A 2019 review article presents a comprehensive update on antibiotic dosing for critically ill adult patients receiving various forms of renal replacement therapy (RRT), including intermittent hemodialysis (IHD), prolonged intermittent renal replacement therapy (PIRRT), and continuous renal replacement therapy (CRRT). This review synthesizes data from studies published between January 2008 and May 2019, evaluating antibiotic dosing recommendations and pharmacokinetic/pharmacodynamic (PK/PD) considerations for these patient populations. The authors conducted a literature search using PubMed to identify relevant English-language publications, subsequently synthesizing empirical dosing recommendations for antibiotics commonly used in critically ill patients undergoing different RRT modalities. These recommendations aim to individualize therapy by considering renal function assessment, RRT system properties affecting drug clearance, and drug properties influencing clearance during RRT. The article underscores the complexity of dosing antimicrobials in critically ill patients with altered pharmacokinetics and the added challenge of concurrent RRT, which can significantly impact drug clearance and therapeutic outcomes. Detailed attention is given to the principles of antimicrobial PK/PD, the variability in RRT modalities, and the lack of standardization in continuous RRT, which can lead to inconsistencies in dosing recommendations. The authors propose empirical dosing strategies for various antibiotics, considering factors such as RRT modality, patient-specific variables like residual renal function, local epidemiology, and resistance patterns, as well as severity of illness and patient response to therapy. The importance of cautious application and customization of these recommendations is emphasized to optimize antibiotic exposure and improve clinical outcomes for this vulnerable patient group. [1]
A 2023 review examined the complexities of individualizing antimicrobial drug dosing in critically ill adults undergoing RRT. It highlighted the importance of achieving adequate antimicrobial dosing to improve survival rates in patients with sepsis admitted to the ICU, who frequently experience renal dysfunction necessitating RRT. The review elaborated on how therapeutic drug monitoring (TDM) is a useful strategy for optimizing drug dosing, yet it is not consistently accessible in all ICU settings and for various antimicrobials. In this context, clinicians must rely on a combination of the patient's clinical status, the pathogen involved, RRT characteristics, and the pharmacokinetic properties of the drugs to make informed dosing decisions. This publication underscores the high variability in the pharmacokinetics of antimicrobials not only among different critically ill patients but also within the same patient throughout their ICU stay. RRT, whether performed as intermittent hemodialysis, continuous therapy, or prolonged intermittent therapy, adds another layer of complexity to predicting drug behavior. The review emphasizes the necessity for individualized dosing approaches and provides practical considerations for clinicians when managing antimicrobial therapy in this patient population. The focus remains on employing strategies that ensure optimal serum drug concentrations at the infection site, facilitating microbial eradication and avoiding toxicity from overexposure to antibiotics. [2]
A 2023 systematic review examined the PK and dosing regimens of antimicrobials in critically ill adults undergoing PIRRT. A total of 39 studies involving 452 patients were included, evaluating 18 antibiotics and 2 antifungal agents and demonstrating substantial variability in drug clearance, PD target attainment, and dosing strategies across agents (Table 1). Vancomycin, meropenem, and piperacillin/tazobactam were among the most frequently studied antimicrobials, with stronger evidence derived from population PK studies supporting dosing recommendations for these agents, whereas most other drugs had limited or low-quality evidence resulting in weaker recommendations. Across studies, drug clearance during PIRRT was generally higher than off PIRRT, though the magnitude varied by agent and study conditions. Overall, significant heterogeneity in study design, PIRRT modalities, and reported PK/PD parameters limited the ability to establish standardized dosing approaches, highlighting the need for additional high-quality population PK studies to better inform dosing strategies. [3]
A 2018 narrative review explored the nuances of antibiotic dosing in critically ill patients undergoing sustained low-efficiency dialysis (SLED). The review aimed to consolidate existing knowledge and identify key challenges in optimizing antibiotic therapy for this patient population, who often present with acute kidney injury (AKI) and hemodynamic instability. The review highlighted a significant challenge: most clinical laboratories can only assay aminoglycosides and vancomycin, complicating the determination of therapeutic doses. Furthermore, existing studies suffer from limitations due to small and heterogeneous patient samples, suggesting a pressing need for standardized guidelines through future large-scale research. The findings underscored the necessity of incorporating pharmacokinetic principles when deciding on antibiotic dosing during SLED. The review emphasized the importance of timing antibiotic administration to align with SLED's initiation, aiming to optimize the time above the minimum inhibitory concentration (MIC) for time-dependent antibiotics, or the peak to MIC ratio for concentration-dependent antibiotics. This balance is pivotal for maximizing efficacy while minimizing toxicity. Table 2 highlights the important studies of antibiotic dosage analysis in SLED. The authors advocated for close collaboration between critical care physicians and nephrologists to tailor antibiotic regimens, ensuring clinical goals are met amidst the challenges posed by SLED's unique drug clearance characteristics. [4]
A 2024 editorial delves into the intricate dynamics of PK/PD variability in critically ill patients undergoing RRT in the Intensive Care Unit (ICU). These patients often experience profound PK alterations due to factors such as inflammation, hypoalbuminemia, and organ failure, which affect both the volume of distribution (Vd) and drug clearance. The complexity is further heightened by treatment modalities such as PIRRT and Continuous Kidney Replacement Therapy (CKRT), which introduce additional variables influencing drug clearance. The authors emphasize that while TDM remains the gold standard for optimizing antibiotic therapy, particularly for antibiotics with a narrow therapeutic index, ensuring adequate drug exposure is critical for patient survival. The editorial also highlights the challenges posed by the use of colistin, a polymyxin antibiotic, for treating multidrug-resistant gram-negative infections such as those caused by carbapenem-resistant Acinetobacter baumannii. It is noted that colistin is administered as a prodrug, colistin methanesulphonate (CMS), with its conversion in plasma being influenced by renal function. Critically ill patients on CKRT face significant challenges in achieving appropriate drug levels due to various PK variables, including those related to extracorporeal therapy methods. Notably, using coupled plasma filtration and adsorption CKRT can lead to substantial drug clearance, necessitating careful dosage adjustments to avoid underdosing. The authors underscore the importance of maintaining appropriate antibiotic levels to prevent both therapeutic failure and nephrotoxicity, advocating for active monitoring of drug levels in this vulnerable patient population. [5]
The 2019 prospective clinical pharmacokinetic study evaluated the pharmacokinetics of colistin and its prodrug colistin methanesulfonate in eight critically ill ICU patients with acute kidney injury undergoing prolonged intermittent renal replacement therapy (PIRRT). The study aimed to assess the pharmacokinetics after both single and multiple doses, focusing on determining the appropriate dosing regimen. Each patient, comprising two females and six males, received an initial loading dose of 6 million international units (MIU) of colistin methanesulfonate followed by a maintenance dose of 3 MIU every 8 hours. PIRRT was performed using a high-flux dialyzer, and the study collected data over several days, specifically on day 1 and days 5 to 9 of treatment, contingent on the timing of dialysis. The results demonstrated that PIRRT significantly removed colistin and colistin methanesulfonate, eliminating approximately half of the administered colistin dose daily. Despite an initial loading dose, peak colistin plasma concentrations were not immediately sufficient in all patients. The study further highlighted that colistin peak concentrations increased from day 1 to days 5-9, indicating accumulation. Crucially, an inverse correlation was observed between body weight and the maximum plasma concentrations of colistin, suggesting that dosing adjustments based on body weight and the intensity of renal replacement therapy are necessary to optimize therapeutic outcomes and minimize toxicity. This investigation underscores the need for individualized colistin dosing strategies, particularly in critically ill patients undergoing renal replacement therapies. [6]
A 2013 review examined medication dosing in critically ill patients with acute kidney injury receiving RRT, with particular emphasis on the pharmacokinetic and pharmacodynamic challenges associated with different RRT modalities, including intermittent hemodialysis, PIRRT and CRRT. The authors highlight that drug dosing in this population is highly complex and dependent on the interplay between patient-specific factors, drug characteristics, and the selected RRT modality, with substantial variability and limited standardization across practices. With respect to PIRRT, the review specifically notes a paucity of available pharmacokinetic data, reporting that studies had been published for only 11 drugs at the time, which significantly limits clinicians’ ability to make evidence-based dosing decisions. The authors further emphasize that variability in PIRRT techniques (including differences in duration, dialyzer type, and flow rates) and challenges in timing drug administration relative to therapy contribute to difficulty in achieving pharmacodynamic targets, particularly for antibiotics. While the article provides example dosing strategies and summarizes available literature-based and author-recommended regimens for select agents, it underscores that effective and rational drug dosing during PIRRT remains challenging due to limited evidence and lack of standardized guidance, and that therapeutic drug monitoring, when available, is important to guide dosing adjustments. [7]
A 2026 clinical investigation evaluated levetiracetam dosing in critically ill patients undergoing PIRRT using Monte Carlo simulation (MCS) techniques. This paper highlighted the pharmacokinetic challenges faced when dosing levetiracetam in such a population due to its significant removal during PIRRT. Researchers designed a one-compartment model with first-order elimination, incorporating PIRRT modalities such as hemodialysis and hemofiltration with varying durations and effluent rates. The simulations were executed for 10,000 virtual patients per regimen over a 48-hour period. The pharmacodynamic target focused on maintaining an area under the concentration-time curve (AUC) between 222–666 mg⋅h/L, aiming for regimens achieving a ≥90% probability of target attainment (PTA). The results elucidated numerous conventional dosing regimens were insufficient for achieving the desired therapeutic exposure in PIRRT. Specifically, the study determined that for alternate-day PIRRT with hemofiltration, dosing regimens of 500 mg every 12 hours or 1000 mg every 24 hours were optimal. Alternatively, for those undergoing alternate-day PIRRT with hemodialysis, 750 mg every 12 hours or 1250 mg every 24 hours were recommended. For daily PIRRT irrespective of the modality, a consistent regimen of 750 mg every 12 hours reliably met PTA targets. These outcomes emphasize the necessity for individualized dosing strategies based on the specific PIRRT modality and schedule, underscoring the need for clinical validation to ensure both efficacy and safety in this vulnerable patient population. [8]
A 2019 investigation described the pharmacokinetics of benzylpenicillin (penicillin G) during PIRRT in two critically ill patients. The report involved critically ill patients diagnosed with penicillin-susceptible Staphylococcus aureus (PSSA) bacteremia complicated by infective endocarditis. The primary aim was to elucidate the alterations in benzylpenicillin pharmacokinetics attributable to PIRRT, which is increasingly used for patients with severe acute kidney injury. Data collection included extensive blood sampling over multiple dosing periods during PIRRT and off PIRRT, with a particular focus on the clearance and volume of distribution parameters using a two-compartment model. The report highlighted a significant increase in benzylpenicillin clearance during PIRRT sessions compared to non-PIRRT periods, with clearance rates of 6.61 L/h versus 3.04 L/h, respectively. During the study, benzylpenicillin was administered at a dose of 1,800 mg (3 million units) every 6 hours, which effectively maintained plasma concentrations well above the minimum inhibitory concentration (MIC) for PSSA, achieving the desired pharmacokinetic/pharmacodynamic targets. The research emphasized the necessity of adjusting dosing regimens to accommodate the pharmacokinetic shifts observed with PIRRT, ensuring therapeutic drug concentrations are met to optimize treatment efficacy and prevent antimicrobial resistance. The authors advocated for further population-based investigations to refine the dosing recommendations for benzylpenicillin in patients undergoing PIRRT, with the ultimate goal of improving clinical outcomes and managing severe infections in this vulnerable patient population. [9]