all cause fatality. There
was no significant difference
between monotherapy and
combination therapy when we
combined these studies (relative
risk 0.90, 95% confidence interval
0.77 to 1.06). There was no
difference among the 12 studies
with 1381 patients that compared
the same β lactam (1.02, 0.76 to
1.38) or among studies that
compared different β lactams
(0.85, 0.69 to 1.05). The
heterogeneity for this comparison
was low (I2 = 7.7%).

Clinical Failure: We
compared clinical failures in 63
trials, monotherapy was not
significantly different from
combination therapy among
studies that compared the same
β lactam. Monotherapy was
significantly superior to
studies that compared different
β lactams. The overall
comparison favored
monotherapy for clinical failure
(0.87, 0.78 to 0.97; 6616
patients; number needed to
treat 34, 20 to 147)

Bacteriologic Failure: We
compared bacteriological
failures in 43 trials,
monotherapy was not
significantly different from
studies that compared the same
β lactam. Monotherapy was
significantly superior to
studies that compared different
β lactams. The overall
comparison favored
monotherapy for
bacteriological failure (0.86,
0.72 to 1.02; 3511 patients)

All cause fatality in comparison of β lactam monotherapy v β
lactam-aminoglycoside combination therapy for treatment of
sepsis: subgroup analyses

Clinical failure in comparison of β lactam monotherapy v β
lactam-aminoglycoside combination therapy for treatment
of sepsis: subgroup analyses

Nephrotoxicity was more
common with
combination therapy in
nearly all studies, and the
combined relative risk
was 0.36 (0.28 to 0.47)
corresponding to a
number needed to harm
of 15 (14 to 17) for
combination therapy

Objective: To evaluate the therapeutic benefit of early combination therapy comprising
at least two antibiotics of different mechanisms with in vitro activity for the isolated
pathogen in patients with bacterial septic shock
Crit Care Med 2010 Vol. 38, No. 9

Adjusted Mortality Associated With Combination Antibiotic
Therapy of Septic Shock
Monotherapy Combination
ICU mortality 35.7% 28.8%

Supplemental Antibiotic and Outcome

Combination Therapy: Prevent
emergence of resistance
Achieve synergy
Prevent
emergence of
resistance
Better chance
to initial
appropriate
therapy
Bliziotis IA et al:. Clin Infect Dis 2005

Effect of aminoglycoside and beta-lactam combination therapy vs beta-
lactam monotherapy on the emergence of antimicrobial resistance: A
meta-analysis of randomized, controlled trials
Compared with b-lactam monotherapy, the aminoglycoside/b-lactam combination was not
associated with a beneficial effect on the development of antimicrobial resistance among
initially antimicrobial susceptible isolates

Crit Care Med 2001; 29:1109 –1115

Experience with a clinical guideline for the
treatment of VAP
48
14.8
24
94.2
8.6 7.7
0
10
20
30
40
50
60
70
80
90
100
Adequate ATB % Duration d 2nd VAP %
Before
After
Ibrahim EH et al. Crit Care Med 2001
N= 102
Protocol:
◦ Vancomycin
◦ Imipenem
◦ Cipro
Modify 24-48 h
Duration: 7 days
De-escalation rate
62%

Is De-escalation (switch to less broad
spectrum coverage) Safe?

Mortality with VAP according to
Therapy Modification
42.6
23.7
17
0
10
20
30
40
50
Escalated (n=61) No change (n=245) De-escalated (n=61)
Mortality%
Axis Title
Kollef MH et al. Chest 2006
Yes, it is safe to de-escalate in VAP

169 patients with severe sepsis attributable to a hospital-acquired infection
The major sources of infection
◦ Lungs (44%)
◦ Abdomen (38%)
Microbiological data were available in (77%)
Initial antimicrobial therapy was appropriate in (84% of culture-positive
episodes)
Even in a highly focused environment with
close collaboration among intensivists and
infectious disease specialists,
De-escalation may actually be possible in
<50% of cases
Crit Care Med 2012; 40: 1404–1409

Mortality according to Therapy
Modification
60
26
16
0
10
20
30
40
50
60
70
Escalated (n=22) No change (n=77) De-escalated (n=93)
Mortality%
Crit Care Med 2012; 40: 1404–1409
Yes, it is safe to de-escalate in Sepsis

Prospective observational study severe sepsis and septic shock on
Broad-spectrum Antibiotic
Antibiotic strategies once culture available:
– No change: no modification on empirical
–Escalation: switch to or addition of an antibiotic
–De-escalation: …..35%
Intensive Care Med (2014) 40:32–40

De-escalation Strategies: switch to less
broad spectrum coverage
Group I
withdrawal of 2
ATBx
Group II
withdrawal of 1
ATBx
Group III
switch to a new
ATBx (narrower
spectrum)
Group IV
withdrawal of at
least 1 ATBx +
change of another
drug to a new one
with narrower
spectrum

Mortality Rate According to Therapeutic
Strategy
Patients with Adequate Empirical Therapy
All Patients

(p = 0.006)
(p = 0.008)
Patients with Adequate Empirical Therapy
All Patients
De-escalation therapy was a protective factor [Odds-
Ratio (OR) 0.58; 95% confidence interval (CI) 0.36-0.93)

Antibiotic Treatment Pathway
Day 0
• Evaluation for “Empiric
therapy”
Day 2/3
• Evaluation for “De-
Escalation of Therapy”
Day 4+
• Evaluation for
“Duration of therapy”

Antibiotic Management of Suspected Nosocomial ICU-
acquired Infection (NI): Does Prolonged Empiric Therapy
Improve Outcome?
Mary-AnneW. Aarts et al. Intensive Care Med (2007) 33:1369–1378

Improve Outcome?
Antibiotics were prescribed for 143 of 195
(73.3%) patients with suspected NI
39 of 195 (20.0%) Infection
Confirmed
156 of 195 (80%) No
infection
44% Stopped
antibiotics < 4 days
56% Had antibiotics
for > 4 days
To determine the impact of prolonged therapy in the absence of infection

Improve Outcome?
Mortality 32%
Mortality 7.7%
OR = 5.7
Prolonged empiric
therapy was not
independently
associated with
mortality!

Kaplan-Meier Estimates of the Probability of Survival Probability of
survival is for the 60 days after ventilator-assisted pneumonia onset as a
function of the duration of antibiotics
Chastre, J. et al. JAMA 2003;290:2588-2598
No excess mortality
No more recurrent infections
More antibiotic-free days
Not for non-lactose fermenters

Systematic review and meta-analysis of procalcitonin (PCT)-
guided antibiotic therapy algorithms for critically ill adult
patients
Primary outcomes
◦ 28-day mortality
◦ duration of antibiotic therapy

Duration of antibiotic therapy for the first
episode of infection
Procalcitonin-guided antibiotic therapy
algorithms could help in reducing the duration
of antimicrobial administration without having
a negative impact on survival

56 yo ICU Day # 15
ESRD due to DM with
recurrent septic episodes,
ventilator dependant
Fever
Hypoxia
WBC 9000 to 15000
Purulent sputum
Previous course of
antibiotics: Tazocin, Cipro,
ceftazidimeNext day post dialysis

Rational Use of Antibiotic
Therapy in ICU
How can you do it? …

EMPIRIC THERAPY (85%)
Infection not well defined (“best
guess”)
Broad spectrum
Multiple drugs
Evidence usually only 2
randomized controlled trials
More adverse reactions
More expensive
DIRECTED THERAPY (15%)
Infection well defined
Narrow spectrum
One, seldom two drugs
Evidence usually stronger
Less adverse reactions
Less expensive
Principles of Antibiotic Therapy

Goals of Antimicrobial Stewardship
Program
Stewardship
Program
Decrease
Resistance
Improve
Outcome
Cost
Control
Lawrence KL, Kollef MH. Am J Resp Crit Care Med. 2009;179:434-438

Stewardship Strategies in the
Prescribing Workflow
• Computer-assisted
strategies
• Computer-assisted
strategies
• Review & feedback
• Education
• Antibiogram
• Guidelines
• Pre-authorization
• Formulary restriction
• Education
• Guidelines
Patient
Evaluation
Choice of
Antimicrobial
Prescription
& Ordering
Dispensing &
Follow Up
Take an “antibiotic time-
out,” reassessing
antibiotics after 48-72
hours
Ensure all orders
have dose, duration,
and indications
Get cultures
before starting
antibiotics Force infectious
Disease Involvement

Antibiotic Stewardship Improves Clinical
Outcomes
90 91
5
32
55
31
0
10
20
30
40
50
60
70
80
90
100
Appropriate Cure Failure
AMP UP
RR 2.8 (2.1-3.8) RR 1.7 (1.3-2.1) RR 0.2 (0.1-0.4)Percent
AMP = Antibiotic Management Program
UP = Usual Practice
Fishman N. Am J Med 2006;119:S53.

Pledge
Use antibiotic
wisely, only
when necessary
Re-evaluate
therapy Day 2-3
of therapy
Stop antibiotics
when not
needed

Optimal Antibiotic Strategies in ICU

Optimal Antibiotic Strategies in ICU

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