Impacto del monitoreo terapéutico de vancomicina y amikacina en la optimización de dosis de antimicrobianos en pacientes pediátricos / Impact of the vancomycin and amikacin therapeutic monitoring in the optimization of antimicrobial dose in pediatric patients

INTRODUCCIÓN: La monitorización de antimicrobianos mediante sus concentraciones plasmáticas permite determinar la posología óptima de éstos, conducta esencial en pediatría. OBJETIVOS: Describir la monitorización de concentraciones plasmáticas de antimicrobianos y el ajuste de dosis en población pediátrica para determinar si las dosis utilizadas alcanzan rangos terapéuticos. PACIENTES Y MÉTODOS: Estudio descriptivo, retrospectivo, utilizando una base de datos con medición de concentraciones plasmáticas de amikacina y vancomicina en pacientes pediátricos del Hospital San Borja Arriarán, entre 2015-2018. Se determinó el número de pacientes que alcanzó rango terapéutico con dosis inicial, cuántos requirieron ajuste y sus características. RESULTADOS: Se monitorizó 104 concentraciones totales. Para vancomicina 65 concentraciones plasmáticas eran basales encontrándose fuera de rango terapéutico 56,5%; de los que requirieron ajuste, 25% fueron neonatos con mayor probabilidad de estar fuera de rango versus otros (p = 0,022). Para amikacina la Cpeak estuvo en rango en 60% de mediciones; 15,4% requirió ajuste incluyendo pacientes con fibrosis quística y oncológicos. No fue necesario efectuar ajustes en pacientes sin co-morbilidad. CONCLUSIÓN: La medición de concentraciones plasmáticas es necesaria para ajustar de forma individualizada la dosis, especialmente en pacientes pediátricos con fibrosis quística, oncológicos y en neonatología, donde es más probable no alcanzar rango terapéutico con las dosis iniciales.

BACKGROUND: The monitoring of antimicrobial therapy through plasma levels makes it possible to determine the optimal dosage of antimicrobials, an essential approach in pediatrics. AIM: To describe the monitoring of plasma antimicrobial levels and dose adjustment in the pediatric population to determine if the doses used reach therapeutic ranges. METHODS: Retrospective, descriptive study using a database with measurement of plasma levels of amikacin and vancomycin in pediatric patients at San Borja Arriarán Hospital between 2015-2018. The number of patients who reached the therapeutic range with the initial dose, how many required adjustment and their characteristics were determined. RESULTS: 104 total levels were monitored. For vancomycin 65 plasmatic levels were baseline, being outside the therapeutic range 56.5%; 25% of those requiring adjustment were neonates with a higher probability of being out of range versus others (p = 0.022). For amikacin, Cpeak was in range in 60% of measurements; 15.4% required adjustment, including patients with cystic fibrosis and cancer, without adjustments in patients without comorbidity. CONCLUSION: Measurement of plasma levels is necessary to individually adjust the dose, especially in pediatric patients with cystic fibrosis, oncology and in neonatology where it is more likely not to reach a therapeutic range with initial doses.

Pioderma gangrenoso ampollar como forma de presentación de leucemia mieloide agudo: informe de un caso / Acute myeloid leukemia presented in the form of bullous pyoderma gangrenosum: a case report

El pioderma gangrenoso ampollar es una variedad infrecuente de pioderma gangrenoso, que se asocia en el 50-70% de los casos con trastornos oncohematológicos. Se comunica el caso de una paciente de 59 años, que consultó por fiebre y ampollas purpúricas de rápida progresión, con compromiso cutáneo mucoso. Con sospecha de una enfermedad neutrofílica, ampollar, o infección por gérmenes oportunistas, se realizó biopsia de piel para estudio histopatológico, inmunofluorescencia directa y cultivo. Los cultivos y la inmunofluorescencia directa fueron negativos, y la anatomía patológica reveló un denso infiltrado inflamatorio con predominio neutrofílico en dermis. Ante el diagnóstico de pioderma gangrenoso ampollar, se realizó una punción-aspiración de médula ósea cuyo resultado fue compatible con leucemia mieloide aguda. Se instauró tratamiento con corticosteroides sistémicos, a pesar de lo cual la paciente evolucionó desfavorablemente y falleció a los 15 días de su ingreso hospitalario. Este caso ilustra la asociación de esta enfermedad cutánea con trastornos oncohematológicos y el mal pronóstico que esto implica a corto plazo. (AU)

Bullous pyoderma gangrenosum is an infrequent type of pyoderma gangrenosum, associated with onco hematological diseases in 50-70% of cases. We present the case of a 59-year-old patient with fever and mucocutaneous hemorrhagic bullous of rapid progression. A biopsy for histopathology, direct immunofluorescence (DIF) and skin culture was made, considering the possibility of neutrophilic dermatoses, bullous dermatosis or an opportunistic infection. The results of both the culture and the DIF were negative. The histopathological examination of the specimen revealed a dense dermal polymorphic infiltrate composed primarily of neutrophils. Considering bullous pyoderma gangrenosum as a potential diagnosis, a bone-marrow biopsy was performed. This study revealed an acute myeloid leukemia. Although systemic corticosteroid therapy was begun, the patient presented an unfavorable evolution that led to her death 15 days after her admission at the hospital. This case shows the association between bullous pyoderma gangrenosum and onco hematological diseases. In addition, it highlights the poor prognosis related to these diseases in the short term. (AU)

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.

Comparison of intermittent versus continuous-infusion vancomycin for treating severe patients in intensive care units

Abstract Purpose The aim of this study was to compare pharmacokinetic characteristics between intermittent infusion and continuous infusion of vancomycin for critically ill patients admitted to intensive care units. Methods Intermittent therapy was administered for 60 minutes and prescribed as a loading dose of 30 mg/kg and continued with 15 mg/kg q12 h. Continuous infusion was prescribed as a loading dose of 30 mg/kg followed by 30 mg/kg on constant infusion pump. Blood samples from vancomycin intermittent infusion group were collected 1 h before third dose, 1 h, 8 h and 24 h after third dose infusion. Blood samples from vancomycin continuous infusion group were collected 1 h after loading dose, 12 h, 24 h, 36 h, and 48 h after continuous infusion initiation. Results Median serum concentration of continuous infusion group at 24-hour was 23.59 µg/mL [14.52-28.97], while of intermittent infusion group at 23-hour was 12.30 µg/mL [7.27-18.12] and on 25-hour was 17.58 µg/mL [12.5-22.5]. Medians AUC24-48h were 357.2 mg.h/L and 530.2 mg.h/L for intermittent infusion and continuous infusion groups, respectively (p = 0.559). Conclusion Vancomycin CI reached steady state earlier, which guaranteed therapeutic levels from the first day and made it possible to manage therapeutic drug monitoring faster.

Dosificación empírica de vancomicina en neonatos: relación entre recomendación de dosis iniciales y relación área bajo la curva en 24 h/concentración inhibitoria mínima / Empiric vancomycin dosing in neonates: relationship between initial dose and 24 h area under the curve/minimum inhibitory concentration ratio

Resumen Introducción: Vancomicina es un antimicrobiano ampliamente utilizado para infecciones por Staphylococcus coagulasa negativa en neonatos; sin embargo, no existe claridad sobre la dosis empírica que asegure su eficacia terapéutica. Objetivo: Evaluar la relación entre las dosis iniciales de vancomicina utilizadas en una Unidad de Cuidado Intensivo Neonatal (UCIN) con la eventualidad de alcanzar el objetivo terapéutico de área bajo la curva sobre concentración inhibitoria mínima (ABC/CIM) mayor a 400 µg/h/mL. Materiales y Método: Estudio descriptivo y retrospectivo, realizado entre febrero 2016 y marzo 2018. Se incluyeron neonatos en tratamiento con vancomicina por sospecha/confirmación de infección por cocáceas grampositivas y medición de concentraciones plasmáticas de vancomicina al inicio del tratamiento. La probabilidad de alcanzar el objetivo terapéutico se evaluó mediante re-muestreo de valores de ABC y CIM. Resultados: Se incluyeron 38 pacientes con 49 concentraciones plasmáticas de vancomicina. Los aislados microbiológicos se confirmaron en 94,7% de los pacientes (n = 36). Los valores de ABC/CIM en dos grupos (según niveles valle de vancomicina < 10 µg/mL y ≥ 10 µg/mL), fueron de una mediana de 327 (IQ 25-75 = 174-395) y 494 (IQ 25-75 = 318-631), respectivamente (p = 0,035). Las dosis empíricas utilizadas logran logran un objetivo terapéutico (ABC/CIM > 400) de sólo 47,7% considerando CIMs en nuestra institución. Conclusiones: Teniendo en cuenta las sensibilidades institucionales, no es posible asegurar alcanzar ABC/CIM > 400 µg/h/mL. Se debe seguir investigando para replantear las actuales estrategias de dosificación y así determinar la más apropiada para neonatos.

Abstract Background: Vancomycin is used for treating coagulase-negative staphylococcus infections in neonates. However, concerns about the appropriate empirical dosing required for optimal efficacy, still remain. Aim: To assess the relationship between the initial doses of vancomycin used in a Neonatal Intensive Care Unit (NICU) with the possibility of achieving therapeutic target of AUC024h/MIC > 400 µg/h/mL. Methods: Retrospective and descriptive study carried out between February 2016 and March 2018. All neonates treated with vancomycin for suspected/proven Gram-positive infection and with at least one trough serum concentration level were included. Probability of target attainment (PTA) was evaluated through resampling of AUC and MIC values. Results: Final dataset included 38 patients and 49 trough vancomycin levels; 94.7% of these cases (n = 36) were confirmed Gram-positive infections. The median AUC/MIC values for the trough values vancomycin < 10 µg/mL group and for the ≥ 10 µg/mL group were 327 (IQR 174-395) and 494 (IQR 318-631) respectively (p = 0.035). Current empirical dosing strategy has a 47.7% PTA (AUC/MIC > 400) when taking institutional MICs into account. Conclusions: It is not possible to assure achieving a AUC/MIC > 400 µg/h/mL when considering institutional sensibilities. Current empiric dosing strategies should be reconsidered and further investigation needs to be done to help determine the appropriate empirical dosing required for optimal efficacy in neonates.

Valor do ecocardiograma na Endocardite Infecciosa associada aos dispositivos cardíacos implantáveis / Use of echocardiography in Infectious Endocarditis associated with implantable cardiac devices

Nas últimas décadas, o aumento das indicações para dispositivos cardíacos eletrônicos implantáveis tem sido acompanhado pela elevação dos casos de complicações relacionadas ao seu uso, dentre elas a endocardite infecciosa. Apesar dos avanços diagnósticos e terapêuticos da doença, esta mantém elevada morbimortalidade. Os casos relacionados aos dispositivos apresentam importantes limitações referentes aos critérios e aos métodos diagnósticos que implicam na tomada de decisão terapêutica sobre retirada do dispositivo, com risco de morte e outras complicações. Ainda assim, o ecocardiograma mantém um grande valor no diagnóstico da endocardite infecciosa relacionada a dispositivos cardíacos e de suas complicações. O entendimento das limitações e dos desafios acerca do diagnóstico reforça a necessidade de mais estudos sobre do tema. O presente artigo visa descrever a epidemiologia, a microbiologia, os fatores de risco, a patogenia, o diagnóstico e o tratamento da endocardite infecciosa associada aos dispositivos cardíacos eletrônicos implantáveis, visando demonstrar, principalmente, o valor dos exames de imagem na abordagem dessa condição clínica, com ênfase nos achados ao ecocardiograma.

In recent decades, the increase in indications for implantable electronic cardiac devices has been accompanied by an increase in cases of complications related to their use, including infectious endocarditis. Despite the diagnostic and therapeutic advances of the disease, it maintains high morbidity and mortality. The cases related to the devices have important limitations regarding the criteria and diagnostic methods that imply in making a therapeutic decision about removing the device, with risk of death and other complications. Still, echocardiography remains of great value in the diagnosis of infective endocarditis related to cardiac devices and their complications. Understanding the limitations and challenges regarding diagnosis reinforces the need for further studies on the topic. This article aims to describe the epidemiology, microbiology, risk factors, pathogenesis, diagnosis and treatment of infective endocarditis associated with implantable electronic cardiac devices, aiming to demonstrate, mainly, the value of imaging tests in addressing this clinical condition , with emphasis on echocardiogram findings.

Meningitis por Streptococcus pneumoniae resistente a ceftriaxona: reporte de un caso / Ceftriaxone-resistant Streptococcus pneumoniae meningitis: case report

RESUMEN La meningitis infecciosa es una emergencia médica. Dentro del espectro de agentes infecciosos, el más importante es el Streptococcus pneumoniae, agente etiológico más frecuente de la meningitis bacteriana. El inicio de tratamiento antimicrobiano empírico es de gran importancia y considera a las cefalosporinas de tercera generación como la primera alternativa. Sin embargo, casos de resistencia a ceftriaxona han sido reportados en diversas partes del mundo, siendo un problema emergente, por lo que necesita una reconsideración de los esquemas antibióticos empíricos actuales. Presentamos el caso de un varón de 56 años que presenta meningitis aguda infecciosa por Streptococcus pneumoniae resistente a ceftriaxona, que respondió favorablemente al tratamiento empírico combinado con ceftriaxona y vancomicina y que durante su estadía hospitalaria se detectó la presencia de hipotiroidismo y megacisterna magna.

ABSTRACT Infectious meningitis is a medical emergency. Within the spectrum of infectious agents, the most important is Streptococcus pneumoniae, the most frequent etiological agent of bacterial meningitis. The initiation of empirical antimicrobial treatment bears great importance and considers third-generation cephalosporins as the first alternative. However, cases of ceftriaxone resistance have been reported in several regions of the world. This has become an emerging problem in need of reconsideration of the current empirical antibiotic treatment schemes. We present the case of a 56-year old man with acute infectious meningitis caused by ceftriaxone-resistant Streptococcus pneumoniae, who responded favorably to combined empirical treatment with ceftriaxone and vancomycin and to whom, during his hospital stay, the presence of hypothyroidism and mega cisterna magna was diagnosed.

Intraoperative vancomycin powder and post-operative infection after spinal surgery: a systematic review and meta-analysis

SUMMARY

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.

Manejo actualizado de la diarrea asociada a Clostridium difficile / Updated management of diarrhea associated with Clostridium difficile

The management of Clostridium difficile (CD) infection has changed in recent years. The latest clinical guidelines and systematic reviews suggest the use of vancomycin orally as the first line of treatment regardless the severity of the crisis (main difference compared to previous recommendations), this is due to changes in its epidemiology, the decrease in effectiveness and the increase of recurrences with the use of metronidazole, particularly in severe crisis. In addition, the use of new agents such as fidaxomicin has been approved. Fulminant crisis require an aggressive management combining oral treatment, enemas and intravenous therapy in addition to a collaborative management with the surgery team. With respect to recurrences, the use of vancomycin in pulses and with extended therapy schemes is suggested; fecal microbiota transplantation (FMT) is also an attractive therapy for patients with multiple recurrences. The following is a summary of the latest recommendations and available evidence regarding the management of CD infection in the most frequent situations, both in first crisis and in its recurrences.

El manejo de la infección por Clostridium difficile (CD) ha tenido modificaciones los últimos años. Las últimas guías clínicas y revisiones sistemáticas sugieren el uso de vancomicina vía oral como primera línea de tratamiento independiente de la severidad de la crisis (diferencia principal con recomendaciones previas), esto debido a cambios en su epidemiología, la disminución de la efectividad y al aumento de las recurrencias con el uso de metronidazol, particularmente en crisis severas. Además, han sido aprobados el uso de nuevos agentes como la fidaxomicina. Las crisis de carácter fulminante requieren un manejo agresivo combinando terapia oral, vía enemas e intravenosa, además de un manejo en conjunto con el equipo de cirugía. Respecto a las recurrencias se sugiere el uso de vancomicina en pulsos y con esquemas de terapia extendida siendo además, el trasplante de microbiota fecal (FMT) una terapia atractiva para pacientes con múltiples recurrencias. A continuación se resumen las últimas recomendaciones y evidencia disponible respecto del manejo de la infección por CD en las situaciones más frecuentes, tanto en la primera crisis como en sus recurrencias.

Individualized vancomycin dosing for a patient diagnosed as severe acute pancreatitis with concurrent extracorporeal membrane oxygenation and continuous veno-venous hemofiltration therapy: a case report / 北京大学学报(医学版)

Pharmacokinetic parameters can be significantly altered for acute kidney injury (AKI), extracorporeal membrane oxygenation (ECMO) and continuous veno-venous hemofiltration therapy (CVVH). Here we reported a case of individualized vancomycin dosing for a patient diagnosed as severe acute pancreatitis treated with concurrent ECMO and CVVH. A 65 kg 32-year-old woman was admitted to hospital presented with severe acute pancreatitis (SAP), respiratory failure, metabotropic acidosis and hyperkalemia. She was admitted to intensive care unit (ICU) on hospital day 1 and was initiated on CVVH. She progressed to multiple organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) on ICU day 2, and veno-venous ECMO was instituted. Several catheters were inserted into the body to support ECMO, CVVH and pulse indicator continuous cardiac output (PiCCO), so vancomycin was prescribed empirically on ICU day 3 for prevention of catheter-related infection. Given the residual renal function and continuous hemofiltration intensity on day 3, vancomycin bolus of 1 000 mg was prescribed, followed by a maintenance dose of 500 mg every 8 hours. On ICU day 4, a vancomycin trough serum concentration of 14.1 mg/L was obtained before the fourth dose, which was within the target range of 10-20 mg/L. By ICU day 7, vancomycin dosage was elevated to 1.0 g every 12 hours because of aggravated infection and improved kidney function. On ICU day 14, a vancomycin trough serum concentration of 17 mg/L was obtained. Her white blood cell (WBC) and neutrophil percentage (Neut%) dropped to the normal level by ICU day 19. This vancomycin regimen was successful in providing a target attainment of trough serum concentration ranging from 10-20 mg/L quickly and in controlling infection-related symptoms and signs properly. With the help of this case report we want to call attention to the clinically significant alteration in vancomycin pharmacokinetics among critically ill patients. Individualized vancomycin dosing regimens and therapeutic drug monitoring are necessary for critically ill patients receiving CVVH and ECMO to ensure that the target serum vancomycin levels are reached to adequately treat the infection and avoid nephrotoxicity.

Clinical study of vancomycin for appropriate dosing in severe infective patients with augmented renal clearance / 中华危重病急救医学

OBJECTIVE@#To explore the impact of augmented renal clearance (ARC) on vancomycin pharmacokinetic target attainment in severe infective patients, and to analyze the initial dose of vancomycin based on the measured 12-hour urinary creatinine clearance (12 h-CLCR).@*METHODS@#A retrospective observational study was conducted. The patients with severe infection, who receiving vancomycin empiric or targeted therapy, admitted to intensive care unit (ICU) of the Affiliated Drum Tower Hospital of Nanjing University Medical School from February 2013 to December 2017 were enrolled. All patients were treated with vancomycin intravenously by intermittent bolus every 6-12 hours. After four or five doses, blood samples were drawn before the next dosage for serum trough vancomycin concentration (Cmin), and target concentration was defined between 15 mg/L and 20 mg/L. The urine creatinine (UCr) was measured, and CLCR was calculated. ARC was defined as 12 h-CLCR > 130 mL×min-1×1.73 m-2. According to 12 h-CLCR before treatment, the patients were divided into ARC group and non-ARC group. The basic renal function of the patients was monitored, and the dosage of vancomycin and the dosage of vancomycin when the blood concentration reached the target were recorded. The correlations between 12 h-CLCR and the dosage of vancomycin when the blood concentration reached the target as well as the blood concentration of vancomycin were analyzed by Spearman correlation analysis. Dosage stratification analysis was carried out according to different 12 h-CLCR. The predictive value of 12 h-CLCR for vancomycin dosage when the blood concentration reached the target was evaluated by using the receiver operator characteristic curve (ROC).@*RESULTS@#Data was provided from a total of 135 patients with severe infection, in which 102 patients met the inclusion criteria. The patients with vancomycin treatment duration less than 72 hours, chronic kidney disease V phase, vancomycin treatment before entering ICU and those with incomplete data were excluded. The mean 12 h-CLCR was (114.31±73.38) mL×min-1×1.73 m-2. The 12 h-CLCR in ARC group (n = 44, 43.14%) was significantly higher than that in non-ARC group (n = 58, 56.86%) (mL×min-1×1.73 m-2: 179.37±59.04 vs. 65.95±35.71, P < 0.01). Target Cmin of vancomycin was achieved in 50.98% of patients (52/102), the target rate in ARC group was significantly lower than that in non-ARC group [29.55% (13/44) vs. 67.24% (39/58), P < 0.01], and the Cmin of vancomycin in ARC group was significantly lower than that in non-ARC group (mg/L: 10.98±6.09 vs. 14.67±6.20, P < 0.01). Spearman correlation analysis showed that there was a significantly negative correlation between 12 h-CLCR and initial Cmin of vancomycin (n = 102, r = -0.436, P < 0.001), but a positive correlation was found between 12 h-CLCR and vancomycin dosage when the blood concentration reached the target (n = 52, r = 0.275, P = 0.048). The patients with ARC need higher dosage for blood concentration reaching the target than those without ARC (mg×kg-1×d-1: 42.47±13.17 vs. 31.53±14.43, P < 0.01). According to 12 h-CLCR, the patients with initial treatment reaching the target were divided into five subgroups, < 40, 40-70, 71-100, 101-130 and > 130 mL×min-1×1.73 m-2. The results showed that as 12 h-CLCR increased, the attained dosage of vancomycin was also increased correspondingly. ROC curve analysis showed that when 12 h-CLCR≥69.83 mL×min-1×1.73 m-2, the attained dose of vancomycin when the blood concentration reached the target was greater than conventional dosage of 30 mg×kg-1×d-1.@*CONCLUSIONS@#Patients with ARC have low concentrations of vancomycin and often fail to achieve therapeutic target. The initial dose of vancomycin can be selected according to 12 h-CLCR, the higher the 12 h-CLCR, the more the dosage of vancomycin is. When 12 h-CLCR is greater than or equal to 69.83 mL×min-1×1.73 m-2, the dosage of vancomycin should be higher than the conventional dosage.

Research of optimal dosing regimens and therapeutic drug monitoring for vancomycin by clinical pharmacists: analysis of 7-year data / 中华危重病急救医学

OBJECTIVE@#To investigate the effectiveness and safety of clinical pharmacists-directed vancomycin dosing and therapeutic drug monitoring (TDM), and to promote the individualized medication of vancomycin.@*METHODS@#Information of hospitalized patients treated by vancomycin admitted to Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2011 to October 2017 was collected retrospectively during study period, the patients were divided into pharmacists intervention and non-pharmacists intervention groups according to pharmacist-directed vancomycin dosing guideline or not. The individualized dosing regimen of vancomycin for the patients in pharmacists intervention group was guided by clinical pharmacists, this guideline was that pharmacists offered the TDM guidance, made the individualized dosage regimen of vancomycin, etc., which based on the patients' pathophysiology, condition, and the adjustments of increased dose or 24-hour continuous infusion vancomycin were made for patients if the steady-state trough concentrations fell below the target level. Vancomycin dosage was made for patients in the non-pharmacists intervention group by physicians only based on vancomycin instructions or clinical experience. The vancomycin dosing, TDM, microorganism culture, renal function, 30-day mortality rate, and length of hospital stay were recorded. The appropriateness of TDM for vancomycin was defined as a blood collection within 1 hour of the next scheduled dose after steady state achieved. The rationality of the initial dosing regimen was determined based on the vancomycin application guidelines issued by Infectious Diseases Society of America (IDSA) in 2009.@*RESULTS@#A total of 258 patients were enrolled, and there were 158 patients in the non-pharmacists intervention group and 100 in pharmacists intervention group. The appropriateness of TDM for vancomycin in pharmacists intervention group was significantly improved as compared with that in non-pharmacists intervention group [87.0% (87/100) vs. 69.6% (110/158), P < 0.01], the percentage of first trough serum concentrations drawn on day 3 after steady state achieved was significantly increased [51.0% (51/100) vs. 37.3% (53/142), P < 0.05]. Compared with the non-pharmacists intervention group, the percentages of patients who received appropriate initial dosing and attained the initial target therapeutic range in pharmacists intervention group were significantly increased [87.4% (76/87) vs. 68.2% (75/110), 51.7% (45/87) vs. 30.9% (34/110), both P < 0.01], the percentage of patients whose vancomycin dosing regimen was adjusted based on TDM results was also significantly increased [54.0% (47/87) vs. 15.5% (17/110), P < 0.01], the rate of vancomycin serum concentrations reaching the standard was increased [70.1% (61/87) vs. 32.7% (36/110), P < 0.01], and a lower number of patients in sub- or supra-therapeutic range was observed in pharmacists intervention group [27.6% (24/87) vs. 46.4% (51/110), 2.3% (2/87) vs. 20.9% (23/110), both P < 0.01]. In addition, a lower incidence of vancomycin-induced acute kidney injury (AKI) was observed in pharmacists intervention group as compared with that in non-pharmacists intervention group [0 (0/87) vs. 6.4% (7/110), P < 0.01]. No significant difference was observed in the microorganism culture, 30-day mortality rate or length of hospital stay between the two groups. Among the 87 patients in pharmacists intervention group, the vancomycin dosing was adjusted for 42 patients who did not attain the target therapeutic range, increasing the dose of vancomycin was made for 22 patients, 24-hour continuous infusion was made for 20 patients. Compared with the only increasing vancomycin dose group, vancomycin continuous infusion for 24 hours could significantly increase the serum trough concentration (mg/L: 18.0±6.7 vs. 12.5±5.8, P < 0.05), and reduce daily dosage (mg/kg: 27.1±7.1 vs. 36.6±9.2, P < 0.01).@*CONCLUSIONS@#The implementation of a pharmacist-directed vancomycin dosing guideline based on TDM optimized vancomycin dosing regimen, improved the accuracy and timeliness of TDM for vancomycin, achieved a higher percentage of levels within the therapeutic range, and a lower incidence of vancomycin-induced AKI.

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.

Serum levels of vancomycin: is there a prediction using doses in mg/kg/day or m2/day for neonates?

Abstract Coagulase-negative Staphylococcus has been identified as the main nosocomial agent of neonatal late-onset sepsis. However, based on the pharmacokinetics and erratic distribution of vancomycin, recommended empirical dose is not ideal, due to the inappropriate serum levels that have been measured in neonates. The aim of this study was to evaluate serum levels of vancomycin used in newborns and compare the prediction of adequate serum levels based on doses calculated according to mg/kg/day and m2/day. This is an observational reprospective cohort at a referral neonatal unit, from 2011 to 2013. Newborns treated with vancomycin for the first episode of late-onset sepsis were included. Total dose in mg/kg/day, dose/m2/day, age, weight, body surface and gestational age were identified as independent variables. For predictive analysis of adequate serum levels, multiple linear regressions were performed. The Receiver Operating Characteristic curve for proper serum vancomycin levels was also obtained. A total of 98 patients received 169 serum dosages of the drug, 41 (24.3%) of the doses had serum levels that were defined as appropriate. Doses prescribed in mg/kg/day and dose/m2/day predicted serum levels in only 9% and 4% of cases, respectively. Statistical significance was observed with higher doses when the serum levels were considered as appropriate (p < 0.001). A dose of 27 mg/kg/day had a sensitivity of 82.9% to achieve correct serum levels of vancomycin. Although vancomycin has erratic serum levels and empirical doses cannot properly predict the target levels, highest doses in mg/kg/day were associated with adequate serum levels.