Intensive Care Med (2014) 40:4149

DOI 10.1007/s00134-013-3148-9

Djamel Mokart
Geraldine Slehofer
Jerome Lambert
Antoine Sannini
Laurent Chow-Chine
Jean-Paul Brun
Pierre Berger
Segole`ne Duran
Marion Faucher
Jean-Louis Blache
Colombe Saillard
Norbert Vey
Marc Leone
Received: 25 May 2013
Accepted: 26 October 2013
Published online: 14 November 2013
Springer-Verlag Berlin Heidelberg and
ESICM 2013

ORIGINAL ARTICLE

De-escalation of antimicrobial treatment

in neutropenic patients with severe sepsis:
results from an observational study

C. Saillard
N. Vey
Departement dHematologie, Institut PaoliCalmettes, Marseille, France

de-escalation groups.
Results: Cumulative incidence of
de-escalation of the empirical antimicrobial treatment among the 101
patients of the cohort was 44 %, [95 %
confidence interval (CI) 3853 %],
including 30 (68 %) patients with
ongoing neutropenia. A microbiological documentation was available in 63
(63 %) patients. Factors associated
with de-escalation were the adequation
of the empirical antimicrobial treatment in ICU [OR = 10.8 (95 % CI
1.2096)] for adequate documented
treatment versus appropriate empirical
treatment, the compliance with guidelines regarding the empirical choice of
the anti-pseudomonal betalactam
[OR = 10.8 (95 % CI 1.389.5)].
De-escalation did not significantly
modify the hazard of death within the
first 30 days [HR = 0.51 (95 % CI
0.201.33)], nor within 1 year after
ICU discharge [HR = 1.06 (95 % CI
0.542.08)]. Conclusion: Our data
suggest that, in ICU, de-escalation of
the empirical antimicrobial treatment
is frequently applied in neutropenic
cancer patients with severe sepsis. No
evidence of any prognostic impact of
this de-escalation was found.

Abstract Background: In severe

sepsis, guidelines recommend
de-escalating the empirical antimicrobial treatment as soon as the
microbiological results are available.
We aimed to determine the rate of
de-escalation of the empirical antimicrobial treatment in neutropenic
patients with severe sepsis. The
D. Mokart ())
A. Sannini

characteristics of antimicrobial treatL. Chow-Chine
J.-P. Brun

ment associated with de-escalation
M. Faucher
J.-L. Blache
and its impact on short- and long-term
Reanimation Polyvalente et departement
survival were also determined.
dAnesthesie et de Reanimation, Institut
Paoli-Calmettes, 232 Bd Sainte Marguerite, Methods: In the intensive care unit
(ICU) of a cancer referral center, we
13009 Marseille Cedex 09, France
prospectively collected observational
e-mail: [email protected]
Tel.: ?33-49-1223521
data related to the antimicrobial manFax: ?33-49-1223556
agement in neutropenic patients who
developed severe sepsis and were
G. Slehofer
M. Leone
admitted to ICU for at least 48 h.
Service dAnesthesie et de Reanimation,
De-escalation of antimicrobial therapy
Hopital Nord, Assistance Publiqueconsisted either of deleting one of the
Hopitaux de Marseille, Aix Marseille
empirical antibiotics of a combined
Universite, Marseille, France
treatment, or, whenever possible, to use
J. Lambert
a betalactam antibiotic with a narrower
Service de Biostatistique et Information
spectrum of activity. Multivariate
Medicale, Hopital Saint Louis, Universite
logistic regression was conducted to
Paris Diderot, Paris, France
determine the factors associated with
de-escalation, while a Cox proportional Keywords Antibiotics

P. Berger
hazards model with a time-dependent Septic shock
Severe sepsis

Departement de Microbiologie, Institut
Paoli-Calmettes, Marseille, France
covariate was fitted to assess the effect Neutropenia
De-escalation
of de-escalation on 30-day survival.
S. Duran
Finally 1-year survival after ICU
Departement de Pharmacie, Institut
discharge was compared across
Paoli-Calmettes, Marseille, France
Electronic supplementary material
The online version of this article
(doi:10.1007/s00134-013-3148-9) contains
supplementary material, which is available
to authorized users.

42

Introduction

Definitions and data collection

In severe sepsis and septic shock, guidelines recommend

de-escalating the empirical antimicrobial treatment as
soon as the microbiological results are available [1]. This
strategy is aimed to reduce the selection pressure and the
treatment cost [2, 3]. In intensive care units (ICU), previous studies have shown that de-escalation is safe [46].
As routine, de-escalation is performed in around 40 % of
septic patients [7].
Neutropenia remains a constant outcome after
aggressive chemotherapies as part of bone marrow
transplantation, acute leukemia, lymphoma, and certain
solid tumor treatments. The price to pay for increasing
treatment intensity and duration is a rise in treatmentrelated toxicity and susceptibility to infection [8, 9]. Thus,
in neutropenic patients, suspicion of sepsis should lead to
the immediate onset of empirical antimicrobial treatment
[10, 11]. In the neutropenic patient with severe sepsis or
septic shock, use of broad-spectrum antibiotics is recommended [11]. The changes of empirical antimicrobial
treatment should be guided by clinical and microbiological data [12]. To date, there is no study assessing the
safety of de-escalation in neutropenic patients with severe
sepsis.
Our hypothesis was that de-escalation is feasible in
about 40 % of the patients with neutropenia at the onset
of severe sepsis. Our first aim was to assess the rate of
de-escalation of the first antimicrobial treatment in neutropenic cancer patients with severe sepsis or septic shock
admitted to the ICU. Our secondary aims were to test
whether characteristics of the empirical antimicrobial
treatment (namely, adequation to documentation and
compliance to guidelines) were associated with de-escalation, and to determine the impact of the de-escalation on
the patient survival.

Neutropenia was defined as a neutrophil count below

500 cells/mm3 or leucocytes below 1,000 cells/mm3 [12].
Severe sepsis, septic shock, and acute respiratory distress
syndrome (ARDS) were defined according to international criteria [13, 14]. Cancer status at ICU admission
was graded as follows: newly diagnosed, remission, progression, or unknown. Knaus scale definitions were used
to record pre-existing chronic organ failures [15]. Reasons
for the ICU admission were categorized as acute respiratory failure, shock, coma, acute kidney injury, severe
sepsis, tumor lysis syndrome, and others. Simplified acute
physiology score (SAPS) II [16] and sequential organ
failure assessment (SOFA) [17] scores were computed on
day 1. During the first 5 days after ICU admission,
changes in SOFA score (D SOFA) were calculated as
follows: [score on day 5 (or the day of ICU discharge if
discharge occured before day 5) score on day 1]. When
the D SOFA was [1, the SOFA score was considered as
having worsened. Organ failure was defined as a SOFA
score of 3 or more for any system. The patients were
included if they had suspected or proven infection. From
ICU admission, X-rays, computed tomography scan, and
biological and microbiological tests were standardized
and performed as indicated by the clinical presentation
[12, 18, 19].
In agreement to guidelines, antibiotics were administered as early as possible after ICU admission [12, 20].
Aminoglycosides or fluoroquinolones were added in those
patients requiring fluid resuscitation or vasopressors [12,
20]. Antibiotics directed against methicillin-resistant
Staphylococcus aureus (MRSA) were used as recommended by guidelines [12, 20]. Patients with fever and
neutropenia during more than 5 days received an antifungal agent. Our local guidelines recommend continuing
antibiotics until clinical resolution was obtained.
For each patient, the episodes of febrile neutropenia
were classified as fever of unknown origin, clinically
documented or microbiologically documented [21]. A
microbiologically documented infection was defined as
fever with identification of pathogens in blood samples or
samples from the suspected infection site. A clinically
documented infection was defined as fever with a focal
infection (e.g., pneumonia or skin and soft tissue
inflammation) not accessible to specimen sampling or
sampled with negative microbiological results. Fever of
unknown origin was defined as fever [38 C over at least
1 h or twice within 12 h, with no detectable cause. Details
are available in the Online Supplementary File.
The last antimicrobial treatment before ICU admission
and the first antimicrobial treatment after ICU admission
were recorded. Antimicrobial treatment were categorized
in a 4-class variable according to the existence of
microbiological documentation and the compliance with
guidelines. Thus, when microbiological documentation

Methods
All neutropenic cancer patients admitted to the ICU of the
Paoli-Calmettes Institute (Marseille, France) from January 2008 to May 2010 and meeting criteria for severe
sepsis or septic shock were prospectively included in this
observational survey. The patients deceased or discharged
alive from the ICU within the first 48 h were excluded
from the analysis. All patients were followed over a
period of 12 months after ICU admission. The PaoliCalmettes Institute is a 211-bed cancer referral center.
The Institutional Review Board of the Paoli-Calmettes
Institute approved this study and waived the need for
informed consent due to the observational nature of the
study. The methodology adheres to the STROBE
statement.

42

Introduction

Definitions and data collection

In severe sepsis and septic shock, guidelines recommend

de-escalating the empirical antimicrobial treatment as
soon as the microbiological results are available [1]. This
strategy is aimed to reduce the selection pressure and the
treatment cost [2, 3]. In intensive care units (ICU), previous studies have shown that de-escalation is safe [46].
As routine, de-escalation is performed in around 40 % of
septic patients [7].
Neutropenia remains a constant outcome after
aggressive chemotherapies as part of bone marrow
transplantation, acute leukemia, lymphoma, and certain
solid tumor treatments. The price to pay for increasing
treatment intensity and duration is a rise in treatmentrelated toxicity and susceptibility to infection [8, 9]. Thus,
in neutropenic patients, suspicion of sepsis should lead to
the immediate onset of empirical antimicrobial treatment
[10, 11]. In the neutropenic patient with severe sepsis or
septic shock, use of broad-spectrum antibiotics is recommended [11]. The changes of empirical antimicrobial
treatment should be guided by clinical and microbiological data [12]. To date, there is no study assessing the
safety of de-escalation in neutropenic patients with severe
sepsis.
Our hypothesis was that de-escalation is feasible in
about 40 % of the patients with neutropenia at the onset
of severe sepsis. Our first aim was to assess the rate of
de-escalation of the first antimicrobial treatment in neutropenic cancer patients with severe sepsis or septic shock
admitted to the ICU. Our secondary aims were to test
whether characteristics of the empirical antimicrobial
treatment (namely, adequation to documentation and
compliance to guidelines) were associated with de-escalation, and to determine the impact of the de-escalation on
the patient survival.

Neutropenia was defined as a neutrophil count below

500 cells/mm3 or leucocytes below 1,000 cells/mm3 [12].
Severe sepsis, septic shock, and acute respiratory distress
syndrome (ARDS) were defined according to international criteria [13, 14]. Cancer status at ICU admission
was graded as follows: newly diagnosed, remission, progression, or unknown. Knaus scale definitions were used
to record pre-existing chronic organ failures [15]. Reasons
for the ICU admission were categorized as acute respiratory failure, shock, coma, acute kidney injury, severe
sepsis, tumor lysis syndrome, and others. Simplified acute
physiology score (SAPS) II [16] and sequential organ
failure assessment (SOFA) [17] scores were computed on
day 1. During the first 5 days after ICU admission,
changes in SOFA score (D SOFA) were calculated as
follows: [score on day 5 (or the day of ICU discharge if
discharge occured before day 5) score on day 1]. When
the D SOFA was [1, the SOFA score was considered as
having worsened. Organ failure was defined as a SOFA
score of 3 or more for any system. The patients were
included if they had suspected or proven infection. From
ICU admission, X-rays, computed tomography scan, and
biological and microbiological tests were standardized
and performed as indicated by the clinical presentation
[12, 18, 19].
In agreement to guidelines, antibiotics were administered as early as possible after ICU admission [12, 20].
Aminoglycosides or fluoroquinolones were added in those
patients requiring fluid resuscitation or vasopressors [12,
20]. Antibiotics directed against methicillin-resistant
Staphylococcus aureus (MRSA) were used as recommended by guidelines [12, 20]. Patients with fever and
neutropenia during more than 5 days received an antifungal agent. Our local guidelines recommend continuing
antibiotics until clinical resolution was obtained.
For each patient, the episodes of febrile neutropenia
were classified as fever of unknown origin, clinically
documented or microbiologically documented [21]. A
microbiologically documented infection was defined as
fever with identification of pathogens in blood samples or
samples from the suspected infection site. A clinically
documented infection was defined as fever with a focal
infection (e.g., pneumonia or skin and soft tissue
inflammation) not accessible to specimen sampling or
sampled with negative microbiological results. Fever of
unknown origin was defined as fever [38 C over at least
1 h or twice within 12 h, with no detectable cause. Details
are available in the Online Supplementary File.
The last antimicrobial treatment before ICU admission
and the first antimicrobial treatment after ICU admission
were recorded. Antimicrobial treatment were categorized
in a 4-class variable according to the existence of
microbiological documentation and the compliance with
guidelines. Thus, when microbiological documentation

Methods
All neutropenic cancer patients admitted to the ICU of the
Paoli-Calmettes Institute (Marseille, France) from January 2008 to May 2010 and meeting criteria for severe
sepsis or septic shock were prospectively included in this
observational survey. The patients deceased or discharged
alive from the ICU within the first 48 h were excluded
from the analysis. All patients were followed over a
period of 12 months after ICU admission. The PaoliCalmettes Institute is a 211-bed cancer referral center.
The Institutional Review Board of the Paoli-Calmettes
Institute approved this study and waived the need for
informed consent due to the observational nature of the
study. The methodology adheres to the STROBE
statement.

43

was available, antimicrobial treatment was considered as

adequate, inadequate if it was active, or not active
against the identified pathogens based on in vitro susceptibility testing. In the absence of microbiological
documentation, antimicrobial treatment was considered
as appropriate or inappropriate, based on the compliance
with guidelines) [12]. For Gram-negative bacilli,
monotherapy with aminoglycoside was considered as
inappropriate [22].
De-escalation of the empirical antimicrobial treatment
consisted of either deleting one of the antimicrobials of a
combined treatment including anti-MRSA antibiotics,
antifungal treatment, antiviral treatment, or, whenever
possible, the use of betalactams with a narrower spectrum
of activity [5]. Criteria for narrowing the antimicrobial
regimen were based on the results of susceptibility testing
of identified bacteria. In our ICU, de-escalation was not
performed according to a protocol. It was left to the discretion of the senior intensivist. De-escalation was only
evaluated during ICU stay. Escalation of antimicrobial
treatment consisted of either the addition of an antibiotic
of another family to the betalactam or the use of betalactam with a broader-spectrum of activity. A
combination was defined as aminoglycosides or fluoroquinolones given in addition to betalactams.
Statistical analysis
Our hypothesis was that, as reported in non-neutropenic
patients [47], de-escalation was feasible in 40 % of
neutropenic patients with severe sepsis. Thus, the inclusion of 100 patients would permit the estimatation of the
proportion of de-escalation with an imprecision [half the
width of the 95 % confidence interval (CI)] of \10 %.
All data are presented as percentages for qualitative
variables and median (25th75th percentiles) for quantitative variables. The features of patients during their ICU
stay were compared across the groups of patients undergoing de-escalation of the antimicrobial treatment
(de-escalation group) and those who did not (non-deescalation group) by using Fishers exact test and Wilcoxon rank-sum test. Our second hypothesis was that
adequation of antimicrobial treatment was associated with
de-escalation. A multivariate logistic model with AICbased stepwise selection was fitted to identify which of
the covariates that described compliance with guidelines
was significantly independently associated with de-escalation. The HosmerLemeshow test was used to check
goodness-of-fit of the selected logistic model.
Effect of de-escalation on 30-day mortality was
assessed by fitting a Cox proportional hazards model
using de-escalation as a time-dependent covariate. For
patients with de-escalation the same day of antibimicrobial treatment discontinuation (or discharge alive),
de-escalation was considered as having been done 12 h

before. A sensitivity analysis was performed by considering that, for these patients, no de-escalation was
performed. Effect of de-escalation on long-term survival
was estimated on the subset of patients discharged alive
from ICU, by comparing 1-year survival post-ICU
between patients for whom the antimicrobial treatment
had or had not been de-escalated.
All tests were two-sided, and p values lower than 0.05
were considered statistically significant. Analysis was
performed using SPSS, v.16.0 software (SPSS, Chicago,
IL, USA) and R v.2.13 (http://www.R-project.org/).

Results
During the study period, severe sepsis and septic shock
were diagnosed in 118 neutropenic patients out of 1,803
patients admitted to ICU. Seventeen (14 %) patients were
excluded because they died within the first 48 h after
admission. Thus, 101 patients were included in the study.
The underlying cancers were acute leukemia (n = 44),
lymphoma (n = 24), myeloma (n = 12), and miscellaneous (n = 21). Hematopoietic stem cell transplantation
was observed in 24 patients, including 14 autologous and
10 allogeneic transplants (Table 1). ICU admission
occurred 6 days (210) after the onset of neutropenia.
Neutropenia duration was 11 days (816). In 52 patients,
neutropenia was resolutive during the ICU stay. In ICU,
granulocyte colony-stimulating factor (G-CSF) was used
in 55 patients (Table 2).
Major reasons for ICU admission were acute respiratory failure (n = 36) and shock (n = 32) (Table 1). At
ICU admission, sepsis was identified in 83 patients, and
18 patients developed a subsequent sepsis during the ICU
stay. Septic shock and severe sepsis were identified in 54
and 47 patients, respectively (Table 2).
Totals of 63, 21, and 17 patients had microbiologically
documented infections, clinically documented infections,
and fever of unknown origin, respectively (Table 3).
Bacteria (n = 63), fungi (n = 22), and viruses (n = 7)
were identified in 59, 18, and 5 patients, respectively.
Polymicrobial infection was found in 20 patients. The
major sites of infection were lungs (n = 44) and abdomen
(n = 11). Blood cultures were positive in 11 patients
(Table 3). The characteristics of the microbiological
documentation are available in Electronic Supplementary
Material Table 1.
Before ICU admission, antibiotics were administered
to 79 (79 %) patients. Betalactams were used in all but
one patients. In 74 (94 %) of these 79 patients, they were
active against Pseudomonas aeruginosa. Vancomycin and
linezolid were used in 28 (35 %) and 2 (3 %) patients,
respectively. A combined antibiotic was used in 36
(46 %) patients, consisting of aminoglycosides (n = 18)

44

Table 1 Characteristics of patients in the intensive care unit

Age (years)
Gender (male)
SAPS II on day 1
SOFA score on day 1
Time between treatment and the first signs of sepsis in ICU (h)
Comorbidity (Knaus definitions)
Chronic respiratory failure
Chronic heart failure
Chronic renal failure
Diabetes mellitus
Features at ICU admission
Shock
Acute respiratory failure
Severe sepsis
Tumor lysis syndrome
Coma
Cardiac arrest
Acute kidney injury
Metabolic
ICU admission for sepsis
Type of cancer
Acute leukemia
Lymphoma
Chronic leukemia
Myeloma
Other hematologic diseases
Solid tumor
HSCT
No
Autologous
Allogeneic
Status of cancer disease
Newly diagnosed
Remission
Progression
Unknown

All patients
(n = 101)

No de-escalation
(n = 57)

De-escalation
(n = 44)

58 (4867)
52
49 (4266)
8 (611)
1.6 (0.73.1)

60 (5168)
30 (53)
47 (3960)
7 (510)
1.8 (0.64.1)

58 (4864.25)
22 (50)
49 (42.7565.5)
8.5 (610.25)
1.4 (0.72.3)

0.15
0.84
0.097
0.37
0.33

2
12
3
11

0
7
2
7

2
5
1
4

0.19
1
1
0.75
0.51

32
36
12
11
5
2
1
2
83

15 (26)
21 (37)
6 (11)
8 (14)
4 (7)
1 (2)
0 (0)
2 (4)
43 (75)

17 (39)
15 (34)
6 (14)
3 (7)
1 (2)
1 (2)
1 (2)
0 (0)
40 (91)

44
24
2
12
7
12

26 (46)
13 (23)
2 (4)
7 (12)
3 (5)
6 (11)

18 (41)
11 (25)
0 (0)
5 (11)
4 (9)
6 (14)

77
14
10

44 (77)
7 (12)
6 (11)

33 (75)
7 (16)
4 (9)

24
20
49
8

15 (26)
8 (14)
29 (51)
5 (9)

9 (20)
12 (27)
20 (45)
3 (7)

(0)
(12)
(4)
(12)

(5)
(11)
(2)
(9)

0.065
0.86

0.89

0.43

Data are expressed as number (percentage) or median (25th75th percentiles)

G-CSF granulocyte-colony stimulating factor, HSCT hematopoietic stem cell transplantation, ICU intensive care unit, SAPS II simplified
acute physiology score II, SOFA sequential organ failure assessment

and fluoroquinolones (n = 18). Antifungal and antiviral

agents were given to 30 (38 %) and 14 (18 %) patients,
respectively.
In the ward, 79 patients received an empirical antimicrobial treatment. Among them, infection was
microbiologically documented in 49 (62 %) patients, with
adequate treatment in 27 (55 %) of these patients. The
treatment was appropriate for 17 (57 %) out of the 30
patients without microbiological documentation. Twentytwo patients did not receive antibiotics before ICU
admission. Among them, infection was microbiologically
documented in 15 (68 %) cases.
After ICU admission, antimicrobial treatments were
continued in 37 patients and initiated in 22 patients.
Changes were performed in 42 patients. The time elapsed
between the first antimicrobial therapy and the first signs
of severe sepsis in ICU was 1.6 (0.73.1) h (Table 1).

Betalactams were administered to all patients. They were

inactive against Pseudomonas aeruginosa in 2 patients. In
57 patients, aminoglycosides (n = 27) or fluoroquinolones (n = 30) were added. Antibiotics active against
MRSA were used in 48 patients. Antifungal and antiviral
agents were used in 30 and 17 patients, respectively
(Electronic Supplementary Material Table 2). The median duration of antimicrobial treatment was 7 days [414]
for median duration of ICU stay of 9 days [518].
At ICU admission, the empirical antimicrobial treatment was appropriate in 50 patients and adequate in 42
patients. Eight out of the 38 patients without microbiological documentation received an appropriate treatment
(Table 4). Of note, in these 38 patients, the anti-pseudomonal antibiotic was appropriate in 31 (82 %).
The empirical antimicrobial treatment was de-escalated
in 44 patients of the 101 patients (Electronic Supplementary

45

Table 2 Organ failure, support care and neutropenia evolution in ICU

Time between onset of sepsis and its management in ICU (days)

Worsened SOFA scorea
MV
ARDS
RRT
Hepatic failure
Cardiac failure
Septic shock
Stress doses corticoids
Life-sustaining treatment limitation
Neutropenia status
Neutropenia recovery in ICU
Use of G-CSF during ICU stay
Mucositis
Neutropenic colitis

No de-escalation
(n = 57)

De-escalation
(n = 44)

1
17
20
12
15
8
7
29
13
12

(03)
(30)
(35)
(21)
(26)
(14)
(12)
(51)
(23)
(21)

2
15
15
6
11
4
6
25
8
7

(07)
(34)
(34)
(14)
(25)
(9)
(14)
(57)
(18)
(16)

0.057
0.67
1
0.43
1
0.54
1
0.69
0.63
0.61

24
26
4
12

(42)
(46)
(7)
(21)

28
29
3
9

(64)
(66)
(7)
(20)

0.05
0.05
1
1

Data are expressed as number (percentage) or median (25th75th percentiles)

ARDS acute respiratory distress syndrome, ICU intensive care unit, MV invasive mechanical ventilation, RRT renal replacement therapy,
SOFA sequential organ failure assessment
a
Between day 1 and day 5

Table 3 Characteristics of infection

Predominant site of infection

Pulmonary
Abdominal
Bacteremia
Urinary tract
Catheter-related infection
Central nervous system
Skin and soft tissue infection
ENT infection
Unknown
Infection in the ICU
Fever of unknown origin
Clinically documented
Microbiological documented
Type of pathogen (among the 63 patients with
microbiological documentation)
Non fermentative Gram-negative bacilli
Other gram-negative bacilli
Gram-positive cocci
Anaerobe
Fungal
Viral
Polymicrobial infections
Multiple sites
Colonization with MDR pathogens at ICU admission

No de-escalation
(n = 57)

De-escalation
(n = 44)

24
5
6
3
3
2
0
1
13

20
6
5
2
2
2
2
1
4

p
0.64

(42)
(9)
(11)
(5)
(5)
(4)
(0)
(2)
(23)

(45)
(14)
(11)
(4)
(4)
(4)
(4)
(2)
(9)
0.11

13 (23)
13 (23)
31 (54)

4 (9)
8 (18)
32 (73)

9
7
13
2
10
2
12
6
10

7
9
12
0
7
3
8
3
10

(29)
(23)
(42)
(6)
(32)
(6)
(21)
(19)
(18)

(22)
(28)
(38)
(0)
(22)
(9)
(18)
(9)
(23)

0.57
0.77
0.80
0.24
0.41
1
0.80
0.30
0.62

Data are expressed as number (percentage) or median (25th75th percentiles)

MDR multi-drug-resistant, ENT eye, nose, throat, ICU intensive care unit

Material Fig. 1). Cumulative incidence of de-escalation

in ICU at day 15 was 44 % (95 % CI 3853 %) (Fig. 1).
De-escalation was performed in 32 of the 63 (51 %) patients
with microbiological documentation and 12 of the 38

(32 %) patients without microbiological documentation.

The betalactam spectrum was narrowed in 22 (35 %)
patients with microbiological documentation and 1 (3 %)
patient without microbiological documentation. In 26

46

Table 4 Compliance with antibiotics guidelines and adequation of antimicrobial treatment to microbiological documentation

Empirical antibiotic treatment initiated in ICU

Documented, adequate
Documented, inadequate
Not documented, appropriate
Not documented, inappropriate
Compliance with antibiotic guidelines (ICU)
Empirical anti-pseudomonal betalactam
Empirical anti Gram positive cocci
Regarding combination therapy

No de-escalation
(n = 57)

De-escalation
(n = 44)

18
13
7
19

24
8
1
11

p
0.075

(32)
(23)
(12)
(33)

46 (81)
39 (68)
34 (60)

(55)
(18)
(2)
(25)

43 (98)
25 (57)
24 (55)

0.01
0.30
0.69

Data are expressed as number (percentage) or median (25th75th percentiles)

ICU intensive care unit

1.0

Fig. 1 Cumulative incidence of

de-escalation, death in ICU
without de-escalation, and
discharge alive without
de-escalation

0.6
0.4
0.0

0.2

Probability

0.8

Discharge without deescalation

Death without deescalation
Deescalation

10

20

30

40

50

60

Days since initiation of antimicrobial treatment

patients, the antibiotic directed against MRSA was discontinued. All de-escalation were performed within the first
12 days (Fig. 1). Of note, de-escalation of antifungal and
antiviral agents was always concomitant to that of antibiotics. The severity of organ failures at ICU admission was
similar in the de-escalation group and the non-de-escalation
group (Table 1). The time elapsed between the severe sepsis
onset and its ICU management was longer in the de-escalation group, compared to the non-de-escalation group but
the difference did not reach statistical significance [2 (07)
vs. 1 (03) days, p = 0.057] (Table 2). In 30 (30 %)
patients, de-escalation was performed during neutropenia.
The rate of escalation after de-escalation was 5 % (Electronic Supplementary Material Table 3).
Using a multivariate analysis, the characteristics of
antimicrobial treatment independently associated with deescalation were adequation of the empirical antimicrobial
treatment used in ICU [OR = 10.8 (95 % CI 1.2096)]
for adequate documented treatment versus appropriate

empirical treatment), and compliance with guidelines

regarding the empirical anti-pseudomonal betalactam
used in ICU [OR = 10.8 (95 % CI 1.389.5)] (Electronic
Supplementary Material Table 4).
The ICU mortality rate was 23 %. The 23 deaths
included 6 patients undergoing de-escalation during
neutropenia, 2 patients undergoing de-escalation after
neutropenia recovery, and 15 patients in the non-deescalation group (p = 0.57). De-escalation was not
associated with the hazard of death within the first
30 days [HR = 0.51 (95 % CI 0.201.33)], nor within the
1-year post-ICU-discharge [HR = 1.06 (95 % CI
0.542.08)] (Electronic supplementary material Fig. 2).
Among patients discharged alive, median duration of
antibiotherapy in ICU was 9 days [412] in the de-escalation group versus 5 days [38] in the non-de-escalation
group (p = 0.005). In the de-escalation group, cancer
status and G-CSF use were not associated with ICU death.
During the ICU stay, 7 (22 %) out of 32 patients in the

47

no-remission group died, compared to 1 (8 %) out of 12

patients in the remission group (p = 0.15). Five (17 %)
out of 29 patients treated with GCS-F and 3 (20 %) out of
15 patients not treated with G-CSF died (p = 1).

Discussion
To our knowledge, this study is the first evaluation of deescalation in neutropenic cancer patients requiring ICU.
As expected, the empirical antimicrobial treatment was
de-escalated in about 40 % of this population. In ICU, an
adequate empirical antimicrobial treatment and the compliance to guidelines regarding the first anti-pseudomonal
betalactam agent are critical for initiating the process of
de-escalation. De-escalation did not affect the patient
outcomes.
In the hematological patients with sepsis and neutropenia, the empirical choice of antimicrobials remains a
matter of debate [23]. Two approaches are opposed to
each other. The escalation approach consists of avoiding
the use of broad-spectrum antibiotics. In this strategy, the
treatment is escalated in the patient with clinical worsening or after the identification of a resistant pathogen.
This strategy reduces toxicity, selection pressure, and
cost. However, the delayed use of an effective treatment
can negatively impact the outcomes [24, 25]. In contrast,
de-escalation consists of the empirical use of broadspectrum antibiotics. This strategy is efficient in covering
all possible pathogens [2], but it exposes broad-spectrum
antibiotics to overuse [24, 26]. Previous studies showed
the safety of de-escalation in patients with septic shock,
although no randomized clinical trials are available [4].
In our series, the empirical antimicrobial treatment
was de-escaladed in 44 % of the neutropenic patients. No
apparent effect on mortality was observed. Initial organ
failures did not affect the strategy, suggesting that the
decision was not guided by the patient severity. The rate
of de-escalation did not differ from that reported in nonneutropenic patients [57, 27]. Importantly, our study was
conducted in ICU. It is important to underline that our
patients were continuously monitored. Thus, our results
cannot be extrapolated to conventional wards. One should
note that 5 % of patients required escalation after deescalation failure [5, 28]. In a cancer ICU, de-escalation
seems feasible and safe.
The neutropenic patients are at high risk of complications, due to altered immune response [29, 30].
Guidelines suggest continuing antimicrobial treatment
until neutropenia recovery. They recommend the changing of antibiotics on the basis of microbiological results
[11, 12]. There are no data supporting this statement [11,
12]. In our study, 68 % of patients underwent de-escalation during neutropenia. We did not find a deleterious
impact of de-escalation on the survival of this specific

subgroup. Future studies are required to confirm this

finding. In our study, the duration of treatment was
increased in the de-escalation group, compared to the
non-de-escalation group. Of importance, in the de-escalated patients, treatment was never interrupted before
neutropenia recovery. In critically ill neutropenic cancer
patients, recovering from neutropenia during the ICU stay
is a critical step; before this time, supportive care
including antimicrobial treatment is usually maintained
[30].
The administration of an adequate empirical antimicrobial treatment was associated with de-escalation. In
line with a previous study [1], this finding underlines the
need to collect blood samples and specimens from the
suspected sources of infection before the antibiotic onset
[31]. In cancer patients, a standardized diagnostic
approach has been associated with improved outcomes
[18, 32]. Using both invasive and non-invasive procedures, this strategy resulted in a microbiological
documentation in up to 60 % of patients [18, 32]. Elsewhere, the identification of pathogens has been associated
with decreased mortality [33]. In agreement with previous
findings, this strategy was associated with a relatively low
rate of positive blood culture [18].
The second factor associated with de-escalation was
the compliance to guidelines regarding the choice of the
antipseudomonal agent [12]. The use of ceftazidime and
ticarcillin/clavulanate was not associated with de-escalation. Of note, international guidelines recommend the
avoidance of ceftazidime for empirical monotherapy of
fever and neutropenia [12]. In contrast, the empirical use
of carbapenem was significantly associated with a high
rate of de-escalation. This suggests that a guidelines
strategy based on an empirical broad-spectrum antimicrobial treatment followed by de-escalation is feasible in
neutropenic patients [4].
In the 38 patients without microbiological documentation, the uses of antipseudomonal belactams, antiMRSA antibiotics, and combined antibiotics were inappropriate in 7 (18 %), 15 (39 %), and 17 (45 %) patients,
respectively. Thus, only 8 (21 %) of these patients
received an antimicrobial treatment in compliance with
the guidelines. In the septic neutropenic patients, initial
antimicrobial treatment using combined antibiotics or
anti-MRSA drugs remains a matter of debate [20]. In the
wards of our institution, anti-MRSA drugs were largely
used although MRSA were rarely identified. In ICU, in
disagreement with the guidelines, the use of these antibiotics was often interrupted, based on our local ecology
and the removal of invasive devices [20]. Surprisingly, we
observed a high rate of patients receiving antifungals in
the de-escalation group. One possible explanation is that,
in those patients, the delay between the onset of sepsis
and its ICU management was longer than in the non-deescalated patients. Thus, an antifungal treatment was prior
introduced as the guidelines recommend [11, 34]. Of note,

48

antifungal treatment was interrupted in 50 % of de-escalated patients.

Our results show that de-escalation did not impact
short-term mortality. Several factors can affect the relationship between de-escalation and mortality: early ICU
discharge, adequacy of empirical antimicrobial therapy,
and timing of antibiotic administration. In our opinion,
de-escalation may probably not alter short-term mortality.
Indeed, no study has reported significant differences
between two adequate antimicrobial treatment in patients
with septic shock [35].
Several limitations should be acknowledged. Deescalation was left to the discretion of the senior physician. This represents a confusing factor, limiting the
application of this strategy. However, our rate of deescalation was similar to that reported in previous studies
[57, 27]. The identification of co-pathogens such as
yeasts and viruses has not been reported elsewhere. The

actual impact of those pathogens on the de-escalated

patient outcomes remains unclear. Finally, our study
cannot document the relationship between a potential
time-varying confounder such as the evolution of organ
failure during ICU and de-escalation.
In conclusion, for the first time, we show that, in ICU,
de-escalation is frequently performed in neutropenic
cancer patients with severe sepsis. This approach appears
not to affect the outcomes. Future studies are required to
confirm these preliminary findings.
Acknowledgments The study was funded by the Department of
Anesthesiology and Critical Care of Paoli-Calmettes Institute.
Conflicts of interest M. L. has received consultancy fees from
LFB Biomedicaments and honoraria from Fresenius Kabi and
Novartis for lectures. D. M., A. S., L. C. C., J. P. B., M. F., G. S., P.
B., S. D., N. V.,C. S., and J. L. B. declare no conflicts of interest.

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