Antibiotic

De-Escalation
Robert G. Masterton, FRCPath, FRCP [Edin & Glas]

KEYWORDS
 De-escalation  Antimicrobial streamlining
 Antimicrobial stewardship

The present topography of clinical sepsis is a landscape populated by increasing and

developing antimicrobial resistance, with a future where ever fewer new antibiotics,
particularly innovative classes,1 are becoming available to meet these challenges.
This prospect has resulted in a new focus on making the best use of the antibiotics
available to maximize their clinical impact and longevity. Such initiatives have become
condensed into 2 main themes that are integrated, with the new treatment paradigm
that deals with serious sepsis, of “hit it hard and hit early”2 being embedded within the
overall encompassing concept of antimicrobial stewardship.3
De-escalation forms one of the key features of the new treatment paradigm (Box 1).
Within this paradigm de-escalation presents probably the most challenging element.
Notwithstanding this, the literature shows that de-escalation has received widespread
support in various review and recommendation documents4–6 over the last decade,
but in a manner that perhaps does not reflect its true standing against the difficulties
attendant to its implementation. Whereas its step-down concept of changing to
a more targeted antibiotic is intrinsically logical, in clinical practice it faces the natural
instinct of the clinician to continue with a treatment that is proving to be effective in
managing the often life-threatening infection affecting a patient. This remains true,
notwithstanding the positive conclusion reached within the recently released guide-
lines on antimicrobial stewardship3 stating that: “Streamlining or de-escalation of
empirical antimicrobial therapy on the basis of culture results and elimination of redun-
dant combination therapy can more effectively target the causative pathogen, result-
ing in decreased antimicrobial exposure and substantial cost savings.”
Crucially, whereas the strength of this recommendation was assigned the top rating
of an “A”, it was acknowledged that the quality of the clinical evidence underpinning
this was only in the middle band. This article therefore reviews the issue of de-esca-
lation to present the current position.

Financial disclosures and/or conflicts of interest: The author has nothing to disclose against the
subject matter and materials discussed in this article.
Funding support: None.
Department of Microbiology, Ayrshire & Arran NHS Board, The Ayr Hospital, Dalmellington
Road, Ayr KA6 6DX, UK
E-mail address: robert.masterton@aaaht.scot.nhs.uk

Crit Care Clin 27 (2011) 149–162

doi:10.1016/j.ccc.2010.09.009 criticalcare.theclinics.com
0749-0704/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
150 Masterton

Box 1
Key principles of the new treatment paradigm

 Get effective antibiotic selection right first time

 Base antimicrobial selection, both empiric and targeted, on knowledge of local susceptibility
patterns
 Use broad-spectrum antibiotics early
 Optimize the antibiotic dose and route of administration
 Administer antibiotics for the shortest possible duration
AND
 Adjust or stop antibiotic therapy as early as possible to best target the pathogen(s) and
remove pressure for resistance development (ie, de-escalation)

DEFINITION OF DE-ESCALATION

The definition of antimicrobial de-escalation is that it is a mechanism whereby the

provision of effective initial antibiotic treatment, particularly in cases of severe sepsis,
is achieved while avoiding unnecessary antibiotic use that would promote the devel-
opment of resistance. This definition therefore encompasses 2 key features. First,
there is the intent to narrow the spectrum of antimicrobial coverage depending on clin-
ical response, culture results, and susceptibilities of the pathogens identified, and
second, there is the commitment to stop antimicrobial treatment if no infection is
established.7 Vidaur and colleagues8 added to this the criterion that where possible
a single rather than multiple antibiotics should be used. The problem as it relates to
clinical practice is the lack of convincing trial evidence demonstrating that de-escala-
tion does not result in a poorer clinical outcome. Solid study data establishing exactly
what criteria should be used, and when, to determine changing and stopping therapy
do not exist.

ANTICIPATED BENEFITS FROM DE-ESCALATION

When considering de-escalation studies, it is important to be aware of the benefits that

this approach is intended to produce (Box 2). Perhaps, peculiarly in assessing thera-
peutic management lines, the key feature for the studies to date in response to the
challenges described above has been to show no detriment to individual patients
rather than a potential improvement in clinical outcome. The primary focus of de-esca-
lation is actually to demonstrate longer-term benefits through a positive impact on

Box 2
Benefits realization in de-escalation therapy

 Treatment outcomes are unaltered from the conventional therapy approach of maintaining
patients on their initially selected antimicrobials
 There is a beneficial impact observed through surveillance on the antimicrobial resistance
profile for the institution at both micro and macro level
 Decrease in antibiotic related adverse events, for example, the incidence of Clostridium
difficile infection and/or of superinfection with resistant bacteria and Candida organisms
 There is a reduction in overall antimicrobial costs
 Antibiotic De-Escalation 151

antibiotic resistance development, with a significant secondary goal being financial

savings through improved cost effectiveness.

THE EVIDENCE FROM CLINICAL DE-ESCALATION STUDIES

The overwhelming majority of the clinical studies assessing patient outcomes per-
formed to date have been focused on nosocomial pneumonia (NP), especially venti-
lator-associated pneumonia (VAP). Their findings are reviewed in Table 1. The table
begins with the seminal short-course antibiotic treatment study of Singh and
colleagues.9 Although not normally found on a literature search for articles on de-
escalation, it is among the first and strongest examples of de-escalating therapy to
a stop when infection is assessed as not being present.
There are some further studies reported that are not presented in Table 1, which are
very few and diverse. These studies demonstrate centers beginning to expand the
boundaries, including the difficulties of evaluating de-escalation outside the narrow field
of NP. A prospective audit among 72 hospital inpatients suffering from amoxicillin-
susceptible Escherichia coli infection in blood and/or urine17 found that only 19% of those
who could be de-escalated to amoxicillin actually received this agent. Amongst the 54%
who had their antibiotic changed 64% of these were actually moved, perversely, to an
unnecessarily broad-spectrum agent, and in 10% this was actually to a drug reported
to be resistant. The investigators concluded that successful implementation of de-esca-
lation demands more than simple protocol distribution. In another recent study that
explored the practical application of de-escalation,18 data from 113 intensive care unit
(ICU) meropenem prescriptions were evaluated. De-escalation was defined as the
administration of an antibiotic with a narrower spectrum within 3 days of the start of mer-
openem. The study found a trend toward a lower mortality rate (7% vs 21%, P 5 .12) in
patients who had been de-escalated. The majority of the infections were either pneu-
monia (46%) or intra-abdominal (31%). De-escalation was performed in 42% of patients,
with the most common reasons for not doing so being the absence of conclusive
microbiology or colonization with a multiresistant gram-negative bacillus. Finally, a retro-
spective study19 has explored the issue of de-escalation in 102 cases of health care–
associated pneumonia where high-quality samples from intubation were not available
and the microbiology findings were culture negative. The Pneumonia Severity Index
was used for risk adjustment. The findings were that de-escalation occurred in 75%
and 77% of the culture-negative and -positive groups, respectively (P 5 1.00). However,
in culture-negative cases de-escalation took place approximately 1 day earlier (3.93 vs
5.04 days, P 5 .03) and this group also showed a shorter length of hospitalization, lower
hospital costs, and lower mortality rates.
In the vast majority of the studies presented, the exact time to re-evaluation with
a view to de-escalation was not set, which tended to reflect the time taken for the results
to become available. In most studies, and against a continuous evaluation of the clinical
response of the patient, microbiology results became available at around 48 to 72
hours, and this seems to be a pragmatic and sensible approach. However, the results20
of a university hospital ICU are illuminating in this regard because they showed that
although de-escalation was successfully implemented in 69% of patients for whom
the microbiological data supported this, there was a mean interval of around 48 hours
from the microbiological data being available to de-escalation action being taken.

BENEFITS REALIZATION IN DE-ESCALATION PRACTICE

Based on the clinical evidence from the now significant numbers of studies that have
been performed, it is reasonable to conclude, given the consistency of these data, that

Table 1
De-escalation studies in nosocomial and ventilator-associated pneumonia
YearReference Principal Features of Study Design
20009 Randomized prospective trial involving
81 patients to minimize unnecessary
antibiotic by using the clinical
pulmonary infection score (CPIS)
to assess ventilator-associated
pneumonia (VAP) as operational
tool for antibiotic therapy
decision-making
200410 Prospective observational study over
43 months in a medical-surgical
ICU involving 115 patients
Brief Methodology Overview
Quantitative bronchoalveolar lavage (BAL)
used for diagnosis. Patients with CPIS 6
(implying low likelihood of pneumonia)
received either standard therapy (antibiotic
choice and duration physician discretion) or
the study group with ciprofloxacin monotherapy
with reevaluation at day 3 when ciprofloxacin
was discontinued if CPIS remained 6
All episodes received initial broad-spectrum
coverage followed by reevaluation according
to clinical response and microbiology.
Quantitative cultures by bronchoscopic
examination or tracheal aspirates were
used to modify therapy
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Masterton
Principal Findings Relevant to
De-Escalation
Antibiotics continued beyond day 3 in 90%
of those on standard approach compared
with 28% in the study group (P 5 .0001).
Where CPIS remained 6 at day 3
antibiotics were continued in 96% in
standard group but 0% in the others
(P 5 .0001). Mortality and length of
intensive care unit (ICU) stay did not
differ despite a shorter duration
(P 5 .0001) and lower cost (P 5 .003) in
the study arm. Antimicrobial resistance,
or superinfections, or both, developed in
15% of study versus 35% of standard
therapy patients (P 5 .017)
Change of therapy in 56.2%, including
de-escalation in 31.4% (increasing to
38% if isolates were sensitive). Overall
ICU mortality was 32.2%. The de-
escalation mortality rate was lower than
those who continued initial regimen
(18% vs 43%; P<.05). De-escalation was
lower (P<.05) in the presence of
nonfermenting gram-negative bacillus
(2.7% vs 49.3%) and in the presence of
late-onset pneumonia (12.5% vs 40.7%).
When the pathogen remained unknown,
50% died and de-escalation was not
performed
200611 An observational cohort study involving
104 patients to assess the impact of
locally developed antimicrobial
guidelines in the initial empiric
treatment of ICU patients with severe
hospital-acquired pneumonia (HAP)
200612 Observational prospective study
conducted in 24 Spanish ICUs to assess
a carbapenem-based de-escalating
strategy in nosocomial pneumonia (NP)
in 244 critically ill patients
Evaluation pre- and post-guideline introduction
where decision to change was based on
quantitative BAL. Imipenem the main guideline
empiric drug
NP treated empirically with imipenem 
aminoglycoside/ glycopeptide. 91% were
late-onset NP where primary outcome was
therapeutic success 7–9 days post therapy.
Culture-positive rate 54%, based on tracheal
aspirates in 82%, protected specimen brush
in 33%, and BAL in 4%
Guideline followed in 75%. Imipenem
continued as directed therapy in 27 cases.
De-escalation possible in 34 patients but
therapy continued beyond
recommendation in 16 of these. The
guideline patients showed greater
adequate treatment (81% vs 46%; P<.01)
with a lower mortality rate at 14 days (8%
vs 23%, respectively; P 5 .03). There was
no increase in imipenem resistance
related to its increased used during the
study period
Initial antibiotics inadequate for 9%.
De-escalation in 23% and unchanged for
6%; 16% of patients did not receive
de-escalation despite favorable
microbiology. 46% therapy not altered,
as no pathogen found. De-escalation
implemented in only 23% with
potentially multiresistant pathogens,
compared with 68% in the rest (P<.001).
Response rates were 53% and 50%,
respectively in those receiving and not
receiving de-escalation. No differences in
superinfection rates and costs associated
with de-escalation mainly dependent on
Antibiotic De-Escalation
the duration of hospitalization, though
the duration of stay and costs in the ICU
were higher for patients who were not
de-escalated (P<.001 and P 5 .001,
respectively)
(continued on next page)
153

Table 1
(continued)
YearReference Principal Features of Study Design
200613 Prospective, observational, cohort
study in 20 ICUs in United States
involving 398 ICU patients with
suspected VAP to evaluate clinical
characteristics and treatment patterns
amongst VAP cases, including the
implementation of and outcomes
associated with de-escalation therapy
200714 Prospective observational study
over 36 months to evaluate
de-escalation in 115 medical-surgical
ICU patients treated according to
local pathway
Brief Methodology Overview
Therapy escalation was a switch to or addition
of a drug class or classes with a broader
spectrum or additional coverage. De-escalation
was a switch to or discontinuation of a drug class
resulting in a less broad spectrum of coverage.
Diagnosis was by a range of methods
All enrollments had positive cultures and were
treated with limited-spectrum antibiotics (ie,
without activity against Pseudomonas aeruginosa)
if they had no prior hospitalization (within
21 days) or prior administration of antibiotics
(within 10 days). Quantitative cultures by
bronchoscopy or tracheal aspiration used to
reassess empiric therapy
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Masterton
Principal Findings Relevant to
De-Escalation
61.6% of patients had neither escalation
nor de-escalation. Overall, escalation
occurred in 15.3% and de-escalation in
22.1%. De-escalation was significantly
more common where 3 or more
antibiotics were prescribed. De-escalation
occurred more frequently when a major
pathogen was isolated (26.8% vs 6.5%).
Most patients with no pathogen had no
change in therapy (87.1%), compared
with 57.6% when a major pathogen was
isolated. In those who initially received
adequate therapy de-escalation took
place in 27.1%, compared with 16.6% in
those whose initial therapy was not
adequate (c2 5 6.15; P 5 .013). De-
escalation took place in 27.7% of BAL (c2
5 3.59; P 5 .06); 20.5% of tracheal
aspirate patients (c2 5 0.84; P 5 .36) and
8.3% of those where neither was
performed. The mortality rate was
significantly reduced in de-escalated cases
(17% de-escalation; 23.7% no change &
42.6% escalation [c2 5 13.25; P 5 .001])
Limited spectrum used in 79 patients (69%).
De-escalation in respectively 26% and 72%
of patients with early- and late-onset
ventilator-associated pneumonia;
treatment escalated in 27 (23%). Overall
de-escalation was feasible in 42% of
patients with no differences in outcome
observed
200715 Prospective observational study
involving 143 patients with VAP in
a multidisciplinary ICU
200916 An observational study to evaluate
de-escalation in 138 surgical
patients, including those with
septic shock
Diagnosis by positive quantitative
cultures of either tracheal aspirate
or BAL and assessment by appropriateness
of treatment for all significant isolates
Surgical ICU patients with quantitative
bronchoalveolar lavage with a positive
threshold of 10,000 CFU/mL
Therapy de-escalated in 40.5% with
decreased mortality at day 15 (5.1% vs
31.7%) and day 28 (12% vs 43.5%) and
shorter intensive care unit (17.2  1.2 vs
22.7  6.3 days) and hospital (23.7  2.8
vs 29.8  11.1 days) stay (P<.05). In
tracheal aspirate patients there was 21%
de-escalation with reduced 15-day
mortality (5.8% vs 34.3%), reduced
28-day mortality (11.6% vs 45.3%), and
shorter intensive care unit (17.2  1.6 vs
22.4  6.4 days) and hospital (23.1  4.4
vs 29.9  11.1 days) stay (P<.05). In BAL
patients there was 66.1% de-escalation
with decreased 15-day mortality (4.8% vs
23.8%), decreased 28-day mortality
(12.1% vs 38%), and shorter ICU (17.2 
1.1 vs 23.2  6 days) and hospital (23.8 
2.4 vs 29.8  11.4 days) stay (P<.05)
The recurrent pneumonia rate was not
significantly different at 27.3% and
35.1%, respectively in those receiving and
not receiving de-escalation. Mortality did
not differ (33.8% vs 42.1%, respectively).
De-escalation of therapy occurred in 55%
of patients with appropriate initial
Antibiotic De-Escalation
therapy whereas 8% required escalation
155
156 Masterton

de-escalation is appropriate to implement and delivers at least the same clinical

outcome as the conventional approach of maintaining the initial therapy started
when this was being successful. Although the majority of these findings come from
work in NP, there is now evidence for other infections including septicemia and
intra-abdominal infections. With particular regard to NP, the specter of de-escalation
provoking an increased incidence of relapses or recurrences has been proven not to
be real. This position should now promote a scenario where further trials are used to
explore how best to de-escalate rather than whether to do it.
There are several studies10,11,13,15,19 suggesting that clinical outcome may actually
be improved where de-escalation is practiced. It is difficult to hypothesize why the
impact of de-escalation should be to improve clinical outcome, and therefore it
remains to be determined whether this effect is genuine or merely reflects the charac-
teristics of the patients in whom de-escalation is both feasible and chosen. Another
possibility is that continued potent, broad-spectrum empiric therapy may be intrinsi-
cally detrimental in some patients. A recent meta-analysis/meta-regression demon-
strated that empiric combination therapy in serious infections can be detrimental in
patients at low risk of mortality even while providing significant clinical benefit in
high-risk patients.21 Patients who have already responded to potent, broad-spectrum
antimicrobial therapy are similarly at a low risk of death and therefore may derive more
harm than benefit from continued broad-spectrum therapy where de-escalation is not
implemented, perhaps as a consequence of the modest but measurable toxicity/side
effects of such regimens.
The data available on cost-effectiveness is much less in both quantity and quality.
From the perspective of drug acquisition and administration, it is persuasive that
de-escalation should produce savings and there is evidence to support this. As
described earlier, a small number of trials that demonstrate clinical benefit appear
to point to potential cost reductions through reduced complications and shorter
lengths of stay, both in the ICU and in the hospital. Further determination of these
aspects will clearly be linked to the future work that explores whether such clinical
benefits are truly related to de-escalation as opposed to being an apparent effect.
Paradoxically, given that one of the fundamental themes underlying its promotion is
the perceived potential for this intervention to positively affect antimicrobial resistance,
there is a surprising lack of relevant evidence available. Indeed, this is the feature where
there are the fewest data in terms of the impact of de-escalation, with very few studies
exploring this aspect at all. The main question to be addressed is whether the initial use
of potent broad-spectrum antibiotics in association with de-escalation will successfully
protect against the development of resistance to the primary agent being used. Only
one study has presented on this question11 and, although it did demonstrate no
increase in resistance to the carbapenem being used, its conclusion must be viewed
with caution because of the relatively short reporting period of 6 months related to
the trial. Another study9 evaluated whether the use of de-escalation would have a posi-
tive impact on resistance development in the individual patient being treated, and
concluded that it did indeed reduce the propensity to resistance development. There
is clearly an overwhelming need for well-constructed de-escalation studies to identify
whether short- and/or long-term benefits are truly associated with this tactic in terms
of modifying the risk of resistance development.

CHALLENGES IN IMPLEMENTING DE-ESCALATION

The outcome of the adoption of de-escalation is intended to be that, based on micro-

biology results around the day 3 therapy point, the empiric antibiotic(s) that were
 Antibiotic De-Escalation 157

started are stopped or reduced in number and/or narrowed in spectrum. Experience

has shown that several factors in practice work against achieving this goal.

Adoption of De-Escalation
Rates of de-escalation range from about 10% in studies of clinical practice to about
70% in specifically designed trials; this suggests that getting clinicians to actually
use de-escalation is a principal barrier. There is a natural propensity, particularly in
severe sepsis when the patient who has been very seriously ill is starting to get better,
to stick with a treatment regimen that is working rather than change to an alternative
agent. The solution to this is to gain clinical confidence in de-escalation.
Two principal lines of attack exist to help achieve this result. First, there is the ability
for the health care professional to use a robust clinical assessment so that there can
be a reasonable degree of certainty about whether an infection is present. Two
studies, both in respiratory tract infections,9,19 have evaluated this type of approach,
showing that it is a useful component in enabling decision-making toward de-escala-
tion where a risk-based clinical assessment suggests that infection is very probably
not present and that this is supported by negative microbiology. The potential exists
to apply this type of approach in other clinical areas, for example, intra-abdominal
sepsis.22 Second, several of the trials presented in Table 1 point to the value of diag-
nostic certainty where they have shown that de-escalation is most likely to take place
against higher quality samples, such as bronchoalveolar lavage, when compared with
less invasive tests such as tracheal aspirates. This concept was specifically explored
in a study15 where VAP was diagnosed by positive quantitative cultures of either
tracheal aspirate or bronchoalveolar lavage, and where it was conclusively shown
that the latter promoted the greater adherence to de-escalation.
Leaving aside the issue of what best the clinician should do in the face of uncertainty
resulting from negative microbiology cultures, which is addressed later, it has also
been shown that where other, more general sepsis concerns exist, physicians choose
to cover these potentially pathogenic organisms rather than focus on the proven
etiology. This situation is documented particularly for multiresistant gram-negative
bacilli10,12 and results in de-escalation not taking place. There are insufficient data
yet available to clarify the optimum course of action in these circumstances.
It has also been shown that providing appropriate support to clinicians in the decision-
making frontline can have a positive impact on action being taken when opportunities to
de-escalate are present. In a before-and-after study, prescriptions of 13 selected intra-
venous antibiotics from surgical and medical wards were evaluated against 3 strategies
over 3 consecutive 8-week periods: conventional management by the attending physi-
cian (control group); distribution of a questionnaire to the physician (questionnaire group);
or distribution of the questionnaire followed by advice from an infectious disease physi-
cian (Q-IDP group).23 The primary outcome was the percentage of modifications of anti-
biotic therapy at day 4, including withdrawal of therapy, de-escalation, oral switch, or
reducing the planned duration of therapy. The greatest effects were seen in the Q-IDP
phase where discontinuation was much more likely to happen than within the control
group (P<.001). In addition, more prescriptions were modified in the Q-IDP group as
compared with the control group (P 5 .004), and stopping therapy in the absence of
apparent infection also occurred significantly more often in the Q-IDP group than in the
control (P<.0001) or questionnaire groups (P 5 .002).
Those seeking to introduce de-escalation strategies must recognize this funda-
mental issue of clinician confidence, and respond positively and proactively to it in
order to give implementation its greatest chance of success.
 158
Masterton
Patient on empiric
antibiotic and
improving

Stop antibiotic De-escalate antibiotic Maintain antibiotic

Clinical risk score Clinical assessment Microbiology cultures Clinical assessment of

Clinical assessment of Microbiology
does not support of patient does not positive & show evidence patient demonstrates
patient demonstrates investigations
presence of support presence of of de-escalation that infection is
infection improving negative
infection infection opportunity improving

Microbiology cultures Other investigations Other investigations

do not support do not support demonstrate that
presence of infection presence of infection infection is improving

Fig. 1. Algorithm for de-escalation decision-making at day 3 in an improving patient.

 Antibiotic De-Escalation 159

Patient on empiric
antibiotic and not
improving

Maintain/escalate
Escalate antibiotic and
antibiotic and repeat
repeat microbiology
microbiology
investigations
investigations

Clinical assessment of Microbiology cultures Clinical assessment of Microbiology

patient demonstrates positive & show patient demonstrates investigations positive
infection getting evidence of escalation that infection is not and appear to be
worse opportunity improving covered

Other investigations OR Other investigations OR

demonstrate that demonstrate that
infection is getting Microbiology patient is not Microbiology
worse investigation negative improving investigation negative

Fig. 2. Algorithm for de-escalation decision-making at day 3 in a patient not improving on

the empiric antibiotic therapy.

Decision-Making in De-Escalation
One of the features that promotes clinician uncertainty is a lack of clarity about how to
take decisions to de-escalate; this permeates to varying degrees each of the
scenarios that the health care professional faces. However, the therapeutic approach
to each setting is actually similar, though the respective contributions of the various
components depend on the different clinical situations. The part that clinical risk
assessments can contribute to the decision-making moment has been described in
the preceding section. The other 2 features that are relevant are consideration of
the clinical progress of the patient and the investigation information that is available.

Box 3
A practical clinical bedside approach to de-escalation

1. Every patient with severe sepsis on antibiotic therapy should have the need for this
considered and formally documented every day
2. No later than day 3, a full assessment of investigation results and clinical progress should be
performed and a positive decision should be captured to:
Stop the treatment (eg, no infection is present)
Narrow the spectrum of the therapy
Reduce the number of antibiotics being used, for example, there is redundancy in the
therapy or such clinical progress that multiple agents active against the same pathogen(s)
are not necessary
Not to de-escalate, for example, the specific reason for not de-escalating is documented
(eg, lack of microbiology results, lack of clinical improvement)
3. Every day thereafter a positive decision to stop, change, or continue the therapy should be
made against specific reasons
4. At every assessment the goal is to stop the therapy, or elements of the therapy, unless
a positive and persuasive need for their continuation exists
160 Masterton

Figs. 1 and 2 present algorithms for de-escalation decision-making at around day 3

of therapy, when the microbiology results normally first become available, in the 2
common scenarios where the patient either is improving or is not. Each of these is
set against the assumptions that effective therapy with appropriate empiric antibiotic
selection and dosage has been delivered and that source control for the infection has
been identified and achieved. The clinical assessment of the patient incorporates not
just the standard observations such as pulse, temperature, blood pressure, and
oxygen saturation, but also a full physical evaluation. It is essential to consider other
noninfectious causes for the patient’s condition at each overall evaluation. Other
investigations that can shed light on the decision-making process are evaluation of
inflammatory markers such as white blood cell count, C-reactive protein, and procal-
citonin as well as appropriate use of imaging modalities. Escalation of the antibiotic
therapy in the face of a deteriorating patient with negative microbiology is a value judg-
ment set against a risk assessment of the perceived gaps in the spectrum of cover and
any likely potential foci of infection.
Following the initial day 3 assessment, continued consideration must be given to
further opportunities for de-escalation. Key in this context is the situation where the
patient is improving but microbiology cultures were negative and so the initial empiric
antibiotics were continued at day 3. At a future juncture it will be necessary to decide
when the treatment can be stopped at its earliest or converted to a narrower spectrum
and/or oral agent. This last will be a judgment against an assessment of the clinical
response, the likely source of sepsis, and also the potential pathogens to be covered.
Within this envelope is the natural concern of the attending clinician to avoid making
a mistake. This factor is more pressing when the patient remains seriously unwell as
opposed to when the patient has improved so that organ support and mechanical venti-
lation are either much reduced or no longer needed. Where ongoing clinical concerns
are high, it may be felt necessary to maintain the empiric antibiotic throughout the
course of treatment, when it should be ensured that this is for the minimum duration
possible.
Fig. 2 captures the very problematic, but by no means uncommon, midway position
where the patient’s condition has not improved at day 3. This scenario has never been
explored in any of the clinical trials available, so it is not possible to state the best
course of action. In view of this, it is probably unrealistic at present to expect de-esca-
lation to be applied to this group of patients. Although clearly continuing clinical and
investigation assessment, including microbiology tests, must be maintained, the deci-
sion whether to continue with, or escalate, the antibiotic care will be constructed on an
individual patient basis depending on an overall assessment of the risks.
In summary, key elements within a successful de-escalation program at the bedside
level are captured in Box 3 as a practical aid. The formal and rigorous consideration
and documentation suggested is designed to ensure that the approach is applied
consistently and in a sustained way to every relevant patient every day. It is only by
doing so that the benefits of such schemes can be captured.

SUMMARY

De-escalation is a critical component that lies at the center of antimicrobial steward-

ship programs and the “hit it hard, hit it early” serious sepsis paradigm. The data pre-
sented demonstrate that it is a clinically effective concept. However, significant and
serious shortfalls in the available evidence are highlighted. These shortfalls include
the need to establish the real impact of de-escalation on antimicrobial resistance
development; its true cost-effectiveness profile; and, while emphasizing that it is
 Antibiotic De-Escalation 161

now well demonstrated that there is no downside for patients, whether it genuinely
does improve clinical outcomes. Significant work needs to be done to establish the
most effective tools to implement de-escalation, particularly in terms of providing clear
guidelines to clinicians to enable them to be confident in applying this maneuver. It is
interesting that this concept of de-escalation is now being explored in other types of
infection.24 There is little doubt that de-escalation is now here to stay, and the issue
should no longer be whether the clinician should do it but how best it can be delivered.

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