Managing Febrile Neutropenia in Pediatric Oncology Patients: Wise Antimicrobial Stewardship

Lincy Varughese, Pharm.D.

PGY1 Pharmacy Resident
The Childrens Hospital of San Antonio, San Antonio, Texas
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
University of Texas Health Science Center at San Antonio
February 10, 2017

Learning Objectives

1. Understand the basics of febrile neutropenia

2. Review the current guidelines and institutional practices on the management of febrile neutropenia
3. Evaluate literature on the de-escalation of antimicrobial therapy in pediatric febrile neutropenia
4. Given a patient case scenario, apply the literature, guidelines, and outside institutional resources to determine
appropriate therapy
 Varughese 2

I. Febrile Neutropenia
A. What is febrile neutropenia?
i. Background1
1. Febrile neutropenia is an oncologic emergency
2. Spectrum of infection is influenced by:
a. Nature and intensity of chemotherapy
b. Antimicrobial prophylaxis
c. Catheters and other medical devices
ii. Pathophysiology:2
1. Decreased production of white blood cells in the bone marrow
2. Chemotherapy causes disruption of the integrity of the gastrointestinal mucosa predisposing
patients to severe invasive infections
a. Gut flora (also from mouth/esophagus/nose) translocates into the blood stream
b. Reduced hematopoiesis leads to pancytopenia:
i. Anemia
ii. Neutropenia
iii. Thrombocytopenia
iii. Definition:3
1. 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 one hour period
2. Neutropenia:
a. Absolute neutrophil count (ANC) of <500 cells/mm3 or an ANC that is expected to
decrease to <500 cells/mm3 during the next 48 hours
iv. Population at risk:4
1. It is an important cause of morbidity and mortality in oncology patients receiving cytotoxic
antineoplastic therapy
a. With aggressive management in the last few decades mortality has fallen from 30
40% to 1%.
Table 1: Pathogens of concern5
Gram Positive Gram Negative Anaerobes Fungal species
Coagulase-negative Escherichia coli Bacteriodes fragelis Pneumocystis jiroveci
Staphylococcus aureus Klebsiella species Candida spp.
(including MRSA) Enterobacter species Aspergillosis
Enterococcus species Pseudomonas aeruginosa Zygomycosis
(including VRE) Citrobacter species
Viridans group Acinetobacter species
streptococci Stenotrophomonas
Streptococcus maltophilia
pneumonia
Streptococcus pyogenes

II. Management of Febrile Neutropenia

A. Guideline Based Management Recommendations:
i. Risk Stratification:
1. Factors to consider: patient, treatment, and episode specific (Table 2)
2. International risk stratification scoring systems have been included in the Journal of Clinical
Oncology guidelines (Table 3)
a. Notable variations across countries and institutions
3. These are not necessarily adopted in all pediatric institutions and some institutions may
have their own scoring system to stratify patients into high and low risk categories
 Varughese 3

Table 2: Risk Stratification Factors to Consider1

Patient Specific Treatment Specific Episode Specific
Age Type of chemotherapy Height of fever
Malignancy type Timing of chemotherapy Hypotension
Disease status Mucositis
Blood counts/CRP

Table 3: Validated pediatric risk stratification strategies for low-risk patients6-11

Patient and Rule Formation Demonstrated to

Strategy Factor disease related Episode-specific factors be valid in these
factors Low High countries
Rackoff et al. AMC 100
None AMC HSCT United States
(1996) cells/uL
AML, Burkitt's
Hypotension, Tachypnea,
lymphoma,
Hypoxia<94%, New CXR
Induction ALL, Absence of United Kingdom
Alexander et Changes, AMS, Severe
Progressive any risk HSCT
al. (2002) Mucositis, Vomiting or
disease, Relapsed factor
Abdominal Pain, Focal
with marrow
Infection
involvement
Site of infection (4.5)
Rondinelli et Total score Total score
CVC (2) No URTI (2.5)
al. (2006) <6 >6 Brazil
5 years old (1) HgB 70 g/L (1)
(Points) HSCT
Fever >38.5C (1)
Zero risk
Relapsed leukemia factors, Only
CRP 90mg/L
Santolaya et Chemotherapy low platelets, South America
Hypotension All others
al. (2001) within 7 days of or only < 7
Platelets 50g/L
episode days from
chemo
Bone marrow Absence of clinical signs
Three or
involvement, of viral infection
Ammann et fewer risk
central venous CRP>50 mg/L, HSCT Europe
al. (2003) factors
catheter, preB- WBC500 cells/uL,
cell leukemia HgB>100 g/L
Ammann et Chemo more Hemoglobin 9 g/dL (5) Total score < Total score >
al. (2010) intensive than ALL WBC <300cells/uL (3) 9 9 Europe;
(Points) maintenance (4) Platelets <50g/L (3) HSCT

ii. Initial Management of FN1

1. Low-risk FN:
a. Appropriate oral agents for gram positive and gram negative coverage include:
i. Cefixime OR
ii. Fluoroquinolone + amoxicillin-clavulanate
b. Consider initial or step-down outpatient management if infrastructure is in place to
ensure careful monitoring and follow-up
c. Consider oral antimicrobial administration if child is able to tolerate this route of
administration reliably
2. High-risk FN:
a. Empiric monotherapy with an antipseudomonal -lactam or carbapenem
b. Reserve addition of a second Gram-negative agent or glycopeptide for patients
when:
i. Clinically unstable OR
ii. Suspicion exists for a resistant infection OR
iii. Located at a center with a high rate of resistant pathogens
 Varughese 4

iii. Ongoing Management of FN: > 24 to 72 hours after initiation of empiric antibacterial treatment
1. Modification of High-risk FN:1
a. In children with persistent fever who become clinically unstable, escalate initial
empiric antibacterial regimen to include coverage for resistant gram-negative,
gram-positive, and anaerobic bacteria
b. Do not modify initial empiric antibacterial regimen based solely on persistent fever
in children who are clinically stable
c. After 24 to 72 hours, if there is no specific microbiologic indication to continue
combination therapy, discontinue empiric glycopeptide or agents added for double
coverage of gram-negative bacteria
2. Cessation of Treatment:1,3
a. All patients:
i. Discontinue empiric antimicrobials if:
1. Negative blood cultures at 48 hours
2. Afebrile for at least 24 hours
3. Evidence of marrow recovery
b. Low-risk FN (IDSA data: predominantly in adults):
i. Discontinue empiric antimicrobials without regard to marrow recovery in
patients at 72 hours if:
1. Negative blood cultures
2. Afebrile for at least 24 hours

Table 5: Summary of guideline recommendations:1,3

What antimicrobials should be
Guidelin What are appropriate antifungal When to narrow and/or
used empirically for in-patient
e agents to add-on? discontinue antimicrobials?
management?
If no evidence for a gram-positive
infection after 2 days discontinue
vancomycin
Low-risk Patients
Infectious Disease Society of

Ciprofloxacin + Low-risk: all antimicrobials can

amoxicillin/clavulanate be discontinued at 3 days if
Voriconazole
clinically stable, negative
High-risk Patients Echinocandin
cultures, and no discernible
Cefepime AmphotericinB
infection
preparations
Piperacillin/ tazobactam
Ceftazidime Note: Pediatrics: support for
America3

Carbapenem stopping antimicrobial therapy

at ANC <500 cells/mm3 with
cultures negative at 48 hours and
patient afebrile >24 hours
Low-risk Patients
Cefixime
Discontinue empiric
Fluoroquinolone
antimicrobials if cultures
Fluoroquinolone + Amoxicllin-
negative at 48 hours, afebrile >24
Journal of Clinical

Clavulanate
Caspofungin hours, and there is evidence of
Liposomal amphotericinB marrow recovery (Limited
High-risk Patients
research but the panel suggests
Oncology1

Cefepime or
that an ANC >100 cells/mm3
Ceftazidime
post-nadir is reasonable)
Piperacillin-Tazobactam
Meropenem/ Imipenem

B. Institution Based Management Recommendations

i. Detailed List-Serve Survey Responses in Appendix A (Table 1):
1. Institutions:
a. Connecticut Childrens Hospital (Hartford, CT)
b. Childrens Minnesota (Minneapolis, MN)
c. Arnold Palmer Medical Center (Orlando, FL)
 Varughese 5

d. Childrens Mercy Hospital (Kansas City, MO)

e. The Childrens Hospital of Philadelphia (Philadelphia, PA)
f. Ann & Robert H. Lurie Children's Hospital of Chicago (Chicago, IL)
g. Childrens Colorado (Aurora, CO)
h. Nicklaus Childrens Hospital (Miami, FL)
i. Norton Childrens (Louisville, KY)
j. VCU Health (Richmond, VA)
k. Seattle Childrens Hospital (Seattle, WA)
l. Texas Childrens Hospital (Houston, TX)
m. The Childrens Hospital of San Antonio (San Antonio, TX)

Table 6: Responses to Survey Questions

What antimicrobials does your institution use Cefepime 70%

empirically? Other responses: Zosyn and Ceftazidime
Evaluate previous history and duration of current
antimicrobials, if unimproved may consider an additional
At what point do you consider broadening coverage?
agent
Additional options: Vancomcyin, gentamicin, or an
antifungal
Micafungin 50%
What is your antifungal of choice?
Other responses: Voriconazole and Caspofungin
Count recovery
When do you narrow and/or discontinue Afebrile status: between 1 to 5 days
antimicrobials? Signs of infection: no local symptoms
Cultures: negative at 48 hours
Practitioner dependent
54% - Available
Do you have a febrile neutropenia pathway in place for
23% - In Progress
your institution?
33% - No pathway available

III. The Dilemma

A. There are limitations to risk stratification when evaluating a pediatric febrile neutropenia patient
B. There are minimal guideline recommendations on when and how to discontinue antimicrobials in this
population
i. Limited research regarding appropriate cut-offs for ANC or afebrile period
C. The financial burden, social impact, and systemic concerns of keeping patients on antimicrobials
unnecessarily can take a significant toll
D. Clinical question: What are the appropriate parameters to follow before discontinuation of antimicrobial
therapy in pediatric febrile neutropenia?

IV. Literature Analysis

A. Evaluation of literature on pediatric febrile neutropenia
i. Hodgson-Viden H, et al. Early discontinuation of intravenous antimicrobial therapy in pediatric
oncology patients with febrile neutropenia. 2005.
ii. Lehrnbecher T, et al. Short courses of intravenous empirical antimicrobial treatment in selected
febrile neutropenic children with cancer. 2002.
iii. Mueller EL, et al. Hospital Discharges for Fever and Neutropenia in Pediatric Cancer Patients: United
States, 2009. 2015.
 Varughese 6

Table 7: Review of Study by Hodgson-Viden et al.

 Varughese 7

Early discontinuation of intravenous antimicrobial therapy in pediatric oncology patients with febrile neutropenia.
Hodgson-Viden H, Grundy PE, Robinson JL. BMC Pediatr. 2005;5(1).

Background: FN is a common problem with pediatric oncology patients and although few have a MDI, those who do are at
risk for overwhelming sepsis. Standard of practice is to start empiric antibiotic therapy if ANC <500-1000 cells/mm3. There
are no standard criteria or guidelines on endpoints for stopping IVAMT if a bacterial source is not found. Traditionally the
NACCP has initiated broad spectrum IVAMT until the patient was afebrile, blood cultures were negative at >48 hours and
ANC>500 cells/mm3. This study looked to evaluate the outcome of febrile neutropenia patients in the face of a new trend to
discontinue antibiotics at ANC < 500 cells/mm3.

Methods:
1. Objective:
a. To evaluate the outcome of a large cohort of children with FN who were initiated on IVAMT and
discontinued before ANC reached 500/mm3.
2. Study Design:
a. Retrospective chart review completed of patients in the North Alberta Childrens Cancer Program (Canda)
with FN and no apparent clinical source of fever from June 1, 1997 to July 1, 2002.
i. Inpatient charts were reviewed for these patients at the Stollery Childrens Hospital in Edmont,
Canada
ii. Outpatient charts were reviewed to determine if the fever recurred after hospital discharge
b. Study Criteria
Inclusion Exclusion
Age < 17 years receiving therapy for a primary or Children with leukemia who were not yet in remission
recurrent malignancy
Fever > 38.0C measured at home or in hospital -hemolytic streptococci from throat culture
ANC < 500cells/mm 3 Clostridium difficile in stool
Common skin organism isolates in blood
3. Data Collected:
a. If cultures done during the first 48 hours of admission were positive for an organism that would account
for the fever, then no further data was collected
b. Data collection on admissions where infectious etiology was not identified from cultures within 48 hours:
i. Choice and duration of IVAMT
ii. Oral antibiotic use for FN treatment
iii. Systemic anti-fungal agents used
iv. Microbiologic laboratory results
v. Cell Counts: APC, ANC, AMC
vi. Length of stay in hospital attributable to FN
vii. Duration of fever and recurrence of fever during or after the admission
1. Recurrent fever: new fever that occurred after the patient has been afebrile for > 24
hours, and before they reached an ANC >500 cells/mm3
4. Outcomes:
a. Patients and episodes of FN
b. Microbiologically documented infections
c. Duration of fever
d. Antimicrobial therapy
e. Clinical course and outcome
5. Data Analysis:
a. Descriptive statistics were used to summarize the patient cohort
Results:
6. Evaluation of outcomes
a. Patients and episodes of FN
i. Appendix B Table 1: Episodes of febrile neutropenia by diagnosis in 275 pediatric oncology
patients
 Varughese 8

148 Patients Not

Admitted
275 FN Patients
127 Patients 276 Epsiodes of FN
Admitted Admission

b. MDI
i. Appendix B Table 2: Incidence of proven bacterial or viral infections
1. Identified within 1st 48 hours of admission in 21% of 276 episodes (76% bacterial, 24%
viral)
2. Identified after 48 hours of admission in 8 episodes
c. Duration of fever
i. Documented only prior to hospitalization in 72/217 episodes of FN without proven infection
ii. Documented during hospitalization in 145 episodes and median duration of the initial fever was 2
days (range 1-33 days)
1. 39 of these episodes: fever recurred prior to discharge and persisted for a median of 3
days (range 2-19 days)
d. Antimicrobial therapy
i. Most frequently prescribed IVAMT: piperacillin+tobramycin (75% of episodes)
ii. Median duration: 5 days (range 1-28 days)
e. Clinical course and outcome
i. Appendix B Table 3: Hematologic parameters when antibiotics were discontinued and at
discharge in pediatric oncology patients with FN with negative cultures at admission
1. Median length of stay: 5 days (range 1-33 days)
2. Median ANC at discontinuation of IVAMT was 400 cells/mm3, and in 14% of patients
IVAMT was discontinued prior to ANC rising to 100 cells/mm3. In 7% IVAMT was
discontinued when the APC was <100 cells/mm3.
3. Two patients died during their admission for FN: unrelated to infectious process
4. None of the patients required readmission related to clinical deterioration, suspected
infection, or recurrent fever prior to neutropenia resolution
Discussion:
Strengths Limitations
Fevers were not attributed to hemolytic streptococci Exclusion of children with leukemia (unless in remission)
from throat culture
Fevers were not attributed Clostridium difficile in stool Utilization of antibiotics that are not preferred: piperacillin
(without tazobactam) + tobramycin
Exclusion of patients with common skin organism isolates Use of statistical median instead of mean
in single blood culture
No re-admission criteria

Authors Conclusions: There is limited consensus on the appropriate discontinuation of antibiotics in pediatric febrile
neutropenia. In this retrospective review of patients charts, clinicians were able to select patients who could safely be
discontinued from IVAMT even if ANC was <500 cells/mm3. These patients did not require readmission related to their
initial fever and did not experience any adverse events from early discontinuation of IVAMT.

Personal Conclusions: This retrospective analysis of 276 FN episodes reviewed the outcomes related to early
discontinuation of IVAMT. Patients were able to be safely discharged after early discontinuation of IVAMT without re-
admission. This study provided support to help move away from extended IVAMT therapy by safely analyzing patients
based on fever status and notable marrow recovery in FN pediatric patients.

ANC = Absolute Neutrophil Count FN=Fever and Neutropenia

IVAMT= Intravenous Antimicrobial Therapy MDI=Microbiologically Documented Infection
APC=Absolute Phagocytic Count AMC=Absolute Monocyte Count
 Varughese 9

Table 8: Review of Study by Lehrnbecher et al.

Short courses of intravenous empirical antibiotic treatment in selected febrile neutropenic children with cancer.
Lehrnbecher T1, Stanescu A, Khl J. Infection. 2002;30(1):17-21.

Background: In oncology patients, therapy-induced alterations of host defense influence the predisposition to infection,
but neutropenia is the major risk factor for serious bacterial and fungal infections. The use of IV empiric broad-spectrum
antibiotics has greatly reduced morbidity and mortality related to febrile neutropenia episodes. However the optimal
duration of treatment is not clear, especially in patients who present with FUO. This retrospective review analyzed
discontinuation of IV antibiotics and early hospital discharge in pediatric cancer patients with FUO regardless of ANC or
evidence of bone marrow recovery. Discontinuation was allowed as long as patients were afebrile for at least 24 hours and
had been treated with IV antibiotics for a minimum duration of 72 hours.

Methods:
1. Objective:
a. To evaluate the safety and efficacy of short courses of IV antibiotic treatment in selected pediatric cancer
patients admitted for fever and neutropenia.
2. Study Design:
a. Retrospective analysis of short courses of IV antibiotic therapy in pediatric cancer patients with FUO
b. From January 1994 through June 1996 at the Childrens Hospital of the University of Wrzburg, Germany

56 FN Patients 106 FN Episode Admissions 84 Episodes of FUO

c. Study Criteria:
Inclusion Exclusion
ANC: <500 cells/mm3 Antibiotic exposure in the last 72h prior to admission
Fever: >38.5C x 1 or >38-38.4C x 2 within a 4 hour
interval

3. Data Collected:
a. Clinical assessment at admission:
i. Complete blood cell count with differential
ii. Blood cultures from lumen of central venous catheter, peripheral vein, urine culture, and any
clinically suspicious sites of infection
b. New blood cultures were performed if the patient developed new temperature rises or remained febrile
for more than 72 hours
c. Diagnostic criteria classified initial fever episode as FUO or fever attributed to clinically/microbiologically
documented infection
d. Initial empiric antibiotic therapy
i. January 1994 April of 1995: Ceftazidime 150 mg/kg/day in three divided doses and teicoplanin
10 mg/kg/day twice the first day then once daily
ii. May 1995 June 1996: Imipenem 50 mg/kg/day divided into four doses; if fever persisted then
teicoplanin 10 mg/kg/day was added
e. Discharge criteria
i. Clinically stable
ii. Negative blood culture results
iii. Absence of fever for at least 24 hours without antipyretics
iv. IV antibiotic treatment for a minimum 72 hours
v. ANC >500 cells/mm3 or evidence of bone marrow recovery were not a precondition for the
discontinuation of antibiotic therapy
f. Evaluation of response
i. Success in FUO: defervescence during the antibacterial regimen and no recurrent fever until the
recovery of neutrophils
4. Outcomes:
a. Primary:
i. Modification of therapy based on fever status
b. Secondary
 Varughese 10

i. Duration of fever
ii. Duration of therapy
iii. Relapse of fever
iv. Re-hospitalization
v. Deaths
5. Data Analysis:
a. Descriptive statistics were used to summarize the patient cohort
Results:
1. Characteristics of the Study Population:

106 FN Episodes:
52 FN 54 FN
Episodes: Similar patient
Episodes: characteristics
Ceftazidime + Imipenem
Teicoplanin Similar outcomes

2. Clinical Outcomes
a. Appendix C Table 1: Clinical outcome in patients with FUO (n=84)
i. Modification of therapy based on fever status
1. No modification required in 68% FUO patients
2. Modification required in 32%
ii. Duration of fever
1. Mean days: 3 (range: 1-17)
iii. Duration of therapy
1. Mean days: 5 (range: 3-18)
iv. Relapse of fever = 2
v. Re-hospitalization = 0
vi. Deaths = 0

Discussion:
Strengths Limitations
Inclusion of patients with ANC drops within 72 hours of Population size
chemotherapy
Two treatment regimens with similar outcomes Antibiotic choices
Re-admission criteria of 3 weeks

Authors Conclusions: In both treatment regimens, IV antibiotic discontinuation was achievable regardless of ANC or
evidence of bone marrow recovery. In this review of outcomes this goal seems safe and effective in pediatric cancer patients
with FUO if children are afebrile for at least 24 hours and are treated for a minimum of 72 hours. However, only the overall
evaluation of inpatient treatments with short and long antibiotic courses and of outpatient management within the scope of
a large randomized study will allow a final judgment about safety, efficacy and the reduction in cost of the different
strategies.

Personal Conclusions: This study supported the discontinuation of IV antibiotic therapy in patients classified as FUO
regardless of ANC when patients were afebrile for >24 hours and were treated for a minimum of 72 hours with IV
antibiotics. No death or major complication occurred and none of the patients were re-hospitalized for recurrent fever or
infection. The treatment strategy outlined in this study potentially provided patients and their families with improved
quality of life resulting from shorter hospital stays, decreased treatment costs, and the reduced impact of antibiotic overuse.
The antibiotics chosen are not used in recent practice making the study less generalizable to current therapy. The use of
fever and treatment duration as discharge criteria without evaluating bone marrow recovery could be controversial in most
institutions however the positive outcomes of the study do provide support for this form of management.

FN = Febrile Neutropenia FUO=Fever of Unknown Origin ANC=Absolute Neutrophil Count

IV=Intravenous
 Varughese 11

Table 9: Review of Study by Mueller et al.

Hospital Discharges for Fever and Neutropenia in Pediatric Cancer Patients: United States
Mueller EL, Walkovich KJ, Mody R, Gebremariam A, and Davis MM. BMC Cancer. 2015;15:388.

Background: Hospital utilization patterns for fever and neutropenia are poorly described. Despite the fact that
hospitalizations for FN are common among pediatric cancer patients, recent data is limited regarding hospitalizations for
pediatric FN at the national level. No aggregate evaluation of hospitalizations for FN in pediatric cancer patients across the
United States has been published. A more comprehensive understanding of those patients with a short LOS may help inform
future research aimed at decreasing the need for hospitalization of pediatric FN patients at low risk for serious
complications.

Methods:
1. Objective:
a. The purpose of this study was to characterize discharge criteria for pediatric cancer patients admitted non-
electively and discharged with a diagnosis of fever and neutropenia, across the United States.
b. The authors hypothesized that a substantial portion of pediatric cancer admissions would have a SLOS
with few serious infections and qualified encounters could lead to interventions for future out patient
management.
2. Study Design:
a. Retrospective chart review of the KID, an all-payer US hospital database, for 2009.
i. The KID is a nationally representative database compiled by the Agency for Healthcare Research
and Quality.

Inclusion Exclusion
Age < 19 years Age > 19 years
Admit type: urgent or emergent Non-emergent admit
ICD-9 Codes: Fever& Neutropenia [or decreased White Inaccurate Codes
Blood Cell Count]
Non-transferred patients

3. Data Collected:
a. Identified FN patient discharges associated with a relatively short, uneventful inpatient course and to
assess variables associated with these discharges.
i. These discharges associated with a SLOS would be potential candidates for future outpatient
management strategies
4. Outcomes:
a. Primary:
i. Frequency of discharges with a SLOS defined as < 3 days in order to capture all hospitalizations
that would have lasted 48 hours or less
1. This threshold was selected because of the clinical relevance of negative blood cultures at
48 hours
b. Secondary:
i. Population-adjusted frequency of discharges
ii. Mean LOS
iii. Mean and total hospital charges per discharge for FN
5. Data Analysis:
a. Descriptive statistics were used for gender, age, race, ethnicity, payer, hospital teaching status and location,
and hospital census region
b. A weighted multivariate logistic regression model was used to estimate factors associated with SLOS for
pediatric cancer patient encounters for FN
i. The authors hypothesized that socio-demographic and hospital level factors may influence
admission and/or discharge decision making based on resources of the individual and within the
community
Results:
6. Characteristics of the Study Population:
a. Appendix D (Table 1): Characteristics of discharges for non-transferred pediatric cancer patients: overall
and for FN discharges
 Varughese 12

i. Age: majority were 0-9 years of age

ii. Sex: predominately male
iii. Ethnicity: non-Hispanic white race.
iv. Insurance: most FN patients were insured
b. In 2009 there were a total of 7,370,203 weighted pediatric discharges in the United States
i. 1.5% (n=110,967) were associated with a diagnosis of cancer
ii. 49% of pediatric patients were admitted non-electively and coded at either urgent or emergent
iii. 19.3% of non-elective pediatric cancer discharges met criteria for FN
7. Outcomes
a. Primary:
i. Frequency of discharges with a SLOS defined as < 3 days
1. 41% of patients were discharged at < 3 days
2. 33% were discharged within 4 to 7 days
3. 16% were discharged within 8 to 14 days
4. 7% were discharged within 15 to 30 days
5. 3% were discharged after 31 days
b. Secondary:
i. Appendix D Table 1: Population-adjusted frequency of discharges
1. Occurred at a rate of 13.4 per 100,000 US children each year using national Census data
for 200916
ii. Appendix D Table 2: Mean and total hospital charges per discharge for FN
1. Charges were adjusted from 2009 to 2014 using the Consumer Price Index17
2. The overall mean hospital charge for a pediatric cancer patient discharge for FN was
$52,160 and total costs was $587.3 million
3. FN discharges with a SLOS accounted for ~$66 million of the total costs
iii. Appendix D Table 3: Comparison of proportion of infectious diagnoses by LOS category among
pediatric cancer FN discharges
1. No infections were identified in ~76% of patients
2. Occurrences of pneumonia, blood stream, and urinary tract infections increased with LOS
iv. Appendix D Table 4: Multivariate logistic regression to evaluate factors associated with a Short
LOS (3 days) among pediatric cancer fever and neutropenia discharges
1. Age categories of 0 to 4 and 5 to 9 were associated with shorter lengths of stay
2. Acute otitis media and viral infections were also associated with shorter lengths of stay
Discussion:
Strengths Limitations
Utilization of national database No data on antibiotic regimens used
Population Size Categorization of Shortened Length of Stay
Non-transferred patients Accuracy of ICD-9-CM codes
Analysis of variables Admission information unavailable
Updated with 2012 study

Summary of 2012 Study Update:15

Outcomes:
a. Average charge for a SLOS was $17,437
b. Average LOS for FN discharges was 7.5 days and 39% of discharges had a SLOS (n=5230).
c. SLOS discharges accounted for $91.2 million in charges for 2012

Authors Conclusions: Identification of the burden of FN is a key step in the process of developing awareness and
motivation for a multi-center or national study to improve care of pediatric cancer patients experiencing FN. This study
demonstrates the substantial impact on healthcare of pediatric oncology patients with discharges for FN. Discharges with a
short LOS would be potential candidates for future outpatient management strategies.

Personal Conclusions: The authors of this study provided significant data that can be used to limit/eliminate hospital
length of stay for FN patients who are low-risk. There is clearly a financial burden associated with unnecessary hospital stay
but also an increased risk for patients to develop hospital acquired infections. The results of this study were updated with a
2012 study that provided similar data with a continuing climb of healthcare costs related to FN LOS. Both studies suggest
that hospitals and practitioners should objectively analyze and risk stratify their patients to determine if the patient
requires hospital admission or if outpatient management may be more appropriate.
 Varughese 13

SLOS = Shortened Length of Stay LOS = Length of Stay FN=Fever and Neutropenia
KID = Kids Inpatient Database

V. Conclusion
A. Application to Patient Case12,15
i. The continued documentation of the burden of FN will be key in expanding awareness and increasing
motivation for a larger study to improve the care of pediatric oncology patients.
ii. Prospective randomized studies could determine if use of objective criteria in addition to clinical
judgment could increase the number of children who can safely have intravenous antimicrobial
therapy discontinued while still neutropenic.
B. Summary
i. Requiring admission for all patients with febrile neutropenia creates a significant impact in our
healthcare system.
ii. By appropriately risk stratifying based on the patient, episode, and treatment factors we can reduce
the number of patients that are admitted and started on IV antimicrobials.
iii. By revising our outlook on ANC goals for antimicrobial discontinuation/de-escalation we can
decrease the overuse of parenteral antimicrobials.
iv. Benefits of limiting the duration of therapy:11
1. Decreasing the emotional, social, and financial burdens associated with prolonged
hospitalization and extended antimicrobials regimens
2. Decreasing the risk of antimicrobial-related adverse effects and toxicities
3. Possibly decreasing the risk of secondary infection with organisms that are resistant to the
antimicrobials that were used for empiric treatment of febrile neutropenia
C. Future Research
i. Appendix E: Stern et al. Intervention Protocol: Early discontinuation of antimicrobials for febrile
neutropenia versus continuation until neutropenia resolution
1. Objective: To assess the safety of protocol-guided discontinuation of antimicrobials
regardless of neutrophil count compared to continuation of antimicrobials until neutropenia
resolution in cancer patients with fever and neutropenia, in terms of mortality and
morbidity.
D. Recommendations for discontinuation/de-escalation of anti-microbial therapy
i. Institutions should implement criteria for risk stratification to differentiate between high and low
risk patients.
ii. Institutions should incorporate criteria for discontinuation/de-escalation of antimicrobial therapy
based on the following parameters
1. Afebrile period of 24 hours
2. Negative cultures at 48 hours
3. Absolute neutrophil count
a. Low risk population: ANC > 100 cells/microL
b. High risk population: ANC > 200 cells/microL
4. No signs or symptoms of infection
 Varughese 14

References

1. Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, et al. Guideline for the management of fever and
neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J ClinOncol.
2012;30(35):4427-38. doi: 10.1200/JCO.2012.42.7161.
2. Schwartzberg LS. Neutropenia: etiology and pathogenesis. Clin Cornerstone. 2006;8 Suppl 5:S5-11.
doi:10.1016/S1098-3597(06)80053-0.
3. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA et al. Clinical practice guideline for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america.
Clin Infect Dis. 2011;52(4):e56-93. doi: 10.1093/cid/cir073.
4. Ziino O, Tucci F, and Rossi MR. Outpatient management of febrile neutropenia in children with cancer. Pediatr Rep.
2011;3(1): e8. doi: 10.4081/pr.2011.e8.
5. Kanamaru A, Tatsumi Y. Microbiological data for patients with febrile neutropenia. Clin Infect Dis. 2004;39 Suppl 1:S7-
S10.
6. Rackoff WR, Gonin R, Robinson C, Kreissman SG, Breitfeld PB. Predicting the risk of bacteremia in children with fever
and neutropenia. J Clin Oncol. 1996;14: 919 924. doi: 10.1200/jco.1996.14.3.919. Abstract.
7. Alexander SW, Wade KC, Hibberd PL, Parsons SK. Evaluation of risk prediction criteria for episodes of febrile
neutropenia in children with cancer. J Pediatr Hematol Oncol. 2002;24: 38 42.
8. Rondinelli PI, Ribeiro Kde C, de Camargo B. A proposed score for predicting severe infection complications in children
with chemotherapy-induced febrile neutropenia. J Pediatr Hematol Oncol. 2006;28: 665 670. doi:
10.1097/01.mph.0000212996.94929.0b.
9. Santolaya ME, Alvarez AM, Becker A, et al. Prospective, multicenter evaluation of risk factors associated with invasive
bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol. 2001;19: 3415 3421. doi:
10.1200/JCO.2001.19.14.3415.
10. Ammann RA, Hirt A, Lthy AR, Aebi C. Identification of children presenting with fever in chemotherapy-induced
neutropenia at low risk for severe bacterial infection. Med Pediatr Oncol. 2003; 41: 436 443. doi:
10.1002/mpo.10320.
11. Ammann RA, Bodmer N, Hirt A , et al. Predicting adverse events in children with fever and chemotherapy-induced
neutropenia: The prospective multicenter SPOG 2003 FN study. J Clin Oncol. 2010; 28: 2008 2014. doi:
10.1200/JCO.2009.25.8988.
12. Hodgson-Viden H, Grundy PE, Robinson JL. Early discontinuation of intravenous antimicrobial therapy in pediatric
oncology patients with febrile neutropenia. BMC Pediatr. 2005;5(1). doi: 10.1186/1471-2431-5-10.
13. Lehrnbecher T1, Stanescu A, Khl J. Short courses of intravenous empirical antibiotic treatment in selected febrile
neutropenic children with cancer. Infection. 2002;30(1):17-21.
14. Mueller EL, Walkovich KJ, Mody R, Gebremariam A, and Davis MM. Hospital Discharges for Fever and Neutropenia in
Pediatric Cancer Patients: United States, 2009. BMC Cancer. 2015;15:388. doi: 10.1186/s12885-015-1413-8.
15. Mueller EL, Croop J, Carroll AE. Fever and neutropenia hospital discharges in children with cancer: A 2012 update.
Pediatr Hematol Oncol. 2016;33(1):39-48. doi: 10.3109/08880018.2015.1102998.
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17. Consumer Price Index Inflation Calculator. [http://data.bls.gov/cgi-bin/cpicalc.pl]
 Varughese 15

VI. Appendices

Table 1: Institution Based Management Recommendations:

What antimicrobials do
you use empirically?
Ann & Robert H. Lurie Ceftazidime central line: consider ceftriaxone +
Children's Hospital of
Chicago Zosyn if presenting with
(Chicago, IL) abdominal symptoms
Arnold Palmer Medical
Center Cefepime high risk for MRSA or if patient has
(Orlando, FL)
Cefepime Vancomycin for patients with high
Childrens Colorado
AML patients will also get dose Ara-C), add fungal coverage if
(Aurora, CO)
empiric antifungal with
voriconazole
AML/Relapsed ALL in
induction/MRSA: Cefepime
The Childrens Hospital
+ vancomycin (24 hour
of Philadelphia
rule-out) + gentamicin
(Philadelphia, PA)
What is your When do you narrow
When do you broaden your Do you have a
antifungal of and/or discontinue
coverage? FN pathway?
choice? antimicrobials?
Ill appearing and CV stable with Stop vancomycin or
second gram stain
vancomycin negative after 48 hours
Micafungin Available
CV unstable: ceftazidime + Stop ceftazidime after
tobramycin + vancomycin count recovery
Add Micafungin if
Add vancomycin if patient has a
patient remains
Varies based on
febrile after 3-5 No
persistent fever at 48-72 hours physician
days on cefepime/
with no source
vancomycin
Depends on chemo
regimen, usually
ends up being
voriconazole or if
risk for S. viridans (IE s/p high Afebrile
we cannot get an In Progress
azole due to drug
febrile for >4/5 days, add flagyl if ANC >100 (>150 if AML)
interactions then
concern for typhilitis
micafungin (issues
with prophylaxis
breakthrough)
Liposomal
If not improving then consider Continue cefepime until
amphotericin B or Available
empiric antifungal therapy count recovery
caspofungin

May add vancomycin/gentamicin Stop vancomycin at

The Childrens Hospital
of San Antonio
(San Antonio, TX)
Childrens Mercy
Hospital
(Kansas City, MO)
based on protocol criteria If febrile at >96 cultures negative x48
Cefepime hours add hours In Progress
If abdominal symptoms switch micafungin therapy Afebrile X24 hours
from cefepime to Zosyn ANC rising
Voriconzole (at 5-6
Discharge to home if
days) unless drug
Add vancomycin in 2-3 days (with afebrile for 24 hours and
interactions; then
Cefepime a 48 hour rule-out infection) cultures negative for 48 No
either micafungin
hours
or liposomal
amphotericin B
 Varughese 16

Childrens Minnesota
Cefepime See treatment guidelines Micafungin If clinically stable Available
(Minneapolis, MN)
Micafungin (when
Connecticut Childrens
Add vancomycin if concern for no CNS concern); if
Hospital Zosyn Practitioner dependent No
MRSA or Streptococcus viridans CNS concern then
(Hartford, CT)
use ambisome
Negative cultures
Nicklaus Childrens Cefepime +/- vancomycin Escalate cefepime to meropenem if
Afebrile for 5 days
Hospital (48hr rule-out) remains febrile Micafungin In Progress
Clinically stable
(Miami, FL)
Negative cultures at 48
hours
Norton Childrens Cefepime Voriconazole/
With mucositis add vancomycin Afebrile for 24 hours Available
(Louisville, KY) caspofungin
Evidence of marrow
recovery
Discontinue once ANC
Seattle Childrens Ceftazidime >200 and patient is
If hemodynamically unstable then Based on fungal
Hospital If AML post high-dose ARA- afebrile for 24 hours and Available
add vancomycin and gentamicin infection guidelines
(Seattle, WA) C then Cefepime blood cultures are
negative at 48 hours
Afebrile for 24 hr
Low Risk: Ceftazidime If fever continues Negative blood culture
If febrile > 48 hrs Add vancomycin
on antibiotics for > for 48hrs
Texas Childrens Hospital
High Risk: Vancomycin+ 5 days begin No signs of focal Available
(Houston, TX) Or consider changing medications
Piperacillin/tazobactam + antifungal agents infection
if already on triple antibiotics
Gentamicin ANC > 100/mm and
climbing
Discontinue vancomycin
Add vancomycin if mucositis or and gentamicin if
cellulitis or history of high-dose cultures are negative
cytarabine after 48 hours
Ceftriaxone at presentation
VCU Health
Not answered Available
(Richmond, VA) If septic: cefepime + vancomycin + Discontinue all
Cefepime if neutropenic
gentamicin antibiotics if cultures are
OR negative to date,
Meropenem + vancomycin afebrile, and ANC is
trending upward
 Varughese 17

Appendix B:
Table 1: Episodes of febrile neutropenia by diagnosis in 275 pediatric oncology patients11 (Abbreviated)
Diagnosis Number of patients Number of patients Mean number of Range of number of
(%) with FN episodes episodes per patient episodes per patient
(%)
Osteogenic sarcoma 8 (3%) 7 (87%) 3.13 07
Ewings sarcoma 5 (2%) 4 (80%) 2.20 05
Rhabdomyosarcoma 15 (5%) 11 (79%) 1.93 06
Hepatoblastoma 9 (3%) 5 (56%) 1.22 05
Acute myeloid 16 (6%) 7 (44%) 1.00 05
leukemia (AML)
Neuroblastoma 23 (8%) 11 (48%) 0.83 05
Non-Hodgkin's 24 (9%) 14 (58%) 0.75 04
lymphoma
Acute lymphoblastic 85 (31%) 41 (48%) 0.73 07
leukemia (ALL)
Others * 22 (8%) 9 (41%) 0.41 03
Hodgkin's lymphoma 25 (9%) 8 (32%) 0.36 05
Central nervous 26 (9%) 7 (27%) 0.23 03
system tumors
Wilms tumor 17 (6%) 3 (18%) 0.12 01
Total 275 127 (46%)
*adrenocortical carcinoma, epithelial tumor, juvenile myelomonocytic leukemia, Langerhans cell histiocytosis, small cell
tumor, teratoma

Table 2: Incidence of proven bacterial or viral infections11

Type of infection Age 01 year, n = 40 Age 24 years, n = 91 Age 5 years, n = 145
Viral infection 2 (5%) 6 (7%) 7 (5%)
Bacterial infection 9 (23%) 17 (19%) 18 (12%)
Cultures negative 29 (73%) 68 (75%) 120 (83%)
n = number of episodes of FN in this age range

Table 3: Hematologic parameters when antibiotics were discontinued and at discharge in pediatric oncology patients
with FN with negative cultures at admission11
Median Range Number (%) Number (%) Number (%)
<100 cells/mm3 100500 cells/ > 500 cells/
cells/mm3 cells/mm3
ANC when antibiotics 400 034900 28 (14%) 84 (42%) 87 (44%)
discontinued
(n = 199)
Monocyte count when 400 04400 20 (10%) 117 (59%) 62 (31%)
antibiotics
discontinued
(n = 199)
APC when antibiotics 800 039300 13 (7%) 56 (28%) 129 (65%)
discontinued
(n = 199)
ANC at discharge 500 042200
(n = 194)
n = number of episodes of FN; ANC absolute neutrophil count; APC absolute phagocyte count
 Varughese 18

Appendix C:
Table 1: Clinical outcome in patients with fever of unexplained origin (FUO)12
Initial therapy Imipenem(n = 41) Ceftazidime/teico- planin Total group (n = 84)
group (n = 43)
No modification required 27 30 57
Afebrile within first 72 24 23 47
hours
Afebrile > 72 hours 3 7 10
Modification required* 14 13 27
Subsequent antibiotic 14 12 26
regimen
Other antibiotic modification 1 1 2
Addition of antifungal agents 5 5 10
Addition of antiviral agents 0 1 1
Duration of fever, mean 3 (110) 3 (117) 3 (117)
(range) days
Duration of therapy, mean 5 (313) 5 (318) 5 (318)
(range) days
Relapse of fever 1 1 2
Re-hospitalization 0 0 0
Deaths 0 0 0
* Some patients had more than one change of therapy (e.g. change of antibiotics, addition of antifungal or antiviral agent)

Appendix D:
Table 1: Characteristics of discharges for non-transferred pediatric cancer patients: overall and for fever and
neutropenia (FN) discharges United States, 200913 (Adapted)
Proportion of overall pediatric cancer Proportion of pediatric FN
discharges discharges
% (95 % CI)
Patient characteristics
Gender
Female 45.0 (44.245.8) 46.5 (45.048.0)
Age
04 years 28.9 (27.830.0) 36.7 (34.638.8)
59 years 22.0 (21.222.7) 27.9 (26.629.3)
1014 years 21.3 (20.622.0) 18.2 (17.019.5)
1519 years 27.8 (26.629.1) 17.2 (15.818.7)
Race/Ethnicity
White 48.4 (44.252.7) 55.7 (50.560.9)
Black 9.7 (8.411.2) 7.1 (5.78.7)
Hispanic 21.2 (17.725.3) 17.1 (13.621.3)
Asian/pacific islander 7.9 (6.79.4) 7.6 (6.09.4)
Type of cancer
ALL 24.6 (23.525.8) 44.3 (41.647.0)
Bone cancer 12.8 (12.013.6) 10.4 (9.112.0)
CNS tumor 9.6 (8.810.4) 6.2 (5.17.5)
AML 5.9 (5.56.3) 7.4 (5.99.1)
Soft tissue sarcoma 5.1 (4.75.6) 4.6 (3.95.4)
Neuroblastoma 4.5 (3.95.1) 4.7 (3.76.0)
Hodgkin lymphoma 3.2 (2.93.5) 2.9 (2.53.4)
Wilms tumor 2.7 (2.53.0) 3.0 (2.53.6)
NonHodgkin lymphoma 2.6 (2.32.9) 3.6 (3.14.3)
Ovarian or testicular tumor 1.7 (1.51.9) 0.7 (0.51.0)
 Varughese 19

Table 2: Mean charges for pediatric cancer fever and neutropenia discharges: overall and by length of stay category -
United States, 200913
Mean charges Total charges
Overall $52,160 $587,398,210
Length of stay category
3 days Short LOS $14,549 $67,296,971
47 days $33,423 $125,499,734
814 days $72,552 $128,683,775
1530 days $166,316 $128,267,528
>30 days $412,730 $138,805,796

Table 3: Comparison of proportion of infectious diagnoses by LOS category among pediatric cancer FN discharges13
Overall LOS category
Short LOS 4-7 days 8-14 days 15-30 days 31+ days
3 days
Proportion (%)
Proportion of FN DCs 41 33 16 7 3
No infection identified 75.9 82.7 77.3 66.9 62.7 44.4
Type of infection
Upper respiratory infection 5.4 6.0 5.6 4.0 4.3 5.3
Acute otitis media 2.9 3.7 2.3 2.3 2.2 3.3
Bloodstream infection 10.4 3.1 9.5 20.8 23.9 35.6
Viral infection 2.3 3.1 2.3 1.6 0.2 0
Urinary tract infection 1.9 1.1 2.4 2.2 2.5 4.6
Pneumonia 1.2 0.3 0.6 2.3 4.1 6.8

Table 4: Multivariate logistic regression to evaluate factors associated with a Short LOS (3 days) among pediatric
cancer fever and neutropenia discharges13
Factors Adjusted odds ratio (OR) 95% CI P-value
Gender
Female 1.06 1.021.10 0.006
Age
1519 years Ref
1014 years 1.06 0.991.13 0.076
59 years 1.20 1.111.30 <0.001
04 years 1.08 1.011.15 0.029
Type of infection
Upper respiratory infection 1.07 0.971.18 0.165
Acute otitis media 1.26 1.101.44 0.001
Bloodstream infection 0.21 0.180.24 <0.001
Viral infection 1.82 1.552.15 <0.001
Urinary tract infection 0.44 0.390.50 <0.001
Pneumonia 0.27 0.220.32 <0.001
Type of cancer
ALL 0.84 0.780.89 <0.001
Bone cancer 0.77 0.710.85 <0.001
Central nervous system tumor 0.99 0.921.07 0.787
AML 0.40 0.360.45 <0.001
Soft tissue sarcoma 1.25 1.131.37 <0.001
Neuroblastoma 0.56 0.480.66 <0.001
Hodgkin lymphoma 1.66 1.451.91 <0.001
Wilms tumor 0.59 0.520.68 <0.001
Non-Hodgkin lymphoma 0.46 0.390.54 <0.001
Ovarian or testicular tumor 0.63 0.520.76 <0.001
 Varughese 20

Controlled for Race; CI=Confidence Interval, ALL=Acute Lymphoblastic Leukemia; AML=Acute Myelogenous Leukemia;
Type of Infection and Type of Cancer are presented as dichotomous variables

Appendix E

Intervention Protocol: Early discontinuation of antibiotics for febrile neutropenia versus continuation until
neutropenia resolution.
Stern A, Carrara E, Yahav D, Leibovici L, et al. Cochrane Database of Systematic Reviews. 2016.

Objective
To assess the safety of protocol-guided discontinuation of antibiotics regardless of neutrophil count, compared to continuation
of antibiotics until neutropenia resolution in cancer patients with fever and neutropenia, in terms of mortality and morbidity.
To assess the emergence of resistant bacteria in patients treated with short courses of antibiotic therapy compared with
patients treated until resolution of neutropenia.

Currently there is no consensus between different practice guidelines with regards to the duration of antibiotic therapy.
Recommendations are variable and sometimes imprecise, leaving clinicians in doubt regarding the appropriate course of
management.

Methods
Criteria for considering studies for this review:
1. Studies:
a. Randomized control trials
2. Participants
Inclusion
Adults and children with fever and neutropenia caused by cancer-related chemotherapy, treated with any antibiotic
regimen Fever of unknown origin: single oral temperature higher than 38.3C or higher than 38.0C sustained >1 hour
Neutropenia: ANC <500 cells/mm3
Clinically documented infections
Microbiologically documented infections
3. Outcome Measures
a. Primary: Thirty-day all-cause mortality; if all-cause mortality is not available at 30 days, we will use the time
point reported by the study and document it
b. Secondary:
i. Fever days, defined as the number of consecutive febrile days (starting from the beginning of the
febrile neutropenia episode or as defined by study)
ii. Total antibiotic days during follow-up/hospitalization, including initial antibiotic course and any
subsequent antibiotic therapy initiated after randomization
iii. Clinical failure, as defined in study.
iv. Any bacteremia developing after the time point defined for the short-course antibiotic arm or after
randomization and during the follow-up period
v. Any documented infection diagnosed after the time point defined for the short-course antibiotic arm
or after randomization and during the follow-up period
vi. Any invasive fungal infection diagnosed after randomization (including invasive candida infections,
any mold infection and others as defined by study)
vii. Clostridium difficile infections diagnosed after randomization
viii. MDR acquisition, defined as any isolation of a resistant pathogen after randomization, including
methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and
multidrug-resistant Gram-negative (MDR GN), as defined in study
ix. Secondary infections caused by bacteria resistant to the initial antibiotic treatment, as defined in
each trial
x. Number of hospitalization days
xi. Any need for chemotherapy delay as reported in study
4. Subgroup analysis and investigation of heterogeneity
a. Adult patients versus children (adults defined as 18+ years).
b. Documented infection (clinically or microbiologically) versus fever of unknown etiology.
c. High-risk patients versus low-risk patients, preferably defined by MASCC score, but we will accept and
document the study definitions.
d. Solid tumor patients versus hematologic malignancy patients
 Varughese 21

e. Severity of neutropenia (ANC < 100 versus 100 < ANC < 500), referring to the lowest ANC count documented
(nadir of neutropenia).