Safety of Procalcitonin Guided Discontinuation of Antibiotic Therapy among Children Receiving Cancer Chemotherapy and Having Low Risk Febrile Neutropenia – A Randomized Non-Inferiority Trial

Children with low risk febrile neutropeniawithout any identified focus will be started on IV antibiotics as perinstitutional protocol which usually includes combination therapy withantipseudomonal penicillin (piperacillin + tazobactam -if platelet countsis<20,000/mm3) or cephalosporin (cefoperazone + sulbactam – if plateletcount is >20,000/mm3) and an aminoglycoside (amikacin). Whenever there is arespiratory focus, the child is started on Amoxycillin-clavulanic acid andamikacin. Whenever there is a gastrointestinal focus, the child will be startedon cefoperazone + sulbactam and ofloxacin or metronidazole. The patients willreceive these antibiotics at age and weight appropriate dosage on outpatientbasis from day care.

The baseline investigations like completeblood counts (CBC), serum electrolytes, renal function tests (RFTs), liverfunction tests (LFTs), chest X-ray (CXR), blood culture and sensitivity andother microbiological samples if required will be sent routinely as per unit’spolicy before initiation of empirical antibiotics. Along with theabove-mentioned samples, 2 ml serum will also be taken for procalcitonin (PCT)estimation. The parents will be instructed to record temperature at least 3times daily and also whenever the child is febrile and bring the temperaturerecord for review. The child will be closely followed up clinically and arepeat sample for CBC and PCT estimation will be sent at 48 hours of startingempirical antibiotics. The child will be reviewed again at 72 hours of startingempirical antibiotics along with CBC, PCT and blood C/S report. Those childrenwith negative/normalisation of PCT at 48 hours, afebrile period of atleast 24hours and sterile blood culture will be randomised into two groups.

**Intervention arm:**Early discontinuation of empirical antibiotics (at 72 hours).

Control arm:Standard therapy with continuation of antibiotics for at least 7 days or untilrecovery of neutropenia i.e. ANC >500/mm3 which will beascertained by repeat CBC every 2/3 days or as and when needed till 14 days ofrandomization.

We shall use computer generatedblock randomization with variable block size, to ensure an equal number ofparticipants in each group. The randomisation blocks, thus generated, will bekept with an individual not involved in the enrolment of the subjects,administration of the intervention or the analysis of the data.

The randomisation data will be provided to an individual in theDepartment of Biostatistics, AIIMS, New Delhi, who will be involved in labellingof the envelopes as serial numbers that correspond to a given randomisedpatient number. The principal investigator shall open the next seriallynumbered envelopes upon enrolment of the patient. All the opened envelopesalong with the patient allocation details and date of opening the envelopeswill be kept safe by the principal investigator for future reference.

Allocation concealment will be ensured by using randomisation andidentical opaque sealed envelopes.

The children belonging to both the groups will befollowed by clinically for 14 days after randomization for primary andsecondary end points and for 28 days for all-cause mortality.

Primary end points:

• Any recurrence of fever or any clinical signs/symptoms of infection relapse requiring restarting/upgradation of Antibiotics
• Need for hospitalization due to infectious etiology
• Death due to infectious etiology

Secondaryend points:

• Number of days with antibiotic exposure
• Death due to any cause

During follow up, we will use the same criteria as mentioned earlier (single oral temperature of≥ 38.3◦C (101◦F) or oral temperature of ≥ 38◦C(100.4◦F) for 1 hour for the definition of fever which is one of ourprimary end points. Restarting and upgradation of antibiotics will be done asper unit’s protocol for management of febrile neutropenia. However, we willkeep low threshold for admission to wards in case the child developedinfectious relapse during the study follow up in order to ensure safety.