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

Publication: 10/11/2014  --
Last review: 26/01/2018  
Next review: 26/01/2021  
Clinical Guideline
CURRENT 
ID: 4006 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the Management of Suspected Neutropenic Sepsis / Febrile Neutropenia

Summary
Neutropenic Sepsis / Febrile Neutropenia ( Paediatrics )

These guidelines are designed for the management of infection in children, adolescents and young adults 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, especially with the current problems with C. difficile infections

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 and microbiological advice should be sought in any areas of uncertainty.  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 temperature of ≥ 38ºC (i.e. convincing history of fever even if patient is afebrile at the time of assessment).[ C] 10a

Neutropenia: Absolute neutrophil count (ANC) ≤ 0.5 x 109/L [C] 10a

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 collapse2 and infection is suspected, do not wait for the full blood count result before initiating antibiotic treatment as per protocol. [C]

Any patient with severe graft versus host disease immediately post allogeneic stem cell transplantation (SCT) that has required treatment with high dose steroid or immunotherapy (for example basiliximab or etanercept) within the past year must be treated as per febrile neutropenia guidelines irrespective of neutrophil count with intravenous antibiotics. Other non-neutropenic allogeneic SCT recipients re-admitted with fever should usually be managed as dictated by their clinical condition & discussed with a Consultant in Haematology/Oncology. [D]

Where the presence of fever is “equivocal”, take history and carry out investigations as below, but paracetamol or other anti-pyretics should be avoided until the decision about antimicrobials has been made.

Risk stratification

Patients are stratified according to their risk of severe infectious complications of febrile neutropenia on the basis of two elements:

Part 1: stratified on the patient’s condition at presentation, related to the predicted risk of serious medical complications.

Part 2: stratified on the basis of whether their disease or chemotherapy protocol is considered “higher risk” of prolonged or repeated episodes of myelosuppression and so increased risk of severe complications.

If a patient is considered “low risk” in this second part stratification as well as the first, they should be considered for step-down to oral antibiotic therapy

Figure 1: Risk assessment overview

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Clinical Diagnosis

History

Chemotherapy drugs received and date of most recent treatment.10.  This helps to determine the expected severity and duration of this neutropenic episode. [C]

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. 10.[C]

Recent anti-microbial agents including prophylaxis. 10. [C]

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. 10.  Note specific microbiology advice may also have been given regarding an appropriate empirical regimen for any subsequent febrile neutropenic episode. [C]

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

Thorough questioning for localising symptoms of infection10., 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
  • other invasive devices e.g. VP shunt, (brain tumour patients) PEG or urinary catheter
  • 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.
  • respiratory or coryzal symptoms: runny nose, cough, sputum, nasal/sinus congestion, sore throat, earache

Known exposures: household (including pets), travel or recent blood products 10. [C]

Any major co-morbidities 10. [C]

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.  [C]

Features suggestive of genuine drug allergy 8, 16, 19

Severe, including

(i) Immediate Hypersensitivity (“Type I”) reactions: Anaphylaxis, difficulty breathing / bronchospasm, urticarial rash, hypotension, lip or other facial swelling / angioedema

(ii) Idiopathic e.g. severe skin reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis or widespread exfoliative dermatitis; seizures; loss of consciousness

Mild – Moderate:

(i) Other skin rashes: e.g. maculopapular (morbilliform).

(ii) 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 [D]

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, capillary refill time, blood pressure, respiratory rate (and Blood Glucose if collapsed/ altered conscious level/ known diabetic), Glasgow Coma Score (if brain tumour patient or any signs of altered consciousness) and fluid balance. Calculate Paediatric Advanced Warning Score (PAWS: see Appendix W) and manage appropriately. [D]

Careful general physical examination [C] of the patient for any subtle localising signs, especially in relation to 3,9,10.

  • mouth / pharynx
  • skin including vascular catheter access/exit sites and sites of any other indwelling devices or known scars
  • chest
  • abdomen
  • perianal area: NB: rectal and vaginal examinations are contra-indicated in  patients with suspected / confirmed neutropenia

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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 [C] 6,10, 21

Collecting the central line and peripheral blood cultures approximately simultaneously may be of value in diagnosing line associated infections, as if a luminal blood culture flags positive two hours or more before the peripheral with the same organism (i.e. a significant “differential time to positivity”), this suggests the catheter is the likely source of the bacteraemia. [C] 3,10

If no CVC in situ – ideally from two different peripheral veins (though often practically limited to one) [C] 3,10

b). Other routine blood tests [C]

  • Full blood count and differential
  • Creatinine, urea and electrolytes, liver function tests
  • C-reactive protein (CRP)
  • Serum lactate 10a

c). Other tests as appropriate:

Urine sample for microscopy and culture if <5yrs, urinary symptoms or urethethral catheter10a

Blood gases if clinically significant sepsis10a

If signs or symptoms of local infection present, swab(s) or preferably sample of fluid or pus if available, for bacterial & fungal culture from [C] 3, 9, 10.

  • Skin lesion(s)
  • Vascular catheter exit site (or site of any other indwelling device)
  • 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. [C] 3, 9, 10.

Stool if diarrhoea present (for C difficile testing and enteric pathogen screen) [C]3, 9, 10.

Sputum culture for bacteriology if productive cough present [C]10

Chest X-ray : If presence of respiratory symptoms and/ or signs [A] 10a, 22

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. [C]3,10 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 appropriate antifungal guidelines.

If upper respiratory tract infection symptoms are present (e.g. coryzal symptoms), test for respiratory viruses 6. 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 [C]3,10

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Treatment
Non-Antimicrobial Treatment

Treat with appropriate fluid resuscitation and organ support (e.g. oxygen) as required

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Empirical Antimicrobial Treatment

Initiate antibacterial therapy urgently if:

  • Strong clinical suspicion of infection in patients who have recently received myelosuppressive therapy (even if definition of neutropenia &/or fever is not met, or while results of FBC are awaited)
  • ANC ≤ 0.5 x 109/l and definition of fever is met. [C]3, 9,10a.

To achieve antibacterial therapy within 1 hour

Any patient with severe graft versus host disease post-bone marrow transplantation that has required treatment with immunotherapies (e.g. basiliximab or etanercept) within the past year must be treated as febrile neutropenic irrespective of neutrophil count with intravenous antibiotics. There should be a low threshold for the initiation of antifungal therapy in these patients.

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 [C]3, 9,10a.

Patient referral and transfer
Patients should be transferred from the shared care unit (POSCU) to the PTC if:

(i) The POSCU does not have in-patient shared care arrangements
(ii) The patient is clinically unstable and may require PICU care
(iii) There is a strong suspicion of fungal infection or need for surgical intervention
(iv) The patient or family request such a transfer

One dose of intravenous antibiotics should be administered prior to transfer, and the patient reassessed for signs of sepsis post administration.

If patients present to A&E or to an admissions ward in a hospital that does not provide Shared Care, the Paediatric Oncology/Haematology consultant on call in Leeds should be contacted. Arrangements should be made to transfer the patient to Leeds, and a dose of intravenous antibiotics should be administered prior to transfer and the patient reassessed for signs of sepsis.

Appropriate arrangements should be made for transfer dependent on the clinical condition of the patient.

First line antibiotic therapy

Recent 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. [A] 2, 4, 5, 10, 10a, 12An aminoglycoside should be used only in selected patients. [D]

If patient is not allergic or intolerant to penicillins the first line agent should be Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam intravenously (IV) [A] 2, 3, 5, 6, 9, 10,10a, 11,13,18.. (See below for other settings where Meropenem electronic Medicines Compendium information on Meropenem should be used instead.)

Consider addition of aminoglycoside if:

  • Severely unwell or moribund at presentation (especially if hypotensive) or rapidly clinically deteriorating 3,10,19,
  • High risk for Pseudomonas aeruginosa infection, e.g. history of previous colonisation or infection; presence of ecthyma gangrenosum skin lesions10.
  • Has recent past history of frequent cephalosporin exposure3.

A “once daily” regimen should normally be followed.

Aminoglycosides should normally only be prescribed if the measured (e.g. by recent DTPA-GFR) or estimated GFR is greater than 60 ml/min/ 1.73m2. If GFR is less than 60 m/min/1.73m2 and a aminoglycoside treatment is being considered then discuss choice of antibiotics and dosing with the consultant on call and/or pharmacist.

For patients physically located in Leeds General Infirmary Tobramycin electronic Medicines Compendium information on Tobramycin is the aminoglycoside of choice. (This is to avoid confusion of different drugs being given for the same indication within the same clinical delivery unit.) (see Tobramycin (Paediatric version of Neutropenic Sepsis Guideline))

If patient has history of ALLERGY to penicillins:

(see local Trust allergy guidance for further definitions):

If mild – moderate (including unknown nature) or Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam intolerance reported: Meropenem electronic Medicines Compendium information on Meropenem (IV) (with close monitoring of first dose for allergic reaction) [A]1,2,3, 5, 9,10,11,13,15,20.

If severe - Immediate hypersensitivity reaction:

Vancomycin electronic Medicines Compendium information on Vancomycin (IV) and Aztreonam electronic Medicines Compendium information on Aztreonam (IV) [A] 3, 13, 14, 16, 17

If severe - idiopathic (e.g. Stevens-Johnson syndrome); known allergy specifically to Aztreonam electronic Medicines Compendium information on Aztreonam or ceftazidime; or Aztreonam electronic Medicines Compendium information on Aztreonam unavailable: Vancomycin electronic Medicines Compendium information on Vancomycin (IV) & Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin (IV) [C] 3  

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

Indications for the use Meropenem electronic Medicines Compendium information on Meropenem in place of Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam

If patient known to be colonised/ previously infected with Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam resistant* & / or extended spectrum β- lactamase (ESBL) producing Gram negative bacilli*. [D]

If Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam has been stopped recently (e.g. < 48 hours)  [D]

If a patient is receiving high dose methotrexate chemotherapy, is due such therapy in the next 48 hours or is still eliminating recently administered methotrexate chemotherapy.[C]

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

NOTE

*If Pseudomonas aeruginosa or Stenotrophomonas maltophilia (inherently Meropenem electronic Medicines Compendium information on Meropenem resistant), or if severe penicillin allergy: consult Microbiology.

Starting Clinically Directed Additional Antimicrobial Treatment 

Add Metronidazole electronic Medicines Compendium information on Metronidazole (IV) if:

Suspicion of anaerobic infection in patients receiving Aztreonam electronic Medicines Compendium information on Aztreonam or Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin (these agents have relatively poor anti-anaerobe activity).  [C]10

Severe symptoms / signs suggestive of anaerobic infection in patients receiving Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam or Meropenem electronic Medicines Compendium information on 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

Add Clarithromycin electronic Medicines Compendium information on Clarithromycin (PO/IV depending on severity) if:

Symptoms / signs of severe lower respiratory tract infection requiring additional oxygen and/ or new infiltrate(s) on CXR  [C]10

Add Vancomycin electronic Medicines Compendium information on Vancomycin (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 [C] 3,10.

On Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam or Meropenem electronic Medicines Compendium information on Meropenem AND has severe mucositis (Grade III or IV) AND any of: [C] 3,9,10;20:

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

Follow local guidance to ensure therapeutic Vancomycin electronic Medicines Compendium information on Vancomycin levels are reached. Within LTHT specific paediatric Vancomycin electronic Medicines Compendium information on Vancomycin charts are available, and should be followed to achieve therapeutic levels.

Renal function should be checked (or estimated) before prescribing Vancomycin electronic Medicines Compendium information on Vancomycin.[C]

Consider immediate antiviral agents in rare circumstances [C] 3,10

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

In the setting of an influenza exposure, outbreak or seasonal peak, neutropenic patients presenting with influenza-like illness should receive appropriate anti-viral treatment empirically as recommended under current national guidance. [C] 3

Other antiviral agents should usually be added only on the basis of positive laboratory results and in consultation with Microbiology &/or Pharmacy. 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

(i) genuine allergy to a proposed non β – lactam agent

(ii) β lactam resistant P.aeruginosa reported

(iii) previous meropenem-resistant Gram negative organism reported

(iv) Vancomycin electronic Medicines Compendium information on Vancomycin addition indicated, and patient known to be colonised with or previously infected with vancomycin-resistant Gram positive pathogen (e.g. Vancomycin Resistant Enterococcus species)

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

Antimicrobial therapy should be reviewed when microbiology results are available and modified usually in discussion with microbiology; see “directed antimicrobial treatment”.

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Monitoring and modifying antimicrobial therapy

Review at least every 24 hours:

(i) To consider step-down to oral antimicrobial therapy (see oral switch section) [A] 3,10,10a.
(ii) To consider discharge home [C]
(iii) To consider cessation of aminoglycoside [D]
(iv) To consider narrowing the focus of antibiotic treatment in light of positive microbiological results [D]
(v) To consider the cessation of antibiotic therapy [C] 3,10,10a
(vi) To consider the need for additional or alternative agents [C] 3,10,10a

Regular review

Review should include:
At least daily site-specific history and examination and for unwell patients at least twice daily [C]10,10a

Further or repeat investigations as clinically indicated [C]10,10a

Repeat blood cultures if:

  • fever persists at 48-72  hour review (see below) and at empiric therapy changes [C] 3, 9
  • 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 [C] 3, 9 and daily if receiving nephrotoxic agents, e.g. aminoglycoside, Vancomycin electronic Medicines Compendium information on Vancomycin, amphotericin (AmBisome®) or IV fluids.

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

Monitor aminoglycoside and Vancomycin electronic Medicines Compendium information on Vancomycin levels as indicated by local guidelines (e.g. Vancomycin electronic Medicines Compendium information on Vancomycin chart). Additionally, repeat levels if a significant change in renal function, i.e. an increase of 25% or more above the serum creatinine when the last level was taken.

Liver function tests as clinically indicated

Aspergillus antigen test twice weekly if neutropenia & pyrexia persist longer than 5 days and consider chest HRCT scan; +/-  CT sinuses if clinically indicated (fungal guidelines)

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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Step-down to oral antimicrobial therapy

Patients stratified as low risk of serious medical complications occurring during each febrile neutropenic episode should be considered for step-down to oral antimicrobial therapy at 24 hours and subsequent daily reassessments.

If “low risk” as determined by initial assessment of risk of serious medical complications, step-down to oral antimicrobial therapy at 24 hours may be suitable (see below) with possible discharge from hospital at 48 hours. [A]10,10a

Patients classified as “high risk” for serious complications at initial assessment require at least 48 hours IV antibiotics before discharge can be considered if reclassified later as “low risk”. [A]10,10a

Assessment of risk of serious medical complications in children (=<18 years)

The presence of one or more of the following problems would lead to the patient being classified as being at high risk of serious medical complications during this febrile neutropenic episode and not suitable for step-down to oral antimicrobial therapy: [A]10,10a

(i) On a specified protocol with likely prolonged & profound immunosuppression
(ii) Haemodynamically/ clinically unstable
(iii) Major organ dysfunction (including requiring supplemental oxygen)
(iv) Significant vomiting/ diarrhoea/ abdominal pain/ mucositis necessitating IV fluids
(v) Signs or symptoms of significant infection requiring IV antibiotics (including signs of central line infection)
(vi) Neutrophil count ≤ 0.1 x 109L

All other children are at low risk of serious medical complications during this febrile neutropenic episode and should be considered for step-down to oral antimicrobial therapy at 24 hours.

Patients at high risk should be under intensified senior review, and reviewed by ST3 or more senior twice-daily. [D]

They may be considered for step-down 24 hours after the above criteria are no longer met. [A]10a

Empiric oral therapy consists of Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and Co-amoxiclav electronic Medicines Compendium information on Co-amoxiclav, unless pencillin allergy, when Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and Clindamycin electronic Medicines Compendium information on Clindamycin can be considered. Patients with a history of previous C difficile infection or ‘excretor’ status should have management discussed with microbiology as quniolones may be inappropriate. [A]10,10a

Specified High Risk Patients by Protocol/Disease

  • Acute lymphoblastic leukaemia: all treatment phases until patients have completed full 4 weeks of maintenance therapy
  • Acute lymphoblastic leukaemia in patients with Down’s syndrome (regardess of phase of therapy)
  • Acute myeloid leukaemia (including APML)
  • B Cell lymphoma: ‘Group C’ unless on M1-M4 phases
  • Anaplastic lymphoma: Only low-risk when on maintenance therapy
  • Haemophagocytic lymphohistiocytosis
  • Severe Aplastic Anaemia
  • Post haemopoietic stem cell transplant [SCT]
    • within 30 days of transplant &/or pre engraftment
    • graft failure
    • severe graft vs. host disease (received immunotherapy e.g. basiliximab or etanercept)
  • Phase 1 and 2 studies: discuss on an individual basis with consultant

Note 1 - The ‘High Risk Neuroblastoma’ patients do not necessarily fall into the high risk of serious complications of febrile neutropenia group
Note 2 - Patients with infant ALL or philadelphia postive ALL are high risk (patients with ALL)

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Consideration of discharge home at 48+ hours

If a low-risk patient remains clinically well, afebrile >24 hours, they may be considered for discharge at 48 hours and subsequently providing they meet minimum criteria.

If they have been afebrile less than 48h consider providing with oral treatment as appropriate (24h only unless specific documented alternative).

These minimum criteria for discharge home are:

  • Patient/Parent or carer knows and understands the risks, and consents.
  • Patient and/or carer has telephone
  • Adequate home environment
  • Patient can reach hospital within one hour
  • Patient and carer understand and agree to act upon indications to return to hospital. These are:
    • 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.

If fever recurs:

Re-admit [D]
Re-review investigations and treatment; commence first line IV therapy [D]
Colony stimulating factors are not recommended for routine treatment of neutropenic fever/ sepsis. [A]10a

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Duration of Treatment: Cessation of aminoglycoside and review of first line agent

For those patients who have commenced first-line dual antibiotic therapy, cessation of aminoglycoside should be considered if, upon clinical review at 24 hours, the patient is afebrile, clinically stable and blood cultures negative thus far. [C]10,10a

If the patient was started on Meropenem electronic Medicines Compendium information on Meropenem due to renal impairment, consider switching to Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam if, upon clinical review at 24 hours, the patient is afebrile, clinically stable and blood cultures negative thus far. [D]

If the patient was treated presumptively with additional agents (for example Vancomycin electronic Medicines Compendium information on Vancomycin, Metronidazole electronic Medicines Compendium information on Metronidazole or Clarithromycin electronic Medicines Compendium information on Clarithromycin) these indications should be reviewed and consideration given to discontinuing additional agents. [D]

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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.[D]

A patient with negative blood cultures, did not present with signs of severe infection (“culture negative sepsis”), and no current clinical source of infection must have been apyrexial for at least 48 hours before stopping antibiotics unless alternative cause for pyrexia has been found. [D]

There is no requirement for a minimum neutrophil count to be achieved before discontinuing antibacterial treatment, nor minimum duration of antibiotic therapy for a “fever of unknown origin” regardless of ‘risk’ group. [C]10a

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Duration of Treatment: Directed Antimicrobial Treatment

Antimicrobial therapy should be reviewed when microbiology results are available and modified usually in discussion with microbiology. [C] 2,10;.

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.

In patients with clinically or microbiologically documented infection it may be appropriate to narrow the spectrum of antimicrobial treatment but this should always be discussed with both Microbiology and Haem/Onc Consultant.

Patients who present with signs of severe sepsis but do not have an organism identified should be considered to have “culture negative sepsis” and receive an appropriate course of antibiotic therapy (usually a minimum of 5 days).

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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 suggestive of significant infection requiring IV treatment

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Modifying empiric therapy: second line empirical therapy

Consider discussion with Paediatric Haematology/Oncology Consultants +/- Microbiology concerning instituting an appropriate second line therapy. Meropenem electronic Medicines Compendium information on Meropenem is the most common second line choice.[D]

If patient stable or improving i.e. clinically stable and decreasing fever (which may take 2-7 days to settle) [C] 2, 10 consider continuing initial empirical regime rather than using a second line choice. [D]

Second line empirical therapy should be considered in patients deteriorating on first line therapy. [D]

If patient remains neutropenic (ANC ≤ 0.5) and has been febrile for ≥ 5-7 days, aspergillus antigen tests should be sent and addition of empirical antifungal therapy should be considered (see Appendix W antifungal therapy guidance)

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Appendix: Simplified Treatment Pathway

Patient presents with suspected febrile neutropenia / neutropenic sepsis

Unwell, recent chemotherapy (<28 days) >> Treat
Febrile (temp >38 C), recent chemotherapy (<28 days) >> Treat

(If well, temperature not >38 C, treat as clinically indicated)

Take bloods and blood cultures (peripheral and central)

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

Treatment is usually IV Piperacillin/Tazobactam

Only consider alternative or additional antibiotics in specific clinical circumstances e.g.:

If severely allergic to pencillins: IV Aztreonam electronic Medicines Compendium information on Aztreonam / Vancomycin electronic Medicines Compendium information on Vancomycin
If mild/moderate allergy: IV Meropenem electronic Medicines Compendium information on Meropenem (close observation at 1st dose)
If resistant organisms previously isolated: follow patient specific advice
If clearing / due high dose methotrexate: use Meropenem electronic Medicines Compendium information on Meropenem

Use FBC results and clinical assessments to undertake a risk stratification

If not neutropenic (<0.5 * 109) and not unwell, even if febrile, treat as clinically indicated

Reassess high risk patients at least twice daily by ST3 or more senior

Ongoing treatment and assessment

Reassess ‘”risk group” daily

High Risk
Patients classified as “high risk” for serious complications at initial assessment require at least 48 hours IV antibiotics before discharge can be considered.

Stop antibiotics and discharge if:

Well and afebrile >48 hours
No identified microbiological cause for fever requiring longer IV antibiotics
Did not present severely unwell despite negative cultures (“culture negative sepsis”)

Continue antibiotics if:

Microbiological reason to continue
Remains febrile &/or unwell
Presented with culture negative sepsis (5 days treatment course)

Change or add antibiotics

If microbiologically indicated
If clinically deteriorating (usual second line agent is Meropenem electronic Medicines Compendium information on Meropenem)

Discontinue additional antibiotics (e.g. aminoglycosides / Vancomycin electronic Medicines Compendium information on Vancomycin) as soon as stable / no demonstrable reason to continue

Low Risk
Patients classified as “low risk” as determined by initial assessment of risk of serious medical complications

Step-down to oral antimicrobial therapy at 24 hours if well and able to tolerate PO medication

Consider discharge from hospital at 48 hours if:

  • Afebrile >24 hours and can tolerate 24 hours oral antibiotics at home
    AND
  • Patient/Parent or carer knows and understands the risks, and consents.
  • Patient and/or carer has telephone
  • Adequate home environment
  • Patient can reach hospital within one hour
  • Patient and carer understand and agree to act upon indications to return to hospital. These are:
    • 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.

If remaining in-patient, stop antibiotics and discharge if:

Well and afebrile >48 hours
No identified microbiological cause for fever requiring antibiotics

Change or add antibiotics

If microbiologically indicated
If clinically deteriorating (usual second line agent is Meropenem electronic Medicines Compendium information on Meropenem)

If fever recurs:
Re-admit
Re-review investigations and treatment; commence first line IV therapy

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Provenance

Record: 4006
Objective:

Aims

Until 2012, three separate guidelines for the management of patients with suspected neutropenic fever/ sepsis existed within LTHT: Yorkshire Regional Centre for Paediatric and Adolescent Oncology Antibiotic Policy, Antimicrobial Agents in Adult Oncology Patients and Adult Haematology Neutropenic Fever Guidelines. Following a consultation process, and with the aim of creating a safer environment for patients by simplifying the management of suspected neutropenic fever/ sepsis, a “unified” document was written to replace the three pre-existing guidelines – which were subsequently divided into two pathways for adults & children.

Objectives

  • To provide evidence-based recommendations for appropriate diagnosis and investigation for all patients with suspected neutropenic fever/ sepsis.
  • To provide evidence-based recommendations for appropriate non-antimicrobial management for all patients with suspected neutropenic fever/ sepsis.
  • To provide evidence-based recommendations for appropriate empirical and directed antimicrobial therapy for all patients with suspected neutropenic fever/ sepsis.
  • To recommend appropriate dose, route of administration and duration of antimicrobial agents.
  • To advise in the event of antimicrobial allergy.
  • To set-out criteria for referral to specialists.
Clinical condition:

Neutropenic Sepsis (Children)

Target patient group: Neutropenic Haemato-Oncology patients (Children)
Target professional group(s): Secondary Care Doctors
Secondary Care Nurses
Pharmacists
Adapted from:

Evidence base

1. Cordonnier, Buzyn A, Leverger G et al. Epidemiology and risk factors for Gram positive coccal infections in neutropenia: toward a more targeted antibiotic strategy.
Clin Infect Dis 2003; 36: 149-158.

2. Fred Hutchinson Cancer Research Center. Antibiotic indications (prophylactic systemic and empiric regimens for febrile neutropenia in adults). 2002.

3. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical Practice Guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52:e56-e93.

4. Furno P, Bucaneve G, Del Favero A. Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis. Lancet Infect. Dis 2002; 2: 231-242.

5. Glasmacher A, von Lilienfeld-Toal M, Schulte S et al. An evidence-based evaluation of important aspects of empirical antibiotic therapy in febrile neutropenic patients. Clin Microbiol Infect 2005 11 (Suppl 5):17-23

6. Harter C, Schulze B, Goldschmidt H et al. Piperacillin / tazobactam vs. ceftazidime in the treatment of neutropenic fever in patients with acute leukemia or following autologous peripheral blood stem cell transplantation: a prospective randomized trial. Bone Marrow Transplantation 2006 37: 373-379.

7. Klastersky J, Paesmans M, Rubenstein EJ et al. The Multinational Association for Supportive Care in Cancer Risk Index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol. 2000; 18; 3038-51

8. Leeds Teaching Hospitals Trust. Penicillin allergy. Medicines Safety Alert 2006 No 2.

9. Link H, Bohme A, Cornely OA et al. Antimicrobial therapy of unexplained fever in neutropenic patients, Guidelines of the Infectious Diseases Working Party (9) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003 82 (Suppl 2):S105-117.

10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Prevention and treatment of cancer-related infections (v.1.2013). Jenkintown, PA, USA: National Comprehensive Cancer Network, 2013. http://www.nccn.org

10a. National Institute for Health and Clinical Excellence. Prevention and management of neutropenic sepsis, CG151. 2012.

11. Paul M, Yahav D, Fraser A et al. Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2006; 57:176-189.

12. Paul M, Soares-Weiser K, Grozinsky S, Liebovici L. Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. The Cochrane Database of Systematic Reviews 2003, Issue 3. Art. No. CD0030388. DOI: 10.1002/14651858.

13. Paul M, Yahav D, Bivas A et al. Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. The Cochrane Database of Systematic Reviews 2010, Issue 11. Art. No. CD005197. DOI: 10.1002/14651858.CD005197.pub3.

14. Raad II, Whimbey EE, Rolston KVI et al. A comparison of aztreonam plus vancomycin and imipenem plus vancomycin as initial therapy for febrile neutropenic cancer patients. Cancer 1996; 77:1386-1394

15. Rolston KVI and Bodey GP. Comment on: Empirical antibiotic monotherapy for febrile neutropenia: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother 2006 57: 478.

16. Riedl MA and Casillas AM. Adverse drug reactions: types and treatment options. American Family Physician 2003; 68: 1782 – 1790.

17. Saxon A, Hassner A, Swabb EA et al. Lack of cross-reactivity between aztreonam, a monobactam antibiotic and penicillin in penicillin-allergic patients. J Infect Dis 1984; 149: 16-22.

18. Viscoli C, Cometta A, Kern WV et al. Piperacillin-tazobactam monotherapy in high-risk febrile and neutropenic cancer patients. Clin Microbiol Infect 2006 12:212-216.

19. Weiss ME and Adkinson NF. b - lactam allergy. In Principles and Practice of Infectious Diseases (ed Mandell GL, Bennett JE, Dolin R), Elsevier Inc, Philadelphia, PA, USA. 2005, p318 – 326.

20. Xiao Jun H, Zhixiang S, Chun W et al. Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever. Int J Antimicrob. Agents 2005 26S S128-132.

21. Utility of peripheral blood cultures in patients with cancer and suspected blood stream infections : a systematic review.  Rodríguez, Laura; Ethier, Marie-Chantal; Phillips, Bob; Lehrnbecher, Thomas; Doyle, John; Sung, Lillian.Supportive care in cancer, Vol. 20, No. 12, 01.12.2012, p. 3261-3267

22. Phillips, B, Wade, R, Westwood, M, Riley, R & Sutton, AJ 2012, 'Systematic review and meta-analysis of the value of clinical features to exclude radiographic pneumonia in febrile neutropenic episodes in children and young people' Journal of paediatrics and child health, vol 48, no. 8, pp. 641-8

The evidence base used to develop these guidelines comprises:

  • Published information: 
    • national clinical practice guidelines, notably that of NICE 10a
    • meta-analyses
    • trials data, expert opinion, available guidelines from internationally recognised centres and other relevant reports e.g. NCAG report 2009

The level of evidence is graded A – D in accordance with LTHT Antimicrobial Guidelines practice:

A: Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B: Robust experimental or observational studies
C: Expert consensus.
D: Leeds consensus. [Where no guidance exists or there is wide disagreement with a level C recommendation]

  • A review of relevant antimicrobial susceptibility data of organisms isolated in blood cultures from patients in LTHT Adult and Paediatric Oncology and Haematology Wards (2009-2010) guided decisions regarding antimicrobial agents.

Please note these are guidelines only: antimicrobial prescribing must always involve clinical appraisal. If any practitioner is uncertain with regards to the application of these guidelines in the management of an individual patient, s/he must consult a more experienced colleague +/- LTHT Microbiology.

Drug doses are not included in the main text: see Appendix Y for paediatric dosing.

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

Related information

Appendix W

‘Surviving Oncological Sepsis’ guideline for children
PAWS
Antifungal therapy

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Appendix Y

Doses of Intravenous Antibiotics: Paediatric and Adolescent Oncology Patients

Drug

Age

Dose

Frequency

Period of Administration

Max daily

Notes

Levels

Administration details

Aztreonam Description: electronic Medicines Compendium information on Aztreonam

>7days -2yrs
>2yrs - 12yrs
>12 years

30mg/kg
30-50mg/kg
1g (can be increased to  2g in severe infections)

6-8 hourly
6-8 hourly
6-8 hourly

Infusion: 20 to 60 minutes
Bolus: 3-5 minutes

8g (in divided doses)

Normally 8 hourly
Reduce dose in renal impairment.

---

For IV infusion: Sodium
chloride 0.9% or glucose 5%.
Final concentration must
be less than 20mg/ml

Amikacin electronic Medicines Compendium information on Amikacin

>1 month
- 18yrs

12 - 18 years only

7.5mg/kg

Can increase dose to 7.5mg/kg tds in severe infections.

12 hourly

Slow IV bolus
3-5 minutes

Max starting dose: 500mg bd

Reduce dose in renal impairment

In obese patients dose on 98th centile weight

Monitor after 24hrs.
Trough: <10mg/L
Peak: 20-30mg/L
Peak: 1 hour post dose.

---

Benzyl penicillin Description: electronic Medicines Compendium information on Benzyl penicillin

1 month -18 years

25mg/kg
(increase to 50mg/kg for severe infections)

6 hourly

Slow IV bolus 3-5 minutes
Doses of 50mg/kg should be given over 30 to 60 minutes to avoid CNS toxicity.

Meningitis: 50mg/kg 6 times daily. Max dose 2.4g four hourly.

 

---

For IV infusion: Dilute with
glucose 5% or sodium
chloride 0.9%

Ceftazidime Description: electronic Medicines Compendium information on Ceftazidime

7-21days

>21 days

25mg/kg
(50mg/kg severe infections)
25mg/kg  (50mg/kg for severe infections)

12 hourly

8 hourly

Slow IV bolus 3-5 minutes OR
Infusion over 30 minutes

2g tds

Decrease dose in renal impairment

 

For IV infusion: Dilute with glucose 5% or sodium
chloride 0.9%

Ciprofloxacin Description: electronic Medicines Compendium information on Ciprofloxacin

1month - 18 years

6mg/kg
(Increase to 10mg/kg in severe infections)

8 hourly

IV infusion 30-60 minutes

Doses of 400mg should be infused over 60 minutes.

400mg tds

Dose depends on susceptibility of infecting organism.  Discuss with clinical microbiologist
Reduce dose in renal impairment

---

Flush with sodium
chloride 0.9%

Co-trimoxazole Description: electronic Medicines Compendium information on Co-trimoxazole
(High Dose for pneumocystis jiroveci infection)

1 month- 18 years

30mg/kg
Or
60mg/kg

6 hourly

12 hourly

IV infusion
60-90 minutes

---

Treat for  a minimum of 14 days. Switch to oral once clinically indicated.
Reduce dose in renal impairment.

---

IV infusion - dilute with glucose 5% or sodium
chloride 0.9%.
Contact pharmacy for dilution details. In severe
fluid restriction can be given
undiluted via a central
venous line

Flucloxacillin Description: electronic Medicines Compendium information on Flucloxacillin

  1 month -
18 years

12.5 -25mg/kg
(max 1g)
(increase to 50mg/kg in severe infection)

6 hourly

Slow IV bolus
3-5 minutes

Dose can be doubled in severe infection. Max  dose 2g QDS in severe infection.

Reduce dose in severe renal impairment

---

---

Gentamicin
See additional information on page

         

 

 

 

Metronidazole Description: electronic Medicines Compendium information on Metronidazole

1 month-18 years

7.5mg/kg

8 hourly

IV infusion
20 to 30 minutes

500mg tds

---

---

---

Meropenem Description: electronic Medicines Compendium information on Meropenem

1 month- 12 years

12 to 18 years

20mg/kg
1g

8 hourly

8 hourly

IV bolus over 5 minutes or IV infusion over
15 to 30 minutes

1g tds
(40 mg/tds used in meningitis and severe infections. Max 2g tds)

Reduce dose in renal impairment

---

IV infusion - dilute with glucose 5% or sodium chloride 0.9%.

Piperacillin/tazobactam Description: electronic Medicines Compendium information on Piperacillin/tazobactam

1 month- 18 years

90mg/kg

6 hourly

IV bolus over 3 to 5 minutes or IV infusion 20 to 30 minutes

4.5g qds

Reduce dose in renal impairment

---

For IV infusion -
with glucose 5% or sodium chloride 0.9% at a concentration between 15 and 90mg/ml. Incompatible with Tobramycin Description: electronic Medicines Compendium information on Tobramycin. Flush between doses.

Teicoplanin Description: electronic Medicines Compendium information on Teicoplanin

1 month - 18 years

10mg/kg (max 400mg)

Every 12 hours for 3 doses, then once daily

I
Slow IV bolus
3 to 5 minutes
Or
 IV infusion over 30 minutes

400mg/dose

Reduce dose in renal impairment

Levels are sometimes required to optimise therapy.
Blood samples sent to Bristol
Trough - immediately pre-dose
Trough level should  be between 10 and 60 mg/L

IV infusion - dilute
with glucose 5%
or sodium chloride
0.9% and infuse
over 30mins.

Tobramycin Description: electronic Medicines Compendium information on Tobramycin
(Divided daily dose regime. Refer to protocol for ONCE daily regime)

1 month - 18 years

>1mth-40kg - 3mg/kg
>40kg - 120mg

(these are starting doses only dose should be adjusted according to levels)

8 hourly

Slow IV bolus
  3 to 5 minutes

---

Reduce dose in renal impairment

Refer to dosing guidelines on page 27.

Monitor at 4th dose. Then TWICE weekly.
Pre: <1 mg/L.
Post: 7-10 mg/L.

Post level: 1 hr after dose. Pre immediately pre dose.

 

 

NB: Give previous therapeutic dose if child has received Tobramycin Description: electronic Medicines Compendium information on Tobramycinin the last four weeks and renal function remains unchanged.  Check renal function before prescribing.

 

Vancomycin Description: electronic Medicines Compendium information on Vancomycin

1 month- 16 years

15mg/kg

6 hourly

IV infusion over at least 60 minutes. Rate must not exceed 10mg per minute for doses > 600mg.

 (Max initial total daily dose 2g ie 500mg qds)

Reduce dose in renal impairment

Monitor after 24 hours.
Pre: 10-20 mg/L
Take pre dose level immediately prior to the dose.

Dilute with glucose
5% or sodium
chloride 0.9%
Maximum conc peripherally 5mg/ml
Maximum conc

centrally 10mg/ml

 

NB: Give previous therapeutic dose if child has received Vancomycin electronic Medicines Compendium information on Vancomycin in the last four weeks and renal function remains unchanged.

 

Doses of Oral Antibiotics Paediatric and Adolescent Oncology

Drug

Indication

Age

Dose

Frequency

Notes

Ciprofloxacin Description: electronic Medicines Compendium information on Ciprofloxacin

Neutropenic sepsis

1 month to 18 yrs

15mg/kg
Maximum 750mg bd

TWICE daily

 

Co-amoxiclav Description: electronic Medicines Compendium information on Co-amoxiclav

Neutropenic sepsis

1month- 1yr
1 to 6 yrs
6 to 12 yrs
12 to 18 yrs

0.25ml/kg of 125/31 in 5ml suspension
5ml of 125/31 suspension
5ml of 250/62 suspension
One 250/125 tablet

TDS
TDS
TDS
TDS

Double dose in severe infections.

Clindamycin Description: electronic Medicines Compendium information on Clindamycin

Neutropenic sepsis

1 month to 12
yrs
12 to 18 yrs

3 to 6 mg/kg
(< 10kg minimum dose is 37.5mg tds)
150mg to 300mg

QDS
QDS

Doses of 450mg QDS have been given in severe infections.

Metronidazole Description: electronic Medicines Compendium information on Metronidazole

Clostridium difficile
Non severe infection

1 month to 12 yrs
12 to 18 yrs

7.5mg/kg

400mg

TDS

TDS

Maximum dose = 400mg.

Treatment duration usually 10 days.

Vancomycin Description: electronic Medicines Compendium information on Vancomycin

Clostridium difficile Severe Infection

1 month to 5 yrs

5 to 12 yrs

 

12 to 18 yrs

5mg/kg
( Can be increased to 10mg/kg if no response or is life threatening)

62.5mg
(Can be increased up to 250mg if no response or life threatening)

125mg
(Can be increased up to 500mg if no response or life threatening)

QDS



QDS


QDS

Treatment duration usually 10 days.

References
           
BNF for children 2010-2011.
Paediatric Formulary 8th Edition, Guys and St Thomas’, King college and University Lewisham Hospitals, 2010.

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