Neutropenic fever: quick reference for emergency management

Key message

Fever in a neutropenic patient is an emergency. Infection can progress rapidly, while the typical local signs of inflammation may be faint or absent. Take cultures immediately, but never let sampling, imaging, the blood count or contact with the patient's own clinic delay empirical antibiotics [1].

A practical target: give the first dose of broad-spectrum antibiotics within 60 minutes of triage or arrival. This is supported by international guidelines on neutropenic fever [2]. The direct evidence for exactly one hour in neutropenic fever is limited, but delayed antibiotics are associated with a worse outcome in sepsis and in several studies of neutropenic patients. In septic shock, or where sepsis is highly likely, antibiotics must be given immediately [3].

This quick reference applies chiefly to adults with neutropenia related to cancer treatment. Children, pregnant women, patients after allogeneic stem cell transplantation and patients treated with CAR T cells or other advanced immunotherapies may require separate local protocols.

Definition

International guidelines generally use a single temperature of 38.3 degrees as the threshold [4,5]. Some Swedish and local care programmes use 38.5 degrees instead. Follow the local definition where one exists, but a neutropenic patient who is clinically unwell must be managed as an emergency even at a lower temperature.

Suspect neutropenia in anyone who has received cytotoxic chemotherapy in the past three weeks, even before a blood count is available. The nadir often occurs 7 to 14 days after a course of chemotherapy, but the timing varies considerably between regimens. Neutropenia can also be caused by haematological malignancy, stem cell transplantation, immunosuppressive drugs, radiotherapy, bone marrow failure and certain targeted cancer treatments.

Fever is not obligatory

Hypothermia, new confusion, tachypnoea, hypotension, rigors, abdominal pain or a rapid deterioration in general condition may be the only signs of infection. Corticosteroids and other immunosuppressive treatments can blunt the febrile response. A neutropenic patient with a suspected infection and organ dysfunction must therefore be managed as neutropenic sepsis even if the temperature criterion is not met.

The first hour

The diagnostic work-up must be rapid and targeted. Blood cultures should be taken before antibiotics when this can be done without delay. At least two separate sets are recommended, and with a central venous catheter a culture is also taken from the catheter. With a multi-lumen catheter, sampling from each lumen can increase the diagnostic yield [1].

Do not do this

• Do not wait for the blood count before giving antibiotics if neutropenia is likely.
• Do not wait for the CRP, lactate, radiography or culture results.
• Do not wait for a response from the patient's own clinic.
• Do not perform a rectal examination.
• Do not use a rectal thermometer.
• Do not give suppositories.
• Do not incise or aspirate suspected infections without specialist assessment.
• Do not give intramuscular injections if thrombocytopenia may be present.

Gentle inspection of the perianal region is, however, important. Pain, swelling or discoloration may be a sign of deep infection despite the absence of redness or pus.

Targeted history

Ask early about:

• the cancer and the current treatment
• the date of the most recent chemotherapy course or cell therapy
• the previous and expected duration of the neutropenia
• any stem cell transplantation
• current antibacterial, antiviral or antifungal prophylaxis
• colonisation with, or previous infection by, ESBL producers, carbapenem-resistant bacteria, MRSA or VRE
• previous culture results and resistance patterns
• recent hospital care or antibiotic treatment
• a central venous catheter, an implanted port or another foreign body
• penicillin allergy and the exact nature of the reaction
• cough, dyspnoea, pleuritic pain or hypoxia
• diarrhoea, abdominal pain, vomiting, constipation or perianal pain
• dysuria or flank pain
• headache, neck stiffness, focal neurological signs or confusion
• mucositis, dental problems, skin lesions or a painful rash
• treatment with corticosteroids or other immunosuppressive drugs

A reported penicillin allergy should be described carefully. Many patients with a non-specific or remote reaction do not have a genuine immediate beta-lactam allergy. Allergy investigation must not, however, delay emergency treatment. With a history of anaphylaxis or another serious immediate reaction, an alternative is chosen according to the local protocol and an infectious diseases physician is contacted early [1].

Examination and investigation

Clinical examination

Local signs of infection can be subtle. Examine:

• the mouth, teeth, throat and any mucositis
• the skin, particularly wounds, pressure points, nail folds and painful nodules
• the central line, including the insertion site, the tunnel and the port pocket
• the lungs and the oxygenation
• the abdomen, including focal tenderness, guarding, distension and bowel sounds
• the perianal region by external inspection
• the urinary tract and genital region if there are symptoms
• the neurological status in headache, confusion or focal neurological signs

Repeat the examination at least daily in inpatients, and more often if the patient is unstable. A focus of infection may become clinically apparent only after several hours, or when the neutrophils return.

Laboratory tests

Baseline tests:

• full blood count with a differential
• CRP
• creatinine and estimated renal function
• sodium, potassium, calcium and magnesium
• liver function tests and bilirubin
• glucose
• lactate
• a blood gas in circulatory or respiratory compromise
• coagulation tests in sepsis, bleeding or liver failure

The CRP can be normal early on and must never be used to exclude serious infection. Procalcitonin can contribute to the assessment of probable bacteraemia and of a complicated course, but neither procalcitonin nor CRP is reliable enough on its own to determine whether to start antibiotics or to discharge the patient [1]. A recent systematic review of prediction models shows that all the models examined had a substantial risk of bias, which further underlines that risk scores and biomarkers must be combined with clinical judgement [4].

Microbiology

As a general rule, take:

• at least two peripheral sets of blood cultures
• blood cultures from a central line if present
• a urine culture with urinary symptoms or unexplained sepsis
• respiratory samples for the relevant viruses with respiratory symptoms or during local transmission
• a sputum culture if a representative sample can be obtained
• a wound or skin swab with discharge or a clear focus
• stool diagnostics in diarrhoea, including targeted testing for Clostridioides difficile after clinical assessment

Routine repeated blood cultures after antibiotics have been started have a low diagnostic yield. New cultures are, however, needed on clinical deterioration, with a new fever, with a failure to respond, or with bacteraemia caused by pathogens where documented clearance is required, for example Staphylococcus aureus and Candida [1].

Rapid molecular tests can shorten the time to identification of a pathogen, but they do not replace blood cultures and often give limited information about antibiotic susceptibility. A positive multiplex result must also be weighed against the possibility of colonisation [5].

Imaging

Imaging is directed by the symptoms and must not delay the first dose of antibiotic.

• With respiratory symptoms, hypoxia or unexplained respiratory compromise, CT of the thorax is more sensitive than conventional chest radiography.
• A normal chest radiograph does not exclude pneumonia in a neutropenic patient.
• With abdominal pain, diarrhoea, peritonism or suspected neutropenic enterocolitis, CT of the abdomen with intravenous contrast is performed where possible.
• With focal neurological signs or impaired consciousness, urgent neuroimaging is performed.
• With persistent fever without a focus, repeat CT and, in selected cases, PET-CT can help to find an infection or another cause of the fever [1].

The empirical choice of antibiotic

Basic principle

Monotherapy with an antipseudomonal beta-lactam is the standard for most adult inpatients. The agent and the dose are chosen according to the local protocol, taking into account renal function, weight, allergy, previous culture results and local resistance epidemiology.

Common options are:

• piperacillin with tazobactam
• cefepime
• meropenem
• imipenem with cilastatin

A network meta-analysis of 50 randomised trials with 10,872 patients supports piperacillin with tazobactam, meropenem and imipenem with cilastatin as reasonable first-line options. The comparisons rest largely on older trials, and the local resistance situation matters more than small differences in ranking between the agents [6].

An aminoglycoside must not be given routinely

Beta-lactam monotherapy is at least as effective as routine combination with an aminoglycoside and causes less nephrotoxicity. In a Cochrane review of 71 trials, infection-related mortality was lower with monotherapy, while adverse effects were commoner with combination therapy [7]. A more recent systematic review likewise found no definite mortality benefit or reduction in treatment failure from the routine addition of an aminoglycoside, but confirmed an increased risk of renal impairment [8].

An aminoglycoside may nevertheless be considered as an initial, situation-specific addition in:

• septic shock
• a very high risk of resistant Gram-negative bacteraemia
• previous culture results in which an aminoglycoside is expected to be active
• severe infection where the activity of the chosen beta-lactam is uncertain

The decision must be reviewed promptly once culture and susceptibility results are available.

Vancomycin or other Gram-positive cover

A glycopeptide must not be included routinely. A Cochrane review of 14 randomised trials showed no reduction in mortality or in overall treatment failure from routine empirical Gram-positive cover [9].

Consider vancomycin or another suitable agent according to the local protocol in:

• haemodynamic instability or septic shock
• suspected central line infection
• skin or soft tissue infection
• pneumonia where MRSA is a reasonable differential diagnosis
• known MRSA colonisation or previous MRSA infection
• blood cultures showing Gram-positive cocci before speciation, when the clinical picture suggests serious infection
• severe mucositis, particularly where penicillin-resistant viridans streptococci are suspected

Mucositis alone is not always sufficient reason for vancomycin if the antipseudomonal beta-lactam has relevant streptococcal activity and the patient is stable. Stop the Gram-positive cover if the indication no longer applies after culture results and clinical reassessment.

When a carbapenem should be considered

A carbapenem is not necessary for everyone. Consider meropenem or another locally recommended option in:

• previous infection with, or current colonisation by, ESBL-producing bacteria
• septic shock with a substantial risk of resistant Gram-negative bacteria
• recent broad-spectrum antibiotics together with a known local resistance problem
• a microbiological finding that requires a carbapenem

Meta-analyses show high treatment success with carbapenems, but a general survival benefit compared with other suitable beta-lactams has not been reliably demonstrated. The choice of agent must therefore be governed by previous findings, local epidemiology and the risk of further selection of resistance [10].

Known colonisation with a resistant organism does not automatically mean that a reserve antibiotic must be added. Assess whether the chosen empirical agent is likely to cover the patient's own previous isolate, and discuss the case early with an infectious diseases physician or a microbiologist.

Anaerobic cover

Ensure anaerobic activity in:

• an abdominal focus
• perianal infection
• neutropenic enterocolitis
• odontogenic infection
• necrotising soft tissue infection
• any other clinical picture suggesting polymicrobial infection

Piperacillin with tazobactam and the carbapenems generally have their own anaerobic activity. If cefepime is used with a suspected abdominal focus, separate anaerobic cover is often needed according to the local protocol.

Known microbiological findings

Once the pathogen and its susceptibility are known, treatment must be targeted and, where possible, narrowed. About half of episodes nevertheless remain microbiologically and clinically unexplained despite an adequate work-up [1].

A single blood culture growing coagulase-negative staphylococci or other skin flora may be a contaminant, but the finding must be weighed against the number of positive bottles, the time to positivity, the presence of a central line and the clinical picture. Do not automatically dismiss a finding in an unstable patient.

Particular clinical situations

Neutropenic enterocolitis

Neutropenic enterocolitis, also called typhlitis, must be suspected with neutropenia in combination with fever, abdominal pain and diarrhoea, particularly around the nadir after chemotherapy. The caecum and right colon are often affected, but the whole gastrointestinal tract can be involved.

A systematic review of 227 published cases found abdominal pain in 81 per cent, fever in 62 per cent and diarrhoea in 43 per cent. The reported mortality was 33.5 per cent, but the evidence consisted mainly of case reports and case series [11]. An older systematic review proposed fever, abdominal pain and bowel wall thickening of more than 4 mm on ultrasound or CT as practical diagnostic criteria [12].

Management:

• perform CT of the abdomen with contrast where possible
• give antibiotics covering Gram-negative bacteria, Pseudomonas and anaerobes
• give intravenous fluid and correct electrolyte disturbances
• consider bowel rest and nutrition in consultation with the haematologist, the surgeon and the dietitian
• consult a surgeon early in peritonitis, perforation, necrosis, uncontrolled bleeding or continuing deterioration
• avoid colonoscopy in the acute phase unless there are compelling reasons

Surgery is not routine treatment when there is an uncomplicated response to conservative management, but it must not be delayed in perforation, necrosis or uncontrolled sepsis.

Risk assessment

The risk assessment determines the level of care and the possibility of oral or outpatient treatment. It must never delay the first dose of antibiotic.

The high-risk patient

Admit the patient and give intravenous treatment in the presence of any of the following:

• neutropenia expected to last longer than 7 days
• haematological malignancy on intensive treatment
• acute leukaemia
• allogeneic stem cell transplantation
• profound neutropenia, particularly below 0.1 × 10⁹/L
• haemodynamic compromise
• hypoxia, pneumonia or other respiratory compromise
• renal or hepatic impairment
• neurological symptoms
• severe mucositis or an inability to swallow medication
• abdominal pain, diarrhoea or suspected enterocolitis
• a central line with suspected infection
• a documented infection requiring intravenous treatment
• uncontrolled cancer
• significant comorbidity
• ongoing antibacterial prophylaxis when breakthrough fever occurs
• uncertain adherence, or an inadequate ability to return quickly

Patients after high-dose treatment and stem cell transplantation have particular infection risks and may be on prophylaxis that affects both the microbiology and the empirical choice of antibiotic [13].

The low-risk patient

Outpatient treatment can be considered only if all the clinical, medical and logistical requirements are met. The typical prerequisites are:

• neutropenia expected to last no more than 7 days
• a solid tumour or another low-intensity cancer situation
• a haemodynamically stable patient
• no pneumonia, hypoxia, organ failure or deep focal infection
• no severe mucositis, vomiting or diarrhoea threatening oral absorption
• no significant uncontrolled comorbidity
• no suspected central line infection
• the patient can take oral medication
• secure accommodation and a working telephone
• a responsible adult available if needed
• a short travelling time to hospital
• the possibility of daily clinical review and immediate return

A MASCC score of at least 21 indicates low risk, but it is not sufficient on its own as a basis for discharge. CISNE can be used in apparently stable patients with a solid tumour to detect those who are nevertheless at risk of complications. CISNE must not be used to turn an unstable patient into a low-risk patient. The qSOFA has inadequate sensitivity and must not be used as the sole sepsis screening tool in neutropenic fever [1,4].

The limitations of the risk scores

A systematic review of 90 studies of prediction models found a high risk of bias in all of them and limited external validation. MASCC and CISNE therefore provide support, not an answer [4]. Clinical judgement, the expected duration of the neutropenia, organ function, the focus of infection and the patient's ability to follow an outpatient plan all carry at least as much weight.

Oral and outpatient treatment

For carefully selected low-risk patients, oral treatment can be equivalent to intravenous treatment. A Cochrane review of 22 randomised trials found no definite difference in mortality or treatment failure between oral and intravenous antibiotics in selected stable low-risk patients [14].

The commonly recommended international oral option is the combination of:

• a fluoroquinolone
• amoxicillin with clavulanic acid

The agent and dose must follow the local protocol. The combination is unsuitable if the patient has already received fluoroquinolone prophylaxis, has known quinolone resistance, cannot take oral medication, or has no secure follow-up arrangements [2].

Give the first dose of antibiotic within 60 minutes even if the patient is later to be discharged. Observe the patient for at least four hours after the first dose before deciding on outpatient treatment [2].

Randomised trials show no clear difference in treatment failure or mortality between outpatient and inpatient care in selected low-risk patients, but the confidence intervals are wide and the results must not be extended to high-risk patients [15]. In systematic reviews, 6 to 20 per cent of patients treated as outpatients have required readmission [16].

The outpatient plan must include:

• a named responsible clinic
• daily contact or review
• clear instructions on measuring the temperature
• immediate return if the patient deteriorates
• access to a direct telephone number around the clock
• a plan for repeat investigations
• a planned reassessment no later than the following day

Admit the patient if the fever persists, if the patient deteriorates, or if follow-up cannot be guaranteed. International guidelines recommend reassessment and consideration of hospital care if there is no improvement after two to three days [2].

Persistent fever

Fever can persist for three to five days despite adequate treatment. Continuing fever in an otherwise stable patient is not in itself evidence of treatment failure and is not sufficient reason to change the beta-lactam or add vancomycin routinely [1].

With persistent fever:

1. Repeat the full history and examination.
2. Check the antibiotic dose, the administration, the renal function and any missed doses.
3. Review previous cultures, colonisation and local resistance.
4. Assess the central line.
5. Take new blood cultures on clinical deterioration or with a new febrile episode.
6. Perform targeted CT, particularly of the thorax and abdomen depending on the symptoms.
7. Consider drug fever, tumour fever, thrombosis, a transfusion reaction and other non-infectious causes.
8. Assess the risk of invasive fungal infection.

Change the empirical antibiotic on clinical deterioration, with a resistance finding, with a new focus, or for another concrete reason. Do not broaden the treatment reflexively merely because the patient still has a fever after 72 to 96 hours.

When should invasive fungal infection be considered?

Consider invasive fungal infection early in high-risk patients with:

• neutropenia lasting longer than 7 days
• acute leukaemia
• allogeneic stem cell transplantation
• high-dose corticosteroids
• a previous invasive fungal infection
• prolonged broad-spectrum antibiotics
• pulmonary infiltrates, nodules, pleuritic pain or haemoptysis
• sinus symptoms or focal skin lesions
• persistent or recurrent fever after 72 to 96 hours

Fungal diagnostics can include:

• CT of the thorax
• serum galactomannan
• beta-glucan
• blood cultures
• bronchoscopy with bronchoalveolar lavage where there are relevant infiltrates
• culture, direct microscopy, galactomannan and molecular diagnostics on respiratory samples
• targeted biopsy where this is safe and clinically justified

Galactomannan is relevant above all to aspergillosis. Beta-glucan can be positive in several fungal infections and in Pneumocystis jirovecii, but it is not specific. Prophylaxis with a mould-active agent can reduce the sensitivity of the tests. Biomarkers do not replace clinical judgement, radiology and microbiology [5].

Empirical or diagnostic-driven antifungal treatment

Traditionally, empirical antifungal treatment has been considered after four to seven days of persistent fever in a high-risk patient despite broad-spectrum antibiotics. Modern practice is moving towards a diagnostic-driven strategy where rapid access to CT and fungal markers is available.

A Cochrane review of seven randomised trials with 1,480 high-risk patients found no definite difference in overall or fungus-related mortality between diagnostic-driven and empirical treatment. Diagnostic-driven treatment probably reduced exposure to antifungal drugs, but the evidence was of low or very low certainty [17].

In practice:

• In a high-risk patient with persistent fever, a fungal work-up is performed after 72 to 96 hours, and earlier with specific symptoms or radiological findings.
• Where the clinical or radiological suspicion is strong, treatment is started without awaiting all the results.
• The choice of antifungal is governed by previous prophylaxis, the suspected organism, organ function, drug interactions and the local protocol.
• Empirical antifungal treatment is not recommended routinely for a stable low-risk patient with short-lived neutropenia and isolated persistent fever [1].

The central line

Culture both peripherally and from the central line. With a multi-lumen catheter, a culture from each lumen may be needed. Assess the insertion site, the tunnel and the port pocket.

Suspect catheter-related infection with:

• local redness, pain, discharge or swelling
• rigors in connection with flushing or infusion
• blood cultures from the catheter becoming positive earlier than peripheral ones
• repeated positive cultures without another focus
• persistent bacteraemia despite adequate treatment

Removal should be considered early in:

• tunnel or port pocket infection
• septic thrombosis
• endocarditis
• haemodynamic instability
• persistent bacteraemia or fungaemia despite adequate treatment
• bacteraemia with S. aureus, Pseudomonas aeruginosa or a fungus, after specialist assessment

The catheter must not be removed as a matter of routine in every patient with a fever. The decision is influenced by the pathogen, the type of catheter, the depth of infection, the need for continued access and the possibility of microbiological eradication.

Duration, narrowing and stopping of antibiotics

Antibiotic treatment must be reviewed daily on the basis of:

• the clinical course
• the culture results
• any identified focus
• organ function
• the trend in the neutrophil count
• previous prophylaxis
• the risk of fungal infection
• the possibility of narrowing the treatment

With a documented infection, the patient is treated according to the site of infection, the pathogen and any complications, adjusted for the immunosuppression and for the need for infection control.

With fever and no identified focus, older practice has often been to continue antibiotics until the neutrophils have recovered. That principle is no longer absolute. The updated AGIHO guideline states that empirical treatment can be stopped after three to five days without fever and with clinical recovery, irrespective of the neutrophil count, provided the patient is stable and has no documented infection [1].

The evidence is, however, not entirely unequivocal. A Cochrane review of eight randomised trials could not draw firm conclusions about discontinuation before neutrophil recovery, because of the low certainty of the evidence and the older, heterogeneous studies [18]. A more recent meta-analysis in haematological malignancy found that early de-escalation did not increase the need for intensive care, bacteraemia or recurrent fever, but most of the studies were retrospective and the results may be affected by selection [19].

In practice this means:

• Do not stop antibiotics merely because the fever has settled after a single dose.
• Do not automatically continue broad-spectrum antibiotics until the neutrophils have risen if the patient has been stable and afebrile for several days with no documented infection.
• Make the decision to stop together with a haematologist, oncologist or infectious diseases physician in high-risk patients.
• Restart and investigate if the patient develops a new fever or deteriorates.

A categorical prohibition on discontinuation before neutrophil recovery is therefore not supported. Modern evidence supports an individually determined discontinuation before neutrophil recovery in carefully selected, stable patients.

G-CSF during the current episode

G-CSF must not be given routinely as treatment for every episode of neutropenic fever. A Cochrane review of 14 randomised trials found no definite improvement in overall or infection-related mortality. G-CSF did, however, shorten the duration of the neutropenia, the time to becoming afebrile and the hospital stay, but increased bone pain and influenza-like symptoms [20].

A later systematic review likewise found no definite reduction in infection-related mortality and gave a weak recommendation against routine therapeutic use [21].

Consider G-CSF after haematological or oncological assessment where the risk is particularly high, for example:

• profound and expected prolonged neutropenia
• old age with comorbidity
• pneumonia
• hypotension or sepsis
• multi-organ failure
• invasive fungal infection
• uncontrolled malignancy

This must be distinguished from primary or secondary prophylaxis before future chemotherapy courses. Prophylactic G-CSF is generally recommended when the risk of neutropenic fever with the chemotherapy regimen is around 20 per cent or higher, or at a lower treatment-related risk in combination with significant individual risk factors [22].

Viruses and other opportunistic infections

Consider respiratory viruses with cough, coryza, dyspnoea or epidemiological exposure. A positive viral test does not exclude a concurrent bacterial infection and must not on its own lead to immediate discontinuation of antibiotics in a high-risk patient.

HSV can cause extensive mucositis and ulceration. VZV can be disseminated and lack the typical localised shingles pattern. With vesicular or necrotic lesions, samples must be taken and antiviral treatment considered without delay.

CMV is chiefly relevant after allogeneic stem cell transplantation or in marked T cell immunosuppression. Fever in a patient who is merely neutropenic, without such a risk profile, is rarely sufficient reason for urgent empirical CMV treatment. Pneumocystis pneumonia, toxoplasmosis and other opportunistic infections are governed more by the type of cellular immune deficiency than by the neutrophil count.

Red flags

• a systolic blood pressure below the patient's usual level, or a rising vasopressor requirement
• a rising lactate
• new hypoxia or a rapidly increasing oxygen requirement
• tachypnoea or increased work of breathing
• confusion or focal neurological signs
• oliguria or a rapidly rising creatinine
• severe abdominal pain, peritonism or bloody diarrhoea
• a rapidly progressive skin lesion, or pain out of proportion to the findings
• signs of infection around a central line
• profound neutropenia below 0.1 × 10⁹/L
• acute leukaemia or recent stem cell transplantation
• known colonisation with a multiresistant Gram-negative organism
• breakthrough fever during antibacterial or antifungal prophylaxis
• persistent fever with pulmonary infiltrates
• a positive blood culture with S. aureus, P. aeruginosa, a multiresistant Gram-negative organism or a fungus

Common pitfalls

• Waiting for the blood count. Treat if neutropenia is likely.
• Trusting a normal CRP. A normal early CRP does not exclude serious infection.
• Requiring fever. Hypothermia, or organ dysfunction alone, can be neutropenic sepsis.
• Using the qSOFA as a rule-out test. The score has inadequate sensitivity in this population.
• Forgetting the central line. Culture both peripherally and from the line.
• Adding vancomycin routinely. It does not improve outcomes without a specific indication.
• Giving an aminoglycoside routinely. Monotherapy with a suitable beta-lactam is the standard.
• Escalating antibiotics merely because of persistent fever. The median time to becoming afebrile can be several days.
• Missing an abdominal focus. Neutropenic enterocolitis can progress to perforation and sepsis.
• Being satisfied with a normal chest radiograph. CT of the thorax is more sensitive.
• Giving empirical antifungal treatment to everyone after four days. Assess the risk profile, the prophylaxis, the CT and the fungal markers first.
• Discharging a patient on the basis of a MASCC score of at least 21 alone. The clinical and logistical criteria must also be met.
• Continuing broad-spectrum antibiotics as a matter of routine until the neutrophils have recovered. A stable, afebrile patient with no documented infection can in selected cases stop earlier after specialist assessment.
• Forgetting dose adjustment. Renal function, weight, dialysis and drug interactions must all be taken into account.
• Forgetting non-infectious causes. Drug fever, tumour fever, thrombosis, transfusion reactions and treatment-related inflammation do occur, but they are diagnoses of exclusion in the acute phase.

A practical on-call checklist

1. Suspect neutropenia from the treatment and the time course.
2. ABCDE and a sepsis assessment.
3. Two peripheral sets of blood cultures, plus a culture from the central line.
4. Full blood count with a differential, CRP, creatinine, electrolytes, liver function tests and lactate.
5. A targeted examination of the mouth, skin, vascular access, lungs, abdomen and perianal region.
6. Give an antipseudomonal beta-lactam, aiming for within 60 minutes.
7. Add other cover only where there is a clear clinical or microbiological indication.
8. Perform early CT with respiratory symptoms or abdominal pain.
9. Admit all high-risk patients and everyone in whom follow-up is uncertain.
10. Review the antibiotic, the focus, the vascular access and the fungal risk daily.

References

1. Sandherr M et al. 2024 update of the AGIHO guideline on diagnosis and empirical treatment of fever of unknown origin in adult neutropenic patients with solid tumours and hematological malignancies. Lancet Regional Health Europe 2025. PMID: 39973942
2. Taplitz RA et al. Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. Journal of Clinical Oncology 2018. PMID: 29461916
3. Gretland J et al. Timing of antibiotic initiation in sepsis and neutropenic fever. Frontiers in Medicine 2025. PMID: 40963571
4. Sheehy J et al. Clinical prediction models for febrile neutropenia and its outcomes: a systematic review. Supportive Care in Cancer 2025. PMID: 40467900
5. Keck JM et al. Approach to fever in patients with neutropenia: a review of diagnosis and management. Therapeutic Advances in Infectious Disease 2022. PMID: 36451936
6. Horita N et al. Comparison of antipseudomonal beta lactams for febrile neutropenia empiric therapy: systematic review and network meta-analysis. Clinical Microbiology and Infection 2017. PMID: 28377312
7. Paul M et al. Beta lactam versus beta lactam aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database of Systematic Reviews 2013. PMID: 23813455
8. Ishikawa K et al. Systematic Review of Beta Lactam vs. Beta Lactam plus Aminoglycoside Combination Therapy in Neutropenic Cancer Patients. Cancers 2024. PMID: 38792012
9. Beyar-Katz O et al. Empirical antibiotics targeting gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database of Systematic Reviews 2017. PMID: 28577308
10. Tang X et al. Carbapenems versus alternative beta lactams monotherapy or in combination for febrile neutropenia: Systematic review and meta-analysis of randomized controlled trial. Medicine 2020. PMID: 33120768
11. Nematolahi S et al. Investigating neutropenic enterocolitis: a systematic review of case reports and clinical insights. BMC Gastroenterology 2025. PMID: 39819318
12. Gorschlüter M et al. Neutropenic enterocolitis in adults: systematic analysis of evidence quality. European Journal of Haematology 2005. PMID: 15946304
13. Christopeit M et al. Prophylaxis, diagnosis and therapy of infections in patients undergoing high-dose chemotherapy and autologous haematopoietic stem cell transplantation. Annals of Hematology 2021. PMID: 33079221
14. Vidal L et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database of Systematic Reviews 2013. PMID: 24105485
15. Rivas-Ruiz R et al. Outpatient treatment for people with cancer who develop a low-risk febrile neutropaenic event. Cochrane Database of Systematic Reviews 2019. PMID: 30887505
16. Forcano-Queralt E et al. Ambulatory management of low-risk febrile neutropenia in adult oncological patients. Systematic review. Supportive Care in Cancer 2023. PMID: 37921996
17. Uneno Y et al. Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer. Cochrane Database of Systematic Reviews 2022. PMID: 36440894
18. Stern A et al. Early discontinuation of antibiotics for febrile neutropenia versus continuation until neutropenia resolution in people with cancer. Cochrane Database of Systematic Reviews 2019. PMID: 30605229
19. Chen YH et al. Efficacy and safety of early antibiotic de-escalation in febrile neutropenia for patients with hematologic malignancy: a systematic review and meta-analysis. Antimicrobial Agents and Chemotherapy 2025. PMID: 40079575
20. Mhaskar R et al. Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database of Systematic Reviews 2014. PMID: 25356786
21. Tsuchihashi K et al. Therapeutic use of granulocyte colony-stimulating factor in patients with febrile neutropenia: a comprehensive systematic review. International Journal of Clinical Oncology 2024. PMID: 38696053
22. Smith TJ et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology 2015. PMID: 26169616