Neutropenic Fever Empiric Therapy

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Neutropenic Fever Empiric Therapy

Author: Mary Denshaw-Burke, MD, FACP; Chief Editor: Thomas E Herchline, MD more...
Updated: Sep 4, 2013

Empiric Therapy Regimens

Background
Neutropenia is defined as an absolute neutrophil count (ANC) of less than 500/L or less than 1000/L
with an anticipated decline to less than 500/L in the next 48-hour period.
Neutropenic fever is a single oral temperature of 38.3 C (101 F) or a temperature of greater than 38.0
C ( 100.4 F) sustained for more than 1 hour in a patient with neutropenia.
Upon initial evaluation, each patient should be assessed for risk of complications from severe infection.
Appropriate risk assessment may determine the type of empiric therapy (oral vs IV), duration of
antibiotic therapy, and determination of inpatient versus outpatient management. Patients are classified
into high- and low-risk groups.
High-risk patients are those patients with any one of the following:
Anticipated, prolonged (>7-d duration), and profound neutropenia (ANC < 100/L) following cytotoxic
chemotherapy
Significant medical comorbidities, including hypotension, pneumonia, new-onset abdominal pain, or
neurologic changes
Low-risk patients include the following:
Anticipated brief (< 7-d duration) period of neutropenia
ANC greater than 100/L and absolute monocyte count greater than 100/L
Normal findings on chest radiograph
Outpatient status at the time of fever onset
No associated acute comorbid illness
No hepatic or renal insufficiency
Early evidence of bone marrow recovery
High-risk patients should be admitted to the hospital for empiric therapy and close observation.
Low-risk patients may be candidates for oral empiric therapy and may qualify for outpatient management.
These patients require very close outpatient monitoring and assessment. They should be seen in the office
daily for at least 72 hours.
Formal risk classification can be performed on the basis of the Multinational Association for Supportive Care in
Cancer (MASCC) scoring system.
Empiric regimens for neutropenic fever are outlined below, including regimens for low- and high-risk patients
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and regimens for cases in which the fever persists after 3-5 days.[1, 2, 3, 4, 5]

Low-risk patients
Amoxicillin-clavulanate 500 mg/125 mg PO q8h plus ciprofloxacin 500 mg PO q12h
Moxifloxacin 400 mg PO daily
If penicillin allergic, substitute clindamycin 300 mg PO q6h for amoxicillin-clavulanate

High-risk patients
First-line monotherapy: This must include an agent with antipseudomonal activity. Quinolones and
aminoglycosides are not acceptable as monotherapy. The following antibiotics are appropriate as
monotherapy:
Piperacillin-tazobactam 4.5 g IV q6h or
Cefepime 2 g IV q8h or
Meropenem 1 g IV q8h or
Imipenem-cilastatin 500 mg IV q6h
No single agent has shown superiority in the empiric treatment of febrile neutropenia.
Second-line dual therapy: The use of dual therapy in high-risk patients is indicated for complicated cases
(hypotension or pneumonia) or suspected or proven antimicrobial resistance. Appropriate antibiotic regimens in
this setting include the following:
Piperacillin-tazobactam 4.5 g IV q6h plus an aminoglycoside (see below) or
Cefepime 2 g IV q8h plus an aminoglycoside (see below) or
Meropenem 1 g IV q8h plus an aminoglycoside (see below) or
Imipenem-cilastatin 500 mg IV q6h plus an aminoglycoside (see below)
Aminoglycoside options:
Gentamicin 2 mg/kg IV q8h or 5 mg/kg q24h or
Amikacin 15 mg/kg/day or
Tobramycin 2 mg/kg q8h
Indications for the empiric addition of vancomycin (15 mg/kg IV q12h) to drug regimens listed above:
Clinically suspected serious catheter-related infections (eg, bacteremia, cellulitis)
Known colonization with penicillin and cephalosporin-resistant pneumococci or methicillin-resistant
Staphylococcus aureus (MRSA)
Blood culture positive for gram-positive bacteria
Hypotension
Severe mucositis, if prior fluoroquinolone prophylaxis provided

Recommendations if fever resolves in 3-5 days

Organism identified:
Adjust antibiotics based on specific organism and site of infection.
Continue therapy for at least 7 days until cultures are negative and clinical recovery is noted.
No organism identified and ANC greater than 500/L for 2 consecutive days (see the Absolute Neutrophil
Count calculator):
Change therapy to amoxicillin-clavulanate 500 mg/125 mg PO q8h plus ciprofloxacin 500-750 mg PO
q12h.
Antibiotic therapy may be discontinued after 5-7 days once patient is afebrile for 2 consecutive days.

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No organism identified and ANC less than 500/L:

Continue current antibiotic regimen until day 7.
If patient is initially low risk and clinically stable by day 7, then antibiotics can be discontinued.
If patient is initially high risk then continue antibiotic therapy for 2 weeks or until resolution of
neutropenia.
Change to a prophylactic antibiotic regimen may be considered.

If fever persists after 3-5 days:

ANC greater than 500/L:
Continue current empiric antibiotic regimen.
Stop regimen 4-5 days after ANC has reached >500/L.
Reassess for undiagnosed fungal infection.
ANC less than 500/L:
If patient is not on vancomycin, add vancomycin if criteria are met.
If patient is already on vancomycin, consider discontinuation if cultures are negative for MRSA.
Consider adding empiric antifungal therapy (see below)
Antifungal agents can be withheld in a specific subset of high-risk febrile neutropenic patients. These patients
include those who remain febrile after 4-7 days of broad-spectrum antibiotics but are clinically stable and
without clinical or radiographic signs of fungal infection. In low-risk patients, the risk of fungal infection is low;
therefore, empiric antifungal agents should not be used routinely.
Empiric antifungal therapy:
Amphotericin B liposomal complex 3 mg/kg q24h or
Voriconazole 6 mg/kg q12h X 2 doses, then 4 mg/kg q12 h or
Posaconazole 200 mg PO q6h for 7d, then 400 mg PO q12h or
Itraconazole 200 mg IV q12h for 2d, then 200 mg IV or PO q24h for 7d, then 400 mg PO q24h thereafter
or
Caspofungin 70 mg IV for 1 dose, then 50 mg IV q24h or
Micafungin 100-150 mg IV q24h or
Anidulafungin 200 mg IV for 1 dose, then 100 mg IV q24h
Patients already on antifungal prophylaxis should be switched to a different class if fever persists.
Continue therapy for 2 weeks if patient has stabilized and no infectious nidus is identified.

Special considerations
The prophylactic use of colony-stimulating factors has been shown to reduce the incidence of neutropenic fever
and should be considered for patients in whom the anticipated risk of fever and neutropenia with a specific
chemotherapy regimen is greater than 20%. If the intent of the chemotherapy treatment is palliative in nature,
then chemotherapy dose reduction is usually a more appropriate approach.
At present, the use of myeloid colony-stimulating factors is not recommended in the setting of an established
fever and neutropenia. Several randomized studies have shown a decrease in the days of neutropenia,
duration of fever, and length of hospital stay. However, none of these studies has shown a survival benefit.[6]

Contributor Information and Disclosures

Author
Mary Denshaw-Burke, MD, FACP Clinical Assistant Professor of Medicine, Jefferson Medical College of
Thomas Jefferson University; Clinical Assistant Professor, Affiliated Clinical Faculty of the Lankenau Institute for
Medical Research; Program Director of Hematology/Oncology Fellowship, Education Coordinator for Oncology,
Lankenau Medical Center

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Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of
Physicians
Disclosure: Nothing to disclose.
Coauthor(s)
Aarti Shevade, MD Fellow in Hematology and Oncology, Lankenau Medical Center
Aarti Shevade, MD is a member of the following medical societies: American Society of Clinical Oncology and
American Society of Hematology
Disclosure: Nothing to disclose.
Specialty Editor Board
Jasmeet Anand, PharmD, RPh Adjunct Instructor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Chief Editor
Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine;
Medical Director, Public Health, Dayton and Montgomery County, Ohio
Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious
Diseases Society of America, and Infectious Diseases Society of Ohio
Disclosure: Nothing to disclose.
Additional Contributors
Kelley Struble, DO Fellow, Department of Infectious Diseases, University of Oklahoma College of Medicine
Kelley Struble, DO is a member of the following medical societies: American College of Physicians and
Infectious Diseases Society of America
Disclosure: Nothing to disclose.

References
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of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. Mar 15 2002;34(6):730-51.
[Medline].
2. Bow EJ, Rotstein C, Noskin GA, Laverdiere M, Schwarer AP, Segal BH. A randomized, open-label,
multicenter comparative study of the efficacy and safety of piperacillin-tazobactam and cefepime for the
empirical treatment of febrile neutropenic episodes in patients with hematologic malignancies. Clin Infect
Dis. Aug 15 2006;43(4):447-59. [Medline].
3. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever
and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice
guideline. J Clin Oncol. Feb 20 2013;31(6):794-810. [Medline].
4. Kern WV, Marchetti O, Drgona L, et al. Oral antibiotics for fever in low-risk neutropenic patients with
cancer: a double-blind, randomized, multicenter trial comparing single daily moxifloxacin with twice daily
ciprofloxacin plus amoxicillin/clavulanic acid combination therapy--EORTC infectious diseases group trial
XV. J Clin Oncol. Mar 20 2013;31(9):1149-56. [Medline].
5. Schuler U, Bammer S, Aulitzky WE, Binder C, Bhme A, Egerer G. Safety and efficacy of itraconazole
compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with
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haematological malignancy. Onkologie. Apr 2007;30(4):185-91. [Medline].

6. [Guideline] Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of
white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. Jul 1
2006;24(19):3187-205. [Medline].
7. 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. Feb 15 2011;52(4):427-31. [Medline].
Medscape Reference 2011 WebMD, LLC

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