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Antibiotic protocol for the management of febrile neutropenia

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Definition

Fever:  > 38 deg C on two consecutive occasions > 1 hour apart OR > 38.5 deg C on one occasion 
AND
Neutropenia:  a neutrophil count of <0.5 x 109/L OR recent intensive chemotherapy where neutropenia is expected 

Evaluation of patient

  • Take history and examine patient
  • Full blood count, urea and electrolytes (with reference to when last chemotherapy given)
  • Prior to administration of antibiotics:
    • Culture blood from all lumens.
      Adults and children greater than 30kg require two bottles; 20 ml of blood should be drawn and the volume of blood dispensed equally between two bottles.
      Children less than 30kg require two paediatric sized culture bottles; 0.25ml/kg (min-1ml-max-5ml per bottle). Peripheral culture may be indicated.
    • Culture other sites as clinically indicated
    • Chest X-ray/urine as clinically indicated
    • Sputum/NPA as clinically indicated
    • Check MRO (multi-resistant organisms) status and/or for clinical alerts

Initial treatment

Antibiotic therapy to be commenced within 1 hour of presentation (or fever spike if inpatient)

  Piperacillin/
Tazobactam*
100mg/kg q6h
(combined product) 
Vancomycin
15mg/kg q6h 
Amikacin 
20mg/kg q24h  
Meropenem
40mg/kg q8h  
Febrile neutropenia     tick      
+ High dose cytarabine
AML therapy  
 tick    tick    
+ History of ESBL**       tick      tick  
Shocked patients***      tick    tick    tick  
Suspected meningitis****       tick
(20mg/kg q8h)
   tick

*For patients with minor penicillin allergy (rash or similar); substitute cefepime 50mg/kg q8h (max 2g/dose) or if unavailable, ceftazidime 50mg/kg q8hr (max 2g/dose) plus vancomycin.  For patients with previous life threatening penicillin reaction; substitute ciprofloxacin 10mg/kg q8h plus vancomycin.

**For ESBL with known resistance to amikacin, use meropenem alone 40mg/kg q8h (max 2g/dose)

***If  on-going  cardiovascular  instability  (hypotension  OR  tachycardia  OR  signs  of  inadequate  organ perfusion) following 40ml/kg of intravenous fluid resuscitation contact Intensive Care.

Antibiotic dose will be divided and given down both lumens in patients with double lumen catheters. The empiric protocol for all febrile neutropenic patients is monotherapy with piperacillin/ tazobactam (Tazocin) 100mg/kg q6h (combined product), max 4.5g per dose, and subject to the following exceptions:

  • For patients who have been treated with high dose cytarabine (HD ARA C), are on AML therapy or for BMT inpatients, add vancomycin 15mg/kg q6h (initial max 750mg/dose) due to high risk of streptoccocus mitis infection
  • For patients who are shocked (multiple fluid boluses or PICU), add amikacin 20mg/kg q24h (max 1.5g/dose) and vancomycin 15mg/kg q6h (max 750mg/dose)
  • For patients known to have any ESBL colonisation add amikacin 20mg/kg q24h (unless known resistance to amikacin in which case substitute meropenem  40mg/kg q8h (max 2g/dose)
  • For patients who had exposure to Cisplatin, avoid amikacin due to risk of renal impairment
  • For  patients with suspected meningitis, use meropenem 40mg/kg/q8h and  vancomycin  20mg/kg q8h (initial max 1g/dose)
  • For patients with low risk febrile neutropenia after initial therapy who are suitable for outpatient treatment; ceftriaxone 80mg/kg q24h (max 2g) as a single agent may be considered

****Note: when Vancomycin is prescribed it will most often be in combination with q6h Tazocin, our departmental practice will be for Vancomycin 15mg/kg q6h (max 750mg/dose or 3g/day) and only in exceptional situations, such as suspected meningitis, it could be as Vancomycin 20mg/kg q8h (max 3g/day) in combination with meropenem 40mg/kg q8h.

Risk groups

Please note:

  • If recent FBC not available, estimate which risk group the patient falls into based on previous chemotherapy, and start antibiotics per above
  • Febrile patients with neutrophil count 0.5 - 1.0 x 109/L should be evaluated for need for possible empiric antibiotics
  Low Risk High Risk 
Absolute neutrophil count    0.1 - 0.5 x 109/L    <0.1 x 109/L   
Duration of neutropenia  < 7 Days   ≥ 7-10 Days  
Co morbidity    None    - Toxic/Shocked
- BMT Inpatient
- AML patients   

Evaluate at 48 hours:

  • All culture results should be reviewed and antibiotics adjusted according to isolates and antibiotic sensitivities
  • If afebrile with negative cultures and still neutropenic, consider discharge home on ceftriaxone IV 80mg/kg (max 2g) once daily.   If high risk consider additional once daily amikacin 20mg/kg until neutrophil counts start to increase or until neutrophil count > 0.5 x 109/L
  • Daily ceftriaxone is not recommended for inpatient use
  • If cultures are negative for gram-positive organisms stop vancomycin after 48 hours
  • Discontinue empiric antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours and who have evidence of marrow recovery.

Note on microbiology regarding change in febrile neutropenic regimens:
Pathogens that are not covered by piperacillin/tazobactam include
1) enterococcus
2) coagulase negative staphylococcus
3) Stenotrophomonas (This is, however, an environmental pathogen that is uncommonly seen, usually of a lower virulence, and can be treated with cotrimoxazole or timentin once culture result is available).

Blood Cultures:
To be collected at 24 hrs if patient still febrile and again at 48 hrs if remaining febrile. Thereafter blood cultures only as directed.

Escalation of therapy:
If  patient  is  clinically  well or  improving,  but  persistently febrile  at  24-72  hours,  do  not modify empiric antibacterial regime based solely on persistent fever. If there is clinical deterioration, change to meropenem and add vancomycin.

Febrile at 4-5 days:

  • Reassess and consider more invasive investigative procedures and imaging
  • Consider switching to meropenem 40mg/kg q8h*
  • In high risk children with persistent fever beyond 96 hours perform evaluation for invasive fungal disease (IFD), e.g. CT scan lung, brain and sinuses plus abdomen (if LFTs deranged) and other clinically suspected areas of infection
  • Add Liposomal Amphotericin (AmBisome ®) IV 3mg/kg once daily*
    Ambisome can be commenced before  4-5  days (at the discretion of the Paediatric Oncology consultant in conjunction with a Paediatric Infectious Disease Specialist) regardless of fever status for children who are neutropenic on steroids and with a prior history of prolonged antibiotics or otherwise considered high risk for IFD.
    (Prescribe as Ambisome or Liposomal Amphotericin B to avoid confusion or errors)
    Close monitoring of electrolytes and renal function is essential every 24 to 48 hours
    If renal impairment or previous adverse reaction to AmBisome consider Caspofungin and consult Paediatric Infectious Disease (ID) team.

The use of other nephrotoxic antibiotics and sepsis means patients are at risk of renal impairment.

*All patients with persistent fever on meropenem and/or empiric liposomal amphotericin should be discussed with Paediatric ID team

Remember  possibility  of  viral  infection HSV, VZV, CMV, EBV, Adenovirus  etc. Consider acyclovir IV 500mg/m2/dose q8h for children under 12 years, and 10mg/kg q8hr for children over 12 years.

Indications for line removal

  • Bacillus species infections
  • Staphylococcus aureus infection (unwell or with persistent bacteraemia)
  • Recurrent infection with the same organism in the same line
  • Shock and sepsis in a neutropenic patient
  • Tunnel infections
  • Exit site infection with aspergillus or mycobacterium
  • Fungal line infections
  • Blood cultures still positive after 48-72 hours of IV antibiotics or failure to improve clinically
  • Valvular vegetation/endocarditis
  • Fever + hypotension after line flush

Nursing

Administration Guidelines

  • Starship nurses - please refer to Starship Guardrails Administration Guidelines
  • Outreach nurses - please refer to your local hospital guidelines

Monitoring levels

Amikacin:

  • Trough levels required, take level prior to second dose and every 3 to 5 days if normal renal function.  Aim for trough less than 1mg/L.
    - If impairment of renal function or other nephrotoxic agents being administered take levels more frequently
    - If trough levels high may need to space out dosage interval eg 24-36 hours
  • Peaks not required for once daily dosing.

Vancomycin:

  • Take trough level immediately prior to fourth dose and every 3 to 5 days if normal renal function and vancomycin levels within range
  • Aim for trough: 10mg-15mg/L, up to 20mg/L in certain cases
  • Peaks not required

Associated Documents

Starship Children's Health Neutropenia Nursing Care (ADHB staff only) http://adhbintranet/adhb_policies_and_procedures/2HSGs/Child_Health/NeutropeniaNursingCare.htm

AHDB Blood Cultures: When Where and How to Take (ADHB staff only) \\ahsl6.adhb.govt.nz\main\Groups\Everyone\POLICY\Master file of Intranet\Clinical Practice\Board\Blood Cultures.pdf 

References

1.    New Zealand Formulary for Children (NZFC) 2014

2.    Febrile Neutropenia Guideline, The Royal Children's Hospital Melbourne 2014

3.    Medsafe Datasheet. Piperacillin/Tazobactam Tazocin EF 2014

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Document Control

  • Date last published: 01 August 2016
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network
  • Author(s): Jane Skeen, Lochie Teague
  • Owner: Jane Skeen
  • Review frequency: 2 years