What is the treatment for neutropenic fever (fever in the setting of neutropenia, a condition characterized by a low neutrophil count)?

From the Guidelines

Neutropenic fever requires immediate empiric broad-spectrum antibiotic therapy to prevent life-threatening infections, and treatment should begin within one hour of presentation, after blood cultures are drawn but without waiting for results, as recommended by the Infectious Diseases Society of America 1. The initial empirical antibiotic regimen should include an antipseudomonal beta-lactam such as cefepime, piperacillin-tazobactam, or meropenem as initial monotherapy.

• For patients with severe illness, hemodynamic instability, or suspected resistant organisms, vancomycin and an aminoglycoside like amikacin should be added to the initial regimen.
• Antibiotics should continue until the neutrophil count recovers to >500 cells/mm³ and the patient has been afebrile for at least 48 hours, as stated in the clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer 1.
• Patients with persistent fever after 3-5 days may need antifungal coverage with fluconazole, voriconazole, or an echinocandin, as supported by randomized, international, multicenter trials that found caspofungin and voriconazole to be suitable alternatives to amphotericin B in this patient population 1. Some key points to consider in the management of neutropenic fever include:
• The urgency of treatment stems from neutropenic patients' compromised ability to mount inflammatory responses, allowing infections to progress rapidly without typical symptoms, potentially leading to sepsis and death within hours if treatment is delayed.
• Outpatient management may be considered for low-risk patients using oral ciprofloxacin plus amoxicillin-clavulanate, but most patients require hospitalization, as low-risk patients who are anticipated to have a short duration of neutropenia (<7 days) do not require antibiotic prophylaxis, according to the clinical practice guideline 1.
• Antimicrobial changes or additions to the initial empirical antibiotic regimen should be based on clinical, radiographic, or microbiological evidence of infection and not on the persistence of fever alone in a patient whose condition is otherwise stable, as recommended by the Infectious Diseases Society of America 1.

From the FDA Drug Label

14.1 Empirical Therapy in Febrile, Neutropenic Patients A double-blind study enrolled 1111 febrile, neutropenic (<500 cells/mm 3) patients who were randomized to treatment with daily doses of caspofungin (50 mg/day following a 70-mg loading dose on Day 1) or AmBisome (3 mg/kg/day) An overall favorable response required meeting each of the following criteria: no documented breakthrough fungal infections up to 7 days after completion of treatment, survival for 7 days after completion of study therapy, no discontinuation of the study drug because of drug-related toxicity or lack of efficacy, resolution of fever during the period of neutropenia, and successful treatment of any documented baseline fungal infection.

Treatment for Neutropenic Fever: Caspofungin is effective as empirical therapy for febrile, neutropenic patients, with a favorable response rate similar to AmBisome. The recommended dose is 50 mg/day following a 70-mg loading dose on Day 1 2.

• Key Points:
  • Caspofungin is as effective as AmBisome in empirical therapy of persistent febrile neutropenia.
  • The overall favorable response rate was 33.9% for caspofungin and 33.7% for AmBisome.
  • Caspofungin can be used to treat febrile, neutropenic patients, including those with prior antifungal prophylaxis.

From the Research

Treatment Options for Neutropenic Fever

• The empirical administration of a broad-spectrum beta-lactam antibiotic, either as monotherapy or in combination with an aminoglycoside, is an essential component of the initial management of patients with fever and severe neutropenia 3.
• Cefepime, a fourth-generation cephalosporin, has been studied as monotherapy for the treatment of febrile neutropenia, with a response rate of 61% in evaluable episodes 3.
• The duration of neutropenia is a significant factor in the response to therapy, with patients having prolonged neutropenia being at higher risk for failure 3.

Antifungal Therapy

• Empirical antifungal therapy is considered if the fever persists despite broad-spectrum antibiotics, including vancomycin 4.
• The timing of initiating empirical antifungal therapy can vary from 3 to 8 days of non-response to antibiotics, with early addition of empirical amphotericin B leading to early defervescence and decreased dose requirement 4.

Dosing Strategies for Cefepime

• Smaller doses of cefepime given more frequently may be non-inferior to traditional dosing strategies, with a study showing comparable time to defervescence between 1g every 6h and 2g every 8h 5.
• The use of cefepime 1g every 6h may be a viable alternative to traditional dosing strategies, with similar trends in achieving time to defervescence 5.

Outpatient Treatment and Time to Antibiotic Administration

• Outpatient treatment of neutropenic fever with oral antibiotics and granulocyte colony-stimulating factor (G-CSF) is a feasible and effective approach for low-risk patients 6.
• Prompt treatment with empiric broad-spectrum antibiotics is crucial to ensuring best outcomes for patients, with practice guidelines recommending antibiotic administration within one hour of fever onset 7.