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Immediate management of neutropenic fever

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This document was developed from the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients,r with an aim to standardise the clinical approach to the management of neutropenic fever. Implementation of these guidelines requires consideration of local factors.

Definition

For the purpose of this document neutropenic fever is defined as:

  • temperature of 38.0°C or greater and neutrophil count of less than 0.5 x 109 cells/L, or less than 1.0 x 109 cells/L and predicted to fall to lower than 0.5 x 109 cells/L.

Note:

  • Patients with neutropenic sepsis may present with haemodynamic compromise without fever (e.g. if elderly, or on steroids).
  • Neutropenic sepsis with or without fever is a medical emergency.
  • All clinical signs indicating sepsis need to be acted upon immediately.
  • The administration of empiric antibiotics should not be delayed in order to perform blood cultures.

Any delay in the commencement of antibiotics may cause increased morbidity and mortality.

Symptoms and signs

Patients with a temperature of 38.0°C or higher and neutrophil count of less than 0.5 x 109 cells/L, or less than 1.0 x 109 cells/L and predicted to fall to lower than 0.5 x 109 cells/L.

Other symptoms and signs may include:

  • tachycardia
  • tachypnoea 
  • hypotension
  • cough
  • dyspnoea
  • hypoxia
  • rigors
  • diaphoresis
  • altered mental status
  • decreased capillary refill, cyanosis or mottling
  • decreased urine output
  • signs and symptoms specific to an infectious source (e.g. pain or purulent exudate from wound or catheter site).

All patients presenting with fever following chemotherapy should be managed as neutropenic, and receive empiric antibiotics until proven otherwise. Management may be subsequently modified if neutrophil count and function are found to be adequate.

Time to first dose:

  • patients with features of systemic compromise (such as hypotension, hypoxia, confusion, major organ dysfunction) should receive antibiotics within 30 minutes of presentation. Where possible, blood culture samples should be taken before administering antibiotics (grade C)*
  • clinically stable patients should receive antibiotics within 1 hour of presentation after appropriate cultures have been taken (grade C)*
  • administration of antibiotics should not be delayed by the conduct of laboratory or radiological investigations (grade C)*

* Refers to the levels of evidence and grades of recommendations used in the published guidelines.

Refer to flow diagram for more information regarding initial patient evaluation and risk assessment.

Step 1: Perform septic workup

Blood cultures and other tests:

  • 1 set (aerobic and anaerobic bottles) from each lumen of CVAD (if in situ)
  • 1 set from peripheral blood
  • blood tests: FBC (with differentials), EUC, CMP, LFTs
  • mid stream urine/catheter specimen urine
  • sputum (if clinically indicated)
  • faeces (if clinically indicated)
  • swab of central venous catheter exit site (only if clinically indicated)
  • swab of any other suspicious wounds/focal lesions.

Chest x-ray (if unavailable still proceed to step 2 and ensure arrangements for CXR have been made).

DO NOT WAIT FOR RESULTS

Step 2: Commence empiric antibiotic therapy (doses are for normal renal function)

Immediate management of neutropenic fever
Patient group Recommendation (grading and level of evidence)
Patients without features of systemic compromise
(Beta-lactam monotherapy is recommended unless allergy to the recommended agent/s)

No penicillin allergy:

Piperacillin-tazobactam 4.5 g IV 6 hourly* (grade A) OR
Cefepime 2 g IV 8 hourly
Other reasonable choice for monotherapy is ceftazidime 2 g IV 8 hourly (grade A)

Non-life threatening penicillin allergy (rash):

Cefepime 2 g IV 8 hourly (grade C)
Other reasonable choices for monotherapy are ceftazidime 2 g IV 8 hourly or meropenem 1 g IV 8 hourly (grade C)

Life-threatening (immediate) penicillin allergy or beta-lactam allergy:

Aztreonam 1-2 g IV 8 hourly OR ciprofloxacin 400 mg IV 12 hourly (expert opinion)
+ vancomycin 1.5 g IV 12 hourly (if CrCl >90 mL/min) OR 1 g IV 12 hourly (if CrCl 60-90 mL/min)†‡
Patients with systemic compromise
(The combination of a beta-lactam antibiotic with an aminoglycoside is the regimen of choice)

As for patients without features of systemic compromise (expert opinion) (see above):

+ gentamicin 4 to 7 mg/kg** IV once daily, adjusted to level
+/– vancomycin 1.5 g IV 12 hourly (if CrCl >90 mL/min) OR 1 g IV 12 hourly (if CrCl 60-90 mL/min)†‡
Patients with cellulitis, obviously infected vascular devices, or MRSA carriers with extensive skin breaks/desquamation

As for patients without features of systemic compromise (see above):

+ vancomycin 1.5 g IV 12 hourly (if CrCl >90 mL/min) OR 1 g IV 12 hourly (if CrCl 60-90 mL/min)†‡
Patients with features of abdominal or perineal infection

As for patients without features of systemic compromise (see above):

+ metronidazole 500 mg IV/PO 12 hourly if receiving cefepime, ceftazidime or ciprofloxacin first-line (grade D)

Alternatively, piperacillin-tazobactam or meropenem will provide adequate anaerobic cover, if required (grade B), other than for suspected or proven Clostridium difficile-associated diarrhoea or colitis

© Adapted from Internal Medicine Journal 2011

* For patients with severe sepsis or septic shock, giving the 6-hourly dose of piperacillin-tazobactam as an extended infusion over 3 to 4 hours may achieve better outcomes, as this increases the percentage time above minimum inhibitory concentration r
†Clinicians caring for a patient with immediate hypersensitivity to one beta-lactam who have subsequently tolerated an alternative suitable antipseudomonal beta-lactam agent may elect to administer this second agent under careful supervision.
‡Refer to the Therapeutic Guidelines version 15 for dosing guidance. For vancomycin, individual institutions may use alternative loading-dose protocols
** In adults, if actual body weight is more than 20% over ideal body weight, use ideal body weight to calculate the dose. For morbidly obese patients, seek expert advice. In non-critical sepsis or septic shock patients use dose at lower end of the range (4 to 5mg/kg) r

Note: Recommendations for individual antibiotics may not align directly with the Therapeutic Goods Administration (TGA) approved indications. Therefore, following these recommendations may lead to off-label use of some agent

Summary

  • Beta-lactam monotherapy, such as piperacillin-tazobactam (Tazocin®) or cefepime, is the empiric therapy of choice for all clinically stable patients with neutropenic fever.
  • An antipseudomonal beta-lactam antibiotic plus gentamicin is recommended for patients with systemic compromise.
  • All patients in septic shock should receive antibiotics within 30 minutes of presentation, and all other patients within 1 hour.
  • Vancomycin is not recommended as initial empiric therapy unless there is systemic compromise or an approved indication for its use.
This is initial immediate therapy only and subsequent treatment should be based on clinical findings and at the discretion of the treating clinician.

 

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Version 4

Date Summary of changes
08/09/2009 Reviewed and transferred to eviQ.
20/05/2011 Reviewed and information changed to reflect the Australian consensus guidelines for the management of neutropenic fever in adult cancer patients Volume 41, Issue 1b, pages 90-101, January 2011.
09/02/2015 Reviewed and incorporated ACI id 240 into the body of the text, and removed link.
22/03/2016 Reviewed and some changes to layout. Symptoms and signs added. Review in 2 years.
31/05/2017

Transferred to new eviQ website. Version number changed to V.3
17/08/2018 Reviewed and some changes. Minor changes to definition of neutropenic fever and  dosing and frequency of antibiotics. Review in 2 years. Version number changed to V.4

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22 Sep 2019