Symptoms and General Pathology

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All Conditions

Blood and Lymph Conditions

Rare Diseases

Hyperthermia

Neutropenia

Fever

Body Temperature Changes

Agranulocytosis

Leukopenia

Cytopenia

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Leukocyte Disorders

Granulocytopenia

Anti-Infective Agents

All Drugs and Chemicals

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Amoxicillin

Ciprofloxacin

Antibiotics, Antitubercular

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

ciprofloxacin and amoxicillin

Outpatient management

i.v. antibiotics

inpatient management

Roland A Ammann, MD

Christoph Aebi, MD

Maja Beck-Popovic, MD

Eveline SJM de Bont, MD

Thomas Kuehne, MD

David Nadal, MD

Felix Niggli, MD

Arne Simon, MD

Nicole Bodmer, MD

Hulya Ozsahin, MD

The purpose of this study is to determine whether, in children with cancer presenting with fever in severe chemotherapy-induced neutropenia at low risk for medical complications, oral antibiotics in an outpatient setting after an initial phase of intravenous antibiotics and in-hospital observation for 8 to 22 hours, is not inferior as to safety and efficacy compared to continued intravenous antibiotics given in-hospital.

Details on antimicrobial therapy

* At presentation with FN (fever and neutropenia) and during an initial inpatient observation period of 8 to 22 hours, empirical intravenous broad-spectrum antibiotics are given. Type and dosage are chosen by the treating physician.
* Patients randomized to continued intravenous antibiotics continue with these antibiotics.
* Patients randomized to oral antibiotics receive a combination of oral ciprofloxacin (25 to 30 mg/kg/day, top dose 1500 mg/day) plus oral amoxicillin (65 to 80 mg/kg/day, top dose 2250 mg/day), both given in two doses per day.
* In both groups, the study gives guidelines (for certain situations) and rules (for other situations) when to change and when to stop antibiotics.

Details on clinical and laboratory controls

* During antibiotic therapy, patients are seen daily, either as inpatients or as outpatients according to randomization. Complete blood counts are performed at least every second day.
* After stopping antibiotic therapy and until resolution of severe neutropenia (if applicable), patients are seen every other day, with a complete blood count.
* Patients randomized to outpatient management have the possibility to contact at any time of the day (and night) a pediatric oncologist in case of problems, in order to discuss necessity for emergency control and/or rehospitalization.

Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting

A Prospective Multi-Center Study on Pediatric Patients With Fever in Severe Chemotherapy Induced Neutropenia, Including a Randomized Comparison of Outpatient Management and Oral Antimicrobial Therapy Versus Inpatient Management and Intravenous Antimicrobial Therapy in a Subgroup With Low Risk of Adverse Events (Low-Risk Subgroup Study)

Swiss Cancer League

Bayer

GlaxoSmithKline

Swiss Pediatric Oncology Group

Behaviors and Mental Disorders

Febrile Neutropenia

Chemotherapy-Induced Febrile Neutropenia

Stress Disorders, Traumatic

Heat Stress Disorders

Cefepime

Cefixime

After randomization, participants assigned to receive outpatient treatment with oral cefixime at a dose of 8 mg/kg/day were discharged. Treatment was provided by the researchers. Subjects were evaluated daily 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 ANC increased to above 500 per microliter. If fever resumed 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.

After randomization, participants continued intravenous inpatient antibiotic with cefepime 150 mg/kg/day according to local standard of care guidelines. Subjects were evaluated daily. All patients underwent a blood count every 48 to 72 hours. FN event resolution was defined as when the patient remained afebrile and the ANC increased to above 500 per microliter. If fever resumed, treatment was changed according to clinical guidelines. 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.

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).

Outpatient oral treatment.

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).

Inpatient intravenous treatment.

Martha J. Aviles Robles

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.

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.

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.

Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Children With Febrile Neutropenia

Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Pediatric Patients With Cancer and Febrile Neutropenia: a Non-inferiority Multicenter Randomized Clinical Trial

Occurrence of 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.

Presence of a new focus of infection, documented both by the clinical condition and by laboratory and other diagnostic tests.

Presence of 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.

Moderate and severe adverse reaction to antibiotics given, described as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.

Instituto Nacional de Pediatria

Hospital Juarez de Mexico

Hospital Infantil de Mexico Federico Gomez

Chief of Pediatric Infectious Diseases Service

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting	NCT00107081	Fever Neutropenia Cancer	ciprofloxacin a... Outpatient mana... i.v. antibiotic... inpatient manag...	1 Year - 18 Years	Swiss Pediatric Oncology Group
Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting	NCT00107081	Fever Neutropenia Cancer	ciprofloxacin a... Outpatient mana... i.v. antibiotic... inpatient manag...	1 Year - 18 Years	Swiss Pediatric Oncology Group
Safety and Efficacy of Ambulatory Versus In-hospital Antibiotic Treatment in Children With Febrile Neutropenia	NCT04000711	Chemotherapy-In...	Outpatient oral... Inpatient intra...	1 Year - 18 Years	Hospital Infantil de Mexico Federico Gomez

Spots Global Cancer Trial Database for outpatient treatment