Table 1.
General recommendations and levels of evidence
| Diagnostic/treatment recommendation | Level, Grade |
|---|---|
| Initial clinical evaluation | |
| The initial assessment should include the clinical history, physical examination, complete blood count, and basic biochemistry, and chest Rx | III, B |
| Two pairs of blood cultures and microbiological specimens, as clinically indicated, should be obtained prior to initiating empirical antibiotic therapy | III, A |
| Initial evaluation may include procalcitonin levels for the diagnosis of presumed bacterial infection and prognostic stratification | II, B |
| Consider a more comprehensive microbiological study in patients with clinical suspicion or history of specific infections, or with severe immunosuppression | III, B |
| Perform a computerized tomography of the chest in patients with clinically relevant respiratory symptoms and inconclusive chest Rx, or in patients with persistent fever (72 h or more) and risk factors for complications | II, B |
| Initial prognostic evaluation | |
| An initial prognostic evaluation according to clinical criteria is recommended to identify unstable patients or those at risk of severe complications | III, B |
| The application of the CISNE score is recommended in patients with apparent clinical stability and solid tumors on moderate-intensity chemotherapy | II, B |
| Initial empirical treatment | |
| Empirical antibiotic therapy should be initiated within the first hour of arrival at the ED (after sampling for cultures) | II, A |
| Initial parenteral antibiotherapy should include a beta-lactam with activity against Pseudomonas spp. (piperacillin/tazobactam, meropenem, imipenem–cilastatin, cefepime) | I, A |
| In high-risk patients meeting criteria for severity, initial parenteral antibiotherapy should include a beta-lactam with activity against Pseudomonas spp. (preferably a carbapenem) in combination with amikacin | II, A |
| In high-risk patients with suspicion of catheter-related infection or infection with a skin focus, pneumonia, or hemodynamic instability, it is recommended to associate vancomycin, linezolid (of choice if the focus is either pulmonary or cutaneous, but not recommended in catheter-related infections), or daptomycin (of choice in severe patients with quick SOFA ≥ 2 points and suspicion of cutaneous or catheter focus) to initial antibiotherapy. Tigecycline should be used only as a last option | II, A |
| In high-risk patients with enterocolitis or perirrectal infection, metronidazole should be associated to a beta-lactam with antipseudomonal activity | II, A |
| In patients who are allergic to penicillin, we recommend aztreonam and vancomycin, with association of amikacin in situations of severity or Pseudomonas aeruginosa infection | II, B |
| In low-risk patients without prior prophylaxis with fluoroquinolones, after parenteral administration of the first doses, oral treatment can be undertaken with the combination of amoxicillin–clavulanic and levofloxacin or ciprofloxacin | II, B |
| In low-risk patients, oral fluoroquinolones in monotherapy should not be used | II, D |
| Therapeutic use of G-CSF is recommended in patients at high risk for infectious complications, with neutropenia < 100 neutrophils/mm3 or in the presence of risk factors (age > 65, clinical instability, widespread infection, or severe complication) | I, A |
| Treatment in special situations | |
| Antimicrobial treatment should be adapted to the isolates and patterns of resistance (detailed in Table 3) | II, A |
| Empirical antifungal treatment should be considered if the fever persists after 5–7 days and microbiological diagnoses are negative | I, A |
| If the fever persists after 5–7 days and microbiological diagnoses are negative, studies aimed at ruling out invasive fungal infection should be performed (determination of blood galactomannan titers, studies guided by clinical suspicion) | III, A |
| Hygiene-dietary measures | |
| Prescription of a low-bacteria diet may be considered in patients with febrile neutropenia | III, C |
| Strict hand-washing protocols should be followed before and after contact with a patient with febrile neutropenia (FN) | I, A |
| Oral and skin hygiene should be optimized in patients with FN | II, A |
| Patients with resistant bacterial infections (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp, carbapenemase-resistant Enterococcus spp, or ESBL-producing Enterobacteriaceae, non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa or Acznetobacter baumannii, with a multi-resistant pattern) should be isolated | II, A |
| Reverse isolation is recommended only in patients treated with chemotherapy associated with profound, prolonged neutropenia | II, A |
| Follow-up and adjusting treatment | |
| Daily clinical and analytical follow-up, with blood cultures every 48 h (and samples from other sites if applicable) in situations of persistent fever are recommended in patients with FN | III, A |
| Prevention and treatment of associated complications (thrombosis, cytopenias, mucositis) should be performed in patients with FN | III, A |
| Antibiotic treatment should be adapted to clinical suspicion, the infectious focus, and microbiological isolate in cases of persistence of fever and/or identification of the infectious focus | I, A |
| Specific empirical treatment against Gram-positive germs should be withdrawn if suspicion is not confirmed within 48 h of initiation | II, B |
| Antibiotic coverage should be extended to Gram-negative bacilli, Gram-positive bacterium, and anaerobes in patients whose fever persists for more than 48 h associated with hemodynamic instability or clinical progression | I, A |
| Consultation with a specialist in infectious disease is recommended in bacteremias due to S. aureus, high-risk situations, multi-resistant germs, atypical sites or treatments, or HIV infection | III, C |
| Empirical antibiotic treatment should be maintained for at least 7 days in low-risk FN without a clinical or microbiological focal site | III, A |
| Consider switching to oral antibiotic treatment in patients with low risk for FN without clinical or microbiological focal site with neutrophil count exceeding 500/mm3 and without fever for at least 72 h | III, A |
| Antibiotic spectrum should be restricted according to infection focal site, severity, and the antibiogram of microorganisms identified as causing the infection after febrile neutropenia have resolved | II, A |
| Maintenance of antibiotherapy should be adjusted at least to the recommended duration for the underlying infection | III, B |
| Antibiotic treatment should last for at least 10–14 days in infections of the skin and soft tissue, pneumonias, and urinary tract infections | II, B |
| Hospital or ambulatory treatment | |
| Patients meeting severity criteria should be treated as inpatients | II, A |
| Patients not meeting severity criteria and who appear to be clinically stable and present high-risk CISNE scores (≥ 3 points) should be treated as inpatients | II, A |
| Patients not meeting severity criteria and who appear to be clinically stable and present high-risk CISNE scores (CISNE 3 or CISNE 2 with additional risk factors) should not be discharged from the hospital until clinical stability and negative results on blood culture are confirmed | II, B |
| Early discharge or ambulatory treatment with close follow-up may be considered in clinically stable patients not meeting criteria for severity, who exhibit low or intermediate risk scores on the CISNE model (CISNE 0–1) and who also meet the criteria for proximity, support, accessibility, and compliance with treatment and follow-up. However, CISNE does not specifically seek to select candidates for outpatient management, and standard hospitalization is also acceptable for these patients | III, B |
| In low-risk patients for whom ambulatory treatment has been decided on, the first dose of antibiotic should be administered via IV within the first hour and the patient should remain in observation at the hospital for at least 4 h | III, B |
| Close supervision should be maintained of low-risk patients for whom ambulatory treatment has been decided on | III, B |
| In low-risk patients for whom ambulatory treatment has been decided on, detailed oral and written information should be provided regarding warning signs and symptoms, and contact data | III, B |
| Hospital readmission is recommended in low-risk patients for whom ambulatory treatment has been decided on who continue to have febrile neutropenia after 48–72 h of empirical treatment or/and who present new information about infection, oral intolerance, or for whom a change of antibiotic is indicated | III, B |
| Prevention of febrile neutropenia | |
| Primary prophylaxis with filgrastim, pegfilgrastim, or biosimilar drugs is recommended when the probability of FN exceeds 20% | I, A |
| The indication for primary prophylaxis with filgrastim, pegfilgrastim, or biosimilar drugs in patients with intermediate risk for neutropenic fever (10–20%) should be individualized. The qualitative consequences of neutropenic infections, and not just their probabilities, must be considered | II, A |
| Secondary prophylaxis with filgrastim, pegfilgrastim, or biosimilar drugs is recommended in patients with a previous episode of FN in whom delaying or lowering the dose can negatively impact survival | I, A |
| As a general recommendation, antibiotic prophylaxis for FN should not be administered to patients undergoing mild–moderate-intensity chemotherapy | I, A |
| In patients undergoing mild–moderate-intensity chemotherapy, antibiotic prophylaxis for FN may considered in exceptional cases with very high risk of infection | III, B |
| Prophylaxis should be assessed for patients with specific risks for P. jirovecii, tuberculosis, or hepatitis | II, A |
| Influenza vaccination is recommended in patients with solid tumors with active disease or/and undergoing chemotherapy | II, A |
| Vaccination against pneumococcus is recommended in patients with solid tumors with active disease or/and undergoing chemotherapy | III, A |