What are the management and treatment options for Neutropenic (having an abnormally low number of neutrophils, a type of white blood cell) Fever (elevated body temperature)?

From the Guidelines

Neutropenic fever requires immediate empiric broad-spectrum antibiotic therapy, and the initial regimen should be guided by clinical and microbiologic data, as well as local patterns of infection and antibiotic susceptibilities 1, 2. For patients with neutropenic fever (defined as a single oral temperature ≥38.3°C or ≥38.0°C sustained over one hour, with an absolute neutrophil count <500 cells/mm³),

• start with an anti-pseudomonal beta-lactam such as cefepime 2g IV every 8 hours, piperacillin-tazobactam 4.5g IV every 6 hours, or meropenem 1g IV every 8 hours. Initial therapy should be given as a single agent unless there are specific concerns for resistant organisms or complicated infections.
• Blood cultures should be obtained before starting antibiotics, along with cultures from any suspected sites of infection. Patients should undergo thorough physical examination focusing on potential infection sources including the oral cavity, lungs, skin, perineum, and vascular access sites. Antibiotics should be continued until the neutrophil count recovers to >500 cells/mm³ and the patient has been afebrile for at least 48 hours. For persistent fever after 3-5 days of appropriate antibiotics, consider adding antifungal coverage with an echinocandin or liposomal amphotericin B, as recommended by the Infectious Diseases Society of America 1. The urgency of treatment stems from the compromised immune response in neutropenic patients, which allows infections to progress rapidly and become life-threatening within hours, as neutrophils are the primary defense against bacterial infections. It is also important to note that modifications to the initial antibiotic regimen should be guided by clinical and microbiologic data, and unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen 1. Additionally, patients who remain hemodynamically unstable after initial doses with standard agents for neutropenic fever should have their antimicrobial regimen broadened to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria and fungi 1. Low-risk patients who have initiated IV or oral antibiotics in the hospital may have their treatment approach simplified if they are clinically stable, and an IV-to-oral switch in antibiotic regimen may be made if patients are clinically stable and gastrointestinal absorption is felt to be adequate 1. Selected hospitalized patients who meet criteria for being at low risk may be transitioned to the outpatient setting to receive either IV or oral antibiotics, as long as adequate daily follow-up is ensured 1. However, if fever persists or recurs within 48 h in outpatients, hospital re-admission is recommended, with management as for high-risk patients 1. It is crucial to monitor patients closely for response, adverse effects, emergence of secondary infections, and the development of drug-resistant organisms, and to adjust the treatment regimen accordingly 1, 2.

From the FDA Drug Label

14 CLINICAL STUDIES 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. Table 9: Favorable Response of Patients with Persistent Fever and Neutropenia Caspofungin AmBisome % Difference (Confidence Interval) †

• Caspofungin: 70 mg on Day 1, then 50 mg once daily for the remainder of treatment (daily dose increased to 70 mg for 73 patients); AmBisome: 3 mg/kg/day (daily dose increased to 5 mg/kg for 74 patients) ‡ Analysis population excluded subjects who did not have fever or neutropenia at study entry. Number of Patients ‡556539 Overall Favorable Response190 (33. 9%)181 (33.7%)0.2 (-5.6, 6.0) No documented breakthrough fungal infection527 (94.8%)515 (95.5%)-0.8 Survival 7 days after end of treatment515 (92.6%)481 (89.2%)3.4 No discontinuation due to toxicity or lack of efficacy499 (89.7%)461 (85.5%)4.2 Resolution of fever during neutropenia229 (41.2%)223 (41.4%)-0. 2

The caspofungin study 3 shows that caspofungin was as effective as AmBisome in empirical therapy of persistent febrile neutropenia.

• Key findings: + Overall favorable response: 33.9% for caspofungin and 33.7% for AmBisome + Resolution of fever during neutropenia: 41.2% for caspofungin and 41.4% for AmBisome
• Clinical decision: Caspofungin can be considered as an option for the empirical therapy of febrile neutropenia. However, the cefepime study 4 does not provide sufficient information to support its efficacy in patients with febrile neutropenia who are at high risk for severe infection.
• Key findings: Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection.
• Clinical decision: Cefepime monotherapy should be used with caution in patients with febrile neutropenia who are at high risk for severe infection.

From the Research

Definition and Treatment of Neutropenic Fever

• Neutropenic fever is a life-threatening condition that requires prompt recognition and treatment, as it can herald a serious bacterial illness in patients with neutropenia 5.
• The empirical administration of broad-spectrum antibiotics is an essential component of the initial management of patients with fever and severe neutropenia 6, 7.

Antibiotic Regimens for Neutropenic Fever

• Ceftazidime is an appropriate initial therapy for febrile neutropenic patients, and the addition of vancomycin is only necessary when fever persists after 4 days of monotherapy or when fever recurs following an initial response 8.
• Cefepime monotherapy is effective in treating febrile neutropenia, but patients with prolonged neutropenia are at higher risk for failure 6.
• Continuous infusion of ceftazidime can be a safe and effective treatment for neutropenic patients after high-dose chemotherapy and peripheral blood stem cell transplantation 9.

Considerations for Antibiotic Therapy

• The choice of empirical antibiotic regimen should be based on knowledge of predominant pathogens and antibiotic susceptibilities at each institution 7.
• The routine use of vancomycin may be appropriate at some institutions, but its widespread use may lead to resistance 7.
• Outpatient antibiotic therapy can be used in selected neutropenic patients, but close monitoring for development of complications is necessary 9.