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).
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
55
Given if patient has no known allergies, until ANC recovery at 100mg/kg (max 4g) 6 hourly.
Given if patient has non life-threatening hypersensitivity (preferred option), until ANC recovery at 50mg/kg (max 2g) 8 hourly.
If non life-threatening hypersensitivity (second option), given until ANC recovery at 50mg/kg (max 2g) 8 hourly
Royal Children's Hospital
Melbourne, Victoria, Australia
Unfavourable clinical course occurring during the same period of severe neutropenia
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
Time frame: During the same episode of neutropenia, up to 28 days post-enrolment.
Fever recurrence
Incidence of fever recurrence (temperature ≥38 degrees Celsius)
Time frame: Up to 28 days post-enrolment
Clinical instability
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.
Time frame: Up to 28 days post-enrolment
Admission to intensive care unit (ICU)
Incidence of admission to intensive care unit (all cause)
Time frame: Up to 28 days post-enrolment
New positive blood culture
Incidence of positive blood culture
Time frame: Up to 28 days post-enrolment
28 day all-cause and infection-related mortality
Incidence of all-cause and infection-related mortality, as defined post-mortem
Time frame: Up to 28 days post-enrolment
Duration of neutropenia
Mean days of neutropenia defined as ANC \<500 cells/mm3
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
If life-threatening hypersensitivity given with ciprofloxacin, given until ANC recovery at 15mg/kg (max 500mg) 6 hourly
Given until ANC recovery at 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s.
If life-threatening hypersensitivity given with vancomycin, given until ANC recovery at 10 mg/kg (max 400 mg) 12 hourly
Given if patient has no known allergies at 100mg/kg (max 4g) 6 hourly, stopping 48 hours post-fever resolution.
If non life-threatening hypersensitivity (preferred option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution
If non life-threatening hypersensitivity (second option) at 50mg/kg (max 2g) 8 hourly, stopping 48 hours post-fever resolution
If life-threatening hypersensitivity given with ciprofloxacin at 15mg/kg (max 500mg) 6 hourly, stopping 48 hours post-fever resolution
At 18-22.5mg/kg (max 1.5g) daily in combination with other antibiotic/s, stopping 48 hours post-fever resolution
If life-threatening hypersensitivity given with vancomycin at 10 mg/kg (max 400 mg) 12 hourly, stopping 48 hours post-fever resolution
Time frame: During the same episode of neutropenia or up to 28 days post-enrolment
Clinician confidence and acceptability
Measured by number of patients for which randomisation is overridden in the Early Stopping arm and the recorded reason
Time frame: Up to 28 days post-enrolment
Total antibiotic duration
Mean number of days antibiotics are administered
Time frame: Up to 28 days post-enrolment
Length of hospital stay
Mean number of days admitted to the study site hospital ward
Time frame: Up to 28 days post-enrolment, or until discharge from hospital (whichever is the later)
Readmission to hospital
Incidence of unplanned admission to the study site hospital
Time frame: Up to 28 days post-enrolment
Development of C. difficile infection
Incidence of C. difficile infection detected in unformed stool
Time frame: Up to 28 days post-enrolment
Development of an antibiotic resistant infection or colonisation
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)
Time frame: Up to 28 days post-enrolment
Patient/parent/caregiver confidence
Number of patients that consent to study as proportion of patients eligible
Time frame: Within 48 hours of having informed consent discussion with the study team
Patient/parent/caregiver acceptability
Number of patients for which randomisation is overridden in the Early Stopping arm due to withdrawn consent
Time frame: Within 48-96 hours post assignment to intervention arm