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.

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.

Assessment of Therapeutic Drug Monitoring of Vancomycin in Elderly Patients According to New Guidelines

BACKGROUND: Concerns regarding increasing microbial resistance to vancomycin have resulted in recommendations for a higher trough serum vancomycin concentration. This study aimed to assess the dosage guidelines targeting vancomycin trough concentrations of 15-20 mg/L. METHODS: About 216 adult patients (age, >60 yr) were treated with intravenous vancomycin. The patients were divided into 2 groups according to their target vancomycin trough concentrations: the previous guideline group (n=108) treated with targeted vancomycin trough concentrations of 5-15 mg/L from Jan 2009 through April 2011 and the new guideline group (n=108) treated with targeted concentrations of 15-20 mg/L from November 2011 through July 2012. RESULTS: The 2 groups were not significantly different with respect to age, weight, initial serum creatinine, initial creatinine clearance, predictive trough levels, doses, serum drug concentrations, and area under the curve/minimal inhibitory concentrations. Regarding the proportions of vancomycin trough concentrations, the target range was achieved in 50% in the previous guideline group and in 16% in the new guideline group. In the previous and new guideline groups, the trough concentrations of 10-20 mg/dL were observed in 32.4% and 52.8% patients, respectively, and those of <10 mg/L were observed in 45.4% and 29.6%, respectively. CONCLUSIONS: Compared to the previous guideline group, the new guideline group showed higher proportions in the therapeutic range of 10-20 mg/L and lower proportions in trough concentrations <10 mg/L. The strictly managed vancomycin therapeutic drug monitoring in the new guideline group was assessed as more effective.

Vancomicina en infusión continua en pacientes pediátricos críticos / Continuous infusion of vancomycin in pediatric critical care

La administración de vancomicina en infusión continua es una estrategia de tratamiento posible en pacientes críticos que no alcancen niveles plasmáticos adecuados. Existe escasa bibliografía acerca de este tipo de administración. Se presentan 6 niños (2 meses a 7 años; 4 varones y 2 mujeres) que ingresaron en la unidad de cuidados intensivos del Hospital de Pediatría Garrahan con un cuadro clínico de sepsis por Staphylococcus aureus resistente a la meticilina, tratados con vancomicina, en dosis de entre 40 y 60 mg/kg/día cada 8-6 horas. Debido a la evolución clínica no favorable, la persistencia de la fiebre, los cultivos positivos y los niveles plasmáticos del antibiótico insuficientes, se implementó la infusión continua a 50 mg/kg/día. Todos los pacientes alcanzaron niveles entre 10 y 25 µg/ml, evolucionaron favorablemente y negativizaron los cultivos, sin signos de nefrotoxicidad. El tiempo de tratamiento en infusión continua fue entre 9 y 18 días. La infusión continua de vancomicina fue eficaz en estos pacientes, sin evidencias de nefrotoxicidad asociada.

Continuous infusion of vancomycin may be a strategy for critically ill patients who do not achieve adequate plasma levels. There is few literature on this dosage regimen. We present six children (2 months to 7 years, 4 male and 2 female), admitted to the Intensive Care Unit of the "Prof. Dr. Garrahan Children Hospital", with methicillin-resistant Staphylococcus aureus sepsis, treated with vancomycin 40 and 60 mg/kg/day every 8-6 hrs. Continuous infusion at 50 mg/kg/day was implemented due to poor outcome, persistent fever, positive cultures and inadequate vancomycin plasma levels. All patients achieved levels between 10 and 25 ug/ml, their outcome was favorable and cultures became negative, with no signs of nephrotoxicity. Treatment duration of the continuous infusion was 9 to 18 days. Continuous infusion of vancomycin was effective in these patients without evidence of associated nephrotoxicity.

Serum Cystatin C Is a Major Predictor of Vancomycin Clearance in a Population Pharmacokinetic Analysis of Patients with Normal Serum Creatinine Concentrations

We developed a population pharmacokinetic model of vancomycin by integrating the effects of cystatin C and other demographic factors in a large population of Korean patients with normal serum creatinine concentrations to elucidate the precise role of serum cystatin C concentrations in the prediction of vancomycin clearance. A population pharmacokinetic model of vancomycin was developed using NONMEM software from a total of 1,373 vancomycin concentration measurements in 678 patients whose serum creatinine concentrations were lower than 1.2 mg/dL. Covariate selection revealed that cystatin C was the most influential factor and had negative influence (-0.78) in the relationship. Total body weight, sex, age, and serum creatinine were also significantly correlated with the clearance. The estimated intersubject variabilities of clearance and volume of distribution were 24.7% and 25.1%, respectively. A 14-fold difference in predicted trough concentrations was observed according to only cystatin C concentrations in a population of simulated individuals with median demographic characteristics. The use of serum cystatin C as marker of vancomycin clearance for more accurate predictions of serum vancomycin concentrations could be useful, particularly among patients with normal serum creatinine concentrations.

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.

Vancomycin: the need to suit serum concentrations in hemodialysis patients

The vancomycin dose for hemodialysis (HD) patients should be adjusted by monitoring drug serum concentrations. However, this procedure is not available in most health services in Brazil, which usually adopts protocols based on published studies. The trials available are controversial, and several have not been conducted with current dialyzers. This study aimed at assessing the suitability of vancomycin serum concentrations in HD patients at a public hospital. Blood samples of HD patients were collected from November 2006 to May 2007, at time intervals of 48, 96, 120, or 168 hours after vancomycin administration. Drug measurement was performed with polarized light immunofluorescence. Approximately 86 percent of trough vancomycin serum concentrations were below the recommended value, indicating exposure to subtherapeutic doses and a higher risk for selecting resistant microorganisms.

Monitoramento terapêutico e modelagem farmacocinética de antimicrobianos em pacientes queimados da unidade de terapia intensiva / Therapeutic drug monitoring and pharmacokinetics of antimicrobial agents in burn patients from the Intensive care unit

A sepse após a injúria térmica é a maior causa de morbidade e mortalidade em pacientes queimados, uma vez que profundas alterações ocorrem na farmacocinética de agentes antimicrobianos. Investigaram-se trinta e um pacientes, portadores de sepse documentada e apresentando lesões ativas; utilizou-se o tratamento empírico conforme seguem os regimes de dose: 1 g, 12/12 h para a vancomicina, 1 g, 6/6 h para o imipenem e 2 g, 8/8 h para o cefepime. Sete coletas seriadas de sangue foram realizadas através de cateter venoso (2 mL/cada); o plasma foi obtido pela centrifugação e armazenado no congelador (-80o C) até o ensaio. A concentração plasmática dos antimicrobianos foi determinada simultaneamente pela aplicação do método bioanalítico desenvolvido no estudo. O método de cromatografia líquida de alta eficiência demonstrou boa linearidade, precisão e exatidão para a determinação simultânea da vancomicina, cefepime e imipenem plasmáticos; a plicação desse método bioanalítico permitiu o monitoramento plasmático terapêutico e o estudo farmacocinético. Com base nos resultados obtidos de concentração plasmática versus tempo, aplicou-se a modelagem para investigar a farmacocinética desses agentes antimicrobianos nos pacientes queimados. Os parâmetros cinéticos foram estimados com base no modelo aberto de um compartimento pela aplicação do programa PK Solutions v. 2.0; a estatística foi realizada pela utilização do programa GraphPad Prism v. 4.0. Com base na farmacocinética alterada, as concentrações obtidas para a vancomicina e imipenem se mostraram abaixo dos valores recomendados para atingir eficácia; por outro lado, as concentrações obtidas para o cefepime se mostraram dentro da faixa recomendada para atingir eficácia, uma vez que não se registrou alteração da farmacocinética deste antimicrobiano nos pacientes queimados. Desta forma, o monitoramento plasmático terapeutico se mostrou importante, permitindo o ajuste de dose para a vancomicina e para o imipenem, uma vez que...

Sepsis after thermal injury is the major cause of morbidity and mortality in burn patients, once deep changes on the pharmacokinetics of antimicrobials agents are expected. Thirty one burn patients were investigated, all of them had documented sepsis and presented active lesions; they were treated with empirical dose regimen as follows: 1 g, 12/12 h for vancomycin, 1 g, 6/6 h for imipenem and 2 g, 8/8 h for cefepime. A serial of seven blood samples were collected from the venous catheter (2 mL/each); plasma was obtained by centrifugation and storaged in an ultra-low freezer (-80o C) until assay. Drug plasma concentration was determined simultaneously by application of a bioanalytical method described previously. High performance liquid chromatographic method showed good linearity, precision and accuracy for vancomycin, cefepime and imipenem plasma measurements; its application permitted therapeutic drug monitoring and pharmacokinetic studies. Pharmacokinetic modeling was applied to data obtained based on drug plasma concentrations versus time, to investigate those antimicrobial agents in burn patients. Estimated kinetic parameters were based on the one compartment open model by application the software PK Solutions v. 2.0; statistics was performed by using the software GraphPad Prism v. 4.0. Based on altered pharmacokinetics, obtained plasma concentrations to reach drug efficacy were below the recommended values for vancomycin and imipenem; on the other hand, cefepime plasma concentrations to reach drug efficacy were in the recommended range, once its pharmacokinetics didnt change in burn patients. Then, therapeutic plasma monitoring was cost-effective permitting dose adjustment for vancomycin and imipenem, once the minimum effective concentration (MEC) wasnt reached for both antimicrobial agents by using the empirical dose regimen for burn patients. On the other hand, cefepime plasma monitoring was also cost-effective, since burn patients long term therapy can...

Vancomycin use in a large teaching hospital in Shiraz, Islamic Republic of Iran, 2003

We investigated adherence to the Hospital Infection Control Practice Advisory Committee [HICPAC] guidelines on vancomycin prescription in a large university-affiliated hospital in Shiraz. From August to December 2003, 200 hospitalized patients received vancomycin. For only 12 [6%] of these patients was vancomycin prescribed appropriately according to HICPAC guidelines. The main reasons why vancomycin use did not comply with HICPAC recommendations were: surgical prophylaxis in patients with negative cultures for resistant Gram-positive organisms, no investigation of vancomycin serum levels in patients receiving > 48 hours of vancomycin, vancomycin serum levels not repeated in patients receiving > 1 week of vancomycin, no appropriate adjustment of dosage with respect to serum levels in patients receiving vancomycin

Septicemia por Staphylococcus aureus em crianças: tolerância bacteriana à vancomicina e poder bactericida do soro / Staphylococcus aureus septicemia in children: bacterial tolerance to vancomycin and serum bactericidal test

OBJETIVO. Analisar a sensibilidade e tolerância das cepas de Staphylococcus aureus isoladas de crianças com septicemia e avaliar o poder bactericida sérico na monitorizaçäo terapêutica desses casos. MÉTODOS. Foram estudados 17 casos de crianças com septicemia por Staphylococcus aureus internadas na Enfermaria de cuidados semi-Intensivos do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de Säo Paulo. Foram realizados testes de sensibilidade antimicrobiana pelo método de difusäo em disco e diluiçäo em tubo. Foram realizados 29 testes no pico e 23 no vale dos antibióticos utilizados, determinando o poder bactericida do soro. RESULTADOS. As cepas de Staphylococcus aureus de origem hospitalar mostraram resistência a quase todos os antibióticos, exceto vancomicina e pefloxacina. Observou-se fenômeno de tolerância em cinco (50 por cento) das cepas testadas para vancomicina, sendo que quatro apresentaram má evoluçäo clínica. Os testes para determinaçäo do poder bactericida sérico revelaram títulos no pico ò1/8 em 55,5 por cento das observaç 8es; neste grupo a evoluçäo clínica foi melhor. CONCLUSäO. As cepas de Staphylococcus aureus de origem hospitalar estudadas säo multirresistentes. O fenômeno de tolerância antimicrobiana, assim como o poder bactericida do soro em níveis baixos, pode estar associado a má resposta terapêutica. A valorizaçäo do PBS como critério de avaliaçäo terapêutica em infecçöes graves e o papel da tolerância do Staphylococcus aureus à vancomicina merecem maiores estudos