Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Network for Research in Infectious Diseases (REIPI) and the Spanish Society of Haematology and Haemotherapy (SEHH) on the management of febrile neutropenia in patients with hematological malignancies | Enfermedades Infecciosas y Microbiología Clínica (English Edition)

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de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Farmacología, Universidad Clínica de Navarra, Pamplona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Microbiología Clínica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Microbiología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Servicio de Enfermedades Infecciosas, Hospital Clínic, Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Servicio de Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, & CIBERONC, Instituto Carlos III, Valencia, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Unidad de Enfermedades Infecciosas, Hospital Universitario “12 de Octubre”, Instituto de Investigación Hospital “12 de Octubre” (i+12), Universidad Complutense, Madrid, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Hematología, Institut Català d’Oncologia (ICO), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] 11 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Clínic, Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain" "etiqueta" => "l" "identificador" => "aff0060" ] 12 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain" "etiqueta" => "m" "identificador" => "aff0065" ] 13 => array:3 [ "entidad" => "Servicio de Onco-hematología, Hospital de la Princesa, Madrid, Spain" "etiqueta" => "n" "identificador" => "aff0070" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Resumen ejecutivo del documento de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), la Red Española de Investigación en Patología Infecciosa (REIPI) y la Sociedad Española de Hematología y Hemoterapia (SEHH) sobre el manejo de la neutropenia febril en el paciente hematológico" ] ] "textoCompleto" => "Executive summaryIntroduction: justification and objectivesRecent years have witnessed the re-emergence of bacterial infections with a gram-negative etiology in patients with febrile neutropenia (FN), together with a significant increase in their resistance to antimicrobials. These epidemiological changes are of particular importance in hematologic patients with FN because inadequate initial empirical antibiotic therapy can have a serious adverse effect on prognosis in high-risk patients. Likewise, the management of infections caused by multidrug-resistant bacteria is a major clinical problem in this population.The management of hematologic patients has also changed in recent years, with a tendency towards outpatient care and new types of immunosuppressive treatment. In the era of multidrug resistance, the objective of these new guidelines is to update the recommendations for the initial management of hematologic patients who develop FN. This document focuses basically on bacterial infection. Other aspects associated with opportunistic infections, such as fungal infections or those due to other microorganisms, especially in hematopoietic stem cell transplantation (HSCT), are also touched upon. Only infections in adult patients will be discussed.MethodologyThe two participating Societies, the Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica) and the Spanish Association of Hematology and Hemotherapy (Sociedad Española de Hematología y Hemoterapia) nominated two coordinators, who selected the rest of the members of the panel of experts. The scientific committees of both societies approved the proposal. The questions to be considered were approved by both scientific societies involved and then distributed among the various members of the panel of experts. The present Document was written following the SEIMC guidelines for consensus documents (<a href="http://www.seimc.org/">www.seimc.org</a>), as well as the recommendations of the AGREE collaboration (<a href="http://www.agreecollaboration.org/">www.agreecollaboration.org</a>) for evaluating the methodological quality of clinical practice guidelines. The PubMed search engine (<a href="http://www.ncbi.nlm.nih.gov/pubmed">http://www.ncbi.nlm.nih.gov/pubmed</a>) was used to perform a literature search of the MEDLINE database for relevant scientific publications. The key words used for each question are also shown. Only complete articles published in English or Spanish were selected. No specific period of inclusion was defined, although authors were instructed to gather the most recent evidence from the literature to form the basis of their answers. The coordinators wrote the first draft, which was submitted for review by the panel of experts and by SEIMC members after being published on the web page of that society. The complete text has been approved by all authors. The criteria used to evaluate the strength of the recommendation and the quality of the evidence are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. Possible conflicts of interest associated with all members of the panel of experts are listed at the end of the document.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>RecommendationsClassification of febrile neutropenia risk<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.What tools are available to determine risk in a patient with FN? When should they be applied and in what contexts?</li></ul>Search terms: “Risk factors” “Risk stratification”, “Febrile neutropenia”, “Cancer patients”.<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">1.Patients presenting with FN should undergo risk assessment for complications, preferably in the first hour of contact with the healthcare system (A-II).</li><li class="elsevierStyleListItem" id="lsti0015">2.The MASCC (Multinational Association for Supportive Care in Cancer) risk index is a prognostic scale that can be used to assess the risk of complications in patients with FN (B-II).</li><li class="elsevierStyleListItem" id="lsti0020">3.A patient with a MASCC risk index score of <21 is defined as high risk (B-II) and should be hospitalized and receive intravenous empirical antibiotic treatment (B-II).</li><li class="elsevierStyleListItem" id="lsti0025">4.A patient with a MASCC risk index score of ≥21 is defined as low risk (B-II). Some of these patients may be candidates for a regimen of oral antibiotics and can be managed as outpatients, provided that they are not receiving induction chemotherapy for acute myeloid leukemia or in the pre-engraftment phase of allogeneic hematopoietic stem cell transplantation (B-II).</li><li class="elsevierStyleListItem" id="lsti0030">5.Clinical criteria can also be used to determine risk in patients with FN.</li><li class="elsevierStyleListItem" id="lsti0035">6.Patients with an absolute neutrophil count (ANC) of ≤100/mm3, expected neutropenia duration of >7 days, and/or significant comorbidities (hypotension, pneumonia, gastrointestinal symptoms, neurological symptoms) are considered high-risk. These patients should be admitted to hospital and receive intravenous empirical therapy (A-II).</li><li class="elsevierStyleListItem" id="lsti0040">7.Patients with ANC<500/mm3, expected neutropenia duration ≤7 days and having no or few comorbidities or significant evidence of renal or hepatic impairment are considered as at low-risk. These patients may be candidates for oral empirical therapy and outpatient care (A-II).</li></ul>Diagnostic management<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045">1.What microbiology diagnostic tests should be carried out in patients with FN?</li></ul>Search terms: “Febrile neutropenia” AND “Etiology”. “Febrile neutropenia” AND “Microbiological diagnosis”.<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050">1.It is recommended that at least two, and preferably three, sets of blood cultures be collected from any patient with FN, whether they are in-patients or seen in the emergency room, high-risk or low-risk. Blood should be drawn through all available catheterized venous access in the patient, paying special attention to long-term devices, as well as samples taken by venipuncture from peripheral vein sites (A-I).</li><li class="elsevierStyleListItem" id="lsti0055">2.If an infection of extravascular origin is suspected, it is recommended to send representative samples from the possible focus of infection. Rapid microbiological tests can be performed on these samples (A-I).</li><li class="elsevierStyleListItem" id="lsti0060">3.For patients being monitored in an outpatient setting with symptoms or radiological signs of respiratory infection, rapid urine antigen tests for the detection of Streptococcus pneumoniae and Legionella pneumophila antigens can be used (A-II).</li><li class="elsevierStyleListItem" id="lsti0065">4.During annual flu epidemics, molecular methods should be used for early diagnosis. In the case of flu, rapid techniques on nasopharyngeal swabs are preferred (B-II).</li><li class="elsevierStyleListItem" id="lsti0070">5.If the patient presents diarrhea, it is advisable to request a Clostridium difficile toxin stool test, on which rapid immunochromatographic assays or PCR can be performed (C-III).</li></ul><ul class="elsevierStyleList" id="lis0360"><li class="elsevierStyleListItem" id="lsti0075">2.When and how should pre-emptive screening for fungal infection be carried out?</li></ul>Search terms: “Febrile neutropenia AND fungal infection diagnosis”, “Febrile neutropenia AND investigation for invasive fungal infection”.<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0080">1.In patients with FN, pre-emptive screening for fungal infection should be considered when fever persists for 4–7 days after having started broad-spectrum antibiotics, expected duration of neutropenia is >7 days, and in clinically compatible cases (A-I).</li><li class="elsevierStyleListItem" id="lsti0085">2.Blood cultures are the microbiological test of choice for the diagnosis of yeast infections (A-I).</li><li class="elsevierStyleListItem" id="lsti0090">3.In clinically stable patients who are not receiving antifungal prophylaxis against filamentous fungi, it is recommended to screen for Aspergillus infection by carrying out serial testing for circulating galactomannan (GM) in serum twice a week. In the event of a positive GM test, a CT scan of the lungs is recommended (A-I).</li><li class="elsevierStyleListItem" id="lsti0095">4.In patients receiving antifungal prophylaxis against filamentous fungi, a CT scan of the thorax is recommended if fever persists (>7 days after initiating broad-spectrum antibiotics, with no other identifiable cause of fever). In the event of findings suggestive of invasive fungal infection, bronchoscopy is recommended for galactomannan testing, and pan-fungal PCR on the bronchoalveolar lavage (BAL) fluid. If results are negative, lesion puncture is recommended (B-II).</li></ul><ul class="elsevierStyleList" id="lis0370"><li class="elsevierStyleListItem" id="lsti0100">3.Are biomarkers useful for infection diagnosis in FN and for determining length of antibiotic treatment?</li></ul>Search terms: “Biomarkers and infection diagnosis”, “Febrile neutropenia”, “Bacteremia and biomarkers”, “Length of antibiotics in febrile neutropenia”.<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0105">1.Biomarkers are not recommended as a guide to antibiotic use in FN, due to the lack of studies demonstrating the safety and usefulness of basing clinical decisions on their results (B-III).</li><li class="elsevierStyleListItem" id="lsti0110">2.It has been demonstrated that neutropenic patients with bacteremia present significantly higher procalcitonin (PCT), C-reactive protein, IL-6, and presepsin levels than those without bacteremia. (A-II). The possible impact of this information on the future management of FN is yet to be clarified.</li><li class="elsevierStyleListItem" id="lsti0115">3.Biomarkers are not useful for determining length of antibiotic treatment (A-II).</li><li class="elsevierStyleListItem" id="lsti0120">4.C-reactive protein levels, especially those that are elevated (>20–30mg/dl), are correlated with greater mortality. This relationship has not been demonstrated with the other biomarkers (PCT, presepsin, IL-6) (C-III).</li></ul>Empirical antibiotic treatment<ul class="elsevierStyleList" id="lis0380"><li class="elsevierStyleListItem" id="lsti0125">1.What empirical treatment strategies are there for patients with NF?</li></ul>Search terms: “Febrile neutropenia”, “Empirical antibiotic treatment”.<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0130">1.Any febrile patient with an ANC of <500/mm3 and those with ANC of 500–1000/mm3 and predicted to decline imminently should receive early empirical antibiotic treatment (A-II) with an appropriate broad-spectrum antibiotic (A-I) and a bactericidal agent.</li><li class="elsevierStyleListItem" id="lsti0135">2.Surveillance programs (antimicrobial stewardship) established in the center for the appropriate use of antibiotic treatment should be taken into consideration (B-III).</li><li class="elsevierStyleListItem" id="lsti0140">3.A strategy of dose-escalation can be applied in patients with an uncomplicated clinical presentation, no previous colonization/infection with multidrug-resistant bacteria, and in centers where there is a low incidence of drug-resistant microorganisms (B-II). In other situations, a de-escalation strategy should be applied (B-II).</li></ul><ul class="elsevierStyleList" id="lis0390"><li class="elsevierStyleListItem" id="lsti0145">2.What is the empirical antibiotic treatment of choice when there is no obvious clinical focus of infection?</li></ul>Search terms: “Febrile neutropenia”, “Empirical antibiotic treatment”, “Fever unknown origin”.<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0150">1.It is recommended to use a beta-lactam antibiotic with antipseudomonal activity as monotherapy, or in combination with another antibiotic, depending on the risk of infection due to multidrug-resistant microorganisms and clinical presentation (A-I).</li><li class="elsevierStyleListItem" id="lsti0155">2.For the escalation strategy:</li><li class="elsevierStyleListItem" id="lsti0160">2.1Use of piperacillin-tazobactam (A-I), or cefepime (A-I), or ceftazidime (B-II) is recommended.</li><li class="elsevierStyleListItem" id="lsti0165">2.2In settings with a high prevalence of ESBs, cephalosporins and piperacillin-tazobactam in monotherapy are not recommended (B-II).</li></ul><ul class="elsevierStyleList" id="lis0720"><li class="elsevierStyleListItem" id="lsti0170">3.For the de-escalation strategy:</li></ul><ul class="elsevierStyleList" id="lis0560"><li class="elsevierStyleListItem" id="lsti0175">3.1Imipenem or meropenem in monotherapy are recommended for use (B-II), or a combination of antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone (if it has not been used as prophylaxis) (B-III). Carbapenems should be reserved for critically ill patients.</li><li class="elsevierStyleListItem" id="lsti0180">3.2The aminoglycoside should be given in a single daily dose (A-II). The need to continue the aminoglycoside should be reassessed at 48–72h.</li><li class="elsevierStyleListItem" id="lsti0185">3.3If there is risk of infection due to multidrug-resistant nonfermenting gram-negative bacilli, it is recommended to combine the beta-lactam with the lowest antimicrobial resistance rate in the center+amikacin or colistin (B-III).</li><li class="elsevierStyleListItem" id="lsti0190">3.4The need for empirical treatments with other combinations can be considered, according to local epidemiology or in outbreak settings (C-III).</li><li class="elsevierStyleListItem" id="lsti0195">3.5The use of antibiotics with activity against gram-positive cocci resistant to beta-lactams (vancomycin, daptomycin, linezolid) would be indicated only in cases of hemodynamic instability and/or risk of methicillin-resistant Staphylococcus aureus (MRSA) infection (B-III).</li><li class="elsevierStyleListItem" id="lsti0200">3.6The empirical addition of vancomycin to initial antibiotic therapy is not recommended if fever persists at 3 days (A-I).</li><li class="elsevierStyleListItem" id="lsti0205">3.7In hemodynamically unstable patients, treatment should be started immediately with a broad-spectrum beta-lactam with antipseudomonal activity together with an antibiotic active against beta-lactam-resistant gram-negative bacilli, and a drug with activity against methicillin-resistant gram-positive cocci (B-III). In patients with septic shock not receiving antifungal prophylaxis, consider adding active treatment against Candida spp to the initial regimen (C-III).</li></ul><ul class="elsevierStyleList" id="lis0400"><li class="elsevierStyleListItem" id="lsti0210">3.What is the empirical treatment of choice when there is an obvious clinical source of infection?</li></ul>Search terms: “Febrile neutropenia”, “Empirical antibiotic treatment”<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0215">1.Oropharyngeal mucositis/esophagitis</li></ul><ul class="elsevierStyleList" id="lis0565"><li class="elsevierStyleListItem" id="lsti0220">1.1In patients with mild forms of mucositis, anaerobic coverage is not essential and cefepime may be used (B-III).</li><li class="elsevierStyleListItem" id="lsti0225">1.2In more severe forms, ensure anaerobe coverage with piperacillin-tazobactam, imipenem or meropenem (A-III).</li><li class="elsevierStyleListItem" id="lsti0230">1.3Consider initiating antiviral and/or antifungal treatment in patients not receiving prophylaxis who have suggestive oral lesions or symptoms compatible with esophagitis (C-III).</li></ul><ul class="elsevierStyleList" id="lis0690"><li class="elsevierStyleListItem" id="lsti0235">2.Neutropenic enterocolitis (typhlitis)</li></ul><ul class="elsevierStyleList" id="lis0570"><li class="elsevierStyleListItem" id="lsti0240">2.1Start treatment with a broad-spectrum antibiotic such as piperacillin-tazobactam, imipenem or meropenem that includes activity against gram-negatives, Gram-positives and anaerobes (A-III).</li><li class="elsevierStyleListItem" id="lsti0245">2.2Consider adding treatment for C. difficile if there is a high index of suspicion (C-III).</li></ul><ul class="elsevierStyleList" id="lis0695"><li class="elsevierStyleListItem" id="lsti0250">3.Perianal infection</li></ul><ul class="elsevierStyleList" id="lis0575"><li class="elsevierStyleListItem" id="lsti0255">3.1Performing a digital rectal examination is contraindicated in the neutropenic patient. Nevertheless a thorough examination of the perianal region is fundamental (B-III).</li><li class="elsevierStyleListItem" id="lsti0260">3.2The treatments of choice are piperacillin-tazobactam, imipenem or meropenem (A-III).</li><li class="elsevierStyleListItem" id="lsti0265">3.3If there is clinical suspicion of a perianal abscess, ensure active treatment against gram-negative bacilli, Enterococcus spp. and anaerobes (A-III).</li></ul><ul class="elsevierStyleList" id="lis0700"><li class="elsevierStyleListItem" id="lsti0270">4.Skin and soft tissue infection (SSTI)</li></ul><ul class="elsevierStyleList" id="lis0580"><li class="elsevierStyleListItem" id="lsti0275">4.1Start treatment with a broad-spectrum, antipseudomonal beta-lactam agent with activity against Gram-positive cocci, including S. aureus (A-III).</li><li class="elsevierStyleListItem" id="lsti0280">4.2Consider adding an antibiotic with activity against MRSA if there is a history of previous colonization/infection (B-III).</li><li class="elsevierStyleListItem" id="lsti0285">4.3It is recommended to obtain a sample of tissue for microbiological and histopathologic analysis from any skin lesion suspected of being a source of infection (B-III).</li><li class="elsevierStyleListItem" id="lsti0290">4.4The possibility of a serious necrotizing soft tissue infection should always be ruled out (B-III).</li><li class="elsevierStyleListItem" id="lsti0295">4.5If a serious necrotizing infection is suspected, it is recommended to use agents such as clindamycin that inhibit protein synthesis, and so inhibit toxin production (A-III).</li></ul><ul class="elsevierStyleList" id="lis0270"><li class="elsevierStyleListItem" id="lsti0300">5.Intravascular catheter-related infection</li></ul><ul class="elsevierStyleList" id="lis0585"><li class="elsevierStyleListItem" id="lsti0305">5.1Start treatment with an antipseudomonal beta-lactam together with an agent with specific activity against drug-resistant Gram-positive organisms such as vancomycin or daptomycin (A-III).</li><li class="elsevierStyleListItem" id="lsti0310">5.2Linezolid is not recommended in this situation (B-III).</li><li class="elsevierStyleListItem" id="lsti0315">5.3If the infection is considered serious and the catheter is the obvious source of infection, remove the catheter promptly before the microbiological results are known (B-III).</li></ul><ul class="elsevierStyleList" id="lis0280"><li class="elsevierStyleListItem" id="lsti0320">6.Paranasal sinuses</li></ul><ul class="elsevierStyleList" id="lis0590"><li class="elsevierStyleListItem" id="lsti0325">6.1Start treatment with a broad-spectrum antipseudomonal beta-lactam with activity against Gram-positive cocci, including S. pneumoniae and S. aureus (A-III).</li><li class="elsevierStyleListItem" id="lsti0330">6.2In risk patients (prolonged neutropenia, corticotherapy), consider adding treatment with activity against Aspergillus or Mucorales, which can give a picture of sinusitis that is initially difficult to differentiate from one with a bacterial etiology (B-III).</li></ul><ul class="elsevierStyleList" id="lis0705"><li class="elsevierStyleListItem" id="lsti0335">7.Pneumonia</li></ul><ul class="elsevierStyleList" id="lis0595"><li class="elsevierStyleListItem" id="lsti0340">7.1Start with a broad-spectrum beta-lactam with activity against S. pneumoniae and P. aeruginosa (A-III).</li><li class="elsevierStyleListItem" id="lsti0345">7.2In critically ill patients, nosocomial cases and patients previously colonized/infected with MDR gram-negative bacilli, it is advisable to combine with a second antibiotic, according to local epidemiology (B-III).</li><li class="elsevierStyleListItem" id="lsti0350">7.3If the infection is community-acquired and an atypical pneumonia is suspected, consider combining with fluoroquinolones or macrolides (B-III).</li><li class="elsevierStyleListItem" id="lsti0355">7.4In patients with MRSA colonization or epidemiological settings of high endemicity, combination with an active agent such as linezolid or vancomycin must be considered. (B-III).</li><li class="elsevierStyleListItem" id="lsti0360">7.5During flu epidemics, add empirical treatment with oseltamivir (C-III). Once samples have been collected and the results are known, continuation or withdrawal of treatment can be assessed.</li><li class="elsevierStyleListItem" id="lsti0365">7.6In risk patients with bilateral infiltrates, consider other possible etiologies (Pneumocystis jirovecii, cytomegalovirus) (B-III).</li></ul><ul class="elsevierStyleList" id="lis0710"><li class="elsevierStyleListItem" id="lsti0370">8.Urinary tract infection</li></ul><ul class="elsevierStyleList" id="lis0600"><li class="elsevierStyleListItem" id="lsti0375">8.1Start with a beta-lactam with antipseudomonal activity (A-III).</li><li class="elsevierStyleListItem" id="lsti0380">8.2Consider adding a second antibiotic in critically ill patients, those with indwelling urinary catheters, and/or a previous history of colonization/infection with multidrug-resistant bacteria, according to local epidemiology (aminoglycoside, glycopeptide) (B-III).</li></ul><ul class="elsevierStyleList" id="lis0715"><li class="elsevierStyleListItem" id="lsti0385">9.Central nervous system infections</li></ul><ul class="elsevierStyleList" id="lis0605"><li class="elsevierStyleListItem" id="lsti0390">9.1In cases of acute meningitis, antibiotic treatment should include a beta-lactam with activity against S. pneumoniae and P. aeruginosa with good penetration into cerebrospinal fluid (CSF) (cefepime or meropenem) and ampicillin to cover Listeriamonocytogenes (A-III).</li><li class="elsevierStyleListItem" id="lsti0395">9.2In risk patients with suggestive clinical forms, or patients with space-occupying lesions, consider other etiologies (Cryptococcus, Listeria, Nocardia, filamentous fungi, toxoplasmosis and Mycobacterium tuberculosis (B-III).</li></ul><ul class="elsevierStyleList" id="lis0450"><li class="elsevierStyleListItem" id="lsti0400">4.What is the duration of antibiotic treatment in patients with FN without clinically or microbiologically documented infection?</li></ul>Search terms: “Duration OR discontinuation” AND “Neutropenia” AND “Antimicrobial OR antibiotic” AND “Therapy OR treatment”.<ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0405">1.Empirical antibiotic treatment can be stopped in hematologic patients with FN who do not have clinically or microbiologically documented infection, if they have been afebrile for at least 72h, and hemodynamically stable and asymptomatic since presentation, regardless of neutrophil count or expected duration of neutropenia (A-II).</li><li class="elsevierStyleListItem" id="lsti0410">2.After treatment is discontinued, the patient should be kept under close clinical observation for at least 24–48h, so that antibiotic treatment can be restarted early if fever returns (B-II).</li><li class="elsevierStyleListItem" id="lsti0415">3.Centers that provide antibacterial prophylaxis should consider restarting it after stopping empirical antimicrobial therapy for as long as the neutropenia lasts (C-III).</li></ul><ul class="elsevierStyleList" id="lis0460"><li class="elsevierStyleListItem" id="lsti0420">5.Can patients with FN be treated with oral antibiotics? When? Which antibiotics?</li></ul>Search terms: “Febrile neutropenia”, “Oral treatment”, “Hematological malignancies”.<ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0425">1.Patients considered to be at low risk for complications can be treated with oral antibiotics provided that they are also properly followed-up in the outpatient setting (A-II).</li><li class="elsevierStyleListItem" id="lsti0430">2.Treatment must include a fluoroquinolone with antipseudomonal activity (ciprofloxacin 750mg/12h/po) and an agent fully active against Gram-positive cocci, such as amoxicillin/clavulanic acid (875mg/8h/po), or clindamycin (300–600mg/8h po), if the patient has a proven allergy to all beta-lactams or a history of hypersensitivity (A-I). Another alternative is a combination of ciprofloxacin with cefixime or cefuroxime (A-II).</li><li class="elsevierStyleListItem" id="lsti0435">3.Other oral regimens including levofloxacin or ciprofloxacin in monotherapy have been studied less (B-III).</li><li class="elsevierStyleListItem" id="lsti0440">4.Fluoroquinolones should not be used as initial empirical treatment in patients who have received them as prophylaxis. (A-III).</li><li class="elsevierStyleListItem" id="lsti0445">5.Any patient, whether in the emergency room or after admission, who presents signs and symptoms of hemodynamic instability, focality, oral intolerance, new clinical signs and symptoms, or microbiological species not susceptible to initial empirical therapy are isolated, should be admitted to hospital or continue as an inpatient in order to expand the tests for fever syndrome and modify empirical treatment according to the protocol for high-risk patients (A-III).</li></ul><ul class="elsevierStyleList" id="lis0470"><li class="elsevierStyleListItem" id="lsti0450">6.When is empirical antifungal treatment indicated in a patient with NF?</li></ul>Search terms: “Febrile neutropenia AND empirical antifungal treatment”. “Febrile neutropenia AND pre-emptive antifungal therapy OR diagnostic-driven approach”.<ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0455">1.High-risk neutropenia patients not receiving prophylaxis against filamentous fungi can be given empirical antifungal treatment if fever with no other obvious cause persists after 4–5 days of broad-spectrum antibiotics and hemodynamic instability (B-II).</li><li class="elsevierStyleListItem" id="lsti0460">2.Alternative treatment strategies, such as biomarker-guided treatment using galactomannan (GM) or beta-D-glucan (BDG), reduce the use of antifungals safely and without affecting mortality in neutropenic patients (A-I).</li><li class="elsevierStyleListItem" id="lsti0465">3.Empirical antifungal treatment is not recommended in the vast majority of hematologic patients with high-grade neutropenia who receive antifungal prophylaxis covering filamentous fungi (A-II).</li></ul>Targeted antibiotic treatment<ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0470">1.In documented cases of microbiological isolates, can antibiotic treatment be adjusted to the susceptibility of the microorganism identified, even if neutropenia persists?</li></ul>Search terms: “targeted OR de-escalation” AND “therapy OR treatment” AND “febrile neutropenia” AND “antimicrobial OR antibiotic”.<ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0475">1.In patients with documented microbiological isolates, treatment should be targeted at the isolate, taking into account its in vitro activity (including MIC), pharmacokinetic/pharmacodynamic properties, as well as the individual characteristics of the patient (A-I).</li><li class="elsevierStyleListItem" id="lsti0480">2.If the microorganism isolated is considered to be the only causative agent of the febrile episode, it is preferable to use an antimicrobial, normally a beta-lactam, with a narrower spectrum when active (B-III).</li><li class="elsevierStyleListItem" id="lsti0485">3.Beta-lactam monotherapy is appropriate for targeted treatment of most cases of gram-negative bacteremia (A-I).</li></ul><ul class="elsevierStyleList" id="lis0485"><li class="elsevierStyleListItem" id="lsti0490">2.What is the duration of antibiotic treatment in patients with FN and clinically or microbiologically documented infection?</li></ul>Search terms: “duration OR discontinuation” AND “neutropenia” AND “antimicrobial OR antibiotic” AND “therapy OR treatment”.<ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0495">1.In hematologic patients with FN and clinically documented infection, antibiotic treatment can be discontinued when the clinical signs and symptoms of infection have resolved and the patient has been afebrile for at least 72h (B-II).</li><li class="elsevierStyleListItem" id="lsti0500">2.In hematologic patients with FN and microbiologically documented infection, treatment should be maintained until clinical and microbiological cure of infection (resolution of signs and symptoms of infection and microbiological eradication) and after at least 4 days of apyrexia and a minimum of 7 days of antibiotic treatment (B-III).</li><li class="elsevierStyleListItem" id="lsti0505">3.In both situations, if neutropenia persists after treatment has been discontinued the patient should be kept under close clinical observation for at least 24–48h, so that antibiotic treatment can be restarted promptly if fever recurs (B-II).</li><li class="elsevierStyleListItem" id="lsti0510">4.Centers that give prophylactic antibacterial agents should consider renewing this regimen when empirical antibiotics have been discontinued for as long as the neutropenia continues (C-III).</li></ul><ul class="elsevierStyleList" id="lis0495"><li class="elsevierStyleListItem" id="lsti0515">3.When is removal of a central venous catheter indicated?</li></ul>Search terms: “central venous catheter removal”, “catheter-related infection”, “management of central venous catheter infection” “catheter-related bloodstream infection”.<ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0520">1.When CVC infection is documented, consider removal of the catheter wherever possible, weighing up the advantages of removal against the difficulty of obtaining new venous access (A-II).</li><li class="elsevierStyleListItem" id="lsti0525">2.It is recommended to remove the CVC when there is documented catheter-related bloodstream infection (CRBSI) and local signs at the insertion site (suppuration), along the tunnel tract (tunnel infection), or if the patient presents criteria for severe sepsis with hemodynamic instability (septic shock) (A-II).</li><li class="elsevierStyleListItem" id="lsti0530">3.To improve the prognosis of the patient, it is recommended to remove the CVC when there is documented CRBSI due to fungi (normally Candida spp), S. aureus, enterococci, gram-negative bacilli (especially P. aeruginosa) and mycobacteria (A-II). Removal is also recommended in infections with associated bacteremia caused by microorganisms that are difficult to eradicate (Bacillus spp., Micrococcus spp. and Propionibacterium spp.) (B-II).</li><li class="elsevierStyleListItem" id="lsti0535">4.In uncomplicated infections or where bacteremia is caused by microorganisms different from those mentioned above, systemic targeted antibiotic treatment can be applied without removing the CVC and antibiotic lock therapy should be considered (B-II).</li><li class="elsevierStyleListItem" id="lsti0540">5.Removal of the CVC is recommended if persistent bacteremia is detected (evidenced in positive follow-up control cultures) 48h-72h after starting targeted antibiotic treatment (A-II), if there is no other obvious clinical focus (B-II), if there is infective endocarditis or peripheral embolism (A-II) or an early relapse due to the same microorganism after completion of antibiotic treatment, or failure of conservative treatment (B-II).</li><li class="elsevierStyleListItem" id="lsti0545">6.If fever persists in a neutropenic patient with an indwelling catheter after other focalities have been ruled out, but catheter-related infection has not been confirmed, consider removal of the catheter if there is sepsis or local erythema in the pericatheter area (B-II), or if fever persists and there is no other possible cause despite the absence of sepsis or local signs of infection (C-III).</li></ul>Treatment of infections caused by multidrug-resistant Gram-negative bacilli (MDR-GNB)<ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0550">1.What is the treatment of choice for cephalosporin-resistant Enterobacteriaceae?</li></ul>Search terms: “(ESBL or extended-spectrum beta-lactamase) and treatment and outcome”; “AmpC and Enterobacter* and treatment and outcome”.<ul class="elsevierStyleList" id="lis0725"><li class="elsevierStyleListItem" id="lsti0555">1.1Targeted therapy in infections caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae</li></ul><ul class="elsevierStyleList" id="lis0640"><li class="elsevierStyleListItem" id="lsti0560">1.1.1In stable patients, the targeted therapy of choice against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is a beta-lactam/beta-lactamase inhibitor (BLBLI) combination, provided that in vitro susceptibility is shown (B-II).</li><li class="elsevierStyleListItem" id="lsti0565">1.1.2Use of carbapenems is recommended for patients with sepsis or septic shock criteria (C-I).</li><li class="elsevierStyleListItem" id="lsti0570">1.1.3Piperacillin-tazobactam and meropenem should be administered in extended infusion, since this has been shown to improve prognosis in severe infections compared with short-term infusions (A-I).</li><li class="elsevierStyleListItem" id="lsti0575">1.1.4Piperacillin-tazobactam should be avoided for treating high-inoculum infections caused by strains with MIC≥4mg/L (B-II).</li></ul><ul class="elsevierStyleList" id="lis0350"><li class="elsevierStyleListItem" id="lsti0580">1.2Targeted therapy in infections caused by AmpC-producing Enterobacteriaceae</li></ul><ul class="elsevierStyleList" id="lis0645"><li class="elsevierStyleListItem" id="lsti0585">1.2.1Cefepime and fluoroquinolones are the preferred treatment options for infections due to AmpC-producing Enterobacteriaceae susceptible to these antimicrobials (B-II).</li><li class="elsevierStyleListItem" id="lsti0590">1.2.2Piperacillin-tazobactam is a valid therapeutic option if in vitro activity is shown (B-II), but should be avoided for treating high-inoculum infections caused by AmpC- producing Enterobacteriaceae with MIC≥4mg/L (B-III).</li><li class="elsevierStyleListItem" id="lsti0595">1.2.3Use of carbapenems is recommended for patients without alternative treatment options, or with sepsis or septic shock criteria (C-I).</li><li class="elsevierStyleListItem" id="lsti0600">1.2.4We recommend that piperacillin-tazobactam, cefepime and meropenem be administered in extended infusion, since this has been shown to improve the prognosis in severe infections when compared with short-term infusions (A-I).</li></ul><ul class="elsevierStyleList" id="lis0340"><li class="elsevierStyleListItem" id="lsti0605">2.What is the treatment of choice for carbapenem-resistant Gram-negative bacilli?</li></ul><ul class="elsevierStyleList" id="lis0730"><li class="elsevierStyleListItem" id="lsti0610">2.1Targeted treatment of infections caused by carbapenem-resistant Enterobacteriaceae (CRE).</li></ul>Search terms: “(carbapenemase or KPC or OXA or NDM or VIM) and treatment and outcome”.<ul class="elsevierStyleList" id="lis0650"><li class="elsevierStyleListItem" id="lsti0615">2.1.1Severe infections caused by KPC-producing Enterobacteriaceae in neutropenic patients should be treated with a combination of at least two active drugs from the options included in the antibiogram (meropenem, colistin, tigecycline, fosfomycin and aminoglycosides) (B-II). We recommend the same approach for treating severe infections caused by other carbapenemase-producing Enterobacteriaceae (CRE) (C-III).</li><li class="elsevierStyleListItem" id="lsti0620">2.1.2For infections caused by strains with meropenem MICs<16mg/L, the combination regimen should include high-dose meropenem (2g every 8h) in extended infusion (over 3h) (B-II).</li><li class="elsevierStyleListItem" id="lsti0625">2.1.3Ceftazidime-avibactam may be an alternative for severe infections due to KPC-producing or OXA-48-producing Enterobacteriaceae (C-III). We do not have well-designed comparative studies available that enable this drug to be positioned against other treatment options (undecided). Nor are there data to support its use in combination therapy (undecided).</li><li class="elsevierStyleListItem" id="lsti0630">2.1.4In this type of infection, it is especially important to ensure control of the source of infection and to administer high-dose antibiotics with optimized dosage regimens, monitoring plasma levels whenever possible (Table 4) (B-II).</li></ul><ul class="elsevierStyleList" id="lis0510"><li class="elsevierStyleListItem" id="lsti0635">2.2Targeted therapy of extensively drug-resistant (XDR) and pandrug-resistant (PDR) non-fermenting gram-negative bacilli (NFGNB).</li></ul>Search terms: BGN-NF XDR and PDR: (Acinetobacter or Pseudomonas) and (resistant or resistance or MDR or XDR or PDR) and treatment and outcome.<ul class="elsevierStyleList" id="lis0175"><li class="elsevierStyleListItem" id="lsti0640">2.2.1In the case of XDR NFGNB infections for which there is a fully active therapeutic alternative, single-agent treatment is recommended with optimized administration (B-I), prioritizing the use (in the following order) of beta-lactams, sulbactam (in infections due to A. baumannii) and colistin, provided that in vitro susceptibility is shown (C-II). Avoid monotherapy with aminoglycosides or tigecycline for the treatment of severe infections (A-II, A-I).</li><li class="elsevierStyleListItem" id="lsti0645">2.2.2For severe infections due to XDR-NFGNB strains with borderline susceptibility to the available treatment options, optimized administration of combination therapy using two or more agents should be considered, based on the best options specified in the antibiogram (B-II).</li><li class="elsevierStyleListItem" id="lsti0650">2.2.3For XDR or PDR P. aeruginosa infections, use of ceftolozane-tazobactam may be considered (C-II) or ceftazidime-avibactam (C-I), although there is as yet limited experience of their use in this setting.</li><li class="elsevierStyleListItem" id="lsti0655">2.2.4If these options are not available or the infection is caused by pan-resistant isolates, it will be necessary to develop combination therapy regimens using two or more agents, choosing those with intermediate susceptibility, or whose MICs are closest to the susceptibility cut-off (C-III).</li><li class="elsevierStyleListItem" id="lsti0660">2.2.5It is particularly important in these infections to ensure control of the source of infection and to administer high-dose antibiotics with optimized administration regimens, monitoring plasma levels whenever possible (B-II).</li></ul><ul class="elsevierStyleList" id="lis0515"><li class="elsevierStyleListItem" id="lsti0665">3.Targeted treatment of Stenotrophomonas maltophilia infections.</li></ul>Search terms: “Stenotrophomonas and treatment”.<ul class="elsevierStyleList" id="lis0660"><li class="elsevierStyleListItem" id="lsti0670">3.1The treatment of choice for infections due to S. maltophilia is co-trimoxazole (trimethoprim 15mg/kg/day in 3–4 divided doses) (C-II).</li><li class="elsevierStyleListItem" id="lsti0675">3.2In patients with infections with co-trimoxazole-resistant strains, or those who cannot take co-trimoxazole (because of hypersensitivity, for example), the recommended treatment is minocycline (C-II) or fluoroquinolones (C-II) if they are active. There is more limited experience of the use of ceftazidime, tigecycline and colistin in monotherapy (C-III). In the case of patients with serious or refractory infections who require second-line therapy, consider combining two drugs with in vitro activity categorized as susceptible.</li></ul>Adjuvant measures and prevention<ul class="elsevierStyleList" id="lis0185"><li class="elsevierStyleListItem" id="lsti0680">1.Is the use of colony-stimulating factors indicated for treatment of FN? When?</li></ul>Search terms: “febrile neutropenia”, “colony stimulating factor”, “treatment”.<ul class="elsevierStyleList" id="lis0665"><li class="elsevierStyleListItem" id="lsti0685">1.Colony-stimulating factors (CSF) are not routinely recommended in the treatment of FN (B-II).</li><li class="elsevierStyleListItem" id="lsti0690">2.They can be considered for therapeutic use in patients with increased-risk for infection-related complications or predictive factors of poor prognosis (B-II).</li></ul><ul class="elsevierStyleList" id="lis0520"><li class="elsevierStyleListItem" id="lsti0695">2.When would granulocyte transfusion be indicated?</li></ul>Search terms: “febrile neutropenia”, “granulocyte transfusion”.<ul class="elsevierStyleList" id="lis0195"><li class="elsevierStyleListItem" id="lsti0700">1.There is insufficient evidence of the efficacy of granulocyte transfusion in patients with FN and documented infection (C-III).</li><li class="elsevierStyleListItem" id="lsti0705">2.Granulocyte transfusions should be administered only in the context of prospective clinical trials (B-III).</li></ul><ul class="elsevierStyleList" id="lis0530"><li class="elsevierStyleListItem" id="lsti0710">3.Is antibacterial prophylaxis indicated? Which drugs?</li></ul>Search terms: “febrile neutropenia”, “antibacterial prophylaxis”.<ul class="elsevierStyleList" id="lis0200"><li class="elsevierStyleListItem" id="lsti0715">1.Antibacterial prophylaxis is not recommended in low-risk patients (A-I).</li><li class="elsevierStyleListItem" id="lsti0720">2.In high-risk patients (ANC<500/mm3>7 days), use of antibacterial prophylaxis should be evaluated on an individual basis in accordance with the characteristics of the patient and local hospital epidemiology, owing to the lack of benefit for mortality and the increasing levels of resistance in gram-negative bacteria (B-I). If prophylaxis is used, epidemiological surveillance for MDRO detection should be implemented.</li></ul><ul class="elsevierStyleList" id="lis0540"><li class="elsevierStyleListItem" id="lsti0725">4.Is prophylaxis with colony stimulating factors indicated? When?</li></ul>Search terms: “febrile neutropenia”, “colony stimulating factor”, “prophylaxis”<ul class="elsevierStyleList" id="lis0205"><li class="elsevierStyleListItem" id="lsti0730">1.The decision to use colony-stimulating factor prophylaxis for the prevention of FN should be based on the relative myelotoxicity of the chemotherapy regimen and the presence of potential risk factors, which should be evaluated before each cycle of chemotherapy is administered.</li><li class="elsevierStyleListItem" id="lsti0735">2.In situations where chemotherapy dose intensity or dose density strategies confer a survival benefit, prophylaxis with G-CSF should be used as supportive treatment (A-I).</li><li class="elsevierStyleListItem" id="lsti0740">3.Primary prophylaxis is recommended from the first chemotherapy cycle for patients whose overall risk of FN is ≥ 20%, based on patient-related, disease-related and regimen-related risk factors (A-I).</li><li class="elsevierStyleListItem" id="lsti0745">4.When the overall risk of FN is 10%–20%, attention should be focused on additional risk factors (such as comorbidities or advanced age), which increase the risk of FN and support an indication of prophylaxis with G-CSF (A-I).</li><li class="elsevierStyleListItem" id="lsti0750">5.Prophylaxis with G-CSF is not recommended if chemotherapy has an FN risk of <10% (A-I).</li><li class="elsevierStyleListItem" id="lsti0755">6.Secondary prophylaxis is recommended for patients who experienced neutropenic complications in a previous cycle of chemotherapy and in whom a dose reduction or delay in treatment could compromise progression-free or overall survival, or treatment outcome (A-I).</li><li class="elsevierStyleListItem" id="lsti0760">7.Prophylaxis can be given with any of the following factors (filgrastim, lenograstim and pegfilgrastim) or any of their available biosimilars (A-I), preferably subcutaneously.</li></ul>Conflicts of interestCarlota Gudiol has served as speaker at scientific meetings sponsored by Pfizer, MSD, Astellas and Gilead. Rafael de la Cámara has participated as speaker at scientific meetings sponsored by MSD, GSK, Novartis, Astellas, Pfizer and Gilead; and in consultancy and advisory activities for Novartis, MSD, Janssen, Clinigen and Astellas. Manuel Lizasoain has participated as speaker at scientific meetings sponsored by Pfizer, MSD and Gilead. Jordi Carratalà has participated as speaker at scientific meetings sponsored by Pfizer, MSD, Gilead and Angelini. Rafael Cantón has participated as speaker at scientific meetings sponsored by Angelini, ERN Laboratorios, MSD, Pfizer and Zambon and has received funding for research projects from AstraZeneca and MSD. Manuela Aguilar-Guisado has participated as speaker at scientific meetings sponsored by Pfizer and MSD. Manuela Aguilar-Guisado has participated as speaker at scientific meetings sponsored by Pfizer and MSD. José Molina Gil-Bermejo has received lecturing fees in activities financed by Merck Sharp & Dohme, and has received grants to attend conferences organized by Astellas Pharma. Carlos Solano has participated as speaker at scientific meetings sponsored by Pfizer, MSD, Astellas and Gilead He has received grants for clinical and preclinical research from Pfizer and Astellas. Carolina García-Vidal has received fees for speaking at events sponsored by Gilead Science, Merck Sharp and Dohme, Pfizer, Janssen and Novartis, and has received a subsidy from Gilead Science. María Lourdes Vázquez López has participated as speaker at scientific meetings sponsored by Pfizer, MSD, Gilead, Astellas, Amgen. José Ramón Azanza has participated as speaker at scientific meetings sponsored by Pfizer, MSD, Gilead, Janssen, AstraZeneca, Roche. José Ramón Azanza has participated as speaker at scientific meetings sponsored by Pfizer, MSD, Gilead, Janssen, AstraZeneca, Roche Francisco Javier Candel has participated as speaker scientific meetings sponsored by Pfizer, MSD, Gilead, Angelini, Astellas, and ERN. Isabel Ruiz-Camps has participated as speaker at scientific meetings sponsored by Astellas, Celgene, Gilead, MSD, Pfizer and in scientific consultancy for Astellas, Gilead, and Pfizer. María Suárez-Lledó has participated as speaker at scientific meetings and has collaborated in scientific studies sponsored by Pfizer and MSD. Isidro Jarque has participated as speaker at scientific meetings sponsored by Gilead, MSD, and Pfizer. Isabel Sánchez-Ortega has no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres1323648" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1220574" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1323647" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1220575" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Executive summary" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Introduction: justification and objectives" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Methodology" ] ] ] 5 => array:3 [ "identificador" => "sec0020" "titulo" => "Recommendations" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Classification of febrile neutropenia risk" ] ] ] 6 => array:2 [ "identificador" => "sec0055" "titulo" => "Conflicts of interest" ] 7 => array:2 [ "identificador" => "xack456720" "titulo" => "Acknowledgements" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1220574" "palabras" => array:6 [ 0 => "Febrile neutropenia" 1 => "Neutropenia" 2 => "Hematological disease" 3 => "Empirical antibiotic therapy" 4 => "Targeted antibiotic therapy" 5 => "Antibiotic resistance" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1220575" "palabras" => array:6 [ 0 => "Fiebre neutropénica" 1 => "Neutropenia" 2 => "Enfermedad hematológica" 3 => "Tratamiento antibiótico empírico" 4 => "Tratamiento antibiótico dirigido" 5 => "Resistencia antibiótica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Febrile neutropenia is a very common complication in patients with hematological malignancies receiving chemotherapy, and is associated with high morbidity and mortality. 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Para la elaboración de este documento, las 2 sociedades implicadas (la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica y la Sociedad Española de Hematología y Hemoterapia) designaron expertos en este tema, quienes han realizado recomendaciones basadas en la evidencia, en respuesta a cuestiones clínicas habituales. Este documento está enfocado básicamente a la infección bacteriana. 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Consensus statement

Executive summary of the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Network for Research in Infectious Diseases (REIPI) and the Spanish Society of Haematology and Haemotherapy (SEHH) on the management of febrile neutropenia in patients with hematological malignancies

Resumen ejecutivo del documento de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), la Red Española de Investigación en Patología Infecciosa (REIPI) y la Sociedad Española de Hematología y Hemoterapia (SEHH) sobre el manejo de la neutropenia febril en el paciente hematológico

Carlota Gudiola,

Corresponding author

carlotagudiol@gmail.com

Corresponding author.

, Manuela Aguilar-Guisadob, José Ramón Azanzac, Francisco Javier Candeld, Rafael Cantóne, Jordi Carratalàa, Carolina Garcia-Vidalf, Isidro Jarqueg, Manuel Lizasoainh, José Molina Gil-Bermejob, Isabel Ruiz-Campsi, Isabel Sánchez-Ortegaj, Carlos Solanok, María Suárez-Lledól, Lourdes Vázquezm, Rafael de la Cámaran

a Servicio de Enfermedades Infecciosas, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, IDIBELL, Universitat de Barcelona, Spain

b Unidad Clínica de Enfermedades Infecciosas, Microbiología Clínica y Medicina Preventiva, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain

c Servicio de Farmacología, Universidad Clínica de Navarra, Pamplona, Spain

d Servicio de Microbiología Clínica, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain

e Servicio de Microbiología, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

f Servicio de Enfermedades Infecciosas, Hospital Clínic, Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain

g Servicio de Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, & CIBERONC, Instituto Carlos III, Valencia, Spain

h Unidad de Enfermedades Infecciosas, Hospital Universitario “12 de Octubre”, Instituto de Investigación Hospital “12 de Octubre” (i+12), Universidad Complutense, Madrid, Spain

i Servicio de Enfermedades Infecciosas, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain

j Servicio de Hematología, Institut Català d’Oncologia (ICO), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain

k Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain

l Servicio de Hematología, Hospital Clínic, Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain

m Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain

n Servicio de Onco-hematología, Hospital de la Princesa, Madrid, Spain

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with a tendency towards outpatient care and new types of immunosuppressive treatment&#46; In the era of multidrug resistance&#44; the objective of these new guidelines is to update the recommendations for the initial management of hematologic patients who develop FN&#46; This document focuses basically on bacterial infection&#46; Other aspects associated with opportunistic infections&#44; such as fungal infections or those due to other microorganisms&#44; especially in hematopoietic stem cell transplantation &#40;HSCT&#41;&#44; are also touched upon&#46; Only infections in adult patients will be discussed&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Methodology</span><p id="par0015" class="elsevierStylePara elsevierViewall">The two participating Societies&#44; the Spanish Society of Infectious Diseases and Clinical Microbiology &#40;<span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Enfermedades Infecciosas y Microbiolog&#237;a Cl&#237;nica</span>&#41; and the Spanish Association of Hematology and Hemotherapy &#40;<span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Hematolog&#237;a y Hemoterapia&#41;</span> nominated two coordinators&#44; who selected the rest of the members of the panel of experts&#46; The scientific committees of both societies approved the proposal&#46; The questions to be considered were approved by both scientific societies involved and then distributed among the various members of the panel of experts&#46; The present Document was written following the SEIMC guidelines for consensus documents &#40;<a href="http://www.seimc.org/">www&#46;seimc&#46;org</a>&#41;&#44; as well as the recommendations of the AGREE collaboration &#40;<a href="http://www.agreecollaboration.org/">www&#46;agreecollaboration&#46;org</a>&#41; for evaluating the methodological quality of clinical practice guidelines&#46; The PubMed search engine &#40;<a href="http://www.ncbi.nlm.nih.gov/pubmed">http&#58;&#47;&#47;www&#46;ncbi&#46;nlm&#46;nih&#46;gov&#47;pubmed</a>&#41; was used to perform a literature search of the MEDLINE database for relevant scientific publications&#46; The key words used for each question are also shown&#46; Only complete articles published in English or Spanish were selected&#46; No specific period of inclusion was defined&#44; although authors were instructed to gather the most recent evidence from the literature to form the basis of their answers&#46; The coordinators wrote the first draft&#44; which was submitted for review by the panel of experts and by SEIMC members after being published on the web page of that society&#46; The complete text has been approved by all authors&#46; The criteria used to evaluate the strength of the recommendation and the quality of the evidence are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; Possible conflicts of interest associated with all members of the panel of experts are listed at the end of the document&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Recommendations</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Classification of febrile neutropenia risk</span><p id="par0020" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What tools are available to determine risk in a patient with FN&#63; When should they be applied and in what contexts&#63;</span></p></li></ul></p><p id="par0835" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Risk factors&#8221; &#8220;Risk stratification&#8221;&#44; &#8220;Febrile neutropenia&#8221;&#44; &#8220;Cancer patients&#8221;&#46;<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">1&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Patients presenting with FN should undergo risk assessment for complications&#44; preferably in the first hour of contact with the healthcare system &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">2&#46;</span><p id="par0035" class="elsevierStylePara elsevierViewall">The MASCC &#40;Multinational Association for Supportive Care in Cancer&#41; risk index is a prognostic scale that can be used to assess the risk of complications in patients with FN &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">3&#46;</span><p id="par0040" class="elsevierStylePara elsevierViewall">A patient with a MASCC risk index score of &#60;21 is defined as high risk &#40;<span class="elsevierStyleBold">B-II</span>&#41; and should be hospitalized and receive intravenous empirical antibiotic treatment &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">4&#46;</span><p id="par0045" class="elsevierStylePara elsevierViewall">A patient with a MASCC risk index score of &#8805;21 is defined as low risk &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46; Some of these patients may be candidates for a regimen of oral antibiotics and can be managed as outpatients&#44; provided that they are not receiving induction chemotherapy for acute myeloid leukemia or in the pre-engraftment phase of allogeneic hematopoietic stem cell transplantation &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">5&#46;</span><p id="par0050" class="elsevierStylePara elsevierViewall">Clinical criteria can also be used to determine risk in patients with FN&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">6&#46;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Patients with an absolute neutrophil count &#40;ANC&#41; of &#8804;100&#47;mm<span class="elsevierStyleSup">3</span>&#44; expected neutropenia duration of &#62;7 days&#44; and&#47;or significant comorbidities &#40;hypotension&#44; pneumonia&#44; gastrointestinal symptoms&#44; neurological symptoms&#41; are considered high-risk&#46; These patients should be admitted to hospital and receive intravenous empirical therapy &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">7&#46;</span><p id="par0060" class="elsevierStylePara elsevierViewall">Patients with ANC<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>500&#47;mm<span class="elsevierStyleSup">3</span>&#44; expected neutropenia duration &#8804;7 days and having no or few comorbidities or significant evidence of renal or hepatic impairment are considered as at low-risk&#46; These patients may be candidates for oral empirical therapy and outpatient care &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li></ul></p><p id="par1080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Diagnostic management</span><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">1&#46;</span><p id="par0070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What microbiology diagnostic tests should be carried out in patients with FN&#63;</span></p></li></ul></p><p id="par0840" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia&#8221; AND &#8220;Etiology&#8221;&#46; &#8220;Febrile neutropenia&#8221; AND &#8220;Microbiological diagnosis&#8221;&#46;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">1&#46;</span><p id="par0075" class="elsevierStylePara elsevierViewall">It is recommended that at least two&#44; and preferably three&#44; sets of blood cultures be collected from any patient with FN&#44; whether they are in-patients or seen in the emergency room&#44; high-risk or low-risk&#46; Blood should be drawn through all available catheterized venous access in the patient&#44; paying special attention to long-term devices&#44; as well as samples taken by venipuncture from peripheral vein sites &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">2&#46;</span><p id="par0080" class="elsevierStylePara elsevierViewall">If an infection of extravascular origin is suspected&#44; it is recommended to send representative samples from the possible focus of infection&#46; Rapid microbiological tests can be performed on these samples &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">3&#46;</span><p id="par0085" class="elsevierStylePara elsevierViewall">For patients being monitored in an outpatient setting with symptoms or radiological signs of respiratory infection&#44; rapid urine antigen tests for the detection of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> and <span class="elsevierStyleItalic">Legionella pneumophila</span> antigens can be used &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">4&#46;</span><p id="par0090" class="elsevierStylePara elsevierViewall">During annual flu epidemics&#44; molecular methods should be used for early diagnosis&#46; In the case of flu&#44; rapid techniques on nasopharyngeal swabs are preferred &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">5&#46;</span><p id="par0095" class="elsevierStylePara elsevierViewall">If the patient presents diarrhea&#44; it is advisable to request a <span class="elsevierStyleItalic">Clostridium difficile</span> toxin stool test&#44; on which rapid immunochromatographic assays or PCR can be performed &#40;<span class="elsevierStyleBold">C-III&#41;</span>&#46;</p></li></ul></p><p id="par1105" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0360"><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">2&#46;</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">When and how should pre-emptive screening for fungal infection be carried out&#63;</span></p></li></ul></p><p id="par0848" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia AND fungal infection diagnosis&#8221;&#44; &#8220;Febrile neutropenia AND investigation for invasive fungal infection&#8221;&#46;<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">1&#46;</span><p id="par0105" class="elsevierStylePara elsevierViewall">In patients with FN&#44; pre-emptive screening for fungal infection should be considered when fever persists for 4&#8211;7 days after having started broad-spectrum antibiotics&#44; expected duration of neutropenia is &#62;7 days&#44; and in clinically compatible cases &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">2&#46;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Blood cultures are the microbiological test of choice for the diagnosis of yeast infections &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">3&#46;</span><p id="par0115" class="elsevierStylePara elsevierViewall">In clinically stable patients who are not receiving antifungal prophylaxis against filamentous fungi&#44; it is recommended to screen for <span class="elsevierStyleItalic">Aspergillus</span> infection by carrying out serial testing for circulating galactomannan &#40;GM&#41; in serum twice a week&#46; In the event of a positive GM test&#44; a CT scan of the lungs is recommended &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">4&#46;</span><p id="par0120" class="elsevierStylePara elsevierViewall">In patients receiving antifungal prophylaxis against filamentous fungi&#44; a CT scan of the thorax is recommended if fever persists &#40;&#62;7 days after initiating broad-spectrum antibiotics&#44; with no other identifiable cause of fever&#41;&#46; In the event of findings suggestive of invasive fungal infection&#44; bronchoscopy is recommended for galactomannan testing&#44; and pan-fungal PCR on the bronchoalveolar lavage &#40;BAL&#41; fluid&#46; If results are negative&#44; lesion puncture is recommended &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par1110" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0370"><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">3&#46;</span><p id="par0125" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Are biomarkers useful for infection diagnosis in FN and for determining length of antibiotic treatment&#63;</span></p></li></ul></p><p id="par0853" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Biomarkers and infection diagnosis&#8221;&#44; &#8220;Febrile neutropenia&#8221;&#44; &#8220;Bacteremia and biomarkers&#8221;&#44; &#8220;Length of antibiotics in febrile neutropenia&#8221;&#46;<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">1&#46;</span><p id="par0130" class="elsevierStylePara elsevierViewall">Biomarkers are not recommended as a guide to antibiotic use in FN&#44; due to the lack of studies demonstrating the safety and usefulness of basing clinical decisions on their results &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">2&#46;</span><p id="par0135" class="elsevierStylePara elsevierViewall">It has been demonstrated that neutropenic patients with bacteremia present significantly higher procalcitonin &#40;PCT&#41;&#44; C-reactive protein&#44; IL-6&#44; and presepsin levels than those without bacteremia&#46; &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46; The possible impact of this information on the future management of FN is yet to be clarified&#46;</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">3&#46;</span><p id="par0140" class="elsevierStylePara elsevierViewall">Biomarkers are not useful for determining length of antibiotic treatment &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">4&#46;</span><p id="par0145" class="elsevierStylePara elsevierViewall">C-reactive protein levels&#44; especially those that are elevated &#40;&#62;20&#8211;30<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#44; are correlated with greater mortality&#46; This relationship has not been demonstrated with the other biomarkers &#40;PCT&#44; presepsin&#44; IL-6&#41; &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Empirical antibiotic treatment</span><ul class="elsevierStyleList" id="lis0380"><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">1&#46;</span><p id="par0155" class="elsevierStylePara elsevierViewall">What empirical treatment strategies are there for patients with NF&#63;</p></li></ul></p><p id="par0855" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia&#8221;&#44; &#8220;Empirical antibiotic treatment&#8221;&#46;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">1&#46;</span><p id="par0160" class="elsevierStylePara elsevierViewall">Any febrile patient with an ANC of &#60;500&#47;mm<span class="elsevierStyleSup">3</span> and those with ANC of 500&#8211;1000&#47;mm<span class="elsevierStyleSup">3</span> and predicted to decline imminently should receive early empirical antibiotic treatment &#40;<span class="elsevierStyleBold">A-II</span>&#41; with an appropriate broad-spectrum antibiotic &#40;<span class="elsevierStyleBold">A-I</span>&#41; and a bactericidal agent&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">2&#46;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Surveillance programs &#40;antimicrobial stewardship&#41; established in the center for the appropriate use of antibiotic treatment should be taken into consideration &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">3&#46;</span><p id="par0170" class="elsevierStylePara elsevierViewall">A strategy of <span class="elsevierStyleItalic">dose-escalation</span> can be applied in patients with an uncomplicated clinical presentation&#44; no previous colonization&#47;infection with multidrug-resistant bacteria&#44; and in centers where there is a low incidence of drug-resistant microorganisms &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46; In other situations&#44; a <span class="elsevierStyleItalic">de-escalation</span> strategy should be applied &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par1115" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0390"><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">2&#46;</span><p id="par0175" class="elsevierStylePara elsevierViewall">What is the empirical antibiotic treatment of choice when there is no obvious clinical focus of infection&#63;</p></li></ul></p><p id="par0833" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia&#8221;&#44; &#8220;Empirical antibiotic treatment&#8221;&#44; &#8220;Fever unknown origin&#8221;&#46;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">1&#46;</span><p id="par0180" class="elsevierStylePara elsevierViewall">It is recommended to use a beta-lactam antibiotic with antipseudomonal activity as monotherapy&#44; or in combination with another antibiotic&#44; depending on the risk of infection due to multidrug-resistant microorganisms and clinical presentation &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">2&#46;</span><p id="par0185" class="elsevierStylePara elsevierViewall">For the escalation strategy&#58;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">2&#46;1</span><p id="par0190" class="elsevierStylePara elsevierViewall">Use of piperacillin-tazobactam &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#44; or cefepime &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#44; or ceftazidime &#40;<span class="elsevierStyleBold">B-II</span>&#41; is recommended&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">2&#46;2</span><p id="par0195" class="elsevierStylePara elsevierViewall">In settings with a high prevalence of ESBs&#44; cephalosporins and piperacillin-tazobactam in monotherapy are not recommended &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par0955" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0720"><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">3&#46;</span><p id="par0200" class="elsevierStylePara elsevierViewall">For the de-escalation strategy&#58;</p></li></ul></p><p id="par0960" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0560"><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">3&#46;1</span><p id="par0205" class="elsevierStylePara elsevierViewall">Imipenem or meropenem in monotherapy are recommended for use &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#44; or a combination of antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone &#40;if it has not been used as prophylaxis&#41; &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46; Carbapenems should be reserved for critically ill patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">3&#46;2</span><p id="par0210" class="elsevierStylePara elsevierViewall">The aminoglycoside should be given in a single daily dose &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46; The need to continue the aminoglycoside should be reassessed at 48&#8211;72<span class="elsevierStyleHsp" style=""></span>h&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">3&#46;3</span><p id="par0215" class="elsevierStylePara elsevierViewall">If there is risk of infection due to multidrug-resistant nonfermenting gram-negative bacilli&#44; it is recommended to combine the beta-lactam with the lowest antimicrobial resistance rate in the center<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>amikacin or colistin &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">3&#46;4</span><p id="par0220" class="elsevierStylePara elsevierViewall">The need for empirical treatments with other combinations can be considered&#44; according to local epidemiology or in outbreak settings &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">3&#46;5</span><p id="par0225" class="elsevierStylePara elsevierViewall">The use of antibiotics with activity against gram-positive cocci resistant to beta-lactams &#40;vancomycin&#44; daptomycin&#44; linezolid&#41; would be indicated only in cases of hemodynamic instability and&#47;or risk of methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span> &#40;MRSA&#41; infection &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">3&#46;6</span><p id="par0230" class="elsevierStylePara elsevierViewall">The empirical addition of vancomycin to initial antibiotic therapy is not recommended if fever persists at 3 days &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">3&#46;7</span><p id="par0235" class="elsevierStylePara elsevierViewall">In hemodynamically unstable patients&#44; treatment should be started immediately with a broad-spectrum beta-lactam with antipseudomonal activity together with an antibiotic active against beta-lactam-resistant gram-negative bacilli&#44; and a drug with activity against methicillin-resistant gram-positive cocci &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46; In patients with septic shock not receiving antifungal prophylaxis&#44; consider adding active treatment against <span class="elsevierStyleItalic">Candida</span> spp to the initial regimen &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1120" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0400"><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">3&#46;</span><p id="par0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What is the empirical treatment of choice when there is an obvious clinical source of infection&#63;</span></p></li></ul></p><p id="par0865" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia&#8221;&#44; &#8220;Empirical antibiotic treatment&#8221;<ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">1&#46;</span><p id="par0245" class="elsevierStylePara elsevierViewall">Oropharyngeal mucositis&#47;esophagitis</p></li></ul></p><p id="par1210" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0565"><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">1&#46;1</span><p id="par0250" class="elsevierStylePara elsevierViewall">In patients with mild forms of mucositis&#44; anaerobic coverage is not essential and cefepime may be used &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">1&#46;2</span><p id="par0255" class="elsevierStylePara elsevierViewall">In more severe forms&#44; ensure anaerobe coverage with piperacillin-tazobactam&#44; imipenem or meropenem &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">1&#46;3</span><p id="par0260" class="elsevierStylePara elsevierViewall">Consider initiating antiviral and&#47;or antifungal treatment in patients not receiving prophylaxis who have suggestive oral lesions or symptoms compatible with esophagitis &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1215" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0690"><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">2&#46;</span><p id="par0265" class="elsevierStylePara elsevierViewall">Neutropenic enterocolitis &#40;typhlitis&#41;</p></li></ul></p><p id="par0975" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0570"><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">2&#46;1</span><p id="par0270" class="elsevierStylePara elsevierViewall">Start treatment with a broad-spectrum antibiotic such as piperacillin-tazobactam&#44; imipenem or meropenem that includes activity against gram-negatives&#44; Gram-positives and anaerobes &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">2&#46;2</span><p id="par0275" class="elsevierStylePara elsevierViewall">Consider adding treatment for <span class="elsevierStyleItalic">C&#46; difficile</span> if there is a high index of suspicion &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par0980" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0695"><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">3&#46;</span><p id="par0280" class="elsevierStylePara elsevierViewall">Perianal infection</p></li></ul></p><p id="par1220" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0575"><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">3&#46;1</span><p id="par0285" class="elsevierStylePara elsevierViewall">Performing a digital rectal examination is contraindicated in the neutropenic patient&#46; Nevertheless a thorough examination of the perianal region is fundamental &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel">3&#46;2</span><p id="par0290" class="elsevierStylePara elsevierViewall">The treatments of choice are piperacillin-tazobactam&#44; imipenem or meropenem &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel">3&#46;3</span><p id="par0295" class="elsevierStylePara elsevierViewall">If there is clinical suspicion of a perianal abscess&#44; ensure active treatment against gram-negative bacilli&#44; <span class="elsevierStyleItalic">Enterococcus</span> spp&#46; and anaerobes &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li></ul></p><p id="par0300" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0700"><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel">4&#46;</span><p id="par0990" class="elsevierStylePara elsevierViewall">Skin and soft tissue infection &#40;SSTI&#41;</p></li></ul></p><p id="par1135" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0580"><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel">4&#46;1</span><p id="par0305" class="elsevierStylePara elsevierViewall">Start treatment with a broad-spectrum&#44; antipseudomonal beta-lactam agent with activity against Gram-positive cocci&#44; including <span class="elsevierStyleItalic">S&#46; aureus</span> &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel">4&#46;2</span><p id="par0310" class="elsevierStylePara elsevierViewall">Consider adding an antibiotic with activity against MRSA if there is a history of previous colonization&#47;infection &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0285"><span class="elsevierStyleLabel">4&#46;3</span><p id="par0315" class="elsevierStylePara elsevierViewall">It is recommended to obtain a sample of tissue for microbiological and histopathologic analysis from any skin lesion suspected of being a source of infection &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0290"><span class="elsevierStyleLabel">4&#46;4</span><p id="par0320" class="elsevierStylePara elsevierViewall">The possibility of a serious necrotizing soft tissue infection should always be ruled out &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0295"><span class="elsevierStyleLabel">4&#46;5</span><p id="par0325" class="elsevierStylePara elsevierViewall">If a serious necrotizing infection is suspected&#44; it is recommended to use agents such as clindamycin that inhibit protein synthesis&#44; and so inhibit toxin production &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li></ul></p><p id="par0330" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0270"><li class="elsevierStyleListItem" id="lsti0300"><span class="elsevierStyleLabel">5&#46;</span><p id="par1000" class="elsevierStylePara elsevierViewall">Intravascular catheter-related infection</p></li></ul></p><p id="par1140" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0585"><li class="elsevierStyleListItem" id="lsti0305"><span class="elsevierStyleLabel">5&#46;1</span><p id="par0335" class="elsevierStylePara elsevierViewall">Start treatment with an antipseudomonal beta-lactam together with an agent with specific activity against drug-resistant Gram-positive organisms such as vancomycin or daptomycin &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0310"><span class="elsevierStyleLabel">5&#46;2</span><p id="par0340" class="elsevierStylePara elsevierViewall">Linezolid is not recommended in this situation &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0315"><span class="elsevierStyleLabel">5&#46;3</span><p id="par0345" class="elsevierStylePara elsevierViewall">If the infection is considered serious and the catheter is the obvious source of infection&#44; remove the catheter promptly before the microbiological results are known &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li></ul></p><p id="par0350" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0280"><li class="elsevierStyleListItem" id="lsti0320"><span class="elsevierStyleLabel">6&#46;</span><p id="par1010" class="elsevierStylePara elsevierViewall">Paranasal sinuses</p></li></ul></p><p id="par1145" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0590"><li class="elsevierStyleListItem" id="lsti0325"><span class="elsevierStyleLabel">6&#46;1</span><p id="par0355" class="elsevierStylePara elsevierViewall">Start treatment with a broad-spectrum antipseudomonal beta-lactam with activity against Gram-positive cocci&#44; including <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">S&#46; aureus</span> &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0330"><span class="elsevierStyleLabel">6&#46;2</span><p id="par0360" class="elsevierStylePara elsevierViewall">In risk patients &#40;prolonged neutropenia&#44; corticotherapy&#41;&#44; consider adding treatment with activity against <span class="elsevierStyleItalic">Aspergillus</span> or Mucorales&#44; which can give a picture of sinusitis that is initially difficult to differentiate from one with a bacterial etiology &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li></ul></p><p id="par0365" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0705"><li class="elsevierStyleListItem" id="lsti0335"><span class="elsevierStyleLabel">7&#46;</span><p id="par1020" class="elsevierStylePara elsevierViewall">Pneumonia</p></li></ul></p><p id="par1150" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0595"><li class="elsevierStyleListItem" id="lsti0340"><span class="elsevierStyleLabel">7&#46;1</span><p id="par0370" class="elsevierStylePara elsevierViewall">Start with a broad-spectrum beta-lactam with activity against <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">P&#46; aeruginosa</span> &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0345"><span class="elsevierStyleLabel">7&#46;2</span><p id="par0375" class="elsevierStylePara elsevierViewall">In critically ill patients&#44; nosocomial cases and patients previously colonized&#47;infected with MDR gram-negative bacilli&#44; it is advisable to combine with a second antibiotic&#44; according to local epidemiology &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0350"><span class="elsevierStyleLabel">7&#46;3</span><p id="par0380" class="elsevierStylePara elsevierViewall">If the infection is community-acquired and an atypical pneumonia is suspected&#44; consider combining with fluoroquinolones or macrolides &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0355"><span class="elsevierStyleLabel">7&#46;4</span><p id="par0385" class="elsevierStylePara elsevierViewall">In patients with MRSA colonization or epidemiological settings of high endemicity&#44; combination with an active agent such as linezolid or vancomycin must be considered&#46; &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0360"><span class="elsevierStyleLabel">7&#46;5</span><p id="par0390" class="elsevierStylePara elsevierViewall">During flu epidemics&#44; add empirical treatment with oseltamivir &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46; Once samples have been collected and the results are known&#44; continuation or withdrawal of treatment can be assessed&#46;</p></li><li class="elsevierStyleListItem" id="lsti0365"><span class="elsevierStyleLabel">7&#46;6</span><p id="par0395" class="elsevierStylePara elsevierViewall">In risk patients with bilateral infiltrates&#44; consider other possible etiologies &#40;<span class="elsevierStyleItalic">Pneumocystis jirovecii</span>&#44; cytomegalovirus&#41; &#40;<span class="elsevierStyleBold">B-III&#41;</span>&#46;</p></li></ul></p><p id="par0400" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0710"><li class="elsevierStyleListItem" id="lsti0370"><span class="elsevierStyleLabel">8&#46;</span><p id="par1030" class="elsevierStylePara elsevierViewall">Urinary tract infection</p></li></ul></p><p id="par1035" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0600"><li class="elsevierStyleListItem" id="lsti0375"><span class="elsevierStyleLabel">8&#46;1</span><p id="par0405" class="elsevierStylePara elsevierViewall">Start with a beta-lactam with antipseudomonal activity &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0380"><span class="elsevierStyleLabel">8&#46;2</span><p id="par0410" class="elsevierStylePara elsevierViewall">Consider adding a second antibiotic in critically ill patients&#44; those with indwelling urinary catheters&#44; and&#47;or a previous history of colonization&#47;infection with multidrug-resistant bacteria&#44; according to local epidemiology &#40;aminoglycoside&#44; glycopeptide&#41; &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li></ul></p><p id="par0415" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0715"><li class="elsevierStyleListItem" id="lsti0385"><span class="elsevierStyleLabel">9&#46;</span><p id="par1040" class="elsevierStylePara elsevierViewall">Central nervous system infections</p></li></ul></p><p id="par1225" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0605"><li class="elsevierStyleListItem" id="lsti0390"><span class="elsevierStyleLabel">9&#46;1</span><p id="par0420" class="elsevierStylePara elsevierViewall">In cases of acute meningitis&#44; antibiotic treatment should include a beta-lactam with activity against <span class="elsevierStyleItalic">S&#46; pneumoniae</span> and <span class="elsevierStyleItalic">P&#46; aeruginosa</span> with good penetration into cerebrospinal fluid &#40;CSF&#41; &#40;cefepime or meropenem&#41; and ampicillin to cover <span class="elsevierStyleItalic">Listeria</span><span class="elsevierStyleItalic">monocytogenes</span> &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0395"><span class="elsevierStyleLabel">9&#46;2</span><p id="par0425" class="elsevierStylePara elsevierViewall">In risk patients with suggestive clinical forms&#44; or patients with space-occupying lesions&#44; consider other etiologies &#40;<span class="elsevierStyleItalic">Cryptococcus</span>&#44; <span class="elsevierStyleItalic">Listeria&#44; Nocardia&#44;</span> filamentous fungi&#44; toxoplasmosis and <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li></ul></p><p id="par1050" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0450"><li class="elsevierStyleListItem" id="lsti0400"><span class="elsevierStyleLabel">4&#46;</span><p id="par0430" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What is the duration of antibiotic treatment in patients with FN without clinically or microbiologically documented infection&#63;</span></p></li></ul></p><p id="par0849" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Duration OR discontinuation&#8221; AND &#8220;Neutropenia&#8221; AND &#8220;Antimicrobial OR antibiotic&#8221; AND &#8220;Therapy OR treatment&#8221;&#46;<ul class="elsevierStyleList" id="lis0110"><li class="elsevierStyleListItem" id="lsti0405"><span class="elsevierStyleLabel">1&#46;</span><p id="par0435" class="elsevierStylePara elsevierViewall">Empirical antibiotic treatment can be stopped in hematologic patients with FN who do not have clinically or microbiologically documented infection&#44; if they have been afebrile for at least 72<span class="elsevierStyleHsp" style=""></span>h&#44; and hemodynamically stable and asymptomatic since presentation&#44; regardless of neutrophil count or expected duration of neutropenia &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0410"><span class="elsevierStyleLabel">2&#46;</span><p id="par0440" class="elsevierStylePara elsevierViewall">After treatment is discontinued&#44; the patient should be kept under close clinical observation for at least 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#44; so that antibiotic treatment can be restarted early if fever returns &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0415"><span class="elsevierStyleLabel">3&#46;</span><p id="par0445" class="elsevierStylePara elsevierViewall">Centers that provide antibacterial prophylaxis should consider restarting it after stopping empirical antimicrobial therapy for as long as the neutropenia lasts &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1160" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0460"><li class="elsevierStyleListItem" id="lsti0420"><span class="elsevierStyleLabel">5&#46;</span><p id="par0450" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Can patients with FN be treated with oral antibiotics&#63; When&#63; Which antibiotics&#63;</span></p></li></ul></p><p id="par0875" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58; &#8220;</span>Febrile neutropenia&#8221;&#44; &#8220;Oral treatment&#8221;&#44; &#8220;Hematological malignancies&#8221;&#46;<ul class="elsevierStyleList" id="lis0115"><li class="elsevierStyleListItem" id="lsti0425"><span class="elsevierStyleLabel">1&#46;</span><p id="par0455" class="elsevierStylePara elsevierViewall">Patients considered to be at low risk for complications can be treated with oral antibiotics provided that they are also properly followed-up in the outpatient setting &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0430"><span class="elsevierStyleLabel">2&#46;</span><p id="par0460" class="elsevierStylePara elsevierViewall">Treatment must include a fluoroquinolone with antipseudomonal activity &#40;ciprofloxacin 750<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h&#47;po&#41; and an agent fully active against Gram-positive cocci&#44; such as amoxicillin&#47;clavulanic acid &#40;875<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h&#47;po&#41;&#44; or clindamycin &#40;300&#8211;600<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h po&#41;&#44; if the patient has a proven allergy to all beta-lactams or a history of hypersensitivity &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46; Another alternative is a combination of ciprofloxacin with cefixime or cefuroxime &#40;A-II&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0435"><span class="elsevierStyleLabel">3&#46;</span><p id="par0465" class="elsevierStylePara elsevierViewall">Other oral regimens including levofloxacin or ciprofloxacin in monotherapy have been studied less &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0440"><span class="elsevierStyleLabel">4&#46;</span><p id="par0470" class="elsevierStylePara elsevierViewall">Fluoroquinolones should not be used as initial empirical treatment in patients who have received them as prophylaxis&#46; &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0445"><span class="elsevierStyleLabel">5&#46;</span><p id="par0475" class="elsevierStylePara elsevierViewall">Any patient&#44; whether in the emergency room or after admission&#44; who presents signs and symptoms of hemodynamic instability&#44; focality&#44; oral intolerance&#44; new clinical signs and symptoms&#44; or microbiological species not susceptible to initial empirical therapy are isolated&#44; should be admitted to hospital or continue as an inpatient in order to expand the tests for fever syndrome and modify empirical treatment according to the protocol for high-risk patients &#40;<span class="elsevierStyleBold">A-III</span>&#41;&#46;</p></li></ul></p><p id="par1165" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0470"><li class="elsevierStyleListItem" id="lsti0450"><span class="elsevierStyleLabel">6&#46;</span><p id="par0480" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">When is empirical antifungal treatment indicated in a patient with NF&#63;</span></p></li></ul></p><p id="par0880" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;Febrile neutropenia AND empirical antifungal treatment&#8221;&#46; &#8220;Febrile neutropenia AND pre-emptive antifungal therapy OR diagnostic-driven approach&#8221;&#46;<ul class="elsevierStyleList" id="lis0120"><li class="elsevierStyleListItem" id="lsti0455"><span class="elsevierStyleLabel">1&#46;</span><p id="par0485" class="elsevierStylePara elsevierViewall">High-risk neutropenia patients not receiving prophylaxis against filamentous fungi can be given empirical antifungal treatment if fever with no other obvious cause persists after 4&#8211;5 days of broad-spectrum antibiotics and hemodynamic instability &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0460"><span class="elsevierStyleLabel">2&#46;</span><p id="par0490" class="elsevierStylePara elsevierViewall">Alternative treatment strategies&#44; such as biomarker-guided treatment using galactomannan &#40;GM&#41; or beta-D-glucan &#40;BDG&#41;&#44; reduce the use of antifungals safely and without affecting mortality in neutropenic patients &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0465"><span class="elsevierStyleLabel">3&#46;</span><p id="par0495" class="elsevierStylePara elsevierViewall">Empirical antifungal treatment is not recommended in the vast majority of hematologic patients with high-grade neutropenia who receive antifungal prophylaxis covering filamentous fungi <span class="elsevierStyleBold">&#40;A-II&#41;</span>&#46;</p></li></ul></p><p id="par1090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Targeted antibiotic treatment</span><ul class="elsevierStyleList" id="lis0125"><li class="elsevierStyleListItem" id="lsti0470"><span class="elsevierStyleLabel">1&#46;</span><p id="par0505" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">In documented cases of microbiological isolates&#44; can antibiotic treatment be adjusted to the susceptibility of the microorganism identified&#44; even if neutropenia persists&#63;</span></p></li></ul></p><p id="par0845" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;targeted OR de-escalation&#8221; AND &#8220;therapy OR treatment&#8221; AND &#8220;febrile neutropenia&#8221; AND &#8220;antimicrobial OR antibiotic&#8221;&#46;<ul class="elsevierStyleList" id="lis0130"><li class="elsevierStyleListItem" id="lsti0475"><span class="elsevierStyleLabel">1&#46;</span><p id="par0510" class="elsevierStylePara elsevierViewall">In patients with documented microbiological isolates&#44; treatment should be targeted at the isolate&#44; taking into account its in vitro activity &#40;including MIC&#41;&#44; pharmacokinetic&#47;pharmacodynamic properties&#44; as well as the individual characteristics of the patient &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0480"><span class="elsevierStyleLabel">2&#46;</span><p id="par0515" class="elsevierStylePara elsevierViewall">If the microorganism isolated is considered to be the only causative agent of the febrile episode&#44; it is preferable to use an antimicrobial&#44; normally a beta-lactam&#44; with a narrower spectrum when active &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0485"><span class="elsevierStyleLabel">3&#46;</span><p id="par0520" class="elsevierStylePara elsevierViewall">Beta-lactam monotherapy is appropriate for targeted treatment of most cases of gram-negative bacteremia &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li></ul></p><p id="par1170" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0485"><li class="elsevierStyleListItem" id="lsti0490"><span class="elsevierStyleLabel">2&#46;</span><p id="par0525" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What is the duration of antibiotic treatment in patients with FN and clinically or microbiologically documented infection&#63;</span></p></li></ul></p><p id="par0890" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;duration OR discontinuation&#8221; AND &#8220;neutropenia&#8221; AND &#8220;antimicrobial OR antibiotic&#8221; AND &#8220;therapy OR treatment&#8221;&#46;<ul class="elsevierStyleList" id="lis0135"><li class="elsevierStyleListItem" id="lsti0495"><span class="elsevierStyleLabel">1&#46;</span><p id="par0530" class="elsevierStylePara elsevierViewall">In hematologic patients with FN and clinically documented infection&#44; antibiotic treatment can be discontinued when the clinical signs and symptoms of infection have resolved and the patient has been afebrile for at least 72<span class="elsevierStyleHsp" style=""></span>h &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0500"><span class="elsevierStyleLabel">2&#46;</span><p id="par0535" class="elsevierStylePara elsevierViewall">In hematologic patients with FN and microbiologically documented infection&#44; treatment should be maintained until clinical and microbiological cure of infection &#40;resolution of signs and symptoms of infection and microbiological eradication&#41; and after at least 4 days of apyrexia and a minimum of 7 days of antibiotic treatment &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0505"><span class="elsevierStyleLabel">3&#46;</span><p id="par0540" class="elsevierStylePara elsevierViewall">In both situations&#44; if neutropenia persists after treatment has been discontinued the patient should be kept under close clinical observation for at least 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h&#44; so that antibiotic treatment can be restarted promptly if fever recurs &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0510"><span class="elsevierStyleLabel">4&#46;</span><p id="par0545" class="elsevierStylePara elsevierViewall">Centers that give prophylactic antibacterial agents should consider renewing this regimen when empirical antibiotics have been discontinued for as long as the neutropenia continues &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1175" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0495"><li class="elsevierStyleListItem" id="lsti0515"><span class="elsevierStyleLabel">3&#46;</span><p id="par0550" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">When is removal of a central venous catheter indicated&#63;</span></p></li></ul></p><p id="par0895" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;central venous catheter removal&#8221;&#44; &#8220;catheter-related infection&#8221;&#44; &#8220;management of central venous catheter infection&#8221; &#8220;catheter-related bloodstream infection&#8221;&#46;<ul class="elsevierStyleList" id="lis0140"><li class="elsevierStyleListItem" id="lsti0520"><span class="elsevierStyleLabel">1&#46;</span><p id="par0555" class="elsevierStylePara elsevierViewall">When CVC infection is documented&#44; consider removal of the catheter wherever possible&#44; weighing up the advantages of removal against the difficulty of obtaining new venous access &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0525"><span class="elsevierStyleLabel">2&#46;</span><p id="par0560" class="elsevierStylePara elsevierViewall">It is recommended to remove the CVC when there is documented catheter-related bloodstream infection &#40;CRBSI&#41; and local signs at the insertion site &#40;suppuration&#41;&#44; along the tunnel tract &#40;tunnel infection&#41;&#44; or if the patient presents criteria for severe sepsis with hemodynamic instability &#40;septic shock&#41; &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0530"><span class="elsevierStyleLabel">3&#46;</span><p id="par0565" class="elsevierStylePara elsevierViewall">To improve the prognosis of the patient&#44; it is recommended to remove the CVC when there is documented CRBSI due to fungi &#40;normally <span class="elsevierStyleItalic">Candida</span> spp&#41;&#44; <span class="elsevierStyleItalic">S&#46; aureus</span>&#44; enterococci&#44; gram-negative bacilli &#40;especially <span class="elsevierStyleItalic">P&#46; aeruginosa</span>&#41; and mycobacteria &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#46; Removal is also recommended in infections with associated bacteremia caused by microorganisms that are difficult to eradicate &#40;<span class="elsevierStyleItalic">Bacillus</span> spp&#46;&#44; <span class="elsevierStyleItalic">Micrococcus</span> spp&#46; and <span class="elsevierStyleItalic">Propionibacterium</span> spp&#46;&#41; &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0535"><span class="elsevierStyleLabel">4&#46;</span><p id="par0570" class="elsevierStylePara elsevierViewall">In uncomplicated infections or where bacteremia is caused by microorganisms different from those mentioned above&#44; systemic targeted antibiotic treatment can be applied without removing the CVC and antibiotic lock therapy should be considered &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0540"><span class="elsevierStyleLabel">5&#46;</span><p id="par0575" class="elsevierStylePara elsevierViewall">Removal of the CVC is recommended if persistent bacteremia is detected &#40;evidenced in positive follow-up control cultures&#41; 48<span class="elsevierStyleHsp" style=""></span>h-72<span class="elsevierStyleHsp" style=""></span>h after starting targeted antibiotic treatment &#40;<span class="elsevierStyleBold">A-II</span>&#41;&#44; if there is no other obvious clinical focus &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#44; if there is infective endocarditis or peripheral embolism &#40;<span class="elsevierStyleBold">A-II</span>&#41; or an early relapse due to the same microorganism after completion of antibiotic treatment&#44; or failure of conservative treatment &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0545"><span class="elsevierStyleLabel">6&#46;</span><p id="par0580" class="elsevierStylePara elsevierViewall">If fever persists in a neutropenic patient with an indwelling catheter after other focalities have been ruled out&#44; but catheter-related infection has not been confirmed&#44; consider removal of the catheter if there is sepsis or local erythema in the pericatheter area &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#44; or if fever persists and there is no other possible cause despite the absence of sepsis or local signs of infection &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li></ul></p><p id="par1095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Treatment of infections caused by multidrug-resistant Gram-negative bacilli &#40;MDR-GNB&#41;</span><ul class="elsevierStyleList" id="lis0145"><li class="elsevierStyleListItem" id="lsti0550"><span class="elsevierStyleLabel">1&#46;</span><p id="par0590" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What is the treatment of choice for cephalosporin-resistant Enterobacteriaceae&#63;</span></p></li></ul></p><p id="par0850" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;&#40;ESBL or <span class="elsevierStyleItalic">extended-spectrum beta-lactamase</span>&#41; and treatment and outcome&#8221;&#59; &#8220;AmpC and <span class="elsevierStyleItalic">Enterobacter</span>&#42; and treatment and outcome&#8221;&#46;<ul class="elsevierStyleList" id="lis0725"><li class="elsevierStyleListItem" id="lsti0555"><span class="elsevierStyleLabel">1&#46;1</span><p id="par0595" class="elsevierStylePara elsevierViewall">Targeted therapy in infections caused by extended-spectrum beta-lactamase &#40;ESBL&#41;-producing Enterobacteriaceae</p></li></ul></p><p id="par1055" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0640"><li class="elsevierStyleListItem" id="lsti0560"><span class="elsevierStyleLabel">1&#46;1&#46;1</span><p id="par0600" class="elsevierStylePara elsevierViewall">In stable patients&#44; the targeted therapy of choice against extended-spectrum beta-lactamase &#40;ESBL&#41;-producing Enterobacteriaceae is a beta-lactam&#47;beta-lactamase inhibitor &#40;BLBLI&#41; combination&#44; provided that in vitro susceptibility is shown &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0565"><span class="elsevierStyleLabel">1&#46;1&#46;2</span><p id="par0605" class="elsevierStylePara elsevierViewall">Use of carbapenems is recommended for patients with sepsis or septic shock criteria &#40;<span class="elsevierStyleBold">C-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0570"><span class="elsevierStyleLabel">1&#46;1&#46;3</span><p id="par0610" class="elsevierStylePara elsevierViewall">Piperacillin-tazobactam and meropenem should be administered in extended infusion&#44; since this has been shown to improve prognosis in severe infections compared with short-term infusions &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0575"><span class="elsevierStyleLabel">1&#46;1&#46;4</span><p id="par0615" class="elsevierStylePara elsevierViewall">Piperacillin-tazobactam should be avoided for treating high-inoculum infections caused by strains with MIC<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par0620" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0350"><li class="elsevierStyleListItem" id="lsti0580"><span class="elsevierStyleLabel">1&#46;2</span><p id="par1060" class="elsevierStylePara elsevierViewall">Targeted therapy in infections caused by AmpC-producing Enterobacteriaceae</p></li></ul></p><p id="par1180" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0645"><li class="elsevierStyleListItem" id="lsti0585"><span class="elsevierStyleLabel">1&#46;2&#46;1</span><p id="par0625" class="elsevierStylePara elsevierViewall">Cefepime and fluoroquinolones are the preferred treatment options for infections due to AmpC-producing Enterobacteriaceae susceptible to these antimicrobials &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0590"><span class="elsevierStyleLabel">1&#46;2&#46;2</span><p id="par0630" class="elsevierStylePara elsevierViewall">Piperacillin-tazobactam is a valid therapeutic option if in vitro activity is shown &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#44; but should be avoided for treating high-inoculum infections caused by AmpC- producing Enterobacteriaceae with MIC<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>mg&#47;L &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0595"><span class="elsevierStyleLabel">1&#46;2&#46;3</span><p id="par0635" class="elsevierStylePara elsevierViewall">Use of carbapenems is recommended for patients without alternative treatment options&#44; or with sepsis or septic shock criteria &#40;<span class="elsevierStyleBold">C-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0600"><span class="elsevierStyleLabel">1&#46;2&#46;4</span><p id="par0640" class="elsevierStylePara elsevierViewall">We recommend that piperacillin-tazobactam&#44; cefepime and meropenem be administered in extended infusion&#44; since this has been shown to improve the prognosis in severe infections when compared with short-term infusions &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li></ul></p><p id="par0645" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0340"><li class="elsevierStyleListItem" id="lsti0605"><span class="elsevierStyleLabel">2&#46;</span><p id="par1070" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">What is the treatment of choice for carbapenem-resistant Gram-negative bacilli&#63;</span></p></li></ul></p><p id="par1075" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0730"><li class="elsevierStyleListItem" id="lsti0610"><span class="elsevierStyleLabel">2&#46;1</span><p id="par0650" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Targeted treatment of infections caused by carbapenem-resistant Enterobacteriaceae &#40;CRE&#41;&#46;</span></span></p></li></ul></p><p id="par0851" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;&#40;carbapenemase or KPC or OXA or NDM or VIM&#41; and treatment and outcome&#8221;&#46;<ul class="elsevierStyleList" id="lis0650"><li class="elsevierStyleListItem" id="lsti0615"><span class="elsevierStyleLabel">2&#46;1&#46;1</span><p id="par0655" class="elsevierStylePara elsevierViewall">Severe infections caused by KPC-producing Enterobacteriaceae in neutropenic patients should be treated with a combination of at least two active drugs from the options included in the antibiogram &#40;meropenem&#44; colistin&#44; tigecycline&#44; fosfomycin and aminoglycosides&#41; &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46; We recommend the same approach for treating severe infections caused by other carbapenemase-producing Enterobacteriaceae &#40;CRE&#41; &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0620"><span class="elsevierStyleLabel">2&#46;1&#46;2</span><p id="par0660" class="elsevierStylePara elsevierViewall">For infections caused by strains with meropenem MICs<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>mg&#47;L&#44; the combination regimen should include high-dose meropenem &#40;2<span class="elsevierStyleHsp" style=""></span>g every 8<span class="elsevierStyleHsp" style=""></span>h&#41; in extended infusion &#40;over 3<span class="elsevierStyleHsp" style=""></span>h&#41; &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0625"><span class="elsevierStyleLabel">2&#46;1&#46;3</span><p id="par0665" class="elsevierStylePara elsevierViewall">Ceftazidime-avibactam may be an alternative for severe infections due to KPC-producing or OXA-48-producing Enterobacteriaceae &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46; We do not have well-designed comparative studies available that enable this drug to be positioned against other treatment options &#40;undecided&#41;&#46; Nor are there data to support its use in combination therapy &#40;undecided&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0630"><span class="elsevierStyleLabel">2&#46;1&#46;4</span><p id="par0670" class="elsevierStylePara elsevierViewall">In this type of infection&#44; it is especially important to ensure control of the source of infection and to administer high-dose antibiotics with optimized dosage regimens&#44; monitoring plasma levels whenever possible &#40;Table 4&#41; &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par1185" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0510"><li class="elsevierStyleListItem" id="lsti0635"><span class="elsevierStyleLabel">2&#46;2</span><p id="par0675" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Targeted therapy of extensively drug-resistant &#40;XDR&#41; and pandrug-resistant &#40;PDR&#41; non-fermenting gram-negative bacilli &#40;NFGNB&#41;&#46;</span></span></p></li></ul></p><p id="par0910" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> BGN-NF XDR and PDR&#58; &#40;<span class="elsevierStyleItalic">Acinetobacter</span> or <span class="elsevierStyleItalic">Pseudomonas</span>&#41; and &#40;resistant or resistance or MDR or XDR or PDR&#41; and treatment and outcome&#46;<ul class="elsevierStyleList" id="lis0175"><li class="elsevierStyleListItem" id="lsti0640"><span class="elsevierStyleLabel">2&#46;2&#46;1</span><p id="par0680" class="elsevierStylePara elsevierViewall">In the case of XDR NFGNB infections for which there is a fully active therapeutic alternative&#44; single-agent treatment is recommended with optimized administration &#40;<span class="elsevierStyleBold">B-I</span>&#41;&#44; prioritizing the use &#40;in the following order&#41; of beta-lactams&#44; sulbactam &#40;in infections due to <span class="elsevierStyleItalic">A&#46; baumannii</span>&#41; and colistin&#44; provided that <span class="elsevierStyleItalic">in vitro</span> susceptibility is shown &#40;<span class="elsevierStyleBold">C-II</span>&#41;&#46; Avoid monotherapy with aminoglycosides or tigecycline for the treatment of severe infections &#40;<span class="elsevierStyleBold">A-II&#44; A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0645"><span class="elsevierStyleLabel">2&#46;2&#46;2</span><p id="par0685" class="elsevierStylePara elsevierViewall">For severe infections due to XDR-NFGNB strains with borderline susceptibility to the available treatment options&#44; optimized administration of combination therapy using two or more agents should be considered&#44; based on the best options specified in the antibiogram <span class="elsevierStyleBold">&#40;B-II&#41;</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0650"><span class="elsevierStyleLabel">2&#46;2&#46;3</span><p id="par0690" class="elsevierStylePara elsevierViewall">For XDR or PDR <span class="elsevierStyleItalic">P&#46; aeruginosa</span> infections&#44; use of ceftolozane-tazobactam may be considered &#40;<span class="elsevierStyleBold">C-II</span>&#41; or ceftazidime-avibactam &#40;<span class="elsevierStyleBold">C-I</span>&#41;&#44; although there is as yet limited experience of their use in this setting&#46;</p></li><li class="elsevierStyleListItem" id="lsti0655"><span class="elsevierStyleLabel">2&#46;2&#46;4</span><p id="par0695" class="elsevierStylePara elsevierViewall">If these options are not available or the infection is caused by pan-resistant isolates&#44; it will be necessary to develop combination therapy regimens using two or more agents&#44; choosing those with intermediate susceptibility&#44; or whose MICs are closest to the susceptibility cut-off &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0660"><span class="elsevierStyleLabel">2&#46;2&#46;5</span><p id="par0700" class="elsevierStylePara elsevierViewall">It is particularly important in these infections to ensure control of the source of infection and to administer high-dose antibiotics with optimized administration regimens&#44; monitoring plasma levels whenever possible &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par1190" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0515"><li class="elsevierStyleListItem" id="lsti0665"><span class="elsevierStyleLabel">3&#46;</span><p id="par0705" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic"><span class="elsevierStyleBold">Targeted treatment of Stenotrophomonas maltophilia infections&#46;</span></span></p></li></ul></p><p id="par0915" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;</span> &#8220;<span class="elsevierStyleItalic">Stenotrophomonas</span> and treatment&#8221;&#46;<ul class="elsevierStyleList" id="lis0660"><li class="elsevierStyleListItem" id="lsti0670"><span class="elsevierStyleLabel">3&#46;1</span><p id="par0710" class="elsevierStylePara elsevierViewall">The treatment of choice for infections due to <span class="elsevierStyleItalic">S&#46; maltophilia</span> is co-trimoxazole &#40;trimethoprim 15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day in 3&#8211;4 divided doses&#41; &#40;<span class="elsevierStyleBold">C-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0675"><span class="elsevierStyleLabel">3&#46;2</span><p id="par0715" class="elsevierStylePara elsevierViewall">In patients with infections with co-trimoxazole-resistant strains&#44; or those who cannot take co-trimoxazole &#40;because of hypersensitivity&#44; for example&#41;&#44; the recommended treatment is minocycline &#40;<span class="elsevierStyleBold">C-II</span>&#41; or fluoroquinolones &#40;<span class="elsevierStyleBold">C-II</span>&#41; if they are active&#46; There is more limited experience of the use of ceftazidime&#44; tigecycline and colistin in monotherapy &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46; In the case of patients with serious or refractory infections who require second-line therapy&#44; consider combining two drugs with in vitro activity categorized as susceptible&#46;</p></li></ul></p><p id="par1100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Adjuvant measures and prevention</span><ul class="elsevierStyleList" id="lis0185"><li class="elsevierStyleListItem" id="lsti0680"><span class="elsevierStyleLabel">1&#46;</span><p id="par0725" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Is the use of colony-stimulating factors indicated for treatment of FN&#63; When&#63;</span></p></li></ul></p><p id="par0860" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58;&#160;&#8220;</span>febrile neutropenia&#8221;&#44;&#160;&#8220;colony stimulating factor&#8221;&#44; &#8220;treatment&#8221;&#46;<ul class="elsevierStyleList" id="lis0665"><li class="elsevierStyleListItem" id="lsti0685"><span class="elsevierStyleLabel">1&#46;</span><p id="par0730" class="elsevierStylePara elsevierViewall">Colony-stimulating factors &#40;CSF&#41; are not routinely recommended in the treatment of FN &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0690"><span class="elsevierStyleLabel">2&#46;</span><p id="par0735" class="elsevierStylePara elsevierViewall">They can be considered for therapeutic use in patients with increased-risk for infection-related complications or predictive factors of poor prognosis &#40;<span class="elsevierStyleBold">B-II</span>&#41;&#46;</p></li></ul></p><p id="par1195" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0520"><li class="elsevierStyleListItem" id="lsti0695"><span class="elsevierStyleLabel">2&#46;</span><p id="par0740" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">When would granulocyte transfusion be indicated&#63;</span></p></li></ul></p><p id="par0925" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58; &#8220;</span>febrile neutropenia&#8221;&#44; &#8220;granulocyte transfusion&#8221;&#46;<ul class="elsevierStyleList" id="lis0195"><li class="elsevierStyleListItem" id="lsti0700"><span class="elsevierStyleLabel">1&#46;</span><p id="par0745" class="elsevierStylePara elsevierViewall">There is insufficient evidence of the efficacy of granulocyte transfusion in patients with FN and documented infection &#40;<span class="elsevierStyleBold">C-III</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0705"><span class="elsevierStyleLabel">2&#46;</span><p id="par0750" class="elsevierStylePara elsevierViewall">Granulocyte transfusions should be administered only in the context of prospective clinical trials &#40;<span class="elsevierStyleBold">B-III</span>&#41;&#46;</p></li></ul></p><p id="par1200" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0530"><li class="elsevierStyleListItem" id="lsti0710"><span class="elsevierStyleLabel">3&#46;</span><p id="par0755" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Is antibacterial prophylaxis indicated&#63; Which drugs&#63;</span></p></li></ul></p><p id="par0930" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58; &#8220;</span>febrile neutropenia&#8221;&#44; &#8220;antibacterial prophylaxis&#8221;&#46;<ul class="elsevierStyleList" id="lis0200"><li class="elsevierStyleListItem" id="lsti0715"><span class="elsevierStyleLabel">1&#46;</span><p id="par0760" class="elsevierStylePara elsevierViewall">Antibacterial prophylaxis is not recommended in low-risk patients <span class="elsevierStyleBold">&#40;A-I&#41;</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0720"><span class="elsevierStyleLabel">2&#46;</span><p id="par0765" class="elsevierStylePara elsevierViewall">In high-risk patients &#40;ANC<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>500&#47;mm<span class="elsevierStyleSup">3</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>7 days&#41;&#44; use of antibacterial prophylaxis should be evaluated on an individual basis in accordance with the characteristics of the patient and local hospital epidemiology&#44; owing to the lack of benefit for mortality and the increasing levels of resistance in gram-negative bacteria <span class="elsevierStyleBold">&#40;B-I&#41;</span>&#46; If prophylaxis is used&#44; epidemiological surveillance for MDRO detection should be implemented&#46;</p></li></ul></p><p id="par1205" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0540"><li class="elsevierStyleListItem" id="lsti0725"><span class="elsevierStyleLabel">4&#46;</span><p id="par0770" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Is prophylaxis with colony stimulating factors indicated&#63; When&#63;</span></p></li></ul></p><p id="par0935" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Search terms&#58; &#8220;</span>febrile neutropenia&#8221;&#44; &#8220;colony stimulating factor&#8221;&#44; &#8220;prophylaxis&#8221;<ul class="elsevierStyleList" id="lis0205"><li class="elsevierStyleListItem" id="lsti0730"><span class="elsevierStyleLabel">1&#46;</span><p id="par0775" class="elsevierStylePara elsevierViewall">The decision to use colony-stimulating factor prophylaxis for the prevention of FN should be based on the relative myelotoxicity of the chemotherapy regimen and the presence of potential risk factors&#44; which should be evaluated before each cycle of chemotherapy is administered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0735"><span class="elsevierStyleLabel">2&#46;</span><p id="par0780" class="elsevierStylePara elsevierViewall">In situations where chemotherapy dose intensity or dose density strategies confer a survival benefit&#44; prophylaxis with G-CSF should be used as supportive treatment &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0740"><span class="elsevierStyleLabel">3&#46;</span><p id="par0785" class="elsevierStylePara elsevierViewall">Primary prophylaxis is recommended from the first chemotherapy cycle for patients whose overall risk of FN is &#8805; 20&#37;&#44; based on patient-related&#44; disease-related and regimen-related risk factors &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0745"><span class="elsevierStyleLabel">4&#46;</span><p id="par0790" class="elsevierStylePara elsevierViewall">When the overall risk of FN is 10&#37;&#8211;20&#37;&#44; attention should be focused on additional risk factors &#40;such as comorbidities or advanced age&#41;&#44; which increase the risk of FN and support an indication of prophylaxis with G-CSF &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0750"><span class="elsevierStyleLabel">5&#46;</span><p id="par0795" class="elsevierStylePara elsevierViewall">Prophylaxis with G-CSF is not recommended if chemotherapy has an FN risk of &#60;10&#37; &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0755"><span class="elsevierStyleLabel">6&#46;</span><p id="par0800" class="elsevierStylePara elsevierViewall">Secondary prophylaxis is recommended for patients who experienced neutropenic complications in a previous cycle of chemotherapy and in whom a dose reduction or delay in treatment could compromise progression-free or overall survival&#44; or treatment outcome &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0760"><span class="elsevierStyleLabel">7&#46;</span><p id="par0805" class="elsevierStylePara elsevierViewall">Prophylaxis can be given with any of the following factors &#40;filgrastim&#44; lenograstim and pegfilgrastim&#41; or any of their available biosimilars &#40;<span class="elsevierStyleBold">A-I</span>&#41;&#44; preferably subcutaneously&#46;</p></li></ul></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0810" class="elsevierStylePara elsevierViewall">Carlota Gudiol has served as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Astellas and Gilead&#46; Rafael de la C&#225;mara has participated as speaker at scientific meetings sponsored by MSD&#44; GSK&#44; Novartis&#44; Astellas&#44; Pfizer and Gilead&#59; and in consultancy and advisory activities for Novartis&#44; MSD&#44; Janssen&#44; Clinigen and Astellas&#46; Manuel Lizasoain has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD and Gilead&#46; Jordi Carratal&#224; has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Gilead and Angelini&#46; Rafael Cant&#243;n has participated as speaker at scientific meetings sponsored by Angelini&#44; ERN Laboratorios&#44; MSD&#44; Pfizer and Zambon and has received funding for research projects from AstraZeneca and MSD&#46; Manuela Aguilar-Guisado has participated as speaker at scientific meetings sponsored by Pfizer and MSD&#46; Manuela Aguilar-Guisado has participated as speaker at scientific meetings sponsored by Pfizer and MSD&#46; Jos&#233; Molina Gil-Bermejo has received lecturing fees in activities financed by Merck Sharp &#38; Dohme&#44; and has received grants to attend conferences organized by Astellas Pharma&#46; Carlos Solano has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Astellas and Gilead He has received grants for clinical and preclinical research from Pfizer and Astellas&#46; Carolina Garc&#237;a-Vidal has received fees for speaking at events sponsored by Gilead Science&#44; Merck Sharp and Dohme&#44; Pfizer&#44; Janssen and Novartis&#44; and has received a subsidy from Gilead Science&#46; Mar&#237;a Lourdes V&#225;zquez L&#243;pez has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Gilead&#44; Astellas&#44; Amgen&#46; Jos&#233; Ram&#243;n Azanza has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Gilead&#44; Janssen&#44; AstraZeneca&#44; Roche&#46; Jos&#233; Ram&#243;n Azanza has participated as speaker at scientific meetings sponsored by Pfizer&#44; MSD&#44; Gilead&#44; Janssen&#44; AstraZeneca&#44; Roche Francisco Javier Candel has participated as speaker scientific meetings sponsored by Pfizer&#44; MSD&#44; Gilead&#44; Angelini&#44; Astellas&#44; and ERN&#46; Isabel Ruiz-Camps has participated as speaker at scientific meetings sponsored by Astellas&#44; Celgene&#44; Gilead&#44; MSD&#44; Pfizer and in scientific consultancy for Astellas&#44; Gilead&#44; and Pfizer&#46; Mar&#237;a Su&#225;rez-Lled&#243; has participated as speaker at scientific meetings and has collaborated in scientific studies sponsored by Pfizer and MSD&#46; Isidro Jarque has participated as speaker at scientific meetings sponsored by Gilead&#44; MSD&#44; and Pfizer&#46; Isabel S&#225;nchez-Ortega has no conflicts of interest&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Febrile neutropenia is a very common complication in patients with hematological malignancies receiving chemotherapy&#44; and is associated with high morbidity and mortality&#46; Infections caused by multidrug-resistant bacteria have become a therapeutic challenge in this high-risk patient population&#44; since inadequate initial empirical treatment can seriously compromise prognosis&#46; However&#44; reducing antimicrobial exposure is one of the most significant cornerstones in the fight against resistance&#46; The objective of these new guidelines is to update recommendations for the initial management of hematological patients who develop febrile neutropenia in this scenario of multidrug resistance&#46; The two participating Societies &#40;the <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Enfermedades Infecciosas y Microbiolog&#237;a Cl&#237;nica</span> &#91;Spanish Society of Infectious Diseases and Clinical Microbiology&#93; and the <span class="elsevierStyleItalic">Sociedad Espa&#241;ola de Hematolog&#237;a y Hemoterapia</span> &#91;Spanish Society of Haematology and Haemotherapy&#93;&#41;&#44; designated a panel of experts in the field to provide evidence-based recommendations in response to common clinical questions&#46; This document is primarily focused on bacterial infections&#46; Other aspects related to opportunistic infections&#44; such as those caused by fungi or other microorganisms&#44; especially in hematopoietic stem cell transplantation&#44; are also touched upon&#46;</p></span>"
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Article information

ISSN: 2529993X
Original language: English

DOI:10.1016/j.eimce.2019.01.012

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2021 November	20	9	29
2021 October	32	10	42
2021 September	11	13	24
2021 August	18	8	26
2021 July	11	12	23
2021 June	18	11	29
2021 May	17	5	22
2021 April	26	15	41
2021 March	17	11	28
2021 February	12	6	18
2021 January	19	7	26
2020 December	16	10	26
2020 November	22	6	28
2020 October	20	7	27

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