Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy

Publication Date: February 20, 2018

Triage to Initial Empirical Antibiotic Therapy

Figure 1. Triage to Initial Empirical Antibacterial Therapy

Figure 1. Triage to Initial Empirical Antibacterial Therapy—Footnotes

a Fever is defined as a single oral temperature of ≥38.3°C (101°F), or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period.

b In the absence of an alternative explanation, clinicians should assume that fever in a patient with neutropenia from cancer therapy is the result of an infection. The initial diagnostic approach should maximize the chances of establishing clinical and microbiologic diagnoses that may affect antibacterial choice and prognosis. A systematic evaluation should include:

  • Complete history and physical examination to identify infectious foci.
  • Complete blood count with leukocyte differential count, hemoglobin and platelet count; serum electrolytes; serum creatinine and blood urea nitrogen; serum lactate; and liver function tests including total bilirubin, alkaline phosphatase, and transaminases.
  • At least two sets of blood cultures from different anatomic sites, including a peripheral site as well as at least one line lumen of a central venous catheter if present, although the Expert Panel recognizes that that some centers may modify this practice and use only peripheral cultures, given the potential for false positive results with blood cultures from the line lumen of a central venous catheter.
  • Cultures from other sites such as urine, lower respiratory tract, CSF, stool, or wounds, as clinically indicated.
  • Chest imaging study for patients with signs and/or symptoms of lower respiratory tract infection, and consider chest imaging for other patients.
Patients with an influenza-like illness (sudden onset of a respiratory illness characterized by fever and cough and ≥ one of malaise, sore throat, coryza, arthralgias, or myalgias) in the setting of seasonal community-acquired respiratory illnesses should have a nasopharyngeal swab obtained for detection of influenza. In some settings, such as patients with such symptoms in the setting of hematologic malignancy and HSCT, strong consideration should be given to obtaining expanded viral panels for detection of additional respiratory viruses (Influenza virus, Parainfluenza virus, Adenovirus, Coronavirus, Respiratory syncytial virus, Human metapneumovirus, and Rhinovirus). ( IC , L , M )
c Administration of empirical antibiotics:
  • Assessment should occur soon (e.g., within 15 minutes) after triage for patients presenting with febrile neutropenia (FN) within 6 weeks of receiving chemotherapy. This assessment is intended to be a sensitive test with low specificity, emphasizing inclusivity rather than exclusivity.
    • High-risk patients require hospitalization for IV empirical antibiotic therapy.
  • The first dose of empirical therapy should be administered within one hour after triage from initial presentation. In addition, the following recommendations from the 2010 IDSA guidelines are endorsed:
    • Patients who are seen in clinic or the ED for FN and whose degree of risk has not yet been determined to be high or low within one hour should receive an initial IV dose of therapy while undergoing evaluation.
    • Monotherapy with an antipseudomonal β-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), or piperacillin-tazobactam, is recommended. Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (e.g., hypotension and pneumonia) or if antimicrobial resistance is suspected or proven.
    • Vancomycin (or other agents active against microaerophilic Gram-positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia. These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability.
    • Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria. These include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended-spectrum β-lactamase (ESBL)–producing Gram-negative bacteria, and Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria. Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity.
      • MRSA: Consider early addition of vancomycin, linezolid, or daptomycin.
      • VRE: Consider early addition of linezolid or daptomycin.
      • ESBLs: Consider early use of a carbapenem.
      • KPCs: Consider early use of polymyxin-colistin or tigecycline, or a newer β-lactam with activity against resistant gram negative organisms as a less toxic and potentially more effective alternative.
( IC , L , S )

 Identification of Candidates for Outpatient Management

Figure 2. Identification of Candidates for Outpatient Managementa

Figure 2. Identification of Candidates for Outpatient Management—Footnotes

a Clinical judgment should be used when selecting candidates for outpatient management. ( IC , L , S )
b The MASCC index or Talcott’s rules are recommended tools for identifying patients who may be candidates for outpatient management (Table 2, Table 3, respectively). ( EB , I , M )
c In the setting of a high prevalence of ESBL-producing Gram-negative bacilli or fluoroquinolone resistance hospital admission and initial empirical anti-bacterial treatment with an anti-pseudomonal carbapenem is recommended. In the setting of a high prevalence of MRSA and VRE and concern for pneumonia or central line-associated bloodstream infection hospital admission and targeted therapy is recommended. Patients undergoing hematopoietic stem cell transplantation (HSCT) or induction therapy for acute leukemia are unlikely to be appropriate candidates for outpatient therapy.
d Patients with febrile neutropenia who are eligible for discharge and outpatient management must also meet the following psychosocial and logistic requirements:
  • Residence ≤1 hour or ≤30 miles (48 km) from clinic or hospital
  • Patient’s primary care physician or oncologist agrees to outpatient management
  • Able to comply with logistic requirements, including frequent clinic visits
  • Family member or caregiver at home 24 hours a day
  • Access to a telephone and transportation 24 hours a day
  • No history of noncompliance with treatment protocols
  • The following additional measures are recommended:
    • Frequent evaluation for ≥3 days in clinic or at home
    • Daily or frequent telephone contact to verify (by home thermometry) that fever resolves
    • Monitoring of ANC and platelet count for myeloid reconstitution
    • Frequent return visits to clinic.
( IC , L , M )
e Low-risk outpatients with febrile neutropenia who do not defervesce after two to three days of an initial empirical broad-spectrum antibiotic regimen should be re-evaluated to detect and treat a new or progressing anatomic site of infection and be considered for hospitalization. Patients should also be evaluated for admission to the hospital if any of the following occur: fever recurrence after a period of defervescence, new signs or symptoms of infection, use of oral medications is no longer possible or tolerable, change in the empirical regimen or an additional antimicrobial drug becomes necessary, or microbiologic tests identify species not susceptible to the initial regimen. ( IC , L , M )
f In patients with fever and neutropenia who are appropriate candidates for outpatient management, the first dose of empirical therapy should be administered in the clinic, emergency room, or hospital department after fever has been documented and pretreatment blood samples drawn. ( IC , L , M )
g For patients with FN who are undergoing outpatient antibiotic treatment, oral empirical therapy with a fluoroquinolone (ciprofloxacin or levofloxacin) plus amoxicillin/clavulanate (or plus clindamycin for those with a penicillin allergy) is recommended. ( IC , I , M )

Recommendation Grading




Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy

Authoring Organizations

Publication Month/Year

February 20, 2018

Document Type


External Publication Status


Country of Publication


Target Patient Population

Patients with cancer who require treatment of fever and neutropenia.

Target Provider Population

Oncologists, infectious disease specialists, emergency medicine physicians, nurses

Inclusion Criteria

Male, Female, Adolescent, Adult, Child, Older adult

Health Care Settings

Emergency care, Hospital

Intended Users

Nurse, nurse practitioner, physician, physician assistant


Treatment, Management

Diseases/Conditions (MeSH)

D064147 - Febrile Neutropenia


cancer, neutropenia, neutropenic fever, Fever and Neutropenia

Source Citation

DOI: 10.1200/JCO.2017.77.6211 Journal of Clinical Oncology 36, no. 14 (May 10, 2018) 1443-1453.

Supplemental Methodology Resources

Data Supplement, Methodology Supplement


Number of Source Documents
Literature Search Start Date
May 1, 2011
Literature Search End Date
November 1, 2016
Specialties Involved
Emergency Medicine, Infectious Disease, Oncology, Medical Oncology, Hematology Oncology, Oncology, Hematology