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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 only in patients with respiratory signs and symptoms
    • Urine as clinically indicated
    • Sputum/NPS 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.

****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.

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) or are on AML therapy, add vancomycin 15mg/kg q6h (initial max 750mg/dose) due to high risk of streptoccocus mitis infection. For BMT inpatients, the decision to add vancomycin should be discussed with the on-call Haematologist/Oncologist.
  • 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 there is known resistance to amikacin, in which case substitute meropenem 40mg/kg q8h (max 2g/dose)
  • For patients who have known renal impairment or are at high risk of renal impairment, use meropenem and vancomycin (doses may need adjustment depending on severity of renal impairment) to avoid using aminoglycoside in addition to Tazocin and vancomycin
  • 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 (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

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  (any of the following)
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   
- ALL patients on induction

Evaluate at 48 hours:

  • All culture results should be reviewed and antibiotics adjusted according to isolates and antibiotic sensitivities
  • Low risk patients after initial therapy who are afebrile with negative cultures but still neutropenic, may still be considered for discharge home, provided there is daily follow-up until evidence of neutrophil recovery. A dose of ceftriaxone IV 80mg/kg (max 2g) may be considered before discharge with further daily doses dependent on the daily review while awaiting neutrophil recovery. Neutrophil recovery is variably defined as between 0.2 x 109/L and 0.5 x 109/L and clinical judgement is required as to which threshold is considered most appropriate.  
  • High risk patients will generally not be discharged until evidence of neutrophil recovery, but if earlier discharge before this time is considered, the discharge plan should be discussed with regional Paediatric Haematologist/Oncologist
  • Daily ceftriaxone is not recommended for inpatient use
  • If cultures are negative for gram-positive organisms stop vancomycin after 48 hours
  • For patients who were commenced on initial meropenem, step down to Tazocin at 48 hours if there is no specific indication to continue cover for multi-resistant organisms
  • 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) Coagulase negative staphylococcus
3) Stenotrophomonas (This can be treated with cotrimoxazole 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.

Modification of therapy

Escalation of therapy:
If  patient  is  clinically  well or  improving,  but  persistently febrile  at  24-72  hours,  do  not modify empiric antibacterial regimen based solely on persistent fever. ONLY 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*
  • Assess fungal risk

Children at high risk of invasive fungal disease (IFD) are those with AML, high risk ALL, relapsed acute leukaemia, children with prolonged neutropenia and children receiving high dose corticosteroids. In high risk children with persistent fever beyond 96 hours perform evaluation for IFD, eg CT scan lung, brain and sinuses plus abdomen 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) (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
    -  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 12-24 hours
  • 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

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
  4. Thomas Lehrnbecher, Paula Robinson, Lillian Sung et al, Guideline for the Management   of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update. J Clin Oncol 35, no.18 (June 2017) 2082-2094. 

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Document Control

  • Date last published: 15 November 2018
  • Document type: Clinical Guideline
  • Services responsible: National Child Cancer Network
  • Author(s): Jane Skeen, Lochie Teague
  • Owner: Jane Skeen
  • Review frequency: 2 years