A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy

Abstract

A careful management of antimicrobials is essential in the critically ill with acute kidney injury, especially if renal replacement therapy is required. Acute kidney injury may lead per se to clinically significant modifications of drugs' pharmacokinetic parameters, and the need for renal replacement therapy represents a further variable that should be considered to avoid inappropriate antimicrobial therapy. The most important pharmacokinetic parameters, useful to determine the significance of extracorporeal removal of a given drug, are molecular weight, protein binding, and distribution volume. In many cases, the extracorporeal removal of antimicrobials can be relevant, with a consistent risk of underdosing-related treatment failure and/or potential onset of bacterial resistance. It should also be taken into account that renal replacement therapies are often not standardized in critically ill patients, and their impact on plasma drug concentrations may substantially vary in relation to membrane characteristics, treatment modality, and delivered dialysis dose. Thus, in this clinical scenario, the knowledge of the pharmacokinetic and pharmacodynamic properties of different antimicrobial classes is crucial to tailor maintenance dose and/or time interval according to clinical needs. Finally, especially for antimicrobials known for a tight therapeutic range, therapeutic drug monitoring is strongly suggested to guide dosing adjustment in complex clinical settings, such as septic patients with acute kidney injury undergoing renal replacement therapy. The most important factors able to affect drug PK during RRT are volume of distribution (V), protein binding, and molecular weight (MW); the knowledge of these parameters, along with total body clearance (CL TB ), allows determination of the significance of extracorporeal removal of a given drug.The volume of distribution corresponds to the ratio of the amount of drug in the body at a given time and plasma concentration at that time (11). In other terms, it represents the theoretical volume necessary to contain the total amount of an administered drug at the same concentration measured in plasma (12), and it should be regarded as a proportionality factor between a plasma concentration and the corresponding amount of drug in the whole body (11). As snapshot plasma drug concentrations may vary according to the state of drug disposition (i.e., just after intravenous [i.v.] administration, during the distribution phase, during the terminal phase of drug disposition, or at equilibrium), the proportionality ratio between the amount of drug in the body and the plasma concentration will change; thus, several V will be obtained in different situations (11). In clinical practice, V at equilibrium (V ss ), obtained when plasma concentrations are measured under steady-state conditions (i.e., during continuous i.v. drug infusion or multiple-drug administration once steady-state plasma concentrations have been achieved), represents the most appropriate V to compute a "loading dose" (11)...

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy

“…The SC and the SA indicate the ratio of solute concentration in ultrafiltrate (SC) or the dialysate (SA) to solute concentration in the blood (Wong et al, 2015). CRRT clearance can be calculated by SC/SA and effluent flow rates as follows: convention clearance (ml/min) = SC × ultrafiltrate flow rate (ml/min); diffusion clearance = SA × dialysate flow rate (ml/min) (Pistolesi et al, 2019). SC or SA = 0 represents all drugs cannot pass through the membranes, while SC or SA =1 represents that all drugs can be filtered through the CRRT membrane.…”

“…A standard dose of these antimicrobials can be recommended for patients during CRRT. Although little is known about the PK parameters of clindamycin and azithromycin during different CRRT modalities, considering their non-renal elimination, studies suggested that no dose adjustment is required during CRRT (Pistolesi et al, 2019).…”

“…Inappropriate doses of antimicrobial agents may lead to increased adverse drug reactions, pathogen resistance, and clinical treatment failure. With the improvement of CRRT equipment, techniques, prescriptions (Macedo and Mehta, 2016), and as the PK/PD studies go on, previous studies do not reflect contemporary CRRT techniques (Trotman et al, 2005;Seyler et al, 2011) and prescriptions (Shaw and Mueller, 2017;Pistolesi et al, 2019) or include only a small number of agents (Hoff et al, 2019).…”

Pharmacokinetics Alterations in Critically Ill Pediatric Patients on Extracorporeal Membrane Oxygenation: A Systematic Review

“…Such heterogeneity is further compounded by physiological derangements associated with critical illnesses, renal replacement therapy, drug-drug interactions, genetic polymorphisms and the use of ECMO. [49][50][51][52] Much deeper understanding of the interplay between these factors is critical in improving our ability to provide personalized dosing to pediatric patients on ECMO. Pediatric pharmacokinetic research presents specific challenges, some of which can be circumvented with the use of model-based approaches to study design and analysis, such as population pharmacokinetic modeling and physiologically based pharmacokinetic modeling.…”

<p>Antiviral Agent Therapy Optimization in Special Populations of COVID-19 Patients</p>

“…74 Pharmacokinetics of drugs could be altered during RRT. 75 For patients receiving hemodialysis or peritoneal dialysis, the dosage of chloroquine should be as same as patients with GFR< 10 mL/min, namely, administer 50% of the original dose. For patients receiving CRRT, no dosage adjustment is necessary.…”