Guidelines for the Management of Suspected Neutropenic Sepsis / Febrile Neutropenia (Paediatrics)

• Summary
• Background
• Clinical diagnosis
• Treatment
• Duration of treatment
• Appendix 1: PPM+ proforma
• Appendix 2: Parent information leaflet

Summary

Neutropenic Fever/ Sepsis

These guidelines are designed for the management of infection in children and adolescents with cancer and other haematological conditions.

This includes guidance regarding the treatment of unexplained fever in neutropenic children and adolescents with specific details on the following aspects of treatment:

• Initial patient assessment and the investigations to be performed
• Empirical antimicrobial therapy and subsequent modifications
• Patient risk stratification
• Ensuring that patients receive the required treatment without use of inappropriate or unnecessary antibiotics, limiting hospitalisation and providing clear safety netting

Neutropenic patients are at risk of rapidly developing life-threatening sepsis. Neutropenic sepsis is a medical emergency. Failure to recognise and treat this condition appropriately may result in unnecessary morbidity and mortality.

These are guidelines only. Antibiotic prescribing during neutropenia must always involve clinical appraisal. Modifications may need to be made to these guidelines. Regular clinical examination of the patient, at least daily, is essential to detect evolving local infection.

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Background

Definitions

The diagnosis of neutropenic fever/ sepsis requires a combination of the following:

Fever: A single axillary temperature of ≥ 38ºC (including convincing history of fever at home even if patient is afebrile at the time of assessment).

Neutropenia: Absolute neutrophil count (ANC) ≤ 0.5 x 10⁹/L [D]

Infections may present without fever and on occasion with a low temperature. If a patient is severely unwell, especially if hypotensive, tachycardic or if there is a history of sudden deterioration or collapse and infection is suspected, do not wait for the full blood count result before initiating antibiotic treatment as per protocol.

Post allogenic stem cell transplant patients require assessment as if ‘febrile neutropenic’ regardless of neutrophil count if:

• Parental concern that ‘unwell’
• <6 months from transplant
• On immunosuppressive drugs
• Severe graft versus host disease (GvHD) requiring treatment with antibody therapy, immunotherapies or high dose steroids must be treated as febrile neutropenia irrespective of neutrophil count.

Other non-neutropenic allogeneic SCT recipients who are off immunosuppressive drugs and assessed with fever should usually be managed as dictated by their clinical condition.

Where the presence of fever is “equivocal”, paracetamol or other anti-pyretics should be avoided until the decision about antimicrobials has been made

Febrile non-neutropenia (i.e. neutrophils >0.5)?
The management of these cases if not covered in this guidelines, and these children do NOT need an extended period of observation unless clinically indicated. As with neutropenic patients, if the child is unwell and/or needs a fluid bolus, they should have early senior review.

Risk stratification

Patients are stratified according to risk stratifications on the basis of two elements:

Part 1: stratified on the basis of whether their disease or chemotherapy protocol is considered “higher risk” of prolonged or repeated episodes of myelosuppression, or their home conditions negate out-patient treatment .

Part 2: Patients should also be stratified on the predicted risk of serious medical complications during each febrile neutropenic episode: if a patient is considered “low risk” in this second stratification as well as the first, they may be considered for step-down and outpatient therapy 

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Clinical Diagnosis

History

Chemotherapy drugs received and date of most recent treatment. This helps to determine the expected severity and duration of this neutropenic episode.

Previous febrile episodes and clinically or microbiologically documented infections; especially with meticillin-resistant Staphylococcus aureus (MRSA) or related to a current indwelling intravascular catheter; and any antimicrobial agents used.

Recent anti-microbial agents including prophylaxis.

Previous microbiological results including from other hospitals where available. In particular, if any pathogens were shown to be resistant in vitro to the proposed empirical antimicrobial regimen. Note specific microbiology advice may also have been given regarding an appropriate empirical regimen for any subsequent febrile neutropenic episode.

Previous history of Clostridium difficile or MRSA: this will help determine both choice of antimicrobial agent and clinical management of patient

Thorough questioning for localising symptoms of infection, especially:

• alimentary tract (mouth, pharynx, bowel, rectum)
• skin (including perianal area)
• current intravascular access sites, including temperature or rigors after use or flushing of central venous catheter (within 4 hours), exit site/ tunnel infection or previous history of line infection
• blood products or biological agents having been administered within the previous 6-24 hours which may account for rigors
• fungal infection: previous history of “proven” or “probable” fungal infection, severe oropharyngeal candidiasis with retrosternal chest pain, persistent candiduria in the absence of urinary catheter, sinusitis, haemoptysis or pleuritic chest pain: see Haemato-Oncology antifungal guidelines.
• respiratory or coryzal symptoms: runny nose, cough, sputum, nasal/sinus congestion, sore throat, earache

Known exposures: household (including pets), travel or recent blood products

Any major co-morbidities

All patients should be asked about drug allergies, particularly to penicillins or other β lactams. If a patient reports an “allergy”, it must be clarified whether this is a genuine allergy or probable drug intolerance. It should also be determined as far as possible which antimicrobials (in particular of same or related classes) the patient has previously received without any reported adverse effects.

Features suggestive of genuine drug allergy
Severe, including

1. Immediate Hypersensitivity (“Type I”) reactions: Anaphylaxis, difficulty breathing / bronchospasm, urticarial rash, hypotension, lip or other facial swelling / angioedema
2. Idiopathic e.g. severe skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis or widespread exfoliative dermatitis; seizures; loss of consciousness

Mild – Moderate:

1. Other skin rashes: e.g. maculopapular (morbilliform).
2. If patient / accompanying relatives unable to give a history of the specific features of the allergy & no other available record of nature of previous reaction(s), i.e. nature is “unknown”: treat as if mild-moderate

Features suggestive of drug intolerance - Gastro-intestinal symptoms, e.g. nausea, vomiting, abdominal pain and/or feeling faint developed during or following drug administration.

Examination

Routine observations: temperature, oxygen saturations, heart rate, blood pressure, respiratory rate (and Blood Glucose if collapsed/ altered conscious level/ known diabetic) and fluid balance. Calculate Paediatric Advanced Warning Score (PAWS) and manage appropriately.

Careful general physical examination of the patient for any subtle localising signs, especially in relation to

• mouth / pharynx
• skin including vascular catheter access/exit sites
• chest
• abdomen
• perianal area: NB: rectal and vaginal examinations are contra-indicated in patients with suspected / confirmed neutropenia

Investigation

a). Blood cultures

If indwelling central venous catheter (CVC), aerobic and anaerobic samples from each port of catheter and one peripheral vein, ideally taken at approximately the same time and with adequate volumes

Collecting the luminal and peripheral blood cultures approximately simultaneously is of value in diagnosing line associated infections, and increases the yield of culture positive infections. If a luminal blood culture flags positive two hours or more before the peripheral with the same organism given appropriate inoculum in both sets (i.e. a significant “differential time to positivity”), this suggests the catheter is the likely source of the bacteraemia.

If no CVC in situ – ideally from two different peripheral veins (though often practically limited to one)

b). Other routine blood tests

Full blood count and differential
Creatinine, urea and electrolytes, liver function tests
C-reactive protein (CRP)
Serum lactate

c). Other tests as appropriate:

Currently: COVID19 swab on patient and parent

Urine sample for microscopy and culture if younger than 5 or with urinary symptoms - remember in a neutropenic patient the urinary white cell count (by dip or microscopy) is poorly discriminatory

If signs or symptoms of local infection present, swab(s) or preferably sample of fluid or pus if available, for bacterial & fungal culture from

• Skin lesion(s)
• Vascular catheter exit site
• Throat
• Mouth

If mucosal or cutaneous vesicular or ulcerated lesions: Specimens(s) for viral investigations. Use a “dry” swab or vesicle aspirate, sent in viral transport medium.

Stool if new diarrhoea present (for C difficile testing and enteric pathogen screen)

Sputum culture for bacteriology if productive cough present

Chest X-ray: If presence of respiratory symptoms and/ or signs

If lower respiratory tract symptoms or signs and / or new infiltrate(s) present on CXR: consider sending blood sample requesting acute “atypical pneumonia” serology and urine sample for Legionella pneumophila antigen test. The latter should be collected in a sterile white–topped container. It is essential to state the date of onset of symptoms when requesting these investigations.

Aspergillus antigen test if known history or strong clinical suspicion (e.g. sinusitis or pleuritic chest pain): see Haemato-Oncology antifungal guidelines.

If upper respiratory tract infection symptoms are present (e.g. coryzal symptoms), test for respiratory viruses. Nose and throat swabs for viral PCR to be sent in viral culture medium. Throat swabs should be sent for both bacteriological and viral culture

Other microbiological samples / site-specific imaging as clinically indicated

Appendix 1 contains examples of how you may structure your assessment documentation on admission and for daily reviews

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Treatment

Non-Antimicrobial Treatment

Please refer to the ‘Surviving Oncological Sepsis’ guideline for children.

Empirical Antimicrobial Treatment

Initiate antibacterial therapy urgently if:

• ANC ≤ 0.5 x 10⁹/l and definition of fever is met.
• ANC ≤ 0.5 x 10⁹/l and patient is hypotensive, tachycardic &/or other symptoms/signs present consistent with systemic infection, even if definition of fever is not met.
• Suspicion of neutropenia with strong clinical suspicion of infection in patients who have recently received myelosuppressive therapy even if definition of neutropenia is not met (or while results of FBC are awaited)

Post allogenic stem cell transplant patients require assessment as if ‘febrile neutropenic’ regardless of neutrophil count if:

• Parental concern that ‘unwell’
• <6 months from transplant
• Immunosuppressive drugs
• Severe graft versus host disease (GvHD) requiring treatment with antibody therapy, immunotherapies or high dose steroids must be treated as febrile neutropenia irrespective of neutrophil count.

For patients who present with suspected neutropenic sepsis, the first dose of an antimicrobial should be administered within one hour of arrival at hospital or development of such symptoms on the ward, ideally immediately after blood cultures are obtained and before any other diagnostic procedures

Patient transfers

Patients should be transferred from the POSCU to the PTC if:

1. The POSCU does not have in-patient shared care arrangements
2. The patient is clinically unstable and may require PICU care
3. There is a strong suspicion of fungal infection or need for surgical intervention

Notification to the patient’s Haematology /Oncology clinical team must be made as soon as possible if a patient presents to A&E or to an admissions ward.

Risk stratification:

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 on the ward, ideally immediately after blood cultures are obtained and before any other diagnostic procedures.

At Leeds, first line antibiotics for most children is IV piperacillin/tazobactam (unless allergy or previous history of resistant organisms). In these cases, first line antibiotics would usually be Meropenem  although alternatives should be considered in true penicillin allergies due to a risk of cross-reaction.

However, some antibiotics, particularly penicillins, should be avoided if a patient is receiving high dose methotrexate (methotrexate >1g/m2), is due such therapy in the next 48 hours or is still eliminating recently administered methotrexate chemotherapy.

Then consideration will be made for briefer hospitalisation
This consists of consideration of the AUS-score (which risk stratifies by risk of a positive culture), and consideration of their home circumstances

 Who is eligible for discharge?

Home score criteria: Must be YES to all to proceed to home care

When to discharge home?
Provided the above criteria for early discharge above are met, early discharge could be considered after a minimum observation period according to the AUS score below.

Try to avoid discharges 12pm-9am unless absolutely necessary and after discussion with the on-call consultant

Antibiotics for discharge home
All children eligible for early discharge, who have not yet reached ‘stopping criteria’ for antibiotics, should receive oral antibiotics on discharge (see additional information) and be given a 5 day supply.

If penicillin allergic, discuss with paediatric haematology/oncology consultant on-call as options depend on degree of risk.

What needs to be done before discharge home?
Prior to discharge home/parent-led care, the patient must:

• be reviewed by the Paediatric Haem/Onc team to ensure they are suitable
• receive appropriate education and information leaflet, including need to check temperature every 4 hours during waking hours (Appendix 2)
• have tolerated one dose of oral antibiotics in the hospital

What is the follow up on discharge home?
The child/family needs a daily phone call for the next 5 days and daily review of blood culture results.

Please add these patients to the haematology/oncology handover sheet. The consultant on call will delegate who is responsible for the telephone follow up of these patients which should be documented on PPM.

Minimum questions to be asked on days 1-5 of telephone follow up:

• Is patient alert and orientated?
• Any chills or shakes?
• Tolerating normal diet without vomiting?
• Any reported concerns over dehydration?
• Is child passing normal amounts of urine in the past 24 hours?
• Normal bowel patterns with no diarrhoea over previous 24 hours?
• Check parents/carers understand reasons to trigger contact with hospital?

When do children need further review in hospital?

• Review if fever persists on day 3
• Admit if fever persists on day 5
• 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

When to stop oral antibiotics?
Home antibiotics will be provided for 5 days duration. Antibiotics can be stopped when the patient is:

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

In-Patient Risk Stratification of Empirical Treatment

Monotherapy instead of dual antibiotic therapy

Multiple meta-analyses of empirical antibacterial regimens in febrile neutropenia have shown the routine addition of an aminoglycoside to a suitable beta- lactam agent to be detrimental. An aminoglycoside should be used only in selected patients.

If patient is not allergic or intolerant to penicillins the first line agent should be Piperacillin/tazobactam  intravenously (IV). (See below for other settings where Meropenem  should be used instead.)

Consider addition of aminoglycoside if:

• Severely unwell or moribund at presentation (especially if hypotensive) or rapidly clinically deteriorating on any of other above regimes
• High risk for Pseudomonas aeruginosa infection, e.g. history of previous colonisation or infection; presence of ecthyma gangrenosum skin lesions
• Has recent past history of frequent cephalosporin exposure

A “once daily” regimen should normally be followed.

For LTHT patients, Gentamicin is the aminoglycoside of choice for adults and children ≥13 years old and Tobramycin is the aminoglycoside of choice for children <13 years old.

First-line antibiotics for those requiring first-line dual antibiotic therapy:

If patient is not allergic or intolerant to penicillins:Piperacillin/tazobactam  and AMINOGLYCOSIDE IV

If aminoglycoside contra-indicated due to significant renal impairment (e.g. if eGFR < 30 ml/min): Meropenem  (see below).

If patient has history of ALLERGY to penicillins:

If mild – moderate (including unknown nature) or piperacillin-tazobactam intolerance reported: Meropenem  (IV) (with close monitoring of first dose for allergic reaction).

If severe - Immediate hypersensitivity reaction:

Vancomycin  (IV) and Aztreonam  (IV)

If severe - idiopathic (e.g. Stevens-Johnson syndrome); known allergy specifically to aztreonam or ceftazidime; or aztreonam unavailable: Vancomycin  (IV) & Ciprofloxacin  (IV)

Consider a referral to immunology for skin testing to guide future management.

Indications for the use MEROPENEM in place of PIPERACILLIN-TAZOBACTAM

If patient known to be colonised/ previously infected with piperacillin-tazobactam resistant* & / or extended spectrum β- lactamase (ESBL) producing Gram negative bacilli*.
*If Pseudomonas aeruginosa or Stenotrophomonas maltophilia, or if severe penicillin allergy: consult Microbiology.

If piperacillin-tazobactam has been stopped recently (e.g. < 48 hours)

If patient due receiving recently received “high-dose” methotrexate chemotherapy, and awaiting its’ elimination. (This is ‘anyone who has had methotrexate and whose last level was greater than 0.2micro-mol/L’)

If Meropenem  is used, an aminoglycoside is NOT usually required. BUT consider adding one if patient remains acutely unwell / deteriorating post Meropenem  or if previous P aeruginosa infection. Consult with a Consultant Haematology/Oncology colleague on call +/- Microbiology

Additional antibiotics

AddMetronidazole  (IV) if:
Suspicion of anaerobic infection in patients receiving aztreonam or ciprofloxacin (these agents have relatively poor anti-anaerobe activity).

Severe symptoms / signs suggestive of anaerobic infection in patients receiving Piperacillin/tazobactam  or Meropenem  (these agents have good anti-anaerobe activity – excluding C difficile - and so additional cover is rarely required)

Signs/symptoms suggestive of anaerobic infection (not including C difficile):

• perianal symptoms/signs
• generalised / lower abdominal pain
• necrotising oral ulceration / gingivitis

AddClarithromycin (IV) if:
Symptoms / signs of severe lower respiratory tract infection and/ or new infiltrate(s) on CXR

AddVancomycin (IV) if:
Indwelling catheter is present and suspicion of catheter related infection, either at exit site or symptoms/signs associated with catheter use

Clinical evidence of a skin or soft-tissue infection at another site

Patient known to be positive (currently or previously) with MRSA or penicillin resistant Streptococcus pneumoniae

On Piperacillin/tazobactam  or Meropenem  AND has severe mucositis (Grade III or IV) AND any of:

• hypotension (systolic BP < 90 mmHg)
• high fever (temperature ≥ 40⁰C)
• receiving quinolone prophylaxis

Consider antiviral agents in rare circumstances.
Iif skin or mucous membrane lesions are present which are clinically suspected to be due to herpes simplex or varicella zoster viruses, treatment doses of IV aciclovir should be instigated. This should be in addition to an appropriate antibacterial empiric regimen.

In the setting of an influenza exposure or outbreak, neutropenic patients presenting with influenza-like illness should receive appropriate anti-viral treatment empirically. Other antiviral agents should usually be added only on the basis of positive laboratory results and in consultation with Microbiology. This should usually be in addition to an appropriate antibacterial empirical regimen.

Other difficult antibiotic situations:
Consult with a Consultant Haematology/Oncology colleague on call +/- Microbiology

1. genuine allergy to a proposed non β – lactam agent
2. β lactam resistant P.aeruginosa reported
3. previous meropenem-resistant Gram negative organism reported
4. vancomycin addition indicated, and patient known to be colonised with or previously infected with vancomycin-resistant Gram positive pathogen.

If another specific infective focus is suspected or identified (e.g. meningitis), additional antimicrobial agents may be appropriate – consult with a more experienced colleague if required +/- Microbiology

Directed Antimicrobial Treatment (when microbiology results are known)

Recommendation: Antimicrobial therapy should be reviewed when microbiology results are available and modified usually in discussion with microbiology.

In patients with clinically or microbiologically documented infection, the duration of therapy is dictated by the particular organism &/or site, and should be discussed with Microbiology. Antimicrobial therapy is usually administered for a minimum of 7 days and that the patient has been afebrile for ≥48 hours.

Monitoring and modifying antimicrobial therapy

Review at least every 24 hours:

1. To consider step-down to oral antimicrobial therapy (see oral switch section)
2. To consider cessation of aminoglycoside
3. To consider discharge home
4. To consider the cessation of antibiotic therapy
5. To consider the need for additional or alternative agents

Review should include:
At least daily site-specific history and examination and for unwell patients at least twice daily

Further or repeat investigations as clinically indicated

Repeat blood cultures if:

• fever persists at 72 hour review (see below) and at subsequent therapy changes due to non-response
• clinical picture significantly deteriorates
• required to aid clinical interpretation of positive microbiology results.

FBC to assess neutrophil count alternate days

Renal function tests: at least twice weekly during in-patient therapy and daily if receiving nephrotoxic agents, e.g. aminoglycoside, vancomycin, amphotericin (AmBisome®) or IV fluids.

CRP days 1 to 3 then clinical decision about continuation / frequency of monitoring

Monitor aminoglycoside and vancomycin levels

Liver function tests as clinically indicated

See fungal guidelines for detail on suspected fungal infection

Consider if any specific focus now clinically / radiologically apparent

• Repeat initial investigations, such as blood cultures.
• Consider if additional investigations are warranted

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Duration of Treatment: Cessation of aminoglycoside

For those patients who have commenced first-line dual antibiotic therapy, cessation of gentamicin should be considered if, upon clinical review at 24 hours, the patient is afebrile, clinically stable and blood cultures negative thus far. If the patient was started on Meropenem  due to renal impairment, consider switching to Piperacillin/tazobactam .

Duration of Treatment: Cessation of antimicrobial therapy

Broad spectrum antimicrobial cover must continue whilst a patient is febrile and neutropenic according to these guidelines unless otherwise advised by microbiology or in discussion with the Consultant in Paediatric Haematology/Oncology.

A patient with negative blood cultures must be apyrexial for at least 24 hours before stopping antibiotics unless alternative cause for pyrexia has been found.

Modifying empiric therapy: altering treatments when stepped-down

Oral antibiotics may be changed back to IV therapy if one or more of the following criteria are met:

• New clinically significant positive cultures
• New symptoms reported by the patient
• Persistent or recurrent fever two days or more after discharge
• Inability to tolerate oral regimen.
• Subsequent Clinical Evaluation
• Readmission from the home-care pathway

Modifying empiric therapy: second line empirical therapy

Consider discussion with Paediatric Haematology/Oncology Consultants +/- microbiology concerning instituting an appropriate second line therapy. This should usually be undertaken because of clinical deterioration.

If patient improving i.e. clinically stable and decreasing fever (which may take 2-7 days to settle), consider continuing initial empirical regime rather than using a second line choice.

If patient remains neutropenic (ANC ≤ 0.5) and has been febrile for ≥5-7 days, fungal investigation and addition of empirical antifungal therapy should be considered (see antifungal therapy guidance)