Medication Dosing in Critically Ill Patients With Acute Kidney Injury Treated With Renal Replacement Therapy

Sepsis is the most common cause of death in critically ill patients and is associated with multiorgan failure, including acute kidney injury (AKI). This situation can require acute renal support and increase mortality. Therefore, it is essential to administer antimicrobials in doses that achieve adequate serum levels, avoiding both overdosing and drug toxicity as well as underdosing and the risk of antibiotic resistance and higher mortality. Currently, there are no validated guidelines on antibiotic dose adjustments in septic patients with AKI. The current recommendations were extrapolated from studies conducted in noncritical patients with end‐stage chronic kidney disease receiving chronic renal replacement therapy. This study aimed to review and discuss the complexity of this issue, considering several factors related to drug metabolism, the characteristics of critically ill patients, the properties of antimicrobial drugs and dialysis methods.

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“…Various mechanisms influence antimicrobial pharmacokinetics in critically ill patients (Scoville and Mueller 2013;Blot et al 2014) (Fig. 2).…”

Section: Pharmacokinetics and Pharmacodynamics Of Antibiotics In Critmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of antibiotics in critically ill acute kidney injury patients

Zamoner

Freitas

Garms

et al. 2016

Pharmacol Res Perspect

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“…Interestingly, when both cefepime and ceftazidime were administered at T16 (drug and prolonged intermittent renal replacement therapy were maximally apart), the probability of virtual patients reaching the toxic trough concentration at the 48‐hour point drastically decreased while maintaining the high probability of target attainment for the pharmacodynamic efficacy goals (compare Figure A with Figure B and Figure A with Figure B). It is well known that the timing of administration of a drug relative to prolonged intermittent renal replacement therapy greatly influences attainment of the pharmacodynamic target . However, this study highlights that the importance of the timing of drug administration relative to prolonged intermittent renal replacement therapy initiation may influence drug toxicity risk as well.…”

Section: Discussionmentioning

confidence: 82%

“…It is well known that the timing of administration of a drug relative to prolonged intermittent renal replacement therapy greatly influences attainment of the pharmacodynamic target. 65 However, this study highlights that the importance of the timing of drug administration relative to prolonged intermittent renal replacement therapy initiation may influence drug toxicity risk as well.…”

Section: Discussionmentioning

confidence: 92%

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

Jang

Gharibian

Lewis

et al. 2018

The Journal of Clinical Pharma

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Cefepime, ceftazidime, and piperacillin/tazobactam are commonly used beta-lactam antibiotics in the critical care setting. For critically ill patients receiving prolonged intermittent renal replacement therapy (PIRRT), limited pharmacokinetic data are available to inform clinicians on the dosing of these agents. Monte Carlo simulations (MCS) can be used to guide drug dosing when pharmacokinetic trials are not feasible. For each antibiotic, MCS using previously published pharmacokinetic data derived from critically ill patients was used to evaluate multiple dosing regimens in 4 different prolonged intermittent renal replacement therapy effluent rates and prolonged intermittent renal replacement therapy duration combinations (4 L/h × 10 hours or 5 L/h × 8 hours in hemodialysis and hemofiltration modes). Antibiotic regimens were also modeled depending on whether drugs were administered during or well before prolonged intermittent renal replacement therapy therapy commenced. The probability of target attainment (PTA) was calculated using each antibiotic's pharmacodynamic target during the first 48 hours of therapy. Optimal doses were defined as the smallest daily dose achieving ≥90% probability of target attainment in all prolonged intermittent renal replacement therapy effluent and duration combinations. Cefepime 1 g every 6 hours following a 2 g loading dose, ceftazidime 2 g every 12 hours, and piperacillin/tazobactam 4.5 g every 6 hours attained the desired pharmacodynamic target in ≥90% of modeled prolonged intermittent renal replacement therapy patients. Alternatively, if an every 6-hours cefepime regimen is not desired, the cefepime 2 g pre-prolonged intermittent renal replacement therapy and 3 g post-prolonged intermittent renal replacement therapy regimen also met targets. For ceftazidime, 1 g every 6 hours or 3 g continuous infusion following a 2 g loading dose also met targets. These recommended doses provide simple regimens that are likely to achieve the pharmacodynamics target while yielding the least overall drug exposure, which should result in lower toxicity rates. These findings should be validated in the clinical setting.

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“…Indeed, the start of the IHD or PIRRT session too close to drug administration (i.e., during the distribution phase) could have a much higher impact on drug removal-sometimes also for molecules with relatively low dialyzability (33,34). Thus, different timing of antibiotic administration could lead to profound differences in the area under the curve (AUC) of the drug plasma concentration, with a large effect on the attainment of PD targets, especially for time-dependent antibiotics (35). On this basis, IHD or PIRRT sessions ideally should be started at the end of a dosing interval; moreover, due to possible extensive removal, several antibiotics could require a supplemental dose at the end of dialysis (34).…”

Section: Drug Removal In Different Rrt Modalitiesmentioning

confidence: 99%

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

Pistolesi

Morabito

Mario

et al. 2019

Antimicrob Agents Chemother

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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)...

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Medication Dosing in Critically Ill Patients With Acute Kidney Injury Treated With Renal Replacement Therapy

Cited by 35 publications

References 88 publications

Pharmacokinetics and pharmacodynamics of antibiotics in critically ill acute kidney injury patients

Pharmacokinetics and pharmacodynamics of antibiotics in critically ill acute kidney injury patients

A Monte Carlo Simulation Approach for Beta‐Lactam Dosing in Critically Ill Patients Receiving Prolonged Intermittent Renal Replacement Therapy

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

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