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Management of Neutropenic Fever – Adult – Inpatient/Ambulatory

Management of Neutropenic Fever – Adult – Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Oncology


Management of Neutropenic Fever Guidelines 1
Management of Neutropenic Fever (NF) –
Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ...................................................................................................................................... 4
METHODOLOGY ...................................................................................................................... 4
DEFINITIONS ............................................................................................................................ 5
INTRODUCTION ....................................................................................................................... 6
RECOMMENDATIONS .............................................................................................................. 6
TABLE 1: CISNE SCORE TO IDENTIFY ADULT PATIENTS AT LOW RISK FOR MEDICAL
COMPLICATIONS ..................................................................................................................... 7
TABLE 2. OUTPATIENT MANAGEMENT OF PATIENTS WITH NF ........................................10
UW HEALTH IMPLEMENTATION ............................................................................................11
DISCLAIMER............................................................................................................................11
REFERENCES .........................................................................................................................12
APPENDIX A. DEFINITIONS OF COMPLICATIONS AND OTHER VARIABLES IN USING
THE CISNE SCORE .................................................................................................................15
APPENDIX B. EMPIRIC TREATMENT OF ADULTS WITH SUSPECTED NF PRESENTING
TO THE EMERGENCY DEPARTMENT OR ONCOLOGY CLINIC ...........................................16
APPENDIX C. ADULT NF MANAGEMENT ALGORITHM .......................................................17
APPENDIX D. ADULT PERSISTENT FEVER MANAGEMENT ALGORITHM .........................18
CPG Contact for Changes: CPG Contact for Content:
Name: Philip Trapskin Name: Lucas Schulz
Phone Number: 608-263-1328 Phone Number:
Email Address: PTrapskin@uwhealth.org Email Address: LSchulz2@uwhealth.org
Note: Active Table of Contents
Click to follow link
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Management of Neutropenic Fever Guidelines 2
Guideline Author(s):
Angela Green, PharmD
Mary Mably, RPh, BCOP
Cameron Ninos, PharmD
Lucas Schulz, PharmD, BCPS, AQ-ID
Review Individuals/Bodies:
Barry Fox, MD (Infectious Disease)
Walter Longo, MD (Medicine-Hematology/Oncology)
Alex Lepak, MD (Infectious Disease)
Ryan Mattison, MD (Hematology/Oncology)
Rory Makielski, MD (Hematology/Oncology)
Teresa Darcy, MD (Pathology)
Kurt Reed, MD (Pathology)
Andy Lee, MD (Emergency Medicine)
Kelin O’Donnell, PA (OB/Gyn Oncology)
Kendra O’Connell, RN (Chemotherapy clinic coordinator)Vicki Hubbard, RN
(Hematology, Oncology & BMT)
Ruth O’Reagan, MD (Hematology/Oncology)
Rena Shah, MD (Hematology/Oncology)
Chris D’Angelo, MD (Hematology/Oncology)
Michael Safa, MD (Emergency Medicine)
Brian Sharp, MD (Emergency Medicine)
Coordinating Team Members:
Joshua Vanderloo, PharmD
Angela Green, PharmD
Committee Approvals/Dates:
Chemotherapy Council March 2015
Laboratory Practice Committee April 2015
Antibiotic Use Committee May 2015
Pharmacy and Therapeutics Committee June 2015
Release Date:
June 2015
Next Review Date:
June 2017
Copyright © 2017 University of Wisconsin Hospitals and Clinics Authority
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Management of Neutropenic Fever Guidelines 3
Executive Summary
Guideline Overview
These clinical practice guidelines have been organized to guide the assessment,
management and monitoring of adult patients with neutropenic fever. These
recommendations have been compiled from nationally published clinical practice
guidelines.
Target Population
Adult inpatients and outpatients who have received chemotherapy for the treatment of
malignancy and who present with neutropenic fever (NF). NF is defined as an absolute
neutrophil count (ANC) < 500 cells/mm
3
or an ANC expected to decrease to < 500
cells/mm
3
within 48 hours; and temperature ≥ 38ºC (100.4ºF)
1,2

Key Revisions – Interim Update 8/2017
1. Change the preferred assessment tool for triage from the MASCC to the CISNE
score.
2. Addition of Emergency Department and Oncology Clinic triage workflow to
appendix.
Key Revisions – Interim Update 4/2017
1. Adjustment of exclusion criteria for empiric outpatient treatment for low-risk
patients.
2. Specify providers to be consulted prior to initiation of empiric outpatient
neutropenic fever treatment.
3. Specify patient follow-up for empiric outpatient neutropenic fever treatment.
4. Change the definition of fever to a single temperature ≥ 38°C.
Key Practice Recommendations
• Initial assessment and evaluation of patients presenting with neutropenic fever
with the CISNE scoring system to determine risk level and outpatient versus
inpatient management
• Initial antimicrobial selection and timing in neutropenic fever patients
o Appendix B describes adult neutropenic fever management.
• General considerations for monitoring management
• Defining duration of therapy for neutropenic fever and addition of antifungal
coverage in persistent fever
o Persistent fever management is described in Appendix C.
Companion Documents
• Beta-Lactam Allergy – Adult – Inpatient – Clinical Practice Guideline
• Antibiotics for the Treatment of Gram-Negative Infections – Adult – Inpatient –
Clinical Practice Guideline
• Renal Function-Based Dose Adjustments - Adult - Inpatient – Clinical Practice
Guideline
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Management of Neutropenic Fever Guidelines 4
Scope
Disease/Condition(s):
Adult patients with malignancy, potential neutropenic fever (NF), and confirmed NF in
the ambulatory, emergency department, or inpatient setting
NF is defined as an absolute neutrophil count (ANC) < 500 cells/mm
3
or an ANC
expected to decrease to < 500 cells/mm
3
within 48 hours; and a temperature ≥ 38ºC
(100.4ºF)
Clinical Specialty:
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, nurses, pharmacists, nurse practitioners and physician assistants
CPG objective(s):
Standardize assessment and treatment of adult patients with NF.
Target Population:
Adult inpatients and outpatients (18 years or older) who have received chemotherapy
for the treatment of malignancy and who are experiencing NF.
Interventions and Practices Considered:
Supportive care, treatment, laboratory monitoring
Major Outcomes Considered:
Administration of antibiotics within 1 hour of presentation
Initiation of vancomycin only for appropriate indications
De-escalation of antibiotics when appropriate
Reduced amount of unnecessary admissions
Guideline Metrics:
Measure impact of project implementation on selection of antibiotic agent, dose,
admission rates, length of hospital stay, duration of therapy, and outcomes
Methodology
Methods Used to Collect/Select the Evidence:
1. Recommendations for the management of neutropenic fever from the Infectious
Diseases Society of America (IDSA), the National Comprehensive Cancer Network
(NCCN), and the American Society of Clinical Oncology were evaluated for inclusion
in the guideline.
2. MEDLINE was searched using terms febrile neutropenia and neutropenic fever.
Articles were evaluated for inclusion in the guideline.
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Management of Neutropenic Fever Guidelines 5


Rating Scheme for the Strength of the Evidence/Recommendations:
1. A modified Grading of Recommendations Assessment, Development and Evaluation
(GRADE) developed by the American Heart Association and American College of
Cardiology (Figure 1) was used to assess the Quality and Strength of the Evidence
in this Clinical Practice Guideline.


Definitions
3,4

1. Fever: Oral temperature ≥ 38ºC (100.4 ºF).
2. Neutropenia: Absolute neutrophil count (ANC) < 500 cells/mm
3
or an ANC expected
to decline to < 500 cells/mm
3
within the next 48 hours
3. Profound neutropenia: ANC < 100 cells/mm
3

4. Prolonged neutropenia: Duration > 7 days
5. High-risk patients: patients with increased risk for severe infection, expected to have
prolonged and profound neutropenia, significant medical co-morbidities (uncontrolled
cancer, chronic obstructive pulmonary disease, poor functional status, or advanced
age), clinical instability (hypotension, pneumonia, new-onset abdominal pain, or
neurologic changes), acute leukemia or received induction for acute leukemia,
hematopoietic stem-cell transplant (HSCT), or have a Clinical Index of Stable Febrile
Neutropenia (CISNE) score ≥ 3.
6. Intermediate-risk patients: expected brief (≤7 days duration) neutropenia, clinically
stable, no or few comorbidities, and a CISNE score = 1 or 2
7. Low-risk patients: expected brief (≤7 days duration) neutropenia, clinically stable
(see appendix A), no or few comorbidities, and a CISNE score equal to zero.

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Management of Neutropenic Fever Guidelines 6


Introduction
Patients with chemotherapy induced neutropenia frequently present with fever. Fever during neutropenia
may be the only indication of a severe underlying infection as patients have a muted inflammatory
response and reduced signs and symptoms of inflammation.
3
Fever develops in 10%-50% of patients with
solid tumors and > 80% of patients with hematologic malignancies.
5
Clinically documented infections
occur in 20%-30% of febrile episodes, and bacteremia occurs in 10%-25% of patients.
3
Most patients who
develop fever during neutropenia do not have an identifiable site of infection or positive culture results.
3

However, infection can progress rapidly in neutropenic patients due to their attenuated immune response,
and early use of treatment management pathways results in better outcomes.
3,6
Early use of empiric
antibiotics (as opposed to waiting for microbiology results) reduces deaths from infection.
7
Clinical
practice guidelines recommend starting broad-spectrum antibiotics within one hour of documented fever
in neutropenic patients.
1


Not all patients have the same level of risk for developing severe infections and life-threatening
complications during neutropenia.
8
Studies have found that low-risk patients with NF who were treated in
an outpatient setting experienced higher quality of life and maintained similar adverse event rates,
complications, and fever duration.
9,10
Studies report similar safety and efficacy with oral empiric antibiotics
compared to intravenous (IV) antibiotics for NF in hemodynamically stable oncology patients without
organ failure, acute leukemia, severe soft tissue infection, pneumonia, or a central venous catheter
(CVC).
1

In patients with NF, risk of developing severe infectious complications should be assessed prior to
determining empiric antibiotic, route, venue of treatment (inpatient vs. outpatient), duration, and timing of
hospital discharge.
3


Recommendations
1. Initial Assessment of Adults Presenting with Neutropenic Fever
1.1 The provider should evaluate the patient with NF systematically to identify the infectious
agent and anatomic focus.
1
(Class I, Level C)
1.2 Risk assessment for complications of severe infection should be performed to determine
empiric antibiotics, route, venue, and duration of therapy.
3,11
(Class l, Level B)
1.3 It is reasonable to use the CISNE scoring system (Table 1) to select low-risk patients
possibly eligible for outpatient management and oral therapy
4,12,13
(Class Ila, Level B).
1.3.1 The CISNE score outperformed the MASCC score in identification of high-risk
patients, demonstrating a sensitivity of 77.7%; specificity of 78.4%; positive
predictive value of 36.1%; negative predictive value of 95.7% compared to the
MASCC score which had the following predictive parameters: sensitivity 34.8%;
specificity, 86.9%; PPV, 29.3%; NPV, 89.6%
4,13

1.3.2 The CISNE score demonstrated greater specificity in identification of low-risk
patients compared (98.2%) to the MASCC evaluation (54.2%)
13

1.3.3 A CISNE score equal to zero indicates low risk, and probable eligibility for
outpatient treatment
4,12,13
(Class IIa, Level B)
1.3.4 If the clinician has reservations regarding the accuracy of an index for a patient,
the patient should be cared for in the hospital. (Class I, Level C)
1.4 High and intermediate-risk patients should be admitted to the hospital
3,11
(Class l, Level
B)


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Management of Neutropenic Fever Guidelines 7


Table 1: CISNE Score to Identify Adult Patients at Low Risk for Medical Complications
Characteristic Points
ECOG PS ≥ 2
Ambulatory and capable of all self-care but unable to carry out any work activities;
up and about more than 50% of waking hours)
2
Stress-Induced Hyperglycemia
Glucose ≥ 121 mg/dL or ≥250 mg/m
2
in diabetic patient or patients receiving
corticosteroids
2
Chronic Obstructive Pulmonary Disease

1
Chronic Cardiovascular Disease

1
Mucositis NCI grade ≥ 2
At least presence of patchy ulcerations or pseudomembranes, or moderate pain with
modified diet indicated
1
Monocytes < 200 per μL 1
Scoring:

≥ 2: high risk for complications
= 1: intermediate risk for complications
= 0: low risk for complications
Abbreviations: CISNE, Clinical Index of Stable Febrile Neutropenia; ECOG PS, Eastern Cooperative
Oncology Group performance status; NCI, National Cancer Institute
Please see appendix A for full table of CISNE definitions

1.5 It is reasonable to obtain blood and body fluid samples for culture and assay before
providing the first dose of antibiotics.
1,3
(Class IIa, Level A)
1.6 At least two sets of blood cultures should be drawn.
14,15
(Class I, Level C)
1.6.1 If an existing central venous catheter (CVC) is present, it is recommended to
collect blood cultures from both lumens of the CVC, and from a peripheral vein
site.
16,17
(Class I, Level C)
1.6.2 If no CVC is present, 2 blood cultures from separate contralateral venipunctures
should be obtained.
1,3,14
(Class l, Level C)
1.7 Suspected infection sites should be cultured as clinically indicated (urine, lower
respiratory tract, cerebral spinal fluid, stool, skin, or wounds)
1,3
(Class l, Level C)
1.8 Laboratory tests: complete blood cell (CBC) count with differential, creatinine, blood urea
nitrogen, electrolytes, AST, ALT, AlkPhos, total bilirubin, albumin, and Gamma-glutamyl
transferase (GGT) should be performed.
1,3
(Class l, Level C)
1.9 If the patient has respiratory symptoms, a chest radiograph, sputum culture, or
nasopharyngeal swab to detect respiratory viruses may be considered
1,3,18,19
(Class IIb,
Level B)
1.9.1 If the patient is clinically stable, it is reasonable to consider a nasopharyngeal
swab to detect respiratory viruses (influenza, parainfluenza, adenovirus, and
RSV)
3,18
(Class IIa, Level C)
1.9.2 If the patient is critically ill and can tolerate bronchoscopy, it is reasonable to
consider a respiratory viral panel to detect human metapneumovirus.
20
(Class
IIa, Level C)
1.10 It is reasonable to give the first dose of empiric antibiotic therapy within one hour of triage
from initial presentation in the clinic, emergency room, or hospital.
1,21
(Class IIa, Level C)
1.11 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.
1
(Class I, Level A)

2. Initial Treatment of Neutropenic Fever in High-Risk Adults
2.1 Empiric IV antibiotics should include a bactericidal anti-pseudomonal β-lactam
1,3,21-23

(Class l, Level A)
2.1.1 Empiric IV antibiotics should be initiated within one hour of documented fever
(Class I, Level C)
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Management of Neutropenic Fever Guidelines 8


2.1.2 Cefepime should be used as a first-line agent
21,23-29
(Class I, Level A)
2.1.2.1 If anaerobic infection is suspected such as neutropenic typhlitis, and
cefepime is used initially, metronidazole should be added.
3,26
(Class
I, Level B)
2.1.3 Piperacillin-tazobactam monotherapy is recommended in patients with an intra-
abdominal source or those with suspected anaerobic infection.
3,30-36
(Class I,
Level A)
2.1.4 It is reasonable to reserve carbapenems for patients with proven, documented,
multi-drug resistant organisms
21,24,26,36-40
(Class IIa, Level A)
2.2 For patients with severe or immediate IgE-mediated beta-lactam allergies, beta lactams
should be avoided and the Beta-Lactam Allergy – Adult – Inpatient Guideline should be
used. (Class l, Level C)
2.2.1 Vancomycin plus ciprofloxacin or vancomycin plus aztreonam should be used.
3,41

(Class I, Level B)
2.2.1.1 If anaerobic infection is suspected such as neutropenic typhlitis or
there is suspected intra-abdominal infection, metronidazole should
be added.
3,26
(Class I, Level B)
2.3 Vancomycin should not be used as part of the initial regimen unless there is suspicion for
catheter-related infection, skin and soft-tissue infection, severe mucositis, healthcare-
associated pneumonia, or hemodynamic instability.
3,27,42-48
(Class III, Level A)
2.3.1 If vancomycin is used empirically, consider discontinuation within 48 hours if
cultures are negative
3,42,45,47-49
(Class III, Level B)
2.4 If antimicrobial resistance is suspected or proven or if complications (hypotension and
pneumonia) exist, it is reasonable to consider additional antimicrobials (aminoglycosides,
fluoroquinolones, and/or vancomycin)
3
(Class lla, Level C)
2.4.1 Vancomycin or daptomycin are reasonable options for MRSA or MRSE
3
(Class
lla, Level C)
2.4.1.1 Daptomycin may be considered if approved by infectious disease
(ID) when the patient is unable to take vancomycin, or if the patient
has a history of vancomycin-resistant enterococcus (VRE) or
documented VRE (Class IIa, Level C)
2.4.1.1.1 ID Approval should not delay therapy (Class I, Level C)
2.4.2 For patients with a history of extended-spectrum beta-lactamase (ESBL)
producing infection, a carbapenem may be considered for empiric therapy.
3

(Class lla, Level C) Once susceptibilities are known, or if no organism is
identified, antibiotic de-escalation should be considered. (Class I, Level C)
2.5 It is recommended to switch from IV to oral antibiotics when patients are clinically stable if
gastrointestinal absorption is adequate.
3,50-53
(Class l, Level A)
2.5.1 The UW Medication Route Interchange Adult Inpatient Clinical Practice Guideline
may be useful
2.6 It is reasonable for hospitalized patients who meet low-risk criteria to switch to outpatient
management with IV or oral antibiotics if adequate daily follow-up is provided
3,50,53-55

(Class lla, Level A)

3. Initial Treatment of Neutropenic Fever in Low-Risk Adults
3.1 Low-risk patients with solid tumors should be considered for oral antibiotic treatment in an
outpatient setting
3,50,53,56
(Class l, Level A)
3.1.1 It is reasonable to provide the first dose of antibiotics intravenously with
monitoring for improvement or clinical stability
3,5
(Class IIa, Level A)
3.1.2 The decision to initiate empiric outpatient neutropenic fever treatment must be
discussed with an attending physician from the oncology or hematology service
(Class I, Level C)
3.1.3 Initial empiric oral treatment with ciprofloxacin or levofloxacin plus
amoxicillin/clavulanate is recommended.
1,3,27,57,58
(Class I, Level A)
3.1.3.1 Fluoroquinolones should not be used as empiric therapy in patients
who received fluoroquinolone prophylaxis
1,3
(Class III, Level C)
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Management of Neutropenic Fever Guidelines 9


3.1.3.2 Alternative agents such as cefpodoxime might be reasonable for
those who do not tolerate amoxicillin-clavulanic acid. (Class IIb,
Level C)
3.1.4 Clindamycin is recommended in place of amoxicillin/clavulanate for patients with
severe or immediate IgE- mediated beta-lactam allergies.
1
(Class I, Level C)
3.2 For clinically stable, low-risk patients who received IV antibiotics in the hospital and
responded to therapy, early discharge with outpatient follow-up and monitoring is
recommended.
1,3,50,54,55
(Class l, Level A)
3.2.1 Outpatient management after a brief inpatient stay is recommended if fulminant
infection is excluded, the patient is clinically stable and at low or intermediate risk
for complications, cultures are available, and a family support assessment has
been completed.
10,27,58
(Class I, Level A)
3.2.1.1 If outpatient management is chosen, the patient should have vigilant
observation and prompt access to appropriate medical care at all
times.
3
(Class I, Level C)
3.2.1.2 Patients should be able to reach their medical facility within one
hour.
3
(Class I, Level C)
3.2.1.3 Patients must have transportation and a home caregiver.
3
(Class I,
Level C)
3.2.1.4 A provider should follow-up with the patient within 48 hours of
presentation to the hospital (Class I, Level C)
3.3 If fever persists after 48 hours, the patient should be re-evaluated, and broad-spectrum
IV antibiotics should be given in the hospital.
3
(Class l, Level C)

4. General Considerations for Adults
4.1 The median time to defervescence after initiation of empiric antibiotics is five days for
hematologic malignancies and two days for patients with solid tumors.
3

4.1.1 Unexplained persistent fever in a stable patient rarely requires a change in the
antibiotic regimen.
3

4.2 Initial regimens should be replaced with targeted antibiotics based on culture and
susceptibility results or identification of focal infection associated with a known pathogen
and susceptibility.
1
(Class I, Level C)
4.3 Antibiotic coverage should be broadened to cover resistant organisms if patients are
hemodynamically unstable after receiving initial standard therapies
3
(Class l, Level C)
4.4 In patients with recurrent or persistent fever, non-infectious sources should be considered
such as drug-related fever, thrombophlebitis, underlying cancer, or blood resorption from
a large hematoma.
3
(Class I, Level C)
4.5 If a patient has a second episode of NF, it is recommended to treat with an antibiotic from
a different class (Ex: If previously treated with cefepime, try a piperacillin-tazobactam or a
carbapenem). (Class I, Level C)


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Management of Neutropenic Fever Guidelines 10


Table 2. Outpatient Management of Patients with NF
1,53,59

Clinical Exclusion Criteria for Empiric Outpatient Therapy
Clinical instability as defined by:
a

• presence of organ failure (renal, cardiac, or respiratory)
• decompensation of chronic organ insufficiency
• presence of septic shock or hypotension (systolic pressure < 90 mmHg)
• severe infections known or suspected (including typhlitis, pneumonia, catheter associated, etc.)
a

• presence of other serious complications, constituting admission criteria in and of themselves
b

• Uncontrolled diarrhea
CISNE Score ≥ 1
Antibiotics within 96 hours of presentation
c

Hepatic dysfunction (defined as: AST/ALT > 5x ULN or T bili or ALP > 3x ULN)
Inability to tolerate oral medications
Uncontrolled/progressive cancer (patients with evidence of disease progression after more than 2 courses
of chemotherapy)

Social Criteria for Empiric Outpatient Therapy
Residence ≤ 1 hour or ≤ 30 miles from clinic or hospital
Primary care physician or treating oncologist notified of outpatient management
Patient complies with frequent clinic visits
Family member or caregiver at home 24 hours a day
Access to telephone and transportation 24 hours a day
No noncompliance history with treatment protocols

Appropriate Outpatient Monitoring
Physical assessment within 2-4 days and as needed thereafter
Telephone follow-up within 12-24 hours to verify patient response and indications for change in therapy
Monitoring of ANC and platelet count for myeloid reconstitution

When to Re-evaluate for Hospital Admission
Persistent neutropenic fever for > 48 hours
New signs or symptoms of infection
Oral medications not tolerated or no longer possible
Empiric regimen changes or an additional antimicrobial drug becomes necessary
Microbiologic tests identify species not susceptible to initial empiric regimen
a
See appendix A for full list of definitions
b
This is does not replace the need for clinical judgment while making decisions for patient disposition
c
Does not include Pneumocystis jiroveci pneumonia prophylaxis




5. Duration of Empiric Antibiotics
5.1 If the infection source is identified, it is reasonable to base the duration of antibiotics on
the organism, site of infection, and the patient’s immune status.
3,21
(Class lla, Level C)
5.1.1 For documented bacterial bloodstream infection, soft-tissue infection, and
pneumonia, it is reasonable to continue antibiotic therapy for ten to fourteen
days.
3
(Class IIa, Level C)
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Management of Neutropenic Fever Guidelines 11


5.1.1.1 It can be beneficial to narrow the antibiotic spectrum to treat the
identified pathogen once fever has resolved.
3
(Class IIa, Level C)
5.1.1.2 If the antibiotic course is finished and the patient remains afebrile but
still neutropenic, it may be reasonable to resume fluoroquinolone
prophylaxis
3
(Class IIb, Level C)
5.2 In patients with unexplained fever who are responding to antibiotics, it is reasonable to
continue broad spectrum beta-lactam monotherapy until the patient is afebrile for at least
two days, and the neutrophil count is greater than 500 cells/mm
3
and rising.
3
(Class IIa,
Level C)
5.2.1 In low-risk patients with unexplained fever, it may be reasonable to discontinue
antibiotic therapy before the ANC is greater than or equal to ≥ 500 cells/mm
3
if
cultures are negative at 48 hours and the patient is afebrile for at least 24
hours.
3,24,60-62
(Class IIb, Level B)
5.2.2 In high-risk patients with unexplained fever, profound, persistent
myelosuppression, and no identifiable source of infection, antibiotics are probably
indicated until evidence of marrow recovery.
3
(Class IIa, Level C)
5.2.2.1 Patients with unexplained fever who remain afebrile for four to five
days may be considered to have empirical antibiotics switched back
to fluoroquinolone prophylaxis for the duration of neutropenia.
3,15

(Class IIb, Level C)
5.2.2.2 Patients who have defervesced may be considered for a switch from
inpatient antibiotics to outpatient oral or IV regimens combined with
careful daily follow-up; rather than prolonged hospitalization until
bone marrow recovery.
3
(Class IIb, Level C)

6. Persistent Fever
6.1 Consider empiric antifungal therapy in high-risk patients with persistent or recurrent fever
after four to seven days of broad-spectrum antibiotics if the neutropenia is expected to be
greater than seven days.
3
(Class I, Level A)
6.2 Do not use empiric antifungal therapy in low-risk patients as their risk of invasive fungal
infections is low.
3
(Class l, Level C)

UW Health Implementation
Potential Benefits:
Appropriate diagnosis, risk assessment, treatment, and reduced cost of managing adult patients with NF.
This guideline will standardize the delineation of high risk versus low risk patients, and guide
corresponding treatment

Potential Harms:
Side effects and adverse events associated with various medical/drug treatments.

Implementation Plan/Tools
The guideline will be implemented via electronic distribution on Uconnect, and will be housed on a
webpage dedicated to UW Health clinical practice guidelines. Educational meetings and computer-based
training will be provided for pharmacists, nurses and physicians, and an electronic medical record risk-
assessment guided order set will be created based on recommendations in the guideline.

Disclaimer
This clinical practice guideline is to assist clinicians by providing a framework for evaluation and treatment
of patients. This Clinical Practice Guideline outlines the preferred approach for most patients. It is not
intended to replace clinical judgement or 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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09/2017CCKM@uwhealth.org

Management of Neutropenic Fever Guidelines 12



References
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Management of Neutropenic Fever Guidelines 13


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Management of Neutropenic Fever Guidelines 14


48. Gedik H, Yıldırmak T, Simşek F, et al. Vancomycin-resistant enterococci colonization and bacteremia in
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Management of Neutropenic Fever Guidelines 15


Appendix A. Definitions of Complications and Other Variables in
using the CISNE score
Variable Definition
Clinical Stability
All of the following within first 3 hours of first assessment: absence of acute organ failure
(renal, cardiac, respiratory) or decompensation of chronic insufficiency, absence of
septic shock or hypotension (systolic pressure < 90 mm/Hg), no known severe infections,
and absence of other serious complications constituting admission criteria by themselves
(pulmonary thromboembolism, arrhythmias, disseminated intravascular coagulation,
bleeding)
Major Infections
Pneumonia, empyema, peritonitis, cellulitis > 5 cm, suspected typhlitis, enteritis NCI
grade 3 to 4, appendicitis, cholecystitis or other complicated abdominal infections,
meningitis, encephalitis, endocarditis, and pyelonephritis
Hypotension
Persistent systolic blood pressure < 90 mm/Hg requiring inotropes or aggressive fluid
resuscitation
Acute Respiratory Failure
Oxygen saturation < 90%, partial pressure of oxygen in arterial blood < 60 mm/Hg, or
partial pressure of carbon dioxide in arterial blood < 45 mm/Hg
Acute Renal Failure
Increase in creatinine ≥ 0.3 mg/dL within 48 hours, increase in creatinine to ≥ 1.5 x
baseline within prior 7 days, or urine volume < 0.5 mL/kg per hour for 6 hours
Acute Heart Failure
Rapid onset of dyspnea, pulmonary edema, and oxygen desaturation requiring urgent
therapy
Arrhythmias Arrhythmias considered as complications whenever they alter cardiovascular stability
Delirium Acute, fluctuating alteration of mental state with cognitive impairment
Major Bleeding
Episodes associated with death, occurring in critical localization (intracranial, intraspinal,
intraocular, retroperitoneal, or pericardial), or associated with reduction in hemoglobin
values ≥ 2 g/dL or bleeding that requires transfusion of two units of concentrated RBCs
Acute abdomen
Acute abdomen defined as syndrome because of variety of pathogenic conditions that
require urgent medical or surgical management
COPD
Emphysema, chronic bronchitis, decrease in forced expiratory volumes or need for
oxygen therapy, corticosteroids, or bronchodilators
Chronic Cardiovascular
Disease
Chronic heart conditions (eg, cor pulmonale, heart failure, cardiomyopathy, hypertensive
heart disease, arrhythmias, valvular heart disease, or other structural malformations) at
risk of acute exacerbations in FN setting; single isolated episodes of atrial fibrillation in
past were not considered here as chronic cardiovascular diseases
SIH
Glucose ≥ 121 mg/dL or ≥ 250 mg/m2 in diabetic patient (or in patient receiving
corticosteroids
Mucositis NCI grade ≥ 2
At least presence of patchy ulcerations or pseudomembranes, or moderate pain with
modified diet indicated
Abbreviations: COPD, chronic obstructive pulmonary disease; FN, febrile neutropenia; NCI, National Cancer Institute;
SIH, stress-induced hyperglycemia.


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Management of Neutropenic Fever Guidelines 16


Appendix B. Empiric Treatment of Adults with Suspected NF
presenting to the Emergency Department or Oncology Clinic

Is the patient clinically
stable?
A
Emergency
care, fluid
resuscitation,
blood cultures,
A

CBC with Diff
No
Admit to
inpatient care
per figure 1
Draw blood
cultures
B
and
CBC with Diff
Yes
Administer one
dose of
cefepime
C
in
less than 1
hour
D
A: Clinical Stability is defined as all of the following within the first 3 hours of first of assessment: Absence of acute organ failure (renal,
cardiac, respiratory) or decompensation of chronic insufficiency, absence of septic shock or hypotension (SBP < 90 mmHg), no known
severe infections, and absence of other serious complications constituting admission criteria by themselves (see appendix A for full
definitions)
B: Culture all lumens of central line and peripheral site.
C: Use anti-infective order set; consider aztreonam plus vancomycin if IgE-mediated allergy or severe reaction to B-lactam
D: Do not wait for lab results to start antibiotics; check vital signs every 15 minutes; initial cefepime dose is 2 grams once
E: as listed in Table 2 of NF treatment guideline
F: Pager 5566; Inpatient oncology attending to initiate patient follow-up
G: Antibiotic Dosing (use Anti-Infective order set): Cefepime 1 g IV q6h; Ciprofloxacin 750 mg PO q12h;
Amoxicillin/clavulanate XR 2000/125 mg PO q12h; Clindamycin 300 mg PO q6h
Is the patient
neutropenic?
Ongoing
management
per provider
No
Is the patient low
risk per CISNE
evaluation?
(Score=0)
Yes
Other exclusions to
outpatient
treatment
E
Yes
Admit for observation and
continue current antibiotics;
consider for discharge once
patient meets criteria
IgE-mediated
allergy or severe
reaction to B-
lactam
Discharge with
ciprofloxacin plus
amoxicillin-clavulanate
therapy
G
No
No
Contact admitting
oncology or
hematology
attending to initiate
outpatient therapy
F
Discharge with
oral FQ
(ciprofloxacin or
levofloxacin) +
clindamycin
G
Yes
No
Yes
Patient presents with
suspicion for neutropenic
fever

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Management of Neutropenic Fever Guidelines 17


Appendix C. Adult NF Management Algorithm

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Management of Neutropenic Fever Guidelines 18


Appendix D. Adult Persistent Fever Management Algorithm


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