Development of Antimicrobial Defined Daily Dose (DDD) for the Pediatric Population.

Antimicrobial stewardship programs (ASPs) optimize antimicrobial use, improve patient outcomes, and reduce resistance. To assess the effectiveness of ASPs, it is necessary to have indicators that can be widely used. Defined daily dose (DDD) was designed by WHO for the adult population as a consumption indicator. However, there are no DDDs adapted to the pediatric population. The main objective of this study is to establish the most appropriate DDD values in this population. An observational, retrospective, multicenter study was conducted. Antimicrobial prescriptions were collected from pediatric wards of seven Spanish tertiary hospitals for 2 years. The DDDs obtained from the prescriptions were compared with the theoretical DDDs agreed upon in the first stage. To select the optimal DDD, the following were analyzed: power value, magnitude obtained from the differences in the DDD, statistical significance, and degree of agreement in the stipulated doses. A total of 4788 prescriptions were collected. Pediatric DDD was defined for 30 different antimicrobials. A potency >80% was obtained in 24 antibiotics. 51.2% of the selected DDD correspond to Phase I and 39.5% from Phase II. Pediatric DDD of different antimicrobials was obtained, providing an indicator that can be used globally in different hospitals to analyze the consumption and efficacy of ASPs.

Infective endocarditis in paediatric patients from Andalusia (Spain), 2008-2020.

INTRODUCTION: Paediatric infective endocarditis (IE) is a serious condition associated with significant mortality. Information in Spain is limited and comes from case series from single centres. The aim was to describe the epidemiology, clinical features, microbiology and outcome of paediatric IE in Andalusia. PATIENTS AND METHODS: Multi-centre descriptive observational retrospective study of patients <18 years old with a diagnosis of IE who were admitted to six Andalusian hospitals during 2008-2020. RESULTS: 44 episodes of IE (41 patients) with a median age of 103 months (IQR 37-150 months) were identified. Congenital heart disease (CHD) was the main predisposing factor, identified in 34 cases (77%). A total of 21 (48%) episodes of IE occurred in patients with prosthetic material. These had higher rate of CHD (p = 0.002) and increased end organ dysfunction (p = 0.04) compared to those with native valve. Fever was an almost universal symptom, associated in 23% of the episodes with heart failure. Staphylococcus aureus (25%) followed by coagulase-negative staphylococci (18%) and Streptococcus viridans (14%) were the most frequently isolated microorganisms, and three (7%) patients with central venous catheters had a fungal infection. Thromboembolic events were observed in 30% of the episodes, surgical intervention was required in 48% of cases. Mortality rate was 9%. Prosthetic material and CRP > 140 mg/L were independent predictors of complicated IE. CONCLUSIONS: Our findings emphasize the high morbidity of paediatric IE. The information provided could be useful for the identification of epidemiological and clinical profiles of children with IE and complicated forms.

Position statement of the Spanish Society of Paediatric Infectious Diseases on the introduction, implementation and assessment of antimicrobial stewardship programmes in paediatric hospitals.

In the past few years, antimicrobial resistance has increased, becoming a serious public health problem. The irrational use of antimicrobials is one of the main contributors to antimicrobial resistance. The paediatric population is not free from this problem, as antimicrobials are widely prescribed in this age group, often inappropriately. The introduction of antimicrobial stewardship programmes (ASPs) has proven crucial in curbing the emergence of antimicrobial resistance. At the international level, the need to develop specific paediatric ASPs has been recognised on account of the differences between adult and paediatric patients as concerns infection and approaches to diagnosis and treatment. For this reason, paediatric ASPs should be multidisciplinary programmes led by paediatric infectious disease specialists and use specific paediatric indicators (such as days of treatment, antimicrobial susceptibility patterns in the paediatric population, or clinical indicators) to help identify areas of improvement and develop effective targeted interventions. On the other hand, the support and leadership of the pertinent scientific societies are also essential. The purpose of this document is to present the position of the Sociedad Española de Infectología Pediátrica (SEIP, Spanish Society of Paediatric Infectious Diseases) concerning the implementation of paediatric ASPs in hospitals in Spain and to provide tools to facilitate their application in hospitals throughout the regional health care systems in the country.

Impact of cytomegalovirus infection prior to hematopoietic stem cell transplantation in children with inborn errors of immunity.

The presence of active viral infections has an impact on the prognosis of patients undergoing hematopoietic stem cell transplantation (HSCT). Nevertheless, the number of reports of cytomegalovirus infection in patients with inborn errors of immunity (IEI) who undergo HSCT is relatively low. To analyze the effect of cytomegalovirus infection acquired prior to curative treatment on patient survival in 123 children with IEI. An observational and retrospective study was performed with patients younger than 18 years diagnosed with IEI who were candidates for HSCT, gene therapy, or thymus transplantation at five hospitals in Spain between 2008 and 2019. We included 123 children, 25 infected by cytomegalovirus prior to undergoing curative treatment (20.3%). At IEI diagnosis, 24 of the patients were already infected, 21 of whom had symptomatic cytomegalovirus disease (87%), while the other three patients developed disease before undergoing curative treatment. The patients with cytomegalovirus infection had higher mortality than those without (p = 0.006). Fourteen patients developed refractory cytomegalovirus infection (56%), all of whom died, while no patients with non-refractory infection died (p = 0.001) All deaths that occurred before curative treatment and three of the five after the treatment were attributed to cytomegalovirus. Patients with refractory cytomegalovirus disease had the highest pre-HSCT mortality rate (64.3%), compared with the non-infected children and those with non-refractory cytomegalovirus disease (10.1%) (p < 0.0001). CONCLUSION: Prevention and prompt control of cytomegalovirus infection, together with early HSCT/gene therapy, are crucial for improving the prognosis in children with IEI. WHAT IS KNOWN: • Cytomegalovirus is the most frequent viral infection in children with inborn errors of immunity who are candidates to hematopoietic stem cell transplantation (HSCT). • Active viral infections at the time of HSCT lead to worse prognosis. WHAT IS NEW: • In children with inborn errors of immunity and indication of HSCT, refractory cytomegalovirus disease is associated with a very high mortality rate, compared with non-infected children and those with non-refractory cytomegalovirus disease. • In patients with novel transplantation indications, the presence and treatment response of CMV infection should be considered to decide the best possible moment for HSCT.

Efficacy and Safety of Continuous Infusion of Vancomycin in Children: A Systematic Review.

Vancomycin is used to treat a wide variety of infections within the pediatric population. In adults, continuous infusion of vancomycin (CIV) has been evaluated as an alternative to intermittent infusion of vancomycin (IIV) with potential advantages. In children, the use of CIV is increasing; however, data is currently limited. The objective is to provide efficacy and safety evidence for CIV within this population. The review was carried out following PRISMA guidelines. A bibliographic search was performed for studies on PubMed and EMBASE. Clinical trials and observational studies that reported clinical efficacy and/or target attainment of CIV in pediatrics were included. Articles were reviewed to assess their design and target population, characteristics of vancomycin treatment and the main findings in terms of safety and efficacy. A total of 359 articles were identified, of which seven met the inclusion criteria. All of them evaluated the target attainment, six assessed safety but only three assessed clinical efficacy. The best administration method for this antibiotic within the pediatric population is still unknown due to limited evidence. However, studies conducted thus far suggest pharmacokinetic advantages for CIV. Further investigation is required, in particular for studies comparing IIV with CIV for clinical efficacy and toxicity outcomes.

Distinct Laboratory and Clinical Features of Secondary Hemophagocytic Lymphohistiocytosis in Pediatric Visceral Leishmaniasis: A Retrospective Analysis of 127 Children in Andalusia, Spain (2004-2019).

BACKGROUND: Visceral leishmaniasis (VL) is an endemic in Southern Europe. However, details regarding disease burden, clinical presentations, laboratory markers, management and outcome in children are scarce. METHODS: Medical records of children (<14 years) admitted with VL to 10 pediatric units in Andalusia (2004-2019) were retrospectively reviewed. VL diagnosis was based on clinical presentation, serology, microscopy and molecular methods. Diagnosis of secondary hemophagocytic lymphohistiocytosis (sHLH) was established using the hemophagocytic lymphohistiocytosis-2004 criteria. RESULTS: A total of 127 patients were identified. Median age was 14.5 months; the main clinical presentations were fever and splenomegaly (95.3% each). Cytopenias were the most common laboratory abnormalities. Diagnostics as well as treatment regimens varied over time and the participating centers. Liposomal amphotericin B was prescribed in 97.6%; relapses as well as adverse events were rarely observed (3.1% each). Thirty-seven patients, diagnosed with sHLH required longer hospital admission (P = 0.001), an increased number of platelet (P < 0.006) and red blood cell (P = 0.0001) transfusions and pediatric intensive care unit admission (P = 0.007). Monocytopenia (P = 0.011) and high C-reactive protein levels (P = 0.031), variables not included in the hemophagocytic lymphohistiocytosis-2004 criteria, were associated with sHLH. One patient deceased in the context of the Leishmania infection. CONCLUSIONS: We report data on the largest pediatric VL cohort from Europe, commonly associated with sHLH. Raised C-reactive protein levels and monocytopenia appear to be associated with sHLH. The latter may help to identify these patients and to guide decisions regarding need of additional supportive clinical care and immunomodulatory therapies. The observed high rate of heterogeneity in terms of diagnosis and management warrants the establishment of appropriate guidelines.

[Position statement of the Spanish Association of Paediatrics-Spanish Society of Paediatric Infectious Diseases (AEP-SEIP) on the treatment of multidrug-resistant bacterial infections]. / Documento de posicionamiento de la Asociación Española de Pediatría-Sociedad Española de Infectología Pediátrica (AEP-SEIP) sobre el tratamiento de las infecciones por bacterias multirresistentes.

A progressive increase in the incidence of infections caused by multidrug-resistant microorganisms is being reported. Among these resistant microorganisms, the main threats are extended-spectrum ß-lactamase-, AmpC-, and carbapenemase-producing Gram-negative bacilli, methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. To address this important problem, it is essential to establish pediatric Antimicrobial Stewardship programs, perform active epidemiological surveillance and develop an adequate infection control policy. The therapeutic approach of these infections is often complex, frequently requiring antibiotics with less experience in children. In this position document made by the Spanish Association of Pediatrics and the Spanish Society of Pediatric Infectious Diseases, the epidemiology and treatment of these infections are reviewed according to the best available evidence.

Antimicrobial defined daily dose adjusted by weight: a proposal for antibiotic consumption measurement in children.

INTRODUCTION: Antimicrobial defined daily dose (DDD), has limitations for antimicrobial consumption measurement in paediatrics. An alternative DDD design applicable for children is proposed. METHODS: Children (<16 years-old) from 10 Spanish hospitals during a 12-months period were included. Weight for age (50th percentile) was calculated for the median age of the cohort using standardized World Health Organization tables. DDD (g) for each antimicrobial was calculated by multiplying the obtained weight times the recommended dose (mg/kg) of the antimicrobial for the most common infectious indication. RESULTS: A total of 40,575 children were included. Median age was 4.17 (IQR: 1.36-8.98) and 4.81 (IQR: 1.42-9.60) years for boys and girls, respectively. Mean weight for this age was 17.08kg. Standardized DDD for representative antimicrobials were calculated. CONCLUSIONS: A useful method for antimicrobial DDD measurement in paediatrics has been proposed and should be validated in future studies for its use in paediatric antimicrobial stewardship programmes.

Identifying priorities to improve paediatric in-hospital antimicrobial use by cross-sectional evaluation of prevalence and appropriateness of prescription.

INTRODUCTION: Information about paediatric in-hospital antimicrobial usage and prescribing patterns to guide improvement strategies is scant. We aim to use an evaluation of the prevalence and appropriateness of antimicrobial prescription to identify antimicrobial stewardship priorities in children. METHODS: A cross-sectional point study was performed on hospitalised paediatric patients in a Spanish tertiary hospital, assessing the prevalence of antimicrobial prescription (PAP) and appropriateness of antimicrobial prescription (AAP). AAP was defined as a correct indication plus an appropriate prescribing pattern (dose, spectrum and interval). Evaluation was performed using established antimicrobial guidelines. Other factors that may have a bearing on antimicrobial prescription were also analysed. RESULTS: A total of 171 patients were included. PAP was 49.7% (85/171) and AAP was 60.9% (91/161). The most common indications for antimicrobial use were antimicrobial prophylaxis (28.3%, 32/113) and pneumonia (8.2%, 8/113). Overall, 161 antimicrobials were prescribed (1.9 antimicrobials per patient): 55.3% (89/161) were empiric, 16.1% (26/161) were targeted and 28.6% (46/161) were prophylactic. Amoxicillin/clavulanate (8.2%, 14/171) and sulfamethoxazole/trimethoprim (8.2%, 14/171) were the most prescribed antimicrobials. The prescription of antifungals (11.7%, 20/171) and antivirals (1.8%, 3/171) was analysed. Major causes of inappropriate antibiotic use were prolonged prescriptions (21.7%, 35/161) and use of agents with an excessively broad coverage spectrum (21.1%, 34/161). PAP and AAP varied between wards and antimicrobials. CONCLUSIONS: Measurement of PAP and AAP offers valuable information for detecting priorities in hospital settings and monitoring antimicrobial usage prior to the development of antimicrobial stewardship programmes. In our setting, the main areas for improvement are duration of therapy and proper use of broad-spectrum antimicrobials.

Cytomegalovirus DNA Detection by Polymerase Chain Reaction in Cerebrospinal Fluid of Infants With Congenital Infection: Associations With Clinical Evaluation at Birth and Implications for Follow-up.

BACKGROUND: DNA detection of human cytomegalovirus (hCMV) in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) is a marker of central nervous system (CNS) involvement in congenital hCMV infection (cCMV), but its prognostic value is unknown. METHODS: A multicenter, retrospective study was performed using the Spanish Congenital Cytomegalovirus Infection Database (REDICCMV; http://www.cmvcongenito.es). Newborns with cCMV and a lumbar puncture performed were included and classified according to their hCMV-PCR in CSF result (positive/negative). Clinical characteristics, neuroimaging abnormalities, plasma viral load, and audiological and neurological outcomes of both groups were compared. RESULTS: A total of 136 neonates were included in the study: 21 (15.4%) with positive CSF hCMV-PCR and 115 (84.6%) with negative results. Seventeen patients (81%) in the positive group were symptomatic at birth compared with 52.2% of infants in the negative group (odds ratio [OR], 3.86; 95% confidence interval [CI], 1.28-14.1; P = .01). Only 4 asymptomatic newborns (6.8%) had a positive CSF hCMV-PCR. There were no differences between groups regarding the rate of microcephaly, neuroimaging abnormalities, neurological sequelae at 6 months of age, or plasma viral load. Sensorineural hearing loss (SNHL) at birth was associated with a positive CSF hCMV-PCR result (OR, 3.49; 95% CI, 1.08-11.27; P = .04), although no association was found at 6 months of age. CONCLUSIONS: A positive hCMV-PCR result in CSF is associated with symptomatic cCMV and SNHL at birth. However, no differences in neuroimaging studies, plasma viral load, or outcomes at 6 months were found. These results suggest that hCMV-PCR in CSF may not be a useful prognostic marker in cCMV.

Asociación entre infección viral del tracto respiratorio bajo en los dos primeros años de vida y el desarrollo de sibilancias recurrentes en niños de 3 a 8 años / Association between viral lower respiratory tract infection in the first two years of life and the developmentof recurrent wheezing in 3-8 year old children

Objetivos: Determinar la asociación entre infección viral del tracto respiratorio bajo en los dos primeros años devida con el desarrollo de sibilancias respiratorias recurrentes reversibles (SRRR), en niños. Material y métodos: Estudio caso-control incluyendo 400 niños; relación caso-control de 1:1 (α= 5%; β= 20%). Se incluyeron niñoscon diagnóstico de sibilancias respiratorias recurrentes reversibles que acudieron al Hospital Nacional CayetanoHeredia en los servicios de Emergencia y Consulta Externa entre mayo del 2009 y agosto del 2009, clasificándose como casos. Se asignaron 200 controles similares en edad, sexo y servicio de procedencia. Se registró el antecedente de infección viral del tracto respiratorio bajo en los dos primeros años de vida, mediante encuesta directa conlos padres y corroborándose con la historia clínica de los pacientes...

Objectives: To determine the association between lower viral respiratory tract infection in the first two years of lifeand the development of reversible recurrent respiratory wheezing (RRRW) in children. Methods: Case-control (1:1)study involving 400 children (α= 5%; β= 20%). Cases were children with RRRW who attended the emergency room and the outpatient clinic of Hospital Nacional Cayetano Heredia between may and august 2009, controls were 200children matched by age, gender and service of attendance. The history of viral upper respiratory tract infectionwas obtained by interviewing parents and it was corroborated with chart review...

Asociación entre prematuridad, bajo peso al nacer y lactancia materna exclusiva con rinitis alérgica, en niños de 2 a 7 años que acuden al Hospital Nacional Cayetano Heredia, Perú / Association among prematurity, low birth weight and exclusive breastfeeding with allergic rhinitis in 2 to 7 year-old pediatric patients from Hospital Nacional Cayetano Heredia, Peru

Introducción. La asociación entre factores perinatales para el desarrollo de rinitis alérgica es controversial. El objetivo de este trabajo es determinar la asociación entre prematuridad, bajo peso al nacer y lactancia materna exclusiva con rinitis alérgica, en pacientes pediátricos que acuden al Hospital Nacional Cayetano Heredia (HNCH). Métodos. Es un estudio tipo caso-control. Se realizó un cuestionario mediante entrevista directa a los padres para encontrar síntomas de rinitis alérgica, clasificando a los niños como casos y controles. El tamaño de la muestra fue de 366 niños, 122 casos y 244 controles (a= 5%; b= 20%). Se consignaron también los antecedentes de peso al nacer, edad de gestación y lactancia materna exclusiva con los padres; la información se corroboró con la historia clínica de los pacientes y la cartilla de control de crecimiento y desarrollo. Resultados. Ingresaron 369 niños de 2 a 7 años que acudieron a consulta externa de pediatría del Hospital Nacional Cayetano Heredia, entre agosto del 2006 y junio de 2007; de estos, 156 cumplieron con los criterios de caso y 213 cumplieron con los criterios de controles. Se encontró una razón de momios (RM) de 0.53 (IC 95%, 0.35, 0.80, P=0.0025) para la asociación entre rinitis alérgica y lactancia materna exclusiva. La razón de momios para rinitis alérgica y bajo peso al nacer fue de 0.55 (IC 95%, 0.27, 1.12, P=0.0658) y para rinitis alérgica y prematuridad fue de 1.20 (IC 95%, 0.67, 2.17, P=0.5414). Se realizó, además, el análisis estratificado para la relación entre rinitis alérgica y lactancia materna exclusiva con las variables de antecedente de atopia familiar y de exposición temprana a humo de tabaco, se utilizó como prueba estadística la prueba de Mantel-Haenszel. Se encontró una razón de momios Mantel-Haenszel de 0.52 (IC 95%, 0.33, 0.78, P=0.0025) para la asociación entre rinitis alérgica y lactancia materna exclusiva con el antecedente de atopia familiar; y una razón de momios Mantel-Haenszel de 0.56 (IC 95%, 0.36, 0.84, P=0.0064) para la asociación entre rinitis alérgica y lactancia materna exclusiva con el antecedente de exposición temprana a humo de tabaco. Conclusión. Nuestros resultados apoyan un efecto protector para rinitis alérgica en niños que reciben lactancia materna exclusiva; no se encontró asociación entre prematuridad y bajo peso al nacer con rinitis alérgica. Esta asociación protectora no se ve alterada por los antecedentes de atopia familiar ni de exposición temprana al humo del tabaco.

Background. The association among perinatal factors for the development of allergic rhinitis is controversial. The aim of this study was to determine the association among prematurity, low birth weight, and exclusive breastfeeding with allergic rhinitis in pediatric patients from the Hospital Nacional Cayetano Heredia (HNCH). Methods. We carried out a case-control study with a sample size of 366 children (122 cases and 244 controls) (a = 5%; b = 20%). A questionnaire was completed through direct interview with the parents to assess allergic rhinitis symptoms in order to classify the children as cases or controls. Previous medical history such as birth weight, gestational age and exclusive breastfeeding were entered and verified with the clinical chart of the patients as well as with the growth and development chart. Results. There were 369 children included in the study aged 2 to 7 years. They were seen as outpatients at the Pediatric Service at HNCH between August 2006 and June 2007. Of these children, 156 met the criteria for cases and 213 were identified as controls. An odds ratio (OR) of 0.53 was found (95% CI 0.35-0.80, p = 0.0025) for the association between allergic rhinitis and exclusive breastfeeding. Also, an OR of 0.55 (95% CI 0.27-1.12, p = 0.0658) was found for allergic rhinitis and low birth weight and an odds ratio of 1.20 (95% CI 0.67-2.17, p = 0.5414) was found for allergic rhinitis and prematurity. A stratified analysis was executed to evaluate the relationship between allergic rhinitis and exclusive breastfeeding with a family history of atopy and early environmental tobacco smoke exposure. Mantel-Haenszel statistical test was used for this purpose: OR of 0.52 was found (95% CI, 0.33-0.78, p = 0.0025) for the association between allergic rhinitis and exclusive breastfeeding with family history of atopy. Mantel-Haenszel odds ratio of 0.56 (95% CI 0.36-0.84, p = 0.0064) was found for the association between allergic rhinitis and exclusive breastfeeding with early environmental tobacco smoke exposure. Conclusions. Our results support a protective effect for allergic rhinitis in children who receive exclusive breastfeeding. We did not find any association between prematurity and low birth weight with the subsequent development of allergic rhinitis. The previously described protective effect is seemingly not altered by family history of atopy or early exposure to environmental tobacco smoke.