Neutropenic Sepsis ( Adults ) - Guidelines for the Management of Suspected

Publication: 10/11/2014  --
Last review: 21/09/2017  
Next review: 01/09/2020  
Clinical Guideline
CURRENT 
ID: 4007 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2017  

 

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.

Update on aztreonam injection shortage - now only restricted outside of CF and UTI (protected antibiotic codes no longer required for these indications). See alternatives - 22 August 2018

Guidelines for the Management of Suspected Neutropenic Sepsis

(version for use in “Adult” patients; to be read with paediatric half ‘half’)

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  • Treatment Algorithm
  • Summary
    Neutropenic Sepsis ( Adults )

    These guidelines apply primarily to patients being managed in Bexley Wing, SJUH site; with a solid tumour or haematological malignancy.

    The associated parallel guidelines should be consulted for patients < 18 years age, including teenagers being managed in the Children’s Hospital, LGI site / primarily by an LTHT Paediatrician: see childrens version.

    Most patients at risk of developing neutropenia will already be under the care of a haematology or oncology consultant (paediatric or adult team): care of patients with suspected neutropenic sepsis should be coordinated by the relevant team. Commonly, patients who develop neutropenic sepsis are those receiving or who have recently received treatment for malignancy, but this group also includes those with some long-term haematological conditions such as myelodysplastic syndrome.

    These guidelines should also be applicable in the initial management of febrile episodes in patients who are neutropenic due to other causes, including when found unexpectedly / aetiology as yet unknown. 

    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.

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    Background

    Definitions

    The diagnosis of “neutropenic sepsis”  requires a combination of the following:

    Sepsis: A single tympanic temperature of ≥ 38 ºC, [C] 10a or recent temperature ≥ 38 ºC prior to patient’s presentation to hospital, (i.e in this setting, sepsis =  fever “alone” 10a).

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

    NB Infections may present without fever and on occasion with a low temperature. If a patient is severely unwell, especially if hypotensive / tachycardic &/or there is a history of sudden deterioration or collapse2 and infection is suspected, do not wait for the full blood count result (nor temperature to be ≥ 38 ºC ) before initiating antimicrobial treatment as per this protocol.

    Any patient with severe graft versus host disease (GVHD) post allogeneic stem cell transplantation (SCT) that has required treatment with basiliximab or etanercept must be treated as per higher risk febrile neutropenia guidelines (i.e. "Group I" - see below) irrespective of neutrophil count. Other non-neutropenic allogeneic SCT recipients re-admitted with fever should usually be managed as if in "Group 2" at least until patient has been reviewed by own medical team [D].

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

    2-part patient risk stratification

    Within these guidelines there are 2 patient risk stratifications:

    Part 1 The first stratifies patients on the basis of whether their disease or chemotherapy protocol is considered “higher risk” (Group I) or “lower risk” (Group II). Group I patients will usually be on antibacterial prophylaxis, most commonly levofloxacin, whilst neutropenic.10a  (See LTHT Guideline for antimicrobial prophylaxis in Adult patients undergoing myelosuppressive chemotherapy for haematological malignancies) Such patients are at greater risk of infection with a multi-antimicrobial resistant pathogen and so require the empirical addition of an aminoglycoside to the first-line broad spectrum antimicrobial piperacillin-tazobactam.

    Part 2 The second stratifies patients according to risk of serious medical complications during each neutropenic septic episode: if a patient is considered “low risk” in this second stratification as well as the first, they may be considered for step-down to oral antimicrobial therapy at 24 hours and early discharge at 48 hours.

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    Clinical Diagnosis

    History - document:

    • Chemotherapy drugs received and date of most recent treatment. [C] 10 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. [C]10
    • Recent antimicrobial agents including prophylaxis. [C]10
    • 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. [C]10
    • Previous history of Clostridium difficile or MRSA: this will help determine both choice of antimicrobial agent and clinical management of patient. [C]10
    • Thorough questioning for localising symptoms of infection, [C]10 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.
      • respiratory or coryzal symptoms: runny nose, cough, sputum, nasal/sinus congestion, sore throat, earache
    • Known exposures: household (including pets), travel or recent blood products. [C]10
    • Any major co-morbidities. [C]10
    • 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]10
      • Features suggestive of genuine drug allergy8, 16, 19
        • Severe, including
          1. Immediate Hypersensitivity (“Type I”) reactions: Anaphylaxis, difficulty breathing / bronchospasm, urticarial rash, hypotension, lip or other facial swelling / angioedema within 1 hour of administration.
          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. [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- document:

    • 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 National Early Warning Score (NEWS: see Appendix W) and manage in accordance with LTHT protocol (see Critical Care Outreach pages - LTHT Internal Only on Trust Intranet). [D]
    • Careful general physical examination of the patient for any subtle localising signs, especially in relation to: [C] 3,9,10
      • 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

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    Investigation

    a) Blood cultures

    • If indwelling central venous catheter (CVC) in situ, aerobic and anaerobic samples from each port of catheter and one peripheral vein, ideally taken at approximately the same time. [C] 6,10 Collecting the luminal and peripheral blood cultures approximately simultaneously is of great value in diagnosing line associated infections, as then 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. 3,10 (NB there may other concurrent foci.)
    • If no CVC in situ – sample from two different peripheral veins. [C] 3,10

    b) Other routine blood tests

    • 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 microbiological investigation.
    • 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
      • Throat
      • Mouth
    • If mucosal or cutaneous vesicular or ulcerated lesions: Specimens(s) for viral investigations [C] 3, 10. Use a “dry” swab or vesicle aspirate, sent in viral transport medium.
    • 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 [C] 3,10,10a
      • For patients with lung cancer, either primary or lung metastases [D]
      • For all patients under the care of an adult haematologist [D]
    • 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]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): consider repeating test twice weekly if neutropenia & pyrexia persist and consider chest High Resolution CT (HRCT) scan, +/- CT sinuses if clinically indicated (see LTHT Haemato-Oncology 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 should ideally be sent in viral culture medium (i.e. don’t send in charcoal transport medium).  
    • Other microbiological samples / site-specific imaging as clinically indicated. [C]3,10

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    Treatment
    Non-Antimicrobial Treatment

    Please refer to Severe Sepsis Care Bundles for guidance regarding supportive treatment for the acutely unwell adult if appropriate (Appendix W).

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    Empirical Antimicrobial Treatment

    Initiate antibacterial therapy if:

    • ANC < 0.5 x 109/l and definition of sepsis (i.e. 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 not febrile > 38 oC. [C]3, 9,10a
    • There is a 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) .[D]

    Any patient with severe graft versus host disease post-bone marrow transplantation that has required treatment with basiliximab or etanercept must be treated as per high risk febrile neutropenia guidelines irrespective of neutrophil count. There should be a low threshold for the initiation of antifungal therapy in these patients. [D]

    Timing: 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 transfers. If a patient has been initially assessed at another hospital and an empirical regimen initiated, prior to transfer to LTHT; then usually, the antimicrobial agent(s) should be switched if required to the appropriate regimen / agent(s) as detailed below.

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

    If there is any doubt about the appropriate antimicrobial regimen to use, a more senior colleague +/- LTHT Microbiology MUST be consulted.

    a) Risk stratification part 1: Monotherapy versus dual antimicrobial therapy

    Recent meta-analyses of empirical antibacterial regimens in febrile neutropenia have not shown the routine addition of an aminoglycoside to a suitable beta- lactam agent to be beneficial [A] 2, 4, 5, 10, 10a, 12. An aminoglycoside should be used empirically only in selected patients [D]. Patients are stratified on the basis of whether their disease or chemotherapy protocol renders them “higher risk” and thus require the addition of an aminoglycoside ( usually Gentamicin )  to the standard first-line broad spectrum antimicrobial Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam (first-line dual antimicrobial therapy) [D]: Group I. The patient categories classified as higher risk are listed in Table 1. Such patients will usually be on antibacterial prophylaxis whilst neutropenic post chemotherapy (see LTHT “Guideline for antimicrobial prophylaxis in Adult patients undergoing myelosuppressive therapy”) & hence are at greater risk of infection with a multi-antimicrobial resistant pathogen. If such a pathogen has not been isolated from blood cultures by 24 hours post collection, then the aminoglycoside should usually be discontinued. All other diseases and chemotherapy protocols are considered lower risk (Group II) and, as such, are suitable for first-line monotherapy.

    NB For LTHT patients, Gentamicin is the standard aminoglycoside for patients > 18 years age (see Appendix X for dosing regimen).

    Table 1: Group I diseases and chemotherapy protocols requiring first-line dual antimicrobial therapy in adults [D].

    Acute leukaemia

    Post haemopoietic stem cell transplant [SCT] (pre engraftment), or if post allogeneic SCT, graft failure or severe GVHD on basiliximab or etanercept

    Other Haematology patients currently taking levofloxacin prophylaxis 

    Other individual patients if specified by treating Haemato-Oncology consultant

    b) Recommended first-line antimicrobials for those patients suitable for first-line treatment with antimicrobial monotherapy:

    • If patient is not allergic or intolerant to penicillins:

    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)

    c) Recommended first-line antimicrobials for those higher risk patient categories listed in Table 1 requiring first-line dual antimicrobial therapy:

    d) If patient has history of ALLERGY to penicillins:

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

    If severe - Immediate hypersensitivity reaction: Teicoplanin electronic Medicines Compendium information on 

Teicoplanin IV (see dosing guideline. Off-label use and the patient should be informed of this) and AZTREONAM (IV) [A] 3, 13, 14, 16, 17 as first-line treatment for both patient groups.

    If severe - idiopathic (e.g. Stevens-Johnson syndrome); known allergy specifically to Aztreonam electronic Medicines Compendium information on Aztreonam or Ceftazidime; or these are unavailable: Teicoplanin electronic Medicines Compendium information on 

Teicoplanin IV (see dosing guideline. Off-label use and the patient should be informed of this) & CIPROFLOXACIN (IV). [C] 3  (contact Microbiology if on quinolone prophylaxis)

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

    e) Use Meropenem electronic Medicines Compendium information on Meropenem in place of Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam , also

    • 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 patient in Higher risk group (Group I -Table I) but Gentamicin is considered contra-indicated due to significant renal impairment (e.g. eGFR < 30ml/min).
    • If patient is severely unwell e.g. if NEWS > 7. [D]
    • If Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam has been stopped recently. (e.g. < 48 hours)
    • If patient receiving or recently received “high-dose” methotrexate chemotherapy, and awaiting its’ elimination (i.e. “high-dose” methotrexate is usually when the subsequent elimination is actively monitored. [D])

    If Meropenem electronic Medicines Compendium information on Meropenem is used, Gentamicin is NOT usually required in addition BUT consider using if patient remains acutely unwell / deteriorating post Meropenem electronic Medicines Compendium information on Meropenem (e.g. assess at two hours post first Meropenem electronic Medicines Compendium information on Meropenem dose) or if previous P.  aeruginosa infection.

    f) Consult with a more senior colleague +/- LTHT Microbiology, if:

    • genuine allergy to a proposed non β-lactam agent
    • β-lactam resistant P. aeruginosa reported
    • previous meropenem-resistant Gram-negative organism reported
    • Teicoplanin electronic Medicines Compendium information on 

Teicoplanin addition indicated (see criteria below), and patient known to be colonised with or previously infected with vancomycin-resistant Gram positive pathogen.

    g)  Additional antimicrobials

    • Add Metronidazole electronic Medicines Compendium information on Metronidazole (IV) [C]10 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).
    • 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

    See LTHT antimicrobial guidelines with respect to C. difficile for symptoms & signs suggestive of this infection, and appropriate management.

    • Add Clarithromycin electronic Medicines Compendium information on Clarithromycin (IV) if:
      • symptoms / signs of lower respiratory tract infection and/ or new infiltrate(s) on CXR. [C]10
    • Add Teicoplanin electronic Medicines Compendium information on 

Teicoplanin IV (see dosing guideline. Off-label use and the patient should be informed of this)
      • 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 either: [C] 3,9,10;20
        • hypotension (systolic BP < 90 mmHg)
        • high fever (temperature ≥ 400C)  

    If Teicoplanin electronic Medicines Compendium information on 

Teicoplanin is added in a patient who is a candidate for “dual” antimicrobial therapy (i.e. Group I), Gentamicin should usually be omitted. [C] 3, 9,10

    • Add Gentamicin if:
      • The patient is classified as higher risk (Group 1): see Table 1 above. 

    Consider addition of Gentamicin also if:

      • Severely unwell or moribund at presentation (especially if hypotensive (systolic BP < 90 mmHg),3,10,19 or rapidly clinically deteriorating on any of other above regimes
      • High risk for P. aeruginosa infection, e.g. history of previous colonisation or infection; presence of  ecthyma gangrenosum skin lesions.10
      • Has recent past history of frequent cephalosporin exposure.3

    NB As Gentamicin is nephrotoxic, it should usually be avoided if patient has recently received other nephrotoxic agents, such as cisplatin or Vancomycin electronic Medicines Compendium information on Vancomycin . [C]3

     If in doubt: consult with a more experienced colleague +/- LTHT Microbiology

    A “once daily” regimen should normally be followed: refer to Appendix X for dosing advice.

    • 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 +/- LTHT Microbiology.
    • Antiviral agents: Empirical addition of antiviral drugs is not usually indicated [C]3. However, 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 IV aciclovir should be instigated [C] 3,10. 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.3 Other antiviral agents should usually be added only on the basis of positive laboratory results [C]3 and consultation with LTHT Microbiology. This should usually be in addition to an appropriate antibacterial empirical regimen.

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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 LTHT microbiology or a more senior colleague:

    1. blood culture positive: 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 LTHT Microbiology. Antimicrobial therapy is usually administered for a minimum of 7 days and that the patient has been afebrile for ≥48 hours.
    2. blood culture negative: A patient must be apyrexial for at least 48 hours before stopping antimicrobials unless alternative cause for pyrexia has been found.

    If there is any doubt about using these guidelines it is essential that advice is sought from a more senior colleague +/- LTHT Microbiology

    Monitoring and modifying antimicrobial therapy

    Review at / within 24 hours:

    (i) If “Low-risk” on both classifications: Consider step-down to oral antimicrobial therapy (see risk stratification / oral switch section below)

    (ii) Group I patients: Consider stopping Gentamicin .

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    Switch to oral agent(s)

    Risk stratification part 2: Step-down to oral antimicrobial therapy

    None of the patients stratified as higher risk according to disease or chemotherapy protocol (Group I) are suitable for step-down to oral antimicrobial therapy at 24 hours.

    All other patients (i.e. those who have “lower risk” diseases and chemotherapy protocols) can be stratified on the basis of risk of serious medical complications occurring during each febrile neutropenic episode in order to determine whether step-down to oral antimicrobial therapy at 24 hours.

    If “low risk” as determined by assessment of risk of serious medical complications (MASCC score + assessment), step-down to oral antimicrobial therapy at 24 hours may be suitable (see below) [A] 3 with possible discharge from hospital at 48 hours.

    Patients classified as “high risk” for serious complications require at least 48 hours IV antimicrobials before discharge can be considered.

    Patients can be stratified as being at “high risk” or “low risk” of serious medical complications using validated clinical prediction rules: separate assessments have been validated for adults and children. For TYA patients, use the assessment that has been validated for age group of the patient at the time of assessment):

    Assessment of risk of serious medical complications in adults (≥18 years)

    The scoring system below is the MASCC (Multinational Association of Supportive Care in Cancer) risk score which is a validated clinical prediction tool for adults. [A] 3, 7, 9, 10

    Table 2. MASCC risk score: NB a higher score denotes a lower risk.  

    Characteristic

    Score

    Burden of illness (including cancer, co-morbidities and infection)         

    No or mild symptoms
    Moderate symptoms
    Severe or moribund



    5
    3
    0

    Systolic BP > 90 mm Hg

    5

    No chronic obstructive pulmonary disease

    4

    Solid tumour

    4

    Haematological malignancy with no previous invasive fungal infection

    4

    Adequately hydrated & NOT requiring parenteral fluids

    3

    Outpatient at onset of this FNE

    3

    Age <60 years

    2

    Maximum theoretical score possible

    26

    Each patient is given an individual risk score according to the criteria detailed in Table 2. If the MASCC score on admission is ≥ 21, the patient can be classified as being at “low risk” of serious medical complications during this febrile neutropenic episode. The score must be re-calculated for each admission episode.

    Criteria for step-down to oral antimicrobial therapy at 24 hours (adults):

    • MASCC score on admission ≥ 21
    • No critical values on laboratory investigations [C]10
    • Patient can take oral medications, e.g. not vomiting [C]10

    Patients at high risk should be under intensified senior review, and may be considered for step-down 24 hours after the above criteria are no longer met.

    If patient fulfils the age-appropriate criteria: consider switching to oral antimicrobial therapy after 24 hours of IV therapy:

    Table 3 - Suggested oral therapies after 24 hours of IV empirical antimicrobials

    Initial therapy

    Indication for initial therapy

    Suggested oral therapy

    Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam monotherapy

     

    Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and Co-amoxiclav electronic Medicines Compendium information on Co-amoxiclav 3,9, 10,20

    Teicoplanin electronic Medicines Compendium information on 

Teicoplanin#+ Aztreonam electronic Medicines Compendium information on Aztreonam
    (i.e. severe penicillin allergy)

     

    If no diarrhoea or past history of C.difficile  and age <65:
    Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and clindamycin [C] 9, 10;

    Consult with LTHT microbiology if patient has diarrhoea or previous history of C difficile or age >65.

    Teicoplanin electronic Medicines Compendium information on 

Teicoplanin#+ other drug

    Suspected catheter related sepsis

    Risk of MRSA or penicillin resistant S pneumoniae

    Consult with LTHT microbiology

    Meropenem electronic Medicines Compendium information on Meropenem monotherapy

    Penicillin allergy

    If no diarrhoea or past history of C.difficile  and age <65: Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and clindamycin [C] 9, 10

    Empirical therapy started while on / within 7 days of fluoroquinolone use, including prophylaxis [C] 9, 10

     

    Consult with LTHT microbiology

    Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam and Clarithromycin electronic Medicines Compendium information on Clarithromycin

    Chest infection

    Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin and Co-amoxiclav electronic Medicines Compendium information on Co-amoxiclav as above.

    Any other agent added to initial regimen

     

    Consult with LTHT microbiology

    Patient with history of C difficile

     

    Consult with LTHT microbiology

    #Use of teicoplanin for this indication is off-label and the patient should be informed of this.

    Consider step-up back to IV therapy

    Oral antimicrobials may be changed back to initial 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

    For higher-risk patients:

    1. If on initial Gentamicin :
      For those patients who have high risk diseases/ chemotherapy protocols (Group I) and have commenced first-line dual antimicrobial therapy, stop Gentamicin if, upon clinical review at / < 24 hours, the patient is afebrile, clinically stable / improving and blood cultures negative thus far – i.e. such patients “should” only receive a single dose if on the “once daily” protocol (see Appendix X).

    2. 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 no significant positive cultures at 24 hours & no other contra-indication.    

    Each patient should be discussed with a more senior colleague as appropriate. 

    Subsequent Clinical Evaluation

    This will depend upon initial results and response to chosen empirical regime, however whilst an in-patient this would usually include:

    • At least daily site-specific history and examination [C]10 and for unwell patients at least twice daily. [D]
    • Further or repeat investigations as clinically indicated.
    • Repeat blood cultures if:
      • fever persists at 48-72  hour review (see below) [C] 3, 9 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 [C] 3, 9, 10; and daily if receiving nephrotoxic agents, e.g. aminoglycoside, amphotericin (AmBisome®). [D]
    • CRP days 1 to 3 then clinical decision about continuation / frequency of monitoring.
    • Monitor aminoglycoside levels as per LTHT Policy (Appendix X).
    • Liver function tests as clinically indicated.
    • Aspergillus antigen test twice weekly if neutropenia & pyrexia persist and consider chest HRCT scan; +/-  CT sinuses if clinically indicated. (see Appendix W)

    If putative causative agent identified: Adjust choice and duration of therapy accordingly.[C] 2,10 This will usually be in consultation with LTHT Microbiology. On the basis of organism isolated, available in vitro sensitivities, and clinical response: consider de-escalating to “narrower-spectrum” antimicrobial agent(s) as appropriate. [D]

    If no causative agent identified: If clinically unstable (+/- febrile), reassess the patient. [D]

    • Consider if any specific focus now clinically / radiologically apparent.
    • Repeat initial investigations, such as blood cultures.
    • Consider if additional investigations are warranted.
    • Consider discussion with LTHT microbiology concerning appropriate second line therapy; and instituting second line therapy.
    • It is not normally appropriate to switch to second line empirical therapy until at least 48-72 hours on a suitable initial regimen. The decision must always be made after discussion with a specialist registrar or consultant. [D] 3, 10

    Table 4: Suggested empirical second line intravenous switches

    Initial empirical therapy

    Second line empirical therapy

    Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam +/- Gentamicin

    Meropenem electronic Medicines Compendium information on Meropenem IV [C] 3, 9, 10.

    Teicoplanin electronic Medicines Compendium information on 

Teicoplanin# IV (see dosing guideline) & Aztreonam electronic Medicines Compendium information on Aztreonam

    Consult LTH Microbiology

    Teicoplanin electronic Medicines Compendium information on 

Teicoplanin# IV (see dosing guideline) added to Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam

    Review reason for initiation of Teicoplanin electronic Medicines Compendium information on 

Teicoplanin: if recent bacterial cultures negative (including luminal blood cultures): consider cessation if switching to Meropenem electronic Medicines Compendium information on Meropenem or consult LTH Microbiology [C]3,10; 20.

    Meropenem electronic Medicines Compendium information on Meropenem

    Consult with LTH Microbiology

    #Use of Teicoplanin electronic Medicines Compendium information on 

Teicoplanin for this indication is off-label and the patient should be informed of this.

    If patient improving i.e. clinically stable and decreasing fever (which may take 2-7 days to settle) [B]), consider:

    • continuing initial empirical regime [C] 3,10,10a;. If patient on Meropenem electronic Medicines Compendium information on Meropenem due to initial severity (e.g. high initial NEWS) or renal impairment de-escalate to Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam if no contra-indication - discuss with LTHT Microbiology if history of penicillin allergy or resistant organisms isolated previously. [D].
    • cessation of IV antimicrobials if patient has been afebrile for ≥ 48 hours, no specific focus identified, and CRP favourable [C] 10a . ”High-risk” patients, either by disease/chemotherapy protocol ("Group I") or by risk of complications, require at least 48 hours IV antimicrobials [D]
    • stopping Gentamicin if still being given [D]
    • stopping Teicoplanin electronic Medicines Compendium information on 

Teicoplanin unless clinically there is a strong suspicion of intra vascular catheter related source of sepsis or positive microbiological results warranting its use [C]3,10,10a,20
    • if “Low Risk” for serious medical complications as described above, oral antimicrobial therapy may be suitable (see “Oral Switch” section above) [A].

    Consideration of discharge home at 48 hours
    If patient remains clinically well after 24 hours oral therapy, consider discharge home with oral treatment as appropriate (usually 2- 5 days) providing criteria for home therapy met [C]3,9;10. These are:

    • Patient/Parent or carer knows and understands the risks, and consents.
    • 24 hour carer available at home
    • 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 [C]10:
      • 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.

    Reassessments Day 3 – 7

    • If patient afebrile for ≥48 hours and other markers (e.g. CRP) favourable: stop IV antimicrobials [D].
    • If specific focus has now been identified, it may be appropriate to switch to a suitable oral antimicrobial regimen (consider discussing with LTHT Microbiology) [D].
    • If fever remains or recurs:
      • See above re reviewing investigations and treatment
      • Colony stimulating factors are not recommended for routine treatment of neutropenic fever/ sepsis.
      • If patient remains neutropenic and has been febrile for ≥5-7 days, aspergillus antigen tests should be sent and addition of empirical antifungal therapy should be considered [C] 3, 10 after discussion with a more senior colleague if required and LTHT Microbiology. (usually liposomal amphotericin (AmBisome®) in first instance but see Appendix W re antifungal therapy guidance).

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    Treatment Algorithm

    Decision-making pathway for the management of a patient with suspected neutropenic sepsis (Pending)

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    Provenance

    Record: 4007
    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 Antimicrobial 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 (Adults)

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

    Evidence base

    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 antimicrobial strategy.
      Clin Infect Dis 2003; 36: 149-158.
    2. Fred Hutchinson Cancer Research Center. Antimicrobial 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 antimicrobial 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 antimicrobial 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 antimicrobial 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 antimicrobial 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 antimicrobial 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 X for adult dosing.

    Approved By

    Improving Antimicrobial Prescribing Group

    Document history

    LHP version 1.0

    Related information

    Video Resources

    A preventable death part 1
    https://www.youtube.com/watch?v=UBZr1VaerLY

     

     


    A preventable death part 2
    https://www.youtube.com/watch?v=m5wj5eXPCVA

     

    Appendix W

    Severe sepsis care bundles for adults


    Antifungal therapy

    Appendix X

    Doses of Intravenous Antimicrobials in Adult Oncology and Haematology Patients

    NB: Dose reductions may be required in renal impairment: Contact Pharmacy

    Drug

    Dose

    Frequency

    Notes

    Levels

    Administration details and notes

    Aztreonam electronic Medicines Compendium information on Aztreonam

    2g IV

    8 hourly

    Reduce dose in renal impairment.

    ---

    Link to BNF

    Ceftazidime electronic Medicines Compendium information on Ceftazidime

    2g IV

    8 hourly

    Decrease dose in renal impairment

     

    Link to BNF

    Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin

    400mg IV

    8 hourly

     

    ---

    Link to BNF

    Gentamicin

    As per LTHT Policy

    As per policy

     

    As per policy

    Link to policy

    Metronidazole electronic Medicines Compendium information on Metronidazole

    500mg IV

    8 hourly

     

     

    Link to BNF

    Meropenem

    1g IV

    8 hourly

    Reduce dose in renal impairment

    --

    Link to BNF

    Piperacillin/tazobactam

    4.5g IV

    8 hourly

    Reduce dose in renal impairment

    --

    Link to BNF

    Teicoplanin electronic Medicines Compendium information on 

Teicoplanin

    As per LTHT policy

    As per policy

     

    As per policy

    Link to policy

    Doses of Oral Antimicrobials Adult Oncology and Haematology

    Drug

    Dose

    Frequency

    Notes

    Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin

    750mg po

    TWICE daily

    Link to BNF

    Co-amoxiclav electronic Medicines Compendium information on Co-amoxiclav

    625mg po

    TDS

    Link to BNF

    Clindamycin

    300mg po

    QDS

    Link to BNF

    References

    British National Formulary

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