A detailed history of the patients presenting illness, chemotherapy treatment, medication use, previous history of infections, especially with bacterial resistant organisms, and the presence of allergies, should be noted to guide your therapy.[8] Signs of infection may require assessment; Pain and tenderness may be the only indicators of infection. Significant risk factors for the development of febrile neutropenia include older age, comorbidities, the specific type of cancer, and the type and number of myelosuppressive chemotherapy agents in use.[9]

Lab tests should be ordered; complete blood count to determine the patient's neutropenic level; blood, urinalysis, and throat cultures are needed to determine the source of infection. Two sets of blood cultures should be obtained from a peripheral vein and any venous catheters as well as specimens for testing from any sites of infection, before the immediate administration of empirical broad-spectrum antimicrobial therapy. Urinary tract infections should be suspected in asymptomatic patients with a history of such infections.[8] If diarrhea is present, a sample may be checked. If the patients have any respiratory symptoms, a chest x-ray is necessary.

 Two widely used assessment tools, The Multinational Association for Supportive Care in Cancer (MASCC) and The Clinical Index of the Stable Febrile Neutropenia (CISNE), can be part of the patient interview. These tools can help to risk-stratify patients into high risk and low-risk neutropenic fever.

The MASCC was created the assess the risk of serious complications in patients with neutropenic fever. The MAASC index has a max score of 26. Patients with a score greater than 21 are considered low risk, and patients less than 21 are high risk.[10]

MASCC Scoring Index

Characteristic/Score

• The burden of illness: no or mild symptoms/5
• The burden of illness: none or mild/5
• The burden of illness: moderate symptoms/3
• The burden of illness: severe symptoms/0
• No hypotension (systolic BP greater than 90 mmHg)/5
• No chronic obstructive pulmonary disease/4

Type of Cancer

• Solid tumor/4
• Lymphoma with previous fungal infection/4
• Hematologic with previous fungal infection/4
• No dehydration/4
• Outpatient status (at the onset of fever)/3
• Age less than 60 years/2

A more specific scale for classification of low-risk patients is the CISNE and may be more useful in the emergency department setting.[5] One of the components of the scale is the Eastern Cooperative Oncology Group (ECOG) Performance Status, which helps determines the patient’s functional status as a surrogate for the patient’s ability to undergo therapies in serious illnesses.

The Clinical Index of Stable Febrile Neutropenia Score

Characteristics/Score

• ECOG performance status (greater than 2)/2
• Chronic obstructive pulmonary disease (COPD)/1 
• Stree-induced hyperglycemia/2
• Chronic cardiovascular disease/1
• Monocytes less than 200 per mcL/1
• Grade greater than or equal to 2 mucositis/1
• Interpretation

CISNE/Recommendation

• 0-2/Consider outpatient management with oral antibiotics
• Greater than or equal to 3/inpatient management

In low-risk patients, oral empiric therapy with a fluoroquinolone plus amoxicillin/clavulanate is recommended in the outpatient setting.[6] Clindamycin can be used for those with penicillin allergy. If the patient remains febrile for 48 to 72 hours, the patient will require admission.[5]

For high-risk patients presenting with neutropenic fever, an intravenous antibiotic therapy should be given within 1 hour after triage and be monitored more than 4 hours before discharge. The Infectious Disease Society of America (IDSA) recommends monotherapy with antipseudomonal beta-lactam agents such as cefepime, carbapenems, or piperacillin and tazobactam. [5] Vancomycin is not recommended for initial therapy but should be considered if suspecting catheter-related infection, skin or soft tissue infections pneumonia, or hemodynamic instability.[11] If patients do not respond to treatments, coverage should be expanded to include resistant species[5][1][12][13][14][13][12]:

• Methicillin-resistant Staphylococcus aureus (MRSA): vancomycin, linezolid, and daptomycin
• Vancomycin-resistant enterococci (VRE): linezolid and daptomycin
• Extended-spectrum beta-lactamase (ESBL)-producing organisms: carbapenems
• Klebsiella pneumoniae: carbapenems, polymyxin, colistin, or tigecycline

Recommendation for prevention of infection in neutropenic patients:

• Fluoroquinolones as prophylaxis for patients who are high risk
• Antifungal prophylaxis with an oral triazole with patients with profound neutropenia
• Trimethoprim-sulfamethoxazole (TMP-SMX) is the recommended treatment for patients receiving chemotherapy regimens associated with greater than 3.5% risk for pneumonia from Pneumocystis jirovecii
• Yearly influenza vaccination is recommended for all patients receiving chemotherapy
• Treatment with a nucleoside reverse transcription inhibitor is recommended for patients who are at high risk of hepatitis B virus reactivation
• Herpes simplex virus- seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis

In the National Comprehensive Cancer Network (NCCN) guidelines, it is recommended that patients that are at a high risk of neutropenic fever can benefit from granulocyte-colony stimulating factors (G-CSFs).[15]

• Transfusion reaction
• Medication allergies and toxicities
• Tumor-related fever

Febrile neutropenia is an oncological emergency that requires a team of infectious disease specialists, emergency medicine, oncology, pharmacy, and specialty-trained nurses and pharmacists for proper management, working as a collaborative interprofessional team. [Level 5] The most important determining factor of the outcomes of patients is the timing of administrating IV antibiotics.  Early admission of antibiotics has been shown to reduce mortality and the hospital length of these patients.[16][17] [Level 3] A heightened sense of urgency should be present in all staff members when interviewing with patients undergoing chemotherapy presenting with new-onset fever. The pharmacist should assist the team with antibiotic selection and dosing. The nursing staff should provide monitor of the patient and report untoward changes to the team. The best outcomes are achieved by an interprofessional team approach to the diagnosis and management of this life-threatening condition. [Level 5]