Clinical Practice Guidelines

Febrile Neutropenia

  • This guideline has been adapted for statewide use with the support of the Victorian Paediatric Clinical Network

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    Background to condition

    Fever and neutropenia (FN) is a common complication of the treatment of cancer. The risk of serious bacterial infection is related to the degree and duration of neutropenia. Bacteraemia is diagnosed in up to one-third of children with FN.

    Key points

    • Fever and suspected or confirmed neutropenia (FN) is a medical emergency.
    • Children with FN and signs of sepsis require urgent treatment (Triage Category 2) and those at risk of imminent cardiovascular collapse should be seen immediately (Triage category 1). All other children should commence treatment within 30 minutes of hospital arrival (Triage Category 3).
    • Antibiotics must be administered within 30 minutes if there are signs of sepsisandwithin 60 minutes if there are no signs of sepsis.
    • All patients must be discussed with the on-call oncology consultant/fellow (or consultant paediatrician in regional centres) after the 1st dose of intravenous antibiotic.

    Definitions

    Fever

    A single temperature ≥ 38.5°C or a sustained temperature ≥ 38.0°C over 1 hour.

    Neutropenia

    An absolute neutrophil count < 500/mm3 OR < 1000/mm3 with predicted decline to < 500/mm3 over the next 48 hours

    Suspected neutropenia

    Neutropenia should be suspected in any oncology patient that has received chemotherapy (oral or intravenous) within the last 14 days and other children with recurrent neutropenia.

    High risk cancer treatment protocols

    Acute myeloid leukaemia (AML) treatment; Acute lymphoblastic leukaemia (ALL) induction, ALL delayed intensification, infant ALL; lymphoma induction; allogeneic transplant (day-14 to day+356); autologous transplant (day-7 to day +30); re-induction chemotherapy for any relapse.

    Systemic compromise

    Fluid bolus or inotrope requirement, need for any respiratory support and/or altered conscious state

    Primary Treatment Centre

    The centre where the patient was diagnosed and the treatment plan decided. For the majority of children this will be either Royal Children's Hospital or Monash Children's Hospital.

    Initial assessment and management

    Initial treatment algorithm

    Fever_and_suspected_or_confirmed_neutropenia

    Request to see patient's Febrile Neutropenia Treatment Card or Letter. This will have important information regarding cancer diagnosis, risk status and recommended antibiotics

    History and examination with particular attention to:

    • Recognition of sepsis (see Sepsis guideline)
    • Source of infection - children with neutropenia may not have visible signs of infection

    Prompt CVAD or IV access (within 30 minutes of arrival):

    • Central venous access devices (CVAD) should be accessed by appropriately trained staff for blood sampling and antibiotics. If there is a delay in accessing the CVAD, a peripheral intravenous line should be inserted
    • If patient has signs of sepsis, do not delay CVAD or IV access while waiting for anaesthetic cream (ie, EMLA or AnGel) to work
    • CVAD access difficulties:

    Investigations:

    • FBE & differential (do not delay antibiotics while awaiting neutrophil count)
    • Electrolytes and creatinine
    • Blood cultures (2 sets) - see CCC BC algorithm for details
    • Group and hold
    • Venous blood gas and lactate
    • Urine for M/C/S (do not delay antibiotics while awaiting specimen)

    Initial antibiotics (within 30-60 minutes of arrival): 

    • All patients must be given the first antibiotic within 60 minutes (30 minutes if systemic compromise/sepsis)

    Patient group

    Recommended antibiotics

    Patients who are clinically stable

    Piperacillin-tazobactam* 100mg/kg (max 4g) iv 6H

    Non-life threatening penicillin hypersensitivity  (rash):
    Cefepime 50mg/kg (max 2g) iv 8H (preferred)
    OR Ceftazidime** 50mg/kg (max 2g) iv 6H

    Life-threatening (immediate) penicillin or beta-lactam hypersensitivity:
    Ciprofloxacin 10mg/kg (max 400mg) iv 12H
    AND Vancomycin 15 mg/kg (max 500 mg) iv 6H (target trough 10-15 mg/L pre 5th dose)

    Patients who have any of:

    (i) Systemic compromise/sepsis
    (ii) High risk cancer treatment
    (ii) Inpatient onset FN

    As for patients who are clinically stable
    AND Amikacin*** 22.5 mg/kg (18 mg/kg if >10y) (max 1.5 g) iv 24H
    (Target trough <2mg/L pre 3rd dose)

    Regional centres may choose alternate aminoglycoside (i.e. gentamicin) depending on local susceptibility data

    Patients with suspected resistant Gram-positive infection

    (Including patients with cellulitis, obviously infected vascular devices, proven Gram-positive bacteraemia, and known MRSA colonisation with extensive skin breaks)

    As for patients who are clinically stable
    AND vancomycin 15 mg/kg (max 500 mg) iv 6H (target trough 10-15 mg/L pre 5th dose)

    Cease if susceptibilities indicate an alternative agent can be used

    NB. Prolonged fever in a clinically stable patient is NOT an indication to commence vancomycin

    Patients with features of abdominal or perineal infection

    As for patients who are clinically stable
    AND metronidazole 7.5mg/kg (max 500mg) iv/oral 8H if receiving cefepime, ceftazidime or ciprofloxacin as first line antibiotic

    NB. Piperacillin-tazobactam will provide adequate anaerobic cover, other than for suspected Clostridium difficile colitis

    • The first antibiotic should be the most broad-spectrum (ie. Piperacillin-Tazobactam)
    • Patients with a double lumen CVAD should have antibiotics divided and administered down both lumens.
    • Detailed antibiotic recommendations (including doses) – see below table 

     

    • Trade names for piperacillin-tazobactam include Tazocin®, Tazopip®, PiperTaz®, and DBL Piperacillin and Tazobactam®. Doses refer to piperacillin component.
    • ceftazidime has reduced activity against viridans group streptococci. It should be avoided in patients with extensive mucositis, recent high dose methotrexate or cytarabine and ciprofloxacin prophylaxis.
    • IV aminoglycoside antibiotics (i.e. amikacin and gentamicin) should not be given simultaneously through the same line as IV penicillins including piperacillin-tazobactam and ticarcillin-clavulanate. The line should be flushed well with sodium chloride 0.9%, before and after giving each medication.

     

    Fluid resuscitation

    If patient has signs of sepsis:

    • Give initial 20ml/kg Normal Saline IV bolus over a maximum of 10 minutes (not through an infusion pump)
    • Monitor for improvement in vital signs, perfusion and/or conscious state
    • If only transient improvement occurs, consider additional fluid boluses to a maximum volume of 40 ml/kg
    • Total volumes >40 ml/kg should be discussed with senior clinician
    • If no improvement, consider inotropic support (see Sepsis CPG)

    Follow-up assessment

    After the first dose of antibiotic has been given, complete the following:

    A full examination with particular attention to:

    • Upper respiratory tract for otitis media and sinusitis
    • Oropharynx for dental abscess and mucositis
    • Lower respiratory tract for signs of pneumonia, including Pneumocystis jiroveci (PJP) pneumonia (cough, tachypnoea, hypoxia, interstitial infiltrate on CXR)
    • Abdomen for signs of Clostridium difficile colitis (generalised abdominal tenderness) or typhlitis (tenderness over caecum)
    • Skin for cellulitis or vesicular lesions
    • Perineum and perianal area for anal fissure, cellulitis or abscess
    • CVAD for signs of tunnel/exit site infection
    • Signs of anaemia and/or thrombocytopenia

    Additional investigations as indicated:

    • Respiratory symptoms:
      • CXR (there may be no changes while neutropenic)
      • Nasal swab (throat swab if thrombocytopenic), for respiratory virus PCR (only if requested by oncology team after review. Patient placement should NOT be delayed whilst waiting for results (NPA guideline
      • Sputum for M/C/S in older children
    • Diarrhoea:
      • Stool for M/C/S and viral studies
      • Stool for C. difficile toxin assay if recent treatment with antibiotics
    • Skin, CVAD site or mouth lesions:
      • Bacterial swab for M/C/S (including Gram stain slide)
      • Viral swab of vesicular lesions and mouth ulcers for HSV and VZV PCR
    • CNS symptoms
      • CT brain and lumbar puncture may be indicated if there are new CNS symptoms or signs. Please discuss with on call oncologist first.
      • Correction of thrombocytopenia and/or coagulopathy must occur prior to LP.
    • Other
      • Cross-match

    Referral

    • All patients presenting to the Emergency Department with FN must be discussed with the local paediatric team (regional centres only) and the treating oncology team (all centres). To avoid antibiotic delays, this should be done after the 1st dose of antibiotic has been given.
      • Regional centres - contact the local consultant paediatrician on call after the first dose of antibiotic has been given. Daily consultation with the treating oncology team to discuss ongoing care is also recommended.
      • RCH and Monash Children's hospital - contact the treating oncology team after the first dose of antibiotic has been given (see below for contact details)
    • Unless the patient is suitable for discharge, arrange urgent admission to the ward.

    Consider transfer to the patient's Primary Treatment Centre (PTC) if:

    • Severe sepsis
    • Clinical deterioration despite broad spectrum antibiotics
    • Prolonged (>72 hours) FN despite broad spectrum antibiotics

    Transfer should be discussed with the oncology consultant/fellow at the patient's primary treatment centre (see contact details below).

    For further advice and to arrange inter-hospital (including ICU level) transfers ring the Sick Child Hotline: (03) 9345 7007 

    Ongoing Management (beyond the 1st 24 hours) 

    Clinical assessment 

    Patients should undergo daily:

    • Examination for signs of an infective focus
    • Review of microbiology results to guide antibiotic therapy
    • Collection of blood cultures for the first 72 hours. Blood cultures beyond 72 hours are only required if there is a new fever after an afebrile period for >24hrs, or a clinical deterioration

    Modifying antibiotics 

    • Patients who are responding to initial empiric antibiotic therapy (including patients who remain febrile but are clinically stable)Discontinue double coverage for Gram-negative infection (i.e. amikacin or gentamicin) and/or empiric vancomycin (if initiated) after 24 to 48 hours if there is no specific microbiologic indication to continue combination therapy.
    • Patients who become clinically unstable on initial empiric antibiotic therapy – escalate antibiotic regimen to include coverage for resistant Gram-negative, Gram-positive, and anaerobic bacteria
    • Do not broaden initial empiric antibiotic regimen based solely on persistent fever in children who are clinically stable

    All treatment modifications, including cessation of antibiotics, should be discussed with the patient's primary oncology team.

    Stopping antibiotics

    All patients:

    • Evidence of marrow recovery – Discontinue empiric antibiotics in patients who have negative blood cultures at 48 hours and who have been afebrile for at least 24 hours
    • No evidence of marrow recovery and neutropenia expected to be prolonged – The decision to discontinue or continue antibiotic therapy should be made by the primary oncologist taking into account the intensity of recent chemotherapy and associated risk factors. Cessation of antibiotic therapy may be considered if (i) cultures are negative; (ii) skin and mucous membranes are intact and (iii) there are no impending invasive procedures or ablative chemotherapy planned.

    Low-risk FN:

    • Consider discontinuation of empiric antibiotics at 72 hours in low-risk patients (as judged by the treating oncologist) who have negative blood cultures and who have been afebrile for at least 24 hours, irrespective of marrow recovery status, provided careful follow-up is ensured

    All treatment modifications, including cessation of antibiotics, should be discussed with the patient's primary oncology team

    Prolonged (>72 hours) or recurrent fever despite broad-spectrum antibiotic/s

    • Evaluate and consider treatment for invasive fungal infection (IFI) (see below)
    • Regional centres should transfer patients with prolonged or recurrent fever to their primary treatment centre for further investigations
    • Patients considered high-risk for IFI include those with (i) relapsed acute leukemia; (ii) AML; (iii) Graft versus Host Disease (GvHD); (iv) allogeneic HSCT; (v) severe aplastic anaemia; (vi) prolonged corticosteroid use and (vii) prolonged ICU admission. All other patients should be categorised as low-risk for IFI (please note that low-risk does not equal no-risk)

    Evaluation for IFI

    • CT of lungs and CT sinuses (age >2y) and targeted imaging of other clinically suspected areas of infection
    • Bronchoscopy and lavage (BAL) if pulmonary infiltrates detected on CT lungs (consult local Infectious Diseases Unit to ensure appropriate investigations on BAL fluid are done)
    • Fungal cultures from blood, BAL and other sterile sites as indicated
    • Galactomannan (+/- aspergillus PCR if available) on blood and BAL fluid

    Empiric treatment for suspected IFI

    • Consult local Infectious Diseases Unit
    • Recommended empiric antifungal agent is amphotericin (caspofungin or voriconazole if amphotericin contraindicated). For targeted IFI treatment, discuss with local Infectious Diseases Unit.
    • IFI high risk – initiate empiric antifungal treatment for prolonged or recurrent fever of unclear etiology that is unresponsive to broad-spectrum antibacterial agents
    • IFI low risk – consider empiric antifungal therapy in setting of persistent FN

    Information specific to RCH

    Information specific to Monash Children's Hospital 

    • For CVAD access issues – contact the CCC AUM or clinical support nurse (business hours) and 41N AUM (after hours)
    • For referral or discussion of patients with FN - contact the oncology fellow (page 689) during business hours and the oncology consultant on call after hours (via hospital switch)