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Management of Fever and Neutropenia - Pediatric - Inpatient/Ambulatory/Emergency Department

Management of Fever and Neutropenia - Pediatric - Inpatient/Ambulatory/Emergency Department - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Oncology


1
Management of Fever and Neutropenia –
Pediatric – Inpatient/Ambulatory/Emergency
Department – Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 3
METHODOLOGY ...................................................................................................................... 4
DEFINITIONS AND ABBREVIATIONS: .................................................................................... 4
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS .............................................................................................................. 5
TABLE 1. CRITERIA FOR RISK STRATIFICATION OF CHILDREN WITH FEVER AND
NEUTROPENIA ......................................................................................................................... 6
UW HEALTH IMPLEMENTATION ............................................................................................14
APPENDIX A. SUMMARY OF KEY PRACTICE RECOMMENDATIONS .................................15
APPENDIX B. EVIDENCE GRADING SCHEME ......................................................................19
REFERENCES .........................................................................................................................20
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2
Contact for Changes:
Name: Joshua Vanderloo, PharmD, BCPS
Phone Number: 608-890-5931
Email Address: JVanderloo@uwhealth.org
Contact for Content:
Name: Erin McCreary, PharmD, BCPS
Phone Number: (608) 263-1283
Email Address: emccreary@uwhealth.org
Guideline Author:
Erin McCreary, PharmD, BCPS
Coordinating Team Members:
Joshua Vanderloo, PharmD, BCPS; Drug Policy Program
Review Individuals/Bodies:
Monica Bogenschutz, PharmD, BCPS, BCPPS
James Conway, MD, FAAP
Sheryl Henderson, MD, PhD
Inga Hofmann, MD
Margo Hoover-Regan, MD
Nicole Lubcke, PharmD, BCOP
Joseph McBride, MD
Jessica Poehls, PharmD, BCPPS
Joshua Ross, MD
Lucas Schulz, PharmD, BCPS (AQ-ID)
Jill Strayer, PharmD, BCPS
Meghann Voegeli, PharmD, MS
Committee Approvals/Dates:
Pediatric Clinical Operations Committee: March 2017
Pediatric Infectious Diseases Division: March 2017
Antimicrobial Use Subcommittee: April 2017
Pediatric Emergency Medicine Team: April 2017
Pharmacy & Therapeutics Committee: May 2017
Release Date: May 2017
Next Review Date: May 2019
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3
Executive Summary
Guideline Overview
This clinical practice guideline has been organized to guide the assessment, management and
monitoring of pediatric patients with fever and neutropenia. These recommendations have been
adopted from nationally published clinical practice guidelines and other pertinent primary
literature.
Key Practice Recommendations
1. Information on initial presentation of children with fever and neutropenia, as well as how
to triage children for outpatient (low-risk) or inpatient (high-risk) management, can be
found in Section 1.
2. Initial treatment of fever and neutropenia in high-risk patients (those requiring
hospitalization for treatment) can be found in Section 2.
3. Initial treatment of fever and neutropenia in low-risk patients (those appropriate for
outpatient treatment) can be found in Section 3.
4. General considerations for fever and neutropenia can be found in Section 4.
5. The ongoing management of fever and neutropenia in high-risk children can be found in
Section 5.
6. The treatment approach for children with persistent fever can be found in Section 6.
Companion Documents
1. Intravenous Administration of Formulary Medications – Neonatal/Pediatric –
Inpatient/Ambulatory
2. Management of Neutropenic Fever – Adult – Inpatient/Ambulatory
Scope
Disease/Condition
Pediatric patients with suspected or confirmed fever and neutropenia in the emergency
department or inpatient setting.
Clinical Specialty
This guideline may be used by any clinician treating a patient with fever and neutropenia,
including but not limited to those that practice within: oncology, hematology, bone marrow
transplant (BMT), infectious disease, and emergency medicine physicians, nurses, and
pharmacists including inpatient services, ambulatory clinics, and the emergency department.
Intended Users
Physicians, Advanced Practice Providers, Pharmacists, Nurses
Objectives
The objective of this guideline is to guide risk stratification, empiric management, and definitive
treatment of pediatric patients with suspected or confirmed fever and neutropenia in the
emergency department or inpatient setting in order to facilitate prompt and evidence-based
interventions while minimizing treatment variability and improving patient outcomes.
Target Population
Pediatric inpatients and outpatients who have received chemotherapy for the treatment of
malignancy and who present with fever and neutropenia. Neutropenic fever is defined as an
absolute neutrophil count < 500 cells/µL and temperature ≥ 38ºC (100.4ºF).
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4
Interventions and Practices Considered
1. Risk stratification
2. Outpatient versus inpatient management
3. Empiric and definitive antibiotic treatment
4. Diagnostic imaging and culture data

Major Outcomes Considered
Appropriateness of initial evaluation and diagnostic work-up, timeliness of risk stratification and
antimicrobial administration, composite antimicrobial use, hospital length of stay, morbidity and
mortality.

Methodology
Methods Used to Collect/Select the Evidence
Electronic database searches (i.e. PUBMED) were conducted by the guideline author and
workgroup members to collect evidence for review. Search terms included: fever and
neutropenia, children, pediatrics. Hand searches were performed within selected evidence for
other relevant resources. Expert opinion, clinical experience, and regard for patient
safety/experience were also considered during discussions of the evidence.

Methods Used to Formulate the Recommendations
The workgroup members agreed to adopt recommendations developed by external
organizations and/or arrived at a consensus through discussion of the literature and expert
experience. All recommendations endorsed or developed by the guideline workgroup were
reviewed and approved by other stakeholders or committees (as appropriate).

Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations
Internally developed and externally adopted recommendations were evaluated by the guideline
workgroup using an algorithm adapted from the Grading of Recommendations Assessment,
Development and Evaluation (GRADE) methodology (see Figure 1 in Appendix A).

Rating Scheme for the Strength of the Evidence/Recommendations
See Appendix A for the rating scheme used within this document.

Recognition of Potential Health Care Disparities:
Health care disparities exist in cancer care. For example, some diagnostic and therapeutic
measures may be less available at institutions in rural areas or for underserved populations.
Additional factors that may influence outcomes include distrust of the health care system,
stigmas related to cancer and death, literacy and language barriers, and poor expectations
regarding the outcome from cancer care. Careful considerations of these disparities should be
addressed to ensure the best outcome for patients that present with fever and neutropenia.
Definitions and Abbreviations:
1. ANC: Absolute neutrophil count
1.1 (% neutrophils + % bands)*(total WBC)
2. Fever: Any oral, axillary, or temporal artery temperature ≥ 38ºC (100.4 ºF)
3. High-risk: Patients that should be hospitalized for management of fever and neutropenia
4. Low-risk: Patients that are reasonable to consider for outpatient management of fever and
neutropenia
5. Neutropenia: Absolute neutrophil count (ANC) less than 500 cells/mm
3
or an ANC expected
to decline to less than 500 cells/mm
3
within the next 48 hours
6. Profound neutropenia: ANC < 100 cells/mm
3

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5
7. Prolonged neutropenia: Anticipated duration of neutropenia greater than 7 days
8. Functional neutropenia: Any newly diagnosed leukemia or myelodysplasia

Introduction
Fever and neutropenia is a medical emergency in patients with cancer receiving chemotherapy
treatment that can result in significant morbidity and mortality.
1,2
Hematologic malignancy is the
most common form of cancer in children, making fever and neutropenia an even more common
and critical issue for pediatric patients than in adults.
3
Children receive more intensive
chemotherapy treatments, increasing the likelihood and severity of treatment-related
complications.
2,3
Most patients who develop fever during neutropenia do not have an identifiable
site of infection or definitive microbiological data to guide treatment.
1,4
Infection can progress
rapidly in neutropenic patients due to their weakened immune response, especially in young
children who have immature immune systems prior to treatment.
1,3
For these reasons, all acute
care centers should aim to administer antibiotics within one hour of presentation to any patient
that presents with fever and neutropenia.
2,5


It has been documented extensively in the literature that early use of treatment pathways results
in improved patient outcomes.
4,6,7
Regardless, significant variation in management of fever and
neutropenia in children with cancer still exists.
8,9
Lack of a validated risk stratification tool,
greater exposure to viral illnesses, the unclear role of antimicrobial therapy in certain patients,
difficulty of obtaining appropriate diagnostic cultures, and decreased availability of safe,
effective, and tolerable medications compared to adults all contribute to treatment difficulties
and variability in the pediatric population.
3,10
The objective of this guideline is to summarize
available evidence in order to guide initial and definitive treatment of fever and neutropenia in
pediatric patients receiving chemotherapy at UW Health.

Recommendations
1. Initial Presentation of Children with Fever and Neutropenia
11

1.1 Clinical features and laboratory parameters should be used to classify pediatric
patients as low- or high-risk for complications associated with fever and
neutropenia.
2,12
(UW Health moderate level of evidence, strong recommendation)
1.1.1 Standardization of clinical management via an institutionally adopted risk-
stratification tool is recommended to improve outcomes.
2

1.2 Criteria in Table 1 should be used to stratify patients into risk categories. This
table is a summary of the literature and guidelines from peer institutions and has
not been validated.
2,11-20
(UW Health moderate level of evidence, strong
recommendation)
1.2.1 It should be noted that there is not one single rule that is more effective or
reliable than others in predicting outcomes in pediatric patients. There are
no validated tools to determine the patients at highest risk of developing
complications from fever and neutropenia.
2,5



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6
Table 1. Criteria for risk stratification of children with fever and neutropenia
2,12-25

Patients are considered high risk if they meet
ONE of the following criteria in EITHER
category:
Patients are considered low risk if they meet
ALL of the following criteria in ALL
categories:

Disease-specific criteria:
• Acute lymphocytic leukemia in induction
phase
• Acute myeloid leukemia
• Aplastic anemia
• Burkitt leukemia or lymphoma
• Down syndrome with leukemia
• Hematopoietic stem-cell transplantation
within the past 6 months
• High-risk neuroblastoma
• Graft-versus-host disease

Patient-specific or clinical criteria:
• Altered mental status
• Hypotension
• Less than 12 months of age
• Receiving non-chemotherapy
immunosuppressive medications
• Respiratory distress or hypoxia
• Suspected typhilitis

Suitable for outpatient management:
• Access to acute care facility within one
hour of fever onset
• Telephone access
• Vigilant family or caregiver

Disease-specific criteria:
• No comorbidities related to the heart or
lungs
• Predicted duration of neutropenia less
than 7 days

Patient-specific or clinical criteria:
• Ability to take medication orally
• Adequately hydrated
• Clinically stable (well-appearing)
• Not currently on antibiotic therapy
except for Pneumocystic jirovecii
prophylaxis
• No GI symptoms present at fever onset
• No shaking or chills

1.3 The provider should evaluate the patient with fever and neutropenia
systematically to identify the anatomic focus of fever and to consider infectious
and non-infectious causes of fever.
2
(UW Health low level of evidence, strong
recommendation)
1.4 Blood samples for culture should be obtained prior to administering antibiotic
therapy for all patients, regardless of suspected infection source.
2,5,26

1.4.1 It is preferred that two sets of blood cultures are drawn in accordance with
the UW Health Blood Culture Collection Policy.
2
(UW Health moderate
quality evidence, strong recommendation)
1.4.1.1 It is reasonable to draw blood cultures from all lumens of
central venous catheters (CVC). Culture bottles should be
clearly labeled by lumen. (UW Health moderate quality
evidence, strong recommendation)
1.4.1.2 Providers can consider obtaining peripheral cultures.
Peripheral cultures may help diagnose CVC-related infections
by serving as a measure of differential time to positivity, which
can lead to CVC salvage for certain patients.
26

1.4.2 Obtaining blood cultures should not delay antibiotic administration in
unstable patients.
26
(UW Health moderate quality evidence, strong
recommendation)
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1.5 Consider urinalysis and urine culture in symptomatic patients only if the patient is
able to provide a clean-catch, midstream urine specimen.
2,5
(UW Health very low
quality evidence, weak/conditional recommendation)
1.5.1 Routine urinalysis and culture during initial fever and neutropenia
evaluation is controversial in pediatric patients, as pyuria is rarely
detected in pediatric patients with neutropenia and nitrite testing is less
effective in pediatric patients than older patients.
2

1.5.2 Urine collection should not delay antibiotic administration. (UW Health
moderate quality evidence, strong recommendation)
1.5.3 A catheterized urine specimen should not be obtained in patients with
suspicion of neutropenia. (UW Health moderate quality evidence, strong
recommendation)
1.6 Chest radiography (CXR) should be obtained only for patients that exhibit
respiratory signs and symptoms.
2,5
(UW Health moderate quality evidence,
strong recommendation)
1.6.1 Asymptomatic patients that do not receive a CXR have similar outcomes
to those that receive a CXR. Pneumonia is detected in fewer than 5% of
asymptomatic patients.
2

1.7 Other suspected infection sites should be cultured as clinically indicated based
on the patient’s signs and symptoms (e.g. lower respiratory tract, cerebral spinal
fluid, stool, skin, or wounds).
2,5,10
(UW Health low quality evidence, moderate
recommendation)
1.8 The first dose of empiric antibiotic therapy should be administered within one
hour of initial evaluation.
27,28
(UW Health high quality evidence, strong
recommendation)
1.8.1 Early broad-spectrum antibiotics should be started prior to the return of
culture and assay results as this has shown to decrease mortality and
morbidity.
2,5,7

1.8.2 Antibiotic administration should not be delayed if providers are unable to
obtain cultures or imaging within one hour of presentation. (UW Health
moderate quality evidence, strong recommendation)
1.8.3 It is reasonable to write orders and prepare antibiotics for patients prior to
arrival in the Emergency Department if the physician is aware the patient
is en route.
7,28
(UW Health low quality evidence, weak/conditional
recommendation)
1.9 High-risk, neutropenic patients should be admitted to the hospital.
2,7,18
(UW
Health moderate quality evidence, strong recommendation)
1.10 It is reasonable to consider low-risk, neutropenic patients for outpatient
management.
17,29,30
(UW Health moderate quality evidence, strong
recommendation)

2. Initial Treatment of Fever and Neutropenia in High-Risk Children
11

2.1 If high-risk children present to the Emergency Department and are clinically
stable, it is reasonable to administer a dose of ceftriaxone as soon as possible,
prior to the complete blood count (CBC) laboratory test results. (UW Health low
quality evidence, strong recommendation)
2.1.1 If the patient is found to be neutropenic upon CBC results, they should
receive an anti-pseudomonal β-lactam as soon as possible. (UW Health
low quality evidence, strong recommendation)
2.1.2 If the patient is found to be non-neutropenic but has received a
hematopoietic stem-cell transplantation (HSCT) within the past 6 months,
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8
is an HSCT patient receiving non-chemotherapy immunosuppressive
medications, and/or an HSCT patient with graft-versus-host disease, they
should receive an anti-pseudomonal β-lactam as soon as possible. (UW
Health low quality evidence, strong recommendation)
2.2 If high-risk children present to the Emergency Department and are clinically
unstable, they should receive an anti-pseudomonal β-lactam as soon as
possible, prior to the CBC laboratory test results. (UW Health low quality
evidence, strong recommendation)
2.3 Monotherapy with an anti-pseudomonal β-lactam should be used as empiric
intravenous antibiotic therapy in high-risk, neutropenic patients.
2,5,7
(UW Health
high quality evidence, strong recommendation)
2.3.1 Cefepime is reasonable to be used as the first-line agent.
2,7

2.3.1.1 If anaerobic infection is suspected such as neutropenic
typhlitis, metronidazole should be added.
2

2.3.2 Piperacillin-tazobactam monotherapy can be considered in patients with
an intra-abdominal source or those with suspected anaerobic infection.
2,31

2.3.2.1 Piperacillin-tazobactam has adequate anaerobic activity. It is
not necessary to add metronidazole to piperacillin-tazobactam
unless the patient has Clostridium difficile or an undrained
abscess.
2.3.2.2 It is reasonable to use piperacillin-tazobactam if cefepime is
unavailable due to market shortage or other circumstance.
2.4 It is reasonable to reserve carbapenem therapy (e.g. meropenem) for patients
with proven, documented multidrug-resistant organisms.
2,7,31,32
(UW Health
moderate quality evidence, weak/conditional recommendation)
2.4.1 For patients with a history of extended-spectrum beta-lactamase (ESBL)
producing infection, a carbapenem should be considered for empiric
therapy.
2.4.2 Meropenem has adequate anaerobic activity. It is not necessary to add
metronidazole to meropenem for any suspected infection.
2.3 Patients with a severe, non-IgE mediated reaction or an IgE-mediated β-lactam
allergy to β-lactam antibiotics should avoid β-lactam antibiotics. (UW Health
moderate quality evidence, strong recommendation)
2.3.1 It is reasonable to use aztreonam plus vancomycin as empiric
intravenous antibiotic therapy in these patients.
2

2.3.2 If anaerobic infection is suspected such as neutropenic typhlitis,
metronidazole should be added.
2

2.4 A second antibiotic with activity against Gram-negative organisms can be added
if patients are clinically unstable, a multidrug-resistant infection is suspected, or
there is a high rate of resistant pathogens in the area in which the patient is being
treated.
2,7
(UW Health moderate quality evidence, strong recommendation)
2.4.1 An aminoglycoside (e.g. tobramycin) is the preferred agent to add to the
empiric regimen in these patients.
2.4.2 If an aminoglycoside is used empirically, consider discontinuation within
24-48 hours if cultures are negative and the patient is clinically stable.
2,5

(UW Health moderate quality evidence, strong recommendation)
2.4.3 Randomized, controlled trials have demonstrated that aminoglycoside-
containing combination therapy did not improve outcomes when
compared with antipseudomonal β-lactam monotherapy for fever and
neutropenia therefore aminoglycosides should not be added unless the
patient meets the criteria in recommendation.
2,5,33

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2.5 Vancomycin should be used as part of the initial antibiotic regimen if the patient is
clinically unstable, has acute myeloid leukemia, has a history of methicillin-resistant
Staphylococcus aureus or β-lactam-resistant Streptococcus spp., or has received
high-dose cytarabine.
2
(UW Health moderate quality evidence, strong
recommendation)
2.5.1 It is reasonable to consider adding vancomycin in patients with suspicion
for catheter-related infection, skin and soft-tissue infection, grade 3 or 4
mucositis, and hospital-acquired pneumonia.
2,5
(UW Health moderate
quality evidence, moderate recommendation)
2.5.2 If vancomycin is used empirically, consider discontinuation within 24-48
hours if cultures are negative and the patient is clinically stable.
2,5
(UW
Health moderate quality evidence, strong recommendation)
2.5.3 Clinical trials demonstrated the addition of vancomycin was associated
with more adverse effects without increased treatment success and
therefore it should not be added unless patient meets the criteria in
recommendation.
34

2.6 Daptomycin or linezolid may be considered for specific clinical scenarios. (UW
Health low quality evidence, strong recommendation)
2.6.1 Considerations for daptomycin or linezolid use include a severe, non-IgE
mediated reaction or an IgE-mediated allergy to vancomycin or a
documented history of vancomycin-resistant Enterococcus spp. (VRE) or
methicillin-resistant Staphylococcus aureus with an MIC of 2 or greater.
(UW Health moderate quality evidence, strong recommendation)
2.6.2 Consider Pediatric Infectious Diseases consult in these patients.
2

2.6.3 Infectious Diseases approval should not delay daptomycin or linezolid
administration in patients for whom it is clinically indicated. (UW Health
low quality evidence, strong recommendation)
2.6.4 Daptomycin should not be used empirically for patients with clinical
suspicion for pneumonia due to inactivation of daptomycin by pulmonary
surfactant.
2.7 Patients receiving trimethoprim-sulfamethoxazole for Pneumocystis jiroveci
prophylaxis should continue to receive this medication while being treated for
fever and neutropenia.

3. Initial Treatment of Fever and Neutropenia in Low-Risk Children
11

3.1 Low-risk, neutropenic patients as identified by critiera in Table 1 should be
considered for outpatient management if they receive careful monitoring and
follow-up, as this will significantly increase health-related quality of life for
children and decrease costs.
2,7,17,30,35
(UW Health moderate quality evidence,
strong recommendation)
3.1.1 If outpatient management is chosen, the patient should have vigilant
observation and prompt access to appropriate medical care at all times.
3.1.2 A provider should follow-up with the patient within 24 hours if possible.
Follow-up should be complete within 48 hours of initial presentation. (UW
Health moderate quality evidence, strong recommendation)
3.1.3 If fever persists or recurs within 48 hours, the patient should return to an
acute care setting for hospitalization to receive broad-spectrum,
intravenous antibiotic therapy. (UW Health low quality evidence, strong
recommendation)
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10
3.2 Ceftriaxone should be administered within one hour of presentation with fever
and neutropenia for low-risk patients. This provides 24 hours of antibiotic
coverage. (UW Health moderate quality evidence, strong recommendation)
3.3 Following ceftriaxone administration, low-risk patients who are able to reliably
take oral medications should be prescribed 2-4 days of oral antibiotics to take in
the outpatient setting.
15,30,36,37
(UW Health moderate quality evidence, strong
recommendation)
3.3.1 Ciprofloxacin plus amoxicillin-clavulanate is a reasonable first-line
option.
7,17,30
It is suggested to determine insurance coverage before
ciprofloxacin is prescribed.
3.3.2 Levofloxacin is a reasonable alternative to ciprofloxacin plus amoxicillin-
clavulanate in patients with a severe, non-IgE mediated reaction or an
IgE-mediated allergy to β-lactam antibiotics.
3.3.2.1 Levofloxaxcin is also reasonable when one antibiotic is
preferred.
17

3.3.2.2 It is suggested to determine insurance coverage before
levofloxacin is prescribed.
3.3.3 Cefixime monotherapy is a reasonable alternative.
36
It is suggested to
determine insurance coverage before cefixime is prescribed.
3.3.4 It is reasonable to limit total duration of antibiotic therapy to 3-5 total days
if no source of infection is identified.
37,38

3.3.5 Systematic reviews have found that oral antibiotics are equal in terms of
efficacy and safety compared with intravenous antibiotics.
30,39

3.4 If low-risk patients are admitted to the hospital for intravenous antibiotics, early
discharge within 48 hours is recommended if they are afebrile for 24 hours or
longer, have negative blood cultures, and are clinically stable.
40-42
(UW Health
moderate quality evidence, strong recommendation)
3.4.1 It is reasonable to consider discontinuation of antibiotics at discharge for
these patients, even if neutropenia persists, if the patient has close
outpatient follow-up.
43
(UW Health low quality evidence, weak/conditional
recommendation)
3.4.2 If fever persists or recurs within 48 hours, the patient should return to an
acute care setting for hospitalization to receive broad-spectrum,
intravenous antibiotic therapy. (UW Health low quality evidence, strong
recommendation)

4. General Considerations
11

4.1 Empiric antibiotic administration should never be delayed to obtain culture data.
All initial antibiotics should be ordered “STAT.” (UW Health moderate quality
evidence, strong recommendation)
4.2 Patients with suspicion for neutropenia should never have a rectal temperature
checked or receive a rectal medication. (UW Health moderate quality evidence,
strong recommendation)
4.3 Non-steroidal antiinflammatory drugs (NSAIDs) should be avoided in all oncology
patients. (UW Health moderate quality evidence, strong recommendation)
4.4 The median time to defervescence after initiation of empiric antibiotics is five
days for hematologic malignancies and two days for patients with solid tumors.
1

4.4.1 Unexplained persistent fever in a clinically stable patient does not require
antibiotic escalation.
1,2,5
(UW Health low quality evidence, strong
recommendation)
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11
4.5 In patients who remain febrile, blood cultures should be drawn no more than
once daily.
44,45
(UW Health low quality evidence, weak/conditional
recommendation)
4.5.1 If the initial blood culture is negative, blood cultures should be drawn once
daily on day two and day three if fever persists. After day three of
persistent fever, blood cultures should only be re-drawn if there is new
culture positivity or evidence of new clinical instability in addition to
fever.
45
(UW Health low quality evidence, weak/conditional
recommendation)
4.5.2 Daily blood cultures are not recommended in afebrile patients.
44,45

4.6 All patients, regardless of antibiotic coverage, should be evaluated daily for
criteria for antibiotic use. Antibiotics should be discontinued when they are no
longer indicated.
2,5,46
(UW Health moderate quality evidence, strong
recommendation)
4.7 It is reasonable to consider narrowing or replacing initial antibiotic regimens with
targeted antibiotics based on culture and susceptibility results or identification of
focal infection associated with a known pathogen and susceptibility if duration of
neutropenia is known or anticipated 7 days or fewer.
46
(UW Health low quality
evidence, weak/conditional recommendation)

5. Ongoing Management of Fever and Neutropenia in High-Risk Children
11

5.1 Discontinue second antibiotic with Gram-negative activity and/or vancomycin 24-
48 hours after initiation for patients who experience a rapid clinical response to
empiric therapy and no microbiologic data exists to warrant the use of either
antibiotic.
1,2,7
(UW Health moderate quality evidence, strong recommendation)
5.2 Patients with a history of multidrug-resistant organisms that were initiated on
carbapenem therapy should switch to cefepime after 24-48 hours if they are
clinically stable and culture data permits de-escalation or if no microbiologic data
exists to warrant the use of a carbapenem.
2,7,31,32
(UW Health low quality
evidence, strong recommendation)
5.2.1 It is reasonable to continue carbapenem therapy in patients that remain
clinically unstable even if no microbiologic data exists. (UW Health low
quality evidence, weak/conditional recommendation)
5.3 Continue meropenem, aminoglycoside, or second antibiotic with Gram-negative
activity if a multidrug-resistant Gram-negative organism grows in culture.
5.3.1 Consider Pediatric Infectious Diseases consult in these patients.
2

5.4 Continue vancomycin if a Gram-positive organism grows in culture that is not
susceptible to a β-lactam or if the patient has a culture-negative skin and soft-
tissue infection with strong clinical suspicion for methicillin-resistant
Staphylococcus aureus.
5.4.1 Consider Pediatric Infectious Diseases consult in these patients.
2

5.5 If no source or organism is identified, antibiotics should be discontinued when
patients have been afebrile for 24 hours or longer, have negative blood cultures
for 48 hours, no focal signs of infection, and have an ANC ≥ 200 and is also
rising.
2
(UW Health low quality evidence, strong recommendation)
5.5.1 If patients do not have a diagnosis of acute myeloid leukemia,
hematopoietic stem cell transplant, or high-risk neuroblastoma then it may
be reasonable to discharge the patient on oral antibiotics even without
evidence of neutrophil recovery if they are clinically stable, afebrile for 24
hours or longer, and duration of neutropenia is anticipated 7 days or
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12
fewer. (UW Health low quality evidence, weak/conditional
recommendation)
5.5.2 Patients with a diagnosis of acute myeloid leukemia, hematopoietic stem
cell transplant, or high-risk neuroblastoma should continue on intravenous
antibiotic therapy until ANC ≥ 200 and rising. Antibiotic therapy should
stop when ANC ≥ 200 and rising. (UW Health low quality evidence,
weak/conditional recommendation)
5.6 If an organism is recovered in culture, it is reasonable to consider antibiotic de-
escalation to the narrowest, acceptable antibiotic if anticipated duration of
neutropenia is 7 days or fewer.
1,2,7
(UW Health low quality evidence,
weak/conditional recommendation)
5.6.1 Continue broad-spectrum antibiotic (e.g. cefepime) if anticipated duration
of neutropenia is 7 days or longer, even if the cultured organism is
susceptible to a narrower spectrum antibiotic. (UW Health low quality
evidence, weak/conditional recommendation)
5.7 If a source of infection is identified, antibiotics should continue for an evidence-
based duration of treatment based on the type of infection (e.g. 7 days for
hospital-acquired pneumonia) even if this duration extends beyond when an ANC
≥ 200 is achieved.
1
(UW Health low quality evidence, strong recommendation)
5.7.1 It is reasonable to treat with antibiotics until ANC ≥ 200 even if this
duration surpasses the evidence-based duration of treatment for the
identified infection.
1
(UW Health low quality evidence, strong
recommendation)
5.8 In patients who remain or become clinically unstable after initiation of empiric
antibiotics, escalate therapy to include coverage for resistant Gram-negative and
Gram-positive pathogens and anaerobic bacteria.
2
(UW Health low quality
evidence, strong recommendation)
5.8.1 Consider Pediatric Infectious Diseases consult in these patients.
5.8.2 For Gram-negative or multidrug resistant coverage, consider addition of
an aminoglycoside or switch from a β-lactam to carbapenem
monotherapy.
2

5.8.3 For Gram-positive coverage, consider addition of vancomycin if not
already present.
5.8.3.1 It is reasonable to switch from vancomycin to daptomycin if
there is suspicion for vancomycin-resistant Enterococcus spp.
or vancomycin-intermediate Staphylococcus aureus.
5.8.4 For anaerobic coverage, consider addition of metronidazole if not already
present.
5.8.5 If suspected or confirmed Clostridium difficile infection, add oral
vancomycin.

6. Approach to Persistent Fever
11

6.1 Consider a Pediatric Infectious Diseases consult in patients who have had a
persistent fever for 96 hours or longer, who have a new fever after
defervescence, and/or who are initiated on antifungal therapy. (UW Health low
quality evidence, strong recommendation)
6.2 It is not indicated to escalate antibiotic therapy in patients with persistent fever
and neutropenia that are otherwise clinically stable.
2,5
(UW Health low quality
evidence, strong recommendation)
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13
6.2.1 Persistent fever alone is not an indication for continuing or adding
vancomycin therapy.
2,5
(UW Health low quality evidence, weak/conditional
recommendation)
6.3 Fungal, viral, and non-infectious etiologies should be considered in a patient who
has been persistently febrile for 96 hours or longer.
2,47,48
(UW Health low quality
evidence, strong recommendation)
6.3.1 Patients at high risk for invasive fungal disease include patients with
acute myeloid leukemia, high-risk acute lymphoblastic leukmeia, relapsed
acute leukemia, undergoing allogenic hematopoietic stem cell
transplantation, or receiving high-dose corticosteroids.
2

6.3.2 Patients that do not meet the above criteria (6.3.1) are at low risk for
invasive fungal disease.
2,5

6.4 Empiric antifungal therapy should be initiated in patients at high risk for invasive
fungal disease who have persistent or recurrent fever after ≥ 96 hours of broad-
spectrum antibiotics and who have not had an etiology of persistent fever
identified (e.g. viral infection).
2,5
(UW Health high quality evidence, strong
recommendation)
6.4.1 Consider Pediatric Infectious Diseases consult in these patients.
6.4.2 If a patient has not been receiving antifungal prophylaxis or has been
receiving fluconazole antifungal prophylaxis, start empiric antifungal
treatment with micafungin.
49
(UW Health low quality evidence, strong
recommendation)
6.4.3 If a patient has been receiving antifungal prophylaxis with micafungin,
voriconazole, or posaconazole, start empiric antifungal treatment with
liposomal amphotericin B. (UW Health low quality evidence, strong
recommendation)
6.5 It is reasonable to withhold empiric antifungal therapy in patients at low risk for
invasive fungal disease who have persistent or recurrent fever after ≥ 96 hours of
broad-spectrum antibiotics.
2
(UW Health low quality evidence, weak/conditional
recommendation)
6.5.1 Consider Pediatric Infectious Diseases consult in these patients.
6.5.2 If empiric antifungal therapy is initiated, the choice of antifungal should
mirror the recommendations for patients at high risk for invasive fungal
disease.
6.6 Patients started on empiric antifungal therapy should receive a diagnostic work-
up for invasive fungal infection.
2,5
(UW Health low quality evidence,
weak/conditional recommendation)
6.6.1 Consider checking a serum galactomannan to evaluate for
Aspergillosis.
2,47
(UW Health low quality evidence, weak/conditional
recommendation)
6.6.1.1 The negative predictive value of serum galactomannan is high
for Aspergillosis.
6.6.1.2 A serum galactomannan test cannot identify non-Aspergillus
molds, which limits the usefulness of this test and limits the
utility of the negative predictive value.
47

6.6.1.3 The positive predictive value of blood galactomannan is poor.
A positive result should not be used alone to make a diagnosis
of an invasive fungal infection.
47

6.6.2 Serum β-D-glucan testing is not recommended in pediatric patients due to
lack of evidence for use and a poor positive predictive value to diagnose
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14
invasive fungal infection.
2,47,50
(UW Health low quality evidence, strong
recommendation)
6.6.3 A CT of the chest should be performed in any patient with strong clinical
suspicion for invasive fungal disease.
11
(UW Health low quality evidence,
strong recommendation)
6.6.3.1 If a pulmonary nodule or infiltrate is present, it is
recommended to obtain a BAL or biopsy. (UW Health low
quality evidence, strong recommendation)
6.6.4 A CT of the sinuses can be considered in patients ≥ 2 years of age with
focal findings such as facial pain.
2,11,51
(UW Health low quality evidence,
weak/conditional recommendation)
6.6.4.1 Consider not routinely performing CT of sinuses in patients
without focal signs or symptoms.
11
(UW Health low quality
evidence, weak/conditional recommendation)
6.6.5 Additional imaging is not necessary unless clinically indicated.
6.6.6 If the diagnostic work-up is negative, antifungal therapy should continue
only until ANC ≥ 200 and rising.
2
(UW Health low quality evidence, strong
recommendation)

UW Health Implementation
Potential Benefits
1. Appropriate initial evaluation and risk stratification
2. Timely initiation of effective treatment
3. Minimized treatment variability

Potential Harms
1. Side effects and adverse events associated with various medical/drug treatments
2. Failure to appropriately categorize patients as low- or high-risk

Guideline Metrics
Selection of antimicrobial agents and dose, timeliness of antimicrobial administration, hospital
admission rates, hospital length of stay, total duration of antimicrobial therapy, and clinical
outcomes including resolution of fever, morbidity, and mortality.

Implementation Plan/Clinical Tools
1. Guideline will be electronically distributed through UConnect in the dedicated location for
Clinical Practice Guidelines.
2. Release of the guideline will be advertised in the Physician/APP Briefing newsletter and
via email communication to all pharmacy staff.
3. Pertinent medication records will be updated to include a link to this guideline.
4. Content and hyperlinks within clinical tools, documents, or HealthLink related to the
guideline recommendations (such as the following) will be reviewed for consistency and
modified as appropriate.

Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.

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15
Appendix A. Summary of Key Practice Recommendations
Is the patient clinically
stable?
A,B
Emergency care, fluid resuscitation,
blood culture(s)
C
, CBC with Diff
Admit to
inpatient, See
Figure 2
Draw blood
culture(s)
C
and
CBC with Diff
Administer one dose of
ceftriaxone
D
in less
than 1 hour
E,F
Is the patient
neutropenic?
Ongoing
management
per provider
From: Management of Fever and Neutropenia – Pediatric – Inpatient/Ambulatory/Emergency Department –
Clinical Practice Guideline
Last Reviewed 6/2017; Last Updated 6/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org
Figure 1. Empiric treatment of children with fever and possible neutropenia presenting to the Emergency Department
regardless of risk status; Empiric and ongoing treatment of low-risk children with fever and neutropenia
bo
Yes
bo
Is the patient
low-risk?
See Figure 2 for
treatment of
high-risk
children with
fever and
neutropenia
Can the patient take
medication orally?
Continue
ceftriaxone and
admit for
observation
Consider discharge within 48 hours
without antibiotics if afebrile
≥ 24 hours, culture negative, and
clinically stable, irrespective of marrow
status
IgE-mediated allergy or
severe reaction to β-
lactam?
Discharge with
levofloxacin for
2-4 days
Yes
Discharge with
ciprofloxacin plus
amoxicillin-clavulanate
therapy for 2-4 days
A
Fever is defined by any temperature ≥ 38°C. Discuss
case with Pediatric Heme/Onc Fellow/Attending and
call the PICU as soon as possible. Neutropenia
defined as ANC <500.
B
Patients with suspicion for neutropenia should never
have a rectal temperature checked or receive a rectal
medication. NSAIDS should be avoided in all oncology
patients.
C
Culture all lumens of central line; peripheral culture not
required. Empiric antibiotic administration should
never be delayed to obtain culture data. All initial
antibiotics should be ordered “STAT” and administered
within one hour.
D
Consider aztreonam plus vancomycin if IgE-mediated
allergy or severe reaction to β-lactam
E
Do not wait for lab results to start antibiotics
F
Check vital signs every 15 minutes

Yes
bo
Yes
bo
Yes
bo





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16
From: Management of Fever and Neutropenia – Pediatric – Inpatient/Ambulatory/Emergency Department –
Clinical Practice Guideline
Last Reviewed 6/2017; Last Updated 6/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org
Figure 2. Empiric treatment of high-risk children with fever and neutropenia
Does the patient meet criteria for
high-risk neutropenia and/or is the
patient clinically unstable?
Use Figure 1: Low risk or non-
neutropenic
IgE-mediated allergy or severe
reaction to β-lactam?
No
Start Aztreonam and Vancomycin
Start Cefepime
History of MDRO?
Clinically
Unstable?
Indication for vancomycin?
F

Suspicion for anaerobes or
abdominal source?
Change to
meropenem
Add tobramycin
and vancomycin
Add vancomycin
Add metronidazole
(or change to piperacillin-
tazobactam if no
β-lactam allergy or reaction)
bo
Yes
Yes
F
Should add vancomycin:
• Acute myeloid leukemia
• Clinically unstable
• History of methicillin-resistant
Staphylococcus aureus
• History of β-lactam-resistant
Streptococcus spp.
• Received high-dose cytarabine
F
Consider adding vancomycin:
• Catheter-related infection
• Grade 3 or 4 mucositis
• Hospital-acquired pneumonia
• Skin and soft-tissue infection


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17
From: Management of Fever and Neutropenia – Pediatric – Inpatient/Ambulatory/Emergency Department –
Clinical Practice Guideline
Last Reviewed 6/2017; Last Updated 6/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org
Figure 3. Ongoing treatment of children with fever and neutropenia at high risk
Reassess antibiotic therapy at 24-48 hours
Only continue…
• Vancomycin: if resistant Gram-positive organism recovered or skin and soft tissue infection present
• Tobramycin: if multidrug-resistant Gram-negative organism recovered
• Meropenem: if organism not susceptible to cefepime recovered
Continue or change to
cefepime ± additional antibiotic
Persistent fever? Use Figure 4Yes
Organism recovered in
culture and/or source
identified?
Duration of neutropenia
≤ 7 days?
Diagnosis of AML,
HSCT, neuroblastoma,
or < 1 year?
Continue broad-spectrum
intravenous antibiotic(s) until
ANC ≥ 200
Consider discharge on oral
antibiotics if afebrile for at
least 24 hours, culture
negative for at least 48
hours, and clinically stable
Narrow antibiotic to
organism. Treat for duration
of infection
E
and until ANC ≥
200
Continue
broad-spectrum antibiotic(s)
for duration of infection
B
and
until ANC ≥ 200
bo
Yes
bo
bo Yes
Yes
bo
E
Day 1 for duration of infection is the
day the last positive culture was drawn,
or the day diagnostic test/imaging that
diagnosed the infection source was
performed.
Ex: pneumonia is treated for 7 days
total from CXR or respiratory culture if
ANC ≥ 200 at day 7. Continue
treatment until ANC ≥ 200 if ANC does
not recover within 7 days.

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18
From: Management of Fever and Neutropenia – Pediatric – Inpatient/Ambulatory/Emergency Department –
Clinical Practice Guideline
Last Reviewed 6/2017; Last Updated 6/2017
Contact: Erin McCreary, PharmD, BCPS; emccreary@uwhealth.org
Figure 4. Evaluation and treatment of persistent fever in children at high risk
Persistent fever
Clinically
stable?
Continue empiric
antibiotic regimen;
do not escalate
therapy
Escalate antibiotic
therapy
≥ 96 hours
since starting
antibiotics?
≥ 96 hours
since starting
antibiotics?
Continue current
antibiotic regimen
Consult Infectious Diseases
On antifungal agent other than
fluconazole?
Start micafungin
Start liposomal
amphotericin B
Diagnostic work-
up for invasive
fungal infection
NoYes
No No
YesYes


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19
Appendix B. Evidence Grading Scheme

Figure 1. GRADE Methodology adapted by UW Health


GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate
We are quite confident that the effect in the study is close to the true effect, but it
is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations For or Against Practice
Strong
The net benefit of the treatment is clear, patient values and circumstances
are unlikely to affect the decision.
Weak/conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.

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20
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22
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