CLINICAL PROCEDURE

FEBRILE NEUTROPENIA
TARGET AUDIENCE
All clinical staff including medical, nursing and pharmacy.

PURPOSE
This document incorporates the key requirements for a hospital neutropenic fever (NF)
guideline/pathway. The document includes evidenced based recommendations for the
assessment and management of NF and sepsis.
1. Consensus definitions
2. Investigations
3. Initial antibiotic therapy based on severity
4. Ongoing antibiotic therapy
5. Prophylaxis
6. Antiviral and antifungal therapy
7. Management of the low risk patient with neutropenic fever

MANAEMENT OF NEEUTROPENIC FEVER

All patients with neutropenic fever as defined above should be initially assessed for the presence
of systemic cardiovascular compromise, and whether they are considered high- or low-risk for
medical complications. These factors determine the initial choice of antibiotic therapy, time to
administration of antibiotics, the likely duration of admission and whether ambulatory care may
be considered (see Figure 1). Recently, evidence has demonstrated that prompt administration of
antibiotics is associated with a measureable decrease in mortality such that now, time to first dose
antibiotic has been included in international sepsis guidelines (Kumar et al., 2006) (Dellinger et al.,
2008)
Importantly, neutropenic patients can present septic with haemodynamic compromise without
fever (if elderly, or on steroids) in which case there should be no delay in treatment while
evaluating for further fever. All patients presenting with fever following chemotherapy should be
managed as if they have neutropenic fever and receive empiric antibiotics without waiting for
laboratory confirmation of neutrophil count (expert opinion). This management may then be
modified if neutrophil count and function are confirmed to be adequate.
Optimal empiric management will be informed by the patient’s presenting clinical status. As such,
all patients presenting with NF should be evaluated using the Sepsis Pathway (Guideline and Pathway
Document MR 63/T).
FIGURE 1: FLOWCHART FOR OP VERSUS IP MANAGEMENT
Empiric Management

Notification lines Unit registrar notified of patient arrival or onset of fever for
neutropenic patients
Review times Inpatients reviewed within 30 minutes of referral to treating medical
team
Emergency department ED presentation triaged ideally as Cat 2 (medical assessment within 10
(ED) Triage Category minutes)
Investigations See Investigations
Time to first dose Within 30 minutes of fever onset if systemically compromised (grade C
antibiotic recommendation). This should follow the immediate collection of at
least one set of blood cultures and administration of intravenous fluids
or other support as medically appropriate.

Within 60 minutes if clinically stable (from presentation) after blood

cultures have been taken according to 6.3.1 (grade C
recommendation).
The commencement of antibiotics should not be delayed by the
competing imperative to conduct further investigations, including CXR
and cultures of sites other than blood (grade C recommendation).
Maintain Sa02 >95% Apply oxygen to achieve a Sa02>95%
Fluid Resuscitation Consider fluid challenge in all patients as venodilation and capillary leak
will be present

If SBP < 90mmHg or lactate ≥ 4:

Rapid fluid challenge with 20ml/kg of Hartmann’s solution (or other
crystalloid fluid) by large bore IV catheter and using rapid infuser (NOT
through PICC line)

If high risk of pulmonary oedema administer minimum 10ml/kg of

Hartmann’s solution for initial bolus
Notification of ICU If initial fluid challenge fails, ie. no increase in SBP (refer above)
If medical emergency team (MET) call criteria is reached (via an
emergency call)
investigations
Blood Cultures (BC) For optimal sensitivity and specificity, ideally at least two separate
blood culture sets should be collected from separate venepuncture
sites prior to commencement of antibiotics.
For optimal sensitivity and specificity, ideally at least two separate
blood culture sets should be collected from separate venepuncture
sites prior to commencement of antibiotics.
Blood cultures (BC) should be avoided from central venous access
devices (CVAD). If there is collection of a blood culture from CVAD
lumen, then peripheral blood cultures should also be performed. This
may assist in the diagnosis of clinically relevant blood stream infections
by allowing the time necessary for blood culture from the peripheral
vein to become positive to be compared to the time until blood culture
from a central venous catheter becomes positive. (Raad et al., 2004) A
differential time to positivity of ≥ 120 minutes has been shown to be
predictive of clinically relevant catheter-related blood stream
infections. (Abdelkefi et al., 2005; Towns, Jarvis, & Hsueh) This
approach is particularly useful in patients in whom catheter retention is
desirable.
At least 20mls of blood should be drawn from each site and 10mls
inoculated into one aerobic and anaerobic bottle. Two sets of blood
cultures in a 24 hour period will detect approximately 90-95% of blood
stream infections in adults. (Lee, Mirrett, Reller, & Weinstein, 2007;
Towns et al.)
In some cases this number of blood cultures may not be possible within
the recommended time constraints for antibiotic administration. In
such cases, the highest priority is the prompt administration of
antibiotics (see 6.2.1).
To minimise the risk of contamination during blood culture collection,
appropriate sterile collection should be used including: hand hygiene
with alcohol rub/gel prior to procedure; Skin disinfection with
chlorhex/alcohol swab, isopropyl alcohol for BC bottle caps and CVAD
caps,use of sterile gloves and no-touch technique for venepuncture;
avoidance of needle exchange prior to inoculation of bottle(s) (Towns
et al.) As per peter Mac procedures Collection of Peripheral Blood
Cultures
Repeat blood cultures prior to Day 3 are not recommended for the
majority of patients with neutropenic fever unless clinically unstable
and/or suspected new infectious foci are present. For patients with
initially positive blood cultures, repeat peripheral cultures should be
performed to document clearance of bacteraemia (expert opinion).
Measurement of A serum lactate ≥2 mmol/L is related to illness severity and poorer
Lactate* patient outcomes. Patients with a lactate ≥4mmol/L, regardless of
hypotension must receive fluid resuscitation (refer above)
Lactate must be measured within minutes via an arterial blood gas
 (ABG) or venous blood gas (VBG) using a blood gas analyser (send on
ice)
* Hyperlactatemia is typically present in patients with severe sepsis or
septic shock and may be secondary to anaerobic metabolism due to
hypoperfusion
Haematology Full blood examination (FBE), Coagulation profile
Biochemistry Electrolytes, Creatinine (Cr), liver function tests (LFTS)
Sepsis workup Chest x-ray (CXR)
Urine – mid stream urine (MSU) for microscopy culture sensitivity
(MCS)
If indicated:
Sputum specimen for MCS
Viral studies if presence of upper respiratory symptoms (sore throat,
cough): respiratory multiplex for viral PCR
Stool specimen for MCS (must be stipulated) and C.difficile
Wound swabs for MCS if bacterial infection suspected or HSV/VZV PCR
if herpes simplex or varicella infection suspected.
Urinary legionella antigen and streptococcal antigen (if pneumonia)
If high risk for fungal High resolution CT scan (chest +/- abdomen / liver / spleen +/-sinus)
infection and/or PET/CT scan (if available)
presence of lung Bronchoscopy
infiltrates or lesions
Non culture based tests (NCBT) for IFI including
- Aspergillus PCR (on serum and BAL)
- Galactomannan from BAL (NOT indicated in serum)
- PJP PCR
Persistent fever despite - Referral to infectious diseases (ID)
intensive investigation - Ix for wider systemic infection based on risk (eg. CMV in allograft
as above transplant)
- Consider PET as high negative predictive value for bacterial or
fungal infection

Symptomatic Management Of The Febrile Patient

Indications for MET call
A sudden or acute deterioration in a patient’s vital signs OR in patients who present unwell at
onset should prompt a MET call.

Management of hypotension
Commence IV fluids as outlined in the sepsis pathway (MR/63T) and commence a fluid record
Management of rigor
Warm patient if experiencing chills or rigor with space blanket (if available) and request an order for IV
pethidine 12.5 - 25mg (if not already prescribed). Administer IV pethidine up to 25mg to ameliorate
rigor. Repeat IV pethidine injection can be used if rigor is not subsiding.
Initial antibiotic choice (for normal renal function or CrCl >50 ml/min)
In view of emerging evidence regarding efficacy and toxicity differences between empiric
treatment regimens, and strong evidence of heterogeneity in clinical practice, the following
recommendations were developed to provide clinicians with initial guidance for selecting an
appropriate empiric strategy in the setting of neutropenic fever (see Table 1 for summary).
The patient's history, allergies, symptoms, signs, recent antibiotic use and culture data, as well as
local antimicrobial flora and infection patterns, should guide the initial choice of antibiotic
therapy. Patients with impaired renal function (creatinine clearance less than 50 mL/min) will
require adjustments to the suggested doses based on calculated creatinine clearance (grade A
recommendation).
Table 1. Initial antibiotic therapy based on severity of presentation
Stable NF / SIRS Sepsis Severe Sepsis Septic Shock
All patients:
- No penicillin allergy:
Piperacillin/tazobactam 4.5g IV 6-hourly
1 OR
- Non-life threatening penicillin allergy (rash):
Cefepime 2g IV 8-hourly
Order of antibiotic administration

OR
- Life-threatening (immediate) penicillin or beta-lactam allergy:
Ciprofloxacin 400mg IV 12-hourly PLUS Vancomycin

Patients with proven previous multi-resistant gram negative infection or ESBL colonised
Meropenem 1g IV 8-hourly
Severe Sepsis to Septic Shock:
Add Gentamicin 5-7mg/kg ideal body weight IV once
2 daily, adjusted to levels
(2 doses max without ID referral)

Add Vancomycin 1-1.5g IV 12hourly (dependent on

creatinine clearance [CrCl]*) as per vancomycin
protocol.
*Creatinine Clearance
Ongoing Antibiotic Therapy
Uncomplicated neutropenic fever
 The antimicrobial regimen should always be reassessed after 48 to 72 hours on the basis of
microbiological and clinical data.
 In the absence of positive cultures for resistant organisms;
 gentamicin should be discontinued after 24–48 hours
 vancomycin should be discontinued after 48–72 hours
 Monotherapy is as effective as combination therapy for uncomplicated NF
 If patient in low risk group (See Low Risk NF), assess MASCC score at 24-48 hours and
consider early IV-Oral Switch
 Antibiotics can be ceased in the following situations;
1. the cause of apparent sepsis is found to be non-infectious
2. if mucous membranes and integument are intact, and there is no impending invasive
procedure or ablative chemotherapy planned
3. when patients become afebrile within 72-96hours, no causative organism is isolated
and the neutrophil count is at least 0.5 x 109 cells/L
 If the neutrophil count is less than 0.5 x 109 cells/L and neutropenia is expected to be
prolonged, the decision to discontinue or continue antibiotic therapy should be based upon
clinical criteria and individual clinicians’ judgement.
 For patients who become afebrile after commencement of on oral antibiotics, the total
minimum duration of antibiotic therapy should be 7 days.

Modification of initial regimen

Use of vancomycin
Empiric vancomycin is considered unnecessary in most clinically stable patients receiving
monotherapy with an anti-pseudomonal beta-lactam who have no definite sites of gram-positive
infection (Grade A recommendation). Routine addition of vancomycin to the initial empiric
antibiotic regimen within 72 hours does not reduce mortality and is associated with an increased
risk of adverse events, mainly nephrotoxicity (level I evidence, grade A recommendation).(Paul,
Borok, Fraser, Vidal, & Leibovici, 2005; Vardakas, Samonis, Chrysanthopoulou, Bliziotis, & Falagas,
2005) There is now good evidence to show that empiric (non-targeted) first-line use of vancomycin
is unnecessary and potentially harmful. (Paul et al., 2005)
The following situation may be deemed appropriate:
 Patients with microbiologically documented Gram-positive infection should receive
vancomycin until identification and susceptibility results are available, at which time therapy
should be modified appropriately (expert opinion).
 Systemic compromise. Evidence regarding glycopeptide use in patients presenting with
neutropenic fever and systemic compromise is lacking. There is currently no consensus
opinion. Vancomycin may be given appropriate consideration.
 Patients at risk of resistant gram-positive infection. For these patients presenting with
shock, addition of vancomycin to empiric therapy is recommended (expert opinion).
 Patients with cellulitis, obviously infected vascular devices or MRSA carriers with extensive
skin breaks/desquamation: Vancomycin, according to a validated protocol, should be added
to the beta-lactam antibiotic regimen described for clinically stable patients in Table 3, for
48–72 hours then reviewed according to culture results (expert opinion)

Multi-drug resistant infections

Patients with multi-drug resistant (MDR) infections are increasingly seen and should be considered
if they have key risk factors. Risk factors for acquiring a multi-drug resistant organism include
overseas travel (within last 6 months), prolonged hospital stay and antibiotic exposure.
It is highly recommended patients with MDR infections should be discussed and managed in
conjunction with the Infectious Diseases service

Broadening of antibiotic coverage

Any subsequent modifications to the initial choice of antibiotic should be guided by repeat clinical
assessment (e.g. emergence of focal sites of infection) and microbiological culture results (expert
opinion).
As the median time to resolution of fever in patients successfully treated with frontline antibiotics
is 3–5 days, escalation of antibiotic coverage should not occur prior to this period in the absence
of clinical instability, isolation of a resistant organism or emergence of new infective foci (expert
opinion).

Duration of antibiotic therapy

The duration of therapy should typically be 7 to 10 days and guided by clinical response. Longer
courses may be appropriate in patients who have a slow clinical response, undrainable foci of
infection, bacteraemia with S. aureus, some fungal and viral infections, or prolonged neutropenia.

Duration of antibiotic therapy including oral antibiotic switch regimens

The treatment course for FN may be parenteral with/without an oral switch.
Patients with a MASCC score of ≥21 at presentation (see risk stratification below) may be
commenced on oral antibiotics at onset or after 24 hours according to physician preference.

Oral antibiotic regimen;

No beta-lactam allergy Amoxicillin-clavulanate 875/125mg BD
Ciprofloxacin 750 mg BD*
Beta-lactam allergy Clindamycin 450 mg TDS
Ciprofloxacin 750 mg BD*
* dose reduction required with renal impairment, consult ID fellow
Fluoroquinolone allergy Amoxicillin-clavulanate 875/125mg BD
When patients become afebrile within 3–5 days while on parenteral therapy and no causative
organism is isolated, it is preferable to stop antibiotic treatment when the neutrophil count
recovers to at least 0.5 x 109 cells/L (expert opinion). This may include oral switch while counts
recover.
If the neutrophil count is less than 0.5 x 109 cells/L and neutropenia is expected to be prolonged,
the decision to discontinue or continue antibiotic therapy should be based upon clinical criteria
and individual clinicians’ judgment. Antibiotic therapy may be ceased if the mucous membranes
and integument are intact, and there is no impending invasive procedure or ablative
chemotherapy planned (expert opinion).(Hughes et al., 2002)
For patients who become afebrile whilst on oral antibiotics, the total minimum duration of
antibiotic therapy should be 7 days (expert opinion). This treatment duration has been used safely
in clinical studies of oral antibiotic therapy (Rolston et al., 2006) and is supported by previous
consensus opinion. (Hughes et al., 2002; Tamura et al., 2004) (Worth LJ, 2010)

Removal of vascular catheters

Venous catheters (including PICCs) should be routinely removed in the setting of Staphylococcus
aureus and Candida spp. bloodstream infection. For other isolates, infectious diseases consultation
should be sought.
Refer to the Infectious Diseases Society of America (IDSA) 2009 Guidelines for the diagnosis and
management of intravascular catheter-related infections (Clin Infect Dis 2009:49).

Antibiotic Prophylaxis
The use of oral prophylactic antibiotics in patients with neutropenia is not universally
recommended due to a lack of evidence showing a reduction in mortality and concerns that such
practice promotes antimicrobial resistance.
Key practice points:
 There is currently insufficient evidence to recommend routine use of fluoroquinolone (FQ)
prophylaxis in patients at low risk of developing neutropenic fever (Slavin MA, 2010)
 FQ prophylaxis should also not be routinely used in high-risk haematology patients
 FQ prophylaxis could be considered in outpatient SCT and palliative patients with bone
marrow failure
 Support is given to use of FQ prophylaxis during the first cycle of TPF protocol (docetaxel
75mg/m2 IV D1 cisplatin and fluorouracil) for head and neck cancer, when G-CSF prophylaxis
is not used. Two RCTs mandated the use of ciprofloxacin as primary prophylaxis. (Vermorken
et al., 2007); (Posner et al., 2007)

Addition of antiviral therapy

Antivirals should not be added to the empiric regimen without clinical or serological evidence of
viral infection. The exception may be the treatment for influenza, in which the patient has an
influenza-like illness during the influenza season and has a history of contact.
The drug of choice is oseltamivir 75 mg oral BD to be continued for 5 days.
Addition of antifungal therapy
Addition of empiric antifungal therapy depends on whether the patient has been receiving yeast
or mould prophylaxis. It should be considered in all high risk haematology patients who continue
to be febrile after 96 hours. Further investigation includes a HRCT chest (+/- CT sinuses) and non-
culture based tests (aspergillus PCR and galactomannan).

Persistent fever
 In the case of persistent or ongoing fever 72- 96hrs after IV antibiotic commencement
further investigations are warranted.
 Review all microbiology and radiology
 Antibiotics should not be altered if patient is clinically stable while investigations are being
undertaken.
 If patient is clinically unstable (worsening sepsis) then consider antibiotics with increased
spectrum:
 Addition of vancomycin and/or gentamicin
 Escalation to meropenem
 Discussion with ID service
 A high resolution CT (chest +/- abdomen / liver / spleen / sinus) or PET (if available) should
be considered if a patient is high risk for invasive fungal infection (IFI)
Management of the LOW RISK patient with neutropenic fever and Ambulatory Program
Related Documentation:
 MR63U Neutropenic Fever Risk Stratification Tool
 MR63V Neutropenic Fever Home Assessment Chart
 Re-admission - Emergency Department Letter
 Patient Information for Early Discharge on Oral Antibiotics

Risk stratification
The risk of a patient with NF experiencing medical complications may be assessed using the
Multinational Association for Supportive Care in Cancer (MASCC) risk index developed by
Klastersky et al. (2000). The MASCC is a well validated tool that is supported by Peter Mac,
national and international guidelines for the management of NF. This tool may be used to guide
the subsequent approach to treatment.
The criteria below need to be fulfilled to be suitable for assessment with the MASCC risk index.
Criteria Eligible Not Eligible
Patient is neutropenic (ANC) of < 1.0 x 109 cells/L Yes No
Fever of ≥38.3oC OR ≥38.0oC on two occasions Yes No
Expected duration of neutropenia < 7 days Yes No
All criteria needs to be fulfilled to continue with MASCC index

MASCC index
Is patient less than 60 years old? Yes 2 No 0
Does the patient have a solid tumour OR
Does the patient have a haematology malignancy Yes 4 No 0
with no previous fungal infection?
Does the patient have COPD? Yes 0 No 4
Was patient an outpatient at time of fever onset? Outpatient 3 Inpatient 0
Was patient dehydrated at first presentation of NF?
(in the absence of clinical markers of dehydration -
Yes 0 No 3
assess recent history of oral intake and /or excess
fluid losses)
Was patient hypotensive at first presentation of NF
Yes 0 No 5
(SBP < 90mmHg)?
What was the patient’s burden of illness?
None or
(Subjective assessment of symptom severity and Moderate
mild 5 3
physiologic reserve – how sick is the patient now?) symptoms
symptoms
Note: If severe symptoms or moribund, score 0
Tallied score for checked boxes (MASCC score) ________
High-Risk (less than 21) Low-Risk (greater or equal to 21)

The maximum value in this system is 26. A score of ≥21 suggests low risk and predicts a <5% risk
for severe complications and a very low mortality (<1%) in NF patients.

Oral Antibiotic switch

Low risk patients (MASCC ≥21) may be commenced on oral antibiotics at onset or after 24hours if
the following criterion is fulfilled and it is the physicians’ preference.
At least one dose of oral antibiotics should be given prior to hospital discharge in order to monitor
for side effects.
No beta-lactam allergy Amoxicillin-clavulanate 875/125mg BD
Ciprofloxacin 750 mg BD*
Beta-lactam allergy Clindamycin 450 mg TDS
Ciprofloxacin 750 mg BD*
* dose reduction required with renal impairment, consult ID fellow
Fluoroquinolone allergy Amoxicillin-clavulanate 875/125mg BD

Eligibility criteria for oral antibiotics;

Criteria Eligible Not Eligible
Stable disease Yes No
No active infection with multi-resistant organism infection (MRSA, VRE, Yes No
MDRGN)
Patient not on antibiotic prophylaxis (excluding PJP prophylaxis) prior to this Yes No
admission
Able to swallow / tolerate oral antibiotics (≤ Grade 2 mucositis and Yes No
maintaining >50% of dietary intake)
Stable mental state^ Yes No
Normal findings on chest x-ray (if applicable)^ Yes No
Haemodynamically stable (SBP ≥100mmHg, HR 60-100 bpm regular)^ Yes No
Minimal diarrhoea, vomiting, electrolyte imbalance^ Yes No
^ reversible elements. If only reversible criteria are not fulfilled, re-assess in 48hours.
- If non reversible elements present continue with IV antibiotics
If all criteria present and the physician’s preference is for oral antibiotics continue to following section
Early discharge
Low risk patients who are eligible for oral antibiotics may be discharged to an ambulatory program
or with close outpatient monitoring. The patient will require outpatient monitoring until
neutrophil count has recovered to ≥1.0 x 109 cells/L.
Eligibility criteria for early discharge:
Criteria Eligible Not Eligible
Availability of a 24hour caregiver Yes No
Good education of patient and carer on reportable symptoms Yes No
No confirmed focus of infection requiring IV antibiotics Yes No
Availability of a telephone Yes No
Availability of 24hour phone advice from Peter Mac Yes No
Within 1-hour of an emergency department or treating hospital Yes No
Suitably resourced follow-up - PM@H visits / NF co-ordinator Yes No
Treating teams preference Yes No
No documented allergy to the required oral antibiotics Yes No
No history of non-compliance with medical care or physical or verbal Yes No
aggression
No previous history of non-compliance or absconding from medical Yes No
care

Ambulatory / Outpatient setting

Once eligibility for early discharge is completed the patient is included in the ambulatory program
with hospital in the home visits organised and follow-up in the Neutropenic Fever Clinic as an
outpatient.
Discharge from hospital is likely to be either 24 – 48hrs after admission or discharge without
admission (ie. from the Emergency department).
Discharge resources should include;
- hospital in the home appointments through PM@H
- Pathology slips
- educational material;
- home observation and assessment chart with instructions for use, (hyperlink here to
document)
- reasons for re-admission with hospital personnel contact numbers
- letter for presentation to an emergency department including description of medical
history, recent treatment received and current situation (hyperlink here to document)
- ensure patient has a thermometer
PeterMac@Home
The following is a recommended schedule for hospital in the home visits and interventions.
- visits organised for Day 1 and 2 (Day 0 is day of discharge) followed by alternate days until
ANC ≥ 1.0 x 109 cells/L (expected that 2 visits will be sufficient)
- interventions to be undertaken during home visit;
- blood specimens taken (FBE, U&E, CRP & LFT’s)
- home assessment chart reviewed / discussed (refer to home assessment chart),
including temperature, oral intake / hydration, bowel patterns
- patients’ blood results monitored daily by Neutropenic Fever (NF) Coordinator who will liaise
with treating team
- patient contacted by telephone by NF Coordinator / treating medical officer on Day 3 to do a
phone review , discuss results and appointment finalised
- patient to return to hospital for a review in Neutropenic Fever Clinic between Day 5 and 7

Ambulatory model
Day Appointments / interventions Responsibility
0 Bloods taken prior to hospital discharge Treating medical team
(day of Follow up Hospital in the home appointments
discharge) Educational material / self-assessments (temp / oral
intake)
Readmission letter
1 Home visit Hospital in the home
Blood tests
Wellbeing check, etc.
2 Home visit Hospital in the home
Blood tests
Wellbeing check, etc.
3 Telephone follow up Treating medical team
Blood results discussed / Nurse co-ordinator
4 Home visit if ANC <1.0 Hospital in the Home
5-7 Attend NF ambulatory care clinic Treating medical team
/ Nurse co-ordinator
Re-admission
The following re-admission criteria need to be reported to the appropriate hospital personnel
immediately;
- Feeling unwell / new signs and symptoms
- New, recurrent or persistent fever (> 48hrs after discharge)
- Decline in ability to self-care or carer no longer available
- Inability to continue with antibiotics (ie. allergy, vomiting, severe diarrhoea)
- Significant decrease in oral intake (ie. < 50% baseline)
- Positive blood culture result (reported after patient hospital discharge)
Prior to discharge all patients will be educated on reportable symptoms and reason for re-
admission (as outlined above).

DEFINITIONS

Fever ≥ 38.3ºC once or ≥ 38.0ºC on two occasions

Neutropenia < 1.0 x 109 cells/L
Stable Neutropenia plus fever with other vital signs (Respiratory rate [RR], Heart
Neutropenic fever rate [HR], blood pressure [BP], oxygen saturation [Sa02]) within normal limits
(NF)
Systemic 2 or more of the following:
inflammatory Temp < 36oC or > 38oC
response
HR > 90b/min
syndrome (SIRS)
RR > 20/min or PaC02<32 mmHg
WCC < 4 x 109/L or > 12 x 109/L
Sepsis SIRS / uncomplicated sepsis triggered by an infection
Hypoperfusion Systolic blood pressure (SBP) ≤ 90 mmHg
Lactate ≥4 mmol/L
Altered conscious state
Urine output ≤0.5ml/kg/hr
Severe sepsis Sepsis with evidence of hypo-perfusion or end-organ dysfunction

Septic shock Severe sepsis with refractory hypo-perfusion or hypotension

Clinically stable RR, HR, BP and Sa02 within normal limits with no evidence of hypo-perfusion
Systemically Signs of hypo-perfusion and hypotension
compromised
Features of Systemic Compromise:
Systolic blood pressure 90 mmHg,or 30 mmHg below that patient’s usual blood pressure, or
requirement for vasopressor support
While breathing room air, an arterial pO2 of 60 mmHg, or arterial oxygen saturation 90%, or
requirement for mechanical ventilation
Confusion or altered mental state
Disseminated intravascular coagulation or abnormal PT/APTT
Cardiac failure or arrhythmia, renal failure, liver failure, or any major organ dysfunction*
*Organ failure only if new or significantly worsening. Disregard stable pre-existing congestive heart failure or chronic pre-existing
arrhythmias (such as AF).

RESPONSIBILITIES

Nursing Staff Initial patient assessment and identification of systemic cardiovascular

compromise
Timely notification of patient status to medical staff
Collection of blood cultures and performance of septic screen
Timely administration of first and subsequent doses of prescribed antibiotic
therapy
Medical Staff Prompt patient assessment and identification of systemic cardiovascular
compromise
Timely prescription of appropriate antibiotics as per these guidelines
Provide other directed therapy as the clinical setting dictates

KEY PERFORMANCE INDICATORS

Time to first dose antibiotic
Re-admission rates

LEGISLATION/REFERENCES/SUPPORTING DOCUMENTS
 Sepsis Pathway (Guideline and Pathway Document MR 63/T)
 PeterMac@Home Neutropenic Fever Assessment Form
 Australian Commission on Safety and Quality in Health Care, 2017, National Safety and
Quality Health Service Standards, Sydney.
 Abdelkefi, A., Achour, W., Ben Othman, T., Torjman, L., Ladeb, S., Lakhal, A., . . . Ben
Abdeladhim, A. (2005). Difference in time to positivity is useful for the diagnosis of catheter-
related bloodstream infection in hematopoietic stem cell transplant recipients. Bone
Marrow Transplant, 35(4), 397-401. doi: 1704773 [pii]
 10.1038/sj.bmt.1704773
 Dellinger, R. P., Levy, M. M., Carlet, J. M., Bion, J., Parker, M. M., Jaeschke, R., . . . Vincent, J.
L. (2008). Surviving Sepsis Campaign: international guidelines for management of severe
sepsis and septic shock: 2008. Crit Care Med, 36(1), 296-327. doi:
10.1097/01.CCM.0000298158.12101.41
 00003246-200801000-00043 [pii]
 Hughes, W. T., Armstrong, D., Bodey, G. P., Bow, E. J., Brown, A. E., Calandra, T., . . . Young, L.
S. (2002). 2002 guidelines for the use of antimicrobial agents in neutropenic patients with
cancer. Clin Infect Dis, 34(6), 730-751. doi: CID011605 [pii]
 10.1086/339215
 Klastersky, J., Paesmans, M., Rubenstein, E. B., Boyer, M., Elting, L., Feld, R., . . . Talcott, J.
(2000). The Multinational Association for supportive Care in Cancer Risk Index: A
Multinational Scoring System for Identifying Low-Risk Febrile Neutropenic Cancer Patients.
Journal of Clinical Oncology, 18(16), 3038-3051.
 Kumar, A., Roberts, D., Wood, K. E., Light, B., Parrillo, J. E., Sharma, S., . . . Cheang, M. (2006).
Duration of hypotension before initiation of effective antimicrobial therapy is the critical
determinant of survival in human septic shock. Crit Care Med, 34(6), 1589-1596. doi:
10.1097/01.CCM.0000217961.75225.E9
 Lee, A., Mirrett, S., Reller, L. B., & Weinstein, M. P. (2007). Detection of bloodstream
infections in adults: how many blood cultures are needed? J Clin Microbiol, 45(11), 3546-
3548. doi: JCM.01555-07 [pii]
 10.1128/JCM.01555-07
 Paul, M., Borok, S., Fraser, A., Vidal, L., & Leibovici, L. (2005). Empirical antibiotics against
Gram-positive infections for febrile neutropenia: systematic review and meta-analysis of
randomized controlled trials. J Antimicrob Chemother, 55(4), 436-444. doi: dki028 [pii]
 10.1093/jac/dki028
 Posner, M. R., Hershock, D. M., Blajman, C. R., Mickiewicz, E., Winquist, E., Gorbounova, V., .
. . Haddad, R. I. (2007). Cisplatin and fluorouracil alone or with docetaxel in head and neck
cancer. N Engl J Med, 357(17), 1705-1715. doi: 357/17/1705 [pii]
 10.1056/NEJMoa070956
 Raad, I., Hanna, H. A., Alakech, B., Chatzinikolaou, I., Johnson, M. M., & Tarrand, J. (2004).
Differential time to positivity: a useful method for diagnosing catheter-related bloodstream
infections. Ann Intern Med, 140(1), 18-25. doi: 140/1/18 [pii]
 Rolston, K. V., Manzullo, E. F., Elting, L. S., Frisbee-Hume, S. E., McMahon, L., Theriault, R. L., .
. . Benjamin, R. S. (2006). Once daily, oral, outpatient quinolone monotherapy for low-risk
cancer patients with fever and neutropenia: a pilot study of 40 patients based on validated
risk-prediction rules. Cancer, 106(11), 2489-2494. doi: 10.1002/cncr.21908
 Slavin MA, L. S., Mileshkin L, Booth DL, Cain MJ, Ritchie DS, Wei A, Thurskin KA (2010). Use of
antibacterial prophylaxis for patients with neutropenia. Intern Med J.
 Tam C, O. R. M., Andresen D, Lingaratnam S, Kelly A, Burbury K, Dawson L. (2010). Use of
empiric antimicrobial therapy in neutropenic fever. Intern Med J.
 Tamura, K., Imajo, K., Akiyama, N., Suzuki, K., Urabe, A., Ohyashiki, K., . . . Masaoka, T.
(2004). Randomized trial of cefepime monotherapy or cefepime in combination with
amikacin as empirical therapy for febrile neutropenia. Clin Infect Dis, 39 Suppl 1, S15-24. doi:
10.1086/383046
 CID32545 [pii]
 Towns, M. L., Jarvis, W. R., & Hsueh, P. R. Guidelines on Blood Cultures. J Microbiol Immunol
Infect, 43(4), 347-349. doi: S1684-1182(10)60054-0 [pii]
 10.1016/S1684-1182(10)60054-0
 Vardakas, K. Z., Samonis, G., Chrysanthopoulou, S. A., Bliziotis, I. A., & Falagas, M. E. (2005).
Role of glycopeptides as part of initial empirical treatment of febrile neutropenic patients: a
meta-analysis of randomised controlled trials. Lancet Infect Dis, 5(7), 431-439. doi: S1473-
3099(05)70164-X [pii]
 10.1016/S1473-3099(05)70164-X
 Vermorken, J. B., Remenar, E., van Herpen, C., Gorlia, T., Mesia, R., Degardin, M., . . .
Lefebvre, J. L. (2007). Cisplatin, fluorouracil, and docetaxel in unresectable head and neck
cancer. N Engl J Med, 357(17), 1695-1704. doi: 357/17/1695 [pii]
 10.1056/NEJMoa071028
 Worth LJ, L. S., Taylor A, Hayward HM, Morrissey S, Cooney J, Wei A. (2010). Use of risk
stratification to guide ambulatory management of neutropenic fever. Intern Med J.

FURTHER INFORMATION
Department of Infectious Diseases

AUTHORISED BY
Monica Slavin, Infectious Diseases Head

AUTHOR/CONTRIBUTORS
Karin Thursky, Infectious Diseases Physician