The effect of renal functional status on drug metabolism is a crucial consideration for clinicians when determining the appropriate dosage of medications to administer. In critically ill patients, there is often a significant increase in renal function, which leads to enhanced drug metabolism and potentially inadequate drug exposure. This phenomenon, known as augmented renal clearance (ARC), is commonly observed in pediatric critical care settings. The findings of the current study underscore the significant impact of ARC on the pharmacokinetics and pharmacodynamics of antimicrobial drugs in critically ill pediatric patients. Moreover, the study reveals a negative correlation between increased creatinine clearance and blood concentrations of antimicrobial drugs. The article provides a comprehensive review of ARC screening in pediatric patients, including its definition, risk factors, and clinical outcomes. Furthermore, it summarizes the dosages and dosing regimens of commonly used antibacterial and antiviral drugs for pediatric patients with ARC, and recommendations are made for dose and infusion considerations and the role of therapeutic drug monitoring.
CONCLUSIONS:  ARC impacts antimicrobial drugs in pediatric patients.
BACKGROUND: • ARC is inextricably linked to the failure of antimicrobial therapy, recurrence of infection, and subtherapeutic concentrations of drugs.
BACKGROUND: • This study provides an updated overview of the influence of ARC on medication use and clinical outcomes in pediatric patients. • In this context, there are several recommendations for using antibiotics in pediatric patients with ARC: 1) increase the dose administered; 2) prolonged or continuous infusion administration; 3) use of TDM; and 4) use alternative drugs that do not undergo renal elimination.

BACKGROUND: Until recently, interest in renal function has focused on impairment to limit drug toxicity and increase medication safety. Augmented renal clearance (ARC) has been increasingly studied in multiple patient populations, including oncology, and could lead to decreased drug efficacy from faster elimination resulting in subtherapeutic concentrations. This scoping review sought to summarize ARC literature in cancer and identify areas of research to better inform pharmacy practitioners.
METHODS: Electronic databases were searched for English articles related to augmented/enhanced renal function/clearance following a framework for scoping reviews.
RESULTS: Fourteen articles were analyzed, divided according to article objective: descriptive studies or ARC\'s impact on pharmacokinetics/pharmacodynamics. ARC was most defined as creatinine clearance >130 mL/min/1.73 m2, reported in 10%-100% of patients. Febrile neutropenia in adult and pediatric patients, and age <50-65 years, hematologic malignancy, and lower serum creatinine in adult patients were notable risk factors for ARC. The impact of ARC has only been evaluated with antimicrobial agents consistently resulting in lower than anticipated trough levels. Identified gaps include: elucidation of ARC\'s mechanism and associated biomarkers, an inclusive ARC definition for relative renal enhancement, and study of additional drug classes to ascertain the breadth of ARC impact on drug therapy.
CONCLUSIONS: ARC is proving to be a frequent phenomenon in patients with cancer which pharmacists could play a vital role. Further research is needed to better understand the impact of ARC in patient care and a potential need to stage ARC based on degree of renal enhancement to establish specific drug dosing recommendations.

Vancomycin is a hydrophilic antibiotic widely used in severe infections, including bacteremia and central nervous system (CNS) infections caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci and enterococci. Appropriate antimicrobial dosage regimens can help achieve the target exposure and improve clinical outcomes. However, vancomycin exposure in serum and cerebrospinal fluid (CSF) is challenging to predict due to rapidly changing pathophysiological processes and patient-specific factors. Vancomycin concentrations may be decreased for peripheral infections due to augmented renal clearance (ARC) and increased distribution caused by systemic inflammatory response syndrome (SIRS), increased capillary permeability, and aggressive fluid resuscitation. Additionally, few studies on vancomycin\'s pharmacokinetics (PK) in CSF for CNS infections. The relationship between exposure and clinical response is unclear, challenging for adequate antimicrobial therapy. Accurate prediction of vancomycin pharmacokinetics/pharmacodynamics (PK/PD) in patients with high interindividual variation is critical to increase the likelihood of achieving therapeutic targets. In this review, we describe the interaction between ARC and vancomycin PK/PD, patient-specific factors that influence the achievement of target exposure, and recent advances in optimizing vancomycin dosing schedules for severe infective patients with ARC.

OBJECTIVE: Augmented renal clearance (ARC) is common in critically ill patients and may lead to subtherapeutic levels of antibiotics, thus influencing clinical outcomes and emergence of multidrug-resistant bacteria. The aim of this systematic review was to search the literature for recommendations concerning dosage adjustment for antibiotics administered to critically ill patients with ARC.
METHODS: A search of three electronic databases (Pubmed, Embase and Cochrane) was conducted from inception until the end of March 2021, using terms related to: 1) pharmacokinetics/pharmacodynamics (PK/PD), 2) antibiotic, 3) ARC and 4) critically ill. Two reviewers searched for relevant data and included studies suggesting specific doses for critically ill patients with ARC.
RESULTS: Forty-seven studies met the inclusion criteria. Dosage recommendations were found for 18 antibiotics. Differences were found in population characteristics, ARC definition, creatinine clearance (CLCR) determination method, PK methodology and definition of PK/PD targets. Cut-off values for CLCR ranged 120-240 mL/min; the most frequently employed method to define CLCR was Cockcroft-Gault estimation; and 83% of studies used population PK models to predict dosing regimens. All antibiotics, except three, needed upward dosing and/or infusion modality adjustments to reach PK/PD targets.
CONCLUSIONS: Despite the lack of high-quality studies and high heterogeneity, incremental dosing adjustment of antibiotics was frequently needed for critically ill patients with ARC to achieve the desired PK/PD targets. More research is needed to enlarge the number of antibiotics with recommendations for ARC and to validate current suggestions based on mathematical models in a clinical scenario.

Kidney function assessment in the critically ill overlooks the possibility for hyperfunctioning kidneys, known as augmented renal clearance (ARC), which could contribute to therapeutic failures in the intensive care unit (ICU). The aim of this research is to conduct a systematic review and meta-analysis of prevalence and risk factors of ARC in the critically ill. MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, ProQuest Dissertations and Theses Global databases were searched on 27 October 2020. We included studies conducted in critically ill adults who reported the prevalence and/or risk factors of ARC. We evaluated study quality using the Joanna Briggs Institute appraisal tool. Case reports, reviews, editorials and commentaries were excluded. We generated a random-effects meta-analytic model using the inverse variance method and visualized the pooled estimates using forest plots. Seventy studies were included. The pooled prevalence (95% CI) was 39% (34.9-43.3). Prevalence for neuro, trauma, mixed and sepsis ICUs were 74 (55-87), 58 (48-67), 36 (31-41) and 33 (21-48), respectively. Age, male sex and trauma were associated with ARC with pooled OR (95% CI) of 0.95 (0.93-0.96), 2.36 (1.28-4.36), 2.60 (1.21-5.58), respectively. Limitations included variations in ARC definition, inclusion and exclusion criteria and studies design. In conclusion, ARC is prevalent in critically ill patients, especially those in the neurocritical care and trauma ICU population. Young age, male sex and trauma are risk factors for ARC in those with apparently normal renal function. Further research on optimal dosing of drugs in the setting of ARC is warranted. (Prospero registration: CRD42021246417).

Augmented renal clearance (ARC), a phenomenon of enhanced elimination of renal solutes, has been described in adult critically ill patients, but little is known about the phenomenon in children. The aim of this scoping review was to gather and summarize all evidence on ARC in pediatric patients to examine its breadth and depth including prevalence, risk factors, and pharmacokinetic alterations and identify any gaps for further areas of inquiry. PubMed, Embase, and Web of Science were searched for titles, abstracts, or keywords that focused on ARC. Non-English studies, reviews, and nonhuman studies were excluded. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. Data were extracted on article type, study details, patient population, ARC definition and prevalence, methods of renal function assessment, and study results. A total of 215 citations were found with 25 citations meeting the criteria for inclusion in pediatrics (2102 total patients); the majority of studies (84%) focused on pharmacokinetics (PK) of antimicrobial agents. The median/mean age range was 1.25-12 years. There were a total of 10 different definitions of ARC. The prevalence of ARC ranged from 7.8% to 78%. The most common method for documenting creatinine clearance (CrCl) was the modified Schwartz equation (64%). Only 20% of studies reported risk factors for ARC including low serum creatinine, increasing age, febrile neutropenia, male, septic shock, and treatment with antibiotics. Glycopeptide antimicrobials were the most evaluated class (42.9%) among the 21 antimicrobial drug studies. All studies reported increased drug clearance and/or poor probability of achieving target concentrations of the agents studied. ARC showed variable prevalence in pediatric patients likely due to the lack of a standard definition and many studies not considering age-related changes in CrCl with pediatric intensive care unit (PICU) patients. ARC was shown to impact PK of antibiotics commonly administered to pediatric patients, which may necessitate changes in standard dosing regimens.