Efecto de las técnicas continuas de reemplazo renal y del aclaramiento renal aumentado en el comportamiento famacocinético/farmacodinámico de linezolid en pacientes críticos.

203 p.La sepsis grave sigue siendo una importante causa de morbi-mortalidad en las unidades de cuidados intensivos. La piedra angular del tratamiento de la infección es el inicio precoz de un tratamiento antibiótico adecuado y el control del foco infeccioso. Además, para optimizar la antibioterapia hay que seleccionar no sólo el antimicrobiano más adecuado, sino que debemos seleccionar el régimen de dosificación óptimo, teniendo en cuenta los índices farmacocinéticos/farmacodinámicos (PK/PD) que mejor se correlacionan con la eficacia y cómo las alteraciones fisiopatológicas que se pueden producir en los pacientes críticos pueden alterar sus propiedades farmacocinéticas.Linezolid es un antibiótico del grupo de las oxazolidinonas, útil como alternativa a la vancomicina para el tratamiento de microorganismos Gram-positivos. Su PK presenta una gran variabilidad interindividual. En pacientes críticos su aclaramiento puede ser superior a lo descrito en individuos sanos, estando en riesgo de alcanzar niveles sub terapéuticos. Por otro lado, en pacientes sometidos a técnicas continuas de reemplazo renal (TCRR), no parece existir aún consenso respecto a si la dosificación actual es adecuada o no, sugiriendo la utilidad de la monitorización de niveles.Por todo ello hemos llevado a cabo un estudio cuyo objetivo principal ha sido caracterizar la farmacocinética de linezolid en diferentes grupos de pacientes críticos, y evaluar si el régimen de dosificación es adecuado o no de acuerdo a criterios PK/PD utilizando la Simulación de Montecarlo (SMC) como herramienta.En una primera parte del estudio evaluamos la PK de linezolid en pacientes sometidos a TCRR, y si la función renal residual del paciente podía tener influencia en la probabilidad de alcanzar el objetivo PD. Se incluyeron 21 pacientes críticos sépticos que precisaron TCRR por diferentes grados de disfunción renal. Además de confirmarse la alta variabilidad interindividual en la farmacocinética de linezolid en pacientes críticos pudimos observar como en pacientes con fracaso renal tratados con TCRR, la presencia de función renal residual, definida como un CLCr >10 mL/min, condiciona un aclaramiento total de linezolid significativamente más alto que en pacientes anúricos. En pacientes anúricos, la dosis recomendada proporciona una probabilidad moderadamente alta de éxito si la infección es debida a microorganismos con CMI¿2 mg/L. Sin embargo, en pacientes con función renal residual, la dosis estándar puede serinsuficiente. Una dosis de 900 mg cada 8 horas incrementa notablemente la probabilidad de éxito sin comprometer la seguridad.En un segundo estudio evaluamos la PK de linezolid en 17 pacientes críticos con diferentes grados de funcionalidad renal, incluyendo pacientes con aclaramiento renal aumentado (ARC). El análisis PK/PD mostró que, en ausencia de ARC, la dosis estándar proporciona una probabilidad de éxito moderada para valores de CMI de 2 mg/L. Además, con la SMC se demuestra que la administración en forma de perfusión continua permitiría cubrir hasta CMIs de 4 mg/L. Sin embargo, si el paciente presenta ARC, con la dosis estándar, hay un riesgo elevado de infradosificación. Para estos pacientes, una dosis mayor de linezolid y administrada en forma de perfusión continua (75 mg/h) podría ser una mejor opción que la dosis estándar administrada en perfusión intermitente.Para confirmar si la administración de linezolid en perfusión continua es capaz de proporcionar mejores índices de eficacia, realizamos un tercer estudio en el que incluimos 26 pacientes con y sin ARC a los que se les administró linezolid en forma de infusión continua de 50 mg/h. En conjunto, la mayoría de los pacientes presentó niveles ¿ 2 mg/L, aunque el porcentaje de pacientes fue mayor en el grupo sin ARC (94 vs 70%). Pudimos observar que la administración linezolid en perfusión continua, especialmente la dosis de 75 mg/h, puede ser una alternativa adecuada para tratar de forma empírica a pacientes con altos valores de aclaramiento de creatinina.La monitorización de niveles de linezolid para optimizar el tratamiento con este antibiótico ha sido recomendada por numerosos autores. La monitorización diaria del aclaramiento de creatinina basado en la medida de creatinina en orina para detectar la presencia de ARC permitiría ajustar la posología y evitar el riesgo de infradosificación. Finalmente, la monitorización de niveles en sangre podría ser una estrategia útil para optimizar la dosificación de linezolid, especialmente en pacientes con riesgo de infradosificación y/o toxicidad

Augmented Renal Clearance in Critically Ill Patients: A Systematic Review

Background Traditionally, renal function in critically ill patients has been assessed to identify renal dysfunction, and dose adjustment is generally accepted in such a context. Nevertheless, augmented renal clearance (ARC) is a less well-studied phenomenon that could lead to faster elimination of drugs, resulting in subtherapeutic concentrations and poorer clinical outcomes when standard dosage guidelines are followed. Objective The aim of this systematic review was to gather and summarise all the available evidence on ARC in critically ill patients, including its definition, underlying mechanisms, epidemiology, diagnosis and impact on both drug pharmacokinetics and clinical outcomes. Method A systematic review was conducted to include all the original studies that provided information on ARC in critically ill patients, and is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Augmented renal clearance, defined as a creatinine clearance (CrCl)[130 mL/min/1.73 m2, preferably measured in urine, is present in 20–65% of critically ill patients. Younger age, polytrauma and lower severity illness have been identified as risk factors. An influence of ARC on antimicrobial pharmacokinetics has been observed, with ARC consistently being associated with subtherapeutic antibiotic plasma concentrations. Conclusion ARC is a prevalent condition in critically ill patients, especially in young people, with urinary CrCl being the best diagnostic method because mathematical estimates tend to underestimate CrCl. ARC increases renal drug elimination and has a clear influence on certain antimicrobial plasma levels, but is yet to define its impact on clinical outcomes and on pharmacokinetics of other types of drugs. Research on the need to stage ARC and establish specific dosing guidelines is warranted.This study was financially supported by the University of the Basque Country (UPV/EHU) (PPG17/65)

Quantification of Ceftaroline in Human Plasma Using High-Performance Liquid Chromatography with Ultraviolet Detection: Application to Pharmacokinetic Studies

This study was conducted to develop a rapid, simple and reproducible method for the quantification of ceftaroline in plasma samples by high-performance liquid chromatography with ultraviolet detection (HPLC-UV). Sample processing consisted of methanol precipitation and then, after centrifugation, the supernatant was injected into the HPLC system, working in isocratic mode. Ceftaroline was detected at 238 nm at a short acquisition time (less than 5 min). The calibration curve was linear over the concentration range from 0.25 to 40 µg/mL, and the method appeared to be selective, precise and accurate. Ceftaroline in plasma samples was stable at −80 °C for at least 3 months. The method was successfully applied to characterize the pharmacokinetic profile of ceftaroline in two critically ill patients and to evaluate whether the pharmacokinetic/pharmacodynamic (PK/PD) target was reached or not with the dose regimen administered.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU 17/32)

Antibiotic susceptibility trend before and after long-term use of selective digestive decontamination: a 16 year ecological study

Objectives: The aim of this study was to compare antimicrobial susceptibility rates in a Spanish ICU before and after the introduction of selective digestive decontamination (SDD) and also to compare these with susceptibility data from other Spanish ICUs without SDD. Methods: We performed a retrospective study in the ICU of the University Hospital of Alava, where SDD was implemented in 2002. The SDD protocol consisted of a 2% mixture of gentamicin, colistin and amphotericin B applied on the buccal mucosa and a suspension of the same drugs in the gastrointestinal tract; additionally, for the first 3 days, systemic ceftriaxone was administered. From 1998 to 2013 we analysed the susceptibility rates for 48 antimicrobial/organism combinations. Interrupted time series using a linear dynamic model with SDD as an intervention was used. Data from other ICUs were obtained fromthe ENVIN-HELICS national registry. Results: Only amoxicillin/clavulanic acid against Escherichia coli and Proteus mirabilis, and a high concentration of gentamicin against Enterococcus faecalis, resulted in a significant decrease in the susceptibility rate after the implementation of SDD, with a drop of 20%, 27% and 32%, respectively. Compared with other Spanish ICUs without SDD, the susceptibility ratewas higher in the ICU of our hospital inmost cases.When itwas lower, differences were <10%, except for a high concentration of streptomycin against Enterococcus faecium, for which the difference was 19%. Conclusions: No relevant changes in the overall susceptibility rate after the implementation of SDD were detected. Susceptibility rates were not lower than those in the Spanish ICUs without SDD.This work was supported by the University of the Basque Country UPV/EHU (GIU17/32, PPG17/65)

Population pharmacokinetics of daptomycin in critically ill patients

Daptomycin has shown activity against a wide range of Gram-positive bacteria; however, the approved dosages usually seem insufficient for critically ill patients. The aim of this study was to develop a population pharmacokinetic model for daptomycin in critically ill patients and to estimate the success of the therapy by applying pharmacokinetic/pharmacodynamic (PK/PD) criteria. Sixteen intensive care unit patients were included, four of whom underwent continuous renal replacement therapies (CRRT). Blood and, when necessary, effluent samples were drawn after daptomycin administration at previously defined time points. A population approach using NONMEM 7.3 was performed to analyse data. Monte Carlo simulations were executed to evaluate the suitability of different dosage regimens. The probabilities of achieving the PK/PD target value associated with treatment success (ratio of the area under the plasma concentration-time curve over 24 h divided by the minimum inhibitory concentration (AUC24/MIC ≥ 666)) and to reach daptomycin concentrations linked to toxicity (minimum concentration at steady-state (Cminss) ≥ 24.3 mg/L) were calculated. The pharmacokinetics of daptomycin was best described by a one-compartment model. Elimination was conditioned by the creatinine clearance (Clcr) and also by the extra-corporeal clearance when patients were subjected to continuous renal replacement therapy (CRRT). The PK/PD analysis confirmed that 280- and 420-mg/d dosages would not be enough to achieve high probabilities of target attainment for MIC values ≥ 1 mg/L in patients with Clcr ≥ 60 mL/min or in subjects with lower Clcrs but receiving CRRT. In these patients, higher dosages (560-840 mg/d) should be needed. When treating infections due to MIC values ≥ 4 mg/L, even the highest dose would be insufficient.This study was supported by the University of the Basque Country UPV/EHU (PPG17/65)

Impact of augmented renal clearance on the pharmacokinetics of linezolid: Advantages of continuous infusion from a pharmacokinetic/pharmacodynamic perspective

Objectives: The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated. Methods: Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h). Results: In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations >= 2 mg/l in 70% of the ARC patients. MCS revealed that concentrations >= 2 mg/l would be reached in >90% of patients receiving 75 mg/h. Conclusions: ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations >= 2 mg/ml.This work was supported by the University of the Basque Country UPV/EHU (PPG17/65, GIU17/32), Spain

Optimization of levetiracetam dosing regimen in critically ill patients with augmented renal clearance: a Monte Carlo simulation study

[EN] Background Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view. Methods Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam. Results According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue. Conclusions Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.This research was funded by Department of Education of the Basque Government (PIBA 2019-57) and by the University of the Basque Country UPV/EHU (GIU20/048)

Pseudomonas aeruginosa Susceptibility in Spain: Antimicrobial Activity and Resistance Suppression Evaluation by PK/PD Analysis

Pseudomonas aeruginosa remains one of the major causes of healthcare-associated infection in Europe; in 2019, 12.5% of invasive isolates of P. aeruginosa in Spain presented combined resistance to ≥3 antimicrobial groups. The Spanish nationwide survey on P. aeruginosa antimicrobial resistance mechanisms and molecular epidemiology was published in 2019. Based on the information from this survey, the objective of this work was to analyze the overall antimicrobial activity of the antipseudomonal antibiotics considering pharmacokinetic/pharmacodynamic (PK/PD) analysis. The role of PK/PD to prevent or minimize resistance emergence was also evaluated. A 10,000-subject Monte Carlo simulation was executed to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) considering the minimum inhibitory concentration (MIC) distribution of bacteria isolated in ICU or medical wards, and distinguishing between sample types (respiratory and non-respiratory). Ceftazidime/avibactam followed by ceftolozane/tazobactam and colistin, categorized as the Reserve by the Access, Watch, Reserve (AWaRe) classification of the World Health Organization, were the most active antimicrobials, with differences depending on the admission service, sample type, and dose regimen. Discrepancies between EUCAST-susceptibility breakpoints for P. aeruginosa and those estimated by PK/PD analysis were detected. Only standard doses of ceftazidime/avibactam and ceftolozane/tazobactam provided drug concentrations associated with resistance suppression.This research was funded by the UPV/EHU (GIU 20/048)

Efecto de las técnicas continuas de reemplazo renal y del aclaramiento renal aumentado en el comportamiento famacocinético/farmacodinámico de linezolid en pacientes críticos.

203 p.La sepsis grave sigue siendo una importante causa de morbi-mortalidad en las unidades de cuidados intensivos. La piedra angular del tratamiento de la infección es el inicio precoz de un tratamiento antibiótico adecuado y el control del foco infeccioso. Además, para optimizar la antibioterapia hay que seleccionar no sólo el antimicrobiano más adecuado, sino que debemos seleccionar el régimen de dosificación óptimo, teniendo en cuenta los índices farmacocinéticos/farmacodinámicos (PK/PD) que mejor se correlacionan con la eficacia y cómo las alteraciones fisiopatológicas que se pueden producir en los pacientes críticos pueden alterar sus propiedades farmacocinéticas.Linezolid es un antibiótico del grupo de las oxazolidinonas, útil como alternativa a la vancomicina para el tratamiento de microorganismos Gram-positivos. Su PK presenta una gran variabilidad interindividual. En pacientes críticos su aclaramiento puede ser superior a lo descrito en individuos sanos, estando en riesgo de alcanzar niveles sub terapéuticos. Por otro lado, en pacientes sometidos a técnicas continuas de reemplazo renal (TCRR), no parece existir aún consenso respecto a si la dosificación actual es adecuada o no, sugiriendo la utilidad de la monitorización de niveles.Por todo ello hemos llevado a cabo un estudio cuyo objetivo principal ha sido caracterizar la farmacocinética de linezolid en diferentes grupos de pacientes críticos, y evaluar si el régimen de dosificación es adecuado o no de acuerdo a criterios PK/PD utilizando la Simulación de Montecarlo (SMC) como herramienta.En una primera parte del estudio evaluamos la PK de linezolid en pacientes sometidos a TCRR, y si la función renal residual del paciente podía tener influencia en la probabilidad de alcanzar el objetivo PD. Se incluyeron 21 pacientes críticos sépticos que precisaron TCRR por diferentes grados de disfunción renal. Además de confirmarse la alta variabilidad interindividual en la farmacocinética de linezolid en pacientes críticos pudimos observar como en pacientes con fracaso renal tratados con TCRR, la presencia de función renal residual, definida como un CLCr >10 mL/min, condiciona un aclaramiento total de linezolid significativamente más alto que en pacientes anúricos. En pacientes anúricos, la dosis recomendada proporciona una probabilidad moderadamente alta de éxito si la infección es debida a microorganismos con CMI¿2 mg/L. Sin embargo, en pacientes con función renal residual, la dosis estándar puede serinsuficiente. Una dosis de 900 mg cada 8 horas incrementa notablemente la probabilidad de éxito sin comprometer la seguridad.En un segundo estudio evaluamos la PK de linezolid en 17 pacientes críticos con diferentes grados de funcionalidad renal, incluyendo pacientes con aclaramiento renal aumentado (ARC). El análisis PK/PD mostró que, en ausencia de ARC, la dosis estándar proporciona una probabilidad de éxito moderada para valores de CMI de 2 mg/L. Además, con la SMC se demuestra que la administración en forma de perfusión continua permitiría cubrir hasta CMIs de 4 mg/L. Sin embargo, si el paciente presenta ARC, con la dosis estándar, hay un riesgo elevado de infradosificación. Para estos pacientes, una dosis mayor de linezolid y administrada en forma de perfusión continua (75 mg/h) podría ser una mejor opción que la dosis estándar administrada en perfusión intermitente.Para confirmar si la administración de linezolid en perfusión continua es capaz de proporcionar mejores índices de eficacia, realizamos un tercer estudio en el que incluimos 26 pacientes con y sin ARC a los que se les administró linezolid en forma de infusión continua de 50 mg/h. En conjunto, la mayoría de los pacientes presentó niveles ¿ 2 mg/L, aunque el porcentaje de pacientes fue mayor en el grupo sin ARC (94 vs 70%). Pudimos observar que la administración linezolid en perfusión continua, especialmente la dosis de 75 mg/h, puede ser una alternativa adecuada para tratar de forma empírica a pacientes con altos valores de aclaramiento de creatinina.La monitorización de niveles de linezolid para optimizar el tratamiento con este antibiótico ha sido recomendada por numerosos autores. La monitorización diaria del aclaramiento de creatinina basado en la medida de creatinina en orina para detectar la presencia de ARC permitiría ajustar la posología y evitar el riesgo de infradosificación. Finalmente, la monitorización de niveles en sangre podría ser una estrategia útil para optimizar la dosificación de linezolid, especialmente en pacientes con riesgo de infradosificación y/o toxicidad