ABSTRACT Introduction: The treatment of acute lymphoblastic leukemia (ALL) has evolved in recent decades, reaching an overall survival rate close to 90%. Currently, approximately 4% of patients with ALL die from secondary complications of chemotherapy. Among these complications, the most frequent is febrile neutropenia (FN). The treatment of acute myeloid leukemias (AMLs) is even more aggressive, being consequently related to a considerable amount of treatment-related toxicity with a high risk of severe infection and death. Method: In order to reduce the infection-related risks in these groups of patients, systemic antibacterial prophylaxis has emerged as a possible approach. Results: Antibiotic prophylaxis during neutropenia periods in those undergoing chemotherapy have .already been proven in adults with acute leukemias (ALs). Among the possible available therapeutic options for bacterial prophylaxis in children with cancer, fluoroquinolones emerged with the most amount of evidence. Within this class, levofloxacin became the best choice. Conclusion: Therefore, the use of levofloxacin seems to be indicated in very specific situations: in children who are known to be neutropenic for a long time, secondary to intensive chemotherapy; in children with AL undergoing chemotherapy to induce remission; or in children undergoing hematopoietic stem cell transplantation (HSCT). This article aims to describe recent evidence focusing on antibiotic prophylaxis in children with ALs. Introduction (ALL decades 90 90% Currently 4 FN. FN . (FN) AMLs (AMLs aggressive treatmentrelated death Method infectionrelated approach Results already ALs (ALs) cancer class choice Conclusion Therefore situations time remission HSCT. HSCT (HSCT) 9 (FN (ALs (HSCT

ABSTRACT Background: Despite high cure rates, treatment-related mortality in children with acute lymphoblastic leukemia (ALL) remains significant. About 4% of patients die during remission induction therapy and approximately two-thirds of treatment-related deaths are due to infectious complications. Methods: From May 2021 to June 2022, children aged one through 18 years, with a recent diagnosis of ALL, admitted to three pediatric oncology centers in Brazil, were enrolled in this multicenter, open-label, randomized, phase 3 clinical trial. Eligible patients were randomly divided into two groups, based on a 1:1 allocation ratio, to receive, or not, levofloxacin as a prophylactic agent during the induction phase. All patients were treated according to the IC-BFM 2009 chemotherapy protocol. Primary endpoints were carbapenemase-producing Enterobacteriaceae (CPE) colonization, Clostridioides difficile diarrhea, and other adverse events related to the use of levofloxacin. The secondary endpoint was febrile neutropenia during induction. The median follow-up was 289 days. Results: Twenty patients were included in this trial, 10 in each group (control and levofloxacin). Mild adverse reactions related to levofloxacin were observed in three patients (30%). Three patients had Clostridioides difficile diarrhea, two in the levofloxacin group and one in the control group (p > 0.99). Only one patient presented colonization by CPE. This patient belonged to the levofloxacin group (p > 0.99). Nine patients presented febrile neutropenia, five in the control group and four in the levofloxacin intervention group (p > 0.99), one patient died due to febrile neutropenia. Conclusion: The use of levofloxacin was shown to be safe in the induction phase in children with de novo ALL. The use of this medication did not increase the rate of colonization by CPE nor the rate of diarrhea by C. difficile. All adverse reactions were mild and remitted either spontaneously or after switching medicine administration from oral to intravenous route. Background rates treatmentrelated treatment ALL (ALL significant 4 twothirds thirds complications Methods 202 2022 1 years Brazil multicenter openlabel, openlabel open label, label open-label randomized trial groups 11 1: ratio receive ICBFM IC BFM 200 protocol carbapenemaseproducing carbapenemase producing (CPE followup follow up 28 days Results . levofloxacin) 30%. 30 30% (30%) p 0.99. 099 0.99 0 99 0.99) 0.99, , Conclusion C route 20 2 (30% 09 0.9 9 (30 0. (3 (

RESUMO Objetivo: Analisar e identificar infecções documentadas e possíveis fatores de risco para infecções por Clostridioides difficile em crianças com câncer. Métodos: Estudo retrospectivo caso-controle em um hospital pediátrico oncológico, que abrangeu os anos de 2016–2019. O pareamento foi realizado por idade e doença de base e, para cada caso, o número de controles variou de um a três. Modelos de regressão logística foram utilizados para avaliar os fatores de risco. Resultados: Analisamos 63 casos de infecção documentados por C. difficile e 125 controles. A diarreia esteve presente em todos os casos, acompanhada de febre acima de 38°C em 52,4% dos pacientes. A mortalidade foi semelhante entre casos (n=4, 6,3%) e controles (n=6, 4,8%; p=0,7). No grupo caso, 71% dos pacientes e, no grupo controle, 53% deles receberam antibióticos de amplo espectro antes da infecção. Para uso prévio de vancomicina, a Odds Ratio para infecção por C. difficile foi de 5,4 (intervalo de confiança [IC95%] 2,3–12,5); para meropenem, 4,41 (IC95% 2,1–9,2) e, para cefepima, 2,6 (IC95% 1,3–5,1). Para os agentes antineoplásicos, a razão de chances para carboplatina foi de 2,7 (IC95% 1,2–6,2), para melfalano de 9,04 (IC95% 1,9-42,3), para bussulfano de 16,7 (IC95% 2,1–134,9) e, para asparaginase, de 8,97 (IC95% 1,9–42,9). Conclusões: A infecção sintomática por C. difficile em crianças com câncer associou-se à internação prévia e ao uso de antibióticos como vancomicina, meropenem e cefepime nos últimos três meses. Os quimioterápicos carboplatina, melfalano, bussulfano e asparaginase também foram fatores de risco. Objetivo Métodos casocontrole caso controle oncológico 20162019 2016 2019 2016–2019 Resultados 6 C 12 38C 38 524 52 4 52,4 n=4, n4 n (n=4 6,3% 3 n=6, n6 (n=6 4,8% 48 8 p=0,7. p07 p p=0,7 . 0 7 p=0,7) 71 53 vancomicina 54 5 5, intervalo IC95% IC95 IC [IC95% 2,3–12,5 23125 2 2,3–12,5) 441 41 4,4 (IC95 2,1–9,2 2192 1 9 cefepima 26 2, 1,3–5,1. 1351 1,3–5,1 1,3–5,1) antineoplásicos 27 1,2–6,2, 1262 1,2–6,2 , 1,2–6,2) 904 04 9,0 1,942,3, 19423 1,9 42,3 42 1,9-42,3) 167 16 16, 2,1–134,9 211349 134 897 97 8,9 1,9–42,9. 19429 1,9–42,9 1,9–42,9) Conclusões associouse associou se meses 2016201 201 2016–201 52, n=4 (n= 6,3 n=6 4,8 p0 p=0, IC9 [IC95 2,3–12, 2312 44 4, (IC9 2,1–9, 219 135 1,3–5, 126 1,2–6, 90 9, 942 1,942,3 1942 19 1, 423 42, 1,9-42,3 2,1–134, 21134 13 89 8, 1,9–42, 201620 20 2016–20 n= (n 6, p=0 [IC9 2,3–12 231 (IC 2,1–9 21 1,3–5 1,2–6 94 1,942, 194 1,9-42, 2,1–134 2113 1,9–42 20162 2016–2 p= [IC 2,3–1 23 2,1– 1,3– 1,2– 1,942 1,9-42 2,1–13 211 1,9–4 2016– 2,3– 2,1 1,3 1,2 1,94 1,9-4 2,1–1 1,9– 2,3 1,9-

Abstract Objective: The aim of this study was to analyze and identify documented infections and possible risk factors for Clostridioides difficile infections in children with cancer. Methods: This is a retrospective case-control study, carried out in a pediatric cancer hospital, covering the years 2016–2019. Matching was performed by age and underlying disease, and for each case, the number of controls varied from 1 to 3. Logistic regression models were used to assess risk factors. Results: We analyzed 63 cases of documented infection by C. difficile and 125 controls. Diarrhea was present in all cases, accompanied by fever higher than 38°C in 52.4% of the patients. Mortality was similar among cases (n=4; 6.3%) and controls (n=6; 4.8%; p=0.7). In all, 71% of patients in the case group and 53% in the control group received broad-spectrum antibiotics prior to the infection. For previous use of vancomycin, the Odds Ratio for C. difficile infection was 5.4 (95% confidence interval [95%CI] 2.3–12.5); for meropenem, 4.41 (95%CI 2.1–9.2); and for cefepime, 2.6 (95%CI 1.3–5.1). For the antineoplastic agents, the Odds Ratio for carboplatin was 2.7 (95%CI 1.2–6.2), melphalan 9.04 (95%CI 1.9–42.3), busulfan 16.7 (95%CI 2.1–134.9), and asparaginase 8.97 (95%CI 1.9–42.9). Conclusions: C. difficile symptomatic infection in children with cancer was associated with previous hospitalization and the use of common antibiotics in cancer patients, such as vancomycin, meropenem, and cefepime, in the last 3 months. Chemotherapy drugs, such as carboplatin, melphalan, busulfan, and asparaginase, were also risk factors. Objective Methods casecontrol hospital 20162019 2016 2019 2016–2019 disease Results 6 C 12 38C 38 524 52 4 52.4 n=4 n4 n (n=4 6.3% n=6 n6 (n=6 4.8% 48 8 p=0.7. p07 p p=0.7 . 0 7 p=0.7) 71 53 broadspectrum broad spectrum vancomycin 54 5 5. 95% 95 (95 95%CI 95CI CI [95%CI 2.3–12.5 23125 2 2.3–12.5) meropenem 441 41 4.4 2.1–9.2 2192 9 2.1–9.2) cefepime 26 2. 1.3–5.1. 1351 1.3–5.1 1.3–5.1) agents 27 1.2–6.2, 1262 1.2–6.2 , 1.2–6.2) 904 04 9.0 1.9–42.3, 19423 1.9–42.3 42 1.9–42.3) 167 16 16. 2.1–134.9, 211349 2.1–134.9 134 2.1–134.9) 897 97 8.9 1.9–42.9. 19429 1.9–42.9 1.9–42.9) Conclusions months drugs 2016201 201 2016–201 52. n= (n= 6.3 4.8 p0 p=0. (9 2.3–12. 2312 44 4. 2.1–9. 219 135 1.3–5. 126 1.2–6. 90 9. 1942 1.9–42. 21134 2.1–134. 13 89 8. 201620 20 2016–20 (n 6. p=0 ( 2.3–12 231 2.1–9 21 1.3–5 1.2–6 194 1.9–42 2113 2.1–134 20162 2016–2 p= 2.3–1 23 2.1– 1.3– 1.2– 19 1.9–4 211 2.1–13 2016– 2.3– 2.1 1.3 1.2 1.9– 2.1–1 2.3 1. 1.9

Resumo Objetivos O objetivo do estudo é identifìcar os principals fatores de risco relacionados a má evolução do tratamento da infecção periprótese. Métodos Foram avaliados de forma retrospectiva os prontuários de 109 pacientes submetidos a cirurgias de endoprótese não convencional (primárias e revisões), no período de 01 de janeiro de 2007 a 31 de dezembro de 2018. Destes, 15 pacientes diagnosticadas com infecção periprótese foram elegíveis para a participação no estudo. As variáveis sexo, idade do diagnóstico, osso acometido, duração da cirurgia, contagem de leucócitos no pré-operatório, infecção do trato urinário no 1° ano pós-operatório e tempo decorrido entre a colocação da endoprótese e o diagnóstico da infecção foram relacionadas aos desfechos utilizando o Teste Exato de Fisher (variáveis bicategóricas) e o Teste Anova (variáveis tricategóricas). A média de tempo entre diagnóstico e desfecho foram comparadas pelo método de t-student. Resultados Os fatores de risco avaliados não demostraram correlação estatisticamente significante com os desfechos. Os dados demonstram haver tendência de diferença entre a média de tempo do aparecimento do processo infeccioso e o desfecho final do paciente. Devido a amostra limitada, acreditamos que estudos com coortes maiores possam comprovar essa tendência. Conclusão Identificamos que o tempo entre a cirurgia de colocação da endoprótese e o aparecimento dos sintomas de infecção tende a ter relação com o desfecho e a evolução do paciente no tratamento da infecção periprótese. Os demais fatores associados, apesar de aparentemente relacionados, também não se mostraram estatisticamente relacionados a má evolução no tratamento.

Abstract Objectives To identify the main risk factors related to poor outcomes after the treatment for periprosthetic infection. Materials and Methods Medical records from 109 patients who underwent non-conventional endoprosthesis surgeries (primary and revision procedures) from January 1’ 2007’ to December 31’ 2018’ were retrospectively evaluated. In total’ 15 patients diagnosed with periprosthetic infection were eligible to participate in the study. Variables including gender’ ageatdiagnosis’ affected bone’ surgery duration’white blood cell (WBC) count before endoprosthesis placement’ urinary tract infection during the first postoperative year, and time elapsed from endoprosthesis placement to infection diagnosis were related to outcomes using the Fisherexact test (for the bicategorical variables) or analysis of variance (ANOVA’ for the tricategorical variables). The mean times from diagnosis to final outcome were compared using the Student t-test. Results These risk factors did not show a statistically significant correlation with the outcomes. The data revealed a trend towards a difference between the mean time for the onset of infection and the final outcome. Due to the limited sample, we believe that studies with larger cohorts can prove this trend. Conclusion We identified that the time from endoprosthesis placement to the onset of the symptoms of infection tends to be related to the outcome and evolution of the patient evolution during the treatment for periprosthetic infection. Although apparently correlated, other associated factors were not statistically linked to poor treatment outcomes.

ABSTRACT Background: Pediatric oncology patients (POP) have a high risk of infections due to impaired immunity. Invasive pneumococcal disease (IPD) is an important cause of severe infection in these patients and it is associated with high mortality. This study aimed to evaluate the incidence and risk factors associated with IPD at a Pediatric Oncology Center in Brazil. Methods: This was a retrospective case-control study. All IPD cases in children with cancer from 2005 through 2016 were reviewed. Each case of IPD was matched with two controls from a cohort of patients matched for year of IPD, age and disease in order to assess risk factors. The incidence density was calculated as the number of IPD per 100,000 patients-year. Results: A total of 51 episodes of IPD in 49 patients was identified. All pneumococci were isolated from blood cultures. The median age was five years and 67% were male; mortality rate was 7.8%. The IPD incidence density rate in POP was 311.21 per 100,000 patients-year, significantly higher than the rate in the general pediatric population. Severe neutropenia was the only risk factor associated with IPD, after multivariate conditional logistic regression analysis. Conclusion: Although pneumococcal disease decreased after the introduction of 10-valent pneumococcal vaccine in the Brazilian national immunization schedule in 2010, there was no decrease in the IPD incidence rate in our cohort. A higher coverage rate of pneumococcal vaccination in children in the general population might be necessary to reduce the incidence rate in this high-risk population.

ABSTRACT In the present paper we summarize the suggestions of a multidisciplinary group including experts in pediatric oncology and infectious diseases who reviewed the medical literature to elaborate a consensus document (CD) for the diagnosis and clinical management of invasive fungal diseases (IFDs) in children with hematologic cancer and those who underwent hematopoietic stem-cell transplantation. All major multicenter studies designed to characterize the epidemiology of IFDs in children with cancer, as well as all randomized clinical trials addressing empirical and targeted antifungal therapy were reviewed. In the absence of randomized clinical trials, the best evidence available to support the recommendations were selected. Algorithms for early diagnosis and best clinical management of IFDs are also presented. This document summarizes practical recommendations that will certainly help pediatricians to best treat their patients suffering of invasive fungal diseases.

ABSTRACT Bloodstream infections (BSIs) are serious infections associated with high rates of morbidity and mortality. Every hour delay in initiation of an effective antibiotic increases mortality due to sepsis by 7%. Turnaround time (TAT) for conventional blood cultures takes 48 h, forcing physicians to streamline therapy by exposing patients to broad-spectrum antimicrobials. Our objective was (1) to evaluate the accuracy and TAT of an optimized workflow combining direct matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) and in-house real-time polymerase chain reaction (PCR) for bacterial identification and antimicrobial resistance profiling directly from positive blood bottles for diagnosing bloodstream infections and (2) to verify the effect of reporting results to medical staff. A total of 103 BSI episodes from 91 patients admitted to three hospitals in São Paulo, Brazil were included. TAT from molecular versus conventional methods was measured and compared. Our protocol showed an overall agreement of 93.5% for genus and 78.5% for species identification; 74.2% for methicillin resistance detection, 89.2% for extended-spectrum β-lactamase profiling, 77.8% for metallo-β-lactamase profiling, and 100% for carbapenemase profile and vancomycin-resistance detection when compared with conventional testing. TAT of molecular sample processing according to our protocol was 38 h shorter than conventional methods. Antimicrobial interventions were possible in 27 BSI episodes. Antimicrobial discontinuation was achieved in 12 BSI episodes while escalation of therapy occurred in 15 episodes. Antimicrobial therapy was inadequate in three (12%) BSI episodes diagnosed using results of molecular testing. Our in-house rapid protocol for identifying both bacteria and antimicrobial resistance provided rapid and accurate results, having good agreement with conventional testing results. These results could contribute to faster antimicrobial therapy interventions in BSI episodes.

BACKGROUND: Usual treatment regimens with vancomycin often fail to provide adequate serum levels in patients with severe infections. METHODS: Retrospective analysis of vancomycin trough serum measurements. The following parameters were calculated by Bayesian analysis: vancomycin clearance, distribution volume, and peak estimated concentrations. The area under the concentration curve (AUC) (total daily dose/24 h clearance of vancomycin) was used to determine the effectiveness of treatment through the ratio of AUC/minimum inhibitory concentration (MIC) above 400, using MIC = 1 µg/mL, based on isolates of Staphylococci in cultures. RESULTS: Sixty-one vancomycin trough measurements were analyzed in 31 patients. AUC/MIC > 400 was obtained in 34 out of 61 dosages (55.7%), but the mean vancomycin dose required to achieve these levels was 81 mg/kg/day. In cases where the usual doses were administered (40-60 mg/kg/day), AUC/MIC > 400 was obtained in nine out of 18 dosages (50%), in 13 patients. Trough serum concentrations above 15 mg/L presented a positive predictive value of 100% and a negative predictive value of 71% for AUC/MIC > 400. CONCLUSION: Higher than usual vancomycin doses may be required to treat staphylococcal infections in children with oncologic/hematologic diseases. Since the best known predictor of efficacy is the AUC/MIC ratio, serum trough concentrations must be analyzed in conjunction with MICs of prevalent Staphylococci and pharmacokinetic tools such as Bayesian analysis.

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.

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.

OBJETIVO: descrever caso clínico de uma criança que desenvolveu septicemia por Salmonella enteritidis, sendo diagnosticada imunodeficiência primária. DESCRIÇÃO: paciente masculino, de um ano e 9 meses, com febre e lesões de pele há 50 dias, internado com lesão perilabial ulcerada com secreção purulenta, lesão ulcerada friável em língua, lesões ulcerocrostosas em membros, pneumonia bilateral com derrame pleural e choque séptico, sendo diagnosticado Salmonella enteritidis como agente etiológico. A identificação desta bactéria direcionou a investigação para a síndrome MIM. O diagnóstico de deficiência do receptor da interleucina-12 (IL-12Rbeta1) foi confirmado através da dosagem de IL-12 e do interferon (IFN)-gama produzido pelas células do paciente em meio de cultura. O resultado demonstrou ausência de produção de IL-12 e do IFN-gama mesmo após estímulo adequado. COMENTÁRIOS: a identificação da Salmonella enteritidis como agente etiológico de septicemia sugere uma disfunção do sistema imunológico. Foi realizada avaliação laboratorial das imunidades humoral, celular e inata. Após avaliação laboratorial direcionada para síndrome MIM, foi confirmada a deficiência do receptor da Interleucina-12 (IL-12Rbeta1). O uso do IFN-gama é recomendado nos casos graves, assim como o tratamento de suporte e o aconselhamento genético.

OBJECTIVE: to present a case report of a child who developed sepsis by Salmonella enteritidis associated with the diagnosis of primary immunodeficiency. DESCRIPTION: a twenty-one months old boy presenting fever and skin lesions, bilateral pneumonia with pleural effusion and septic shock. Salmonella enteritidis was isolated in blood cultures and pleural fluid. The identification of the bacteria suggested the presence of the MIM syndrome. The diagnosis of IL-12Rbeta1 was confirmed after IL-12 and IFN-gamma levels were measured using patient cells in a culture medium. The results showed absence of IL-12 and the IFN-gamma post stimulation using BCG. COMMENTS: a severe infection by Salmonella enteritidis is strongly suggestive of an immune system dysfunction. Laboratory tests for humoral, cellular and innate immunity were performed. Interleukin 12 receptor beta1 (IL-12 Rbeta1) deficiency was confirmed after specific laboratory evaluation. The use of INF-gamma is recommended in severe cases.