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Antibiotic strategies in severe nosocomial sepsis: Why do we not de-escalate

more often?

Article  in  Critical care medicine · March 2012

DOI: 10.1097/CCM.0b013e3182416ecf · Source: PubMed

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Feature Articles

Antibiotic strategies in severe nosocomial sepsis: Why do we not

de-escalate more often?*
Sarah Heenen, MD; Frédérique Jacobs, MD; Jean-Louis Vincent, MD, PhD, FCCM

Objectives: To assess the use of antibiotic de-escalation in
patients with hospital-acquired severe sepsis in an academic
setting.
Design: We reviewed all episodes of severe sepsis treated over
a 1-yr period in the department of intensive care. Antimicrobial
therapy was considered as appropriate when the antimicrobial had
in vitro activity against the causative microorganisms. According to
the therapeutic strategy in the 5 days after the start of antimicro-
bial therapy, we classified patients into four groups: de-escalation
(interruption of an antimicrobial agent or change of antibiotic to
one with a narrower spectrum); no change in antibiotherapy; esca-
lation (addition of a new antimicrobial agent or change in antibi-
otic to one with a broader spectrum); and mixed changes.
Setting: A 35-bed medico-surgical intensive care department
in which antibiotic strategies are reviewed by infectious disease
specialists three times per week.
Patients: One hundred sixty-nine patients with 216 episodes
of severe sepsis attributable to a hospital-acquired infection who
required broad-spectrum -lactam antibiotics alone or in associa-
tion with other anti-infectious agents.
Measurements and Main Results: The major sources of infec-
tion were the lungs (44%) and abdomen (38%). Microbiological
data were available in 167 of the 216 episodes (77%). Initial an-
timicrobial therapy was inappropriate in 27 episodes (16% of
culture-positive episodes). De-escalation was applied in 93 epi-
sodes (43%), escalation was applied in 22 episodes (10%), mixed
changes were applied in 24 (11%) episodes, and there was no
change in empirical antibiotic therapy in 77 (36%) episodes. In
these 77 episodes, the reasons given for maintaining the initial
antimicrobial therapy included the sensitivity pattern of the caus-
ative organisms and previous antibiotic therapy. The number of
episodes when the chance to de-escalate may have been missed
was small (4 episodes [5%]).
Conclusion: Even in a highly focused environment with close
collaboration among intensivists and infectious disease special-
ists, de-escalation may actually be possible in <50% of cases. (Crit
Care Med 2012; 40: 1404–1409)
Key Words: antimicrobials; empiric antibiotics; infection;
microbiology

S evere sepsis and septic shock

are common causes of morbid-
ity and mortality, especially in
the intensive care unit (ICU)
(1). Infection control with effective an-
tibiotic therapy and source elimination
whenever indicated is a cornerstone in
the management of sepsis. Early effec-
tive antibiotic therapy has been shown
to decrease mortality rates (2–5) so that
rapid institution of broad-spectrum an-
tibiotic therapy is recommended if bac-
teriologic information is not available.
However, broad-spectrum antibiotic
*See also p. 1645.
From the Departments of Intensive Care (SH, JLV)
and Infectious Disease (FJ), Erasme Hospital, Université
Libre de Bruxelles, Brussels, Belgium.
Institutional funds only were received.
The authors have not disclosed any potential con-
flicts of interest.
For information regarding this article, E-mail:
­jlvincen@ulb.ac.be
Copyright © 2012 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e3182416ecf
therapy can favor the emergence of resis-
tant organisms (6, 7). Despite no strong
evidence (8), antibiotic de-escalation, in
which wide-spectrum empirical antibi-
otic therapy is started initially but the
spectrum is narrowed as soon as micro-
biological results are available, therefore
has been recommended to reduce selec-
tion pressure and possibly to reduce tox-
icity and limit costs (9–11). Concerns
about the risk of recurrent infection in
de-escalation therapy are probably un-
justified (12, 13).
De-escalating strategies are recom-
mended particularly in hospital-acquired
infections, in which the number of poten-
tial types of causative microorganism is
relatively large and the risk of resistance
is particularly high. Antibiotic de-escalat-
ing strategies have been studied primar-
ily in hospital-acquired pneumonia (9,
12, 14–18). In these studies, the rate of
de-escalation varied considerably, from
6% to 74%. The aim of our study was to
assess how de-escalation is applied in pa-
tients with hospital-acquired severe sepsis
in our intensive care department in which
close collaboration with infectious disease
specialists is associated with frequent re-
assessment of antibiotic regimens. We
also assessed the impact of de-escalation
on outcome and determined which fac-
tors were associated with de-escalation in
our cohort.
PATIENTS AND METHODS
Patients
The study was conducted in the 35-bed
medico-surgical intensive care department
of the academic hospital of the University of
Brussels. We reviewed the files of all adult
(older than 18 yrs) patients over a 1-yr pe-
riod (2007) who were treated for severe sep-
sis (with or without septic shock) because
of a hospital-acquired infection and re-
quired broad-spectrum b-lactam antibiotics,
including piperacillin-tazobactam, ceftazi-
dime, cefepime, and meropenem alone or
in association with other anti-infectious
agents. As a retrospective study, ethics com-
mittee approval was requested but patient
consent was waived. Severe sepsis and septic
shock were defined by standard criteria (19).

1404 Crit  Care  Med  2012  Vol.  40,  No.  5

Patients who died within the first 3 days of
therapy, before de-escalation could be insti-
tuted, were excluded.
The choice of empirical treatment was
made according to local guidelines and re-
sults of any previous microbiological data.
Piperacillin-tazobactam was preferred as
the first-line therapy in proven or suspect-
ed intra-abdominal infections. Ceftazidime
and cefepime were used as first-line ther-
apy in other cases, including ventilator-
acquired and hospital-acquired pneumonia.
Meropenem was used as second-line therapy
(i.e., failure of piperacillin-tazobactam or ce-
phalosporins) or in suspected or previous col-
onization by extended-spectrum b-lactamase
(ESBL)-producing Gram-negative bacteria.
Amikacin was usually added for 1–3 days in
cases of severe sepsis (with high suspicion
of Gram-negative bacteria involvement).
Vancomycin was added when infection with
methicillin-resistant Staphylococcus aureus
or methicillin-resistant Staphylococcus
epidermidis was suspected. An antifungal
drug, generally fluconazole, was added in pa-
tients highly colonized by fungi, mostly in
cases of sepsis resistant to broad-spectrum
antibiotics.
Demographic data, Sequential Organ
Failure Assessment score (20) recorded on
day 1 of the septic episode, source of infec-
tion, bacteriologic data, and antibiotic ther-
apy for the 5 first days of treatment were
noted for each episode. The site of infection,
documented or suspected, was assessed ac-
cording to standard criteria (21). Urine,
bronchoalveolar lavage fluid, and catheters
required quantitative cultures for confirma-
tion of site: 100,000 colonies/mL for urine
(semiquantitative), 10,000 colony-forming
units/mL for bronchoalveolar lavage, and
15 colonies/mL for catheter cultures (22,
23). Cultures of other fluids (pleural, peri-
toneal, abscesses, tracheal aspirates, and
blood) were nonquantitative. We considered
isolated organisms to be colonizing if there
was no clinical evidence of infection or no
leukocytes in the samples (except in samples
from normally sterile sites or from leuko-
penic patients). Microbiology results were
considered as inconclusive when there was
no growth of organism. For our study, mul-
tiresistant organisms were ESBL-producing
Gram-negative rods, methicillin-resistant
Staphylococcus aureus, and methicillin-re-
sistant Staphylococcus epidermidis.
An episode of severe sepsis was consid-
ered to start on the day of sepsis diagnosis
and to end with either resolution of sepsis
(significant decrease in white blood cell
count or C-reactive protein concentration,
resolution of cardiovascular, and other or-
gan dysfunctions), the patient’s death, or a
new episode of sepsis. Worsening of a pa-
tient’s condition (hemodynamic, respira-
tory, neurologic, renal, or hepatic, or a new
increase in blood lactate concentration or
a coagulopathy) in association with signs
Crit  Care  Med  2012  Vol.  40,  No.  5
of sepsis was considered as a new episode
of sepsis only if the patient had transiently
improved before the degradation and the
degradation occurred 5 days after the pre-
vious episode.
In our unit, antimicrobial therapy is pre-
scribed by the ICU doctor after discussion with
infectious disease consultants (a separate spe-
cialty from the microbiologists at our hospital)
who are available 24 hrs per day. Rounds with
infectious disease specialists are held at least
three times per week to discuss all relevant
aspects of management. The ICU team also
includes a clinical pharmacist who reviews all
drug prescriptions.
Antimicrobial therapy was considered
appropriate when the antimicrobial agent
had in vitro activity against the incrimi-
nated organisms. De-escalation was defined
either as the discontinuation of an antimi-
crobial agent (antibiotic or anti-fungal) or
as a change from one antibiotic to another,
i.e., from meropenem to any other b-lactam,
from ceftazidime, cefepime, or piperacillin-
tazobactam to amoxicillin-clavulanic acid or
any other type of penicillin, or from vanco-
mycin to any type of penicillin. Escalation
was defined as the addition of a new anti-
infectious agent or a change in antibiotic
therapy in the reverse direction to that de-
scribed. Changes among cefepime, ceftazi-
dime, and piperacillin-tazobactam were not
considered a significant alteration in the
spectrum of cover.
For the purposes of this study, we grouped
episodes according to the antimicrobial strat-
egy in the 5 days after diagnosis: de-escalation
(group I); no change in the empirical treat-
ment (group II); escalation (group III); and
mixed strategy, in which changes in therapy
were made in both directions (group IV). In
each case, we identified the reasons that led to
the specific strategy.
Statistical Analyses
Statistical analyses were performed using
IBM SPSS Statistics 19 for windows (SPSS Inc,
Chicago, IL). The Kolmogorov-Smirnov test
was used, and histograms and normal-quan-
tile plots were examined to verify if there were
significant deviations from the normality as-
sumption of continuous variables. Difference
testing among groups was performed using
analysis of variance, Student t test, chi-square
test, or Fisher exact test, as appropriate. The
Bonferroni correction was made for multiple
comparisons. To examine differences in out-
comes among groups, we studied only the first
episodes of sepsis.
Logistic regression analysis was used
to identify the factors associated with de-
escalation. Variables associated with de-es-
calation (p  .2) on a univariate basis were
introduced into the multivariable analysis.
Colinearity between variables was excluded
before modeling. A Hosmer-Lemeshow
goodness-of-fit test was performed, and
classification tables and odds ratios with
95% confidence intervals were computed.
Data are presented as mean ± sd or num-
ber (%) as appropriate. All tests were two-
tailed, and p<.05 was considered statistically
significant.
RESULTS
We included a total of 241 episodes of
severe sepsis, of which 25 were excluded
because the patients died within the first
3 days of treatment. Demographic and
infection-related data concerning the
216 evaluable episodes in 169 patients
are presented in Table 1; 136 patients had
1 episode, 24 had 2 episodes, and nine
had 2 episodes of severe sepsis or septic
shock.
Microbiological cultures provided a
conclusive bacteriologic diagnosis in
163 episodes (75%). Table 2 presents
the organisms found in these episodes
and in four additional episodes in which
only surveillance swabs (throat/nose
and rectum swabs) were positive; multi-
ple organisms were found in 86 of these
episodes (51%). At least one Gram-
negative bacillus was involved in 121 of
the culture-positive episodes (72%); 19
of the isolated Gram-negative bacillus
(11%) had ESBL activity. Enterobacter
spp. and ESBL-producing organisms
were more common in episodes in
which escalation was used than in other
groups. At least one Gram-positive coc-
cus was isolated in 87 episodes, of which
33 strains were methicillin-resistant
staphylococci (38%). Fungi were pres-
ent in 29 of the culture-positive epi-
sodes (17%).
Initial antimicrobial therapy was
appropriate in 140 of the 167 culture-
positive episodes (84%). It was more
frequently appropriate in patients who
underwent de-escalation than in pa-
tients in whom treatment was escalated
or who had mixed strategies (Table 2).
The empirical antibiotics are shown in
Table 3 according to therapeutic strat-
egy. Glycopeptides were more commonly
used in episodes for which de-escalation
was performed (group I) than in the
episodes in which escalation was used
(group III). Use of amikacin was more
common in group I than in the other
groups. The use of monotherapy was also
significantly more common in the esca-
lation and unchanged treatment groups
(groups II and III) than in group I.
Figure 1 summarizes the therapeutic
strategy for all episodes according to the
1405
Table 1.  Demographic and infection-related data
Taking a closer look at the 77 group
II episodes to determine why there was
Total Group I Group II Group III Group IV no change in antimicrobial strategy, we
Episodes (De-Escalation) (No Change) (Escalation) (Mixed) found that in 35 of the episodes (46%),
de-escalation was not possible because of
N 216 93 77 22 24 the sensitivity of the microorganisms; the
Male, n (%) 120 (56%) 51 (55%) 44 (57%) 14 (64%) 11 (46%)
Age, yr (mean ± sd) 61 ± 14 61 ± 13 61 ± 15 62 ± 12 59 ± 12 spectrum was already as narrow as it could
Surgical admission, n (%) 106 (49%) 48 (52%) 35 (45%) 11 (50%) 12 (50%) be. In 25 episodes (32%), there was no
Sequential Organ Function 9±3 9±4 9±4 10 ± 4 9±3 change in therapy because of lack of mi-
Assessment score crobiological data (a late culture returned
(mean ± sd) positive in six episodes); in most of these
Septic shock, n (%) 128 (59%) 52 (56%) 47 (61%) 15 (68%) 14 (58%)
Septic source, n (%) cases, patients had already been receiving
Chest 94 (44%) 35 (38%) 32 (42%) 11 (50%) 16 (67%) antibiotics when sepsis developed and had
Abdomen 83 (38%) 34 (37%) 31 (40%) 10 (45%) 8 (33%) only improved by increasing the spectrum
Urinary tract infection 24 (11%) 11 (12%) 6 (8%) 3 (14%) 4 (17%) of cover, so physicians were then reluc-
Soft tissue 35 (16%) 15 (16%) 13 (17%) 5 (23%) 2 (8%)
Catheter 10 (5%) 4 (4%) 3 (4%) 2 (9%) 1 (4%) tant to reduce it without microbiological
Primary bacteremia 11 (5%) 6 (6%) 3 (4%) 0 (0%) 2 (8%) data. In ten episodes (13%), the microbio-
Secondary bacteremia 46 (21%) 24 (26%) 6 (8%)a 5 (23%) 11 (46%)b logical data were considered inconclusive
Multiple 40 (19%) 11 (12%) 17 (22%) 5 (23%) 7 (29%) by the physician and the patient was not
Unidentified 18 (8%) 8 (9%) 8 (10%) 1 (5%) 1 (4%)
Positive microbiological 167 (77%) 73 (78%) 53 (69%) 18 (81%) 23 (96%)b considered a candidate for de-escalation;
documentation n (%) in these episodes, patients had either
been receiving antibiotic therapy when
Statistically different at 5% level vs. group I; bstatistically different at 5% level vs. group II.
a
the sepsis occurred and microbiological
documentation showed microorganisms
sensitive to the previous treatment (six
Table 2.  Detailed microbiological findings for the most frequently isolated microorganisms
episodes), or there were multiples sites
Total Episodes Group I Group II Group III Group IV of infection with negative cultures for
(Culture-Positive) (De-Escalation) (No Change) (Escalation) (Mixed) one or more of them (four episodes). In
three episodes (4%), the patient was colo-
N 167 73 53 18 23 nized with multiresistant organisms and
Gram-negative bacilli, n (%) 121 (72%) 58 (79%) 36 (68%) 12 (62%) 15 (65%)
  Escherichia coli 43 (26%) 24 (33%) 12 (23%) 4 (22%) 3 (13%)
the physician was not comfortable to de-
  Pseudomonas aeruginosa 30 (18%) 11 (15%) 10 (19%) 6 (33%) 3 (13%) escalate and to potentially lose coverage
  Enterobacter sp. 20 (12%) 5 (7%) 7 (13%) 6 (33%) 2 (9%)c of the multiresistant organisms. In four
  Klebsiella sp. 17 (10%) 6 (8%) 4 (8%) 2 (11%) 5 (22%) episodes (5%), there was no good reason
  Nonfermenting Gram-negative 6 (4%) 3 (4%) 0 (0%) 0 (0%) 3 (13%)a
why the antibiotherapy was not changed
  bacteria
  Acinetobacter sp. 4 (2%) 3 (4%) 1 (2%) 0 (0%) 0 (0%) and the opportunity to de-escalate was
  Extended spectrum 19 (11%) 6 (8%) 4 (8%) 7 (39%)a,b 2 (9%) simply missed.
  beta-lactamase In 46 episodes, therapy was escalated
Gram-positive cocci 87 (52%) 33 (45%) 32 (60%) 7 (39%) 15 (65%) or mixed strategies were used (groups III
  Methicillin sensitive 23 (14%) 12 (16%) 6 (11%) 1 (6%) 4 (17%)
and IV), including five episodes in which
  Staphylococcus aureus
  Methicillin resistant 11 (7%) 6 (8%) 3 (6%) 1 (6%) 1 (4%) the microbiological data were nega-
  Staphylococcus aureus tive. Some escalations were performed
  Methicillin resistant 22 (13%) 6 (8%) 10 (19%) 1 (6%) 5 (22%) even when the causative organisms were
  Staphylococcus epidermidis covered by the empirical treatment (15
  Enterococci sp. 31 (19%) 10 (14%) 14 (26%) 4 (22%) 3 (13%) episodes [33%]). The major reasons for
Fungi 29 (17%) 7 (10%) 9 (17%) 5 (28%) 8 (35%)a
Clostridium difficile 8 (5%) 2 (3%) 2 (4%) 1 (6%) 3 (13%) escalation were: in 28 episodes (61%),
Polymicrobial infection 86 (51%) 36 (49%) 27 (51%) 10 (56%) 13 (57%) microbiological findings revealed a mi-
Appropriate initial 140 (84%) 72 (97%) 53 (100%) 8 (44%)a 7 (30%)a croorganism that was potentially not cov-
anti-microbial therapy ered by the empirical therapy (pending
antibiogram and late cultures included);
a
Statistically different at 5% level vs. group I; bstatistically different at 5% level vs. group II;
statistically different at 5% level vs. group III.
c in 11 (24%) episodes, there was an inad-
equate response to the initial empirical
treatment (degradation within the 5 first
microbiological data. In the microbio- therapy was de-escalated in 20 (41%), days of treatment); and in seven episodes
logically documented infections (167 epi- mostly because no resistant bacteria (15%), there was a re-evaluation within
sodes), initial treatment was appropriate were found in any samples. Of the 93 12–24 hrs. The organisms that were not
in 140 episodes (84%). De-escalation was total episodes of de-escalation, 61 in- covered were Candida albicans and non-
possible in 89 episodes and was performed volved stopping an anti-infectious agent, albicans (eight episodes), ESBL-producing
in 72 of these 89 episodes (81%). 20 involved a change in antibiotic, and bacteria (six episodes), methicillin-
In the 49 episodes in which microbio- 12 involved both an interruption and a resistant Staphylococcus epidermidis
logical documentation was inconclusive, change. (three episodes), Clostridium difficile

1406 Crit  Care  Med  2012  Vol.  40,  No.  5

Table 3.  Initial empirical antibiotic therapy according to therapeutic strategy aureus (three), methicillin-resistant
Staphylococcus epidermidis (ten), and
Total Group I Group II Group III Group IV
Enterococcus with either resistance or
Episodes (De-Escalation) (No Change) (Escalation) (Mixed)
intermediate sensitivity to penicillin (sev-
N 216 93 77 22 24 en). The remaining 18 episodes in which
Used agent, n (%) vancomycin was not de-escalated with no
  Piperacillin-tazobactam 81 (38%) 32 (34%) 33 (43%) 11 (50%) 5 (21%) obvious microbiological support to keep
  Ceftazidime 5 (2%) 1 (1%) 2 (3%) 1 (5%) 1 (4%) it were mainly soft tissue infections for
  Cefepime 55 (25%) 28 (30%) 12 (16%) 6 (27%) 9 (38%)
  Meropenem 75 (35%) 32 (34%) 30 (39%) 4 (18%) 9 (38%) which vancomycin was kept for its good
  Amikacin 33 (15%) 29 (31%) 0 (0%)a 0 (0%)a 4 (17%)b soft tissue penetration. There were also
  Vancomycin/linezolid 119 (55%) 62 (67%) 38 (49%) 5 (23%)a 14 (58%) three episodes of previous methicillin-re-
  Fluconazole 34 (16%) 19 (20%) 11 (14%) 2 (9%) 2 (8%) sistant Staphylococcus aureus/methicil-
  Cotrimoxazole 10 (5%) 6 (6%) 3 (4%) 1 (5%) 0 (0%)
  Other 63 (29%) 28 (30%) 21 (27%) 7 (32%) 7 (29%)
lin-resistant Staphylococcus epidermidis
Regimen, n (%) colonization.
  1 agent 55 (25%) 11 (12%) 29 (38%)a 10 (45%)a 5 (17%) In cases of negative culture (49 epi-
  2 agents 90 (40%) 40 (43%) 28 (36%) 10 (45%) 12 (54%) sodes), de-escalation was performed in 20
  3 agents 51 (24%) 27 (29%) 16 (21%) 1 (5%) 7 (29%) episodes, escalation was performed in 5
  3 agents 20 (9%) 15 (16%) 4 (5%) 1 (5%) 0 (0%)
episodes, and no change was performed
a
Statistically different at 5% level vs. group I; bstatistically different at 5% level vs. group II. in 24 episodes. Among these 24 episodes,
the reason for no de-escalation was:
monotherapy (12); soft tissue infections
(four); septic episodes (three) while the
patient was using antibiotics; two cases
of positive Gram-negative stain tests with
no growth; and three cases in which the
patients were immunosuppressed and
using large-spectrum anti-microbial
therapy.
Considering only the 169 first episodes
of sepsis, de-escalation was performed in
79, no change was performed in 58, es-
calation was performed in 15, and mixed
changes were performed in 17. Forty-four
of these 169 patients died, 13 (16%) in
group I, 15 (26%) in group II, 9 (60%) in
group III, and 7 (41%) in group IV (p =
.002). In the multivariable analysis, appro-
priate initial antimicrobial therapy (odds
ratio 2.7; 95% confidence interval 1.27–
5.73; p = .01) was the only factor associ-
ated with increased odds of de-escalation;
monotherapy compared to multitherapy
(odds ratio 0.17; 95% confidence interval
0.06–0.5, p = .001) were associated with
decreased odds of de-escalation.

DISCUSSION
Figure 1.  Overview of the therapeutic strategy in the 216 episodes classified according to positive mi- Current guidelines on the manage-
crobiological results, effectiveness of initial antibiotherapy, and possibility of de-escalation according to ment of severe sepsis recommend early
sensitivity of isolated organisms. broad-spectrum antibiotic therapy with
de-escalation as soon as possible (11). Our
ICU team benefits from a close collabora-
(two episodes), and other organisms was rarely de-escalated in the absence of tion with infectious disease specialists in
(nine episodes). documentation. In contrast, vancomycin addition to microbiologists; nevertheless,
Because the rate of ESBL is relatively is frequently prescribed and de-escalated 16% (27/167 episodes) of patients had
low in our hospital, meropenem is reserved after 2 or 3 days in our hospital. In the organisms that were not covered by the
as a second-line treatment for nosocomial present study, it was prescribed in 119 ep- empirical antibiotic treatment and our
infection or for patients known to carry an isodes and maintained in just 38. Taking de-escalation rate was only 43%.
ESBL-producing Gram-negative rods. In a closer look at these 38 episodes, van- In previous studies of ventilator-as-
these conditions, microbiological results comycin was maintained in 20 episodes sociated pneumonia (VAP) or hospital-
are often inconclusive and meropenem for methicillin-resistant Staphylococcus acquired pneumonia, de-escalation rates

Crit  Care  Med  2012  Vol.  40,  No.  5 1407

have varied broadly, from 6% to 74%
(9, 12, 14–18, 24). Comparisons among
studies are made difficult by the lack of
precise definitions of de-escalation, dif-
ferences in empirical regimens, and the
differences in patient populations and
local microbioloigical epidemiology.
One of the highest de-escalation rates
was reported by Eachampati et al (12) in
135 cases of VAP. These authors used a
wider empirical antibiotic spectrum than
in our present study, with a 23% rate of
Gram-negative bacillus-targeted mono-
therapy and an overall rate of bitherapy
of 77% (including association of van-
comycin with piperacillin-tazobactam,
quinolones, carbapenem, or cefepime).
Their rate of appropriate antibiotic ther-
apy was 93% with these regimens. Only
ten patients required antibiotic escala-
tion (7%).
In 2006, the Canadian Critical Care
Trials groups (18) performed a large ran-
domized study of techniques to diagnose
VAP. They included patients from 28
ICUs in Canada and had a large-spectrum
initial antibiotherapy with meropenem
alone and meropenem in association
with ciprofloxacin. Their de-escalation
rate was high (74%), largely because
21% of the enrolled patients were not
infected and treatment was therefore
stopped, and because the wide spectrum
of the empirical treatment easily allowed
streamlining. Despite their initial broad
antibiotherapy, their adequacy rate was
only 89%.
The lowest de-escalation rate of 6%
was reported by Rello et al in 113 pa-
tients, with changed therapy (not always
de-escalation) reported in 43 patients
(38%) (14). These authors had a rate of
inadequate initial antibiotic therapy of
25%. The low de-escalation rate can be
explained, at least in part, by the use of
monotherapy in 47% of cases. In 2004,
the same group evaluated the practice
of de-escalation in patients with VAP
(15). They analyzed 121 episodes of VAP
and found a total rate of de-escalation of
31%, increasing to 38% when isolates
were sensitive. They used monotherapy
in 41% of the cases. However, their rate
of de-escalation cannot be compared to
ours because 12% of their patients were
treated with amoxicillin/clavulanate, so
that they could not de-escalate in these
patients.
Morel et al (13) recently assessed
antibiotic strategies in 133 episodes of
suspected infection requiring empiri-
cal antibiotic treatment. These authors
1408
reported a de-escalation rate of 45% in
their overall patient population, but this
included patients in whom antibiotics
were stopped because they were later
found to be not infected. They assessed
the risks of re-escalation and of re-in-
fection in their patients and reported a
significant reduction in recurrent infec-
tion in patients in whom de-escalation
was used.
In another recent study, Shime et al
(25) analyzed the rate of de-escalation in
immunocompetent patients with bacter-
emia attributable to antibiotic-sensitive
pathogens. This group studied a narrow
population because they only included
patients with positive blood cultures, a
single causative microorganism covered
by the empirical antibiotic therapy, and
patients in whom it was possible to de-
escalate the empirical treatment. Despite
this selective group, they recorded a rate
of de-escalation of just 39%, whereas in
our study if we limit our population to the
same group of patients, then we achieve
a de-escalation rate of 81%. The authors
do not provide any reason for not per-
forming de-escalation but, interestingly,
show a trend toward reduced mortality
and treatment failures when comparing a
de-escalation group with a group without
de-escalation, although the group with-
out de-escalation included patients with
unchanged and escalated treatments. In
our outcomes analysis, there was higher
mortality in groups III and IV (escala-
tion and mixed strategies) compared
to groups I and II (de-escalation and no
change in treatment). It is not possible to
say whether this simply reflects the sever-
ity of patient condition or if it is a direct
consequence of the antibiotic strategy,
but, importantly, it demonstrates that de-
escalation did not increase mortality in
this cohort.
Even with an initial broad-spectrum
antibiotic therapy that included meropen-
em, piperacillin-tazobactam, or cepha-
losporins, all organisms in our study were
not covered. Hence, antibiotic escalation
was needed in 22 episodes (10%), and a
combination of de-escalation and escala-
tion was used in 24 episodes (11%). In
the 77 episodes in which therapy was not
changed, a reason was identified in most
cases and the number of cases in which
the chance to de-escalate may have been
missed was actually small (4 cases [5%]).
Although the rates of escalation and
not covered organisms in our study may
seem high, the population we studied
(nosocomial severe sepsis and septic
shock) is a more complex subgroup of
patients than patients with VAP or com-
munity-acquired infections with more
resistant organisms and potentially less
microbiological information. Despite
this difficulty, our results are within the
middle of the range compared to previous
studies. There was no difference in the se-
verity of infection between the episodes
in which de-escalation was performed
and other episodes.
The choice of empirical antibiotic
therapy is influenced by local epidemi-
ology with different degrees of bacte-
rial resistance, justifying different initial
strategies and different possibilities for
de-escalation among units; therefore,
rates of de-escalation can vary consider-
ably. Belgium is a country with mixed
resistant patterns, with more resistance
than in Northern European countries
but less resistance than in some south-
ern countries (26). Rates of appropriate
empirical antimicrobial treatment may
be improved by using a wider-spectrum
microbiological policy at the beginning
of the septic episode and de-escalation
could be improved by daily review, with
the help of microbiology or infectious dis-
ease consultants, of the used regimen in
the light of the microbiological results.
Use of more invasive diagnostic strategies
also has been associated with an increase
in de-escalation rates (17).
Our study may have the disadvantage
of having been conducted in a single
center, but interregional variation in mi-
crobial patterns is so large that interpre-
tation of multiregional or international
data may be difficult. Nevertheless, it is
important to emphasize that our results
may not apply everywhere. Although the
retrospective design of our study made it
more difficult to retrieve the reasons lead-
ing to each strategy, a prospective study
design may have influenced therapeutic
changes.
CONCLUSION
We demonstrated that in our academic
environment with close collaboration
with infectious disease specialists, de-es-
calation was possible in 43% of episodes
of severe nosocomial sepsis. Antibiotic
de-escalation is a strategy that is pro-
moted for its potential advantages for the
patient and for the hospital community
by ensuring adequate coverage of causal
infective agents but limiting selection
pressure for multiresistant bacteria.
Further study is needed to better-define
Crit  Care  Med  2012  Vol.  40,  No.  5
appropriate empirical antimicrobial ther-
apies and the use of de-escalation strate-
gies in various groups of ICU patients.
REFERENCES
1. Osmon S, Warren D, Seiler SM, et al: The
influence of infection on hospital mortality
for patients requiring 48 h of intensive care.
Chest 2003; 124:1021–1029
2. Kollef MH, Sherman G, Ward S, et al:
Inadequate antimicrobial treatment of
infections: A risk factor for hospital mortality
among critically ill patients. Chest 1999;
115:462–474
12. Eachempati SR, Hydo LJ, Shou J, et al:
3. Iregui M, Ward S, Sherman G, et al: Clinical
importance of delays in the initiation
of appropriate antibiotic treatment for
ventilator-associated pneumonia. Chest 2002;
122:262–268
4. Garnacho-Montero J, Ortiz-Leyba C, Herrera-
Melero I, et al: Mortality and morbidity
attributable to inadequate empirical
antimicrobial therapy in patients admitted to
the ICU with sepsis: A matched cohort study.
J Antimicrob Chemother 2008; 61:436–441
5. Gaieski DF, Mikkelsen ME, Band RA, et al:
Impact of time to antibiotics on survival in
patients with severe sepsis or septic shock
in whom early goal-directed therapy was
15. Rello J, Vidaur L, Sandiumenge A, et
initiated in the emergency department. Crit
Care Med 2010; 38:1045–1053
6. Lautenbach E, Patel JB, Bilker WB,
et al: Extended-spectrum beta-lactamase-
16. Leone M, Garcin F, Bouvenot J, et al:
producing Escherichia coli and Klebsiella
pneumoniae: risk factors for infection and
impact of resistance on outcomes. Clin Infect
Dis 2001; 32:1162–1171
7. Yates RR: New intervention strategies for
reducing antibiotic resistance. Chest 1999;
115:24S–27S
8. Gomes Silva BN, Andriolo RB, Atallah AN,
et al: De-escalation of antimicrobial treatment
for adults with sepsis, severe sepsis or septic
Crit  Care  Med  2012  Vol.  40,  No.  5
View publication stats
shock. Cochrane Database Syst Rev 2010;
CD007934
9. Alvarez-Lerma F, Alvarez B, Luque P, et al:
Empiric broad-spectrum antibiotic therapy of
nosocomial pneumonia in the intensive care
unit: A prospective observational study. Crit
Care 2006; 10:R78
10. Niederman MS: Impact of antibiotic resistance
on clinical outcomes and the cost of care. Crit
Care Med 2001; 29:N114–N120
11. Dellinger RP, Levy MM, Carlet JM, et al:
Surviving Sepsis Campaign: International
guidelines for management of severe sepsis
and septic shock: 2008. Crit Care Med 2008;
36:296–327
Does de-escalation of antibiotic therapy
for ventilator-associated pneumonia affect
the likelihood of recurrent pneumonia or
mortality in critically ill surgical patients?
J Trauma 2009; 66:1343–1348
13. Morel J, Casoetto J, Jospe R, et al: De-
escalation as part of a global strategy of
empiric antibiotherapy management. A
retrospective study in a medico-surgical
intensive care unit. Crit Care 2010; 14:R225
14. Rello J, Gallego M, Mariscal D, et al: The
value of routine microbial investigation in
ventilator-associated pneumonia. Am J Respir
Crit Care Med 1997; 156:196–200
al: De-escalation therapy in ventilator-
associated pneumonia. Crit Care Med 2004;
32:2183–2190
Ventilator-associated pneumonia: Breaking
the vicious circle of antibiotic overuse. Crit
Care Med 2007; 35:379–385
17. Giantsou E, Liratzopoulos N, Efraimidou
E, et al: De-escalation therapy rates are
significantly higher by bronchoalveolar lavage
than by tracheal aspirate. Intensive Care Med
2007; 33:1533–1540
18. Canadian Critical Care Trials Group: A
randomized trial of diagnostic techniques for
ventilator-associated pneumonia. N Engl J
Med 2006; 355:2619–2630
19. Levy MM, Fink MP, Marshall JC, et al: 2001
SCCM/ESICM/ACCP/ATS/SIS International
Sepsis Definitions Conference. Crit Care Med
2003; 31:1250–1256
20. Vincent JL, Moreno R, Takala J, et al: The SOFA
(Sepsis-related Organ Failure Assessment)
score to describe organ dysfunction/failure.
On behalf of the Working Group on Sepsis-
Related Problems of the European Society of
Intensive Care Medicine. Intensive Care Med
1996; 22:707–710
21. Calandra T, Cohen J, International Sepsis
Forum Definition of Infection in the ICU
Consensus Conference: The international
sepsis forum consensus conference on
definitions of infection in the intensive care
unit. Crit Care Med 2005; 33:1538–1548
22. Garner JS, Jarvis WR, Emori TG, et al: CDC
definitions for nosocomial infections, 1988.
Am J Infect Control 1988; 16:128–140
23. Cooper GL, Hopkins CC: Rapid diagnosis of
intravascular catheter-associated infection by
direct Gram staining of catheter segments.
N Engl J Med 1985; 312:1142–1147
24. Hoffken G, Niederman MS: Nosocomial
pneumonia: the importance of a de-escalating
strategy for antibiotic treatment of pneumonia
in the ICU: Chest 2002; 122:2183–2196
25. Shime N, Satake S, Fujita N: De-escalation of
antimicrobials in the treatment of bacteraemia
due to antibiotic-sensitive pathogens in
immunocompetent patients. Infection 2011;
39:319–325
26. European Center for Disease Prevention
and Control: Antimicrobial resistance
surveillance in Europe 2009. Annual Report
of the European Antimicrobial Resistance
Surveillance Network (EARS-Net). Available at:
http://www.ecdc.europa.eu/en/publications/
Publications/1011_SUR_annual_EARS_
Net_2009.pdf. Accessed December 2, 2011
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