Antimicrobial Dose Reduction in Continuous Renal Replacement Therapy: Myth or Real Need? A Practical Approach for Guiding Dose Optimization of Novel Antibiotics

Abstract

Acute kidney injury represents a common complication in critically ill patients affected by septic shock and in many cases continuous renal replacement therapy (CRRT) may be required. In this scenario, antimicrobial dose optimization is highly challenging as the extracorporeal circuit may cause several pharmacokinetic alterations, which add up to volume of distribution and clearance variations resulting from sepsis. Variations in CRRT settings (i.e. modality of solute removal, type of filter material, blood flow rate and effluent flow rate), coupled with the presence of residual and/or recovering renal function, may cause dynamic variations in the clearance of hydrophilic antimicrobials. This means that dose reduction may not always be needed. Nowadays, the lack of pharmacokinetic data for novel antimicrobials during CRRT limits evidence-based dose recommendations for critically ill patients in this setting, thus making available evidence hardly applicable in real-world scenarios. This review aims to summarize the major determinants involved in antimicrobial clearance, and the available pharmacokinetic studies performed during CRRT involving novel antibiotics used for the management of multidrug-resistant Gram-positive and Gram-negative infections (namely ceftolozane-tazobactam, ceftazidime-avibactam, cefiderocol, imipenem-relebactam, meropenem-vaborbactam, ceftaroline, ceftobiprole, dalbavancin, and fosfomycin), providing a practical approach in guiding dose optimization in this special population.

Place in Therapy of the Newly Available Armamentarium for Multi-Drug-Resistant Gram-Negative Pathogens: Proposal of a Prescription Algorithm

“…Real-life studies disclosed a CZA treatment failure rate of around 10–30% when used on susceptible CR pathogens [ 38 , 39 ]. Some clinical situations have been associated to the risk of in vivo resistance to CZA, probably through an under-exposure effect resulting in a deranged PK/pharmacodynamic (PD) profile [ 40 ]. In 2015, Nicolau et al demonstrated a dose-proportional ELF penetration of only 30% compared to plasma levels in healthy volunteers [ 41 ] and comparable results were observed in infected neutropenic mice [ 42 ].…”

An Evidence-Based Multidisciplinary Approach Focused on Creating Algorithms for Targeted Therapy of Infection-Related Ventilator-Associated Complications (IVACs) Caused by Pseudomonas aeruginosa and Acinetobacter baumannii in Critically Ill Adult Patients

“…It should not be overlooked that the pharmacokinetics of hydrophilic antimicrobial agents, namely beta-lactams and fosfomycin, may be affected among critically ill patients by several pathophysiological conditions that may alter volume of distribution and/or renal clearance [ 97 , 99 ]. Consequently, dose adjustments are needed in critically ill renal patients, especially among those with transient acute kidney injury, augmented renal clearance (ARC), and/or undergoing renal replacement therapy (RRT) [ 97 , 100 ]. In this scenario, adaptative daily therapeutic drug monitoring (TDM) may represent a valuable tool in addressing these issues.…”

Pharmacokinetics of Antibiotics in Pediatric Intensive Care: Fostering Variability to Attain Precision Medicine

“…It has been suggested that continuous RRT (CRRT) may also contribute to additional antibiotic PK variability in critically ill patients. Currently, a priori dose reductions based on drug dosing guidelines or labels are often performed in CRRT patients [147,148]. However, it has been reported that this strategy leads to inappropriate exposure in many of these patients.…”

“…However, it has been reported that this strategy leads to inappropriate exposure in many of these patients. Therefore, a more 'patient-centered approach' should be considered [148]. A recent observational multinational study showed highly variable antibiotic concentrations in adult critically ill patients receiving RRT.…”

“…As a result, recommendations concerning antibiotic dosing in children during CRRT are largely extrapolated from adult studies. It is generally assumed that hydrophilic antibiotics with small molecular weight, and low plasma protein binding are most susceptible to CRRT induced PK alterations [138,148].…”