Antibiotic de escalation_in_the_icu___how_is_it.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
CURRENT
OPINION Antibiotic de-escalation in the ICU: how is it
best done?
Jose Garnacho-Monteroa,b,c
, Ana Escoresca-Ortegaa
, and
Esperanza Fernańdez-Delgadoa
Purpose of review
An antimicrobial policy consisting of the initial use of wide-spectrum antimicrobials followed by a
reassessment of treatment when culture results are available is termed de-escalation therapy. Our aim is to
examine the safety and feasibility of antibiotic de-escalation in critically ill patients providing practical tips
about how to accomplish this strategy in the critical care setting.
Recent findings
Numerous studies have assessed the rates of de-escalation therapy (range from 10 to 60%) in patients with
severe sepsis or ventilator-associated pneumonia as well as the factors associated with de-escalation.
De-escalation generally refers to a reduction in the spectrum of administered antibiotics through the
discontinuation of antibiotics or switching to an agent with a narrower spectrum. Diverse studies have
identified the adequacy of initial therapy as a factor independently associated with de-escalation. Negative
impact on different outcome measures has not been reported in the observational studies. Two randomized
clinical trials have evaluated this strategy in patients with ventilator-associated pneumonia or severe sepsis.
These trials alert us about the possibility that this strategy may be linked to a higher rate of reinfections but
without an impact on mortality.
Summary
Antibiotic de-escalation is a well tolerated management strategy in critically ill patients but unfortunately is
not widely adopted.
Keywords
de-escalation, empirical therapy, hospital-acquired pneumonia, sepsis, survival
INTRODUCTION
Adequate empiric antimicrobial therapy is crucial in
terms of survival in patients with severe infections
[1,2]. Moreover, inadequate empirical therapy sig-
nificantly increases the length of hospitalization in
critically ill patients with severe sepsis or septic
shock [3]. With these premises, when microbiolog-
ical information is not available yet, the use of
broad-spectrum antimicrobial(s) constitutes the
backbone of the empirical therapy in critically
ill patients.
Broad-spectrum antimicrobial treatment is
defined as a combination of antibiotics which acts
against a wide range of disease-causing bacteria.
Certain families of antibiotics (i.e. piperacillin–
tazobactam or carbapenems) pose a wide antimicro-
bial spectrum and their use as monotherapy is
considered as broad-spectrum therapy. It is worth
mentioning that carbapenems are the most com-
monly used antibiotics in the critical care setting,
especially for nosocomial sepsis [4].
However, the use of broad-spectrum antimicro-
bial treatment is not without its drawbacks: anti-
biotic-related side effects, extra costs and the
emergence of bacterial resistance. International
guidelines recommend the use of broad-spectrum
antibiotics to minimize the risk for inadequate anti-
microbial treatment, which has been shown to
increase mortality [5–7]. However, once the patho-
gen(s) are identified, the empiric antibiotic(s)
a
Critical Care and Emergency Department, Intensive Care Unit, Virgen
del Rocıó University Hospital, b
Instituto de Biomedicina de Sevilla (IBIS),
Hospital Universitario Virgen del Rocıó/CSIC/Universidad de Sevilla and
c
Spanish Network for Research in Infectious Disease (REIPI), Virgen del
Rocıó University Hospital, Sevilla, Spain
Correspondence to Jose Garnacho-Montero, MD, Critical Care and
Emergency Department, Intensive Care Unit, Virgen del Rocıó University
Hospital, Avd Manuel Siurot, s/n, 41013, Sevilla, Spain. E-mail: jgarna
chom@gmail.com
Curr Opin Infect Dis 2015, 28:193–198
DOI:10.1097/QCO.0000000000000141
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com
REVIEW

should be stopped or reduced in number and/or
narrowed in spectrum. This strategy termed ‘de-
escalation therapy’ appears theoretically correct,
capable of promoting therapeutic appropriateness
and reducing costs.
HOW CAN WE DEFINE DE-ESCALATION
THERAPY?
Regrettably, a precise consensus definition of de-
escalation is still lacking. De-escalation generally
refers to a reduction in the spectrum of administered
antibiotics through the discontinuation of anti-
biotics providing activity against nonpathogenic
organisms, discontinuation of antibiotics with
similar activity or switching to an agent with nar-
rower spectrum. De-escalation is mostly accom-
plished by a reduction in the number of antibiotics
prescribed [8,9]. Furthermore, the period of time
during which the de-escalation should be performed
has not been determined.
Madaras-Kelly et al. [10
&&
] have developed a
numerical score to measure the microbial spectrum
of antibiotic regimens using a modified Delphi
method. This score could be a tool to quantify the
rate of de-escalation, although its clinical applica-
bility is uncertain.
Selective pressure exerted by broad-spectrum
antibiotics plays a crucial role in the emergence of
multidrug-resistant bacteria. The impact on the
microbiota of some antibiotics remains for extended
periods of time [11]. The capability of the different
antimicrobial agents in altering endogenous flora
should be considered for the election of the directed
therapy.
RATES OF DE-ESCALATION THERAPY IN
CRITICALLY ILL PATIENTS
Roughly, this strategy is accomplished in approxi-
mately 35–50% of the patients with severe sepsis
[8,9,12
&
]. The de-escalation rate in ventilator-
associated pneumonia (VAP) is very similar, although
this strategy is performed only in less than 10%
when multidrug-resistant pathogens are implicated
[13–15]. However, comparisons among studies are
difficult by the absence of standardized definitions of
de-escalation, variability of the empirical regimens
and the differences in patient populations.
Multiple reasons could explain these low rates
of antibiotic de-escalation in the critical care set-
ting: reluctance to change an antibiotic regimen
that has proven to be effective, lack of micro-
biological data, poor understanding of how to
de-escalate and the controversial data about its
effectiveness and safety.
CURRENT EVIDENCE ABOUT
EFFECTIVENESS AND SAFETY OF
DE-ESCALATION THERAPY
Observational studies and randomized clinical trials
have been conducted to evaluate the clinical impact
and safety of de-escalation therapy in patients with
severe infections and sepsis.
Observational studies
De-escalating strategies have been evaluated
particularly in VAP, in which the potential risk of
multidrug-resistant microorganisms is relatively
high. Several studies have shown that de-escalation
therapy can be safely provided to patients with ICU-
acquired pneumonia and is even associated with
lower mortality. Rello et al. [13] found that the
mortality rate of VAP patients de-escalated was sig-
nificantly lower than in patients with no modifi-
cation of the empiric antibiotics (18.4 vs. 43.4%).
Similarly, Kollef et al. [16
&
] analysed 398 patients
with VAP. The mortality rate was significantly lower
among patients in whom therapy was de-escalated
(17.0%), than in those experiencing therapy escala-
tion (42.6%) and those in whom empirical regimen
was not modified (23.7%; P ¼ 0.001) [16
&
]. Giantsou
et al. [17], in a prospective observational study of
VAP patients, found that antibiotic de-escalation
was associated with significantly decreased 28-day
mortality (12 vs. 43.5%). In another retrospective
study, the de-escalation group had a significantly
lower pneumonia-related 30-day mortality rate than
in the group with fixed therapy (2.3 vs. 14%) [15]. Of
note, a multivariate analysis was not performed in
these studies to assess whether this strategy was a
protective factor for mortality. De-escalation
therapy was also associated with shorter length of
stay and with a reduction of resource utilization
[17].
Alvarez-Lerma et al. [18], in a prospective multi-
centre study of patients with VAP, reported that the
KEY POINTS
Clinicians should strive to streamline empiric
antimicrobial therapy once culture results are available.
Current evidence suggests that antibiotic de-escalation
is a well tolerated strategy that may be even associated
with a better outcome.
All initiatives to improve antibiotic prescriptions in
critically ill septic patients are completely warranted
and should include the streamlining of empirical
antibiotics.
A precise consensus definition of de-escalation is
urgently needed.
Respiratory infections
194 www.co-infectiousdiseases.com Volume 28 Number 2 April 2015

ICU length of stay was significantly longer in
culture-positive patients with narrower-spectrum
alternatives who were not de-escalated than in cul-
ture-positive patients whose therapy was modified
accordingly (36.7 vs. 23.7 days). In this study, de-
escalation therapy was not a variable independently
associated with mortality by logistic regression
analysis.
This antibiotic policy has also been assessed in
patients with severe sepsis. Morel et al. [8] evaluated
a heterogeneous group of critically ill patients with
severe infections. Their main finding was that de-
escalation therapy was associated with a significant
reduction of recurrent infection (19 vs. 5%, P ¼ 0.01)
without changes in mortality [8].
To evaluate the effect of antibiotic de-escalation
on outcomes, we conducted a prospective, observa-
tional study involving adults admitted to the ICU
with severe sepsis or septic shock. De-escalation of
the initial regimen was performed in 219 patients
(35%), more commonly in medical than in surgical
patients. The hospital mortality rate was 27% in
patients with therapy de-escalation, 33% in those
with no treatment change and 43% in those with
treatment escalation (P ¼ 0.006). Propensity score
adjusted multivariate regression analysis identified
de-escalation therapy to be as protective for hospital
90-day mortality in the entire cohort, as well as in
patients who had received empirical adequate
therapy [12

].
In 754 patients with bacteremic sepsis, Koupe-
tori et al. [19] evaluated the impact on the outcome
of de-escalation therapy in two periods. Antibiotic
streamlining did not impact final outcome,
although this strategy led to survival benefit in
the second study period [19]. It is worth mentioning
a recent observational study performed in 101 neu-
tropenic patients with severe sepsis. In this selected
population, de-escalation did not negatively affect
any prognostic index including early (30-day) or late
(1-year) mortality [20].
Randomized clinical trials
Two randomized clinical trials have evaluated this
antimicrobial strategy with less positive results.
Kim et al. [21

] compared the use of imipenem as
well as vancomycin and subsequent de-escalation
with maintenance of the above-mentioned anti-
microbial regimen in critically ill patients with
hospital-acquired pneumonia (HAP). Mortality
and length of stay were similar in both arms, but
the emergence of multidrug-resistant organisms,
especially methicillin-resistant Staphylococcus aur-
eus (MRSA), was more frequent in the de-escalation
group.
In patients with severe sepsis [22

], a clinical
trial concluded that, as compared with the continu-
ation of the empirical treatment, de-escalation of
antibiotics resulted in prolonged duration of ICU
stay (primary outcome measure). A new infection
occurred in 16 (27%) patients in the de-escalation
group and six (11%) patients in the continuation
group (P ¼ 0.03). Again, mortality rate was unaf-
fected.
HOW CAN DE-ESCALATION BE DONE?
De-escalation strategies may differ in different
aspects. However, several steps should be always
present (Fig. 1). First, before starting antimicrobial
therapy, it is indispensable to obtain appropriate
cultures in order to identify the pathogens respon-
sible for septic conditions. This is the first step to
carry out the de-escalation of the empirical therapy
because it is challenging to discontinue empirical
antibiotics without microbiological documentation
of the infection.
Second, empirical antibiotic must cover all
likely pathogens administering broad-spectrum
antimicrobial therapy. Several studies have ident-
ified the adequacy of initial antibiotic therapy as an
independent factor associated with de-escalation.
As expected, the presence of multidrug-resistant
bacteria hampered de-escalation [9,13,23]. Third,
once the culprit pathogen(s) are identified, the
empirical regimen should be adapted to the micro-
biological results.
De-escalation may also include switching anti-
biotics from intravenous to oral route. This change
is rarely performed in critically ill patients but is a
suitable option in certain situations.
De-escalation in infections caused by
Gram-positive bacteria
Stopping antimicrobials directed against resistant
Gram-positive bacteria (i.e. MRSA or Enterococcus
faecium) should be the rule when these pathogens
are not isolated in clinical samples. Switching to an
agent with a narrower spectrum is easily performed
for coverage of Gram-positive bacteria susceptible
to beta-lactam antibiotics. There is compelling evi-
dence that mortality and morbidity of severe infec-
tions caused by methicillin-susceptible S. aureus
(MSSA) is significantly higher with a glycopeptide
than with cloxacillin [24]. Similarly, 30-day
mortality of MSSA bacteremia is significantly lower
with a beta-lactam with a high activity against
MSSA (cloxacillin or cefazoline) than with a third-
generation cephalosporin or with piperacillin–
tazobactam [25]. Very recently, glycopeptide use
Treatment of resistant bacteria Garnacho-Montero et al.
0951-7375 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-infectiousdiseases.com 195

was associated with increased mortality in Entero-
coccus faecalis bacteremia [26

].
De-escalation in infections caused by
Gram-negative bacteria
Although the use of two active antimicrobials
against certain Gram-negative bacilli (i.e. Pseudomo-
nas aerugionsa) has been traditionally advocated
[27], recent studies clearly demonstrated that the
use of combination therapy in the directed therapy
does not reduce recurrence rates and is not associ-
ated with any survival benefits [28,29]. Similarly, in
severe infections caused by Acinetobacter baumannii,
the use of monotherapy appears feasible without
any obvious negative clinical impact [30]. Therefore,
if two active antimicrobials have been initiated to
cover Gram-negative bacilli (GNB), switch to mono-
therapy can be safely performed once susceptibility
results are available. Infections caused by carbape-
nemase-producing Klebsiella pneumoniae constitute
an exception to this recommendation of monother-
apy in the directed therapy [31].
More troublesome is usually the spectrum
reduction of the empirically administered antibiotics
for Gram-negative bacilli. Whenever possible, carba-
penems must be stopped and switched to another
antimicrobial with a narrower spectrum and less
impact on resistance development [32]. Carbape-
nems should be reserved because they frequently
constitute the only therapeutic option against GNB
such as extended-spectrum beta-lactamase (ESBL)-
producing Enterobacteriaceae, Pseudomonas aerugi-
nosa or A. baumannii. The likely alternatives are
summarized in Table 1. Piperacillin–tazobactam is
an option frequently used in the directed therapy
when meropenem was used empirically [33]. Recent
studies have reported that the susceptibility of
P. aeruginosa to imipenem improved after the intro-
duction of ertapenem into hospital formularies
[34].
De-escalation of antifungal therapy
Therapy with an antifungal agent should be dis-
continued if fungi (i.e. Candida spp.) are not
present in clinical samples. Regarding the switch
to an antifungal agent with narrower spectrum,
echinocandins are considered the agents of choice
for empirical treatment of critically ill patients
with invasive candidiasis. In patients with candi-
demia, therapy until 14 days after the first negative
blood culture is recommended. Recent guidelines
include the recommendation to step-down to
oral fluconazole after 10 days of intravenous treat-
ment if the patient is clinically stable and blood
cultures have become negative [35]. The appropri-
ate timing of antifungal step-down remains
unclear, but this change might be done early
and the use of intravenous fluconazole is a valid
alternative provided that the strain is susceptible
to the azole.
Empirical therapy
• Early therapy
•
•
Broad spectrum agents
Consider combination
therapy
• Optimization of dose
schedule
Streamlining of empirical therapy
• Stopping of antibiotics
• Agents with narrower spectrum
• Low impact on microbiota
• Optimization of dose schedule
• Use oral route if possible
• Consider cost
Appropriate
cultures
• Blood
• Site of infection
De-escalation
therapy
FIGURE 1. Components of the de-escalation therapy strategy.

De-escalation therapy in culture-negative
infections
Regarding de-escalation therapy, particularly chal-
lenging are the infections with negative cultures. In
a retrospective study, antibiotic therapy was de-
escalated in 75% of the patients with culture-
negative HAP [36]. Conversely, de-escalation was
not performed in patients without a known
pathogen in a series of critically ill patients with
VAP [13]. It is reasonable to cease empirical vanco-
mycin in patients with culture-negative pneumonia
and with no MRSA colonization [37]. In other
patients without microbiological documentation,
streamlining of the empirical therapy should be left
to clinical judgement as long as the patient has a
good clinical course.
CONCLUSION
Antibiotic de-escalation is a well tolerated and
highly recommended approach in critically ill
patients with severe sepsis. The available data
suggest that outcomes can be improved with its
use. These outcomes include less antibiotic use,
shorter duration of therapy and reduced mortality.
Nevertheless, we also need more information
about which patients can have therapy stopped
altogether if cultures are negative and about the
timing to carry out the streamlining of the empirical
therapy.
Acknowledgements
None.
Financial support and sponsorship
No financial support was received for this study.
Conflicts of interest
There are no conflicts of interest.
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READING
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been highlighted as:
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Table 1. Different options for de-escalation of beta-lactams commonly used in the empirical therapy to cover Gram-negative
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Imipenem or meropenem Ertapenem Ertapenem use may improve susceptibility of Pseudomonas spp. to
imipenem/meropenem
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Ceftazidime or cefepime No anaerobic coverage
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pathogens, including gram-negatives, MRSA and VRE.
Ceftriaxone or cefotaxime No anaerobic coverage
Cloxacillin If MSSA is the culprit pathogen
Piperacillin and tazobactam Ceftazidime or cefepime No anaerobic coverage
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pathogens, including Gram-negatives, MRSA and VRE.
Ceftriaxone or cefotaxime
Cloxacillin Lower mortality rate of MSSA bacteremia treated with cloxacillin
Ceftazidime or cefepime Ceftriaxone or cefotaxime No anaerobic coverage
Amoxicillin-Clavulanate Anaerobic coverage
Cloxacillin Only if MSSA is the culprit pathogen
Ceftriaxone or cefotaxime Amoxicillin-clavulanate Anaerobic coverage
Cloxacillin Only if MSSA is the culprit pathogen
MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; VRE, vancomycin-resistant
Enterococcus.
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