Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

high risk of complication or death: initial presentation

1st line – inpatient empirical antibiotic therapy

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ACUTE
|
high risk of complication or death: initial presentation
1st line – 

inpatient empirical antibiotic therapy

Most authorities and published guidelines recommend administration of the first dose of empirical antibiotics within 60 minutes of presentation, and as soon as possible, for a neutropenic patient presenting with fever, regardless of risk status and intended site of care (inpatient or outpatient).[1][45][58] This enables an initial evaluation (history, physical examination, laboratory investigations [including blood culture collection]) and risk assessment to be performed, without undue delay in therapy.

Several validated risk assessment tools (e.g., Talcott system; Multinational Association of Supportive Care in Cancer [MASCC] score; and Clinical Index of Stable Febrile Neutropenia [CISNE] score) are available to help risk-stratify patients presenting with febrile neutropenia. See Criteria section. While these tools may help to inform decisions regarding the optimal venue of care for a particular patient (i.e., inpatient or outpatient), they are not surrogates for clinical decision-making.

Patients are typically managed based on whether they are at high risk or low risk for complications or death. High-risk patients include those who have any of the following: Talcott system group I to III, or MASCC risk score <21, or CISNE ≥3; inpatient status at time of fever onset; significant medical comorbidities or clinically unstable; allogeneic haematopoietic cell transplantation; anticipated prolonged severe neutropenia (absolute neutrophil count [ANC] ≤100 cells/microlitre and duration ≥7 days); hepatic or renal insufficiency; uncontrolled or progressive cancer; pneumonia or other complex infection; use of certain immune and/or targeted treatments (e.g., phosphatidylinositol 3-kinase [PI3K] Inhibitors); severe mucositis (grade 3 to 4).[59][60]

High-risk patients should be treated with empirical broad-spectrum antibiotics and hospitalised for further management.[59][60]

The choice of antibiotic regimen should be based on coverage of the most likely pathogens and local susceptibility patterns (as per local healthcare institution algorithms and guidelines), as well as patient-specific factors (e.g., prior history of antibiotic-resistant infection and allergy history).

Empirical antibiotic monotherapy with a beta-lactam (e.g., cefepime, piperacillin/tazobactam, imipenem/cilastatin, or meropenem) is typically recommended for hospitalised patients with febrile neutropenia.[58][59][60]​ One Cochrane review reported lower risk of mortality, adverse events, and fungal superinfections in patients with febrile neutropenia treated with beta-lactam monotherapy compared with beta-lactam plus an aminoglycoside.[65]

Ceftazidime monotherapy is no longer an appropriate choice for empirical monotherapy at many institutions, owing to its limited gram-positive activity and rising resistance rates among gram-negative bacteria.

In situations where anaerobic bacteria are likely to play a role, it would be appropriate to use piperacillin/tazobactam monotherapy as a first-line option, or combine metronidazole with cefepime, or use a carbapenem (meropenem or imipenem/cilastatin).[1]

Piperacillin/tazobactam monotherapy is a reasonable option in settings where resistance (e.g., extended-spectrum beta-lactamase [ESBL]-producing organisms) is not prevalent, based on local institutional bacterial susceptibilities.[60] Piperacillin/tazobactam has been shown to be non-inferior to cefepime and ceftazidime in randomised clinical trials.[66][67][68] Extended infusion of piperacillin/tazobactam has been found to be associated with superior treatment outcomes compared with bolus infusion in high-risk patients.[69]

Combining a beta-lactam antibiotic with an aminoglycoside (e.g., tobramycin) may be considered if antibiotic resistance is suspected, with early discontinuation of the aminoglycoside if cultures do not reveal evidence of a drug-resistant organism.​[59][60]

Combining a beta-lactam with an aminoglycoside (either tobramycin or amikacin, but not gentamicin) may be preferable in patients with Pseudomonas aeruginosa sepsis, while awaiting susceptibility data, given the often multidrug resistance nature of this organism.[58][70]

At institutions with a high prevalence of multidrug-resistant gram-negative bacilli, combining piperacillin/tazobactam with tigecycline may be an option. A randomised trial found this combination to be safe, well tolerated, and more effective (as measured by resolution of fever without alterations in antibiotics) than piperacillin/tazobactam monotherapy in febrile neutropenic patients with high-risk haematological malignancies.[68] Mortality was similar for combination therapy and monotherapy.[68]

Empirical antibiotic treatment is typically continued until neutrophil recovery (i.e., ANC ≥500 cells/microlitre and increasing).[1][60]

Once empirical antibiotics are started, the median time to clinical response is 5-7 days.

Antibiotics should not be changed empirically in the face of persistent fever for the first 3-5 days, provided the patient is clinically stable.[80]

For clinically stable patients with persistent neutropenia who have defervesced (i.e., afebrile for at least 48 hours) on empirical broad-spectrum parenteral antibiotics and have negative blood cultures and no identified source of infection, antibiotic de-escalation (e.g., to oral fluoroquinolone prophylaxis) or discontinuation can be considered if use of antibiotic prophylaxis is not standard protocol.[60]

Evidence supporting safe early discontinuation of antibiotic therapy in patients with febrile neutropenia is growing, including in high-risk patients.[81][82][83][84][85][86][87]

For patients with documented infection, the duration and de-escalation of antibiotic therapy depends on neutrophil recovery, speed of defervescence, specific pathogen and site of infection, and underlying disease.[60] Duration of treatment is typically 5-14 days for bacterial infections of the skin/soft tissue and lungs, and 7-14 days for bacterial infections of the sinuses and most bacterial bloodstream infections.

Catheter removal is recommended in the context of bloodstream infections with Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium jeikeium, Candida species, Acinetobacter, Stenotrophomonas maltophilia, Bacillus organisms, moulds, non-tuberculous mycobacteria, vancomycin-resistant enterococci (VRE), or other multidrug-resistant organisms.[58][60]​​ 

Catheters should also be removed in patients who have sepsis with a suspected line source; those with persistent bacteraemia despite effective antibiotic therapy; and those with tunnel or port infection.[58][60]

Patients with persistent fever despite neutrophil recovery warrant continued empirical therapy and further diagnostic evaluation.[58]

Primary options

cefepime: 2 g intravenously every 8 hours

OR

piperacillin/tazobactam: 4.5 g intravenously every 6 hours

More

OR

imipenem/cilastatin: 500 mg intravenously every 6 hours

More

OR

meropenem: 1 g intravenously every 8 hours

OR

cefepime: 2 g intravenously every 8 hours

and

metronidazole: 15 mg/kg intravenously initially as a loading dose, followed by 7.5 mg/kg every 6 hours, maximum 4 g/day

Secondary options

cefepime: 2 g intravenously every 8 hours

or

piperacillin/tazobactam: 4.5 g intravenously every 6 hours

More

or

imipenem/cilastatin: 500 mg intravenously every 6 hours

More

or

meropenem: 1 g intravenously every 8 hours

-- AND --

tobramycin: 5-7 mg/kg intravenously every 24 hours

More

or

amikacin: 15-20 mg/kg intravenously every 24 hours

More

OR

piperacillin/tazobactam: 4.5 g intravenously every 6 hours

More

and

tigecycline: 100 mg intravenously initially as a loading dose, followed by 50 mg every 12 hours

Consider – empirical extended-spectrum gram-positive coverage

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ACUTE
|
high risk of complication or death: initial presentation
|
at high risk for serious gram-positive infection (e.g., MRSA)
Consider – 

empirical extended-spectrum gram-positive coverage

Additional treatment recommended for SOME patients in selected patient group

Use of empirical vancomycin (or other extended gram-positive agents, e.g., linezolid, tedizolid, or daptomycin) is not routinely recommended for patients with febrile neutropenia, but may be considered in specific situations where risk of serious gram-positive infection (e.g., MRSA) is high, including suspected catheter-related infection, skin/soft-tissue infection, pneumonia, or haemodynamic instability.[1][58][59][60][71]

The presence of a central venous catheter alone in a patient with febrile neutropenia is not an indication for empirical vancomycin. Furthermore, the addition of vancomycin for patients with persistent fever despite empirical monotherapy with a first-line agent is not advised.[71][72]

Judicious use of vancomycin is warranted due to the increasing prevalence of antibiotic-resistant gram-positive organisms (e.g., vancomycin-resistant enterococci) and the potential for nephrotoxicity associated with this agent.[73][74]

Linezolid, tedizolid, or daptomycin can be used as an alternative in patients who are intolerant of vancomycin, and should be considered for patients with sepsis and known colonisation or prior infection with vancomycin-resistant enterococci.[75]

Daptomycin should not be used in patients with pneumonia as it is inactivated by pulmonary surfactant.

Use of empirical vancomycin (or other gram-positive antibiotics) should be reassessed following 2-3 days of treatment, and discontinued if a gram-positive pathogen is not identified on blood cultures.[60]

Primary options

vancomycin: 20-35 mg/kg intravenously initially as a loading dose, followed by 15-20 mg/kg every 8-12 hours

More

Secondary options

linezolid: 600 mg intravenously every 12 hours

OR

tedizolid phosphate: 200 mg intravenously every 24 hours

OR

daptomycin: 6 mg/kg intravenously every 24 hours

Consider – colony-stimulating factor

Back
ACUTE
|
high risk of complication or death: initial presentation
|
at high risk for infection-associated complications, or have prognostic factors predictive of poor clinical outcomes
Consider – 

colony-stimulating factor

Additional treatment recommended for SOME patients in selected patient group

The use of colony-stimulating factors (CSFs) for treating patients with febrile neutropenia is controversial.

Limited data suggest a benefit with respect to time to neutrophil recovery, duration of antibiotic therapy, and length of hospitalisation, but no benefit with respect to overall mortality.[88] As such, the use of empirical granulocyte colony-stimulating factor (G-CSF), available as filgrastim or pegfilgrastim, or granulocyte-macrophage colony-stimulating factor (GM-CSF), available as sargramostim, for treating patients with febrile neutropenia is typically not recommended.[38]

Consideration may, however, be given to G-CSF or GM-CSF in high-risk patients with pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), invasive fungal infection, or uncontrolled primary disease; or in patients who are persistently febrile (>10 days), have profound neutropenia (absolute neutrophil count <100 cells/microlitre), are age >65 years, were hospitalised at the time of fever development, or who have had a previous episode of febrile neutropenia.[37][38]

In patients who have received prophylactic G-CSF, National Comprehensive Cancer Network guidelines recommend continuation of G-CSF, unless a long-acting G-CSF was used prophylactically.[37]

Primary options

filgrastim: consult specialist for guidance on dose

OR

pegfilgrastim: consult specialist for guidance on dose

OR

sargramostim: consult specialist for guidance on dose

low risk of complication or death: initial presentation

1st line – outpatient empirical antibiotic therapy

Back
ACUTE
|
low risk of complication or death: initial presentation
1st line – 

outpatient empirical antibiotic therapy

Most authorities and published guidelines recommend administration of the first dose of empirical antibiotics within 60 minutes of presentation, and as soon as possible, for a neutropenic patient presenting with fever, regardless of risk status and intended site of care (inpatient or outpatient).[1][45][58] This enables an initial evaluation (history, physical examination, laboratory investigations [including blood culture collection]) and risk assessment to be performed, without undue delay in therapy.

Several validated risk assessment tools (e.g., Talcott system; Multinational Association of Supportive Care in Cancer [MASCC] score; and Clinical Index of Stable Febrile Neutropenia [CISNE] score) are available to help risk-stratify patients presenting with febrile neutropenia. See Criteria section. While these tools may help to inform decisions regarding the optimal venue of care for a particular patient (i.e., inpatient or outpatient), they are not surrogates for clinical decision-making.

Patients are typically managed based on whether they are at high risk or low risk for complications or death.

Low-risk patients include those with no high-risk factors and most of the following: Talcott system group IV, or MASCC score ≥21; or CISNE score 0*; outpatient status at time of fever onset; no comorbidities; good performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] 0-1); anticipated short duration of severe neutropenia (absolute neutrophil count [ANC] ≤100 cells/microlitre for <7 days); no hepatic or renal insufficiency.[59][60][61]

*National Comprehensive Cancer Network guidelines consider CISNE <3 to be low risk at the initial risk assessment of patients with febrile neutropenia.

Patients who are assessed as low risk can be considered for outpatient management.[59][60] Patients require a thorough evaluation and close observation for ≥4 hours before being considered for outpatient management.[59] Patients with stable vital signs, non-critical laboratory results, appropriate social care and home therapy arrangements, and the ability to comply with and tolerate oral antibiotic therapy may be suitable for outpatient treatment.[59]

Several meta-analyses have found outpatient treatment to be a safe and effective alternative to inpatient management for low-risk patients, with no difference in treatment failure and death rates.[62][63][64] However, in one meta-analysis, ANC <100 cells/microlitre was identified as a potential predictor of outpatient treatment failure.[63]

Low-risk patients who are suitable for outpatient management can receive oral therapy with a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) plus amoxicillin/clavulanate (or clindamycin if the patient is allergic to penicillin) if fluoroquinolone prophylaxis was not used before fever onset and provided the patient does not have a history of infection or colonisation with a fluoroquinolone-resistant organism.[59][76]​ Fluoroquinolone monotherapy can also be considered in these patients.[77][78]

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[79]​ Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions.

Some low-risk patients may be treated with an outpatient parenteral regimen, although there are no clinical trials to support their use.

Empirical antibiotic treatment is typically continued until neutrophil recovery (i.e., ANC ≥500 cells/microlitre and increasing).[1][60]

Once empirical antibiotics are started, the median time to clinical response is 5-7 days.

Antibiotics should not be changed empirically in the face of persistent fever for the first 3-5 days, provided the patient is clinically stable.[80]

Patients with persistent fever despite neutrophil recovery warrant continued empirical therapy and further diagnostic evaluation.[58]

Hospital admission and inpatient management should be considered if fevers continue after 2-3 days or if there is evidence of progressive infection.[59]

Primary options

amoxicillin/clavulanate: 875 mg orally twice daily

More

or

clindamycin: 150-450 mg orally four times daily

-- AND --

ciprofloxacin: 500-750 mg orally twice daily

or

levofloxacin: 500-750 mg orally once daily

OR

ciprofloxacin: 500-750 mg orally twice daily

OR

levofloxacin: 500-750 mg orally once daily

ONGOING

persistent fever beyond 3-5 days of treatment

1st line – evaluation for occult infections + continued initial antibiotics

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ONGOING
|
persistent fever beyond 3-5 days of treatment
1st line – 

evaluation for occult infections + continued initial antibiotics

Patients with persistent fever beyond the first 3-5 days of empirical therapy require additional evaluation (e.g., imaging and microbiological testing) for a possible occult fungal infection, bacterial infection with cryptic foci or resistant organisms, or a viral infection.

If a thorough evaluation for infection is unrevealing in the face of persistent fever despite appropriate empirical therapy, a non-infectious cause for fever (e.g., drug fever, tumour fever, thromboembolism) should be considered.

Consider – consideration for inpatient management

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ONGOING
|
persistent fever beyond 3-5 days of treatment
|
low-risk patient
Consider – 

consideration for inpatient management

Additional treatment recommended for SOME patients in selected patient group

Low-risk patients with persistent fever despite 2-3 days of empirical outpatient antibiotic therapy should be re-evaluated, with strong consideration for inpatient management.[59]

Consider – empirical mould-active antifungal therapy

Back
ONGOING
|
persistent fever beyond 3-5 days of treatment
|
high-risk patient
Consider – 

empirical mould-active antifungal therapy

Additional treatment recommended for SOME patients in selected patient group

The addition of empirical mould-active antifungal therapy should be considered for high-risk patients with persistent fever despite ≥4 days of empirical antibiotic therapy.[60]

The choice of antifungal is often dictated by local institutional guidelines, risk for invasive mould infection, severity of illness, and specific risk for drug-drug interactions or toxicity in an individual patient.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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