Enferm Infecc Microbiol Clin.

2020;38(4):174–181

www.elsevier.es/eimc

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夽
Carlota Gudiol a,∗ , Manuela Aguilar-Guisado b , José Ramón Azanza c , Francisco Javier Candel d ,
Rafael Cantón e , Jordi Carratalà a , Carolina Garcia-Vidal f , Isidro Jarque g , Manuel Lizasoain h ,
José Molina Gil-Bermejo b , Isabel Ruiz-Camps i , Isabel Sánchez-Ortega j , Carlos Solano k ,
María Suárez-Lledó l , Lourdes Vázquez m , Rafael de la Cámara n
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

a b s t r a c t

Keywords: Febrile neutropenia is a very common complication in patients with hematological malignancies receiving
Febrile neutropenia chemotherapy, and is associated with high morbidity and mortality. Infections caused by multidrug-
Neutropenia resistant bacteria have become a therapeutic challenge in this high-risk patient population, since
Hematological disease
inadequate initial empirical treatment can seriously compromise prognosis. However, reducing antimi-
Empirical antibiotic therapy
Targeted antibiotic therapy
crobial exposure is one of the most significant cornerstones in the fight against resistance. The objective
Antibiotic resistance 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. The two participat-
ing Societies (the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica [Spanish Society
of Infectious Diseases and Clinical Microbiology] and the Sociedad Española de Hematología y Hemoter-
apia [Spanish Society of Haematology and Haemotherapy]), designated a panel of experts in the field to
provide evidence-based recommendations in response to common clinical questions. This document is
primarily focused on bacterial infections. Other aspects related to opportunistic infections, such as those
caused by fungi or other microorganisms, especially in hematopoietic stem cell transplantation, are also
touched upon.
© 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiologı́a
Clı́nica. All rights reserved.

夽 The complete consensus statement is available as Appendix in supplementary material.

∗ Corresponding author.
E-mail address: [email protected] (C. Gudiol).

https://doi.org/10.1016/j.eimc.2019.01.013
0213-005X/© 2019 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiologı́a Clı́nica. All rights reserved.
 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181 175

Resumen ejecutivo del documento de la Sociedad Española de Enfermedades

Infecciosas y Microbiología Clínica (SEIMC), la Red Española de Investigación en
Palabras clave: Patología Infecciosa (REIPI) y la Sociedad Española de Hematología y
Fiebre neutropénica
Neutropenia Hemoterapia (SEHH) sobre el manejo de la neutropenia febril en el paciente
Enfermedad hematológica hematológico
Tratamiento antibiótico empírico
Tratamiento antibiótico dirigido r e s u m e n
Resistencia antibiótica
La neutropenia febril es una complicación muy frecuente en los pacientes hematológicos que reciben
tratamiento quimioterápico, y se asocia a una importante morbimortalidad. Las infecciones por bacterias
multirresistentes se han convertido en un reto terapéutico en esta población de pacientes de alto riesgo,
en los que un tratamiento empírico inicial inadecuado puede comprometer gravemente su pronóstico.
Sin embargo, reducir la exposición a los antimicrobianos es uno de los pilares más importantes en la lucha
frente a las resistencias. El objetivo de esta nueva guía es actualizar las recomendaciones sobre el manejo
inicial del paciente hematológico que desarrolla neutropenia febril en el escenario actual de multirre-
sistencia. 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 bac-
teriana. Otros aspectos relacionados con las infecciones oportunistas, como las producidas por hongos u
otros microorganismos, sobre todo en el seno del trasplante de progenitores hematopoyéticos, se abordan
de forma tangencial.
© 2019 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiologı́a Clı́nica.
Todos los derechos reservados.

Executive summary (www.agreecollaboration.org) for evaluating the methodological

quality of clinical practice guidelines. The PubMed search engine
Introduction: justification and objectives (http://www.ncbi.nlm.nih.gov/pubmed) was used to perform a
literature search of the MEDLINE database for relevant scien-
Recent years have witnessed the re-emergence of bacterial tific publications. The key words used for each question are also
infections with a gram-negative etiology in patients with febrile shown. Only complete articles published in English or Spanish
neutropenia (FN), together with a significant increase in their were selected. No specific period of inclusion was defined, although
resistance to antimicrobials. These epidemiological changes are of authors were instructed to gather the most recent evidence from
particular importance in hematologic patients with FN because the literature to form the basis of their answers. The coordinators
inadequate initial empirical antibiotic therapy can have a seri- wrote the first draft, which was submitted for review by the panel
ous adverse effect on prognosis in high-risk patients. Likewise, the of experts and by SEIMC members after being published on the
management of infections caused by multidrug-resistant bacteria web page of that society. The complete text has been approved by
is a major clinical problem in this population. all authors. The criteria used to evaluate the strength of the rec-
The management of hematologic patients has also changed in ommendation and the quality of the evidence are summarized in
recent years, with a tendency towards outpatient care and new Table 1. Possible conflicts of interest associated with all members
types of immunosuppressive treatment. In the era of multidrug of the panel of experts are listed at the end of the document.
resistance, the objective of these new guidelines is to update
the recommendations for the initial management of hematologic
Recommendations
patients who develop FN. This document focuses basically on
bacterial infection. Other aspects associated with opportunistic
Classification of febrile neutropenia risk
infections, such as fungal infections or those due to other microor-
ganisms, especially in hematopoietic stem cell transplantation
1. What tools are available to determine risk in a patient with
(HSCT), are also touched upon. Only infections in adult patients
FN? When should they be applied and in what contexts?
will be discussed.

Search terms: “Risk factors” “Risk stratification”, “Febrile neu-

Methodology
tropenia”, “Cancer patients”.
The two participating Societies, the Spanish Society of Infec-
tious Diseases and Clinical Microbiology (Sociedad Española de 1. Patients presenting with FN should undergo risk assessment for
Enfermedades Infecciosas y Microbiología Clínica) and the Spanish complications, preferably in the first hour of contact with the
Association of Hematology and Hemotherapy (Sociedad Española healthcare system (A-II).
de Hematología y Hemoterapia) nominated two coordinators, who 2. The MASCC (Multinational Association for Supportive Care in
selected the rest of the members of the panel of experts. The sci- Cancer) risk index is a prognostic scale that can be used to assess
entific committees of both societies approved the proposal. The the risk of complications in patients with FN (B-II).
questions to be considered were approved by both scientific soci- 3. A patient with a MASCC risk index score of <21 is defined as high
eties involved and then distributed among the various members of risk (B-II) and should be hospitalized and receive intravenous
the panel of experts. The present Document was written following empirical antibiotic treatment (B-II).
the SEIMC guidelines for consensus documents (www.seimc.org), 4. A patient with a MASCC risk index score of ≥21 is defined as
as well as the recommendations of the AGREE collaboration low risk (B-II). Some of these patients may be candidates for a
176 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181

Table 1
Strength of recommendations.

Strength of recommendation
A Strongly supports a recommendation for use
B Moderately supports a recommendation for use
C Marginally supports a recommendation for use

Quality of evidence
I Evidence from at least one randomized controlled trial supports the recommendation being made
II Evidence from at least one well-designed clinical trial without randomization, cohort study or case-controlled study
III Evidence based on expert opinion and clinical experience or descriptive cases

regimen of oral antibiotics and can be managed as outpatients, 1. In patients with FN, pre-emptive screening for fungal infection
provided that they are not receiving induction chemotherapy should be considered when fever persists for 4–7 days after
for acute myeloid leukemia or in the pre-engraftment phase of having started broad-spectrum antibiotics, expected duration
allogeneic hematopoietic stem cell transplantation (B-II). of neutropenia is >7 days, and in clinically compatible cases
5. Clinical criteria can also be used to determine risk in patients (A-I).
with FN. 2. Blood cultures are the microbiological test of choice for the
6. Patients with an absolute neutrophil count (ANC) of ≤100/mm3 , diagnosis of yeast infections (A-I).
expected neutropenia duration of >7 days, and/or significant 3. In clinically stable patients who are not receiving antifungal
comorbidities (hypotension, pneumonia, gastrointestinal symp- prophylaxis against filamentous fungi, it is recommended to
toms, neurological symptoms) are considered high-risk. These screen for Aspergillus infection by carrying out serial testing
patients should be admitted to hospital and receive intravenous for circulating galactomannan (GM) in serum twice a week.
empirical therapy (A-II). In the event of a positive GM test, a CT scan of the lungs is
7. Patients with ANC < 500/mm3 , expected neutropenia duration recommended (A-I).
≤7 days and having no or few comorbidities or significant 4. In patients receiving antifungal prophylaxis against filamen-
evidence of renal or hepatic impairment are considered as at tous fungi, a CT scan of the thorax is recommended if fever
low-risk. These patients may be candidates for oral empirical persists (>7 days after initiating broad-spectrum antibiotics,
therapy and outpatient care (A-II). with no other identifiable cause of fever). In the event of find-
ings suggestive of invasive fungal infection, bronchoscopy is
Diagnostic management recommended for galactomannan testing, and pan-fungal PCR
on the bronchoalveolar lavage (BAL) fluid. If results are nega-
1. What microbiology diagnostic tests should be carried out in tive, lesion puncture is recommended (B-II).
patients with FN?
3. Are biomarkers useful for infection diagnosis in FN and for
Search terms: “Febrile neutropenia” AND “Etiology”. “Febrile determining length of antibiotic treatment?
neutropenia” AND “Microbiological diagnosis”.
Search terms: “Biomarkers and infection diagnosis”, “Febrile
1. It is recommended that at least two, and preferably three, neutropenia”, “Bacteremia and biomarkers”, “Length of antibiotics
sets of blood cultures be collected from any patient with FN, in febrile neutropenia”.
whether they are in-patients or seen in the emergency room,
high-risk or low-risk. Blood should be drawn through all avail- 1. Biomarkers are not recommended as a guide to antibiotic use
able catheterized venous access in the patient, paying special in FN, due to the lack of studies demonstrating the safety and
attention to long-term devices, as well as samples taken by usefulness of basing clinical decisions on their results (B-III).
venipuncture from peripheral vein sites (A-I). 2. It has been demonstrated that neutropenic patients with
2. If an infection of extravascular origin is suspected, it is rec- bacteremia present significantly higher procalcitonin (PCT), C-
ommended to send representative samples from the possible reactive protein, IL-6, and presepsin levels than those without
focus of infection. Rapid microbiological tests can be per- bacteremia. (A-II). The possible impact of this information on
formed on these samples (A-I). the future management of FN is yet to be clarified.
3. For patients being monitored in an outpatient setting with 3. Biomarkers are not useful for determining length of antibiotic
symptoms or radiological signs of respiratory infection, rapid treatment (A-II).
urine antigen tests for the detection of Streptococcus pneumo- 4. C-reactive protein levels, especially those that are elevated
niae and Legionella pneumophila antigens can be used (A-II). (>20–30 mg/dl), are correlated with greater mortality. This rela-
4. During annual flu epidemics, molecular methods should be tionship has not been demonstrated with the other biomarkers
used for early diagnosis. In the case of flu, rapid techniques on (PCT, presepsin, IL-6) (C-III).
nasopharyngeal swabs are preferred (B-II).
5. If the patient presents diarrhea, it is advisable to request Empirical antibiotic treatment
a Clostridium difficile toxin stool test, on which rapid
immunochromatographic assays or PCR can be performed (C- 1. What empirical treatment strategies are there for patients
III). with NF?

2. When and how should pre-emptive screening for fungal Search terms: “Febrile neutropenia”, “Empirical antibiotic treat-
infection be carried out? ment”.

Search terms: “Febrile neutropenia AND fungal infection diag- 1. Any febrile patient with an ANC of <500/mm3 and those with
nosis”, “Febrile neutropenia AND investigation for invasive fungal ANC of 500–1000/mm3 and predicted to decline imminently
infection”. should receive early empirical antibiotic treatment (A-II) with
 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181 177

an appropriate broad-spectrum antibiotic (A-I) and a bacteri- 3. What is the empirical treatment of choice when there is an
cidal agent. obvious clinical source of infection?
2. Surveillance programs (antimicrobial stewardship) estab-
lished in the center for the appropriate use of antibiotic
Search terms: “Febrile neutropenia”, “Empirical antibiotic treat-
treatment should be taken into consideration (B-III).
ment”
3. A strategy of dose-escalation can be applied in patients with
an uncomplicated clinical presentation, no previous colo-
nization/infection with multidrug-resistant bacteria, and in 1. Oropharyngeal mucositis/esophagitis
centers where there is a low incidence of drug-resistant
microorganisms (B-II). In other situations, a de-escalation 1.1 In patients with mild forms of mucositis, anaerobic coverage
strategy should be applied (B-II). is not essential and cefepime may be used (B-III).
1.2 In more severe forms, ensure anaerobe coverage with
piperacillin-tazobactam, imipenem or meropenem (A-III).
2. What is the empirical antibiotic treatment of choice when 1.3 Consider initiating antiviral and/or antifungal treatment
there is no obvious clinical focus of infection? in patients not receiving prophylaxis who have sugges-
tive oral lesions or symptoms compatible with esophagitis
Search terms: “Febrile neutropenia”, “Empirical antibiotic treat- (C-III).
ment”, “Fever unknown origin”.
2. Neutropenic enterocolitis (typhlitis)

1. It is recommended to use a beta-lactam antibiotic with 2.1 Start treatment with a broad-spectrum antibiotic
antipseudomonal activity as monotherapy, or in combination such as piperacillin-tazobactam, imipenem or meropenem
with another antibiotic, depending on the risk of infection due that includes activity against gram-negatives, Gram-
to multidrug-resistant microorganisms and clinical presenta- positives and anaerobes (A-III).
tion (A-I). 2.2 Consider adding treatment for C. difficile if there is a high
2. For the escalation strategy: index of suspicion (C-III).

2.1 Use of piperacillin-tazobactam (A-I), or cefepime (A-I), or cef- 3. Perianal infection

tazidime (B-II) is recommended.
2.2 In settings with a high prevalence of ESBs, cephalosporins and 3.1 Performing a digital rectal examination is contraindicated in
piperacillin-tazobactam in monotherapy are not recommended the neutropenic patient. Nevertheless a thorough examina-
(B-II). tion of the perianal region is fundamental (B-III).
3.2 The treatments of choice are piperacillin-tazobactam,
imipenem or meropenem (A-III).
3. For the de-escalation strategy: 3.3 If there is clinical suspicion of a perianal abscess, ensure
active treatment against gram-negative bacilli, Enterococcus
3.1 Imipenem or meropenem in monotherapy are recommended spp. and anaerobes (A-III).
for use (B-II), or a combination of antipseudomonal beta-lactam
plus an aminoglycoside or a fluoroquinolone (if it has not been 4. Skin and soft tissue infection (SSTI)
used as prophylaxis) (B-III). Carbapenems should be reserved
for critically ill patients. 4.1 Start treatment with a broad-spectrum, antipseudomonal
3.2 The aminoglycoside should be given in a single daily dose (A-II). beta-lactam agent with activity against Gram-positive cocci,
The need to continue the aminoglycoside should be reassessed including S. aureus (A-III).
at 48–72 h. 4.2 Consider adding an antibiotic with activity against MRSA if
3.3 If there is risk of infection due to multidrug-resistant nonfer- there is a history of previous colonization/infection (B-III).
menting gram-negative bacilli, it is recommended to combine 4.3 It is recommended to obtain a sample of tissue for micro-
the beta-lactam with the lowest antimicrobial resistance rate biological and histopathologic analysis from any skin lesion
in the center + amikacin or colistin (B-III). suspected of being a source of infection (B-III).
3.4 The need for empirical treatments with other combinations can 4.4 The possibility of a serious necrotizing soft tissue infection
be considered, according to local epidemiology or in outbreak should always be ruled out (B-III).
settings (C-III). 4.5 If a serious necrotizing infection is suspected, it is
3.5 The use of antibiotics with activity against gram-positive cocci recommended to use agents such as clindamycin that
resistant to beta-lactams (vancomycin, daptomycin, linezolid) inhibit protein synthesis, and so inhibit toxin production
would be indicated only in cases of hemodynamic instabil- (A-III).
ity and/or risk of methicillin-resistant Staphylococcus aureus
(MRSA) infection (B-III). 5. Intravascular catheter-related infection
3.6 The empirical addition of vancomycin to initial antibiotic ther-
apy is not recommended if fever persists at 3 days (A-I). 5.1 Start treatment with an antipseudomonal beta-lactam together
3.7 In hemodynamically unstable patients, treatment should be with an agent with specific activity against drug-resistant
started immediately with a broad-spectrum beta-lactam with Gram-positive organisms such as vancomycin or daptomycin
antipseudomonal activity together with an antibiotic active (A-III).
against beta-lactam-resistant gram-negative bacilli, and a drug 5.2 Linezolid is not recommended in this situation (B-III).
with activity against methicillin-resistant gram-positive cocci 5.3 If the infection is considered serious and the catheter
(B-III). In patients with septic shock not receiving antifungal is the obvious source of infection, remove the catheter
prophylaxis, consider adding active treatment against Candida promptly before the microbiological results are known
spp to the initial regimen (C-III). (B-III).
178 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181

6. Paranasal sinuses presentation, regardless of neutrophil count or expected dura-

tion of neutropenia (A-II).
6.1 Start treatment with a broad-spectrum antipseudomonal beta- 2. After treatment is discontinued, the patient should be kept under
lactam with activity against Gram-positive cocci, including S. close clinical observation for at least 24–48 h, so that antibiotic
pneumoniae and S. aureus (A-III). treatment can be restarted early if fever returns (B-II).
6.2 In risk patients (prolonged neutropenia, corticotherapy), con- 3. Centers that provide antibacterial prophylaxis should consider
sider adding treatment with activity against Aspergillus or restarting it after stopping empirical antimicrobial therapy for
Mucorales, which can give a picture of sinusitis that is ini- as long as the neutropenia lasts (C-III).
tially difficult to differentiate from one with a bacterial etiology
(B-III). 5. Can patients with FN be treated with oral antibiotics? When?
Which antibiotics?
7. Pneumonia
Search terms: “Febrile neutropenia”, “Oral treatment”, “Hema-
7.1 Start with a broad-spectrum beta-lactam with activity
tological malignancies”.
against S. pneumoniae and P. aeruginosa (A-III).
7.2 In critically ill patients, nosocomial cases and patients previ-
ously colonized/infected with MDR gram-negative bacilli, it 1. Patients considered to be at low risk for complications can be
is advisable to combine with a second antibiotic, according treated with oral antibiotics provided that they are also properly
to local epidemiology (B-III). followed-up in the outpatient setting (A-II).
7.3 If the infection is community-acquired and an atypical 2. Treatment must include a fluoroquinolone with antipseu-
pneumonia is suspected, consider combining with fluoro- domonal activity (ciprofloxacin 750 mg/12 h/po) and an
quinolones or macrolides (B-III). agent fully active against Gram-positive cocci, such as
7.4 In patients with MRSA colonization or epidemiological set- amoxicillin/clavulanic acid (875 mg/8 h/po), or clindamycin
tings of high endemicity, combination with an active agent (300–600 mg/8 h po), if the patient has a proven allergy to all
such as linezolid or vancomycin must be considered. (B-III). beta-lactams or a history of hypersensitivity (A-I). Another
7.5 During flu epidemics, add empirical treatment with alternative is a combination of ciprofloxacin with cefixime or
oseltamivir (C-III). Once samples have been collected and the cefuroxime (A-II).
results are known, continuation or withdrawal of treatment 3. Other oral regimens including levofloxacin or ciprofloxacin in
can be assessed. monotherapy have been studied less (B-III).
7.6 In risk patients with bilateral infiltrates, consider other 4. Fluoroquinolones should not be used as initial empirical treat-
possible etiologies (Pneumocystis jirovecii, cytomegalovirus) ment in patients who have received them as prophylaxis.
(B-III). (A-III).
5. Any patient, whether in the emergency room or after admission,
8. Urinary tract infection who presents signs and symptoms of hemodynamic instability,
focality, oral intolerance, new clinical signs and symptoms, or
8.1 Start with a beta-lactam with antipseudomonal activity (A- microbiological species not susceptible to initial empirical ther-
III). apy are isolated, should be admitted to hospital or continue as
8.2 Consider adding a second antibiotic in critically ill patients, an inpatient in order to expand the tests for fever syndrome
those with indwelling urinary catheters, and/or a previous and modify empirical treatment according to the protocol for
history of colonization/infection with multidrug-resistant high-risk patients (A-III).
bacteria, according to local epidemiology (aminoglycoside,
glycopeptide) (B-III). 6. When is empirical antifungal treatment indicated in a patient
with NF?
9. Central nervous system infections
Search terms: “Febrile neutropenia AND empirical antifungal
9.1 In cases of acute meningitis, antibiotic treatment should treatment”. “Febrile neutropenia AND pre-emptive antifungal ther-
include a beta-lactam with activity against S. pneumoniae apy OR diagnostic-driven approach”.
and P. aeruginosa with good penetration into cerebrospinal
fluid (CSF) (cefepime or meropenem) and ampicillin to cover
1. High-risk neutropenia patients not receiving prophylaxis against
Listeria monocytogenes (A-III).
filamentous fungi can be given empirical antifungal treatment
9.2 In risk patients with suggestive clinical forms, or patients
if fever with no other obvious cause persists after 4–5 days of
with space-occupying lesions, consider other etiologies
broad-spectrum antibiotics and hemodynamic instability (B-II).
(Cryptococcus, Listeria, Nocardia, filamentous fungi, toxoplas-
2. Alternative treatment strategies, such as biomarker-guided
mosis and Mycobacterium tuberculosis (B-III).
treatment using galactomannan (GM) or beta-D-glucan (BDG),
reduce the use of antifungals safely and without affecting mor-
4. What is the duration of antibiotic treatment in patients with tality in neutropenic patients (A-I).
FN without clinically or microbiologically documented infec- 3. Empirical antifungal treatment is not recommended in the vast
tion? majority of hematologic patients with high-grade neutropenia
who receive antifungal prophylaxis covering filamentous fungi
Search terms: “Duration OR discontinuation” AND “Neutrope- (A-II).
nia” AND “Antimicrobial OR antibiotic” AND “Therapy OR
treatment”.
Targeted antibiotic treatment
1. Empirical antibiotic treatment can be stopped in hematologic
patients with FN who do not have clinically or microbiolog- 1. In documented cases of microbiological isolates, can antibi-
ically documented infection, if they have been afebrile for at otic treatment be adjusted to the susceptibility of the
least 72 h, and hemodynamically stable and asymptomatic since microorganism identified, even if neutropenia persists?
 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181 179

Search terms: “targeted OR de-escalation” AND “therapy OR 4. In uncomplicated infections or where bacteremia is caused by
treatment” AND “febrile neutropenia” AND “antimicrobial OR microorganisms different from those mentioned above, systemic
antibiotic”. targeted antibiotic treatment can be applied without removing
the CVC and antibiotic lock therapy should be considered (B-II).
1. In patients with documented microbiological isolates, treatment 5. Removal of the CVC is recommended if persistent bacteremia
should be targeted at the isolate, taking into account its in vitro is detected (evidenced in positive follow-up control cultures)
activity (including MIC), pharmacokinetic/pharmacodynamic 48 h-72 h after starting targeted antibiotic treatment (A-II), if
properties, as well as the individual characteristics of the patient there is no other obvious clinical focus (B-II), if there is infective
(A-I). endocarditis or peripheral embolism (A-II) or an early relapse
2. If the microorganism isolated is considered to be the only due to the same microorganism after completion of antibiotic
causative agent of the febrile episode, it is preferable to use an treatment, or failure of conservative treatment (B-II).
antimicrobial, normally a beta-lactam, with a narrower spec- 6. If fever persists in a neutropenic patient with an indwelling
trum when active (B-III). catheter after other focalities have been ruled out, but catheter-
3. Beta-lactam monotherapy is appropriate for targeted treatment related infection has not been confirmed, consider removal of the
of most cases of gram-negative bacteremia (A-I). 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
2. What is the duration of antibiotic treatment in patients with despite the absence of sepsis or local signs of infection (C-III).
FN and clinically or microbiologically documented infection?
Treatment of infections caused by multidrug-resistant Gram-
Search terms: “duration OR discontinuation” AND “neutrope- negative bacilli (MDR-GNB)
nia” AND “antimicrobial OR antibiotic” AND “therapy OR
treatment”. 1. What is the treatment of choice for cephalosporin-resistant
Enterobacteriaceae?
1. In hematologic patients with FN and clinically documented
infection, antibiotic treatment can be discontinued when the Search terms: “(ESBL or extended-spectrum beta-lactamase) and
clinical signs and symptoms of infection have resolved and the treatment and outcome”; “AmpC and Enterobacter* and treatment
patient has been afebrile for at least 72 h (B-II). and outcome”.
2. In hematologic patients with FN and microbiologically docu-
mented infection, treatment should be maintained until clinical
1.1 Targeted therapy in infections caused by extended-spectrum
and microbiological cure of infection (resolution of signs and
beta-lactamase (ESBL)-producing Enterobacteriaceae
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). 1.1.1 In stable patients, the targeted therapy of choice against
3. In both situations, if neutropenia persists after treatment has extended-spectrum beta-lactamase (ESBL)-producing
been discontinued the patient should be kept under close clinical Enterobacteriaceae is a beta-lactam/beta-lactamase
observation for at least 24–48 h, so that antibiotic treatment can inhibitor (BLBLI) combination, provided that in vitro
be restarted promptly if fever recurs (B-II). susceptibility is shown (B-II).
4. Centers that give prophylactic antibacterial agents should con- 1.1.2 Use of carbapenems is recommended for patients with sep-
sider renewing this regimen when empirical antibiotics have sis or septic shock criteria (C-I).
been discontinued for as long as the neutropenia continues 1.1.3 Piperacillin-tazobactam and meropenem should be admin-
(C-III). istered in extended infusion, since this has been shown
to improve prognosis in severe infections compared with
3. When is removal of a central venous catheter indicated? short-term infusions (A-I).
1.1.4 Piperacillin-tazobactam should be avoided for treat-
ing high-inoculum infections caused by strains with
Search terms: “central venous catheter removal”, “catheter-
MIC ≥ 4 mg/L (B-II).
related infection”, “management of central venous catheter
infection” “catheter-related bloodstream infection”.
1.2 Targeted therapy in infections caused by AmpC-producing
1. When CVC infection is documented, consider removal of the Enterobacteriaceae
catheter wherever possible, weighing up the advantages of
removal against the difficulty of obtaining new venous access 1.2.1 Cefepime and fluoroquinolones are the preferred treatment
(A-II). options for infections due to AmpC-producing Enterobac-
2. It is recommended to remove the CVC when there is documented teriaceae susceptible to these antimicrobials (B-II).
catheter-related bloodstream infection (CRBSI) and local signs 1.2.2 Piperacillin-tazobactam is a valid therapeutic option if
at the insertion site (suppuration), along the tunnel tract (tunnel in vitro activity is shown (B-II), but should be avoided for
infection), or if the patient presents criteria for severe sepsis with treating high-inoculum infections caused by AmpC- pro-
hemodynamic instability (septic shock) (A-II). ducing Enterobacteriaceae with MIC ≥ 4 mg/L (B-III).
3. To improve the prognosis of the patient, it is recommended 1.2.3 Use of carbapenems is recommended for patients without
to remove the CVC when there is documented CRBSI due to alternative treatment options, or with sepsis or septic shock
fungi (normally Candida spp), S. aureus, enterococci, gram- criteria (C-I).
negative bacilli (especially P. aeruginosa) and mycobacteria 1.2.4 We recommend that piperacillin-tazobactam, cefepime
(A-II). Removal is also recommended in infections with asso- and meropenem be administered in extended infusion,
ciated bacteremia caused by microorganisms that are difficult to since this has been shown to improve the prognosis in
eradicate (Bacillus spp., Micrococcus spp. and Propionibacterium severe infections when compared with short-term infu-
spp.) (B-II). sions (A-I).
180 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181

2. What is the treatment of choice for carbapenem-resistant antibiotics with optimized administration regimens, moni-
Gram-negative bacilli? toring plasma levels whenever possible (B-II).

2.1 Targeted treatment of infections caused by carbapenem- 3. Targeted treatment of Stenotrophomonas maltophilia infec-
resistant Enterobacteriaceae (CRE). tions.

Search terms: “(carbapenemase or KPC or OXA or NDM or VIM) Search terms: “Stenotrophomonas and treatment”.
and treatment and outcome”.
3.1 The treatment of choice for infections due to S. maltophilia is co-
2.1.1 Severe infections caused by KPC-producing Enterobacte- trimoxazole (trimethoprim 15 mg/kg/day in 3–4 divided doses)
riaceae in neutropenic patients should be treated with (C-II).
a combination of at least two active drugs from the 3.2 In patients with infections with co-trimoxazole-resistant
options included in the antibiogram (meropenem, colistin, strains, or those who cannot take co-trimoxazole (because of
tigecycline, fosfomycin and aminoglycosides) (B-II). We rec- hypersensitivity, for example), the recommended treatment
ommend the same approach for treating severe infections is minocycline (C-II) or fluoroquinolones (C-II) if they are
caused by other carbapenemase-producing Enterobacteri- active. There is more limited experience of the use of cef-
aceae (CRE) (C-III). tazidime, tigecycline and colistin in monotherapy (C-III). In
2.1.2 For infections caused by strains with meropenem the case of patients with serious or refractory infections who
MICs < 16 mg/L, the combination regimen should include require second-line therapy, consider combining two drugs
high-dose meropenem (2 g every 8 h) in extended infusion with in vitro activity categorized as susceptible.
(over 3 h) (B-II).
2.1.3 Ceftazidime-avibactam may be an alternative for severe Adjuvant measures and prevention
infections due to KPC-producing or OXA-48-producing
Enterobacteriaceae (C-III). We do not have well-designed 1. Is the use of colony-stimulating factors indicated for treat-
comparative studies available that enable this drug to be posi- ment of FN? When?
tioned against other treatment options (undecided). Nor are
there data to support its use in combination therapy (unde- Search terms: “febrile neutropenia”, “colony stimulating fac-
cided). tor”, “treatment”.
2.1.4 In this type of infection, it is especially important to ensure
control of the source of infection and to administer high- 1. Colony-stimulating factors (CSF) are not routinely recom-
dose antibiotics with optimized dosage regimens, monitoring mended in the treatment of FN (B-II).
plasma levels whenever possible (Table 4) (B-II). 2. They can be considered for therapeutic use in patients with
increased-risk for infection-related complications or predictive
2.2 Targeted therapy of extensively drug-resistant (XDR) and factors of poor prognosis (B-II).
pandrug-resistant (PDR) non-fermenting gram-negative
bacilli (NFGNB). 2. When would granulocyte transfusion be indicated?

Search terms: BGN-NF XDR and PDR: (Acinetobacter or Pseu- Search terms: “febrile neutropenia”, “granulocyte transfusion”.
domonas) and (resistant or resistance or MDR or XDR or PDR) and
treatment and outcome.
1. There is insufficient evidence of the efficacy of granulocyte trans-
fusion in patients with FN and documented infection (C-III).
2.2.1 In the case of XDR NFGNB infections for which there is a fully 2. Granulocyte transfusions should be administered only in the
active therapeutic alternative, single-agent treatment is rec- context of prospective clinical trials (B-III).
ommended with optimized administration (B-I), prioritizing
the use (in the following order) of beta-lactams, sulbactam 3. Is antibacterial prophylaxis indicated? Which drugs?
(in infections due to A. baumannii) and colistin, provided
that in vitro susceptibility is shown (C-II). Avoid monother-
Search terms: “febrile neutropenia”, “antibacterial prophy-
apy with aminoglycosides or tigecycline for the treatment of
laxis”.
severe infections (A-II, A-I).
2.2.2 For severe infections due to XDR-NFGNB strains with bor-
1. Antibacterial prophylaxis is not recommended in low-risk
derline susceptibility to the available treatment options,
patients (A-I).
optimized administration of combination therapy using two
2. In high-risk patients (ANC < 500/mm3 > 7 days), use of antibac-
or more agents should be considered, based on the best
terial prophylaxis should be evaluated on an individual basis in
options specified in the antibiogram (B-II).
accordance with the characteristics of the patient and local hos-
2.2.3 For XDR or PDR P. aeruginosa infections, use of ceftolozane-
pital epidemiology, owing to the lack of benefit for mortality and
tazobactam may be considered (C-II) or ceftazidime-
the increasing levels of resistance in gram-negative bacteria (B-
avibactam (C-I), although there is as yet limited experience
I). If prophylaxis is used, epidemiological surveillance for MDRO
of their use in this setting.
detection should be implemented.
2.2.4 If these options are not available or the infection is caused by
pan-resistant isolates, it will be necessary to develop combi-
nation therapy regimens using two or more agents, choosing 4. Is prophylaxis with colony stimulating factors indicated?
those with intermediate susceptibility, or whose MICs are When?
closest to the susceptibility cut-off (C-III).
2.2.5 It is particularly important in these infections to ensure con- Search terms: “febrile neutropenia”, “colony stimulating fac-
trol of the source of infection and to administer high-dose tor”, “prophylaxis”
 C. Gudiol et al. / Enferm Infecc Microbiol Clin. 2020;38(4):174–181 181

1. The decision to use colony-stimulating factor prophylaxis for the participated as speaker at scientific meetings sponsored by Pfizer
prevention of FN should be based on the relative myelotoxic- and MSD. Manuela Aguilar-Guisado has participated as speaker at
ity of the chemotherapy regimen and the presence of potential scientific meetings sponsored by Pfizer and MSD. José Molina Gil-
risk factors, which should be evaluated before each cycle of Bermejo has received lecturing fees in activities financed by Merck
chemotherapy is administered. Sharp & Dohme, and has received grants to attend conferences orga-
2. In situations where chemotherapy dose intensity or dose den- nized by Astellas Pharma. Carlos Solano has participated as speaker
sity strategies confer a survival benefit, prophylaxis with G-CSF at scientific meetings sponsored by Pfizer, MSD, Astellas and Gilead
should be used as supportive treatment (A-I). He has received grants for clinical and preclinical research from
3. Primary prophylaxis is recommended from the first chemother- Pfizer and Astellas. Carolina García-Vidal has received fees for
apy cycle for patients whose overall risk of FN is ≥ 20%, based on speaking at events sponsored by Gilead Science, Merck Sharp and
patient-related, disease-related and regimen-related risk factors Dohme, Pfizer, Janssen and Novartis, and has received a subsidy
(A-I). from Gilead Science. María Lourdes Vázquez López has partici-
4. When the overall risk of FN is 10%–20%, attention should be pated as speaker at scientific meetings sponsored by Pfizer, MSD,
focused on additional risk factors (such as comorbidities or Gilead, Astellas, Amgen. José Ramón Azanza has participated as
advanced age), which increase the risk of FN and support an speaker at scientific meetings sponsored by Pfizer, MSD, Gilead,
indication of prophylaxis with G-CSF (A-I). Janssen, AstraZeneca, Roche. José Ramón Azanza has participated
5. Prophylaxis with G-CSF is not recommended if chemotherapy as speaker at scientific meetings sponsored by Pfizer, MSD, Gilead,
has an FN risk of <10% (A-I). Janssen, AstraZeneca, Roche Francisco Javier Candel has partici-
6. Secondary prophylaxis is recommended for patients who expe- pated as speaker scientific meetings sponsored by Pfizer, MSD,
rienced neutropenic complications in a previous cycle of Gilead, Angelini, Astellas, and ERN. Isabel Ruiz-Camps has par-
chemotherapy and in whom a dose reduction or delay in treat- ticipated as speaker at scientific meetings sponsored by Astellas,
ment could compromise progression-free or overall survival, or Celgene, Gilead, MSD, Pfizer and in scientific consultancy for Astel-
treatment outcome (A-I). las, Gilead, and Pfizer. María Suárez-Lledó has participated as
7. Prophylaxis can be given with any of the following factors (fil- speaker at scientific meetings and has collaborated in scientific
grastim, lenograstim and pegfilgrastim) or any of their available studies sponsored by Pfizer and MSD. Isidro Jarque has participated
biosimilars (A-I), preferably subcutaneously. as speaker at scientific meetings sponsored by Gilead, MSD, and
Pfizer. Isabel Sánchez-Ortega has no conflicts of interest.
Conflicts of interest
Acknowledgements
Carlota Gudiol has served as speaker at scientific meetings spon-
sored by Pfizer, MSD, Astellas and Gilead. Rafael de la Cámara has
The authors would like to thank Antonio Gutiérrez-Pizarraya for
participated as speaker at scientific meetings sponsored by MSD,
his comments and technical support in the preparation of this docu-
GSK, Novartis, Astellas, Pfizer and Gilead; and in consultancy and
ment. They would also like to thank the members María Illescas and
advisory activities for Novartis, MSD, Janssen, Clinigen and Astellas.
Juan Manuel García-Lechuz Moya for their comments from society
Manuel Lizasoain has participated as speaker at scientific meetings
members during the revision phase of the document.
sponsored by Pfizer, MSD and Gilead. Jordi Carratalà has partici-
pated as speaker at scientific meetings sponsored by Pfizer, MSD,
Gilead and Angelini. Rafael Cantón has participated as speaker Appendix A. Supplementary data
at scientific meetings sponsored by Angelini, ERN Laboratorios,
Supplementary data associated with this article can be found, in
MSD, Pfizer and Zambon and has received funding for research
projects from AstraZeneca and MSD. Manuela Aguilar-Guisado has the online version, at doi:10.1016/j.eimc.2019.01.013.