Neutropaenic Sepsis

Reviewed and revised 9 December 2021

OVERVIEW

Definition

• Febrile neutropaenia (or neutropaenic fever) is defined as:
  • a single temperature measurement >=38.5C, or a sustained temperature >=38C for more than 1 hour
  • in a patient with a decreased absolute neutrophil count (ANC) of either <0.5 x 109/L, or <1 x 109/L with a predicted nadir of <0.5 x 109/L over the subsequent 48h
• Neutropenic patients with sepsis or severe sepsis may not have a fever (e.g. elderly, patients on corticosteroids)

Key points

• Rapid empirical initiation of broad-spectrum IV antibiotics and source control is essential
• the optimal antibiotic regime remains controversial
• Non-infectious causes of fever are common in patients with haematological malignancy but often difficult to distinguish from infective causes acutely

INFECTIVE ORGANISMS

Organisms of primary concern include

• Gram negative bacilli (GNB)
• Coagulase-negative Staphylococci
• Staphylococcus aureus (MSSA)
• Streptococcus viridans

Others

• resistant organisms in some patient groups / institutions (e.g. MRSA, VRE, ESBL, Pseudomonas, Stenotrophomonas, Acinetobacter)
• fungal infection

Note that GPC now predominate due to the ubiquity of longterm vascular access devices and use of fluroquinolone prophylaxis in patients with neutropaenia

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 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
• Prophylaxis should not be used

First line antibiotic

piperacillin-tazobactam 4.5g IV Q8h (Q6h if septic shock/ critically ill)
OR
cefepime 2 g (child: 50 mg/kg up to 2 g) IV q8h
OR
ceftazidime 2 g (child: 50 mg/kg up to 2 g) IV q8h)

Consider the following:

• add Gentamicin IV 4-7 mg/kg IBW if  local microbiological data suggest there is a risk of resistance to the above antibiotics, or the patient is critically ill with severe sepsis or septic shock
• add Vancomycin for suspected MRSA if
  • patient has severe sepsis / septic shock
  • is known to be colonised with methicillin-resistant Staphylococcus aureus (MRSA)
  • has clinical evidence of a catheter-related infection in a unit with a high incidence of MRSA infection
  • fever persists at 48 hours
• change to meropenem if suspected ESBL
• add antifungal (e.g. voriconazole) if:
  • suspected fungal infection (e.g. candidiasis, aspergillosis, or mucormycosis)
  • fevers persist in high-risk patients beyond 96 hours of antibacterial therapy (seek expert advice)
• add Co-trimoxazole for suspected PJP
• add acyclovir/ganciclovir for suspected HSV or CMV infections

RISK FACTORS

Risk factors for febrile neutropaenia include:

• post-chemotherapy
• post-transplantation
• chronic granulomatous disease
• clozapine-induced agranulocytosis

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:
  • Upper respiratory tract for otitis media and sinusitis
  • Oropharynx for dental abscess 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
  • CVAD for signs of tunnel/exit site infection
  • Signs of anaemia and/or thrombocytopenia
• Do not perform a rectal examination

Investigations

• take blood cultures from a peripheral site in addition to each lumen of all pre-existing intravascular devices before administering antibiotics
• FBC, UEC and LFTs (including albumin), CRP and lactate
• If clinically indicated:
  • CXR (there may be no changes while neutropenic)
  • 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
  • CTB and lumbar puncture (neurological symptoms)
  • CT chest and bronchoscopic alveolar lavage (suspected pulmonary infection)
  • 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 30 minutes if sepsis/ unwell, always within 1 hour)
  • 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 hematology before removing any intravascular devices, required if:
    • CLABSI due to S. aureus, P. aeruginosa, fungi, or mycobacteria
    • port pocket site infection
    • endocarditis
    • septic thrombosis
    • septic shock
    • tunnel infection
    • persistence of bloodstream infection even after 72 h of appropriate antibiotic treatment

Environmental precautions

• protective isolation
• hand hygiene
• full barrier precautions (e.g. mask, gown, gloves, overshoes)

G-CSF

• increases neutrophil count
• reduces rate of serious infections
• decreased mortality in bone marrow transplant (BMT) or dose-intensive chemotherapy
• don’t use in acute leukaemia (may stimulate leukaemic clone)
• cease once neutrophils > 1.0 x 10E9/L
• adverse effects: rash, injection site pain, bone pain, influenza-like symptoms and splenic rupture (rare)

Supportive care and monitoring

Disposition

• Early consultation with hematology (refer after administering first dose of antibiotics)
• a subgroup of low-risk neutropenic patients may be able to be managed (at home) with oral therapy

PROGNOSIS

General

• prognosis proportional to the number of organ failures involved as opposed to underlying malignancy
• outcomes following ICU admission not as dismal as traditionally thought

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

High risk patients are those with comorbidities and prolonged (>7 days) and profound neutropaenia

References and Links

Journal articles

• Alp S, Akova M. Management of febrile neutropenia in the era of bacterial resistance. Therapeutic advances in infectious disease. 1(1):37-43. 2013. [pubmed] [free full text]
• Freifeld AG, Bow EJ, Sepkowitz KA. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 52(4):e56-93. 2011. [pubmed] [free full text]
• Sharma A, Lokeshwar N. Febrile neutropenia in haematological malignancies. Journal of postgraduate medicine. 51 Suppl 1:S42-8. 2005. [pubmed] [free full text]

FOAM and web resources

• RCH CPG — Fever and suspected or confirmed neutropenia
• NICE Guidelines — Neutropenic sepsis: prevention and management in people with cancer (2012)