Use of antimicrobials in pediatric wards of five Brazilian hospitals.

The use of antimicrobials (AMs) in pediatric infections is common practice and use may be inappropriate leading to antimicrobial resistance. Off-label AM use is also common in this group and can result in drug-related problems. There is lack of DUR data in Brazil and in Latin America, specially for AM pediatric use. The aim of this study was to describe the utilization of AMs in hospitalized children in five hospitals in Brazil. We conducted an observational study of the utilization of AMs in pediatric wards in hospitals in the states of Ceará (CE), Sergipe (SE), Rio de Janeiro (RJ), Rio Grande do Sul (RS) and the Federal District (DF). Data derived from patient medical records and prescriptions were collected over a six-month period in each hospital. The number of AMs used by each patient was recorded, and AM use was assessed using Days of therapy (DOT) and Length of therapy (LOT) per 1000 patient days according to different patient characteristics. Off-label (OL) use was described according to age. The study analyzed data from 1020 patients. The sex and age distributions were similar across the five hospitals. However, differences were found for comorbidities, history of ICU admission and length of hospital stay. The most common diseases were respiratory tract infections. There were wide variations in DOT/1000PD (278-517) and LOT/1000PD (265-390). AM utilization was highest in the hospital in SE. The consumption of second-generation penicillins and cephalosporins was high. The prevalence of OL use of AMs was higher for patients in the RJ hospital, in infants, in patients who underwent prolonged hospital stays, and in patients who used multiple AMs. The AM that showed the highest prevalence of OL use was azithromycin, in both oral and parenteral formulations. Overall AM use was high and showed differences in each setting, possibly influenced by local characteristics and by prescribing standards adopted by pediatricians.

Adverse Drug Reactions to Anti-infectives in Hospitalized Children: A Multicenter Study in Brazil.

INTRODUCTION: Adverse drug reactions (ADRs) to anti-infectives affect especially hospitalized children and contribute to increased morbidity, mortality, length of stay, and costs in healthcare systems. OBJECTIVE: To assess ADRs associated with anti-infective use in Brazilian hospitalized children. METHODS: A prospective cohort study was conducted in 5 public hospitals over 6 months. Children aged 0-11 years and 11 months who were hospitalized for more than 48 h and prescribed anti-infectives for over 24 h were included. RESULTS: A total of 1020 patients met the inclusion criteria. Of these, 152 patients experienced 183 suspected ADRs. Most reactions were related to the gastrointestinal system (65.6%), followed by skin reactions (18.6%). Most reactions were classified as probable causality (58.5%), moderate severity (61.1%), and unavoidable (56.2%). Our findings showed that ADRs were associated with increased length of stay (P < .001), increased length of therapy (P < .015), increased days of therapy (P = .038), and increased number of anti-infectives prescribed per patient (P < .001). CONCLUSION: Almost 15% of hospitalized children exposed to anti-infectives presented suspected ADRs. Their occurrence was classified as probable, of moderate severity, and unavoidable. ADRs were significantly influenced by the length of hospital stay and the number of anti-infectives prescribed per patient.

The Utility of the Liverpool Adverse Drug Reaction Assessment Tools in the Evaluation of Chemotherapy-Induced Nausea and Vomiting in Children / Utilidade das Ferramentas de Avaliação de Reações Adversas a Medicamentos de Liverpool na Análise de Náuseas e Vômitos Induzidos por Quimioterapia em Crianças / La Utilidad de las Herramientas de Evaluación de Reacciones Adversas a Medicamentos de Liverpool en la Evaluación de Náuseas y Vómitos Inducidos por Quimioterapia en Niños

Introduction: Chemotherapy-induced nausea and vomiting (CINV) are common adverse drug reactions (ADR) experienced by children undergoing treatment for cancer. New paediatric ADR Assessment Causality and Avoidability tools (LCAT and LAAT) of Liverpool are suitable for categorizing factors related to ADR prevention and improving patient care. Still, no studies to date have compared the utility and results of its application for CINV in countries with different levels of development. Objective: To investigate the utility of the Liverpool Adverse Drug Reaction Causality and Avoidability Assessment Tools (LCAT and LAAT) in assessing CINV in children. Method: Prospective observational study of CINV assessment in children aged 4 to 16 years from Alder Hey Children's Hospital (Liverpool, UK) and "Instituto de Puericultura e Pediatria Martagão Gesteira" (Rio de Janeiro, Brazil). Children (helped by the parents) completed a symptom diary during chemotherapy and for 24 hours after treatment. Information regarding underlying diagnosis, past medical history, and medications administered was collected from the patient record. Case reports were prepared, and the temporal relationship between nausea and vomiting and exposure to chemotherapy, including any strategy to prevent CINV, was recorded. The causality and avoidability were assessed with LCAT and LAAT, respectively. Results: There were 26 reports of CINV in 36 chemotherapy cycles. The causality assessment was 'definite' for 24 cases. Twenty ADRs were deemed 'definitely avoidable' and four 'not avoidable'. Selection of inappropriate therapeutic options and non-administration of antiemetic were the most common factors observed in the hospitals studied. Conclusion: The LCAT and LAAT were helpful for assessing CINV in children in two different hospitals.

Introdução: Náuseas e vômitos induzidos por quimioterapia (NVIQ) são reações adversas a medicamentos (RAM) comuns em crianças em tratamento oncológico. Novas ferramentas de Avaliação de Causalidade e Evitabilidade de RAM de Liverpool (LCAT e LAAT) foram validadas e auxiliam a categorização de fatores de risco. Contudo, até o momento, nenhum estudo comparou a utilidade e os resultados de sua aplicação para NVIQ em países com diferentes níveis de desenvolvimento. Objetivo: Investigar a utilidade da LCAT e LAAT na avaliação de NVIQ. Método: Estudo observacional prospectivo com crianças de 4 a 16 anos do Alder Hey Children's Hospital (Liverpool, Reino Unido) e do Instituto de Puericultura e Pediatria Martagão Gesteira (Rio de Janeiro, Brasil). As crianças (ajudadas pelos pais) preencheram um diário de sintomas durante e até 24 horas após administração da quimioterapia. Informações sobre diagnóstico subjacente, história médica pregressa e medicamentos administrados foram coletadas do prontuário do paciente. Relatos de casos foram preparados e a relação temporal entre náuseas e vômitos e exposição à quimioterapia, incluindo qualquer estratégia para prevenir NVIQ, foi registrada para análise da causalidade e evitabilidade com o auxílio de LCAT e LAAT, respectivamente. Resultados: Houve 26 notificações de NVIQ em 36 ciclos de quimioterapia. A causalidade foi 'definida' para 24 casos. Foram consideradas 'definitivamente evitáveis' 20 RAM e 'não evitáveis', quatro. A seleção de opções terapêuticas inadequadas e a omissão de antieméticos foram os principais problemas evitáveis. Conclusão: O LCAT e o LAAT foram úteis para avaliar NVIQ em crianças em dois hospitais diferentes

Introducción: Las náuseas y vómitos inducidos por quimioterapia (NVIQ) son reacciones adversas a medicamentos (RAM) comunes en niños en tratamiento oncológico. Nuevas herramientas de Evaluación de Causalidad y Evitabilidad de RAM de Liverpool (LCAT y LAAT) han sido validadas y ayudan en la categorización de factores de riesgo. Sin embargo, ningún estudio ha comparado su utilidad y resultados para evaluación de NVIQ en países con diferentes niveles de desarrollo. Objetivo: Investigar la utilidad de LCAT y LAAT en la evaluación de NVIQ. Método: Estudio observacional prospectivo con niños de 4 a 16 años del Alder Hey Children's Hospital (Liverpool, Reino Unido) y del Instituto de Pediatría Martagão Gesteira (Río de Janeiro, Brasil). Los niños (ayudados por los padres) completaron un diario de síntomas durante y hasta 24 horas después de la quimioterapia. La información sobre el diagnóstico subyacente, la historia médica previa y los medicamentos se recopiló de la historia clínica médico del paciente. Se prepararon informes de casos y se registró la relación temporal entre las RAM y la exposición a la quimioterapia, incluyendo cualquier estrategia para prevenir NVIQ, para análisis de causalidad y evitabilidad con LCAT y LAAT, respectivamente. Resultados: Hubo 26 notificaciones de NVIQ en 36 ciclos de quimioterapia. La causalidad fue "definida" para 24 casos. Fueron consideradas "definitivamente evitables" 20 RAM y "no evitables", cuatro. La selección de opciones terapéuticas inadecuadas y la omisión de antieméticos fueron los principales problemas evitables. Conclusión: LCAT y LAAT fueron útiles para evaluar NVIQ en niños en dos hospitales diferentes

Development and evaluation of an assessment of the age-appropriateness/inappropriateness of formulations used in children.

BACKGROUND: Medicines designed for adults may be inappropriate for use in children in terms of strength, dosage form and/or excipient content. There is currently no standardised method of assessing the age-appropriateness of a medicine for paediatric use. AIM: To develop and test a tool to assess whether a dosage form (formulation) is appropriate for children and estimate the proportion of formulations considered 'inappropriate' in a cohort of hospitalised paediatric patients with a chronic illness. METHOD: A multi-phase study: patient data collection, tool development, case assessments and tool validation. Inpatients aged 0-17 years at two UK paediatric/neonatal hospitals during data collection periods between January 2015 and March 2016. Written informed consent/assent was obtained. Medicines assessed were new or regularly prescribed to inpatients as part of their routine clinical care. All medicine administration episodes recorded were assessed using the Age-appropriate Formulation tool. The tool was developed by a consensus approach, as a one-page flowchart. Independent case assessments were evaluated in 2019. RESULTS: In 427 eligible children; 2,199 medicine administration episodes were recorded. Two assessors reviewed 220 episodes in parallel: percentage exact agreement was found to be 91.7% (99/108) and 93.1% (95/102). In total, 259/2,199 (11.8%) medicine administration episodes involved a dosage form categorised as 'age-inappropriate'. CONCLUSION: A novel tool has been developed and internally validated. The tool can identify which medicines would benefit from development of an improved paediatric formulation. It has shown high inter-rater reliability between users. External validation is needed to further assess the tool's utility in different settings.

Serious Adverse Drug Reactions and Safety Signals in Children: A Nationwide Database Study.

Children are more exposed to inappropriate medicine use and its consequent harms. Spontaneous reporting of suspected Serious Adverse Drug Reactions (SADR) increases knowledge and prevention of pharmacotherapy risk. Disproportionality measures are useful to quantify unexpected safety issues associated with a given drug-event pair (signals of disproportionality). This cross-sectional study aimed to assess SADR reporting and safety signals for Brazilian children from 0-12 years old, notified between January 2008 and December 2013 from the Brazilian Surveillance Agency (Notivisa). Information from serious reports (gender and age of the patient, event description, suspected drug) was included. Disproportionality analysis based on Reporting Odds Ratios with a confidence interval of 95% was conducted to identify possible signals of disproportionate reporting (SDR). Almost 30% of 1,977 suspected SADR was related to babies (0-1-year-old). 69% of reports happened with intravenous dosage forms, and 35% of suspected SADR involved off label use according to age. Laronidase, miglustat, imipenem/cilastatin, and clofarabine were involved in six or more suspected deaths among 75 deaths reported. There were 107 SDRs, of which 16 events (15%) were not described in the product labels. There was a relatively higher number of SADRs in Brazilian children compared with studies from other countries. SDRs found, (especially drug-event pairs 'imipenen/cilastatin-pneumonia' and 'laronidase-respiratory insufficiency') should be investigated more. The reports of SADR with IV dosage forms and OL drug use suggest the need for drug research and the use of better dosage forms for children in Brazil.

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool.

AIM: To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. METHODS: The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the 'gold standard' (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). MAIN OUTCOME MEASURES: Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. RESULTS: Preliminary work-Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52-90%. Phase 3: Percentage exact agreement ranged from 35-70%. Overall, individuals had better agreement with the 'gold standard'. CONCLUSION: Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups.

Incidence, characteristics and risk factors of adverse drug reactions in hospitalized children - a prospective observational cohort study of 6,601 admissions.

BACKGROUND: Adverse drug reactions (ADRs) are an important cause of harm in children. Current data are incomplete due to methodological differences between studies: only half of all studies provide drug data, incidence rates vary (0.6% to 16.8%) and very few studies provide data on causality, severity and risk factors of pediatric ADRs. We aimed to determine the incidence of ADRs in hospitalized children, to characterize these ADRs in terms of type, drug etiology, causality and severity and to identify risk factors. METHODS: We undertook a year-long, prospective observational cohort study of admissions to a single UK pediatric medical and surgical secondary and tertiary referral center (Alder Hey, Liverpool, UK). Children between 0 and 16 years 11 months old and admitted for more than 48 hours were included. Observed outcomes were occurrence of ADR and time to first ADR for the risk factor analysis. RESULTS: A total of 5,118 children (6,601 admissions) were included, 17.7% of whom experienced at least one ADR. Opiate analgesics and drugs used in general anesthesia (GA) accounted for more than 50% of all drugs implicated in ADRs. Of these ADRs, 0.9% caused permanent harm or required admission to a higher level of care. Children who underwent GA were at more than six times the risk of developing an ADR than children without a GA (hazard ratio (HR) 6.40; 95% confidence interval (CI) 5.30 to 7.70). Other factors increasing the risk of an ADR were increasing age (HR 1.06 for each year; 95% CI 1.04 to 1.07), increasing number of drugs (HR 1.25 for each additional drug; 95% CI 1.22 to 1.28) and oncological treatment (HR 1.90; 95% CI 1.40 to 2.60). CONCLUSIONS: ADRs are common in hospitalized children and children who had undergone a GA had more than six times the risk of developing an ADR. GA agents and opiate analgesics are a significant cause of ADRs and have been underrepresented in previous studies. This is a concern in view of the increasing number of pediatric short-stay surgeries.

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital.

BACKGROUND: Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs. METHODS: A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring. RESULTS: A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001). CONCLUSIONS: OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.