RATIONALE

           In case of high risk neutropenia in pediatric patients, there is paucity of data regarding the appropriate time of stoppage of antibiotics. Further prolonged usage of antibiotics leads to the emergence of multidrug resistance organisms and Clostridium difficile associated diarrhea and increasing costs. Early discontinuation will also decrease the drug related side effects. So, we propose to conduct a study for early discontinuation of empirical antibiotic therapy at clinical recovery.

HYPOTHESIS

Empirical antibiotic therapy discontinuation guided by a clinical approach without neutrophil recovery in high risk febrile neutropenia patients would reduce antibiotic duration without negative consequences for the patient.                                                              

PRIMARY OBJECTIVE

1.      Recurrent fever

SECONDARY OBJECTIVES

2.      Antibiotic duration

3.      Procalcitonin level

4.      Renal dysfunction

5.      Adverse events (Nausea,vomiting)

6.      Re admission rate

7.      Requirement of third line antibiotics and therapeutic anti-fungal

8.      Mortality

STUDY DESIGN

·         Single center, Randomized, Open label, Non-Inferiority, Phase III

PATIENT POPULATION:

 Children, aged 2 – 18 years, with high risk febrile neutropenia, attending Department of Medical Oncology, IRCH, AIIMS

INCLUSION CRITERIA

1.      Age 2-18 years

2.      AML and ALL Induction and re-induction with febrile neutropenia

3.      Blood culture taken prior or within 24 hrs of start of anti-microbial therapy

4.      Giving consent

EXCLUSION CRITERIA

1.      Already enrolled once in previous episode

2.      Retroviral positive patients

3.      Patients who required therapeutic anti-fungals during febrile neutropenia

4.      Patients who required more than first line(cefoperazone-sulbactam+amikacin, levofloxacin or any oral antibiotics) and second line antibiotics(cefoperazone-sulbactam+meropenem/imipenem+teicoplanin/clindamycin)

5.      Patients who required inotropic support/mechanical ventilation during treatment course for febrile neutropenia

6.      Severe renal function impairment (defined as creatinine clearance below 30 ml/ min)

7.      Clinical or microbiological or radiologic focus of infection

8.      Patient undergone stem cell transplant

RANDOMISATION AND TREATMENT ALLOCATION AND FOLLOW UP

Eligible patients would be enrolled after obtaining written informed consent and fulfilling inclusion and exclusion criteria. Patients with febrile neutropenia would be followed up by temperature charts and alternate hemogram measurement and when they become afebrile for 72 hrs they would be randomized 1:1 as below into experimental arm and control arm. Stratified block randomization will be done and they will be stratified for ALL, AML and relapse cases. Random generated sequence will be transferred to sealed envelopes.

EXPERIMENTAL ARM

Empirical antibiotic therapy discontinuation will occur when the patient is afebrile, with resolution of signs, symptoms and test abnormalities and normalization of vital signs for ≥ 72 h without recovery of neutrophil > 500/mm3

CONTROL ARM

Empirical antibiotic therapy discontinuation will occur when the neutrophil count is above 500/mm3 and the patient is afebrile, with resolution of signs, symptoms and test abnormalities and normalization of vital signs for ≥ 72 h

FOLLOW-UP

After randomization patients would be followed up for primary and secondary objectives until day-35 of induction. At baseline CBC(In case of holiday , the next day) ,RFT/ LFT , Procacitonin(If Feasible), CXR, Blood culture : Central venous catheter and/ or Peripheral blood,Urine routine and culture( if symptomatic) are sent and any investigation required as per Clinical guidelines. Blood cultures are planned to collect prior to start of antibiotics or at least 24hrs within the start of antibiotics.

          On follow up Alternate day CBC (if holiday the next day), Temperature 6 hourly (documented in temperature chart made), Patient recording in dairy of nausea, vomiting

We plan to do analysis of procalcitonin levels as exploratory end point if feasible. Procalcitonin   is planned to be done at following time points: day of febrile neutropenia onset, Clinical recovery, Neutrophil recovery.

           All the patients are monitored for primary and secondary endpoints until d+35 of induction.

SAMPLE SIZE

Based on audit conducted over a period of 2 months in high risk febrile neutropenia the recurrence rate in standard of care is 36%. This new strategy to be statistically significant with 5% alpha error and 80% power and non-inferiority margin of 15%, we require to randomise 250 patients between the two arms. Assuming an attrition rate of 10% we propose to randomize maximum 280 patients who meet inclusion and exclusion criteria.

Working Definitions used:

•   Febrile Neutropenia: Single oral temperature >38.3 degree Celsius (101^oF) or >38.0 degree Celsius (100.4^oF) sustained over one hour and ANC of < 500 cells/mm³ or expected to decrease to < 500 cells/mm³ during the next 48 hours

•   Afebrile : Axillary temperature Ë‚ 37·5º C ≥ 48 hours 

•   Clinical recovery : Resolution of signs and symptoms  of infection and  normal vital signs ≥ 72 hours (Age based charts for Vitals IAP)

•    Recurrent fever episode : New episode of fever  after apyrexia visit during the follow-up 

•   Duration of antibiotic: From the start of antibiotic upto day 35

•   Mortality : Death from any cause during the follow-up upto day 35

•   Clinical focus: Any objective clinical site of infection

•   Radiologic Focus : As decided by the radiologist in the treating unit.

•   First line antibiotics :  Cefoperazone-sulbactam+amikacin, levofloxacin or any oral antibiotics

•   Second line antibiotics :  Cefoperazone-sulbactam+meropenem/imipenem+teicoplanin/clindamycin