What’s new in pharmacokinetics of antimicrobials in AKI and RRT?

Abstract

Acute kidney injury (AKI) remains a very common occurrence in critically ill patients and is associated with decreased survival in severe sepsis [1]. Effective treatment for these patients is mostly through treatment of the underlying pathology as well as supportive care with renal replacement therapy (RRT). Optimised pharmacotherapy is of heightened importance to ensure maximal outcomes for critically ill patients with AKI receiving RRT, although the pharmacokinetics of many drugs can change dramatically in these patients, making effective dosing a challenge.The purpose of this paper is to describe the new developments in antibiotic dosing and pharmacokinetics in critically ill patients with AKI and receiving RRT.The overwhelming body of recent literature aims to understand how to better dose these compounds in critically ill patients receiving different forms of RRT, with far more data being generated for continuous than for intermittent RRT. Little data is available in AKI without RRT. Very few data on other classes of drugs are available which is largely due to the fact that many have negligible RRT clearance because of high protein binding, hepatic clearance or large volumes of distribution (e.g. most anticonvulsants), have dosing that is titrated to effect (e.g. analgesics and sedatives) or have readily available therapeutic drug monitoring (TDM).Recent pharmacokinetic studies of antibiotics have moved away from a drug-based dosing approach, where each drug has a given dose regardless of type of RRT, to a strategy where the specific drug dose accounts for the modality of RRT (e.g. intermittent, prolonged or continuous convective and/or diffusive RRT) and the associated settings (e.g. blood or ultrafiltration flow rate, filter material and surface area).Most of the studies continue to evaluate only pharmacokinetic endpoints and include small cohorts which limits the generalizability of findings. On the other hand, some comparative studies have been useful to better elucidate the effect of different approaches to RRT, including different modalities (i.e. intermittent and prolonged intermittent RRT and CRRT). It is hoped that the forthcoming SaMpling Antibiotics in Renal Replacement Therapy (SMARRT) study (ACTRN12613000241730), endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG), will address many of these issues. Further to this, use of ex vivo models of RRT are providing suitable doses for drugs to be subsequently tested in clinical pharmacokinetic studies [2]. Such models are very useful as the interaction between changing RRT modalities and settings on drug clearance, as well as potentially significant drug adsorption to the RRT membrane, can be more accurately calculated without the complicating effects of biology.Important knowledge has been generated recently that has aimed to quantify the effect of the dose and type of RRT used. Using a meta-review methodology of published studies, Jamal et al. highlighted the importance of CRRT dose where they found th...

Antibiotic Stewardship and Therapeutic Drug Monitoring of β-Lactam Antibiotics: Is There a Link? An Opinion Paper

“…Most data are generated for CRRT, and data on AKI without RRT remain scarce. 33 Accumulated evidence suggests that filtration rates, downtime, and residual diuresis ($500 mL/d) significantly influence the CL of b-lactams. [34][35][36] The effect of RRT on Cs cannot be reliably predicted, hindering accurate dosing recommendations.…”

“…33 Protein binding influences CL independently of RRT: the higher the protein binding, the lower the effect of the antibiotic on the CL. 33 Hypalbuminemia increases the fraction of free (active) drugs and may result in a higher CL. 37…”

Blood Purification with oXiris© in Critically Ill Children with Vasoplegic Shock

“…As generally performed in young children with extracorporeal therapy, we opted for a primary blood priming of the circuit for such patients. The increased patient volume associated with the increased hemofiltration of the device is at risk of the under-therapeutic drug level [28, 29]. In critically ill patients, especially with septic shock, some medications like antibiotics are of prime importance, and drug monitoring is necessary to ensure targeting the adequate therapeutic blood level.…”

Ajuste de fármacos y nutrición en terapias de reemplazo renal continuo

“…En la actualidad existen propuestas en investigación multicéntrica encaminadas a mejorar nuestro conocimiento del comportamiento farmacocinético de los antimicrobianos en TRRC, evaluando diferentes escenarios en el cuidado intensivo y la influencia de diferentes variables dinámicas del paciente crítico 48,49 . En la tabla 3 presentamos al lector información de interés de diferentes antimicrobianos, según la literatura actual disponible, con respecto a variables farmacocinéticas y de aclaramiento, con el fin de facilitar la aplicación de los cálculos expuestos e individualizar los esquemas de dosificación en TRRC.…”