Management of neutropenia & fever: antibiotic policy

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Objectives

Management of neutropenia with a fever, including an antibiotic, anti-viral and anti-fungal policy for this group of patients.

Scope

Children with neutropenia and fever, especially children with haematological and/ oncology conditions. 

Audience

  • The diagnosis and management of febrile neutropenia and fever will be directed by the Consultant/Associate Specialist or a senior member of the medical team.
  • The Medical/Nursing team will be responsible for monitoring & investigating.

Introduction

Neutropenia is defined as a neutrophil count of <1 x 109/L and patients who are neutropenic are vulnerable to overwhelming infection. The frequency and severity of infective episodes correlates inversely with the degree and duration of neutropenia and is particularly marked in children whose neutrophil count is below 0.5 x 109/l.

Related documentation

This policy should be read in conjunction with the Assessment, Diagnosis and Management of Neutropenic Sepsis, Best Practice Statement, publication date: September 2011. 

Authorised personnel / specific staff competences

  • The diagnosis and management of febrile neutropenia and fever will be directed by the Consultant/Associate Specialist or a senior member of the medical team.
  • The Medical/Nursing team will be responsible for monitoring & investigating.

Equipment / materials

None.

Procedure

Febrile neutropenia: criteria for treatment

  • Any child with a single temperature of 38oC or above should receive intravenous antibiotics (in line with the national policy).

  • Paracetamol should not be given until the decision to treat has been taken because it may mask a fever. Particular care should be exercised with HSCT patients who are neutropenic.

  • Any child who deteriorates, looks unwell or rigors regardless of his/her temperature and neutrophil count should receive intravenous antibiotics. Fever may be suppressed by steroids, particularly Dexamethasone, and these children may become septic and deteriorate rapidly without exhibiting fever

  • A well child who is not neutropenic with an obvious focus of infection can receive treatment appropriate for that infection e.g. otitis media.   Err on the side of caution and if in doubt admit the child and give IV antibiotics. Be particularly careful with possible/probable line-related infections because, although lines are most often colonised with coagulase negative staphylococci, they can be colonised with gram-negative organisms, and can result in gram-negative septicaemia and septic shock.

  • It is always better to over rather than under treat these patients. These children can deteriorate rapidly.       

IN A NEUTROPENIC PATIENT, THE OCCURENCE OF FEVER MUST BE REGARDED AS AN EMERGENCY

  • The initial nursing assessment of the patient must happen within 15 minutes of the patient’s arrival. Medical assessment and administration of antibiotics must happen within 60 minutes from the patient’s arrival.

  • An 'ill' child must be assessed immediately even in the absence of a fever.  A DELAY IN ADMINISTERING THE FIRST DOSE OF ANTIBIOTICS MAY PROVE FATAL – and antibiotic administration must not be delayed for any reason (including shift changes, ward rounds, radiological examination, problems with venous access). Blood cultures should be taken before giving the first dose of antibiotics. 

!!!! The first dose of antibiotics can precipitate septic shock!!!! Prepare to resuscitate the patient

  • Patients who are unwell or hypotensive should immediately receive resuscitation fluids and IV antibiotics, even if they are not pyrexial. Remember steroids can mask an inflammatory response.

  • If a patient deteriorates after using/flushing his/her central line consideration should be given to siting a peripheral cannula and stopping using the line.

  • All haematology/oncology patients admitted overnight who are ill, must be seen by the most experienced middle grade doctor on for hospital cover who should discuss the patient causing concern with the consultant haematologist/oncologist on-call.

History and examination:

  • Keep the history brief. The following will help predict the likely degree and duration of neutropenia and identify a potential focus that might guide antibiotic therapy. Note:
    • The diagnosis
    • The date and type of the last chemotherapy given
    • Any recent blood counts
    • The duration of fever
    • The presence of a central line (NB line associated sepsis)
    • The presence of bleeding
    • Any muscle, joint or abdominal pain
    • The presence of mucositis
    • Any local cause for fever 
  • Examination: Ask yourself:
    • Does the child require resuscitation?
    • Is the child septicaemic or shocked?
    • What is the temperature, HR, RR, BP, oxygen saturation and Capillary Refill Time (CRT)
    • Is there an obvious focus for infection?

Investigations:

  • Blood cultures (take a large volume)
  • FBC and differential
  • CRP
  • U&Es 
  • LFTs and Coagulation screen: PT, APTT, Fibrinogen +/- d-dimers if unwell – every child does not require a coagulation screen.
  • Consider a CXR if respiratory signs or symptoms (this must not delay therapy)
  • If upper respiratory symptoms, consider NPA

 

Treatment:

  • Resuscitate the child
  • Give antibiotics
  • Give blood products as indicated

 

Microbiological cultures:

Blood Cultures:

  • Blood cultures should be taken from the central line, or in the absence of a central line from a peripheral stab.
  • The blood volume required is 5 - 10 mls or a minimum of 3-5 mls from an infant. In the case of a double lumen central line, or two separate central lines, blood cultures should be taken from each lumen.
  • Blood cultures should be repeated in the event of:
    • Clinical deterioration
    • Rigors
    • Persistent pyrexia after 48 hours and thereafter 48-72 hourly if the patient remains pyrexial
    • Prior to any antibiotic change
    • Recurrence of fever after an apyrexial period
  • If blood cultures are initially positive, repeat cultures should be taken after 48 hrs to confirm the organism has been eradicated (in vitro sensitivities do not always correlate with in vivo sensitivity).
  • In the case of a central line infection, which is often due to bacterial growth in a biofilm, it is advisable to repeat line cultures after stopping antibiotics to check that the organism has been eradicated.

Additional investigations should be performed:

  • Swab of central line exit site(s)
  • Consider:
    • Viral serology or culture / PCR if symptoms are suggestive of viral infection
    • Nose swab
    • Throat swab
    • Sputum culture
    • Urine culture
    • Stool culture
    • Swabs of any lesion or potential focus
  • A chest X-ray may be indicated. Remember that in pneumocystits carinii pneumonia the chest may be clear to auscultation when there is hypoxia and marked radiological change.
Antibiotic protocol for neutropenic patients

First Line Therapy

  • First line therapy in neutropenic patients is with Tazocin and Gentamicin in the absence of positive blood cultures which would indicate alternative antibiotics. Tazocin is a penicillin based antibiotic and penicillin allergy should be excluded. Patients known to be colonised with ESBL producing organisms should receive Meropenem instead of Tazocin (dosing schedule given under second line therapy).

Dosing regimen: Tazocin (90mg/kg/dose 4 times a day) plus Gentamicin (7mg/kg/once daily)

  • Prescribe Tazocin according to pharmacy dose banding chart.
  • Gentamicin requires caution in patients at risk of renal impairment. However, it is extremely unlikely that one single dose of gentamicin will do harm and a single dose should be given and levels measured before any subsequent doses.
  • Please prescribe Tazocin according to pharmacy dose banding chart, which is available on ward 2a, 2b, A&E and CDU.
  • Tazocin, as a single agent, is first line therapy for patients who are known not to be neutropenic or who are expected not to be neutropenic and considered at low risk for developing severe sepsis.
  • Patients initially started on both Tazocin and Gentamicin can stop gentamicin if subsequently shown not to be neutropenic, if neither septic or shocked.

  • Antibiotic cover for line-related therapy: Teicoplanin should be added to the initial therapy only if there is a proven or a very high suspicion of central line infection. Teicoplanin is preferable to vancomycin for patients receiving other nephrotoxic drugs and most haemato/oncology patients are on other nephrotoxic drugs. Factors suggesting line infection include:
    • Local Sepsis: Erythema at exit site or skin tunnel; pain over tunnel or on moving that arm/shoulder
    • Previously documented catheter related sepsis involving the current central venous line
    • Rigor or fever after flushing line (within 4 hours)
    • Blood culture positive for an organism associated with the related infection

Vancomycin, rather than Teicoplanin should only be used in patients suspected to have a line related infection and who are septicaemic.

Second Line Therapy

  • Patients who remain pyrexial after 72 hours of empirical therapy should change to second line therapy. Second line therapy is with Meropenem and with or with out Gentamicin.

Dosing regimen: Meropenem (20mg/kg/dose three times a day) 
plus/minus Gentamicin (7mg/kg/once daily)

  • Patients who remain pyrexial at 5 days and who are or have been persistently neutropenic with no evidence of line related infection should have Ambisome added. This should be discussed with the consultant responsible for the care of the patient.

Penicillin allergy

  • Serious allergy is one that causes an anaphylactic or urticarial reaction. 10% of patients with reactions to penicillin-based antibiotics will also have a reaction with cephalosporins.
  • Patients who have had an allergic reaction classified as serious should receive Ciprofloxacin & Vancomycin.
  • If ciprofloxacin has been given as prophylaxis, please discuss treatment with Consultant Microbiologist on call.

Duration of antibiotic treatment

This depends on the degree and duration of neutropenia and the organism cultured, but as a general rule:

  • Patients who are blood culture negative; stop antibiotics after 48 hours of apyrexia if the patient is well and if the blood cultures are negative.
  • Patients who are culture positive: this depends on the organism and the degree and duration of neutropenia. The child should be well and apyrexial and have a minimum of 7 days treatment including 48 hours of apyrexia. Preferably repeat blood cultures should be documented to have no growth. Discuss the duration of antibiotics with the microbiology consultant.
  • Gentamicin should not be given for more than 7 days. If the child needs additional gram negative non-aminoglycoside antimicrobial cover, discuss with the microbiologist.
Non-neutropenic fever
  • First line therapy for patients who are known not to be neutropenic or expected not to be neutropenic, and considered low risk for developing severe sepsis, should be single agent at Tazocin.
  • Patients started on both Tazocin and Gentamicin should stop gentamicin if subsequently found not to be neutropenic, if neither septic nor shocked. 
Antibiotic doses

For children aged 1-18 years:

TAZOCIN

  • 90 mg/kg (max 4.5g) four times a day
  • Vial size 2.25g, 4.5g
  • Give by IV bolus over 3-5 mins
  • Renal impairment: 

GENTAMICIN

  • Gentamicin dosing in patients with normal renal function:
    • Gentamicin 7mg/kg/once daily (max 500mg/dose)
    • Give by IV infusion in 50 – 100ml Sodium Chloride 0.9% over 60 minutes
    • Prescribe dose for all patients at 12noon each day
    • Measure level after 1st dose
      Trough:   Plasma samples at 18-24 hrs post-dose (i.e. with morning bloods)
      Expected level <1mg/L
      NB in many patients the reported level will be <0.1mg/L, which is acceptable
    • If trough level is >1mg/L, the dosing interval is normally increased by 12 hours. Please discuss further dosing with pharmacy/microbiology
    • If trough level >2mg/L, patient is unsuitable for pulsed dosing regimen, and subsequent doses should be guided by levels.
    • If there is no change in dosage regimen or renal function, repeat trough levels every 4 days only
  • Renal impairment:
    • Use with caution. Dose reduction required for GFR 70ml/min or less
    • Initial dose - Gentamicin 5mg/kg
    • Trough levels as above
    • Prescribe as a single dose and consult pharmacy/microbiology for further dosage advice
  • Managing patients admitted out of hours:
    • Patients admitted in the afternoon until 12 midnight:
      • Give 7mg/kg dose on admission
      • Trough samples with morning bloods
      • Prescribe at 12 noon the following day
    • Patients admitted between 12 midnight and 6am:
      • Give 7mg/kg dose on admission
      • Arrange with microbiology for emergency levels to be done at 12 noon that day.
      • If trough level is reported at <2.5mg/L, give second dose as close as possible to midday.
      • If trough level is >2.5mg/L, consult pharmacy/microbiology for further dosage advice.
    • Patients admitted between 6am and 12noon:
      • Give 7mg/kg dose on admission
      • Trough levels the following day with morning bloods.
      • Prescribe dose on following and subsequent days 2 hours later, until dosing time of 12 noon is achieved.

NB: Do not forget to indicate on the microbiology request form the actual time the sample was taken – levels taken outwith the recommended times can still be interpreted, if an accurate sampling time is recorded.

CIPROFLOXACIN

  • Ciprofloxacin may be used in children where the benefit is considered to outweigh any potential risk.
  • NB:  Committee on Safety of Medicines (CSM) warning: Quinolone antibiotics may lower seizure threshold & may induce convulsions in patients with or without previous history.
  • Tendon damage is a rare side effect of quinolone antibiotics: if tendinitis is suspected, discontinue immediately.
  • Dosing regimen for prophylaxis against gram negative organisms in patients undergoing HSCT is 10mg/kg bd (max 750mg/dose) (see below for maximum dosing).  Children with Downs syndrome and ALL, and infants with ALL, also receive ciprofloxacin prophylaxis.
  • Dosing regimen for treatment
    • Intravenous: 1month – 18 years 10mg/kg three times a day (maximum dose of 400mg)
    • Oral: 20mg/kg bd (max 750mg/dose)
  • Available preparations:
    • Tablets: 100mg, 250mg, 500mg, 750mg tablets;
    • Oral Suspension: 250/5ml
    • Premixed solution for IV infusion: 2mg/ml (50ml & 100ml bags available)
  • Oral absorption is good but do not use with oral Mg, Ca, or Fe supplements as these affect absorption.
  • Infuse undiluted IV over 30-60 minutes - flush with Sodium Chloride 0.9%.
  • Renal impairment:

VANCOMYCIN

  • Dosing regimen: 15mg/kg three times daily. (NB To achieve optimal plasma profile it is vital to ensure doses are administered as close to an eight hour interval as possible)
  • Infuse over 1-2 hours in Sodium Chloride 0.9%. 
  • Measure trough level before the 3rd dose is given.
  • Target trough: 15-20mg/L.
  • Renal impairment:
    • Use with caution. Dose reduction required for GFR 50ml/min or less.

TEICOPLANIN

  • 10mg/kg (max 400mg) every 12 hours for 3 doses then 10mg/kg (max 400mg) daily
  • Administration: Slow IV bolus or infusion over 30 mins diluted in Sodium Chloride
  • Renal impairment: 
    • Dose adjustment required for GFR 80ml/min or less. Refer to Renal Drug Database
    • No monitoring required

AMBISOME

  • Dosing regimen: dependent on clinical situation
  • 3 mg/kg/day with proven or highly suspicious fungal infection (doses of up to 5 mg/kg/day have been used for proven infections)
  • 2mg/kg (M/W/F) anti-fungal prophylaxis in stem cell transplant patients and 1mg/kg (M/W/F) in other high-risk patients.
  • Infuse in Glucose 5% ONLY at a concentration of 0.2-2.0 mg/ml. If dose ≥5mg/kg infuse over 2 hours otherwise 1 hour.
  • Renal impairment:
    • No dose adjustments regardless of degree of renal impairment. Due to the size of AmBisome liposomes, there is no renal elimination.

MEROPENEM

  • Dosing regimen: 20 mg/kg three times a day (max 1g/dose).Can increase to 40 mg/kg in severe infections (max 2g/dose).
  • Give as IV bolus over 5 minutes or infuse over 15-30 minutes (dilute 1g in at least 50 ml Sodium Chloride 0.9% or Glucose 5%).
  • Renal impairment:
Opportunistic chest infections

General

  • There are a variety of opportunistic lung infections that can occur in long-term immunosuppressed children that must be considered in a child with respiratory symptoms.
  • Note the respiratory rate, any signs of respiratory distress and check pulse oximetry.
  • Give supplemental oxygen therapy if required and arrange blood gases.
  • Ask for ITU consult if the patient’s condition, respiratory rate or oxygen requirements suggest that artificial ventilation may be necessary.
  • Discuss these patients with the consultant on call for haematology/oncology.

Mycoplasma Pneumoniae

  • This may present with a multitude of symptoms.
  • The disease tends to have a prodrome (fevers, chills, headaches) and the cough may persist for several weeks.
  • The chest x-ray may show diffuse patchy consolidation and the MCV may be raised due to cold agglutinins.
  • Treatment is with IV Clarithromycin 7.5mg/kg per dose twice a day (max 500mg/dose). Consider using Azithromycin if patient is able to tolerate oral medications at following doses:
    • Dose: over 6 months 10mg/kg once daily (max 500g) for 3 days
    • Or  15-25kg           200mg once daily for 3 days 
            26-35kg          300mg once daily for 3 days
            36-45kg          400mg once daily for 3 days 
            >45kg             500mg once daily for 3 days

Pneumocystis Carinii 

  • Signs of infection include tachypnoea, dry cough, dyspnoea on exertion and cyanosis. The chest is often clear on auscultation.
  • Check pulse oximetry and blood gases as oxygen desaturation often precedes x-ray changes. CXR may show bilateral infiltrates, but can be similar to viral infection or fluid overload.
  • Although pneumocystis is less common with the use of prophylactic Co-Trimoxazole, it still occurs. Exercise a high level of suspicion in children using alternatives to Co-Trimoxazole as PCP prophylaxis or in those with suspected poor compliance.
  • Treatment is with high dose intravenous Co-Trimoxozole 60mg/kg per dose twice a day.
    • Give by IV infusion over 20-60 minutes. Dilute each 480mg ampoule in 75mls 5% Glucose.
    • In severe fluid restriction, Co-trimoxozole may be given undiluted via a central line only and over at least 60 minutes.
    • Consider the need for concomitant steroids, discuss with on call consultant.

      NOTE: Adenovirus, Paraflu and RSV can be fatal in stem cell transplant patients. Any transplant patient who develops respiratory symptoms or distress should be discussed with the HSCT consultant
  • Renal impairment:
Supportive Care / Miscellaneous

Central lines

  • Central lines can be a source of infections with gram-negative and grampositive organisms in neutropenic and non-neutropenic patients.
  • If a patient becomes pyrexial or deteriorates after flushing or sampling a central line add Teicoplanin. Consider stopping using the central line and insert a cannula for antibiotics.

Antipyrexial treatment

  • Once cultures have been taken and antibiotics started it is acceptable to treat the fever with Paracetamol.
  • Do not give non-steroidal anti-inflammatories such as ibuprofen. Nonsteroidals are contraindicated because of their effect on platelet function.

Chemotherapy

Withhold oral chemotherapy for Acute Leukaemia patients. Refer to individual treatment protocol /guidelines for other haemato/oncology patients to establish if chemotherapy should be stopped temporarily in the neutropenic patient.  Note: In certain protocols, chemotherapy is continued even in the presence of neutropenic fever. Discuss with consultant.

Examination

The child should be examined daily for signs of infection including sites such as the mouth, axillae, ears, perineum and central catheter site.

Constipation

  • Must be avoided if possible. As well as causing distress, it may precipitate septicaemia through mucosal damage.
  • Enemas, suppositories, rectal temperatures and rectal examinations should be avoided in neutropenic patients for the same reason. Ask about bowel function daily and consider laxatives as necessary.

Co-Trimoxazole as PCP Prophylaxis

Continue prophylaxis co-trimoxazole whilst other antibiotics are being given unless the patient is receiving high dose co-trimoxazole intravenously or consultant thinks that co-trimoxazole should be temporarily discontinued to allow count recovery. Prophylaxis need not be given intravenously but can be temporarily withheld in patients who are nil by mouth.

Mouth Ulcers

  • All patients are advised on mouthcare.
  • Swab for virology (herpes simplex) and bacteriology.
  • Consider Aciclovir.

    Aciclovir dosing:

    Herpes Simplex:

    Oral:

    1-23months:100-200mg x 5/day for 5 days

    2-17 years: 200-400mg x 5/day for 5 days
    (Use the higher dose in immunocompromised patients)

    Varicella/Herpes zoster:

    Oral:

    1-23 months: 200mg x4/day for 5 days

    2-5yrs: 400mg x4/day for 5 days

    6-11yrs: 800mg x4/day for 5 days

    12-17yrs: 800mg x5/day for 5 days

     

    IV:

    3mo – 12 years: 250-500mg/m2 three times daily.

    12-18 years: 5-10mg/kg three times daily


    • NB:  Adequate hydration (normal maintenance, as per age and weight of the child) MUST be maintained during IV Aciclovir treatment. Monitor renal functions and fluid balance daily
  • Renal impairment:

Diarrhoea

  • Send stools for viruses, parasites, cryptosporidium and Clostridium difficile toxin.
  • Metronidazole should be considered for mucositis or perianal infections

 

Audit and Review Process

This SOP will be reviewed in 24 months time.

Further information / Exceptions

None

Criteria for Treatment Algorithm

Criteria for treatment

References
  1. Scottish Government. Assessment, Diagnosis and Management of Neutropenic Sepsis - Best Practice Statement (publication date: September 2011) 
  2. BNF – access via www.medicinescomplete.com
  3. BNF for Children – access via www.medicinescomplete.com
  4. www.renaldrugdatabase.com [For access contact ann.lees@nes.scot.nhs.uk
Editorial Information

Last reviewed: 20 March 2020

Next review: 01 March 2022

Author(s): J Sastry

Version: 4

Approved By: Sch Clin Gov Group

Document Id: HAEM-ONC-003