Antibiotic de-escalation

Practical application

Jean Chastre,
www.reamedpitie.com
Conflicts of interest: Consulting or
Lecture fees:
Bayer, Pfizer, Cubist, Basilea, Astellas,
Kenta-Aridis
 Assessment of Empirical Antibiotic
Therapy Optimisation in six Hospitals:
an Observational Cohort Study
Braykov NP, et al. Lancet ID 2014;14:1220-7

Across six study sites in the US, 4119 (60%) of

6812 inpatients received antimicrobials.
Of 730 randomly selected patients with
antimicrobials, 220 (30%) patients were afebrile
AND had normal white blood cell counts at the
start of therapy.
Appropriate cultures were collected from only
59% of patients, and 58% were negative.
By the 5th day of therapy, only 215% were
narrowed or discontinued.
Assessment of empirical
antibiotic therapy
optimisation in 6 hospitals:
an observational cohort
study
Braykov NP, et al. Lancet ID 2014;14:1220-7

Respiratory infection
WBC normal, 45%
Body temperature normal, 68%
Signs of infection on chest x-rays, 50%
Culture collected, 67%
Culture negative, 47%
 ICU Infection as a Source of
Antimicrobial Overuse
o Two factors are driving
antimicrobial overuse when
treating infection in the ICU:
The need to identify and treat all
patients with severe bacterial
infection as soon as possible
The need to use broad-spectrum
antibiotics initially
 ICU Infection as a Source of
Antimicrobial Overuse
1. The absolute impact of early
effective antimicrobial treatment on
outcome in patients with sepsis has
probably been exaggerated, even if
not an issue for debate
2. Bombing patients with broad-
spectrum antibiotics can lead to
catastrophe
 Aggressive versus conservative initiation of
antimicrobial treatment in surgical patients
with suspected ICU-acquired infection
Hranjec, et al. The Lancet ID, Early Online Publication, 28 Aug 2012

2-year, quasi-experimental, before and

after observational cohort study of patients
who were admitted to the SICU (Charlottesville,
VA, USA).
From Sept 1, 2008, to Aug 31, 2009,
aggressive treatment was used: patients
suspected of having an infection had blood
cultures sent and antibiotics immediately
started.
From Sept 1, 2009, to Aug 31, 2010, a
conservative strategy was used, with
antibiotics started only after objective
findings confirmed an infection.
Aggressive versus conservative initiation of
antimicrobial treatment in surgical patients
with suspected ICU-acquired infection
Hranjec, et al. The Lancet ID, Early Online Publication, 28 Aug2012
 ICU Infection as a Source of
Antimicrobial Overuse
1. The absolute impact of early
effective antimicrobial treatment on
outcome in patients with sepsis has
probably been exaggerated, even if
not an issue for debate
2. Bombing patients with broad-
spectrum antibiotics can lead to
catastrophe
 Klebsiella pneumoniae: proportion of
invasive isolates resistant to
carbapenems in 2011
European Antimicrobial Resistance Surveillance Network (EARS-Net)

European Centre for Disease Prevention and Control. Antimicrobial resistance surveillance in Europe 2009. Annual Report of the European Antimicrobial Resistance
Surveillance Network (EARS-Net). Stockholm: ECDC; 2011.
 Most Common Drugs Found to be
Associated with Fatal Adverse Drug Events
in 133 Patients who Died in a Department of
Internal Medicine in Norway
Ebbesen et al. Arch Intern Med 2001
Cardiovascular 46
Antiasthmatic 41
Antithrombotic 34
Anti-infective 11
Antipsychotic 10
Analgesic 10
NSAID 4.5
Other 24
0 10 20 30 40 50%
 Antibiotic De-escalation in the
ICU: A Five-Step Policy
1. Stopping antibiotics in patients without
documented bacterial infection
2. Stopping vancomycin or linezolid if no
MRSA is identified
3. Broad-spectrum betalactams restricted
to infection caused by pathogens only
susceptible to these agents
4. Switching to monotherapy after 3 days
5. Antibiotics stopped ASAP (after a
maximum of 8 days in most cases)
 Step #1: Stopping Antibiotics in
ICU Patients Without
Documented Bacterial Infection
o Obtaining specimens for
appropriate cultures before
antimicrobial administration is
essential to confirm infection,
identify responsible pathogen(s)
and enable therapy de-escalation.
Identification of the responsible
organism is necessary to de-
escalate antimicrobial Rx.
Piperacillin-tazobactam
+ AMK + vanco.

Ceftriaxone
Meropenem
+ linezolid
+ tobramycin
Colistin IV
+ tigecycline
+ caspofongin
???
Obtaining microbiological specimens
after antibiotic introduction considerably
decreases their yield

New Getting pulmonary

ABs secretions

hours
 Step #1: Stopping Antibiotics in
ICU Patients Without
Documented Bacterial Infection
o All antibiotic therapy in the ICU
should be re-evaluated on days
2 or 3, based on the clinical course
of the disease and microbiological
culture results.
The ATS/IDSA
Diagnostic Clinical features
suggesting VAP
Algorithm
YES
1st step Obtain immediately respiratory secretions
and blood cultures before
starting or changing existing antibiotics

2nd step Start empiric antibiotics immediately based on risk factors,

time of onset & local epidemiology of MDR pathogens
Using ATS guidelines

Stop antibiotics if
Positive NO low clinical probability
3rd step cultures and no signs
of severe sepsis
YES
Adjust antibiotics
based on culture results
& clinical response
Early Antibiotic Discontinuation in Patients
With Clinically Suspected VAP and Negative
Quantitative Bronchoscopy Cultures
Raman K, et al. Crit Care Med 2013;41:165663

P=0.003

P=0.04

P=0.008

P <0.001
 Step #2: Stopping vancomycin or
linezolid if no MRSA is identified

o Vancomycin and linezolid

should be stopped if no MRSA
is identified
o Infections caused by MSSA
should be treated with
oxacillin, except in case of
allergy
 Assessment of antibiotic prescribing
among patients treated with IV
vancomycin
Fridkin S, et al. MMWR Morb Mortal Wkly Rep. 2014;63(9):194-200

Patients treated with IV vancomycin N=185 %

No diagnostic culture obtained around 17 9.2
antibiotic initiation
Diagnostic culture showed no Gram-positive 40 20.6
bacterial growth, but patient still treated for
long duration (>3 days)
Diagnostic culture grew only oxacillin- 9 4.9
susceptible Staphylococcus aureus, but patient
still treated for long duration (>3 days)
No. of patients with potential for 66 35.7
improvement in prescribing
Vancomycin versus -Lactam for
Methicillin-Susceptible S. aureus BSI
McConeghy KV, et al. Clinical Infectious Diseases 2013;57(12):17605
 Step #3: Streamlining Antibiotic
Therapy Once Culture Results Are
Available
Restrict use of very broad-spectrum
agents, such as carbapenems, pip./taz., and
cefepime, to infections caused by
pathogens only susceptible to these
agents:
Treat infections caused by Enterobacteriaceae
with a 3rd-gen. cephalosporin (except ESBL-
producing strains and Group 3 GNB)
Treat P. aeruginosa infections caused by
piperacillin-S strains with this specific antibiotic
Restrict use of ciprofloxacin to pts allergic to
-lactams.
 Fluoroquinolone Use and Subsequent
Emergence of Multiple Drug-resistant
Bacteria in ICU Patients
Nseir S., et al. Crit Care Med 2005;33:283-9

Variable Odds ratio P value

(95% CI)
Duration of 1.1 <0.001
antibiotic treatment (1.0-1.2)
Fluoroquinolone 3.3 <0.001
use (1.7-6.5)
 Step #4: Switching to
Monotherapy after 3-5 Days
o Therapy can and should be switched to
monotherapy in most patients after 3-5
days, provided that:
initial therapy was appropriate,
clinical course appears favorable,
and that microbiological data exclude a very
difficult-to-treat microorganism, with a
very high in vitro MIC, as it can be
observed with some nonfermenting-GNB
and/or carbapenemase-producing GNB.
Empirical Treatment With Moxifloxacin and
Meropenem vs Meropenem in Patients
With Severe Sepsis: A Randomized Trial
Brunkhorst FM, et al. JAMA. 2012;307:2390-9
Empirical Treatment With Moxifloxacin and
Meropenem vs Meropenem in Patients
With Severe Sepsis: A Randomized Trial
Brunkhorst FM, et al. JAMA. 2012;307:2390-9
 Step #5: Shortening Duration
of Therapy
A too long duration of treatment
may favor the emergence of
MDR or pandrug-resistant
strains, exposes to antibiotic
toxicity, and increases costs, and
NOT necessarily improves
outcome
Kaplan Meier plot for mortality within 30
days for patients with VAP
Schuetz P, et al. Clin Infect Dis. 2012;55(5):651-62
 Antibiotic De-escalation in the
ICU: A Five-Step Policy
1. Stopping antibiotics in patients without
documented bacterial infection
2. Stopping vancomycin or linezolid if no
MRSA is identified
3. Broad-spectrum betalactams restricted
to infection caused by pathogens only
susceptible to these agents
4. Switching to monotherapy after 3 days
5. Antibiotics stopped ASAP (after a
maximum of 8 days in most cases)