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

NCT04000711 | Completed

• 2 other identifiers: HIM-2014-026233555
• Study Type: interventional
• Target: 117
• Locations: 0 countries
• Sites: N/A

Brief 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.

Conditions

Chemotherapy-Induced Febrile Neutropenia

Keywords

Fever and neutropenia; Febrile neutropenia; Cancer; Outpatient treatment; Children

Outcome Measures

Primary Outcomes (3)

• Therapeutic failure as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic.

  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.

  17 days after randomization.

• New focus of infection as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic.

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

  17 days after randomization.

• Hemodynamic instability as unfavorable clinical outcome of children with fever and neutropenia treated with oral outpatient antibiotic.

  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.

  17 days after randomization.

Secondary Outcomes (1)

• Presentation of any adverse reaction to any given antibiotic (oral or intravenous) of children with fever and neutropenia treated with oral outpatient vs intravenous inpatient management.

  Started on the day of enrollment and concluded 17 days after.

Study Arms (2)

Outpatient oral antibiotic treatment group.

EXPERIMENTAL

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.

Other: Outpatient oral treatment.

Inpatient intravenous antibiotic treatment group.

ACTIVE COMPARATOR

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.

Other: Inpatient intravenous treatment.

Interventions

Outpatient oral treatment. OTHER

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 antibiotic treatment group.

Inpatient intravenous treatment. OTHER

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 antibiotic treatment group.

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Children from 1 to 18 years of age.
• Underlying cancer diagnosis that presented with fever and neutropenia secondary to chemotherapy and after 48-72 hours of inpatient intravenous treatment with Cefepime, were hemodynamically stable, remained afebrile for at least 24 hours, and did not have a documented source of infection.
• Participants whose caretaker knew how to read and write and accepted to be part of the clinical trial.

You may not qualify if:

• Participants with positive cultures.
• Absolute neutrophil count (ANC) \< 100/mm3.
• Thrombocytopenia \< 30,000/mm3.
• Less than 7 days have passed from the start of the last chemotherapy session.
• Leukemia on remission induction therapy.
• Relapsed leukemia.
• Mucositis grade III or IV.
• Participants with allergy to cefixime.
• Need to receive any other medication intravenously.
• Need of oxygen support, parenteral nutrition or intravenous fluids.
• Oral intolerance.

Sponsors & Collaborators

• Hospital Infantil de Mexico Federico Gomez: lead
• Instituto Nacional de Pediatria: collaborator
• Hospital Juarez de Mexico: collaborator

Related Publications (9)

• Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, Raad II, Rolston KV, Young JA, Wingard JR; Infectious Diseases Society of America. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011 Feb 15;52(4):e56-93. doi: 10.1093/cid/cir073.

  PMID: 21258094 BACKGROUND

• Santolaya ME, Rabagliati R, Bidart T, Paya E, Guzman AM, Morales R, Braun S, Bronfman L, Ferres M, Flores C, Garcia P, Letelier LM, Puga B, Salgado C, Thompson L, Tordecilla J, Zubieta M; Sociedad Chilena de Infectologia; Sociedad Chilena de Hematologia. [Consensus: Rational approach towards the patient with cancer, fever and neutropenia]. Rev Chilena Infectol. 2005;22 Suppl 2:S79-113. Epub 2005 Nov 4. Spanish.

  PMID: 16311689 BACKGROUND

• Lehrnbecher T, Phillips R, Alexander S, Alvaro F, Carlesse F, Fisher B, Hakim H, Santolaya M, Castagnola E, Davis BL, Dupuis LL, Gibson F, Groll AH, Gaur A, Gupta A, Kebudi R, Petrilli S, Steinbach WJ, Villarroel M, Zaoutis T, Sung L; International Pediatric Fever and Neutropenia Guideline Panel. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol. 2012 Dec 10;30(35):4427-38. doi: 10.1200/JCO.2012.42.7161. Epub 2012 Sep 17.

  PMID: 22987086 BACKGROUND

• Santolaya ME, Alvarez AM, Aviles CL, Becker A, Cofre J, Enriquez N, O'Ryan M, Paya E, Salgado C, Silva P, Tordecilla J, Varas M, Villarroel M, Viviani T, Zubieta M. Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis. 2002 Sep 15;35(6):678-83. doi: 10.1086/342064. Epub 2002 Aug 23.

  PMID: 12203164 BACKGROUND

• Hakim H, Flynn PM, Srivastava DK, Knapp KM, Li C, Okuma J, Gaur AH. Risk prediction in pediatric cancer patients with fever and neutropenia. Pediatr Infect Dis J. 2010 Jan;29(1):53-9. doi: 10.1097/INF.0b013e3181c3f6f0.

  PMID: 19996816 BACKGROUND

• Vidal L, Ben Dor I, Paul M, Eliakim-Raz N, Pokroy E, Soares-Weiser K, Leibovici L. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst Rev. 2013 Oct 9;2013(10):CD003992. doi: 10.1002/14651858.CD003992.pub3.

  PMID: 24105485 BACKGROUND

• Zapata-Tarrés Marta, Klünder-Klünder Miguel, Cicero-Oneto Carlo, Rivera-Luna Roberto, Ortega-Ríos Velasco Fernando, Cortés Gallo Gabriel et al . Análisis de la atención de las complicaciones durante el tratamiento de niños con leucemia linfoblástica aguda. Bol. Med. Hosp. Infant. Mex.

  BACKGROUND

• Aviles-Robles M, Ojha RP, Gonzalez M, Ojeda-Diezbarroso K, Dorantes-Acosta E, Jackson BE, Johnson KM, Caniza MA. Bloodstream infections and inpatient length of stay among pediatric cancer patients with febrile neutropenia in Mexico City. Am J Infect Control. 2014 Nov;42(11):1235-7. doi: 10.1016/j.ajic.2014.07.021. Epub 2014 Sep 16.

  PMID: 25234044 BACKGROUND

• Aviles-Robles MJ, Reyes-Lopez A, Otero-Mendoza FJ, Valencia-Garin AU, Penaloza-Gonzalez JG, Rosales-Uribe RE, Munoz-Hernandez O, Garduno-Espinosa J, Juarez-Villegas L, Zapata-Tarres M. Safety and efficacy of step-down to oral outpatient treatment versus inpatient antimicrobial treatment in pediatric cancer patients with febrile neutropenia: A noninferiority multicenter randomized clinical trial. Pediatr Blood Cancer. 2020 Jun;67(6):e28251. doi: 10.1002/pbc.28251. Epub 2020 Mar 20.

  PMID: 32196898 DERIVED

MeSH Terms

Conditions

Chemotherapy-Induced Febrile Neutropenia; Fever; Neutropenia; Febrile Neutropenia; Neoplasms

Condition Hierarchy (Ancestors)

Agranulocytosis; Leukopenia; Cytopenia; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukocyte Disorders; Body Temperature Changes; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Martha J. Aviles Robles

  Hospital Infantil de Mexico Federico Gomez

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief of Pediatric Infectious Diseases Service

Model Details: 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.

Study Record Dates

• First Submitted: June 24, 2019
• First Posted: June 27, 2019
• Study Start: July 1, 2015
• Primary Completion: September 30, 2017
• Study Completion: October 8, 2017
• Last Updated: June 27, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will not share