Influenza-Associated Disseminated Aspergillosis in a 9-Year-Old Girl Requiring ECMO Support

Nens; Influenza humana; IsavuconazolNiños; Influenza humana; IsavuconazolChildren; Human influenza; IsavuconazoleA previously healthy 9-year-old girl developed fulminant myocarditis due to severe influenza A infection complicated with methicillin-resistant Staphylococcus aureus pneumonia, requiring extracorporeal membrane oxygenation (ECMO) support. Twelve days after admission, Aspergillus fumigatus was isolated in tracheal aspirate, and 12 h later she suddenly developed anisocoria. Computed tomography (CT) of the head showed fungal brain lesions. Urgent decompressive craniectomy with lesion drainage was performed; histopathology found hyphae in surgical samples, culture-positive for Aspergillus fumigatus (susceptible to azoles, echinocandins, and amphotericin B). Extension workup showed disseminated aspergillosis. After multiple surgeries and combined antifungal therapy (isavuconazole plus liposomal amphotericin B), her clinical course was favorable. Isavuconazole therapeutic drug monitoring was performed weekly. Extensive immunological study ruled out primary immunodeficiencies. Fluorine-18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) follow-up showed a gradual decrease in fungal lesions. Influenza-associated pulmonary aspergillosis is well-recognized in critically ill adult patients, but pediatric data are scant. Clinical features described in adults concur with those of our case. Isavuconazole, an off-label drug in children, was chosen because our patient had severe renal failure. To conclude, influenza-associated pulmonary aspergillosis is uncommon in children admitted to intensive care for severe influenza, but pediatricians should be highly aware of this condition to enable prompt diagnosis and treatment.This work received no external funding

CMV hyperimmune globulin as salvage therapy for recurrent or refractory CMV infection in children undergoing hematopoietic stem cell transplantation

Children; Cytomegalovirus; Hematopoietic stem cell transplantationNens; Citomegalovirus; Trasplantament de cèl·lules mare hematopoètiquesNiños; Citomegalovirus; Trasplante de células madre hematopoyéticasCytomegalovirus (CMV) is a major cause of allogeneic hematopoietic stem cell transplant (HSCT)-related morbidity and mortality. Treatment failure continues to be a major issue in patients with CMV infection due to both drug resistance and intolerance. This single-center brief retrospective analysis of a case series aims to investigate the safety and efficacy of CMV-hyperimmune globulin as salvage therapy for CMV infection in children undergoing HSCT. Fifteen pediatric patients received human CMV-specific immunoglobulin (CMVIG) between July 2018 and December 2021 as a salvage therapy for refractory or recurrent CMV infection. At the time of CMVIG prescription, eight children presented with recurrent CMV infection and seven with refractory CMV infection. The overall response rate was 67% at 50 days from the CMVIG administration [95% confidence interval (CI): 44–88]. Overall survival (OS) from CMVIG administration at 100 days was 87% (95% CI: 56–96), and OS from HSCT at 1 year was 80% (95% CI: 50–93). Four patients died, three unrelated to CMV infection and one due to CMV pneumonia. CMVIG as salvage therapy was well tolerated, and no infusion-related adverse events were observed.Biotest supported the English revision of the manuscript

Voriconazole Use in Children: Therapeutic Drug Monitoring and Control of Inflammation as Key Points for Optimal Treatment

Infeccions fúngiques pediàtriques; Monitorització terapèutica de fàrmacs; VoriconazolInfecciones fúngicas pediátricas; Monitorización terapéutica de fármacos; VoriconazolPaediatric fungal infections; Therapeutic drug monitoring; VoriconazoleVoriconazole plasma concentrations (PC) are highly variable, particularly in children. Dose recommendations in 2–12-year-old patients changed in 2012. Little data on therapeutic drug monitoring (TDM) after these new recommendations are available. We aimed to evaluate voriconazole monitoring in children with invasive fungal infection (IFI) after implementation of new dosages and its relationship with safety and effectiveness. A prospective, observational study, including children aged 2–12 years, was conducted. TDM was performed weekly and doses were changed according to an in-house protocol. Effectiveness, adverse events, and factors influencing PC were analysed. A total of 229 PC from 28 IFI episodes were obtained. New dosing led to a higher rate of adequate PC compared to previous studies; still, 35.8% were outside the therapeutic range. In patients aged < 8 years, doses to achieve therapeutic levels were higher than recommended. Severe hypoalbuminemia and markedly elevated C-reactive protein were related to inadequate PC. Therapeutic PC were associated with drug effectiveness and safety. Higher doses in younger patients and a dose adjustment protocol based on TDM should be considered. Voriconazole PC variability has decreased with current updated recommendations, but it remains high and is influenced by inflammatory status. Additional efforts to control inflammation in children with IFI should be encouraged.This research was funded by an Investigator Sponsored Research Grant from Pfizer (Grant Number WI182544

Voriconazole Use in Children : Therapeutic Drug Monitoring and Control of Inflammation as Key Points for Optimal Treatment

Voriconazole plasma concentrations (PC) are highly variable, particularly in children. Dose recommendations in 2-12-year-old patients changed in 2012. Little data on therapeutic drug monitoring (TDM) after these new recommendations are available. We aimed to evaluate voriconazole monitoring in children with invasive fungal infection (IFI) after implementation of new dosages and its relationship with safety and effectiveness. A prospective, observational study, including children aged 2-12 years, was conducted. TDM was performed weekly and doses were changed according to an in-house protocol. Effectiveness, adverse events, and factors influencing PC were analysed. A total of 229 PC from 28 IFI episodes were obtained. New dosing led to a higher rate of adequate PC compared to previous studies; still, 35.8% were outside the therapeutic range. In patients aged < 8 years, doses to achieve therapeutic levels were higher than recommended. Severe hypoalbuminemia and markedly elevated C-reactive protein were related to inadequate PC. Therapeutic PC were associated with drug effectiveness and safety. Higher doses in younger patients and a dose adjustment protocol based on TDM should be considered. Voriconazole PC variability has decreased with current updated recommendations, but it remains high and is influenced by inflammatory status. Additional efforts to control inflammation in children with IFI should be encouraged

Monitoratge de concentracions plasmàtiques d’antibiòtics en nounats dins d’un programa proa

Introducció En els darrers anys, l’ús inadequat dels antibiòtics i l’augment de les resistències bacterianes ha conduit a l’establiment dels Programes d’Optimització d’ús d’Antimicrobians (PROA). El nostre hospital disposa d’un PROA pediàtric i neonatal (PROA-NEN). L’interès del PROA-NEN en els nounats rau en l’ús d’antibiòtic habitual en aquests pacients i en la important variabilitat de concentracions plasmàtiques (CP), atesa la situació de maduració progressiva i altres factors. Per tal d’assegurar la màxima efectivitat i minimitzar el risc d’efectes adversos, és fonamental garantir unes CP correctes, mitjançant el monitoratge de concentracions plasmàtiques (MCP), recomanat en el protocol local per a tots els nounats amb tractaments amb aminoglicòsids i/o glicopèptids superiors a 3 dies. El present projecte pretén estudiar el MCP de gentamicina, amikacina i vancomicina en nounats dins la part neonatal del programa PROA-NEN. Hipòtesi de treball El MCP permet detectar una proporció significativa de CP incorrectes de gentamicina, amikacina i vancomicina, i conseqüentment modificar la seva dosi. Existeixen factors que influeixen en la decisió de sol·licitud de MCP. Quan es realitza, el MCP millora l’evolució clínica dels nounats. Existeixen factors modificadors que permeten predir CP incorrectes. Objectius Principal 1. Determinar el resultat del MCP de gentamicina, amikacina i vancomicina. Secundaris 1. Determinar l’adherència a les recomanacions de MCP. 2. Conèixer l’evolució dels nounats en els que es realitza MCP. 3. Determinar quins factors s’associen amb CP inadequades. 4. Descriure el MCP de vancomicina en els nounats amb ECMO. Pacients i mètodes Estudi observacional, prospectiu i unicèntric, dels nounats ingressats a UCI Neonatal de l’Hospital Universitari Vall d’Hebron i tractament amb gentamicina, amikacina i/o vancomicina (juny 2017-maig 2019). Resultats Es van analitzar 561 episodis d’ús d’antibiòtic (201 vancomicina, 195 amikacina, 320 gentamicina) en 349 pacients (78% prematurs). La mortalitat atribuïble a infecció, disfunció renal i auditiva van ser del 2,5%, 0,5% i l’11%. Es van realitzar 153 determinacions de CP: 120 de vancomicina, 29 d’amikacina i 4 de gentamicina. Les CP van ser incorrectes en un 48% i 45% per a vancomicina i amikacina, respectivament. Totes les CP de gentamicina van ser correctes. L’adherència global al protocol va ser del 47% (82% vancomicina, 30% amikacina, 6% gentamicina). Els factors relacionats amb major sol·licitud de CP van ser infecció confirmada, patologia de base i major durada del tractament; i prematuritat amb menor adherència al protocol (p <0,05). Durant el període d’estudi, es va observar un augment en la sol·licitud de CP (p <0,05). L’únic factor potencialment modificador de CP que va demostrar relació significativa va ser l’ús de diürètics (p <0,05). El MCP no va demostrar relació amb evolució clínica. Els 6 pacients amb ECMO van presentar un 29% de CP de vancomicina incorrectes. Conclusions 1. El MCP permet identificar CP d’amikacina i vancomicina inadequades en un nombre elevat de pacients. 2. No es va poder demostrar la relació del MCP amb evolució clínica i toxicitat. 3. No sembla necessari realitzar de forma sistemàtica MCP de gentamicina en nounats a terme, amb pes adequat i estables, però sí en la resta de pacients. 4. Tot i l’augment en la sol·licitud de CP, cal dur a terme actuacions que promoguin l’adherència al protocol de MCP. 5. L’ús de diürètics es va relacionar amb menor proporció de CP infraterapèutiques. Cal confirmar aquesta troballa amb estudis més grans. 6. És fonamental realitzar MCP en nounats amb disfunció renal, pel seu efecte sobre CP de vancomicina. 7. Cal fer MCP de vancomicina en els nounats amb ECMO.Introducción En los últimos años, el uso inadecuado de antibióticos y el aumento de resistencias bacterianas ha llevado al establecimiento de Programas de Optimización del uso de Antimicrobianos (PROA). Nuestro hospital dispone de un PROA pediátrico y neonatal (PROA-NEN). El interés en los neonatos del PROA radica en el uso frecuente de antibióticos en estos pacientes y en la importante variabilidad de sus concentraciones plasmáticas (CP), dada la situación de maduración progresiva y otros factores. Para asegurar la máxima efectividad y minimizar el riesgo de efectos adversos, es fundamental garantizar que las CP de antibióticos se encuentran dentro del rango terapéutico, mediante la monitorización de concentraciones plasmáticas (MCP), recomendada en el protocolo localpara todos los neonatos bajo tratamiento con aminoglucósidos y/o glucopéptidos superior a 3 días. El presente proyecto pretende estudiar la MCP de gentamicina, amikacina y vancomicina en neonatos, dentro de la parte neonatal del programa PROA-NEN. Hipótesis de trabajo La MCP permite detectar una proporción significativa de CP incorrectas de gentamicina, amikacina y vancomicina, y modificar consecuentemente sus dosis. Existen factores que influyen en la decisión de solicitud de MCP. Cuando es realizada, la MCP mejora la evolución clínica de los neonatos. Existen factores modificadores que permiten predecir CP incorrectas. Objetivos Principal 1. Determinar el resultado de la MCP de gentamicina, amikacina y vancomicina. Secundarios 2. Determinar la adherencia a las recomendaciones de MCP. 3. Conocer la evolución de los neonatos en los que se realiza MCP. 4. Determinar los factores que se asocian con CP inadecuadas. 5. Describir la MCP de vancomicina en los neonatos con ECMO. Pacientes y métodos Estudio observacional, prospectivo y unicéntrico, de los neonatos ingresados en UCI Neonatal del Hospital Universitari Vall d&#8217;Hebron y en tratamiento con gentamicina, amikacina y/o vancomicina (junio 2017-mayo 2019). Resultados Se analizaron 561 episodios de uso de antibiótico (201 vancomicina, 195 amikacina, 320 gentamicina) en 349 pacientes (78% prematuros). La mortalidad atribuible a infección, disfunción renal y auditiva fueron del 2,5%, 0,5% y 11%. Se realizaron 153 determinaciones de CP: 120 de vancomicina, 29 de amikacina y 4 de gentamicina. Las CP fueron incorrectas en un 48% y 45% para vancomicina y amikacina, respectivamente. Todas las CP de gentamicina fueron correctas. La adherencia global al protocolo fue del 47% (82% vancomicina, 30% amikacina, 6% gentamicina). Los factores relacionados con mayor solicitud de CP fueron infección confirmada, patología de base y mayor duración del tratamiento; y prematuridad con menor adherencia al protocolo (p <0,05). Durante el período de estudio, se observó un aumento en la solicitud de CP (p <0,05). El único factor potencialmente modificador de CP que demostró relación significativa fue el uso de diuréticos (p <0,05). La MCP no demostró relación con evolución clínica. Los 6 pacientes con ECMO presentaron un 29% de CP de vancomicina incorrectas. Conclusiones 1. La MCP permite identificar CP de amikacina y vancomicina inadecuadas en un número elevado de pacientes. 2. No se pudo demostrar la relación de MCP con evolución clínica y toxicidad. 3. No parece necesario realizar de forma sistemática MCP de gentamicina en neonatos a término, con peso adecuado y estables, pero se debe mantener en el resto de pacientes. 4. A pesar del aumento en la solicitud de CP, se deben diseñar actuaciones que promuevan la adherencia al protocolo de MCP. 5. El uso de diuréticos se relacionó con menor proporción de CP infraterapéuticas. Son necesarios estudios mayores para confirmar este resultado. 6. Es fundamental realizar MCP en neonatos con disfunción renal, debido a su efecto sobre CP de vancomicina. 7. Es necesario realizar MCP de vancomicina en neonatos con ECMO.Introduction In recent years, the increase of antibiotic use and the emergence of multi-drug resistant microorganisms has led to the establishment of Antibiotic Stewardship Programs (ASP). Our hospital has a specific paediatric and neonatal ASP (PROA-NEN). Neonates are a high-interest population for pASP because of the wide antibiotic use in the neonatal units and the significant variability in drug plasmatic levels (PL), due to their progressive maturation and other coexisting factors. All this, in addition to the drugs intrinsic characteristics (narrow therapeutic window, interindividual variability) leads to the recommendation of therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin, aimed to achieve the highest effectivity with the lowest risk of adverse effects. Our TDM protocol recommends PL measurement for all neonates receiving treatments longer than 3 days with aminoglycoside and/or vancomycin. The scope of this project is to analyse gentamicin, amikacin and vancomycin TDM in the neonatal population, as an essential component of PROA-NEN. Working hypothesis TDM allows to detect and correct a significant proportion of gentamicin, amikacin and vancomycin plasmatic levels (PL) outside the therapeutic range. Adherence to TDM protocol is variable and there are factors that influence its request. When performed, TDM leads to a better clinical evolution. Finally, some factors are useful to predict incorrect PL. Objectives Main objective 1. To determine the results of gentamicin, amikacin and vancomycin TDM. Secondary objectives 2. To determine the adherence to the TDM protocol. 3. To describe the evolution of newborns with TDM. 4. To determine which factors are associated with incorrect PL. 5. To describe TDM of vancomycin in newborns with ECMO support. Patients and methods Observational, prospective and single-centre study. All newborns receiving vancomycin, amikacin and/or gentamicin in the NICU of Vall d&#8217;Hebron University Hospital were included (June 2017-May 2019). Results Five-hundred sixty-one episodes of antibiotic use in 349 patients (78% preterm) were included (201 vancomycin, 195 amikacin, 320 gentamicin). Infection-attributable mortality rate, renal and auditive dysfunction were 2.5%, 0.5% and 11%. TDM was performed in 153 occasions (120 vancomycin, 29 amikacin and 4 gentamicin). Plasmatic levels were incorrect in 48% and 45% cases for vancomycin and amikacin, respectively. Gentamicin PL were all correct. Global adherence to TDM protocol was 47% (82% vancomycin, 30% amikacin, 6% gentamicin). Confirmed infection, underlying diseases and treatment duration were related with higher request of PL, while prematurity led to lower demand (p <0.05). Concomitant diuretic treatment was the only statistically significant factor, related to a higher proportion of correct PL (p <0.05). TDM was not related with clinical evolution. Six patients with ECMO support presented vancomycin PL outside the therapeutic range in 29% determinations. Conclusions 1. TDM allowed to detect and amend incorrect PL in a high number of patients receiving amikacin and/or vancomycin. 2. Nonetheless, a significant relation could not be established between TDM and clinical evolution. 3. It does not seem necessary to perform systematic gentamicin TDM in term and stable newborns, but it must be maintained for the rest of the patients. 4. Despite the increase in PL request during the study period, new actions shall be designed for TDM promotion by the PROA-NEN team. 5. Concomitant diuretics use was related with lower risk of subtherapeutic PL. Larger studies are needed to confirm this finding. 6. Newborns with renal dysfunction must undergo TDM, due to its effect on PL. 7. It is necessary to perform TDM in newborns receiving ECMO support.Universitat Autònoma de Barcelona. Programa de Doctorat en Pediatria, Obstetrícia i Ginecologi

Five-Year Evaluation of the PROA-NEN Pediatric Antimicrobial Stewardship Program in a Spanish Tertiary Hospital

Antimicrobial stewardship; Bacterial infections; Tertiary care centersInfeccions bacterianes; Resistència als medicaments; Centres d'atenció terciàriaInfecciones bacterianas; Resistencia a los medicamentos; Centros de atención terciariaIntroduction: Actions to reduce and optimize antimicrobial use are crucial in the management of infectious diseases to counteract the emergence of short- and long-term resistance. This is particularly important for pediatric patients due to the increasing incidence of serious infections caused by resistant bacteria in this population. The aim of this study was to evaluate the impact of a pediatric antimicrobial stewardship program (PROA-NEN) implemented in a Spanish tertiary hospital by assessing the use of systemic antimicrobials, clinical indicators, antimicrobial resistance, and costs. Methods: In this quasi-experimental, single-center study, we included pediatric patients (0–18 years) admitted to specialized pediatric medical and surgical units, as well as pediatric and neonatal intensive care units, from January 2015 to December 2019. The impact of the PROA-NEN program was assessed using process (consumption trends and prescription quality) and outcome indicators (clinical and microbiological). Antibiotic prescription quality was determined using quarterly point prevalence cross-sectional analyses. Results: Total antimicrobial consumption decreased during the initial three years of the PROA-NEN program, followed by a slight rebound in 2019. This decrease was particularly evident in intensive care and surgical units. Antibiotic use, according to the WHO Access, Watch and Reserve (AWaRe) classification, remained stable during the study period. The overall rate of appropriate prescription was 83.2%, with a significant increase over the study period. Clinical indicators did not substantially change over the study period. Direct antimicrobial expenses decreased by 27.3% from 2015 to 2019. Conclusions: The PROA-NEN program was associated with reduced antimicrobial consumption, improved appropriate use, and decreased costs without compromising clinical and/or microbiological outcomes in patients

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)