Early Versus Late Stopping of Antibiotics in Children With Cancer and High-risk Febrile Neutropenia
- Conditions
- Febrile Neutropenia
- Interventions
- Registration Number
- NCT04948463
- Lead Sponsor
- Murdoch Childrens Research Institute
- Brief Summary
This randomised controlled trial will determine the non-inferiority of stopping empiric antibiotics prior to absolute neutrophil count (ANC) recovery (Early Stopping) versus stopping antibiotics upon ANC recovery (Standard of Care/ Late Stopping) , in children with cancer and high-risk febrile neutropenia (FN).
- Detailed Description
Febrile neutropenia (FN) is a common complication of childhood cancer treatment and a leading cause of hospital admission and antibiotic exposure. Management typically involves broad-spectrum antibiotics until resolution of fever and absolute neutrophil count (ANC) recovery \>500 cells/mm3. However, despite the frequency with which FN occurs, evidence to guide duration of antibiotics is limited to observational studies and small randomised controlled trials.Current international clinical guidelines provide conflicting recommendations on when to cease empiric antibiotics for FN. Early cessation of antibiotics in FN may translate to reduced antibiotic exposure and limit potential harms including drug side-effects, antimicrobial resistance, Clostridioides difficile infection and microbiome disruption. This randomised controlled trial will use a composite endpoint of fever recurrence, physiological instability, new bacteremia, intensive care admission and death to determine the non-inferiority of stopping antibiotics prior to ANC recovery compared with standard of care (SOC), in children with cancer and high-risk FN. Adopting a health informatics approach, patient identification, consent, randomisation and reporting of outcomes will be embedded within the electronic medical record (EMR). Children with high-risk FN who have been afebrile and clinically stable for at least 48 hours will be randomised to cease antibiotics or continue SOC. Data on primary outcomes, antibiotic duration, length of stay, C. difficile infection and antimicrobial resistance will be automatically collected by the EMR. This is the first study of its kind in children with high-risk FN and adopts a novel embedded trial design. Results will inform optimal antibiotic duration in FN, potentially reducing unnecessary antibiotic exposure.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 312
-
Diagnosis of
- Acute myeloid leukemia (AML) or acute lymphoblastic leukaemia (ALL) in dose-intensive phases of induction/re-induction, intensification or consolidation or
- ALL or acute lymphoblastic lymphoma patients on a TOT17 protocol or
- Any disease within 100 days of allogeneic or autologous HSCT
-
Neutropenia (<500 cells/mm3)
-
Afebrile (temperature <38.0°C) period for at least 48 hours and no more than 96 hours after at least one temperature measured by axillary or tympanic thermometer (≥38.0°C)
-
Commenced on empiric FN antibiotics (any of piperacillin-tazobactam, cefepime, ceftazidime or vancomycin and ciprofloxacin)
- Prolonged febrile neutropenia (documented daily temperature ≥38.0°C for ≥5 days)
- Documented positive blood culture since onset of FN episode and prior to randomisation
- Documented other infection (microbiologically or clinically documented) requiring antibiotic treatment since onset of FN episode and prior to randomisation
- Admitted to the ICU at the time of randomisation
- Clinical instability (One or more conscious state, respiratory rate, blood pressure, heart rate or oxygen saturations in MET criteria OR two or more respiratory rate, blood pressure, heart rate or oxygen saturations simultaneously (+/- 4 hrs) in the clinical review criteria in 48 hours prior to randomisation)
- Within 28 days of last randomisation
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Early Stopping Ciprofloxacin Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC) Standard of care Piperacillin and Tazobactam for Injection Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Standard of care Cefepime Injection Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Standard of care Ciprofloxacin Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Early Stopping Cefepime Injection Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC) Early Stopping Ceftazidime Injection Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC) Early Stopping Vancomycin Injection Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC) Early Stopping Amikacin Injection Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC) Standard of care Ceftazidime Injection Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Standard of care Vancomycin Injection Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Standard of care Amikacin Injection Continuing empiric FN antibiotics until resolution of fever for 48 hours and recovery of ANC as defined by the treating clinician but usually to ≥200-500/mm3 Early Stopping Piperacillin and Tazobactam for Injection Stopping empiric FN antibiotics after resolution of fever for 48 hours, irrespective of absolute neutrophil count (ANC)
- Primary Outcome Measures
Name Time Method Unfavourable clinical course occurring during the same period of severe neutropenia During the same episode of neutropenia, up to 28 days post-enrolment. Incidence of unfavourable clinical course, defined as any of the following: recurrence of fever, clinical instability (see below definition), admission to the intensive care unit, new positive blood culture collected after randomisation, or death
- Secondary Outcome Measures
Name Time Method Clinical instability Up to 28 days post-enrolment Incidence of clinical instability defined as; one or more vital signs (conscious state, respiratory rate, blood pressure, heart rate, oxygen saturation) meeting mandatory emergency (MET) call criteria OR two or more vital signs simultaneously (within 4 hours of each other) meeting clinical review criteria.
Admission to intensive care unit (ICU) Up to 28 days post-enrolment Incidence of admission to intensive care unit (all cause)
28 day all-cause and infection-related mortality Up to 28 days post-enrolment Incidence of all-cause and infection-related mortality, as defined post-mortem
Duration of neutropenia During the same episode of neutropenia or up to 28 days post-enrolment Mean days of neutropenia defined as ANC \<500 cells/mm3
Clinician confidence and acceptability Up to 28 days post-enrolment Measured by number of patients for which randomisation is overridden in the Early Stopping arm and the recorded reason
Total antibiotic duration Up to 28 days post-enrolment Mean number of days antibiotics are administered
Length of hospital stay Up to 28 days post-enrolment, or until discharge from hospital (whichever is the later) Mean number of days admitted to the study site hospital ward
Fever recurrence Up to 28 days post-enrolment Incidence of fever recurrence (temperature ≥38 degrees Celsius)
Readmission to hospital Up to 28 days post-enrolment Incidence of unplanned admission to the study site hospital
Development of C. difficile infection Up to 28 days post-enrolment Incidence of C. difficile infection detected in unformed stool
Patient/parent/caregiver confidence Within 48 hours of having informed consent discussion with the study team Number of patients that consent to study as proportion of patients eligible
New positive blood culture Up to 28 days post-enrolment Incidence of positive blood culture
Development of an antibiotic resistant infection or colonisation Up to 28 days post-enrolment Incidence of antibiotic resistant infection or colonisation including Methicillin-resistant Staphylococcus aureus (MRSA), extended spectrum beta-lactamases (ESBL)-producing enterobacterales, carbapenem-resistant enterobacteriaceae (CRE), Vancomycin-resistant Enterococcus (VRE)
Patient/parent/caregiver acceptability Within 48-96 hours post assignment to intervention arm Number of patients for which randomisation is overridden in the Early Stopping arm due to withdrawn consent
Trial Locations
- Locations (1)
Royal Children's Hospital
🇦🇺Melbourne, Victoria, Australia