Manejo de los episodios de neutropenia febril en niños con cáncer: consenso de la Sociedad Latinoamericana de Infectología Pediátrica 2021 / Management of episodes of febrile neutropenia in children with cancer: consensus of the Latin American Society of Pediatric Infectious Diseases 2021

Resumen El Comité de Infecciones en el Niño Inmunocomprometido de la Sociedad Latinoamericana de Infectología Pediátrica, entrega este documento de Consenso, llamado "Manejo de los episodios de neutropenia febril en niños con cáncer. Consenso de la Sociedad Latinoamericana de Infectología Pediátrica 2021". El documento contiene recomendaciones sobre aspectos de prevención, predicción, diagnóstico, tratamiento y pronóstico de los episodios de fiebre y neutropenia, incluyendo recomendaciones específicas sobre: Análisis de ingreso; evaluación, ajustes y duración de terapias antimicrobianas; diagnóstico y manejo de infección fúngica invasora; análisis de los principales focos clínicos de infección; condiciones ambientales necesarias para hospitales que atienden niños con cáncer y quimioprofilaxis. Se ha puesto especial énfasis en entregar las mejores recomendaciones para optimizar el manejo de los episodios de fiebre y neutropenia en niños con cáncer, buscando la equidad y la excelencia a través de todos los centros que atienden estos pacientes en América Latina.

Abstract The Committee for Infections in Immunocompromised Children of Sociedad Latinoamericana de Infectología Pediátrica, presents this Consensus document, titled "Management of episodes of febrile neutropenia in children with cancer. Consensus of the Sociedad Latinoamericana de Infectología Pediátrica 2021". The document includes recommendations on prevention, prediction, diagnosis, treatment and prognosis of episodes of fever and neutropenia, including specific recommendations on: Analysis at admission; evaluation, adjustments and duration of antimicrobial therapies; diagnosis and management of invasive fungal infection; analysis of the main clinical source of infections; environmental conditions necessary for hospitals caring for children with cancer and chemoprophylaxis. Special emphasis has been placed on providing the best recommendations to optimize the management of episodes of fever and neutropenia in children with cancer, with equity and excellence through all the centers that treat these patients in Latin America.

Caracterización clínica y microbiológica de episodios de bacteriemia por Streptococcus grupo viridans en niños con cáncer y neutropenia febril de alto riesgo / Clinical characteristics and microbiological profile of viridans group streptococci bacteremia in children with cancer and high-risk febrile neutropenia

Resumen Introducción: Streptococcus grupo viridans (SGV) ha adquirido relevancia como microorganismo causante de neutropenia febril, asociándose a morbilidad significativa. Objetivo: Caracterizar episodios de bacteriemia causados por SGV en niños con cáncer que desarrollaron neutropenia febril de alto riesgo (NFAR) desde abril de 2004 a junio de 2018 en seis hospitales pediátricos de Santiago, Chile. Pacientes y Métodos: Análisis retrospectivo de bases de datos de cuatro proyectos FONDECYT sucesivos, prospectivos y multicéntricos, registrando características clínicas y de laboratorio de los pacientes, además de patrón de resistencia antimicrobiana de las cepas aisladas. Resultados: Se registraron 95 episodios de bacteriemia asociada a SGV en 91 niños con NFAR. Destacan: leucemia mieloide aguda como enfermedad de base, neutropenia profunda, hospitalización prolongada (15 días), uso extendido de antimicrobianos (14 días), uso de citarabina en esquemas de quimioterapia (86% episodios). Las manifestaciones clínicas más frecuentes fueron respiratoria y gastrointestinal, asociándose en 26% a síndrome de shock por Streptococcus grupo viridans. Hubo elevada resistencia a β lactámicos, sin cepas no susceptibles a vancomicina. Discusión: SGV es un patógeno relevante en niños con cáncer, fiebre y neutropenia en nuestro medio, asociado a casos de sepsis. La resistencia a β lactámicos es un aspecto que requiere vigilancia epidemiológica estricta en esta población.

Abstract Background: Viridans group streptococci (VGS) has acquired relevance as a microorganism causing febrile neutropenia, associated with significant morbidity. Aim: To characterize episodes of bacteremia caused by VGS in children with cancer who developed high-risk febrile neutropenia (HRFN) during the period from April 2004 to June 2018 in six pediatric hospitals of Santiago, Chile. Method: Database analysis of 4 successive, prospective and multicentric studies recording clinical and laboratory characteristics of patients, as well as antimicrobial susceptibility pattern of isolated strains. Results: 95 episodes of VGS bacteremia in 91 children with HRFN were analyzed. It emphasizes acute myeloid leukemia as cancer type, deep neutropenia, prolonged hospitalization (15 days), with extended use of antimicrobials (14 days) and use of cytarabine in chemotherapy schemes (86% episodes). The most frequent clinical manifestations were respiratory and gastrointestinal, associating up to 26% viridans group shock syndrome. There was high resistance to β lactams. As expected, there were not non-susceptible strains to vancomycin. Discussion: VGS is a relevant microorganism in children with cancer, fever and neutropenia, with a high percentage of sepsis. Resistance to β lactams is an issue that requires strict epidemiological surveillance in this population.

Neutropenia febril. Análisis de casos en un centro de tercer nivel de atención / Febrile neutropenia. Case analysis in a third level attention center

Introducción: La neutropenia febril es una urgencia infectológica con agentes etiológicos diversos. La causa más frecuente es la postquimioterapia, con una incidencia del 80%en inmunocomprometidos. Requiere el uso de antimicrobianos de amplio espectro, que originan mayores gastos en el sistema de salud. Objetivos: identificar los agentes microbiológicos en pacientes con neutropenia febril internados en el Hospital de la Asociación Médica de Bahía Blanca "Dr.Felipe Glasman" (HAMBB), en el periodo enero-diciembre de 2017; evaluar la sensibilidad y resistencia antimicrobiana; determinar el porcentaje de rédito de los cultivos. Materiales y Métodos: Estudio retrospectivo, descriptivo. Se obtuvieron datos de historias clínicas y de registros informatizados de los pacientes hospitalizados por neutropenia febril. Resultados: Se analizaron 52 episodios de 49 de pacientes. Las patologías de base fueron: tumores sólidos (54%); oncohematológicos (36%); enfermedades no neoplásicas (8%). El episodio febril fue postquimioterapia (48 %): por infección (35%); otras causas (17%). El 31% de los episodios postquimioterapia ocurrieron postratamiento (7-15 días). Los cultivos fueron negativos en el 69%. Se identificaron E.coli (15%); S.aureus (8%), P.aeruginosa (4%); 2% enterobacter (2%); E.faecalis ( 2%). Sensibilidad antibiótica: E.coli sensible a aminoglucósidos y fluoroquinolonas en el 87,5%, con resistencia de 50% para betalactámicos; a betalactámicos+IBL, cefalosporinas de 1° generación y cotrimoxazol (37,5%). S.aureus, E.faecalis, Enterobacter y P. aeruginosa fueron 100% sensibles a los antibióticos testeados. Conclusiones: El mayor porcentaje: bacterias Gram (-); principal agente causal: E. coli; principal agente Gram (+): S. aureus. La mayoría fueron pacientes con tumores sólidos. El 50 % de los episodios fue posterior postquimioterapia. El mayor rédito se obtuvo en hemocultivos. La mayor parte de los gérmenes fueron sensibles a la terapéutica empírica utilizada en nuestro hospital. (AU)

Introduction: Febrile neutropenia is an infectious emergency with diverse etiological agents. The most frequent cause is post-chemotherapy, with an incidence of 80% in immunocompromised patients. It requires the use of broadspectrum antimicrobials, which lead to higher expenses in the health system. Objectives: To identify the microbiological agents in patients with febrile neutropenia admitted to Bahía Blanca Medical Association "Dr. Felipe Glasman " Hospital (HAMBB) in the January-December 2017 period; to evaluate antimicrobial susceptibility and resistance; to determine the percentage of positive cultures. Materials and Methods: Retrospective, descriptive study. Data from medical records and computerized records of patients hospitalized for febrile neutropenia were obtained. Results: 52 episodes from 49 patients were analyzed. Underlying pathologies were: solid tumors (54%); oncohaematological (36%); non-neoplastic diseases (8%). The febrile episode was postchemotherapy (48%); due to infection (35%); other causes (17%). Thirty one per cent (31%) of post-chemotherapy episodes occurred after treatment (7-15 days). Cultures were negative in 69% of the cases. We could identify E.coli (15%); S.aureus (8%), P. aeruginosa (4%); 2% enterobacter (2%); E.faecalis (2%). Antibiotic susceptibility: E.coli sensitive to aminoglycosides and fluoroquinolones in 87.5%, with 50% resistance to betalactams; to beta-lactamases + IBL, 1st generation cephalosporins and cotrimoxazole (37.5%). S.aureus, E.faecalis, Enterobacter and P. aeruginosa were 100% susceptible to the antibiotics tested. Conclusions: The highest percentage: Gram bacteria (-); main causal agent: E. coli; Main agent Gram (+): S. aureus. The majority were patients with solid tumors. 50% of the episodes were post-chemotherapy. The occurrence was obtained in blood cultures. Most germs were susceptible to the empirical therapy used in our hospital. (AU)

Piperacillin/tazobactam in continuous infusion versus intermittent infusion in children with febrile neutropenia

Abstract Background Febrile neutropenia (FN) is a common complication in children who receive chemotherapy for cancer. Objective The objective of this study was to evaluate the clinical efficacy of the continuous versus intermittent infusion of piperacillin/tazobactam (TZP) in febrile neutropenic pediatric patients. Methods This is a non-blinded randomized controlled clinical trial. Eligible group consisted of hemato-oncological patients with FN who were candidates to receive TZP. Patients were randomized to one of two groups: Group 1 received antibiotic treatment through intravenous intermittent infusion of TZP 300 mg/kg/day based on piperacillin, divided into four doses, not exceeding 16 g/day; Group 2 received an initial TZP loading dose of 75 mg/kg infusion over 30 min, and then a continuous infusion of TZP 300 mg/kg/day through central line with pump over 24 h. Results There were 176 episodes that could be assessed, 100 in Group 1 and 76 in Group 2. There was no statistically significant difference in treatment failure in the experimental group (continuous infusion) compared with the intermittent group, 21% versus 13% (p = 0.15). The increase in the absolute risk reduction was 0.08% (95% confidence interval 0.12-0.30), and the number needed to treat was 12.4. One patient in each group died. Conclusions There were no differences in fever resolution, clinical cure rate, or mortality when comparing the continuous with the intermittent TZP infusion.

Parte IV. Terapia antimicrobiana en pacientes con cáncer y receptores de trasplante de precursores hematopoyéticos / Antimicrobial therapy in cancer patients and hematopoietic stem cell transplantation receptors

Resumen Este documento incluye los recursos terapéuticos antiinfecciosos necesarios para pacientes inmunocomprometidos por terapia de cáncer o receptores de trasplante de precursores hematopoyéticos (TPH). Se aborda la terapia indicada para pacientes con las situaciones clínicas prevalentes en esta población y la terapia indicada para algunos microorganismos específicos. Según presentación clínica, se aborda el manejo de pacientes con: neutropenia febril sin foco, sepsis, infecciones del sistema nervioso central, neumonía, infecciones de piel y tejidos blandos, enterocolitis neutropénica e infección del tracto urinario. Se describe el arsenal terapéutico necesario, las dosis recomendadas y las precauciones especiales para el uso de antibacterianos, antivirales, antifúngicos y antiparasitarios en esta población, incluida la medición de concentraciones plasmáticas de ciertos fármacos en situaciones específicas.

This manuscript includes the antiinfective therapeutic resources for immunocompromised patients under chemotherapy by cancer or hematopoietic stem cells transplant (HSCT) receptors. The document presents the antimicrobial therapy indicated in the most prevalent clinical situations in this population and the primary and alternative therapy for some specific microorganisms. The clinical situations included in the analysis are: febrile neutropenia without focus, sepsis, infections of the central nervous system, pneumonia, skin and soft tissue infections, neutropenic enterocolitis and urinary tract infection. The therapeutic resources, recommended doses and special precautions for the use of antimicrobial recommended in bacterial, viral, fungal and parasitic infections in this population are described, including the measurement of plasma concentrations of certain drugs in specific situations.

Tailoring antimicrobials in febrile neutropenia: using faster diagnostic and communication tools to improve treatment in the era of extensively resistant pathogens

ABSTRACT Febrile Neutropenia represents a medical emergency and the use of appropriate antimicrobial therapy is essential for a better outcome. Although being time-consuming, conventional cultures and antimicrobial susceptibility tests remain the golden standard practices for microbiology identification. Final reports are typically available within several days. Faster diagnostic tools, such as species identification trough Matrix Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) and molecular techniques might help to shorten time to diagnostic and also guide definitive therapy in this scenario. Here we present a case in which the use of a diagnostic molecular workflow combining MALDI-TOF and real-time PCR for relevant genes codifying antibiotic resistant integrated with instant communication report, led to a tailored and more appropriate treatment in a patient presenting with febrile neutropenia.

Rare severe mycotic infections in children receiving empirical caspofungin treatment for febrile neutropenia

ABSTRACTEmpirical antifungal therapy is most often given to patients with leukemia. However breakthrough fungal infections under antifungal therapy are not uncommon. Four children, with hematologic malignant disease developed mycotic breakthrough infections while on empirical caspofungin treatment for a median of 14 (range 11-19) days. Trichosporon asahii was detected in the blood culture of two patients and Geotrichum capitatum in the other two (one patient also had positive cerebrospinal fluid culture). Because the patients' clinical situation worsened, voriconazole was empirically added for two patients three and five days before the agent was detected. The first sterile blood culture was obtained 3-7 days of voriconazole treatment. All patients reached clear cultures but one patient died. One patient with central nervous system infection with G. capitatum had severe neurological sequelae. Very severe fungal infections can occur during empirical caspofungin therapy. Therefore, patients should be followed closely.

Caracterización de los episodios de neutropenia febril en niños con leucemia mieloide aguda y leucemia linfoblástica aguda / Characterization of episodes of febrile neutropenia in children with acute myeloid leukemia and acute lymphoblastic leukemia

Introduction: Leukemia is the most common cancer in Chilean children. Acute lymphoblastic leukemia (ALL) is more prevalent and longer survival compared to acute myeloid leukemia (AML). Aims: To describe episodes of febrile neutropenia (FN) in children with AML, determining frequency of infections as agent, focus and evolution, comparing children with ALL episodes. Method: A prospective multicenter study. Children presenting with FN at six hospitals in Santiago, Chile, were invited to participate in two consecutive FONDECYT projects, from April 2004 to June 2011. All patients were uniformly evaluated, recording epidemiological, clinical and laboratory variables. Information regarding FN episodes of children with LMA and LLA was used to this study. Results: We evaluated 506 episodes of FN in children with leukemia: 173 children with AML and 333 in children with ALL. NF episodes in children with ALML showed significantly greater depth and duration of neutropenia, febrile remained a > period of time and had a worse clinical outcome, as evidenced by > hemodynamic instability, > sepsis, CRP > 90 mg/L for a longer time, more days of hospitalization, > frequency of hospitalization in ICU, > bacteremia, mainly by Streptococcus viridans group, > change of antimicrobial treatment, > use of antifungal therapy. Conclusions: This study demonstrates that FN episodes in children with ALML further evolve unfavorably, compared with episodes of FN in children with ALL. FN episodes in children with ALML require a more aggressive diagnostic and therapeutic approach, related to its severity.

Introducción: En Chile, la leucemia es el cáncer más frecuente en niños, siendo las dos principales leucemia linfoblástica aguda (LLA) y leucemia mieloide aguda (LMA). Objetivo: Describir los episodios de neutropenia febril (NF) observados en niños con LMA, determinando la frecuencia de infecciones según agente, foco y evolución, comparándolos con episodios de niños con LLA. Método: Estudio prospectivo, multicéntrico. Pacientes < de 18 años con NF que consultaron en uno de los seis hospitales del grupo PINDA de Santiago, Chile (abril de 2004-junio de 2011), enrolados en dos sucesivos proyectos FONDECYT. Se recogió de manera sistemática la información epidemiológica, clínica y de laboratorio relativa a cada episodio de NF; posteriormente se extrajo de la base de datos la información correspondiente a los pacientes con LMA y LLA. Resultados: Se evaluaron 506 episodios de NF en niños con leucemia: 173 en niños con LMA y 333 en niños con LLA. Los episodios de NF en niños con LMA presentaron significativamente mayor duración e intensidad de la neutropenia, se mantuvieron febriles por un mayor período de tiempo y presentaron una peor evolución clínica, evidenciada por mayor inestabilidad hemodinámica, mayor frecuencia de sepsis, PCR > 90 mg/L por un período más prolongado, más días de hospitalización, mayor frecuencia de hospitalización en UCI, mayor presencia de bacteriemia, principalmente por Streptococcus grupo viridans, mayor número de cambio de esquemas antimicrobianos y mayor uso de antifúngicos, particularmente de tipo empírico. Conclusiones: Este estudio demuestra que los episodios de NF en niños con LMA evolucionan en mayor medida en forma desfavorable, comparado con episodios de NF en niños con LLA. Los episodios de NF en niños con LMA requieren un enfoque diagnóstico y terapéutico más agresivo, relacionado a su gravedad.

Efficacy and Safety of Pegfilgrastim in Indian Patients.

Context: Pegfilgrastim, a pegylated recombinant granulocyte colony stimulating factor, promotes the hematopoietic recovery after cytotoxic chemotherapy and is marketed in India as PegstimTM. Aims: This post marketing surveillance study was undertaken to evaluate the efficacy and safety of PegstimTM in clinical practice in Indian patients. Material and Methods: Investigators participating in this post marketing surveillance were asked to capture data of all the patients who were given PegstimTM along with cytotoxic chemotherapy for their underlying malignancy. PegstimTM was given as a single subcutaneous dose approximately 24 hours after administration of cytotoxic chemotherapy and patients were followed up for 14 days with blood counts at baseline and every alternate day. Each cycle of chemotherapy in which PegstimTM was administered was considered as a distinct patient entity for efficacy and safety analysis. Results: PegstimTM injections were used in 213 patients and led to an increase in Absolute Neutrophil Count (ANC) as early as 2 days after administration of the drug with mean percent increase in ANC of 129.8 ± 210.9% at the end of 14 days. The overall incidence of moderate-severe (grade III/IV) febrile neutropenia in the total population studied was 6.1% (13 patients). Intravenous antibiotics were used in 10 (4.7%) patients while 4 (1.9%) patients required hospitalization. A total of 57 adverse events were reported in 32 patients during the entire course of the study, the most common being musculoskeletal pain in 22 (10.3%) patients. Conclusions: The results from this post marketing surveillance study support the efficacy and tolerability of PegstimTM used for preventing neutropenia across various tumor types and regimens in Indian patients.

Características demográficas, morbilidad y mortalidad de los pacientes adultos con neutropenia febril tratados con cefepima / Demographics, morbidity, and mortality febrile neutropenic adult patients treated with cefepime

Introduction: Cefepime efficacy for treatment of febrile neutropenia (FN) in cancer adult patients is a controversial issue. Objective: To describe the demographic characteristics and general mortality of patients suffering from febrile neutropenia treated with cefepime in a fourth-level Latin American hospital. Patients and Methods: A cross-sectional observational study was performed. Study settled at San Ignacio of Bogotá, Colombia. University Hospital from January 2004 to December 2008. Results: A total of 333 patients were treated with cefepime, of whom 125 had suffered FN and met pre established inclusion and exclusion criteria. The general mortality was 14.4%, which was similar to the overall mortality in FN in other reports. Conclusions: Although there is still no clarity regarding the efficacy of cefepime in FN, its use has not been restricted. This study did not identify an excess risk of mortality in patients treated with cefepime.

Introducción: La eficacia de cefepima en pacientes adultos con cáncer y neutropenia febril (NF) es objeto de controversia en las publicaciones científicas. Objetivo: Describir las características demográficas y la mortalidad general de los pacientes adultos con NF tratados con cefepima en un hospital latinoamericano de cuarto nivel. Pacientes y Métodos. Estudio observacional descriptivo, de corte transversal en el que se incluyeron todos los pacientes tratados con cefepima en el Hospital Universitario San Ignacio de Bogotá, Colombia entre enero de 2004 y diciembre de 2008. Resultados: Recibieron cefepime un total 333 pacientes, de los cuales 125 tenían diagnóstico de NF y cumplían criterios pre-establecidos de inclusión y exclusión. Como desenlace final se encontró una mortalidad de 14,4%, un porcentaje similar a la mortalidad general en NF reportada en la literatura médica. Conclusiones: Aún no hay claridad sobre la eficacia del uso de cefepima en NF; sin embargo, tampoco se ha proscrito su uso y los datos del presente estudio no encontraron un riesgo adicional de mortalidad.

Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer: Consenso de la Sociedad Latinoamericana de Infectología Pediátrica / Diagnosis and treatment of febrile neutropenia in pediatric cancer patients: Consensus of the Sociedad Latinoamericana de Infectología Pediátrica

La Sociedad Latinoamericana de Infectología Pediátrica, a través de su Comité de Infecciones en Niños Inmunocomprometidos, propone un documento de consenso sobre "Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer". Este documento-guía aborda el manejo de la neutrope-nia febril orientado a la atención de niños con cáncer en América Latina. Se realizó una búsqueda exhaustiva de la literatura, y se consideró particularmente la experiencia publicada proveniente de centros de nuestro continente, que aporta una mirada regional y adecuada a la realidad de nuestros países. El manuscrito contiene un panorama epidemiológico de la Región y recomendaciones para la evaluación clínica y de laboratorio necesarios para el manejo de estos pacientes, establece criterios de categorización de riesgo de infecciones bacterianas invasoras, analiza las medidas de cuidado general de los pacientes en el ambiente hospitalario y extra-hospitalario, propone diferentes enfoques terapéuticos de acuerdo a las realidades epidemiológicas institucionales, parámetros clínicos y de categorización de riesgo, establece diferentes algoritmos de seguimiento según la evolución de cada paciente, especifica las situaciones en que está indicada algún tipo de profilaxis y da los lineamientos generales sobre el tipo y oportunidad de terapia antifúngica a utilizar en ellos. Se ha puesto especial énfasis en entregar, de forma práctica, y con la mayor evidencia posible, las recomendaciones para el mejor manejo de los niños con cáncer, fiebre y neutropenia, buscando la equidad y la excelencia en todos los centros oncológicos latinoamericanos.

This document is a consensus guideline on the "Diagnosis and treatment of febrile neutropenia in children with cancer" developed by the Committee for Infectious Diseases in Immunocompromised Children of the Sociedad Latinoamericana de Infectología Pediátrica. This guideline discusses the management of febrile neutropenia focused on Latin American children with cancer. It is based on a thorough review of the literature, with particular attention to experiences reported by centers within the continent in order to provide recommendations applicable to the region. The manuscript includes a description of the regional epidemiology of cancer and infections in children, recommendations for clinical and laboratory studies required for patient management, description of a classification method to identify patients at different risk for invasive bacterial infections, outpatient and inpatient general care strategies and differential treatment strategies adjusted to local epidemiological realities, different algorithms for patient follow-up according to clinical course, a discussion of the rationale for prophylaxis strategies in specific situations including general guidelines for antifungal treatment. The Guidelines intend to provide practical, evidence-based recommendations in order to promote the best possible management for children with cancer, fever and neutropenia, throughout oncology centers of Latin America.