Neutropaenic Sepsis

Reviewed and revised 3 January 2016

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
  • changing to Meropenem for suspected ESBL
  • add antifungal (e.g. voriconazole) if:
    • suspected fungal infection (e.g. candida, aspergillus, mucormycosis)
    • fevers persist in high-risk patients beyond 96 hours of antibacterial therapy (seek expert advice)
  • add Co-trimoxazole for suspected PCP
  • 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 (diarhoea); 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 “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 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


CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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