Recommendations

Joint guidelines for the use of antimicrobial agents for prophylaxis and treatment in neutropenic cancer patients have been issued by the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA).^{[1, 2]} Guidelines have also been issued by the National Comprehensive Cancer Network (NCCN).^[3]

Prophylaxis

The ASCO/IDSA guideline recommendations for antimicrobial prophylaxis are as follows^[1]:

Risk of febrile neutropenia should be systematically assessed, with consideration of patient-related, cancer-related, and treatment-related factors (evidence-based; evidence quality: intermediate; strength of recommendation: strong).
Antibiotic prophylaxis with a fluoroquinolone is recommended for patients who are at high risk for febrile neutropenia or profound, protracted neutropenia (eg, most patients with acute myeloid leukemia/myelodysplastic syndromes or hematopoietic stem-cell transplantation [HSCT] treated with myeloablative conditioning regimens) (evidence-based; evidence quality: high; strength of recommendation: moderate).
Antibiotic prophylaxis is not routinely recommended for patients with solid tumors (evidence-based; evidence quality: high; strength of recommendation: moderate).
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients who are at risk for profound, protracted neutropenia, such as most patients with acute myeloid leukemia/myelodysplastic syndromes or HSCT. Antifungal prophylaxis is not routinely recommended for patients with solid tumors. Additional distinctions between recommendations for invasive candidiasis and invasive mold infection are provided within the full text of the guideline (evidence-based; evidence quality: intermediate; strength of recommendation: moderate).
Prophylaxis (eg, with trimethoprim-sulfamethoxazole [TMP-SMX]) is recommended for patients receiving chemotherapy regimens associated with > 3.5% risk for Pneumocystis jirovecii pneumonia (eg, those with ≥ 20 mg prednisone equivalents daily for ≥ 1 month or those receiving purine analogs) (evidence-based; evidence quality: high; strength of recommendation: strong).
Herpes simplex virus–seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis with a nucleoside analog (eg, acyclovir) (evidence-based; evidence quality: high; strength of recommendation: strong).
Treatment with a nucleoside reverse transcription inhibitor (eg, entecavir or tenofovir) is recommended for patients who are at high risk of hepatitis B virus reactivation (consensus based; evidence quality: intermediate; strength of recommendation: moderate.)
Yearly influenza vaccination with inactivated vaccine is recommended for all patients receiving chemotherapy for malignancy and all family and household contacts and health care providers (consensus based; evidence quality: intermediate; strength of recommendation: moderate.)
The Expert Panel also supports other vaccination recommendations for immunosuppressed adult oncology patients that are contained in the IDSA guideline for vaccination of the immunosuppressed host^[4] (consensus based; evidence quality: intermediate; strength of recommendation: moderate).

The NCCN guidelines provide general recommendations for antimicrobial prophylaxis based on overall level of risk, as influenced by specific disease, therapy, and anticipated duration of neutropenia.^[3]In addition, the guidelines offer detailed recommendations for prevention of the following cancer-related infections:

Fungal infections
Herpes simplex virus and varicella-zoster virus reactivation or disease
Cytomegalovirus (CMV) reactivation or disease
Hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) reactivation or disease
Pneumocystis jirovecii infection

The NCCN guidelines also include the following:

Prophylaxis recommendations for patients receiving specific immune-targeted agents
General recommendations for vaccination of patients with cancer
Recommended vaccination schedules after autologous or allogeneic HSCT

Treatment

The ASCO/IDSA guideline recommendations for outpatient management of fever and neutropenia in adult cancer patients are as follows^[2]:

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.
Fever in neutropenic patients 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 1 hour.
Patients who present with febrile neutropenia within 65 weeks after receiving chemotherapy should be assessed within 15 minutes after triage.

Initial assessment

Recommended tests and procedures for the initial assessment (consensus based; evidence quality: low; strength of recommendation: moderate) include the following:

Complete blood cell count (CBC) with differential, hemoglobin, and platelet count;
Serum creatinine and blood urea nitrogen (BUN)
Electrolyte levels
Serum lactate
Liver function tests (total bilirubin, alkaline phosphatase, transaminases)
At least two sets of blood cultures, with samples taken from different sites
Cultures from suspected infection sites (eg, urine, lower respiratory tract, CSF, stool, wounds)
Chest imaging study for patients with clinical manifestations of lower respiratory tract infection
Patients with a flulike illness in the setting of seasonal community-acquired respiratory illnesses should have a nasopharyngeal swab obtained for detection of influenza. In some of these cases (eg, patients with 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, enteroviruses, and rhinovirus.

Risk stratification

Risk stratification is required to determine the management of patients with fever and neutropenia, including the route of antibiotic therapy (oral vs. IV), its duration, and the choice of inpatient or outpatient care. Widely accepted indications of high risk include either or both of the following:

Chemotherapy-related neutropenia that is expected to be prolonged (duration > 7 days) and profound (absolute neutrophil count [ANC] < 100 cells/μL
Significant medical co-morbid conditions (eg, hypotension, pneumonia, new-onset abdominal pain, neurologic changes)

ASCO/IDSA risk assessment recommendations are as follows:

The Multinational Association for Supportive Care in Cancer (MASCC) scoring system or Talcott's rules can be used for a formal assessment of risk; a MASCC score < 21 indicates high risk
Clinical judgment should be used when selecting candidates for outpatient management. Patients with significant co-morbidity may not be candidates for outpatient treatment, even if their MASCC score is ≥ 21.
In patients with solid tumors who have undergone mild- to moderate-intensity chemotherapy, who appear to be clinically stable, and who are in close proximity to an appropriate medical facility that can provide 24-hour access, the Clinical Index of Stable Febrile Neutropenia (CISNE) may be used as an additional tool to determine the risk of major complications.
Patients infected with fluoroquinolone-resistant, gram-negative pathogens that are also resistant to β-lactams/cephalosporins should receive inpatient treatment with a carbapenem-based regimen that likely requires multiple doses per day.
Patients colonized with, or suspected of having methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), or Stenotrophomonas maltophilia infection should be considered as candidates for inpatient management.
Patients undergoing HSCT or induction therapy for acute leukemia are unlikely to be appropriate candidates for outpatient therapy.
Patients whose degree of risk has not yet been determined to be high or low within 1 hour after triage should receive an initial IV dose of therapy while undergoing evaluation

The guidelines also include the following consensus-based recommendations regarding psychosocial and logistic requirements that patients must meet to be eligible for discharge and outpatient management:

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 h/d
Access to a telephone and transportation 24 h/d
No history of noncompliance with treatment protocols

NCCN guidelines recommend outpatient treatment of febrile neutropenic patients whose initial risk evaluation indicates low risk, based on the following^[3]:

No high-risk features
Outpatient status at time of development of fever
Anticipated short duration of severe neutropenia (≤100 cells/mcL for < 7 d)
Good performance status (ECOG 0-1)
No liver or kidney insufficiency
MASCC score of ≥ 21 or CISNE score of < 3

In addition, patients must meet psychosocial and logistic requirements such as those listed above. Patients with no nausea and vomiting who are able to tolerate oral medications and have not been on fluoroquinolone prophylaxis may receive oral antibiotic therapy; otherwise, they can receive IV antibiotics at home or a daily long-acting IV agent, with or without oral therapy, at home or in the medical office.

The NCCN recommends hospitalization for patients with any of the following high-risk factors^[3]:

MASCC score < 21 or CISNE score ≥ 3
Inpatient status at time of development of fever
Significant medical comorbidity or clinically unstable
Allogeneic HSCT
Anticipated prolonged severe neutropenia: ≤ 100 cells/μL and ≥ 7 d
Liver insufficiency (5 times upper limit of normal for aminotransferases)
Kidney insufficiency (creatinine clearance < 30 mL/min)
Uncontrolled or progressive cancer
Pneumonia or other complex infections at clinical presentation
Use of certain immune and/or targeted treatments
Mucositis grade 3–4

Antibiotic agents

NCCN guidelines recommend basing antibiotic therapy on the following:

Infection risk assessment
Broad-spectrum coverage including antipseudomonal activity
Colonization with or prior infection with multidrug-resistant organisms
Site of infection
Local antibiotic susceptibility patterns
Organ dysfunction/drug allergy
Previous antibiotic therapy

For oral antibiotic therapy in low-risk patients (outpatients and select inpatients) who have not received prior quinolone prophylaxis, the NCCN recommends the following:

Ciprofloxacin plus amoxicillin/clavulanate (category 1)
Levofloxacin
Moxifloxacin (category 1), if Pseudomonas coverage is not required

For IV antibiotic therapy, both ASCO/IDSA and NCCN guidelines recommend monotherapy with an antipseudomonal β-lactam agent, such as the following:

The NCCN also includes ceftazidime as a category 2B recommendation.

Other antimicrobials (eg, aminoglycosides, fluoroquinolones, vancomycin) may be added for management of complications (eg, hypotension, pneumonia) or if antimicrobial resistance is suspected or proven.

ASCO/IDSA guidelines advise that vancomycin (or other agents active against aerobic gram-positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia; such agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability.

Early addition of the following modifications to initial empirical therapy may be considered for patients at risk for infection with antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood-culture results suspicious for resistant bacteria (consensus based; evidence quality: low; strength of recommendation: strong):

MRSA - Vancomycin, linezolid, or (if there is no evidence of pneumonia) daptomycin
VRE - Linezolid or daptomycin
Extended-spectrum β-lactamase (ESBL)–producing gram-negative bacteria - A carbapenem (eg, meropenem, imipenem-cilastatin)
Carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC)–producing bacteria - Polymyxin B, colistin, tigecycline, or a newer β-lactam with activity against resistant gram-negative organisms

The NCCN guidelines provide specific recommendations for evaluation and treatment modification based on infection site and findings. For example, patients presenting with diarrhea who are found to have Clostridioides difficile infection should receive vancomycin or fidaxomicin.

Patients should be observed for ≥ 4 hours before discharge. Patients with febrile neutropenia who are at low risk of medical complications, in whom fever is responding to inpatient IV empirical antibiotic treatment, and who remain clinically stable, are considered eligible for transition to an outpatient regimen.

Follow-up

ASCO/IDSA guidelines recommend the following additional measures:

Frequent evaluation for at least 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

Patients who are undergoing outpatient management should be evaluated for admission to the hospital if any of the following occur:

Failure to defervesce after 2 to 3 days of an initial, empirical, broad-spectrum antibiotic regimen
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
Microbiologic tests identify species not susceptible to the initial regimen