Grand Rounds Presentation 40 Min

Febrile Neutropenia Management in
Pediatrics: Monotherapy Cefepime vs.

Piperacillin/Tazobactam
G RA N D R O U N D S 4 2 4 1 FA L L 2 0 1 5
L I N C Y VA R U G H E S E
T T U H S C S O P P H A R M D . C A N D I DAT E
Objectives
Understand the pathophysiology of febrile neutropenia
Review the current guidelines on the management of
febrile neutropenia
Analyze the literature to review the use of monotherapy
Cefepime [CFPM] vs. Piperacillin/Tazobactam [PIP/TAZ]
for empiric treatment in pediatrics
Given a patient scenario, apply the literature,
guidelines, and determine appropriate therapy
Patient Case
MJ is an 8 year-old white female who presents to the
ED with a fever of 101.4F. MJ is an oncology patient
with acute myeloid leukemia [AML] and has been
receiving out-patient chemotherapy at your hospital.
Her last session was 1 week ago.
PMH: AML
CBC: WBC 0.8 Hct 32% Plt 148
Differential: segs 22% bands 1% mono 1% lymph 24%
Absolute Neutrophil Count [ANC] 184
3
Understanding Febrile
Neutropenia
Per the IDSA guidelines:
Fever:
A single oral temperature measurement of >38.3 C
(101 F) or a temperature of >38.0 C (100.4 F)
sustained over a 1-h period
Neutropenia:
ANC of <500 cells/mm3 or an ANC that is expected
to decrease to <500 cells/mm3 during the next 48 h
Freifeld AG, et al. Clin Infect Dis. 2011;52(4):e56-93.
4
Understanding Febrile Neutropenia

Oncologic Emergency:
It is a significant cause of mortality and
morbidity
Spectrum of infection is influenced by:
Nature and intensity of chemotherapy
Antimicrobial prophylaxis
Catheters and other medical devices
Rolston KI. The MD Anderson Manual of Medical Oncology, 2e. 2011.
Understanding Febrile
Neutropenia
Pathophysiology
Decreased bone
marrow production
Sequestering of
neutrophils
Increased
destruction of
neutrophils in
peripheral blood
Schwartzberg LS. Clin Cornerstone. 2006;8

Suppl 5:S5-11.
6
Understanding Febrile Neutropenia

Contributing Pathogens
Gram Positive
Gram Negative
Coagulase-negative Staphylococcus
aureus
[including MRSA]
Escherichia coli
Enterococcus species
[including VRE]
Klebsiella species
Viridans group streptococci
Enterobacter species
Streptococcus pneumonia
Pseudomonas aeruginosa
Streptococcus pyogenes
Citrobacter species
Acinetobacter species
Stenotrophomonas maltophilia
Freifeld AG, et al. Clin Infect Dis. 2011;52(4):e56-93.
7
Risk Stratification
Patient
Specific
Treatmen
t Specific
Episode
Specific
Age
Malignancy type
Disease status
Type of chemotherapy
Timing of chemotherapy
Height of fever
Hypotension
Mucositis
Blood counts/CRP
Lehrnbecher T, et al. J Clin Oncol. 2012;30(35):4427-38.
8
Current Guidelines
Journal of Clinical Oncology Guidelines
Bridging the gap between pediatric febrile
neutropenia management and adult
management through the development of
an evidence-based guideline for empiric
therapy management
Current Guidelines
Outline:
Risk Stratification
Clinical Features and Laboratory Markers
Imaging Studies
Appropriate Empiric Treatments [High-Risk and Low-Risk]
Outpatient vs. Inpatient Management
Therapy Modification
Therapy Discontinuation
Invasive Fungal Disease [Risk, Identification, Therapy]
10
Current Guidelines
Our Focus:
Risk Stratification
Clinical, Laboratory, and Imaging Studies
Empiric Therapy [High-Risk]
11
Risk Stratification
Characteristic
Weight
Burden of illness: no or
mild symptoms
No hypotension
No chronic obstructive
pulmonary disease
Solid tumor or no
previous fungal infection
No dehydration
Burden of illness:
moderate symptoms
Outpatient stats
Age <60 years
Multinational
Association of
Supportive Care in
Cancer [MASCC]
A score of 21 is
considered low risk
and a score of < 21
as high risk
Klastersky J1, Paesmans M. Support Care Cancer. 2013;21(5):1487

12
Clinical Evaluation
Clinical, Laboratory and Imaging Studies:
Blood Cultures:
From all lumens of central venous catheters; may also obtain
peripheral blood cultures
Urinalysis and Urine Culture:

Should be a clean-catch, midstream specimen
Chest Radiography [CXR]:

Only necessary in symptomatic patients
13
Current Guidelines
Empiric Therapy for High-Risk FN:
Monotherapy with an antipseudomonal lactam or a carbapenem
Addition of a second Gram-negative agent or
glycopeptide if:
Clinically unstable
Suspicion of a resistant infection
Centers with a high rate of resistant pathogens
14
Anti-pseudomonal Options
Cefepime/
Ceftazidime
High-risk
patients
PiperacillinTazobactam
Meropenem/
Imipenem
15
Carbapenems
[Imipenem/Cilastin]
Spectrum
Broad!
Anaerobic and aerobic coverage
Anti-pseudomonal
Increased risk of toxicities

Pseudomembranous colitis
Seizures
When do we use them?

Extended spectrum beta-lactamase
Cephalosporin resistant nosocomial infections
Modification therapy
Unique risk patients
Product Information: Primaxin. 2006.
16
Penicillins
[Piperacillin/Tazobactam]
Spectrum
Broadest penicillin
Gram positive/Gram negative/B. fragelis
Anti-pseudomonal

Penicillin G and ampicillin resistant infections
Proteus and Enterobacter spp.
Bacteremia/UTIs/pneumonia
Product Information: Zosyn. 2007.
17
Cephalosporins [Cefepime]
4th generation
Spectrum
Gram negative coverage
Anti-pseudomonal
No coverage for B. fragelis [anaerobe]

Better activity than ceftazidime and piperacillin against:
Enterobacter
Citrobacter
Serratia
Product Information: Maxipime. 2007.
18
Literature Analysis
o To evaluate the use of cefepime [CFPM]versus
piperacillin/tazobactam [PIP/TAZO] in
chemotherapy associated febrile neutropenia we
will evaluate three separate studies
o What to consider when reviewing these studies:
o Efficacy
o Cost
o Safety
19
Cefepime
Streptococcus
pneumoniae
Viridans streptococcus
Escherichia coli
Klebsiella
Pseudomonas
aeruginosa
Piperacillin/
Tazobactam
Streptococcus
pneumoniae
Enterococcus
faecalis/faecium
Escherichia coli
Klebsiella
Pseudomonas
aeruginosa
Gilbert DN, et al. Sanford Guide. 2011;45:72-74

20
Monotherapy with
Piperacillin/Tazobactam Versus
Cefepime as Empirical Therapy for
Febrile Neutropenia in Pediatric
Cancer Patients: A Randomized
Comparison
Corapcioglu F, Sarper N, Zengin E. Pediatr Hematol
Oncol. 2006;23(3):177-86.
21
Objective
Evaluated:
Cost
Hospitalization
Antimicrobial therapy
Supportive treatment
Design:
Prospective, Comparative, Randomized Trial
28 patients with 58 febrile episodes
Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.
22
Study Design
Randomization was consecutive and patient could be
randomized more than once based on distinctiveness of
febrile neutropenic episode or prior antibiotic treatment
[within two weeks]
Study Groups
Intervention:
Cefepime 50
mg/kg every 8
hours [maximum
of 6 g/day]
Piperacillin/
Tazobactam 80
mg/kg every 6
hours [maximum of
13.5 g/day]
23
Patient Selection
Inclusion Criteria
Exclusion Criteria
< 18 years of age
Fever due to malignancy, transfused

blood, or other medications
Primary/refractory/relapsed tumor and

malignancy
ANC < 500 cells/mm3 or < 1000
cells/mm3 with expected < 500
cells/mm3
Fever 38.5 or 38 > 1 hour
Antibiotic use 3 days prior to trial

Allergy to penicillins or cephalosporins
Hepatic or renal Insufficiency
Protocol violation: administration of a
new antibiotic before the first four days of
PIP/TAZO or CFPM have been completed
24
Outcomes
Primary:
The treatment response of both agents
Secondary:
Success without modification
25
Statistical Analysis
Statistical Analysis:
Descriptive evaluation
Continuous variables were measured in mean + SD
Chi-squared or Fishers Exact Test and MannWhitney U tests were used for comparison
Univariate-multivariate analysis was used for
evaluation of variables determining treatment
response and cost
26
Study Definitions
Antibiotic therapy was administered until
success or failure was determined
Definition of Success:
Disappearance of fever, clinical improvement,
eradication of organism, and response
maintenance for 7 days after discontinuation of
therapy
Definition of Failure:
Persistence of fever or organism,
new infections,
or infection related death
27
Results
Characteristics of the episodes
Documentation of infections
Treatment response
Cost analysis
28
Episode Characteristics
Characteristics of Episodes
[Table One]
All
Episodes
[N=50]
PIP/TAZO
[N=25]
CFPM
[N=25]
Underlying disease
P-Value
0.567
Leukemia
29 [58]
16 [64]
13 [52]
Solid tumor
21 [42]
9 [36]
12 [48]
Disease status
0.154
Active
22 [44]
8 [32]
14 [56]
Remission
28 [56]
17 [68]
11 [44]
15 [30]
9 [36]
6 [24]
0.538
5 [10]
2 [8]
3 [12]
0.508
Mean/mm3
53
45
181
0.547
<100/mm3
28 [56]
12 [48]
16 [64]
0.393
CVC
G-CSF Use
ANC
Expected neutropenia duration
29
Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-
Documentation of Infection
Documentation of
Infections in Treatment
Groups
[Table 2]
All episodes
[n = 50]
PIP/TAZO
[n = 25]
CFPM
[n = 25]
9 [18]
3 [12]
6 [24]
Bacteremia
Without bacteremia
14 [28]
6 [24]
8 [32]
Otitis/mastoidits/sinusitis
Lower respiratory tract
Gastrointestinal tract
Skin and soft tissue
27 [54]
16 [64]
11 [44]
Microbiologically
documented
Clinically documented
Fever of unknown origin
30
Treatment Response of Groups

Treatment Response of
the Study Groups
[Table 3]
All
episodes
[n = 50]
PIP/TAZO
[n = 25]
CFPM
[= 25]
P-value
Success without modification
26 [52]
14 [56]
12 [48]
0.778
Persistent fever at 72nd hour
22 [44]
12 [48]
10 [40]
0.776
5.1 [4-10]
4.8 [4-7]
5.3 [4-10]
0.650
35
15
20
0.470
3 [1-28]
3 [1-20]
2 [2-28]
0.777
Mean duration of treatment

[days] [range]
11.3 [4-40]
10.8 [5-25]
11.8 [4-40]
0.882
Mean duration of
neutropenia [days]
[range]
10.4 [3-25]
7.5 [5-25]
8.1 [3-24]
0.218
Modification day
[range]
Total number of modifications
Mean duration of fever
[days] [range]
31
Cost Analysis
Cost Analysis of
Treatment Groups
[Table 4]
All
episodes
PIP/TAZO
CFPM
P-value
1250
1266
1235
0.742
616
616
660
0.662
Hospitalization
100
100
100
0.776
Supportive care
530
530
747
0.331
Daily cost
118
113
126
0.889
Total cost per episode

Antimicrobial therapy
Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-1

32
Conclusions
Authors Conclusions: We suggest that PIP/TAZO
monotherapy is as effective as CFPM monotherapy,
which has an established success in febrile neutropenic
episodes. Although the study group is small, PIP/TAZO
monotherapy may be a good alternative for pediatric
febrile neutropenic episodes of pediatric cancer
patients.

33
Strengths/Limitations
Strengths
Randomized,
Comparative
First trial comparing
these agents in FN
Limitations
Single-center study
Small population size
Infusion details
Disease state variations

34
Piperacillin/Tazobactam Versus
Cefepime for the Empirical Treatment
of Pediatric Cancer Patients With
Neutropenia and Fever: A Randomized
and Open-Label Study
Uygun V, Karasu GT, Ogunc D, et al. Pediatr Blood Cancer.
2009;53(4):610-4.
35
Study Objective/Design
Evaluated: safety and efficacy
Prospective, randomized, and open-label clinical trial
Baseline characteristics: 127 episodes in 69 patients (35 females, 34 males) with a
median age of 4.2 years
Outcomes: duration of fever, neutropenia, hospitalization, the need for modification
of the therapy, and mortality rates were compared between the two groups
Study Groups
Cefepime 50
mg/kg every 8
hours [maximum
of 6 g/day]
Piperacillin/
Tazobactam 80
mg/kg every 6
hours [maximum of
13.5 g/day]
Uygun, et al. Pediatr Blood Cancer. 2009;53(4):610-4.
36
Results
Clinical response was determined at completion of
therapy:
Frequency of success without modification: PIP/TAZO
(60.0%) and CFPM (61.3%) (P>0.05)
The overall response rate, with or without
modification of assigned treatment, was 96.9% for
PIP/TAZO and 98.4% for CEP (P>0.05). Infection
related mortality at the end of the febrile episode was
2.4%.
et al. Pediatr
Blood Cancer. 2009;53(4):610-4.
Duration of fever and hospitalizationUygun,
were
not
different between the treatment groups. No major
37
Conclusions
PIP/TAZO treatment was as effective and safe
as CFPM monotherapy as an initial empirical
regimen in pediatric cancer patients with fever
and neutropenia
Uygun, et al. Pediatr Blood Cancer. 2009;53(4):610-4.

38
Comparison Between
Piperacillin/Tazobactam and Cefepime
Monotherapies as Empirical Therapy
for Febrile Neutropenia in Children
with Hematological and Malignant
Disorders: A Prospective Randomized
Study
Sano H, Kobayashi R, Suzuki D, et al. Pediatr Blood
39
Objective
Evaluated:
Safety
Efficacy
Design:
Prospective, Randomized Trial
53 patients with 213 febrile episodes
Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.
40
Study Design
Pre-treatment:
Evaluated the underlying disease state, history of
hematopoietic stem cell transplantation, and
central venous catheter
Lab tests: CBC, peripheral blood smear,
quantitative CRP, liver and renal function, and
blood cultures from specimens obtained via a PVP
or CVC
214 febrile episodes in 53 patients were
documented, one episode was excluded due to a
viral infection
41
Intervention
Patients were randomly divided into two groups:
Study Groups
Cefepime 100
mg/kg/d in four
divided doses
[maximum 4
grams/day]
Piperacillin/
Tazobactam 337.5
mg/kg/d in three
divided doses
[maximum 13.5
grams/day]
Antibiotics were administered by 1-hour drip intravenous infusions

Antibiotic therapy was administered until success
was
Sano H, or
et al.failure
Pediatr Blood
Cancer. 2015;62:356-358.
determined
42
Patient Selection
Inclusion Criteria
Conventional or Highdose Chemotherapy
Recipient
Temperature >38
ANC <500
Age 0-22
Exclusion Criteria
Viral Infection
Temperature <37.5
ANC >500
Prophylactic Antibiotic
Use
Age > 22
43
Outcomes
Primary:
Clinical response of both agents
Secondary:
44
Statistical Analysis
Data was evaluated using median, mean, ranges, and
percentage values
Mann-Whitney U-test for comparison of independent
continuous variables
Pearsons chi squared test for comparison of
categorical data
Fischers exact tests for categories with low numbers
P-values [two-tailed] less than <0.05 were considered
significant
45
Study Definitions
Definition of Success:
Fever and clinical signs of infection had resolved within 120
hours following initiation of the antibiotic therapy
No recurrence of infection/fever after the end of treatment
Definition of Failure:
Persistence of fever and infectious signs beyond 120 hours
following initiation of the antibiotic therapy and a required
changing in the initial antibiotic therapy
Deterioration/death due to infection
46
Results
Characteristics of the episodes
Clinical response
Isolated organisms
47
Patient Characteristics
Demographic and Clinical
Characteristics of Patients
[Table One]
Gender [M/F]
Age [median, range]
PIP/TAZO
CFPM
P-Value
48/55
53/57
0.310
4 [0-20]
6 [0-22]
0.903
Disease [%]
0.640
ALL
55
44
AML
20
16
Others
28
23
Stem cell transplantation
13
0.858
CV line
75
54
0.246
WBC [at entry]
0.33 (0.01139.0)
0.31 (0.0111.3)
0.974
ANC [at entry]
0.005 (0.01-139)
0.025 (0-10.5)
0.115
CRP [at entry]
0.42 (0.05-17.79)
0.025
(0-10.5)
0.035
48
Clinical Responses
Clinical Responses of Episodes
of Febrile Neutropenia
[Table 2]
PIP/TAZO
[n = 103]
CFPM
[n = 110]
P-value
64/103 [62.1]
65/110 [59.1]
0.650
Success rate in patients with ANC

<500
47/82 [57.3]
41/86 [47.7]
0.211
New breakthrough infections [%]
13/103 [12.6]
21/110 [19.1]
0.198
Success rate in patients with

bacteremia [%]
3/7 [42.9]
6/13 [46.2]
0.888
Death caused by infection [%]
1/103 [1]
0/110 [0]
0.300
Duration [days] of the antibiotic

therapy [median]
10 [2-18]
9 [4-15]
0.251
Success rate [%]

49
Isolated Organisms
Organisms Isolated from Blood
Cultures
[Supp. Table]
PIP/TAZO
[n =7]
CFPM
[n =13]
Total
[n =20]
Staphylococcus epidermis
a-streptococcus
Enterococcus faecium
Klebsiella pneumonia
Pantoea agglomerans
Gram-positive cocci
Gram-negative bacilli
Gram-positive bacilli
Bacillus species

50
Results
In regards to overall success rate, achieving an ANC
<500, new breakthrough infections, success rate in
patients with bacteremia, death caused by
infection, and duration [days] of the antibiotic
therapy no significant difference existed between
the use of CFPM or PIPC/TAZ.
51
Conclusions
Authors Conclusions: This study
demonstrated that PIPC/TAZ and CFPM
monotherapies were both effective and safe for
the empirical treatment of FN in children with
hematological and malignant diseases.
52
Strengths/Limitations
Strengths
Limitations
Randomized,
Comparative
Single-center study
Two - Year Study
Patient population
[Japanese only]
Dosing strategy
Disease state variations
53
Guideline Decision
No difference in treatment failure, mortality, or
adverse effects was seen when antipseudomonal penicillins were compared with
anti-pseudomonal cephalosporins or
carbapenems.
54
Patient Case
MJ is a 8 year-old white female who presents to the ED at your
hospital with a fever of 101.4F. MJ is an oncology patient with
acute myeloid leukemia and has been receiving out-patient
chemotherapy at your hospital. Her last session was 1 week
ago.
ANC 184
MJ can be appropriately treated with either therapy option:
Cefepime 50mg/kg every 8 hours
Piperacillin/Tazobactam 80 mg/kg every 6 hours
May discontinue empiric antibiotics if all of the following criteria met:
Negative blood cultures at 48 hours; afebrile for at least 24 hours, and
evidence of marrow recovery
55
In Practice
In general, the choice of an initial agent for
empiric febrile neutropenia management should
be based on the patterns, costs, and standards of
the specific center.
Cefepime may be preferred due to:
FDA approved indication for febrile neutropenia
Anaerobic coverage of PIP/TAZO isnt always necessary
Convenience of dosing strategy
56
Special Gratitude
Dr. Crystal Brown PharmD, BCPS
Dr. Veronica Nguyen PharmD, BCPS
Dr. Kyana Stewart MS, Pharm D, BCPS
57
References
Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guidelinefor the use
ofantimicrobial agentsinneutropenicpatientswithcancer: 2010 update by the
infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56-93. doi:
10.1093/cid/cir073.
Rolston KI. Chapter 43. Infection in the Neutropenic Patient. In: Kantarjian HM, Wolff
RA, Koller CA. eds. The MD Anderson Manual of Medical Oncology, 2e. New York, NY:
McGraw-Hill; 2011. http://accessmedicine.mhmedical.com/content.aspx?
bookid=379&Sectionid=39902074. Accessed August 26, 2015.
Schwartzberg LS. Neutropenia: etiology and pathogenesis. Clin Cornerstone. 2006;8
Suppl 5:S5-11. doi:10.1016/S1098-3597(06)80053-0.
Lehrnbecher T1, Phillips R, Alexander S, et al. Guideline for the management of fever
and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell
transplantation. J Clin Oncol. 2012;30(35):4427-38. doi: 10.1200/JCO.2012.42.7161.
58
References
Klastersky J1, Paesmans M. The Multinational Association for Supportive Care in Cancer (MASCC) risk
index score: 10 years of use for identifying low-risk febrile neutropenic cancer patients. Support Care
Cancer. 2013;21(5):1487-95. doi: 10.1007/s00520-013-1758-y.
Product Information: PRIMAXIN(R) IV injection, imipenem, cilastatin IV injection. Merck & Co,Inc,
Whitehouse Station, NJ, 2006.
Product Information: ZOSYN(R) IV injection, piperacillin and tazobactam IV injection. Wyeth
Pharmaceuticals Inc., Philadelphia, PA, 2007.
Product Information: MAXIPIME(R) IV, IM injection, cefepime hcl IV, IM injection. Bristol-Myers Squibb
Company, San Diego, CA, 2007.
Gilbert DN, Chambers HF, Eliopoulos GM, et al. The Sanford guide to antimicrobial therapy. Sanford
Guide. Sperryville, VA: Antimicrobial Therapy, INC; 2011;45:72-74.
Corapcioglu F, Sarper N, Zengin E. Monotherapy with piperacillin/tazobactam versus cefepime as
empirical therapy for febrile neutropenia in pediatric cancer patients: A randomized comparison.
Pediatr Hematol Oncol. 2006;23(3):177-86. doi: 10.1080/08880010500506370.
59
References
Uygun V, Karasu GT, Ogunc D, et al. Piperacillin/tazobactam versus cefepime
for the empirical treatment of pediatric cancer patients with neutropenia and
fever: a randomized and open-label study. Pediatr Blood Cancer.
2009;53(4):610-4. doi: 10.1002/pbc.22100.
Sano H, Kobayashi R, Suzuki D, et al. Comparison between
piperacillin/tazobactam and cefepime monotherapies as empirical therapy for
febrile neutropenia in children with hematological and malignant disorders: A
prospective randomized study. Pediatr Blood Cancer. 2015; 62:356-358. doi:
10.1002/pbc.25178.
60
Questions?
61

Grand Rounds Presentation 40 Min

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Grand Rounds Presentation 40 Min

Uploaded by

Copyright:

Available Formats

Febrile Neutropenia Management in

Pediatrics: Monotherapy Cefepime vs.

Understanding Febrile Neutropenia

Schwartzberg LS. Clin Cornerstone. 2006;8

Understanding Febrile Neutropenia

Viridans group streptococci

Lehrnbecher T, et al. J Clin Oncol. 2012;30(35):4427-38.

Age <60 years

Klastersky J1, Paesmans M. Support Care Cancer. 2013;21(5):1487

Urinalysis and Urine Culture:

Chest Radiography [CXR]:

Increased risk of toxicities

When do we use them?

When do we use them?

No coverage for B. fragelis [anaerobe]

When do we use them?

Gilbert DN, et al. Sanford Guide. 2011;45:72-74

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

< 18 years of age

Fever due to malignancy, transfused

Primary/refractory/relapsed tumor and

Antibiotic use 3 days prior to trial

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-186.

Expected neutropenia duration

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-

Lower respiratory tract

Skin and soft tissue

Fever of unknown origin

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-

Treatment Response of Groups

Success without modification

Persistent fever at 72nd hour

Mean duration of treatment

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-

Total cost per episode

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-1

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-1

Corapcioglu, et al. Pediatr Hematol Oncol. 2006;23[3]:177-1

Uygun, et al. Pediatr Blood Cancer. 2009;53(4):610-4.

Antibiotics were administered by 1-hour drip intravenous infusions

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Stem cell transplantation

WBC [at entry]

ANC [at entry]

CRP [at entry]

Success rate in patients with ANC

New breakthrough infections [%]

Success rate in patients with

Death caused by infection [%]

Duration [days] of the antibiotic

Success rate [%]

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.

Two - Year Study

Sano H, et al. Pediatr Blood Cancer. 2015;62:356-358.