Ajuste y dosificación de antibióticos B-Lactáminos aplicando el modelo farmacocinético de Monte Carlo en una unidad de paciente crítico adulto en un hospital docente asistencial : Hospital Clínico San Borja Arriarán
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Archivos
Fecha
2023
Autores
Profesor/a Guía
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Idioma
es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
Introducción: Los β-lactámicos son los antibióticos (ATBs) más utilizados en el
tratamiento de enfermedades infecciosas. En los últimos años, se ha incrementado
la resistencia a ATBs, siendo un preocupante tema de salud pública. El análisis
farmacocinético/farmacodinámico (PK/PD) se postula como una importante
herramienta para combatir la aparición de resistencias mediante la optimización de
los regímenes de dosificación de ATBs. La simulación farmacocinética de Monte
Carlo (MCS) evalúa la exposición-respuesta y permite combinar estas variables
para diseñar regímenes de dosificación que permitan alcanzar el éxito terapéutico
basado en índices PK/PD.
Objetivo: Evaluar propuestas de regímenes de dosificación para β-lactámicos en
una UPC adulto, mediante MCS, calculando la probabilidad de éxito de un
tratamiento ATB basado en el índice PK/PD para una infección, de la cual se conoce
el MO aislado y CIM, de acuerdo a las variables PK y clínicas del paciente crítico.
Metodología: Estudio observacional prospectivo, realizado desde mayo a julio 2022
en UPC adulto HCSBA. Se incluyeron pacientes en tratamiento con:
Piperacilina/Tazobactam (TZP), Meropenem (MEM), Ceftazidima (CAZ), Cefepime
(FEP) y pacientes con cultivos positivos, antibiograma y valor de CIM. Se utilizaron
datos de la distribución local de CIM, UPC 2021, en combinación con parámetros
PK publicados en paciente crítico para realizar MCS. Se realizaron 286 simulaciones
de 10.000 pacientes para calcular la probabilidad de alcanzar el objetivo
farmacodinámico (PTA) y la fracción de respuesta acumulada (CFR) de cada
régimen de dosificación vs la población bacteriana utilizando el software Crystal Ball
(versión 11.1.2.4; Oracle) para evaluar su eficacia. El porcentaje de tiempo durante
el cual la concentración libre de ATB permaneció por sobre la CIM (%ƒT>CIM) como
objetivo farmacodinámico: 60 %T>CIM para CAZ, 70 %T>CIM para FEP, 40
%T>CIM para MEM y 50 %T>CIM para TZP. Los regímenes se modelaron para
determinar la probabilidad de lograr un valor óptimo de PTA y CFR ≥ 90%.
Resultados: De los 26 pacientes incluidos, 14 (53,8%) utilizaron MEM; 5 (19,2%)
TZP; 4 CAZ (15,5%) y 3 FEP (11,5%). Los MO aislados en las pruebas de cultivos
fueron: 11 (42,3%) Ps. aeruginosa; 8 (30,8%) E. coli; 2 (7,7%) para K. pneumoniae,
K. aerogenes y E. cloacae, respectivamente; y 1 (3,8%) P. mirabilis. En 23 pacientes
(88,5%) cumplieron la evaluación del valor de PTA y en 20 pacientes (76,9%) de
CFR. MEM 2g/8h, CAZ 2g/8h y FEP 2g/8h lograron valores de CFR >90% para
todos los aislamientos de Ps. aeruginosa. MEM 0,5g/8h y 1g/8h, TZP 4,5g/8 logró
valores de CFR >90% para todos los aislamientos de E. coli, no así el caso de TZP
4,5 g/12h que logró solo un valor de 74,8%. 19 de 26 pacientes obtuvieron valores
óptimos tanto de PTA y CFR (73,1% de los pacientes).
Conclusión: El uso de MCS, incorporando datos de distribución local de CIM,
proporciona un mecanismo para predecir de manera efectiva la dosis y selección
óptima de antimicrobianos, mejorando la optimización de PK/PD y la eficacia clínica.
Introduction: The β-lactams are the most widely used antibiotics (ATBs) in the treatment of infectious diseases. In recent years, resistance to ATBs has increased, being a concerning public health issue. Pharmacokinetic/pharmacodynamic (PK/PD) analysis is postulated as an important tool to combat the emergence of resistance by optimizing ATB dosing regimens. Pharmacokinetic Monte Carlo simulation (MCS) evaluates the exposure-response and allows combining these variables to design dosing regimens to achieve therapeutic success based on PK/PD indices. Objective: To evaluate dosing regimen designs for β-lactams in an adult UPC, through MCS, calculating the probability of success of an ATB treatment based on the PK/PD index for an infection, of which the MO isolate and MIC are known, according to the PK and clinical variables of the critical patient. Methodology: Observational prospective study, performed from May to July 2022 in UPC adult HCSBA. Patients were included in treatment with: Piperacillin/Tazobactam (TZP), Meropenem (MEM), Ceftazidime (CAZ), Cefepime (FEP) and patients with positive cultures, antibiogram and MIC value. Data from the local MIC distribution, UPC 2021, in combination with published PK parameters in critically ill patients were used to perform MCS. A total of 286 simulations of 10,000 patients were performed to calculate the probability of reaching the probability target attainment (PTA) and cumulative fraction of response (CFR) of each dosing regimen vs. bacterial population using Crystal Ball software (version 11.1.2.4; Oracle) to evaluate efficacy. The percentage of time during which the ATB-free concentration remained above the MIC (%ƒT>CIM) as a pharmacodynamic target: 60 %T>CIM for CAZ, 70 %T>CIM for FEP, 40 %T>CIM for MEM and 50 %T>CIM for TZP. The regimens were modeled to determine the probability of achieving an optimal PTA and CFR value ≥ 90%. Results: From the 26 patients included, 14 (53.8%) used MEM; 5 (19.2%) TZP; 4 CAZ (15.5%) and 3 FEP (11.5%). MO isolated in culture tests were: 11 (42.3%) Ps. aeruginosa; 8 (30.8%) E. coli; 2 (7.7%) for K. pneumoniae, K. aerogenes and E. cloacae, respectively; and 1 (3.8%) P. mirabilis. In 23 patients (88.5%) they met the assessment of PTA value and in 20 patients (76.9%) of CFR. MEM 2g/8h, CAZ 2g/8h and FEP 2g/8h achieved CFR values >90% for all Ps. aeruginosa isolates. MEM 0.5g/8h and 1g/8h, TZP 4.5g/8h achieved CFR values >90% for all E. coli isolates, but TZP 4.5 g/12h achieved only 74.8%. 19 of 26 patients obtained optimal values for both PTA and CFR (73.1% of patients). Conclusion: The use of MCS, incorporating local MIC distribution data, provides a mechanism to effectively predict optimal antimicrobial dosing and selection, improving PK/PD optimization and clinical efficacy.
Introduction: The β-lactams are the most widely used antibiotics (ATBs) in the treatment of infectious diseases. In recent years, resistance to ATBs has increased, being a concerning public health issue. Pharmacokinetic/pharmacodynamic (PK/PD) analysis is postulated as an important tool to combat the emergence of resistance by optimizing ATB dosing regimens. Pharmacokinetic Monte Carlo simulation (MCS) evaluates the exposure-response and allows combining these variables to design dosing regimens to achieve therapeutic success based on PK/PD indices. Objective: To evaluate dosing regimen designs for β-lactams in an adult UPC, through MCS, calculating the probability of success of an ATB treatment based on the PK/PD index for an infection, of which the MO isolate and MIC are known, according to the PK and clinical variables of the critical patient. Methodology: Observational prospective study, performed from May to July 2022 in UPC adult HCSBA. Patients were included in treatment with: Piperacillin/Tazobactam (TZP), Meropenem (MEM), Ceftazidime (CAZ), Cefepime (FEP) and patients with positive cultures, antibiogram and MIC value. Data from the local MIC distribution, UPC 2021, in combination with published PK parameters in critically ill patients were used to perform MCS. A total of 286 simulations of 10,000 patients were performed to calculate the probability of reaching the probability target attainment (PTA) and cumulative fraction of response (CFR) of each dosing regimen vs. bacterial population using Crystal Ball software (version 11.1.2.4; Oracle) to evaluate efficacy. The percentage of time during which the ATB-free concentration remained above the MIC (%ƒT>CIM) as a pharmacodynamic target: 60 %T>CIM for CAZ, 70 %T>CIM for FEP, 40 %T>CIM for MEM and 50 %T>CIM for TZP. The regimens were modeled to determine the probability of achieving an optimal PTA and CFR value ≥ 90%. Results: From the 26 patients included, 14 (53.8%) used MEM; 5 (19.2%) TZP; 4 CAZ (15.5%) and 3 FEP (11.5%). MO isolated in culture tests were: 11 (42.3%) Ps. aeruginosa; 8 (30.8%) E. coli; 2 (7.7%) for K. pneumoniae, K. aerogenes and E. cloacae, respectively; and 1 (3.8%) P. mirabilis. In 23 patients (88.5%) they met the assessment of PTA value and in 20 patients (76.9%) of CFR. MEM 2g/8h, CAZ 2g/8h and FEP 2g/8h achieved CFR values >90% for all Ps. aeruginosa isolates. MEM 0.5g/8h and 1g/8h, TZP 4.5g/8h achieved CFR values >90% for all E. coli isolates, but TZP 4.5 g/12h achieved only 74.8%. 19 of 26 patients obtained optimal values for both PTA and CFR (73.1% of patients). Conclusion: The use of MCS, incorporating local MIC distribution data, provides a mechanism to effectively predict optimal antimicrobial dosing and selection, improving PK/PD optimization and clinical efficacy.
Notas
Seminario (Químico Farmacéutico)
Palabras clave
Antibióticos, Administración y Dosificación, Método de Monte Carlo