Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Children With Febrile Neutropenia
Condition: Chemotherapy-Induced Febrile Neutropenia
MeSH terms: Neutropenia; Febrile Neutropenia; Chemotherapy-Induced Febrile Neutropenia; Hyperthermia; Fever
Study type: Interventional

Summary: 
      Febrile neutropenia (FN) continues to be the infectious complication that most commonly
      requires hospitalization in pediatric cancer patients undergoing chemotherapy. In recent
      years, data have been published on the effectiveness of treatment of FN events with oral
      antibiotics, mainly in developed countries, but data from developing countries continue to be
      scarce.

      Our hypothesis was that early change from initial in-patient intravenous antibiotic treatment
      to oral outpatient antibiotic treatment in children with cancer and FN is as safe and
      effective as in-patient intravenous antibiotic management.

      The purpose of this clinical study was to determine whether early outpatient oral antibiotic
      treatment is not inferior in safety and efficacy to in-hospital intravenous antibiotic
      treatment in pediatric patients with cancer and low-risk FN events.

      A multicenter, non-inferiority randomized clinical trial was conducted in three public
      hospitals in Mexico City. Low-risk FN events were identified in children aged 1 to 18 years.
      After 48 to 72 hours of receiving intravenous in-hospital antibiotics, children were randomly
      allocated to receive outpatient oral treatment (cefixime) or to continue in-hospital
      intravenous treatment (cefepime). Daily monitoring was performed until the resolution of
      neutropenia. Our outcome of interest was the presence of any unfavorable clinical outcome.
    

Detailed description: 
      Introduction: Febrile neutropenia (FN) continues to be the infectious complication that most
      commonly requires hospitalization in pediatric cancer patients undergoing chemotherapy.
      Classically these patients have been managed as inpatient. In recent years, data have been
      published on the effectiveness of treatment of FN events with oral antibiotics, mainly in
      developed countries, but data from developing countries continue to be scarce.

      Hypothesis: Our hypothesis was that early change from initial in-patient intravenous
      antibiotic treatment to oral outpatient antibiotic treatment in children with cancer and FN
      is as safe and effective as in-patient intravenous antibiotic management.

      Objectives: The purpose of this clinical study was to determine whether early outpatient oral
      antibiotic treatment is not inferior in safety and efficacy to in-hospital intravenous
      antibiotic treatment in pediatric patients with cancer and low-risk FN events.

      Methodology: A multicenter, non-inferiority randomized clinical trial was conducted in three
      public hospitals in Mexico City. Low-risk FN events were identified in children aged 1 to 18
      years.

      A complete medical history, physical examination and review of laboratory tests and cultures
      were performed on all subjects with FN events who were considered low risk. According to
      local guidelines for the treatment of FN, all subjects began receiving cefepime at a dose of
      150 mg/kg/day. Subjects were followed-up daily, and those who met the inclusion/exclusion
      criteria after 48 to 72 hours of in-hospital intravenous treatment with cefepime were
      randomly assigned to receive outpatient treatment with oral cefixime at a dose of 8 mg/kg/day
      or to continue in-hospital intravenous treatment. The treatment was administered by the
      researchers.

      Participants in both treatment groups were evaluated daily by a complete physical
      examination. Subjects in the outpatient group were evaluated at the outpatient clinic of the
      hospital. All patients underwent a blood count every 48 to 72 hours. FN event resolution was
      defined as when the patient remained afebrile and the absolute neutrophil count (ANC)
      increased to above 500 per microliter. If fever resumed, the antibiotic regimen was modified.
      If the subjects were in the outpatient group, they were re-admitted to the hospital to
      receive intravenous antibiotics. Resolution of the FN event was defined as the end of
      participation of the subjects in the study, and they were followed up for an additional 72
      hours.

      The occurrence of any of the following conditions was considered an unfavorable clinical
      outcome: 1) therapeutic failure, defined as the resumption of fever in a patient with
      persistent neutropenia. For all patients with resumption of fever, the antibiotic regimen was
      switched, and if the patients were in the outpatient treatment group, they were re-admitted
      to the hospital; 2) new focus of infection, documented both by the clinical condition and by
      laboratory and other diagnostic tests; 3) hemodynamic instability, defined as a decrease in
      blood pressure below the 5th percentile for the patient age that did not revert with the
      administration of crystalloid solutions; and 4) death.

      Sample size: The sample size was calculated to reject a null hypothesis of inferiority, with
      a non-inferiority margin of presentation of unfavorable clinical outcomes of 15%. A formula
      including a statistical power of 80% and a one-tailed alpha value of 0.025 was used to
      calculate the sample size of 2 independent proportions. Based on previous reports of 10% of
      unfavorable clinical outcomes during the management of FN events, the calculation yielded a
      total of 63 FN events per group for a total of 126 events.

      Randomization: A random sequence balanced by blocks of 4 FN events was generated using a
      computer program. A physician who did not participate in the subject selection assigned
      subjects to receive either outpatient oral treatment at home or to continue in-hospital
      intravenous treatment. If the subjects lived more than 1 hour away from the hospital, they
      were assigned to a care home to ensure that they could return to the hospital in case of any
      event. Because the study intervention involved outpatient treatment, the study was open. All
      patients were provided with the antibiotic free of charge.

      Statistical analysis: The focus of analysis was intention-to-treat. For each comparison
      group, measures of central tendency and dispersion were estimated for continuous variables,
      and absolute and relative frequencies were determined for discrete and nominal variables. The
      statistical test performed to test the hypothesis of non-inferiority is very similar to the
      traditional test for comparison of proportions; the only difference is that the
      non-inferiority margin is added to the formula, and a p-value < 0.05 confirms
      non-inferiority. The statistical program STATA version 14.2 was used for the analysis.
    

Intervention name(s): Outpatient oral treatment.; Inpatient intravenous treatment.
Intervention type(s): Other; Other
Intervention description(s): Participants allocated in oral outpatient group were discharged home with oral antibiotic to continue management. Participants were given Cefixime oral suspension (100 mg/5 mL). Antibiotic was given to the caretakers with written instructions about dosage and time of administration. Dosage indicated was 8 mg/kg/day to be given orally as a single dose (max dose 400 mg/day). Oral antibiotic treatment was given until documented ANC > 500, failure to treatment (restart of fever) or when 14 days of antibiotic were completed (whichever occurred first).; Participants allocated in the intravenous inpatient group continued receiving Cefepime 150 mg/kg/day every 8 hours (max dose 2 grams per dose or 6 grams per day) according to local standard of care guidelines. Intravenous antibiotic treatment was given until documented ANC > 500, failure to treatment (restart of fever) or when 14 days of antibiotic were completed (whichever occurred first).
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A multicenter, noninferiority randomized clinical trial was conducted in three public hospitals in Mexico City. A complete medical history, physical examination and review of laboratory tests and cultures were performed on all subjects with FN events who were considered low risk. All subjects began receiving intravenous inpatient treatment with cefepime. Subjects were followed-up daily, and those who met the inclusion/exclusion criteria after 48 to 72 hours of in-hospital intravenous treatment were randomly assigned to receive outpatient treatment with oral cefixime or to continue in-hospital intravenous treatment. The treatment was administered by the researchers.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Fever and neutropenia; Febrile neutropenia; Cancer; Outpatient treatment; Children