Pharmacokinetics and therapeutic target attainment of vancomycin in pediatric post-liver transplant patients.

INTRODUCTION: Vancomycin is widely prescribed to treat or prevent Gram-positive infections in pediatric liver transplant recipients. The objective of this prospective cohort study is to describe vancomycin pharmacokinetics and to evaluate the therapeutic target attainment after initial dose regimen. MATERIALS AND METHODS: Patients with previous renal injury were excluded. Vancomycin therapy started with 40‒60 mg/kg/day. The pharmacokinetic parameters were assessed using two steady-state blood samples and the first-order kinetic equations. Therapeutic target was defined as vancomycin 24-hour Area Under the Curve/Minimum Inhibitory Concentration (AUC/MIC) ≥ 400 and < 600. RESULTS: Sixteen patients were included. The found vancomycin clearance, half-life, and volume of distribution were, respectively: 2.1 (1.3‒2.8) mL/kg/min, 3.3 (2.7‒4.4) hours, and 0.7 (0.5‒0.9) L/kg. With the initial dose, only 6 (37 %) patients reached the therapeutic target against Gram-positive pathogens with MIC 1 mg/L. After individual dose adjustments, all patients reached the target. The correlation between trough levels and AUC was low (R2 = 0.5). CONCLUSIONS: Pediatric patients with preserved renal function after liver transplantation have an increased volume of distribution for vancomycin, and most patients present subtherapeutic levels after the standard initial dosing regimen. With the vancomycin AUC-guided monitoring and dosing, it is possible to improve therapeutic target attainment.

Pharmacokinetics and Therapeutic Target Attainment of Meropenem in Pediatric Post-Liver Transplant Patients: Extended vs Intermittent Infusion.

PURPOSE: The aim of this study is to characterize the concentration-time profile, pharmacokinetics parameters, and therapeutic target attainment of meropenem in pediatric post-liver transplant patients according to the duration of infusion. METHODS: This is a prospective cohort of pediatric transplant recipients with preserved renal function receiving meropenem 40 mg/kg every 8 hours. The patients were stratified into 2 groups based on infusion duration: G1 (15 minutes of intermittent infusion) and G1 (3 hours of extended infusion). Two blood samples per child were collected during the same interval within 48 hours of starting the antimicrobial. Meropenem concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were assessed using a noncompartmental analysis. The therapeutic target was defined as 100% of the time above the minimum inhibitory concentration. FINDINGS: Fourteen patients with 28 measured meropenem concentrations were included. Lower values of volume of distribution and meropenem clearance compared with other critically ill pediatric populations were found. All patients achieved the therapeutic target against gram-negative pathogens with a minimum inhibitory concentration of ≤8 mg/L. Patients receiving a 15-minute infusion had higher values of peak and trough concentrations, resulting in unnecessary increased total drug exposure when compared to patients receiving a 3-hour infusion (P < .05). CONCLUSIONS: Meropenem at 120 mg/kg/d attained the therapeutic target against sensitive microorganisms in pediatric liver transplant recipients. The extended infusion should be preferred for patient safety. Because of the pharmacokinetic changes resulting from liver transplantation, individualized meropenem dosing regimens may be necessary.

Synergistic combination of aztreonam and ceftazidime/avibactam against resistant Stenotrophomonas maltophilia on pancreatitis.

INTRODUCTION: Stenotrophomonas maltophilia is a Gram-negative, opportunistic pathogen associated with a high morbidity and mortality rate. We report our clinical experience in treating a patient with infected pancreatic necrosis caused by multidrug-resistant (MDR) S. maltophilia with a novel drug combination. CASE REPORT: A 65-year-old male with history of type II diabetes was admitted with acute pancreatitis, voluminous ascites, and signs of sepsis after undergoing an echo-endoscopy procedure with pancreas biopsy to investigate a Wirsung duct dilatation. Retroperitoneal fluid culture revealed S. maltophilia resistant to colistin and with intermediate susceptibility to trimethoprim-sulfamethoxazole and levofloxacin. The synergy between aztreonam (ATM) and ceftazidime/avibactam (CZA) was demonstrated using the combined disk pre-diffusion test. CONCLUSIONS: There are sparse data providing guidance on the optimal regimen against MDR S. maltophilia infections. Although in this case a surgical excision was essential, combination of ATM and CZA provided effective synergistic antimicrobial treatment with clinical cure of severe acute pancreatitis infected with S. maltophilia. The combined disk pre-diffusion test with ATM and CZA requires no special equipment and can be routinely performed in clinical microbiology labs. Combination of ATM with CZA should be considered for cases of MDR S. maltophilia infections with limited treatment options.

Pharmacokinetic and pharmacodynamic considerations of antibiotics and antifungals in liver transplantation recipients.

The liver plays a major role in drug metabolism. Liver transplantation impacts the intrinsic metabolic capability and extrahepatic mechanisms of drug disposition and elimination. Different levels of inflammation and oxidative stress during transplantation, the process of liver regeneration, and the characteristics of the graft alter the amount of functional hepatocytes and activity of liver enzymes. Binding of drugs to plasma proteins is affected by the hyperbilirubinemia status and abnormal synthesis of albumin and alpha-1-acid glycoproteins. Postoperative intensive care complications such as biliary, circulatory, and cardiac also impact drug distribution. Renally eliminated antimicrobials commonly present reduced clearance due to hepatorenal syndrome and the use of nephrotoxic immunosuppressants. In addition, liver transplantation recipients are particularly susceptible to multidrug-resistant infections due to frequent manipulation, multiple hospitalizations, invasive devices, and frequent use of empiric broad-spectrum therapy. The selection of appropriate anti-infective therapy must consider the pathophysiological changes after transplantation that impact the pharmacokinetics and pharmacodynamics of antibiotics and antifungal drugs.

Pharmacokinetics and therapeutic target attainment of vancomycin in pediatric post-liver transplant patients

Abstract Introduction Vancomycin is widely prescribed to treat or prevent Gram-positive infections in pediatric liver transplant recipients. The objective of this prospective cohort study is to describe vancomycin pharmacokinetics and to evaluate the therapeutic target attainment after initial dose regimen. Materials and methods Patients with previous renal injury were excluded. Vancomycin therapy started with 40‒60 mg/kg/day. The pharmacokinetic parameters were assessed using two steady-state blood samples and the first-order kinetic equations. Therapeutic target was defined as vancomycin 24-hour Area Under the Curve/Minimum Inhibitory Concentration (AUC/MIC) ≥ 400 and < 600. Results Sixteen patients were included. The found vancomycin clearance, half-life, and volume of distribution were, respectively: 2.1 (1.3‒2.8) mL/kg/min, 3.3 (2.7‒4.4) hours, and 0.7 (0.5‒0.9) L/kg. With the initial dose, only 6 (37 %) patients reached the therapeutic target against Gram-positive pathogens with MIC 1 mg/L. After individual dose adjustments, all patients reached the target. The correlation between trough levels and AUC was low (R2= 0.5). Conclusions Pediatric patients with preserved renal function after liver transplantation have an increased volume of distribution for vancomycin, and most patients present subtherapeutic levels after the standard initial dosing regimen. With the vancomycin AUC-guided monitoring and dosing, it is possible to improve therapeutic target attainment.

Trough-guided Versus AUC/MIC-Guided Vancomycin Monitoring: A Cost Analysis.

PURPOSE: Recent vancomycin dosing and monitoring guidelines recommend monitoring vancomycin area under the 24-hour time-concentration curve instead of traditional trough-only monitoring. This study aimed to compare the total costs of vancomycin dosing and monitoring between trough-guided and AUC-guided approaches in a quaternary hospital from Brazil. METHODS: In this retrospective cohort study, patients were divided into 2 groups according to the monitoring method. Patients with previous renal impairment were excluded. Vancomycin AUC was estimated by using 2 steady-state serum concentrations and first-order kinetics equations. The primary outcome was total cost of vancomycin therapy and monitoring from the hospital perspective, which included costs of cumulative doses, laboratory fees, materials used in blood collection, nursing time for collection, and pharmacist time for result interpretation. FINDINGS: A total of 68 patients were included in the AUC/MIC-guided monitoring group, and 76 patients were included in the trough-guided monitoring group. There were no significant differences between groups regarding baseline serum creatinine level, duration of vancomycin therapy, and cumulative vancomycin dose. The median (interquartile range) total vancomycin drug and monitoring cost was $298.32 ($153.81-$429.85) for the AUC/MIC-guided group compared with $285.59 ($198.81-$435.57) for the trough-guided group (P = 0.9658). IMPLICATIONS: Vancomycin AUC estimation using 2 steady-state serum concentrations and first-order kinetics equations is a feasible alternative for limited-resource institutions that intend to transition from a trough approach to AUC/MIC-guided monitoring.

Vancomycin area under the curve-guided monitoring in pediatric patients. / Monitoramento orientado pela área sob a curva da vancomicina em pacientes pediátricos.

OBJECTIVE: To assess the percentage of vancomycin area under the curve/minimum inhibitory concentration target attainment in pediatric patients after the empirical dose regimen and to demonstrate the applicability of this method for vancomycin monitoring. METHODS: A retrospective cohort study was performed including pediatric patients with normal renal function admitted between January 2020 and December 2020. The one-compartment model with first-order kinetics was used to estimate the pharmacokinetic parameters, and the area under the curve was calculated by the trapezoidal rule. The therapeutic target was defined as area under the curve/minimum inhibitory concentration ≥ 400 and < 600. The Chi-squared test was applied to compare the percentage of target attainment over age groups, while the pharmacokinetic parameters were compared by the Kruskal-Wallis test with Dunn's test for post hoc analyses. We considered significant p-values < 0.05. RESULTS: In total, 42 pairs of vancomycin levels were analyzed from 17 patients enrolled in this study. After empirical vancomycin daily dosing, the therapeutic target was achieved in five (29%) patients; four patients (24%) had a supratherapeutic initial area under the curve/minimum inhibitory concentration value (> 600mg.h/L), and eight (47%) patients had subtherapeutic values (< 400mg.h/L). The most identified pathogens were Staphylococcus spp. (n = 7). Trough levels and areas under the curve showed moderate correlation values (R2 = 0.73). Acute kidney injury occurred in one (6%) patient. CONCLUSION: Most patients did not reach the therapeutic target with a vancomycin empirical dose regimen, and the implementation of area under the curve-based dosing using two sample measurements allowed for real-time dose adjustments based on individuals' pharmacokinetic parameters.

OBJETIVO: Avaliar a probabilidade de atingir o alvo pela razão entre a área sob a curva e a concentração inibitória mínima de vancomicina em pacientes pediátricos após o esquema de dose empírica e demonstrar a aplicabilidade desse método para o monitoramento da vancomicina. METÓDOS: Foi realizado um estudo de coorte retrospectivo que incluiu pacientes pediátricos com função renal normal internados entre janeiro e dezembro de 2020. O modelo de um compartimento com cinética de primeira ordem foi utilizado para estimar os parâmetros farmacocinéticos, e a área sob a curva foi calculada pela regra do trapézio. O alvo terapêutico foi definido como a razão entre a área sob a curva e a concentração inibitória mínima ≥ 400 e < 600. O teste do qui-quadrado foi aplicado para comparar a probabilidade de atingir o alvo nos grupos etários, enquanto os parâmetros farmacocinéticos foram comparados pelo teste de Kruskal-Wallis com o teste de Dunn para análises post hoc. Consideraram-se significativos os valores de p < 0,05. RESULTADOS: Foram analisados, no total, 42 pares de níveis de vancomicina de 17 pacientes inscritos neste estudo. Após a dose diária empírica de vancomicina, o alvo terapêutico foi atingido em cinco (29%) pacientes; quatro pacientes (24%) apresentavam razão entre a área sob a curva inicial supraterapêutica e o valor de concentração inibitória mínima (> 600mg.h/L) e oito (47%) tinham valores subterapêuticos (< 400mg.h/L). Os patógenos mais identificados foram Staphylococcus spp. (n = 7). Os níveis de vale e as áreas sob a curva mostraram valores moderados de correlação (R2 = 0,73). Um (6%) paciente apresentou lesão renal aguda. CONCLUSÃO: A maioria dos pacientes não atingiu o alvo terapêutico com esquema de dose empírica de vancomicina, e a implementação de dosagem baseada na área sob a curva usando duas medições de amostra permitiu ajustes de dose em tempo real com base nos parâmetros farmacocinéticos dos indivíduos.

Beta-Lactams Therapeutic Monitoring in Septic Children-What Target Are We Aiming for? A Scoping Review.

The antimicrobial therapy of sepsis and septic shock should be individualized based on pharmacokinetic/pharmacodynamic (PK/PD) parameters to deliver effective and timely treatment of life-threatening infections. We conducted a literature scoping review to identify therapeutic targets of beta-lactam antibiotics in septic pediatric patients and the strategies that have been applied to overcome sepsis-related altered pharmacokinetics and increase target attainment against susceptible pathogens. A systematic search was conducted in the MEDLINE, EMBASE and Web of Science databases to select studies conducted since 2010 with therapeutic monitoring data of beta-lactams in septic children. Last searches were performed on 02 September 2021. Two independent authors selected the studies and extracted the data. A narrative and qualitative approach was used to summarize the findings. Out of the 118 identified articles, 21 met the eligibility criteria. Population pharmacokinetic modeling was performed in 12 studies, while nine studies reported data from bedside monitoring of beta-lactams. Most studies were conducted in the United States of America (n = 9) and France (n = 5) and reported PK/PD data of amoxicillin, ampicillin, azlocillin, aztreonam, cefazolin, cefepime, cefotaxime, ceftaroline, ceftazidime, doripenem, meropenem and piperacillin/tazobactam. Therapeutic targets ranged from to 40% fT> MIC to 100% fT> 6 × MIC. Prolonging the infusion time and frequency were most described strategies to increase target attainment. Monitoring beta-lactam serum concentrations in clinical practice may potentially maximize therapeutic target attainment. Further studies are required to define the therapeutic target associated with the best clinical outcomes.

Therapeutic Target Attainment of 3-Hour Extended Infusion of Meropenem in Patients With Septic Burns.

PURPOSE: The aim of this prospective cohort study was to evaluate the therapeutic target attainment of 3-hour extended infusion of meropenem in patients with septic burns in the early and late periods of septic shock. METHODS: Meropenem serum levels were determined by liquid chromatography from blood samples collected within 48 hours (early period) of therapy and 10 to 14 days afterward (late period). Pharmacokinetic properties were investigated by noncompartmental analysis, and the therapeutic target was defined as 100% of the time above the MIC (100%fT> MIC). FINDINGS: Fifteen patients with 90 measured meropenem concentrations were included. Throughout the entire course of antimicrobial therapy, the therapeutic target was attained against gram-negative pathogens with an MIC ≤ 2 mg/L. Pathogens with intermediate susceptibility to meropenem were only covered in the early phase of therapy. IMPLICATIONS: Higher-dose regimens or continuous infusions may be necessary to guarantee antimicrobial coverage of meropenem against less sensitive pathogens in patients with septic burns.

Monitoramento orientado pela área sob a curva da vancomicina em pacientes pediátricos / Vancomycin area under the curve-guided monitoring in pediatric patients

RESUMO Objetivo: Avaliar a probabilidade de atingir o alvo pela razão entre a área sob a curva e a concentração inibitória mínima de vancomicina em pacientes pediátricos após o esquema de dose empírica e demonstrar a aplicabilidade desse método para o monitoramento da vancomicina. Metódos: Foi realizado um estudo de coorte retrospectivo que incluiu pacientes pediátricos com função renal normal internados entre janeiro e dezembro de 2020. O modelo de um compartimento com cinética de primeira ordem foi utilizado para estimar os parâmetros farmacocinéticos, e a área sob a curva foi calculada pela regra do trapézio. O alvo terapêutico foi definido como a razão entre a área sob a curva e a concentração inibitória mínima ≥ 400 e < 600. O teste do qui-quadrado foi aplicado para comparar a probabilidade de atingir o alvo nos grupos etários, enquanto os parâmetros farmacocinéticos foram comparados pelo teste de Kruskal-Wallis com o teste de Dunn para análises post hoc. Consideraram-se significativos os valores de p < 0,05. Resultados: Foram analisados, no total, 42 pares de níveis de vancomicina de 17 pacientes inscritos neste estudo. Após a dose diária empírica de vancomicina, o alvo terapêutico foi atingido em cinco (29%) pacientes; quatro pacientes (24%) apresentavam razão entre a área sob a curva inicial supraterapêutica e o valor de concentração inibitória mínima (> 600mg.h/L) e oito (47%) tinham valores subterapêuticos (< 400mg.h/L). Os patógenos mais identificados foram Staphylococcus spp. (n = 7). Os níveis de vale e as áreas sob a curva mostraram valores moderados de correlação (R2 = 0,73). Um (6%) paciente apresentou lesão renal aguda. Conclusão: A maioria dos pacientes não atingiu o alvo terapêutico com esquema de dose empírica de vancomicina, e a implementação de dosagem baseada na área sob a curva usando duas medições de amostra permitiu ajustes de dose em tempo real com base nos parâmetros farmacocinéticos dos indivíduos.

ABSTRACT Objective: To assess the percentage of vancomycin area under the curve/minimum inhibitory concentration target attainment in pediatric patients after the empirical dose regimen and to demonstrate the applicability of this method for vancomycin monitoring. Methods: A retrospective cohort study was performed including pediatric patients with normal renal function admitted between January 2020 and December 2020. The one-compartment model with first-order kinetics was used to estimate the pharmacokinetic parameters, and the area under the curve was calculated by the trapezoidal rule. The therapeutic target was defined as area under the curve/minimum inhibitory concentration ≥ 400 and < 600. The Chi-squared test was applied to compare the percentage of target attainment over age groups, while the pharmacokinetic parameters were compared by the Kruskal-Wallis test with Dunn's test for post hoc analyses. We considered significant p-values < 0.05. Results: In total, 42 pairs of vancomycin levels were analyzed from 17 patients enrolled in this study. After empirical vancomycin daily dosing, the therapeutic target was achieved in five (29%) patients; four patients (24%) had a supratherapeutic initial area under the curve/minimum inhibitory concentration value (> 600mg.h/L), and eight (47%) patients had subtherapeutic values (< 400mg.h/L). The most identified pathogens were Staphylococcus spp. (n = 7). Trough levels and areas under the curve showed moderate correlation values (R2 = 0.73). Acute kidney injury occurred in one (6%) patient. Conclusion: Most patients did not reach the therapeutic target with a vancomycin empirical dose regimen, and the implementation of area under the curve-based dosing using two sample measurements allowed for real-time dose adjustments based on individuals' pharmacokinetic parameters.

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

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.

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.