Neutropaenic Fever and Sepsis

Reviewed and revised 29 July 2026

OVERVIEW

Febrile neutropaenia is a medical emergency requiring prompt assessment and administration of empirical antimicrobial therapy.

Febrile neutropaenia is defined as:

Fever

• Single oral temperature ≥38.3°C,
  OR
• Temperature ≥38.0°C sustained for ≥1 hour

Neutropaenia

• Absolute neutrophil count (ANC) <0.5 × 10⁹/L,
  OR
• ANC <1.0 × 10⁹/L with an anticipated decline to <0.5 × 10⁹/L within 48 hours

Neutropaenic sepsis refers to sepsis occurring in a neutropenic patient and may occur without fever.

Consider infection in any unwell neutropaenic patient, particularly:

• following recent chemotherapy
• following haematopoietic stem cell transplantation
• with haematological malignancy
• with clozapine-associated agranulocytosis
• with congenital or acquired neutropenic disorders

Fever may be absent, particularly in:

• elderly patients
• patients receiving corticosteroids
• profoundly immunocompromised patients
• patients presenting with septic shock

Key points

• Assume infection until proven otherwise
• Early administration of appropriate antibiotics saves lives
• Obtain cultures before antibiotics where possible, but do not delay treatment in sepsis or septic shock.Source identification and source control are essential
• Local epidemiology and antimicrobial resistance patterns should guide therapy
• Daily antimicrobial review and de-escalation are important

INFECTIVE ORGANISMS

Gram-positive bacteria account for a large proportion of microbiologically documented infections; however, Gram-negative bacteraemia remains a major cause of severe sepsis and death in neutropenic patients. Local epidemiology should guide empiric therapy.

Organisms of primary concern include:

• Gram negative bacilli (GNB)
  • Enterbacterales
    • Escherichia coli
    • Klebsiella pneumoniae and oxytoca
    • Enterobacter cloacae complex
    • Others:
      • Citrobacter spp.
      • Serratia marcescens
      • Morganella morganii
      • Proteus spp.
      • Providencia spp.
    • Pseudomonas aerogenosa
• Gram positive cocci (GPC)
  • Coagulase-negative Staphylococci
  • Staphylococcus aureus (MSSA and MRSA)
  • Viridans group streptococci
  • Enterococci

Others

• resistant organisms in some patient groups / institutions (e.g. MRSA, VRE, resistant Enterobaterlaes (ESBL, AmpC-producing, and CPE), multi-drug resistant Pseudomonas, Stenotrophomonas maltophila, Acinetobacter spp)
• Fungi – Candida spp., Aspergillus spp., and Mucor spp

ANTIBIOTIC CHOICE

Rationale

• Need to cover likely causative organisms
• Bacteraemia due to Pseudomonas aeruginosa occurs relatively infrequently but, because morbidity and mortality are high, empirical regimens usually cover this microorganism
• The choice of antimicrobials will also depend on local susceptibility patterns, the patient’s previous microbiology, and the patient’s risk of infection with a multidrug-resistant organism (MDRO)
• Therapy should be reviewed when a causative organism is identified and susceptibilities are known

First line antibiotics

• piperacillin-tazobactam 4.5g IV Q6h
  (extended infusions over 3 hours are commonly used in ICU, and increasingly continuous infusions)
  OR
• cefepime 2 g (child: 50 mg/kg up to 2 g) IV q8h

Consider the following:

• if septic shock OR requires ICU:
  • add aminoglycoside (amikacin or tobramycin, using a dosing calculator)
• If intra-abdominal or prerineal infection:
  • use piperacillin-tazobactam or add metronidazole to cefepime
• If risk factors for infection with MDR GNB (see below), discuss with ID and consider:
  • Antipseudomonal beta-lactam plus aminoglycoside (amikacin or tobramycin, using a dosing calculator), or
  • Meropenem (see below)
• if suspected MRSA (see below)
  • add Vancomycin
• change to meropenem (1g IV Q8H is standard, increase to 2g IV QH if septic shock or use continuous infusion) if:
  • Significant MDR Gram-negative risk factors
  • Aminoglycosides are otherwise contraindicated (e.g. known ototoxicity or severe hypersensitivity)
  • Severe beta-lactam allergy limits alternatives
  • Known or suspected ESBL-producing organisms
• add antifungal (e.g. voriconazole) based on ID specialist advice if:
  • suspected invasive fungal infection (e.g. candidiasis, aspergillosis, or mucormycosis)
  • fevers persist in high-risk patients beyond 96 hours of antibacterial therapy (seek expert advice)
  • Unstable high-risk patients
  • Prolonged or profound neutropenia
• if suspected PJP
  • add Co-trimoxazole
• if suspected HSV or CMV infections:
  • add acyclovir/ ganciclovir
• if penicillin allergy:
  • Non-severe allergy
    • Cefepime-based regimens are generally appropriate
  • Severe immediate allergy (anaphylaxis, airway compromise, angioedema)
    • Consider cefepime in selected circumstances after ID specialist review
    • Otherwise use meropenem
  • Severe delayed reactions (DRESS, SJS/TEN, severe blistering reactions, significant organ involvement)
    • Seek specialist advice urgently
    • Meropenem may be considered only where alternatives are limited

Tips:

• Consult Infectious Diseases (ID) early
• Pseudomonas coverage is mandatory
• Broaden antibiotics early if shock is present
• Culture before antibiotics if possible, but never delay treatment of sepsis or shock
• Vancomycin is not given routinely, but if vancomycin is indicated:
  • Administer beta-lactam therapy first
  • Vancomycin infusion should not delay definitive antipseudomonal coverage
• Initial empirical regimens are intended for the first 48 hours, then review and de-escalate daily
• Modifications of therapy, as well as treatment duration, depends on:
  • pathogen identification / culture results
  • susceptibility testing
  • source identification and control
  • clinical response
  • neutrophil recovery

RISK FACTORS

Risk factors for febrile neutropaenia include:

• Cytotoxic chemotherapy
• Haematological malignancy
• Bone marrow transplantation
• Cellular therapies (CAR-T)
• Prolonged corticosteroid therapy
• Immunosuppressive medications
• Clozapine-induced agranulocytosis
• Congenital neutropenic syndromes

High-risk neutropaenic fever patients include those with:

• Profound neutropenia (ANC <0.1 × 10⁹/L)
• Expected neutropenia >7 days
• Haematological malignancy
• Significant comorbidity
• Mucositis
• Organ dysfunction

Suspect multidrug-resistant (MDR) Gram-negative infection if these risk factors are present:

• Previous colonisation or infection with an MDR Gram-negative organism (the strongest risk factor)
• Recent hospitalisation or long-term care facility stay (within ~6 months), particularly in regions with a high prevalence of MDR Gram-negative organisms or experiencing an MDR Gram-negative outbreak
• Recent overseas travel (within ~6 months), especially if associated with healthcare exposure or antibiotic use
• Frequent or prolonged hospital admissions, particularly with recent antibiotic exposure
• Residence in an aged-care facility, especially with repeated courses of antibiotics

Suspect MRSA if these risk factors are present:

• microbiologically confirmed infection with a beta-lactam resistant GPC
• isolation of GPC on Gram stain from a clinical sample in patients known to be colonised with a beta-lactam resistant GPC
• clinical suspicion of GPC infection in a patient known to be colonised with a MDR PGC
• suspected skin and soft tissue infection, including vascular device infections

ASSESSMENT

History and examination

• suspect neutropaenia in any haematology/ oncology patient that has received chemotherapy (oral or intravenous) within the last 14 days or has a history of recurrent neutropenia
• Assess for risk factors (see above) for:
  • neutropaenic fever
  • high risk of poor prognosis
  • MDROs
• Assess for infection:
  • Upper respiratory tract for otitis media and sinusitis
  • Oropharynx for dental abscess, peritonsillat infection, and mucositis
  • Lower respiratory tract for signs of pneumonia, including Pneumocystis jiroveci (PJP) pneumonia (cough, tachypnoea, hypoxia, interstitial infiltrate on CXR)
  • Abdomen for signs of Clostridium difficile colitis (generalised abdominal tenderness) or typhlitis (tenderness over caecum)
  • Skin for cellulitis or vesicular lesions
  • Perineum and perianal area for anal fissure, cellulitis or abscess
  • vascular access devices for signs of tunnel/exit site infection and CLABSI
  • Signs of anaemia and/or thrombocytopenia
• Do not perform a rectal examination or insert a rectal thermometer

Investigations

• Blood cultures
  • Two sets from separate sites in adults
  • Peripheral culture plus cultures from each lumen of any central venous device
  • obtain promptly, ideally before administering antibiotics
  • do not delay antibiotics in septic shock to obtain cultures.
• FBC, UEC and LFTs (including albumin), CRP and lactate
• If clinically indicated (and no contra-indications):
  • Microbiology
    • Nasal swab (throat swab if thrombocytopenic), for respiratory virus PCR
    • Sputum MCS
    • Stool culture and viral studies (diarrhoea); C. difficile toxin assay if recent treatment with antibiotics
    • Bacterial swab of skin, vascular access site or mouth lesions
    • Viral swab of vesicular lesions and mouth ulcers for HSV and VZV PCR
  • Imaging
    • CXR (there may be no changes while neutropenic)
    • CTB and lumbar puncture (neurological symptoms)
    • CT chest and bronchoscopic alveolar lavage (suspected pulmonary infection and non-diagnostic CXR)
    • CT “pan scan” (suspected occult infection source)
    • Echocardiography (endocarditis)

MANAGEMENT

Immediate care

• Resuscitation
  • address life threats such as septic shock
  • e.g. IV fluid resuscitation, vasopressor support and invasive haemodynamic monitoring
• Early IV antibiotics (within 1 hour if septic shock or neutropaenic fever)
  • see antibiotic choice above
  • seek expert advice regarding duration, influenced by:
    • patient’s response
    • isolation of a causative organism
    • rate of neutrophil recovery
• Early source identification and control
  • discuss with haematology before removing any intravascular devices, recommended if:
    • CLABSI due to S. aureus, P. aeruginosa, fungi, or mycobacteria
    • port pocket site infection
    • endocarditis
    • septic thrombosis
    • tunnel infection
    • persistence of bacteraemia even after 72 h of appropriate antibiotic treatment
    • Septic shock attributable to line infection

Environmental precautions

• protective isolation
• strict hand hygiene
• full barrier precautions (e.g. mask, gown, gloves, overshoes)
• avoid unnecessary invasive procedures

G-CSF

• Use should be guided by a haematologist
• Routine therapeutic G-CSF is not recommended for all patients with established febrile neutropenia.
  • don’t use in acute leukaemia (may stimulate leukaemic clone)
• It may be considered in selected high-risk patients, including:
  • Profound neutropenia
  • Prolonged neutropenia
  • Septic shock
  • High-risk haematological malignancy
• effects:
  • increases neutrophil count
  • reduces rate of serious infections
  • decreased mortality in bone marrow transplant (BMT) or dose-intensive chemotherapy
  • adverse effects:
    • rash, injection site pain, bone pain, influenza-like symptoms and splenic rupture (rare)
• cease once neutrophils > 1.0 x 10⁹/L

Supportive care and monitoring

• FASTHUGSINBED Please

Disposition

• Early consultation with haematology (refer after administering first dose of antibiotics) and infectious diseases
  • a subgroup of low-risk neutropenic patients may be able to be managed (at home) with oral therapy
• Urgent ICU review if:
  • Hypotension
  • Lactataemia
  • Requirement for vasopressors
  • Altered mental state
  • Hypoxaemic respiratory failure
  • Rapid clinical deterioration

PROGNOSIS

Outcomes for critically ill patients with haematological malignancy have improved substantially over recent years

Factors improving ICU survival:

• better patient selection
• early admission before the onset of multi-organ failure
• overall improved prognosis in haematological and solid malignancy
• use of non-invasive ventilation (NIV)
• use of diagnostic bronchoscopy
• improved survival rates in septic shock

Prognosis is driven primarily by:

• Severity of acute illness
• Number of organ failures
• Presence of septic shock
• Timeliness of antimicrobial therapy
• Ability to achieve source control

Poor prognostic factors include:

• Profound neutropenia (ANC <0.1 × 10⁹/L)
• Prolonged neutropenia (>7 days)
• Delayed antibiotic administration
• Invasive fungal infection
• Multiple organ failure

References and Links

LITFL

• CCC – Sepsis Overview
• CCC – Continuous beta-lactam infusions

Journal articles

• Douglas AP, McMullan B, Yap N, Bajel A, Alcorn K, Cooley L, Kinsella P, Laundy N, Bupha-Intr O, Legg A, Roberts J, Trubiano JA, Sasadeusz J, Conyers R, Thursky KA; Australasian Neutropenic Fever Guidelines Steering Committee. Consensus guidelines for the subsequent management of neutropenic fever after empiric therapy. Intern Med J. 2025 Dec;55 Suppl 7:68-94. doi: 10.1111/imj.70249. PMID: 41521414. [fulltext article]
• Douglas AP, Cooley L, McMullan B, Kinsella P, Laundy N, Yap N, Bupha-Intr O, Alcorn K, Bajel A, Weinkove R, Legg A, Roberts JA, Trubiano JA, Conyers R, Thursky KA; Australasian Neutropenic Fever Guidelines Steering Committee. Consensus guidelines for initial management of neutropenic fever. Intern Med J. 2025 Dec;55 Suppl 7:43-67. doi: 10.1111/imj.70248. PMID: 41521406. [fulltext article]

FOAM and web resources

• Therapeutic Guidelines (Australia)
• RCH CPG — Fever and suspected or confirmed neutropenia