Table of Contents
Overview #
Febrile neutropenia is a medical emergency with high mortality rate if not treated with prompt empiric IV antibiotics. It is commonly seen in patients on haematology or oncology wards who have recently had chemotherapy. Have a low threshold to discuss with the unit registrar or call a MET call if concerned.
Key points
- Empiric IV antibiotics WITHIN 30 MINUTES of fever onset
- Take at least two sets of blood cultures prior to commencing antibiotics
- Notify unit registrar promptly if first febrile episode, haemodynamically unstable or any clinical change/concerns
Triage #
Emergency requiring immediate attention
Causes #
Majority are due to infection – consider both common infections and those specific to the immunocompromised.
Infective (majority) [1]
- Unknown source (70-80%)
- Majority assumed due to chemotherapy induced mucositis and spread of endogenous flora in GIT
- Bacteria
- Most common pathogen with bacteraemia identified in 10-25% of cases
- Fungal
- Rarely cause first febrile episode
- Consider in high risk patients with persistent fever >5 days despite empiric antibiotics
- Viral
- Effectively prevented with antiviral prophylaxis (i.e. valaciclovir 500mg daily)
Non-infective (rare) [2]
- Blood transfusion reaction
- Malignancy-related
- Drug-induced
Clinical Features #
History [3, 4]
- Localising symptoms of infection
- PMHx
- Type and staging of malignancy
- High risk medical conditions {{Includes COPD, congestive cardiac failure, diabetes, poor functional status, malnutrition, oral/gastrointestinal mucositis, advanced age}}
- Previous episodes of neutropenic sepsis
- Nadir neutrophil count
- Duration of neutropaenia
- Source of infection
- G-CSF requirements {{Granulocyte colony stimulating factor use (G-CSF) such as filgrastim}}
- Chemotherapy history
- Type(s) of chemotherapy {{High risk patients include induction chemotherapy for acute myeloid leukaemia and conditioning for allogeneic haematopoietic stem cell transplant}}
- Date of most recent cycle
- Drug history
- Compliance with antifungal, antiviral and PJP prophylaxis {{pneumocystitis jirovecci pneumonia (PJP) prophylaxis}}
- Steroids or G-CSF use
- Allergies, especially to penicillin
- Recent procedures (surgical / invasive lines / bone marrow aspirates); note recent blood transfusion(s)
- History of prior infection or colonisation (especially by antibiotic resistant organisms)
Examination [3, 4]
- ABCDE approach if haemodynamically unstable
- Thorough examination to look for source of infection
- Mouth for ulcers or mucositis
- Chest for pneumonia
- Abdomen for neutropenic enterocolitis or other abdominal pathology
- Surgical sites for wound infections
- Skin for cellulitis or skin lesions
- Indwelling devices (PICC, ports, Hickmann’s, cannulas, urinary catheter + sites of previous lines)
Perianal inspection (if appropriate however, do NOT perform digital rectal examination)
Diagnosis #
Neutropenic Fever: [4,5]
Fever: ≥38.3°C OR two occasions of ≥38.0°C
AND
Neutropenia: neutrophils < 0.5 x109/L OR < 1.0 x109/L with predicted fall to < 0.5 x109/L
NOTE: Also treat empirically as febrile neutropenia if: [5]
- If neutropenic AND haemodynamically unstable WITHOUT fever
- If febrile following chemotherapy (and neutrophil count pending)
Investigations #
Initial investigations [3,4,5]
| Investigations | Significance |
| Blood cultures x2Peripheral + central venous access catheter (CVAD) {{Can only be accessed by certain nursing staff}}OR peripheral x2 sites if no CVAD | Detect bacteraemia |
| FBE | Check neutrophil count |
| VBG | If lactate >2.0, high risk of sepsis |
| *Urine MCS, CXR are done routinely (even if asymptomatic) in some hospitals – clarify with unit registrar if unsure |
Further investigations [3,4,5]
| Investigations | Indication |
| Bloods | |
| UEC, LFTs | As baseline if not already done as guides antibiotic doses and defines comorbidities |
| CMP, LDH, uric acid, coagulation studies | As baseline if not already done or if concerned re: tumor lysis syndrome |
| Cultures | Isolating the source {drop down box} |
| Urine MCS or urinalysis* | If urinary symptoms or frequent urinary tract infections (UTI) |
| Stool MCS including Clostridium difficile | If diarrhoea |
| Skin swab for MCS | If purulent discharge from wound, surrounding CVAD site or skin lesion |
| Respiratory PCR& COVID swab | If respiratory symptoms |
| Imaging | |
| CXR* | If respiratory symptoms or non-adherence to PJP/antifungal prophylaxis to rule out pneumonia/pulmonary infiltrate |
| #High resolution CT-chest +/- sinuses | Consider if persistent fevers despite >5 days of empiric antibiotics or previous invasive fungal disease rule out invasive fungal disease or other pulmonary infiltrates |
| #CT abdomen | If diarrhoea or abdominal tenderness or pain, to rule out neutropenic enterocolitis |
Referrals
| Unit Registrar | Discuss with home teamThis is a medical emergency as these patients deteriorate quicklyUrgent referral if any of: Patient’s first episode of febrile neutropeniaHaemodynamically unstableAny other clinical concerns/change |
| Infectious Diseases | Consider referral, especially if:Previous multi-drug resistant organisms or invasive fungal infectionCultures isolate organism to assist antibiotic rationalisation |
Management [5,6,7] #
Please refer to local hospital protocol for preferred first line therapy – hospital policies can vary widely due to difference in local antimicrobial resistance patterns
Management – first fever & haemodynamically stable [5,6,7] #
- Antibiotics within 60 minutes (with x2 blood cultures prior)
WITHOUT septic shock and NOT requiring ICU support
| Piperacillin + Tazobactam 4.5 g IV 6hrly OR Cefepime 2g IV 8 hrlyIf non-severe penicillin allergy: Cefepime 2g IV 8 hrlyIf severe penicillin allergy: Ciprofloxacin 400mg IV 12hrly AND Vancomycin IV loading dose {hyperlink to vancomycin dosing guideline} |
If features of abdominal or perineal infection AND NOT receiving piperacillin-tazobactam or meropenem
| ADD Metronidazole 500mg IV 12hrly |
If obvious vascular device infection OR cellulitis OR known to be colonised or recently infected with MRSA
| ADD Vancomycin IV {hyperlink to vancomycin dosing guideline} |
If known to be colonised or recently infected with multi-drug resistant gram negative bacteria (i.e. ESBL)
| Meropenem 1g IV 8 hrly instead of piperacillin-tazobactam or cefepime |
Management – first fever & haemodynamically unstable [5,6,7] #
- MET call
- IV fluid resuscitation
- Antibiotics within 30 minutes (with x2 blood cultures prior)
WITH septic shock or requiring ICU support
| Piperacillin + Tazobactam 4.5 g IV 6hrly OR Cefepime 2g IV 8 hrlyIf non-severe penicillin allergy: Cefepime 2g IV 8 hrlyIf severe penicillin allergy: Ciprofloxacin 400mg IV 12hrly AND Vancomycin IV loading dose ANDGentamicin IVIf kidney impairment 4-5mg/kg; otherwise 7mg/kg [6] ANDVancomycin 25-30mg/kg IV loading dose [6] If known to be colonised with VRE, consider empiric teicoplanin or linezolid. Discuss with ID |
If features of abdominal or perineal infection AND NOT receiving piperacillin-tazobactam or meropenem
| ADD Metronidazole 500mg IV 12hrly |
If known to be colonised or recently infected with multi-drug resistant gram negative bacteria (i.e. ESBL)
| Meropenem 1g IV 8 hrly instead of piperacillin-tazobactam or cefepime |
Other considerations
- Discuss with home team/infectious diseases re: empiric antifungal
- If there is evidence of colonisation but other multidrug resistant organisms (e.g. Carbapenemase-Resistant Enterobacteraciae (CPE) or Vancomycin Resistant Enterococci (VRE)), seek early infectious diseases input
Management – subsequent fevers [5,7] #
- Generally NO NEED TO CHANGE empiric IV antibiotics unless:
- Haemodynamically unstable
- New infective focus
- Indicated by culture or imaging results
- Repeat blood cultures
- Advised if: ongoing fevers AND >72hr of empiric antibiotics
- Consider if: already 2 sets of cultures taken AND < 72hr of empiric antibiotics
- If haemodynamically unstable
- MET call + notify unit registrar
- Repeat full septic screen
- Add gentamicin and vancomycin (see above)
- Consider discussing with ID re: empiric antifungal
- Consider discussing with unit registrar re G-CSF
- If in doubt, have a low threshold for contacting the home team registrar for advice
References #
- Bow E, Wingard J. Overview of neutropenic fever syndromes [Internet]. UpToDate. 2020 [cited 29 August 2021]. Available from: https://www.uptodate.com/contents/overview-of-neutropenic-fever-syndromes?search=febrile%20neutropenia&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
- Platt J. Neutropenic Sepsis [Internet]. Geeky Medics. 2020 [cited 29 August 2021]. Available from: https://geekymedics.com/neutropenic-sepsis/
- O’Brien J, Watson P. The Junior Doctor Survival Guide. 1st ed. Elsevier; 2017.
- Wingard J. Diagnostic approach to adult cancer patient with neutropenic fever [Internet]. UpToDate. 2020 [cited 29 August 2021]. Available from: https://www.uptodate.com/contents/diagnostic-approach-to-the-adult-cancer-patient-with-neutropenic-fever#H29410331
- Tam C, O’Reilly M, Andresen D, Lingaratnam S, Kelly A, Burbury K et al. Use of empiric antimicrobial therapy in neutropenic fever. Internal Medicine Journal. 2011;41(1b):90-101.
- Kelly H et al. Febrile Neutropenia [Internet]. eTG Complete. 2019 [cited 29 August 2021]. Available from: https://tgldcdp.tg.org.au.acs.hcn.com.au/viewTopic?topicfile=febrile-neutropenia&guidelineName=Antibiotic&topicNavigation=navigateTopic#toc_d1e47
- Wingard J. Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients) [Internet]. UpToDate. 2021 [cited 29 August 2021]. Available from: https://www.uptodate.com/contents/treatment-of-neutropenic-fever-syndromes-in-adults-with-hematologic-malignancies-and-hematopoietic-cell-transplant-recipients-high-risk-patients
Contributors
Reviewing Consultant/Senior Registrar
Dr Kate Drummond
Dr Adam Steinberg
