Neutropenic Fever Empiric Therapy 

Neutropenic Fever Empiric Therapy 

No Results

No Results


Neutropenia is defined as an absolute neutrophil count (ANC) of less than 500/µL, or less than 1000/µL with an anticipated decline to less than 500/µL in the next 48-hour period. Neutropenic fever is a single oral temperature of 38.3º C (101º F) or a temperature of greater than 38.0º C ( 100.4º 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-risk 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/µL) following cytotoxic chemotherapy

Significant medical comorbidities, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes

Low-risk patients are those with the following:

Anticipated brief (<7-d duration) period of neutropenia

ANC greater than 100/µL and absolute monocyte count greater than 100/µL

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. However, 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 and regimens for cases in which the fever persists after 3-5 days. [1, 2, 3, 4, 5, 6]

Regimens include the following:

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

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 [7] :

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


Severe mucositis, if prior fluoroquinolone prophylaxis provided

Additions to initial empirical therapy that may be considered for patients at risk for infection with antibiotic-resistant organisms:

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/µL 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.

No organism identified and ANC less than 500/µL:

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.

ANC greater than 500/µL:

Continue current empiric antibiotic regimen.

Stop regimen 4-5 days after ANC has reached >500/µL.

Reassess for undiagnosed fungal infection.

ANC less than 500/µL:

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.

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 those studies has shown a survival benefit. [8, 9]

[Guideline] Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15. 52 (4):e56-93. [Medline]. [Full Text].

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. 2006 Aug 15. 43(4):447-59. [Medline].

[Guideline] 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. 2013 Feb 20. 31(6):794-810. [Medline]. [Full Text].

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. 2013 Mar 20. 31(9):1149-56. [Medline].

Schuler U, Bammer S, Aulitzky WE, Binder C, Böhme A, Egerer G. Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy. Onkologie. 2007 Apr. 30(4):185-91. [Medline].

Vedi A, Pennington V, O’Meara M, Stark K, Senner A, Hunstead P, et al. Management of fever and neutropenia in children with cancer. Support Care Cancer. 2015 Jul. 23 (7):2079-87. [Medline].

Kroll AL, Corrigan PA, Patel S, Hawks KG. Evaluation of empiric antibiotic de-escalation in febrile neutropenia. J Oncol Pharm Pract. 2015 Jul 30. [Medline].

[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. 2006 Jul 1. 24(19):3187-205. [Medline].

Thursky KA, Worth LJ. Can mortality of cancer patients with fever and neutropenia be improved?. Curr Opin Infect Dis. 2015 Dec. 28 (6):505-13. [Medline].

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

Mary Denshaw-Burke, MD, FACP is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

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 Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Jasmeet Anand, PharmD, RPh Adjunct Instructor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Thomas E Herchline, MD Professor of Medicine, Wright State University, Boonshoft School of Medicine; Medical Consultant, Public Health, Dayton and Montgomery County (Ohio) Tuberculosis Clinic

Thomas E Herchline, MD is a member of the following medical societies: Alpha Omega Alpha, Infectious Diseases Society of America, Infectious Diseases Society of Ohio

Disclosure: Nothing to disclose.

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.

Neutropenic Fever Empiric Therapy 

Research & References of Neutropenic Fever Empiric Therapy |A&C Accounting And Tax Services