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

Publication: 10/11/2014  
Next review: 03/08/2024  
Clinical Guideline
CURRENT 
ID: 4007 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2021  

 

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 IN ADULTS

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

The first dose of antimicrobial should be administered <1 hour after arriving at hospital/developing signs of sepsis on the wards.

For patients < 18 years age, including teenagers being managed in the Children’s Hospital, LGI site / primarily by an LTHT Paediatrician: see children’s version.

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Definitions and Assessment

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

Please note: infections may present without fever. If a patient is severely unwell and infection is suspected, do not wait for the full blood count before initiating antimicrobial therapy.

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

Empirical antibiotic treatment should not be delayed by detailed assessment- brief assessment, blood cultures and antimicrobial treatment should be prioritised

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Empirical 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.
  • 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)

Do not routinely offer G-CSF for the prevention or treatment of neutropenic sepsis in adults receiving chemotherapy unless they are receiving G-CSF as an integral part of the chemotherapy regimen or in order to maintain dose intensity.

  • Careful monitoring of NEWS2 and early consideration of referral to critical care outreach is recommended for patients with neutropenic sepsis. Deterioration can occur rapidly. 
  • See Sepsis Management guidance for red flags and non-antimicrobial management of sepsis.  
  • Please note, atypical presentations of sepsis/infection is recognised in the immune-compromised population. Seek advice from senior clinicians and ID/microbiology as appropriate. 

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Diagnosis

For adult patients with a presumed diagnosis of neutropenic sepsis, the following diagnostic tests should be taken to confirm diagnosis:

All patients

Blood cultures (take prior to administering antibiotics but this should not delay treatment) - minimum 2 sets

  • Paired (same volume, same time from peripheral vein and all lumens) if central/tunnelled line in situ
  • If no CVC, sample from two peripheral veins

FBC, U&E, CRP, LFT, Lactate

Selected patients

Please consider if clinically appropriate:

  • Urine sample - state ‘immunosuppression’ on request, otherwise sample may not be cultured   
  • Swab skin lesions, vascular catheter exit site, throat, mouth - for MC&S 
  • Consider viral swab for skin lesions, oral ulceration 
  • If diarrhoea present, send stool for viral PCR, enteric pathogen screen and C difficile testing 
  • Chest X-ray 
    • If respiratory symptoms/signs present 
    • For all haematology patients with neutropenia 
    • For all patients with lung cancer, or known lung metastases 
  • If community acquired pneumonia present 
    • Send sputum for MC&S 
    • Consider sending urine for legionella Ag 
    • Consider sending respiratory viral throat swab (includes mycoplasma PCR) 
  • If upper respiratory tract infection, please send respiratory viral throat swab  
  • See trust guidance re: COVID-19 testing, remember atypical presentation may occur in immune-compromised patients 

Patients at risk of fungal infection (e.g. prolonged immunosuppression, post haemopoeitic stem cell transplant)

If known history or strong clinical suspicion (e.g. sinusitis or pleuritic chest pain), please send Aspergillus antigen and beta-D-glucan tests and consider further investigation (e.g. high resolution CT chest, or sinus CT)

See LTHT guidance on anti-fungal treatment in haematology patients

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Empirical antimicrobials for adult neutropenic sepsis

Empirical antimicrobials for adult neutropenic sepsis  

Always check previous microbiology results before prescribing, antibiotic regimens may need to be modified if multi-drug resistant organisms are present

(e.g. CPE, MRSA, MR Pseudomonas aeruginosa) 

 

First-line therapy

History of penicillin allergy or patient has received high-dose methotrexate

Haematology patients

Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam
IV 4.5g 6-hourly 

+/- 3

Amikacin electronic Medicines Compendium information on Amikacin4
IV 15mg/kg* over 24 hours
See LTHT Amikacin  guidance for dosage and monitoring advice (essential if renal impairment with eGFR <60 mL/min)

Teicoplanin electronic Medicines Compendium information on Teicoplanin IV 12mg/kg1
(see LTHT guidance)

AND

Aztreonam electronic Medicines Compendium information on Aztreonam2 2g IV 8-hourly

+/- 3

Amikacin electronic Medicines Compendium information on Amikacin4
IV 15* mg/kg over 24 hours
See LTHT Amikacin  guidance for dosage and monitoring advice (essential if renal impairment with eGFR <60 mL/min)

*In confirmed multi-resistant Pseudomonas infection, higher doses of Amikacin electronic Medicines Compendium information on Amikacin may be indicated <22.5mg/kg/day a switch to cefiderocol but only in consultation with microbiology 

Oncology patients

 

Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam 4.5g IV 6-hourly

+/-3

Gentamicin IV as per Hartford nomogram
(only if eGFR ≥30 ml/min if patient specific or microbiological indication)

Teicoplanin electronic Medicines Compendium information on Teicoplanin IV 12mg/kg1
(see LTHT guidance)

AND

Aztreonam electronic Medicines Compendium information on Aztreonam2 2g IV 8-hourly

All patients

Do not switch initial empiric antibiotics in patients with unresponsive fever unless there is clinical deterioration or a microbiological indication

Second line therapy if deterioration on first-line therapy

  • Consider suitability of addition of Gentamicin/Amikacin electronic Medicines Compendium information on Amikacin (as listed above)
    OR
  • Switch toMeropenem electronic Medicines Compendium information on Meropenem1g IV 8 hourly (see note below)
  • Please note, the multi-resistant Pseudomonas aeruginosa seen previously in LTHT haematology patients is resistant to Meropenem electronic Medicines Compendium information on Meropenem, sensitive to Amikacin electronic Medicines Compendium information on Amikacin.

Meropenem electronic Medicines Compendium information on Meropenem resistance is increasing in haematology/oncology patients at LTHT, this agent should be used only when alternatives are unsuitable:

  • If antibiotic regimens above are unsuitable due to hypersensitivity reactions
  • If a patient has an eGFR <30 ml/min and Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam or Teicoplanin electronic Medicines Compendium information on Teicoplanin/Aztreonam electronic Medicines Compendium information on Aztreonam alone thought not to be appropriate (or not responding to first-line regimen at 72 hours).
  • If patient has recently completed a course of Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam AND is on Levofloxacin electronic Medicines Compendium information on Levofloxacin prophylaxis (increasingly likelihood of multi-drug resistant Gram-negative infection)
  • Patient has recent ESBL/AmpC reported in microbiology sample
  • Please commence antibiotic course within 1 hour, all patients commencing Meropenem electronic Medicines Compendium information on Meropenem should be discussed with haematology/oncology or consultant/microbiology (next morning if commenced overnight)
  • Please contact microbiology if previous meropenem-resistant organism reported

All patients

Add Clarithromycin electronic Medicines Compendium information on Clarithromycin500mg PO 12-hourly for 5 days

  • If patient has community acquired pneumonia

Add Teicoplanin electronic Medicines Compendium information on Teicoplanin IV 12mg/kg1 (see LTHT guidance)

  • If intra-vascular catheter related infection is suspected (and teicoplanin is not part of the empiric regimen). Symptoms include exit site infection, fever after line-use or sepsis in the absence of any other clinical source
  • If recent MRSA
  • NB If Teicoplanin electronic Medicines Compendium information on Teicoplanin is added to a regimen with Gentamicin/Amikacin electronic Medicines Compendium information on Amikacin. Discuss with microbiology as combined risk of nephrotoxicity.

Add Metronidazole electronic Medicines Compendium information on Metronidazole 500mg IV or 400mg PO 8-hourly if

  • Peri-anal infection, intra-abdominal infection or necrotising oral ulceration is present and patient is receiving a regimen without anaerobic coverage e.g. Teicoplanin electronic Medicines Compendium information on Teicoplanin/Aztreonam electronic Medicines Compendium information on Aztreonam or Teicoplanin electronic Medicines Compendium information on Teicoplanin/Ciprofloxacin electronic Medicines Compendium information on Ciprofloxacin
  • Peri-anal infection, intra-abdominal infection or necrotising oral ulceration is present and fever/symptoms are not improved after 48 hours of a regimen with anaerobic coverage e.g. Piperacillin/tazobactam electronic Medicines Compendium information on Piperacillin/tazobactam or Meropenem electronic Medicines Compendium information on Meropenem

Add anti-viral agents if clinically indicated e.g. encephalitis, varicella zoster infection, influenza, COVID-19 etc.

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REVIEW BY 72

By 72 hours of antimicrobial treatment, diagnostics should have proven your initial diagnosis or guided to a new diagnosis.

Patients on IV treatment should be reviewed daily.

The review, outcome and future plans (where appropriate) should be documented in the medical notes.

IF FEVER PERSISTS DESPITE APPROPRIATE EMPIRIC THERAPY

REVIEW

  • For patients with confirmed neutropenic sepsis and a high risk of developing septic complications, a healthcare professional with competence in managing complications of anticancer treatment should review the patient’s clinical status daily

ANTIBIOTIC THERAPY

  • Generally, empiric antibiotics do not require change/escalation in patients with unresponsive fever unless there is clinical deterioration or a microbiological indication
  • Escalation to Meropenem electronic Medicines Compendium information on Meropenem may not always be appropriate second line treatment, see notes above. Discussion with senior colleagues/microbiology team recommended
  • Addition of anti-fungal therapy should be considered for haematology patients with prolonged neutropenia if fever is refractory after 5 days of antibiotic therapy. Appropriate investigations such as Aspergillus antigen, beta-D glucan and HRCT chest/ CT sinuses are also recommended

INVESTIGATIONS

  • Repeat blood cultures if:
    • fever persists at 48-72  hour and at subsequent therapy changes
    • clinical picture significantly deteriorates
    • required to aid clinical interpretation of positive microbiology results
  • FBC to assess neutrophil count alternate days
  • Renal function tests: at least twice weekly during in-patient therapy and daily if receiving nephrotoxic agents, e.g. Gentamicin, Amikacin electronic Medicines Compendium information on Amikacin, Teicoplanin electronic Medicines Compendium information on Teicoplanin, amphotericin (AmBisome®).
  • Monitor aminoglycoside levels as per LTHT Policy and send Aspergillus antigen test twice weekly if neutropenia & pyrexia persist and consider chest HRCT scan; +/-  CT sinuses if clinically indicated.  

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Duration of Therapy

Table 3: Recommendations on the duration of therapy - review IV antibiotics daily

1

Patient has neutrophils >0.5  x 109/L but was started on antibiotic treatment for suspected neutropenic sepsis on admission 

  • If ‘functional’ neutropenia is excluded, treat as per general LTHT guidelines for non-neutropenic adult patients.
  • De-escalate antibiotics where possible as per guidance.

2

Blood cultures positive

  • All cases will be liaised by microbiology team
  • Usually minimum 7 days duration from date of blood culture, but longer may be required

3

Culture-negative neutropenic sepsis - Haematology patients

  • Duration of therapy is dependent on source of infection and response to therapy
  • Oral switch at 24 hours is not appropriate
  • Intra-venous antibiotics should be continued until minimum 48 hours after patient becomes apyrexial/CRP improves
  • Stop Amikacin electronic Medicines Compendium information on Amikacin/Gentamicin as soon as patient is afebrial/clinically improving and blood cultures negative at 48 hours (i.e. most patients will receive just one or two doses)

4

Culture-negative neutropenic sepsis - Oncology patients

  • If low risk as determined by MASCC score and assessment (see below), oral switch may be suitable at 24 hours
  • If high risk as determined by MASCC score and assessment (see below), patient requires a minimum of 48 hours IV antibiotics

5

Oral switch appropriate

  • Discuss with microbiology if culture negative 

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MASCC Score

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 teenage/young adult (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.

Table 4. 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 4. 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 6
  • Patient can take oral medications, e.g. not vomiting 6

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.

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CONSIDERATION OF PATIENT DISCHARGE AT 48 hrs

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.3,4,6 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 and appropriate oncology CSU contact details
  • 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 are6:
    • New clinically significant positive cultures
    • New symptoms reported by the patient (discussed at the time of discharge)
    • Persistent or recurrent fever two days or more after discharge
    • Inability to tolerate oral regimen.

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Provenance

Record: 4007
Objective:
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

  • National Institute for Health and Clinical Excellence. Prevention and management of neutropenic sepsis, CG151. 2012.
  • Antimicrobial reference laboratory. Guideline ranges for TDM 2016-17
  • British National Formulary 2 June 2021 published by NICE
  • Fred Hutchinson Cancer Research Center. Antimicrobial indications (prophylactic systemic and empiric regimens for febrile neutropenia in adults). 2002.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • Riedl MA and Casillas AM. Adverse drug reactions: types and treatment options. American Family Physician 2003; 68: 1782 – 1790.
  • 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.
  • 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

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 3.0

Related information

Footnotes

  1. The use of teicoplanin for neutropenic sepsis is off license and the patient should be made aware of this.
  2. Aztreonam should not be given to patients with ceftazidime hypersensitivity, ciprofloxacin 400mg IV 12-hourly (or 500mg PO 12-hourly) is an appropriate alternative if patient has not received prophylaxis with this agent
  3. Consider adding gentamicin for oncology patients (or amikacin for haematology patients) if hypotensive (sys <90mmHg), NEWS >6, or if previous Pseudomonas aeruginosa infection or if ecthyma gangrenosa present. Avoid gentamicin if eGFR <30 ml/min, and amikacin if eGFR <20 ml/min, or if recent nephrotoxic chemotherapy e.g. cisplatin. Discuss with microbiology if concerns about renal function and aminoglycoside therapy.
  4. Amikacin is prescribed using ideal body weight (full details on LTHT amikacin guidance). Amikacin is empiric therapy targeted at multi-resistant Pseudomonas aeruginosa. Treatment should be assessed on a case by case basis including consideration of severity of sepsis, previous LTHT inpatient episodes, previous microbiology/screening results and renal function. Avoid amikacin if eGFR <30 ml/min or if recent nephrotoxic chemotherapy e.g. cisplatin. Discussion with microbiology and a haematology consultant is recommended. If prescribed, monitor for renal deterioration (minimum twice/week), ototoxicity and low magnesium (other medication in haematology patients may exacerbate this effect). 

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