Management of neutropenia & fever: antibiotic policy

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 with the degree and duration of neutropenia and is particularly marked in children whose neutrophil count is below 0.5 x 10⁹/l.  All children undergoing chemotherapy or targeted treatment for cancer and those who are within 3 months from the completion of treatment are at risk of severe infection. Most children present with a fever. Children can also present with low temperature, or just unwell, specifically those who are on steroids and those with Down’s syndrome.

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

If a patient deteriorates after using/flushing their 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.

All Patients admitted with fever and at risk neutropenia are managed as per this policy. Some patients may be eligible for early discharge and outpatient management and are managed as Low Risk (LR) arm. Others are managed as per standard inpatient FN arm of this policy.

Aim of Low-risk FN management:

Background to Risk Stratification:

Recognising that many children with FN remain well throughout admission, and that clinically significant infections are rare, much work has been done to attempt to identify patients with “low-risk” FN. This is important because management of FN episodes accounts for a considerable percentage of bed usage, which is expensive and inconvenient to patients and their families.

A number of strategies designed to reduce the duration of inpatient stay and/or early use of oral antibiotics have been evaluated as non-inferior to existing inpatient intravenous protocols. Seventeen paediatric FN clinical decision rules (CDRs) that risk stratify children with cancer and FN for infection have been derived.

Validation studies tend to show the rules differentiate between risk groups less well when applied to different datasets. The data from the prospective multisite (n=8) Australian-PICNICC study which enrolled 858 FN episodes in children with cancer were used to recalibrate the SPOG (Swiss) rule. This recalibration defined three equally weighted factors (WCC, platelets and chemo intensity). The AUS (Australia-UK-Swiss) rule was then validated in the ‘PICNICC+’ dataset, including over 1500 evaluable episodes of FN from the UK, Europe, North and South America. Published: https://doi.org/10.1002/pbc.28580.  The relationship between AUS score and significant bacterial infection/bacteraemia is shown below:

Table 1. Australian data:

Table 2. PICNICC+ data:

* Deaths in score 1 & 2 were related to disease. Death in score 0 was post-transplant patient with adenoviral reactivation. ICU admissions in this data set came mostly from in-patient episodes, and all were assessed at presentation as ‘seriously clinically unwell’. The 855 case prospective evaluation of FN episodes has demonstrated that by 24 hours, 80% of positive blood cultures will have ‘flagged’.

Graph 1. Time taken for flagging positive blood culture

The CCLG Supportive Care Group is very encouraged by the data above with respect to the safety of the AUS Clinical Decision Rule and its associated management pathway.

The process has been piloted in Royal Children’s Hospital, Melbourne, where it led to a significant reduction in bed occupancy. In their pilot study 63 children out of 336 children with FN were able to safely receive antibiotics at home. The AUS-rule score, when combined with a safety assessment, can assist clinicians in determining when the patient can be safely discharged to home-based FN care.

Inclusion and Exclusion for Early Discharge:

Inclusion

• All children undergoing anticancer treatment with a risk of neutropenia
• Fever ≥ 38.0◦C Sepsis can present with normal or low temperature (overwhelming sepsis, steroids, Trisomy 21)
• Neutrophils: ANC < 1.0 x10⁹ cells/L)
• Others: children on anticancer treatment with or without CVAD and unknown ANC at presentation, but at risk of neutropenia.
• Any child receiving chemotherapy who appears unwell but is not febrile or neutropenic may still need treating with antibiotics. If in any doubt as to whether antibiotics should be given it is usually preferable to err on the side of caution and give them. Discuss with more senior colleague if you are not sure.

Exclusion

• Children undergoing or post haematopoietic stem cell transplantation.
• Children with auto immune neutropenia (as there is no expectation of neutrophil recovery here)
• Benign haematology patients like sickle cell anaemia or aplastic anaemia

2.1 This guideline should be read in conjunction with the Neutropenic Sepsis: Prevention and Management in People with Cancer (CG151) (September 2012)

2.2 CCLG Guidance “Managing Febrile Neutropenia in the UK in 2020 Proposed New Management Pathway” – uploaded for reference in Q-Pulse with this SOP.

3.1   The diagnosis and management of febrile neutropenia will be directed by the Consultant/Associate Specialist or a senior member of the medical team.

3.2   The Medical/Nursing team will be responsible for admitting, assessing, investigating and administrating treatment, and monitoring response.

3.3   The Medical/Clinical team (ie ANPs) will be responsible for discharging patients.

None.

Initial Assessment

Initial assessments and investigations should be as per the centre’s current practice.

Note:  CRP is not included in the AUS score or assessment, and decisions to admit or discharge are safely made without assessing CRP. Multiple studies and a series of systematic reviews have demonstrated the lack of diagnostic ability of CRP to predict significant illness or bacterial infection [ref. 12].

There is almost no data about the value of routine lactate measurement outside of the setting of management of significant sepsis. Notably, lactate may be raised by malignant processes or dexamethasone.

There is no change to the initial assessment of the children on anticancer treatment who present with fever. Full blood count and Blood cultures from CVAD (or peripherally for those without CVAD) are obtained and antibiotic as per our guidelines started. First dose is administered within 60 minutes of arrival to the hospital, or occurrence of fever for those who are already inpatient or in day care for other reasons. Other investigations are carried out as per the FN protocol which includes, bacterial and viral throat swabs, urine culture etc.

Well child: Proceed as above.

Unwell child: Urgent assessment management warranted. Initial management should proceed as per advanced paediatric life support (APLS) guidelines. Early involvement of senior medical team and escalation to PICU may be required immediately, or following inadequate response to resuscitation and should be arranged in line with current hospital guidelines.

Table 3. Initial Investigations:

*  Blood cultures should be repeated in the event of Clinical deterioration’ Rigors, Persistent pyrexia after 24 and 48 hours and thereafter 48-72 hourly if the patient remains pyrexial, Prior to any antibiotic change. Recurrence of fever after period of apyrexia. 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)

Antibiotic Treatment – See Appendix A for doses

Every child will start with 1st line IV antibiotics.

The first dose of an antimicrobial should be administered within one hour of arrival at hospital or development of such symptoms for those who are already on the ward or in day care unit, ideally immediately after blood cultures are obtained and before any other diagnostic procedures.

Tazocin is the current antibiotic of choice at RHC, Glasgow.

Gentamicin is also started for:

1. those patients who have had a recent FBC and are known to be neutropenic
2. Urgent FBC done at admission shows neutropenia
3. those who are systemically unwell suggesting severe gram negative sepsis
   1. severe chills and rigors
   2. mottled, hypotensive or needing fluid bolus

Other antibiotic choice:

Meropenem is the drug of choice for those who are on Methotrexate infusion. Some patients may need a different antibiotic as first choice because of various reasons. These patients have Trakcare alerts and are also highlighted on the hand over charts. The reason for different antibiotic at presentation are clearly documented on Trakcare/portal/handover charts.

Patients with suspected or confirmed penicillin allergy:

Patients with a possible history of suspected allergy should have the nature of this clarified with parents/caregivers. All patients with an allergy should be referred to allergy clinic, and tested for allergy to piperacillin-tazobactam, third generation cephalosporins and meropenem as soon as clinically possible after diagnosis.

For those with penicillin allergy, the following empirical antibiotic choices are advised:

*SEVERE PENICILLIN ALLERGY:  Normally within 1 hour (up to 12 hours) – anaphylaxis, angioedema urticarial rash/pruritus, wheezing/stridor

**NON-SEVERE PENICILLIN ALLERGY: Normally after 24 hours – maculopapular/morbilliform rash, serum sickness (fever, rash, arthralgia, glomerulonephritis)

Table 4. Penicillin Allergy Alternatives:

Initial Assessment for Suitability for Outpatient Febrile Neutropenia Management

Following the first dose of intravenous (IV) antibiotics, patients should, where appropriate, be assessed for suitability for ongoing febrile neutropenia management as an outpatient. Low risk, clinically well patients, may be eligible for discharge home under parental care with oral antibiotics if they fulfil all necessary criteria. If there is any doubt, a patient should remain in hospital on IV antibiotics pending consultant review.

First calculate the AUS-rules score (Table 5) and then review the Eligibility for Outpatient FN Management Criteria (Table 6).

Patients suitable for early discharge and outpatient FN management please follow LR FN section 5.3.

Patients who are found not suitable for early discharge and outpatient FN management, please follow standard Inpatient FN section 5.4.

Early Discharge Criteria (see Appendix B)

Discharge home/parent-led care is recommended after a minimum 4-24 hours of in-hospital observation (duration will depend on the time of admission, scoring rule and score)

Prior to discharge home/parent-led care, the patient must:

1. Have AUS scoring carried out using FBC from admission.
2. Have been observed for a minimum of:
   1. 4 – 8 hours for those scoring AUS 0
   2. 4 – 24 hours for those scoring AUS 1
   3. >24 hours for those scoring AUS 2
   4. >48 hours for those scoring AUS 3
3. Be reviewed by a locally approved competent specialist to ensure they are suitable: Schiehallion unit staff –ANP, Middle grade doctors and Consultants
4. AUS Scoring and eligibility for early discharge checklist sheets to be part of admission nursing folder and to be filled early enough to plan discharge after minimum observation period.
5. AUS scoring and eligibility for early discharge check list to be checked soon after 9 am hand over meeting to identify potential early discharges.
6. Pharmacy to be alerted as early as possible when there is a plan to discharge early for eligible patients
7. Receive appropriate education and information leaflet
8. Have tolerated one dose of oral antibiotics in the hospital

Practical Application of AUS Score:

The score can be calculated for each patient when they are recognised as febrile/neutropenic, using counts on admission.

Table 5: AUS-rule variables and score

* This includes: ALL maintenance, LCH maintenance, or weekly Vinblastine alone (low grade glioma) and all patients on oral targeted therapy.

The score alone is insufficient to determine if discharge home/parent-led is acceptable. Safety and stability criteria need to be fulfilled. These determine if the patient is clinically well, socially safe to be at home, and able to tolerate the oral antibiotic therapy (variation may include home-based IV antibiotics if resources enable this to occur).

Eligibility for home care:

All patients eligible for home care must fulfil all eligibility criteria in Table 5.

Table 6. Eligibility criteria for discharge home/parent-led care (must be Yes to all to proceed to home care):

Antibiotics for home-based management:

Home administered antibiotics can be either:

1. Continuation of intravenous antibiotics (need discussion with OPAT group to check feasibility
2. Oral antibiotics; such care is preferred by many families^13-15.

(Most trials of low-risk (immediate discharge) febrile neutropenia management have used oral antibiotics^{5 -8}. It is recommended in the SIOP-endorsed international paediatric febrile neutropenia guideline¹⁶, and been used in Leeds for over a decade. This practice is supported by the CCLG Supportive Care Group)

When home/parent-led care will be based on oral antibiotics, be sure of compliance and absorption. (Assuming no mucositis, no vomiting, no significant diarrhoea and reliable parent/carer).

The suggested antibiotic regimen is a combination of: Oral ciprofloxacin Plus Oral Augmentin. If allergic to penicillin consider clarithromycin instead.

If the above regimen is not feasible consider keeping patient in hospital for IV therapy unless local circumstances allow ambulatory management.

If severe beta lactam allergy or known resistant bacteria present please discuss with local microbiology.

Duration of Empiric Antibiotics

Antibiotics will be stopped in any patient with negative blood cultures after being apyrexial for at least 24 hours, if clinically well, unless alternative cause for pyrexia has been found. This approach has been used extensively in Sheffield for over a decade⁹, and in other centres in the UK and internationally. NICE guidance is clear in the lack of need for a rising count before stopping antibiotics, and this is supported by data from the recurrent national audits of FN in the UK demonstrating safety¹⁷

Home antibiotics will be provided for 5 days duration, instructions being given to stop when the patient is:

• clinically well, culture negative
• afebrile for >24 hours

If the above criteria have not been met the patient should be reviewed on day 5.

Responsibilities of clinical staff – See Appendix C

Discharging Nursing staff responsibilities:

1. Check that the AUS scoring and eligibility for early discharge check list has been completed
2. Provide patient/parent education and ensure parents know under what circumstances they should return urgently.
3. Ensure that the patients have the home observation chart and parent information sheet for FN.
4. Advise families to take temperature 4-6 hourly during waking hours and to record it on the provided home observation chart
5. Ensure families have the correct contact details for the hospital.
6. Advise families that a medical member of the team will contact them daily and to have the Temperature chart available to discuss.
7. Add patient name to ward list in handover document and on ward whiteboard
8. Keep the PEWS chart, blank Home observation chart and Telephone follow up management guideline in a folder and hand it over to the Medics/ANPs

Discharging medical & clinical staff responsibilities:

1. Record the AUS score and go through eligibility checklist for early discharge
2. Discuss with the senior medical staff suitability for early discharge.
3. Instruct family regarding taking temperature at home and recording it on the home observation chart
4. Instruct family to seek help as per advice on the parent information sheet.
5. Tell them that a medic/ANP will call them by phone daily to advice further management.
6. Keep the patient folder with the PEWS chart, home observation chart, and the telephone follow up management plan in the doctor’s office
7. Check blood culture results at least daily: antibiotics may need to be changed depending on these results.
8. Keep an up-to-date list of all patients being managed as outpatients for febrile Neutropenia on the white board in the doctor’s office/add them to handover document.
9. Daily phone call to parents/carer and record the temperature and observations on copy of the home observation chart as given by the family.
10. Record the discussion and the advice given to parents until antibiotics stopped and the episode is completed on the copy of the home observation chart.
11. Advice parents for hospital medical review or re admission as per criteria below and document that in portal
12. Once the episode is completed, send the documents for scanning to portal.

Table 7:  Appointments Schedule:

Reasons for medical review include:

• Ongoing fever (>72 hours from presentation) or new fever after being afebrile for 24 hours
• Feeling unwell/new symptoms and signs
• Parental concern
• Significant decrease in oral intake or significant increase in output (vomiting and diarrhoea)
• Positive blood culture or new infection identified after transfer home
• Severe or persistent pain
• Chills/rigor/shaking
• Not afebrile by day 5 of home-based care

Reasons for re-admission include:

• Fever > 38oC beyond 5 days from the start of the febrile neutropenic episode
• Clinically unwell / unstable
• Infection requiring in-patient care

If readmission needed, follow standard febrile neutropenia management protocol at the appropriate time point i.e. restart iv antibiotics as per empirical regimen but adjusted for sensitivities of any known organisms and consider antifungal therapy once patient is febrile >96 hours from the start of the febrile neutropenic episode.

Table 8: Standard Inpatient management of febrile neutropenia

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. 

Daily examination

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

Co-Trimoxazole as PCP Prophylaxis

Continue Co-Trimoxazole prophylaxis 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.

This SOP will be reviewed in 2 years.  

None

NB Antibiotic doses in this guideline are appropriate for empirical treatment or sensitive organisms only. For any organism categorised as ‘I’ (Susceptible – increased exposure), seek further advice or refer to local policy for appropriate dose selection’ (see NHS GGC Clinical Guidelines Portal)

Appendix A: Antibiotic dosing guidelines (pdf)

Duration of Empiric Antibiotics

Antibiotics will be stopped in any patient with negative blood cultures after being apyrexial for at least 24 hours, if clinically well, unless alternative cause for pyrexia has been found.

If the above criteria have not been met the patient should be reviewed on day 5.

Reasons for medical review include:

• Ongoing fever (>72 hours from presentation) or new fever after being afebrile for 24 hours
• Feeling unwell/new symptoms and signs
• Parental concern
• Significant decrease in oral intake or significant increase in output (vomiting and diarrhoea)
• Positive blood culture or new infection identified after transfer home
• Severe or persistent pain
• Chills/rigor/shaking
• Not afebrile by day 5 of home-based care

Reasons for re-admission include:

• Fever > 38oC beyond 5 days from the start of the febrile neutropenic episode
• Clinically unwell / unstable
• Infection requiring in-patient care

Appendix D: Home Based Care for Febrile Neutropenia Parent Information Sheet (pdf)

Appendix E: Low Risk Febrile Neutropenia Home observation chart (pdf)