A vancomicina administrada na dose empírica garante a cobertura de pacientes pediátricos contra patógenos Gram-positivos? / Does vancomycin administered at an empirical dose ensure coverage of pediatric patients against gram-positive pathogens?

RESUMO Objetivo: Investigar a efetividade da vancomicina contra Gram-positivos com concentração inibitória mínima de 1mg/L em pacientes pediátricos com base na razão entre área sob a curva e concentração inibitória mínima > 400. Métodos: População de 22 pacientes pediátricos (13 meninos) internados no centro de terapia intensiva pediátrica, com função renal preservada, que foram distribuídos em dois grupos (G1 < 7 anos e G2 ≥ 7 anos). Após a quarta dose de vancomicina (10 - 15mg/kg a cada 6 horas), duas amostras de sangue foram colhidas (terceira e quinta horas), seguidas da dosagem sérica por imunoensaios para investigação da farmacocinética e da cobertura do antimicrobiano. Resultados: Não se registrou diferença entre os grupos com relação à dose, ao nível de vale ou ainda na área sob a curva. A cobertura contra Gram-positivos com concentração inibitória mínima de 1mg/L ocorreu em apenas 46% dos pacientes em ambos os grupos. A farmacocinética se mostrou alterada nos dois grupos diante dos valores de referência, mas a diferença entre grupos foi registrada pelo aumento da depuração total corporal e pelo encurtamento da meia-vida biológica, mais pronunciados nos pacientes mais novos. Conclusão: A dose empírica mínima de 60mg/kg ao dia deve ser prescrita ao paciente pediátrico de unidade de terapia intensiva com função renal preservada. A utilização da razão entre área sob a curva e concentração inibitória mínima na avaliação da cobertura da vancomicina é recomendada para se atingir o desfecho desejado, uma vez que a farmacocinética está alterada nesses pacientes, podendo impactar na efetividade do antimicrobiano.

Abstract Objective: To investigate the vancomycin effectiveness against gram-positive pathogens with the minimum inhibitory concentration of 1mg/L in pediatric patients based on the area under the curve and the minimum inhibitory concentration ratio > 400. Methods: A population of 22 pediatric patients (13 boys) admitted to the pediatric intensive care unit with preserved renal function was stratified in two groups (G1 < 7 years and G2 ≥ 7 years). After the fourth dose administered of vancomycin (10 - 15mg/kg every 6 hours) was administered, two blood samples were collected (third and fifth hours), followed by serum measurement by immunoassays to investigate the pharmacokinetics and antimicrobial coverage. Results: There was no difference between the groups regarding dose, trough level or area under the curve. Coverage against gram-positive pathogens with a minimum inhibitory concentration of 1mg/L occurred in only 46% of patients in both groups. The pharmacokinetics in both groups were altered relative to the reference values, and the groups differed in regard to increased total body clearance and shortening of the biological half-life, which were more pronounced in younger patients. Conclusion: A minimum empirical dose of 60mg/kg per day should be prescribed for pediatric patients in intensive care units with preserved renal function. The use of the ratio between the area under the curve and minimum inhibitory concentration in the evaluation of vancomycin coverage is recommended to achieve the desired outcome, since the pharmacokinetics are altered in these patients, which may impact the effectiveness of the antimicrobial.

Effective vancomycin concentrations in children: a cross-sectional study / Concentrações efetivas de vancomicina em crianças: estudo transversal

ABSTRACT Objective Analyze the microbiological effectiveness, based on the pharmacokinetics/pharmacodynamics correlation of vancomycin in pediatric patients, and to propose dose adjustment. Methods This is an observational, cross-sectional study, conducted in a pediatric hospital, over a 1-year period (2016 to 2017). Children of both sexes, aged 2 to 12 years, were included in the study; burn children, and children in renal replacement therapy were excluded. For the pharmacokinetic analysis, two samples of 2mL of whole blood were collected, respecting the 2-hour interval between each withdrawal. Results Ten pediatric patients with median age of 5.5 years and interquartile range (IQR) of 3.2-9.0 years, median weight of 21kg (IQR: 15.5-24.0kg) and median height of 112.5cm (IQR: 95-133cm), were included. Only one child achieved trough concentrations between 10µg/mL and 15µg/mL. Conclusion The empirical use of vancomycin in the children studied did not achieve the therapeutic pharmacokinetic/pharmacodynamic target for minimum inhibitory concentration of 1µg/mL.

RESUMO Objetivo Analisar a efetividade microbiológica considerando a correlação farmacocinética/farmacodinâmica de vancomicina em crianças e propor uma estimativa de ajuste na dose. Métodos Trata-se de um estudo observacional, transversal, realizado em hospital pediátrico, no período de 1 ano (2016 a 2017). Foram incluídas crianças de 2 a 12 anos de ambos os sexos, tendo sido excluídas crianças queimadas ou submetidas à terapia renal substitutiva. Para análise farmacocinética, foram coletadas duas amostras de 2mL de sangue total, respeitando o intervalo de 2 horas entre cada coleta. Resultados Foram incluídos dez pacientes pediátricos com idade de 5,5 anos (mediana) e intervalo interquartil (IQ) de 3,2-9,0 anos, peso de 21kg (mediana; IQ: 15,5-24,0kg) e altura de 112,5cm (mediana; IQ: 95-133cm). Apenas uma criança alcançou concentrações mínimas entre 10µg/mL e 15µg/mL. Conclusão A utilização empírica de vancomicina na população de crianças não alcançou o alvo farmacocinético/farmacodinâmico terapêutico para concentração inibitória mínima de 1μg/mL.

Monitorización terapéutica de antimicrobianos en pediatría: revisión de la experiencia latinoamericana / Therapeutic monitoring of antimicrobial agents in pediatrics: review based on Latin American experiences

Resumen La presente revisión resume la evidencia sobre la monitorización terapéutica de tres antimicrobianos basada en datos regionales: vancomicina, amikacina y voriconazol en la población pediátrica. Estos datos coinciden con la literatura internacional en relación al requerimiento de dosis mayores que 40 mg/kg/día de vancomicina, la posibilidad de usar monodosis diarias de amikacina y el requerimiento de dosis mayores de voriconazol en relación a las iniciales recomendadas de 8 mg/kg/día. Contar con datos locales sobre el comportamiento farmacocinético/farmacodinámico de diversos antimicrobianos en la pediatría es de gran valor para adecuar la dosificación de los mismos en nuestra población. Se deberían incrementar los estudios de monitorización terapéutica en el uso de antimicrobianos en pediatría que permitan generar pautas de tratamiento adecuadas para este grupo etario.

This review summarizes recommendations of therapeutic monitoring of three antimicrobials based in regional data: vancomycin, amikacin and voriconazole in pediatric population. Regional evidence agrees with international literature regarding the requirement of higher daily doses than 40 mg/kg/day of vancomycin, as well as with the possibility of use one daily doses of amikacin and to recommend higher doses of voriconazole compared to the initially recommended doses of 8 mg/kg/day. Local data on the pharmacokinetic/pharmacodynamic behavior of various antimicrobials in pediatrics are of great value for dosing adjustment in our pediatric population. More studies in therapeutic monitoring in the use of antimicrobials in pediatrics should be performed in order to allow the generation of adequate treatment guidelines for this age group.

Esquema posológico atualmente utilizado para vancomicina falha em obter níveis terapêuticos em 40% dos pacientes internados em unidade de terapia intensiva / Currently used dosage regimens of vancomycin fail to achieve therapeutic levels in approximately 40% of intensive care unit patients

RESUMO Objetivo: Avaliar se a posologia atualmente utilizada de vancomicina para tratamento de infecções bacterianas graves causadas por microrganismos Gram-positivos em pacientes admitidos à unidade de terapia intensiva proporcionam níveis plasmáticos de vale de vancomicina em nível terapêutico, e examinar possíveis fatores associados com níveis de vale de vancomicina adequados nesses pacientes. Métodos: Estudo prospectivo descritivo com amostra de conveniência. Os pacientes que cumpriam os critérios de inclusão tiveram seus dados coletados a partir das anotações da enfermagem e dos registros médicos entre setembro de 2013 e julho de 2014. Incluíram-se 83 pacientes. Os níveis plasmáticos de vale iniciais de vancomicina foram obtidos imediatamente antes da quarta dose de vancomicina. Definiu-se lesão renal aguda como um aumento de, pelo menos, 0,3mg/dL na creatinina sérica dentro de 48 horas. Resultados: Considerando os níveis de vale plasmáticos de vancomicina recomendados para o tratamento de infecções graves por Gram-positivos (15 - 20µg/mL), os pacientes foram categorizados em grupos como níveis de vale de vancomicina baixos, adequados e elevados, respectivamente divididos em 35 (42,2%), 18 (21,7%), e 30 (36,1%) pacientes. Os pacientes com lesão renal aguda tiveram níveis plasmáticos de vale de vancomicina significantemente mais elevados (p = 0,0055, com significância para tendência, p = 0,0023). Conclusão: Preocupantemente, mais de 40% dos pacientes não obtiveram níveis plasmáticos de vale de vancomicina considerados eficazes. São necessários estudos de farmacocinética e de regimes posológicos de vancomicina em pacientes admitidos em unidades de terapia intensiva, para contornar esta elevada proporção de falhas na obtenção de níveis de vale iniciais adequados de vancomicina. Deve ser desencorajado o uso de vancomicina sem monitoramento dos níveis de vale plasmáticos.

ABSTRACT Objective: This study aimed to assess whether currently used dosages of vancomycin for treatment of serious gram-positive bacterial infections in intensive care unit patients provided initial therapeutic vancomycin trough levels and to examine possible factors associated with the presence of adequate initial vancomycin trough levels in these patients. Methods: A prospective descriptive study with convenience sampling was performed. Nursing note and medical record data were collected from September 2013 to July 2014 for patients who met inclusion criteria. Eighty-three patients were included. Initial vancomycin trough levels were obtained immediately before vancomycin fourth dose. Acute kidney injury was defined as an increase of at least 0.3mg/dL in serum creatinine within 48 hours. Results: Considering vancomycin trough levels recommended for serious gram-positive infection treatment (15 - 20µg/mL), patients were categorized as presenting with low, adequate, and high vancomycin trough levels (35 [42.2%], 18 [21.7%], and 30 [36.1%] patients, respectively). Acute kidney injury patients had significantly greater vancomycin trough levels (p = 0.0055, with significance for a trend, p = 0.0023). Conclusion: Surprisingly, more than 40% of the patients did not reach an effective initial vancomycin trough level. Studies on pharmacokinetic and dosage regimens of vancomycin in intensive care unit patients are necessary to circumvent this high proportion of failures to obtain adequate initial vancomycin trough levels. Vancomycin use without trough serum level monitoring in critically ill patients should be discouraged.

Reposicionando la cloxacilina como antibioticoterapia empírica inicial de la sepsis tardía neonatal / Reinstating cloxacilin for empiric antibiotic in late-onset sepsis

Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.

Vancomicina se utiliza hace más de 50 años en unidades de cuidados intensivos neonatales (UCIN) como terapia de elección en sospecha de sepsis neonatal tardía; su principal indicación se fundamenta en que Staphylococcus coagulasa negativa (SCN) es el principal microorganismo que ocasiona sepsis tardía y éste es habitualmente resistente a cloxacilina; sin embargo, su virulencia es baja y la sepsis fulminante es inusual. Lamentablemente la prescripción de vancomicina se ha convertido en un grave problema en las UCIN, debido a diversas razones incluyendo: alta variabilidad farmacocinética del fármaco, dificultad en alcanzar concentraciones plasmáticas apropiadas y aumento de la concentración inhibitoria mínima (CIM), implicando además una mayor probabilidad de seleccionar cepas resistentes y aumento de otro tipo de infecciones ocasionadas por bacilos gramnegativos resistentes y candidiasis invasora. Considerando lo anteriormente señalado y a lo publicado en la literatura médica con respecto a las infecciones en neonatología, debido a su comportamiento clínico diferente a hospederos en otras etapas de la vida, resulta de suma importancia replantear el uso de vancomicina basado en fundamentos teóricos que avalen la seguridad de no utilizar este antimicrobiano como primera línea en sepsis neonatal tardía.

Monitoreo terapéutico de vancomicina intravenosa en una unidad de paciente crítico pediátrico / Therapeutic monitoring of intravenous vancomycin in a pediatric critical care unit

Background: In critically ill pediatric patients vancomycin distribution and elimination is altered underscoring the need for pharmacokinetic monitoring; however the therapeutic trough ranges have not been validated for children. Objective: To describe the pharmacokinetics of intravenous vancomycin in critically ill pediatric patients using plasmatic vancomycin monitoring. Methods: Retrospective, descriptive study performed in a paediatric critical care unit. Vancomycin serum levels (Cmin and Cpeak), t ½ and Vd were determined in 1 month to 12 year old patients receiving ≥ 40 mg per-kg-per day. Plasmatic levels were measured at therapy onset and during follow up, evaluating the proportion of trough level determinations within therapeutic range, the average trough concentration, and the Cpeak achieved. Results: A total of 65 plasmatic vancomycin monitorings were analysed in 45 patients. The average values for Ctrough, Cpeak, t1/2 and Vd were 10.4 μg/mL, 22.7 μg/mL, 3,1 h and 0.7 L/kg, respectively. An average dose of 47,1 mg/kg/day achieved initial Ctrough levels < 10 mg/mL in 60% of patients (n = 27), between 10 and 14,9 μg/mL in 22,2% (n = 10), between 15 to 20 μg/mL in 4% (n: 2), and > 20 μg/mL in 13,3% (n: 6). Conclusions: Vancomycin doses of 40 mg/kg/day are insufficient for critically ill paediatric patients without renal failure. A higher starting dose and monitoring of plasma levels must be considered in this population.

Introducción: Los pacientes críticos pediátricos presentan alteraciones en la distribución y eliminación de vancomicina, lo que hace necesaria su monitorización terapéutica; sin embargo, los rangos basales óptimos no han sido validados en niños. Objetivo: Describir el monitoreo terapéutico de vancomicina intravenosa en pacientes críticos pediátricos, a través de medición de concentraciones plasmáticas terapéuticas. Metodología: Estudio descriptivo, retrospectivo, en una Unidad de Paciente Crítico Pediátrica. Se analizaron concentraciones plasmáticas de vancomicina Cbasales y Cpico, en niños entre 1 mes y 12 años de edad, que recibieron dosis ≥ 40 mg/kg/día. Se registraron concentraciones plasmáticas iniciales y de seguimiento, evaluándose la proporción de concentraciones sanguíneas basales en rango terapéutico, la concentración basal promedio y el Cpeak alcanzado. Resultados. Se analizaron 65 monitoreos terapéuticos, correspondientes a 45 pacientes. Los valores promedio de Cbasal, Cpico, t1/2 Vd fueron 10,4 μg/mL, 22,7 μg/mL, 3,1 h y 0,7 L/kg, respectivamente. Las Cbasales iniciales de los 45 pacientes, usando dosis promedio de 47,1 mg/kg/ día, se encontraron en 60% (n: 27) de los casos < 10 μg/mL, entre 10 y 14,9 μg/mL en 22% (n: 10), en 46% entre 15 y 20 μg/mL (n: 2) y en 13,3% (n: 6) fueron > 20 μg/mL. Conclusión: Vancomicina en dosis de 40 mg/kg/día, es insuficiente para pacientes pediátricos críticos sin disfunción renal, por lo que parece recomendable comenzar con dosis mayores y realizar monitoreo terapéutico de concentraciones plasmáticas en estos casos.

Incremento da depuração renal em pacientes gravemente enfermos: incidência, fatores associados e efeitos no tratamento com vancomicina / Augmented renal clearance in critically ill patients: incidence, associated factors and effects on vancomycin treatment

Objetivo: Foi descrito um incremento da depuração renal em alguns grupos de pacientes gravemente enfermos, o qual pode induzir à eliminação de concentrações de fármacos por filtração glomerular aquém do ideal, principalmente no caso de antibióticos. Sua ocorrência e os fatores determinantes têm sido pouco estudados. Nossos objetivos foram determinar a incidência e os fatores associados ao incremento da depuração renal, bem como seus efeitos nas concentrações e na posologia de vancomicina em uma série de pacientes em unidade de terapia intensiva. Métodos: Estudamos, de forma prospectiva, 363 pacientes admitidos durante 1 ano em uma unidade de terapia intensiva clínico-cirúrgica. Foram excluídos pacientes que tivessem nível de creatinina sérica >1,3mg/dL. A depuração de creatinina foi calculada a partir da coleta de urina de 24 horas. Os pacientes foram agrupados segundo a presença de incremento da depuração renal (depuração de creatinina >120mL/min/1,73m2), e os possíveis fatores de risco foram analisados por meio de análise bivariada e logística. Em pacientes tratados com vancomicina, foram registradas a posologia e as concentrações plasmáticas. Resultados: O incremento da depuração renal esteve presente em 103 pacientes (28%), os quais eram mais jovens (48±15 versus 65±17 anos; p<0,0001), tinham mais frequentemente admissões obstétricas (16 versus 7%; p=0,0006) e por trauma (10 versus 3%; p=0,016), e menos comorbidades. Os únicos determinantes independentes para o desenvolvimento de incremento da depuração renal foram idade (OR=0,95; IC95%=0,93-0,96; p<0,0001;) e ausência de diabetes (OR 0,34; IC95% 0,12-0,92; p=0,03). Doze dos 46 pacientes que receberam vancomicina tinham ...

Objective: An augmented renal clearance has been described in some groups of critically ill patients, and it might induce sub-optimal concentrations of drugs eliminated by glomerular filtration, mainly antibiotics. Studies on its occurrence and determinants are lacking. Our goals were to determine the incidence and associated factors of augmented renal clearance and the effects on vancomycin concentrations and dosing in a series of intensive care unit patients. Methods: We prospectively studied 363 patients admitted during 1 year to a clinical-surgical intensive care unit. Patients with serum creatinine >1.3mg/dL were excluded. Creatinine clearance was calculated from a 24-hour urine collection. Patients were grouped according to the presence of augmented renal clearance (creatinine clearance >120mL/min/1.73m2), and possible risk factors were analyzed with bivariate and logistic regression analysis. In patients treated with vancomycin, dosage and plasma concentrations were registered. Results: Augmented renal clearance was present in 103 patients (28%); they were younger (48±15 versus 65±17 years, p<0.0001), had more frequent obstetric (16 versus 7%, p=0.0006) and trauma admissions (10 versus 3%, p=0.016) and fewer comorbidities. The only independent determinants for the development of augmented renal clearance were age (OR 0.95; p<0.0001; 95%CI 0.93-0.96) and absence of diabetes (OR 0.34; p=0.03; 95%CI 0.12-0.92). Twelve of the 46 patients who received vancomycin had augmented renal clearance and despite higher doses, had lower concentrations. Conclusions: In this cohort of critically ill patients, augmented renal clearance was a common finding. Age and absence of diabetes were the only independent determinants. Therefore, younger and previously healthy patients might require larger vancomycin dosing. .

Implementation of vancomycin dosing nomogram in an electronic prescribing system: an innovative tool in antibiotic stewardship

Vancomycin (VAN) is the gold standard therapy for Methicillin-resistant Staphylococcus aureus (MRSA) infections such as bacteremia and endocarditis. However, VAN suboptimal dosing for serious infections caused by S. aureus isolates that have elevated minimum inhibitory concentration (MIC), could be associated with poor outcome. Better understanding of VAN pharmacokinetics and pharmacodynamics (PK/PD) has led to the creation of new recommendations with optimized dosing regimens for the treatment of MRSA infections. For severe infectious, such as pneumonia and endocarditis, a VAN serum trough concentration of 15-20 mg/L at the steady state should be targeted. The aim of this study was to show how a nomogram with updated VAN dosing was devised and how it was implemented in the electronic prescribing (e-prescribing) system of a teaching hospital. VAN loading dose and maintenance doses were calculated from a pharmacokinetic equation using basic parameters: weight, estimated creatinine clearance, as well as peak and trough serum concentrations. The implementation of the VAN dosing nomogram in the hospital e-prescribing system definitively changed the long-standing medical prescription fallacy of "same dose fits all". Finally, this computer-based electronic program has allowed a wide-ranging intervention and should be recognized as a powerful tool for implementation in antimicrobial stewardship programs.

Vancomicina (VAN) é utilizada como primeira escolha na terapia de infecções causadas por Staphylococcus aureus resistentes à meticilina (MRSA), como bacteremia e endocardite. Entretanto, o aumento na concentração inibitória mínima (CIM) de isolados de S. aureus e doses subterapêuticas de VAN podem estar associados à falha terapêutica. Para o melhor entendimento sobre o perfil farmacocinético e farmacodinâmico (PK/PD) da VAN foram elaboradas novas recomendações para terapia de infecções causadas por MRSA. Para terapia de infecções graves, como pneumonia e endocardite, a concentração sérica do vale de VAN de 15-20 mg/L no estado de equilíbrio dinâmico deve ser o alvo. O objetivo do estudo foi desenvolver um nomograma com doses atualizadas de VAN e demonstrar como ele foi implementado no sistema de prescrição eletrônica em um Hospital Universitário. As doses de ataque e manutenção foram calculadas a partir de equações farmacocinéticas, utilizando parâmetros fundamentais: peso, depuração de creatinina, concentrações séricas do pico e do vale. A implementação de um nomograma de doses de VAN em um sistema de prescrição eletrônica modificou definitivamente o inadequado hábito de que "a mesma dose cabe em todos". Finalmente, esta abrangente ferramenta tecnológica deve ser considerada como uma robusta estratégia num programa de uso racional de antibióticos.

Farmacocinética de vancomicina en niños hospitalizados en una unidad de paciente crítico / Pharmacokinetics of vancomycin in children hospitalized in a critical care unit

Introduction: Monitoring PK/PD of vancomycin with basal and peak serum levels and the area under the curve of drug exposure 24 h/MIC (ABC 24 h/MIC) could optimize the management of children. Objective: To study the PK of vancomycin in children hospitalized in the Pediatric Intensive Care Unit (PICU), assessing PK/PD parameters withABC24 h/MIC. Methods: Retrospective, descriptive study in the PICU (Hospital Luis Calvo Mackenna) between January 2008-March 2010. We included children < 18 years who required antimicrobial treatment with vancomycin for suspected/confirmed staphylococcal infection using a dose of 40 mg/k/day. Plasmatic levels were performed one hour postinfusion and 30 min prior to the next dose. The following PK/PD parameters were calculated: vancomycin clearance, elimination rate constant, volume of distribution, half-life (T1/2) and ABC 24 h/ MIC. Results: We enrolled eighty-four children. According to ABC 24 h/MIC obtained, 54% (45/84) of children reached an optimal level (> 400 mg*hr/L). Based on the traditional PK/PD parameters, 49% of cases (41/84) presented a basal level of vancomycin in the therapeutic range (5-15 μg/mL) and of those, only 39% (16/41) had a ABC 24 h/MIC over 400 mg*h/L. Discussion: Based on our results, children admitted to PICU could be exposed to sub therapeutic doses of vancomycin. We recommend to implement tailored antimicrobial treatment monitoring vancomycin PK/PD parameters.

Introducción: El monitoreo farmacocinético-farmacodinámico (PK/PD) de vancomicina podría optimizar el manejo de niños que reciben vancomicina y se encuentran en shock séptico grave. Objetivo: Estudiar PK/PD de vancomicina en niños hospitalizados en una unidad de paciente crítico, relacionando parámetros farmacocinéticos (PFC) tradicionales con ABC 24 h/CIM. Material y Método: Estudio retrospectivo, descriptivo, en la Unidad de Paciente Crítico Pediátrico (UPCP) del Hospital Luis Calvo Mackenna en el período enero de 2008 - marzo de 2010. Se incluyeron niños < 18 años tratados con vancomicina por sospecha/confirmación de infección estafilocóccica y recibieron dosis de 40 mg/kg/día. Se midieron concentraciones plasmáticas pico y basales. Los PFC calculados fueron realizados con software de farmacocinética TDMS®. Resultados: Se enrolaron 84 niños. En relación del parámetro ABC 24h/CIM obtenido, 54% (45/84) de los niños alcanzaron niveles óptimos (> 400 mg*h/L). Del análisis por PFC tradicionales, 49% de los casos (41/84) presentó concentraciones basales de vancomicina en rango terapéutico (5-15 μg/mL) y de ellos, sólo 39% (16/41) presentó un ABC 24 h/CIM > 400 mg*h/L. Todos los pacientes con concentraciones basales > 15 μg/mL alcanzan un ABC 24 h/CIM > 400 mg*h/L. Discusión: Los pacientes pediátricos que ingresan a la UPCP podrían estar expuestos a dosis sub-terapéuticas de vancomicina. Es recomendable individualizar el tratamiento de vancomicina utilizando monitoreo con parámetros PK/PD.

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.

Clinical pharmacokinetics of vancomycin in the neonate: a review

Neonatal sepsis is common and is a major cause of morbidity and mortality. Vancomycin is the preferred treatment of several neonatal staphylococcal infections. The aim of this study was to review published data on vancomycin pharmacokinetics in neonates and to provide a critical analysis of the literature. A bibliographic search was performed using PubMed and Embase, and articles with a publication date of August 2011 or earlier were included in the analysis. Vancomycin pharmacokinetic estimates, which are different in neonates compared with adults, also exhibit extensive inter-neonatal variability. In neonates, several vancomycin dosing schedules have been proposed, mainly based on age (i.e., postmenstrual and postnatal), body weight or serum creatinine level. Other covariates [e.g., extracorporeal membrane oxygenation (ECMO), indomethacin or ibuprofen, and growth restriction] of vancomycin pharmacokinetics have been reported in neonates. Finally, vancomycin penetrates cerebrospinal fluid (range = 7-42%). Renal function drives vancomycin pharmacokinetics. Because either age or weight is the most relevant covariate of renal maturation, these covariates should be considered first in neonatal vancomycin dosing guidelines and further adjusted by renal dysfunction indicators (e.g., ECMO and ibuprofen/indomethacin). In addition to the prospective validation of available dosing guidelines, future studies should focus on the relevance of therapeutic drug monitoring and on the value of continuous vancomycin administration in neonates.

Optimización de la dosificación de vancomicina en pacientes críticos mediante el análisis de sus niveles plasmáticos / Dosage of vancomycin in critically ill patients: analysis of plasmatic levels

Los pacientes críticos se caracterizan por la presencia de diversos factores que pueden alterar la cinética de vancomicina, antibiótico ampliamente utilizado en las unidades de cuidados intensivos para el tratamiento de infecciones producidas por Staphylococus aureus meticilino resistente. Pacientes y métodos: Este estudio evaluó las dosis de vancomicina comúnmente utilizadas en la Unidad de Paciente Critico del Hospital Dr. Gustavo Fricke y la estrategia de administración inicial de carga endovenosa de vancomicina en dichos pacientes. Resultados: El 55,3 por ciento de los niveles plasmáticos obtenidos fueron menores de 15 mcg/mL. Bajo la estrategia de administración de carga endovenosa, solo el 13,3 por ciento de los resultados se encontraron por debajo de dicho valor. Los resultados fueron dependientes estadísticamente de la edad, índice de masa corporal y función renal del paciente. Conclusiones: La carga endovenosa de vancomicina permite alcanzar los niveles plasmáticos requeridos en pacientes críticos. Es necesario evaluar los factores de la edad, función renal e índice de masa corporal de los pacientes que se les administrará vancomicina y ajustar las dosis según las determinaciones periódicas de sus niveles plasmáticos.

Critically ill patients are characterized by the presence of various factors can alter the kinetics of vancomycin antibiotic widely used in intensive care units for treating infections caused by methicillin resistant Staphylococcusaureus. Patients and methods: This study evaluated vancomycin doses commonly used in critically ill patient Unit Dr. Gustavo Fricke Hospital and initial management strategy of charging intravenous vancomycin in such patients. Results: 55.3 percent of the plasmatic levels obtained were lower than 15 mcg / mL. Under load management strategy IV, 13.3 percent of the results were below this value. The results were statistically dependent on age, body mass index and renal function. Conclusions: The burden of vancomycin intravenously can achieve the required plasma levels in critically ill patients. It is necessary to evaluate the factors of age, renal function and body mass index of patients that will be administered according to vancomycin and adjust these measurements the periodic determination of plasma levels.

Antibioticoterapia para infecções por bactérias gram-positivas no paciente grave / Antibioticotherapy for gram-positive bacteria infections in serious patient

O aumento importante do número de infecções causadas por bactérias Gram-positivas e o surgimento de resistência aos antibióticos destinados a tratar estas infecções são motivos de preocupação das autoridades internacionais em infecção hospitalar. O presente artigo tem como objetivo revisar os principais antibióticos utilizados para o tratamento destes agentes, como oxacilina, vancomicina, teicoplanina, linezolida, quinupristina-dalfopristina, daptomicina e tigeciclina.

Vancomycin pharmacokinetics in preterm infants

OBJETIVE: The objective of the present study was to evaluate the kinetic disposition of vancomycin in preterm infants with emphasis on the apparent volume of distribution, biological half-life, and total body clearance as well as whether their variations cause significant modification of the trough plasma concentration of the drug, depending on the postconceptional age (PCA) and the postnatal age (PNA). MATERIAL AND METHOD: Twenty-five selected patients were distributed into 2 groups which differed significantly in terms of mean PCA (31.2-32.3 weeks in group 1, n = 13; 33.5-34.1 weeks in group 2, n = 12: CI95 percent, P < .001) and PNA (group 1, 12.0-18.5 days; group 2, 18.0-34.0 days, CI95 percent, P < .05). The parents were informed and signed a written consent for participation of the infants in the protocol that had been previously approved by the Ethics Committee of the hospital. RESULTS: Apparent volume of distribution was significantly increased in group 1 compared with patients of group 2 (0.85 vs. 0.56 L/kg, respectively; P = .01,). Additionally multiple linear regression revealed a good linear correlation (r = 0.85) of trough plasma concentration of vancomycin with the apparent volume of distribution and also with the biological half-life in patients of group 1, while a good correlation (r = 0.91) was obtained for the trough plasma concentration with total body clearance in infants of group 2. The influence of these kinetic parameters on the trough concentration of vancomycin in preterm infants seems to vary according to PCA and PNA. CONCLUSION: In conclusion, the trough plasma concentration of vancomycin depends on the pharmacokinetics, and multiple linear correlation indicates that it varies according to the postconceptional and postnatal age of preterm infants.

OBJETIVO: O objetivo do presente estudo foi investigar a farmacocinética da vancomicina em neonatos pretermo, considerando a idade pós-conceptual e também a idade pós-natal para determinar se as alterações no volume aparente de distribuição, meia-vida biológica e depuração plasmática causam variação significativa no vale plasmático da vancomicina. MATERIAL E MÉTODO: Os vinte e cinco pacientes selecionados foram distribuídos em dois grupos, que diferiram significativamente em termos de idade pós-conceptualgrupo 1, n=13: 31,2-32,3 semanas; grupo 2, n=12: 33,5-34,1 semanas, IC95 por cento, p<0,0001) e idade pós-natalgrupo 1: 12,0-18,5 dias; grupo 2: 18,0-34,0 dias, p<0,05). Todos os responsáveis foram informados sobre os detalhes do estudo e assinaram o termo de consentimento livre e esclarecido. O protocolo foi submetido e aprovado previamente pelo Comitê de Ética em Pesquisa do hospital. RESULTADO: O volume aparente de distribuição se mostrou significativamente aumentado no grupo 1 comparado aos pacientes do grupo 2 0,85 vs 0,56 L/kg, p=0,01). Adicionalmente, o teste de regressão linear múltipla mostrou boa correlação linear: 0,85) da concentração plasmática de vale com o volume aparente de distribuição, e também com a meia-vida biológica nos pacientes do grupo 1. Nas crianças do grupo 2 evidenciou-se boa correlação(r: 0,91) entre o vale e a depuração plasmática. A influência desses parâmetros farmacocinéticos sobre o vale nos prematuros parece variar de acordo com a idade pós-conceptual e a idade pós-natal. CONCLUSÃO: Concluindo, a concentração de vale para a vancomicina depende da farmacocinética e a correlação múltipla varia de acordo com a idade pós-conceptual e a idade pós-natal dos recém-nascidos pré-termos.

Farmacocinética da vancomicina em recém-nascidos pré-termo / Vancomycin pharmacokinetics in preterm infants

Avaliou-se a influência dos parâmetros farmacocinéticos da vancomicina sobre a variação da sua concentração plasmática no vale em dois grupos de recém-nascidos pré-termo estatisticamente diferentes quanto à idade pós-conceptual (grupo 1: 32 semanas; grupo 2: 34 semanas) e pós-natal (grupo 1: 15.3 dias; grupo 2: 26 dias). A meia-vida e o volume aparente de distribuição, respectivamente, não apresentaram correlação (p 0,05) com a concentração plasmática de vancomicina no grupo 1 e no grupo 2. Através de regressão linear múltipla, no grupo 1, percebeu-se maior influência do volume aparente de distribuição e também da meia-vida (r = 0,85). No grupo 2, predominou o clearance total de vancomicina (r= 0,90). Concluiu-se que essa influência varia de acordo com a idade pós-conceptual e pós-natal dos recém-nascidos pré-termo/The influence of vancomycin pharmacokinetic parameters on the variation of its trough concentration was evaluated in two groups of preterm infants which were statistically diferent in terms of mean postconceptional age (group 1: 32 weeks; group 2: 34 weeks) and postnatal age (group 1: 15.3 days; group 2: 26 days). The half-life and apparent volume of distribution, respectively, did not present correlation (p 0.05) with the vancomycin serum concentration in group 1 and in group 2. Using multiple linear regression, a stronger influence of the apparent volume of distribution and also of the half-life (r= 0.85) was found in group 1. There was predominant influence of the vancomycin body clearance (r= 0.90) in group 2. In conclusion, that influence varies in accordance with the postconceptional and postnatal ages of preterm infants...

Puesta al día en enterococos año 2001: identificación de especies y estudio de susceptibilidad antimicrobiana / Update on microbiological topics of enterococci year 2001: identification of species and antimicrobial susceptibility technics

In recent years, enterococci have emerged as important pathogens. These organisms are now the third most commonly encountered nosocomial bloodstream infection pathogens in many part of the world. Due to increasing frequency with which multi-drug resistant enterococci are isolated from clinical specimens, there is a need for rapid reporting of results of identification tests and tests for susceptibility testing to antimicrobial agents. In 1999, we published an update of regarding the identification of the different species of enterococci as well as the recommendations for accurately detecting resistance among these isolates. In the current report, we will discuss additional tests for identification of enterococcal species as well as, the current recommendations for susceptibility testing

Emergencia de resistencia a macrólidos en streptococcus pyogenes / Emergence of macrolide resistant streptococcus pyogenes strains

Background: Diseases produced by Streptoccocus pyogenes are still a problem in Chile, as in the rest of the world. It exhibits in vitro susceptibility to different antimicrobials, but penicillin continues to be the treatment of choice. Alternative drugs have been developed for allergic patients, such as erythromycin, new macrolides and cephalosporins. Nevertheless, resistant strains are appearing due to the indiscriminate use of macrolides. Aim: To assess present antimicrobial susceptibility of S Pyogenes strains isolated from chilean patients. Material and Methods: The susceptibility to penicillin, macrolides, clindamycin, cephalotin and vancomycin of 153 S Pyogenes strains, obtained from different health centers of the Metropolitan Region and isolated between 1996 and 1998, was assessed using the Kirby-Bauer method. Agar dilution minimal inhibitory concentration was then determined to macrolide resistant strains. Results: All strains were susceptible to penicillin. There was a 7.2 percent cross-resistance to macrolides. Conclusions: These results confirm that S Pyogenes resistance to macrolides has increased considerably in the Metropolitan Region of Chile during the last years

Puesta al día en aspectos microbiológicos de enterococos / Update on microbiological topics of enterococci

Clinical microbiology laboratories are faced with the challenge of accurate detection of emerging antibiotic resistance among several important gram positive bacterial pahtogens. For enterococci, vancomycin and ampicillin resistance was significantly more prevalent among E. faecium than among E. faecalis. This finding undescores the importance of identifying enterococcal isolates to species for the sake of more precise surveillance. Enterococci are identified to the genus level with tests like pyrrolidine amilaridase, bile esculin and salt tolerance, but in some instances, species identification is desirable. Initial characterization of the species, as well as the antimicrobial susceptibility testing in enterococci, will be discussed in this report

Aislamientos de Enterococcus spp., resistentes a la Vancomicina, en muestras de heces de niños costarricenses / Insulating of Enterococcus spp., resistant a the Vancomicina, in feces of Costarrican children

Se hace referencia a la creación del género Enterococcus y sus especies importantes en patología humana así como su comportamiento ante la vancomicina y otros antimicrobianos. Se presentan los datos de las especies de Enterococcus encontradas en los estudios realizados en materia fecal de niños internados en la Unidad de Cuidados Intensivos del Hospital Nacional de Niños de Costa Rica.