A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer.

BACKGROUND: The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure. OBJECTIVES: To create a pharmacokinetic model that could help to explain the variability. METHODS: Retrospective review of paediatric patients with cancer. Models were built using Pmetrics. RESULTS: We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients. CONCLUSIONS: Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.

Antibiotic prophylaxis in acute childhood leukemia: What is known so far?

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.

Invasive fungal infections in pediatric patients with central nervous system tumors: novel insights for prophylactic treatments?

Background and aims: Invasive fungal disease (IFD) poses significant morbidity and mortality risks, especially in pediatric patients with neoplastic diseases. However, there is a notable lack of data concerning patients with central nervous system (CNS) tumors. Considering vulnerability factors to infections such as neutropenia, corticosteroids, chemotherapy, surgical interventions, and others, this study aims to evaluate the incidence of IFD in pediatric patients with CNS tumors and determine appropriate indications for prophylactic measures. This is a single-center, retrospective study conducted between 2011 and 2022 at the Pediatric Institute of Oncology (IOP-GRAACC-UNIFESP). Results: A total of 38 cases of IFD were diagnosed in 818 children with CNS malignancies (4,6%). The mean age was 3.5 years (0.4-28y), with 22 (57.9%) male patients. Embryonal tumors (18/38, 47.3%) were the most prevalent CNS tumors, followed by low-grade gliomas (13/38, 34.2%). All episodes met the EORTC IFD criteria, and 36/38 (94.7%) were proven. Invasive yeast infections (33/36, 91.6%), predominantly Candida (30/33, 90.9%), were the most common diagnosis. In total, 25 patients (25/38, 65.8%) were receiving chemotherapy, with 13 of them having embryonal tumors. A total of 11 infants were in the Head Start scheme, resulting in a high prevalence of IFD in these group of patients (11/58, 18.9%). In total, 13 (13/38, 34.2%) patients underwent neurosurgery, mostly ventricular-peritoneal shunts revisions (10/13, 76.9%). Nine (9/38, 23.7%) were with prolonged use of corticosteroids, eight of them associated with neurosurgery. Conclusion: Routine systemic antifungal prophylaxis based solely on diagnosis is not recommended for low-risk cases. Evaluating patient- and treatment-specific risk factors is crucial in infants undergoing high-dose chemotherapy with expected neutropenia and in patients requiring prolonged corticosteroid therapy alongside neurosurgical procedures.

Safety of levofloxacin as an antibiotic prophylaxis in the induction phase of children newly diagnosed with acute lymphoblastic leukemia: an interim analysis of a randomized, open-label trial in Brazil.

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.

A case-control study of Clostridioides difficile symptomatic infections in a pediatric cancer hospital.

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.

COVID-19 in HSCT recipients: a collaborative study of the Brazilian Society of Marrow Transplantation (SBTMO).

In the COVID-19 scenario, patients undergoing hematopoietic stem cell transplantation (HSCT) infected with SARS-CoV-2 may have an increased risk of death. Through a national multicenter study, we aimed to describe the impact of COVID-19 on the survival of HSCT recipients in Brazil. Eighty-six patients with a confirmed diagnosis of SARS-CoV-2 (92% by RT-PCR) were included. There were 24 children and 62 adults receiving an autologous (n = 25) and allogeneic (n = 61) HSCT for malignant (n = 72) and non-malignant (n = 14) disorders. Twenty-six patients died, (10 on autologous (38%) and 16 patients (62%) on allogeneic group). The estimated overall survival (OS) at day 40 was 69%. Adults had decreased OS compared to children (66% vs 79%, p = 0.03). The severity of symptoms at the time of diagnosis, ECOG score, laboratory tests (C-reactive protein, urea values) were higher in patients who died (p < 0.05). In conclusion, HSCT recipients infected with SARS-CoV-2 have a high mortality rate mainly in adults and patients with critical initial COVID-19 presentation. These findings show the fragility of HSCT recipients with SARS-CoV-2 infection. Therefore, the importance of adherence to preventive measures is evident, in addition to prioritizing the vaccination of family members and the HSCT team.

Risk Factors Related to Poor Outcomes in the Treatment of Non-conventional Periprosthetic Infection.

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, age at diagnosis, 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 Fisher exact 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.

Safety of levofloxacin as an antibiotic prophylaxis in the induction phase of children newly diagnosed with acute lymphoblastic leukemia: an interim analysis of a randomized, open-label trial in Brazil

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.

Antibiotic prophylaxis in acute childhood leukemia: What is known so far?

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.

A case-control study of Clostridioides difficile symptomatic infections in a pediatric cancer hospital / Um estudo caso-controle de infecções sintomáticas por Clostridioides difficile em um hospital oncológico pediátrico

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.

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.

Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients.

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.

Vancomycin serum concentrations in pediatric oncologic/hematologic intensive care patients

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.