Is there new literature regarding CRRT dosing not only for antibiotics but also for any other type of agents? Please specify if the data is a specific modality (CVVH, CVVHD, etc) or general CRRT dosing?

Comment by InpharmD Researcher

Recent literature evaluating medication dosing during continuous renal replacement therapy (CRRT) consists primarily of pharmacokinetic studies and simulations involving antimicrobials, including meropenem, piperacillin/tazobactam, trimethoprim/sulfamethoxazole, colistin, fluconazole, cefepime, aminoglycosides, and vancomycin. Notably, modality-specific data are available for continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF), although several studies pooled modalities or did not report specific CRRT settings and therefore provide only general CRRT dosing information. Beyond antimicrobials, a 2025 systematic review and pharmacokinetic modeling study evaluated levetiracetam during CVVHF and CVVHDF and reported that 750 to 1,000 mg every 12 hours with an initial 60-mg/kg loading dose should be considered alongside therapeutic drug monitoring. However, many of these dosing recommendations were not prospectively evaluated for clinical efficacy, adverse effects, or drug accumulation, limiting definitive conclusions regarding their clinical application.

Background

A 2024 comparative database study evaluated continuous renal replacement therapy (CRRT) dosing recommendations for 20 antimicrobials, including antibacterial, antiviral, and antifungal agents, using Renal Pharmacotherapy: Dosage Adjustment of Medications Eliminated by the Kidneys as the gold-standard reference. Recommendations from Micromedex, UpToDate, and the Sanford Guide matched the gold standard for 45%, 35%, and 30% of the evaluated antimicrobials, respectively; all three databases provided concordant recommendations only for acyclovir and daptomycin, whereas none matched the gold standard for amikacin, colistin, imipenem-cilastatin, levofloxacin, piperacillin-tazobactam, or vancomycin. An expert panel comprising an intensivist, infectious diseases specialist, clinical pharmacist, and pharmacologist subsequently developed consensus dosing recommendations for all 20 agents specifically for continuous venovenous hemodiafiltration (CVVHDF). The authors noted that the recommendations were not evaluated using therapeutic drug monitoring or assessed prospectively for clinical efficacy or adverse effects and recommended consulting multiple sources when determining antimicrobial doses during CRRT. [1]

A 2025 systematic review and pharmacokinetic modeling study evaluated levetiracetam dosing in critically ill patients receiving CRRT. Seven studies published from 2000 through November 2022, comprising 24 patients treated with continuous venovenous hemofiltration (CVVHF; n= 16) or continuous venovenous hemodiafiltration (CVVHDF; n= 8), were included; five studies were case reports and two were prospective pharmacokinetic studies, and the overall evidence was considered low quality. Mean total levetiracetam clearance was 3.55 L/hour, mean elimination half-life was 9.41 hours, and CRRT accounted for a mean of 54.7% of total clearance. Using a one-compartment model, the investigators simulated dosing regimens in 10,000 patients over 72 hours based on a target trough concentration of 12 to 46 mcg/mL; without a loading dose, 65%, 53%, 34%, and 7.5% of simulated patients receiving levetiracetam 1,000, 750, 500, and 250 mg every 12 hours, respectively, achieved a trough concentration of at least 12 mcg/mL. A 60-mg/kg loading dose, up to a maximum of 4.5 g, achieved therapeutic concentrations within the first 24 hours in almost all simulated patients, although a substantial proportion had trough concentrations exceeding 80 mcg/mL during this period. The authors concluded that available in vivo data did not support levetiracetam dose reduction during CRRT and stated that 750 to 1,000 mg every 12 hours with an initial 60-mg/kg loading dose should be considered alongside therapeutic drug monitoring; however, they noted that further study is needed to evaluate drug accumulation and toxicity. [2]

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-7 for your response.

Meropenem and Piperacillin/Tazobactam Optimised Dosing Regimens for Critically Ill Patients Receiving Renal Replacement Therapy
Design	Prospective, multinational pharmacokinetic study N= 300
Objective	To develop generalisable optimised dosing recommendations for meropenem and piperacillin/tazobactam in critically ill patients receiving renal replacement therapy (RRT)
Study Groups	All patients (n= 300)
Inclusion Criteria	Adult critically ill patients receiving meropenem or piperacillin/tazobactam with severe acute kidney injury (AKI) requiring RRT with continuous veno-venous hemofiltration (CVVHF), continuous veno-venous hemodialysis (CVVHD), continuous veno-venous hemodiafiltration (CVVHDF), or sustained low-efficiency dialysis (SLED) for an expected duration of at least 4 days
Exclusion Criteria	Not explicitly stated
Methods	Antibiotic dosing and RRT settings were determined by the clinical team. Total and unbound drug concentrations were measured in prefilter plasma, postfilter plasma, and effluent samples. Population PK models were developed using data from 234 patients and externally validated in 66 patients. Monte Carlo simulations evaluated short, extended, and continuous-infusion regimens across different RRT modalities, intensities, SLED durations, urine-output categories, and concentration targets.
Duration	December 2011 to March 2017
Outcome Measures	PK factors affecting meropenem and piperacillin/tazobactam clearance during RRT; model predictive performance; and probability of attaining efficacy targets without exceeding toxicity thresholds across different infusion strategies, RRT modalities and intensities, SLED durations, and urine-output categories. Optimized dosing regimens were developed based on these variables.
Baseline Characteristics	The study included 300 patients from 22 intensive care units across 12 countries, including 234 patients in the model-development datasets and 66 in the validation datasets. The mean age ranged from 55.4 to 65.8 years across datasets, 29.9% to 60.0% were female, and mean weight ranged from 78.8 to 85.0 kg. Overall, 13.0% of patients received CVVHD, 23.3% received CVVHF, 48.4% received CVVHDF, and 15.3% received SLED. The median daily doses were 3 g for meropenem and 12 g/1.5 g for piperacillin/tazobactam; 67% of patients received short infusions and 33% received extended or continuous infusions.
Results	RRT intensity significantly increased RRT-mediated clearance, while urine output significantly increased non-RRT-mediated clearance for meropenem, piperacillin, and tazobactam; SLED modality also explained variability in meropenem RRT-mediated clearance (p< 0.05 for all covariates). External validation demonstrated mean prediction errors of −5.2% for meropenem and −16.9% for piperacillin, with mean absolute prediction errors of 25.8% and 29.1%, respectively. Simulations showed that dose requirements depended on RRT intensity, urine output, and SLED duration, with extended or continuous infusions achieving target concentrations more effectively than equivalent doses administered as 30-minute infusions in most scenarios. Continuous infusion provided the highest likelihood of effective and safe exposure when higher concentrations were targeted, and dosing nomograms were developed according to modality, intensity, urine output, SLED duration, and target concentration.
Adverse Events	Not explicitly stated
Study Author Conclusions	This study provides optimised dosing regimens for meropenem and piperacillin/tazobactam in critically ill patients receiving diverse RRT prescriptions. Daily dosing is dependent on the target concentration and the main PK determinants in this population, namely RRT intensity, 24-h urine output, and RRT duration in the case of SLED. As described in the dosing nomogram, extended/continuous infusions facilitate the achievement of optimised antibiotic concentrations in most clinical scenarios, resulting in lower daily doses and a reduced risk of exposure-related toxicity.
Critique	This large, multinational study included multiple RRT modalities, rich PK sampling, external model validation, and dosing simulations stratified by clinically measurable factors, providing directly applicable dosing nomograms for meropenem and piperacillin/tazobactam. However, the recommendations were simulation-based and were not evaluated for clinical efficacy or toxicity; extrapolation to other RRT settings, concurrent extracorporeal therapies, or patients at extremes of body size should be approached cautiously.

Table 1 References:
[3] Roberts JA, Ulldemolins M, Liu X, et al. Meropenem and piperacillin/tazobactam optimised dosing regimens for critically ill patients receiving renal replacement therapy. Intensive Care Med. 2025;51(9):1628-1640. doi:10.1007/s00134-025-08067-w

Population Pharmacokinetics of Trimethoprim/Sulfamethoxazole: Dosage Optimization for Patients with Renal Insufficiency or Receiving Continuous Renal Replacement Therapy
Design	Retrospective multicenter observational cohort study N= 168
Objective	To describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients and to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT)
Study Groups	All patients (n= 168) CRRT subgroup (n= 18) Patients with measured trimethoprim concentrations (n= 52)
Inclusion Criteria	Patients aged ≥18 years who received therapeutic dosages of intravenous or oral cotrimoxazole between January 2016 and December 2021, with plasma concentrations of sulfamethoxazole and/or trimethoprim measured during treatment and at least one serum creatinine measurement available
Exclusion Criteria	Patients with registered objection for the use of their data and patients treated with extracorporeal membrane oxygenation (ECMO) treatment or intermittent hemodialysis during cotrimoxazole treatment
Methods	Routine therapeutic drug monitoring data were obtained from 3 Dutch university medical centers. Two nonlinear mixed-effects population pharmacokinetic models were developed: a trimethoprim model and an integrated sulfamethoxazole/N-acetyl sulfamethoxazole model. eGFR and CRRT were evaluated as clearance covariates. Monte Carlo simulations (n= 1,000) assessed target attainment and dose adjustments across different eGFR values and CRRT. PCP targets were Cmax ≥5 mg/L for trimethoprim and ≥100 mg/L for sulfamethoxazole; upper limits were 15, 200, and 75 mg/L for trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole, respectively. The specific CRRT modality and settings were not reported.
Duration	January 2016 to December 2021
Outcome Measures	Population pharmacokinetic parameters for trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole; effects of eGFR and CRRT on clearance; simulated attainment of PCP efficacy and toxicity concentration targets; and dose adjustments required to produce exposure equivalent to that in a patient with an eGFR of 70 mL/min/1.73 m²
Baseline Characteristics		All patients (n= 168)	Patients with measured trimethoprim concentrations (n= 52)
	Males	108 (64.3%)	33 (63.4%)
	Age, years	58.2 ± 15.2	60.3 ± 11.9
	Weight, kg	76.7 ± 16.2	80.6 ± 18.5
	Height, cm	174.0 ± 10.3	173.8 ± 11.1
	BMI, kg/m2	25.3 ± 5.0	26.5 ± 5.0
	Serum creatinine, μmol/L	119.7 ± 91.8	170.1 ± 101.5
	Serum albumin, g/L	26.6 ± 6.8	29.1 ± 7.2
	eGFR, mL/min/1.73m²	70.8 ± 33.2	49.2 ± 34.7
	Oral administration	75 (44.6%)	22 (42.3%)
	Intravenous administration	93 (55.4%)	30 (57.7%)
	Cotrimoxazole daily starting dose, mg ≤960 1,920–2,400 2,880 3,840–4,800 5,760	10 (6.0%) 27 (16.1%) 15 (8.9%) 35 (20.8%) 81 (48.2%)	6 (11.5%) 19 (36.6%) 6 (11.5%) 7 (13.5%) 14 (27.0%)
	Corticosteroids	62 (36.9%)	18 (34.6%)
	CRRT	18 (10.7%)	14 (27%%)
	Stem-cell transplantation	13 (7.7%)	3 (5.8%)
	Solid organ transplantation	35 (20.8%)	24 (46.2%)
	Malignancy	23 (13.7%)	6 (11.5%)
	HIV	19 (11.3%)	0
Results	Among 168 hospitalized patients, including 18 (10.7%) receiving CRRT, CRRT increased sulfamethoxazole clearance 2.2-fold (95% confidence interval [CI] 2.0–2.4) but did not meaningfully increase trimethoprim clearance (1.12-fold; 95% CI 0.77–1.57); N-acetyl sulfamethoxazole clearance was 0.68-fold (95% CI 0.53–0.83) relative to the population estimate. In CRRT simulations, cotrimoxazole 1,920 mg 3 times daily produced trimethoprim concentrations within the target range in 94.0% of patients, whereas sulfamethoxazole concentrations were below target in >50% of patients with all lower regimens. However, this regimen produced toxic N-acetyl sulfamethoxazole concentrations in 38.2% of patients, and none of the evaluated regimens achieved adequate sulfamethoxazole target attainment in most simulated patients. To achieve exposure equivalent to that in patients with an eGFR of 70 mL/min/1.73 m², the model indicated that the sulfamethoxazole dose should be doubled while the trimethoprim dose remained unchanged.
Adverse Events	Concentration-dependent adverse events include hematological toxicity, hyperkalemia, renal failure, and central nervous system adverse effects
Study Author Conclusions	Sulfamethoxazole and trimethoprim pharmacokinetics show large IIV in hospitalized patients, and are affected by eGFR and CRRT. Notably, in patients treated with CRRT, sulfamethoxazole clearance is increased. Therefore, doubling the sulfamethoxazole dose is needed to reach similar exposure to patients without renal failure. Monitoring with TDM is necessary in patients treated with CRRT as high doses might lead to N-acetyl sulfamethoxazole accumulation.
Critique	This multicenter study used the largest reported cotrimoxazole population pharmacokinetic cohort and incorporated the active components and N-acetyl sulfamethoxazole into dosing simulations. However, only 18 patients received CRRT, and the specific CRRT modalities, effluent rates, and settings were unavailable; therefore, the findings apply to general CRRT dosing and cannot support modality-specific recommendations.

Table 2 References:
[4] Leegwater E, Baidjoe L, Wilms EB, et al. Population Pharmacokinetics of Trimethoprim/Sulfamethoxazole: Dosage Optimization for Patients with Renal Insufficiency or Receiving Continuous Renal Replacement Therapy. Clin Pharmacol Ther. 2025;117(1):184-192. doi:10.1002/cpt.3421

High-dose colistin pharmacokinetics in critically ill patients receiving continuous renal replacement therapy
Design	Prospective, open-label, observational study N= 20
Objective	To describe colistin pharmacokinetic/pharmacodynamic (PK/PD) profile in critically ill patients with infections due to carbapenem-resistant (CR) bacteria undergoing continuous renal replacement therapy (CRRT)
Study Groups	All patients (N= 20)
Inclusion Criteria	Age >18 years; duration of treatment planned >48 h; documented or suspected infection with a CR bacteria; stage 3 Acute Kidney Injury (AKI) according to the KDIGO classification; half-life of the CRRT filter <48 h
Exclusion Criteria	Pregnant women; patients with high probability of short-term death according to the simplified acute physiology score (SAPS II)
Methods	Patients received colistin for at least 48 h at the dosage of 6.75 MUI q12, after 9 MIU loading dose, and underwent CRRT. Blood serial sampling was conducted after the seventh dose during a 24 h time frame. Pharmacokinetic parameters were determined using first order kinetics. Colistin and CMS concentrations were measured using a modified Gobin assay
Duration	2021 to 2022
Outcome Measures	Primary: Colistin plasmatic levels above bacterial MIC90 Secondary: Probability of target attainment of colistin pharmacodynamics according to the fAUC_0 − 24/MIC target ≥ 12
Baseline Characteristics		All patients (N= 20)
	Age, years	70 [65.3–75.3]
	Gender, male	16 (80%)
	BMI	30.5 [27-32.9]
	SAPS II	41 [34.5–59.3]
	Charlson Comorbidity Index	4.5 [2–5]
	CKD	4 (20%)
	VAP	20 (100%)
	Concomitant bacteremia	6 (30%)
	Septic Shock	13 (80%)
	ARDS	18 (90%)
	SOFA	9 [6.7–11]
	BAL Acinetobacter spp. isolation	20 (100%)
	Colisitn MIC mcg/mL	1[1-1.5]
	Serum albumin, g/dL	2.1 [2-2.3]
	Fluid balance, mL	+651.5 [323–797.5]
	Hematocrit, %	28 [27–29]
	Residual diuresis, mL/24 h	0
	CVVHDF dose intensity, mL/kg/h	32.5 [30–35]
	CRRT duration, days	12.5 [10–23.25]
	MV duration, days	26 [21.25–37.25]
	Vasopressors duration, days	6.5 [4.5-11.25]
	Death in ICU	15 (75%)
	Treatment failure	14 (70%)
	Renal Recovery*	6 (37.5%)
	Nebulized colistin therapy	18 (90%)
	Intravenous colistimethate therapy, days	13 [9.25-12]
	BMI: body mass index; VAP: Ventilator Associated Pneumonia; SAPS II: Simplified Acute Physiology Score II; CHD: Chronic Heart Disease; COPD: Chronic Obstructive Pulmonary Disease; CKD: Chronic Kidney Disease; MV: mechanical ventilation; ICU: Intensive Care Unit; ARDS: Acute Respiratory Distress Syndrome; SOFA: Sequential Organ Failure Assessment; BAL: bronchoalveolar lavage; BSI: Blood Stream Infection; MIC: Minimal Inhibitory Concentration; CRRT: continuous renal replacement therapy; CVVHDF: continuous veno-venous haemodiafiltration
Results	Colistin PK/PD parameters	All patients (N= 20) - Median [IQR]
	C_max, mcg/mL	16.65 [14.77–20.64]
	C_min, mcg/mL	3.93 [3.29–4.37]
	C_ss, avg, mcg/mL	8.07 [7.1–8.69]
	t_1/2, h	20.89 [14.45–22.84]
	Vd, L	126.37 [79.57-139.17]
	CL_TOT, L/h	2.08 [1.94–2.37]
	CL_CRRT, L/h	1.21 [0.88–1.35]
	%CL_TOT, L/h	49.2 [39.25–64.2]
	%E	17.65 [14.98–21.67]
	AUC_0 − 24, mcg h/mL	193.86 [170.6–208.65]
	fAUC_0 − 24, mcg h/mL	58.16 [51.18–62.6]
	fAUC_0 − 24/0.5 mcg/mL ≥ 12	20 (1)
	fAUC_0 − 24/1 mcg/mL ≥ 12	20 (1)
	fAUC_0 − 24/2 mcg/mL ≥ 12	20 (1)
	fAUC_0 − 24/4 mcg/mL ≥ 12	17 (85)
	fAUC_0 − 24/6 mcg/mL ≥ 12	1 (5)
	CMS: colistimethate; Cssavg: average steady-state concentration;. Cmax: maximum concentration; Cmin: minimum concentration; AUC: Area Under The Curve; Vd: distribution volume; t1/2: half-life; CL: clearance; %E: % filter extraction
Adverse Events	N/A
Study Author Conclusions	The use of recommended high dose colistimethate in critically ill patients undergoing CRRT resulted in steady-state average concentrations above colistin MIC90 of commonly isolated bacteria, but exceeding the recommended safety threshold. Apart from the early phase of empirical therapy, lower CMS daily dosages should be adopted in the clinical practice, especially when colistin therapeutic drug monitoring or alternative drugs are not available.
Critique	The study provides valuable insights into the PK/PD profile of colistin in critically ill patients undergoing CRRT, highlighting the potential for exceeding safe concentration levels. However, the study is limited by its small sample size and lack of a control group, which may affect the generalizability of the findings. Additionally, the study did not evaluate potential neurotoxicity or measure the adsorption fraction of nebulized CMS, which could have provided a more comprehensive understanding of colistin's safety profile in this setting.

Table 3 References:
[5] De Pascale G, Lisi L, Cutuli SL, et al. High-dose colistin pharmacokinetics in critically ill patients receiving continuous renal replacement therapy. Ann Intensive Care. 2024;14(1):152. doi:10.1186/s13613-024-01384-1

Population Pharmacokinetics of Fluconazole in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation And Continuous Renal Replacement Therapy: An ASAP ECMO Study
Design	Multicenter study N= 8
Objective	To describe the population pharmacokinetics of fluconazole in critically ill adult patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and to identify dosing strategies that provide maximal exposures for clinical efficacy
Study Groups	Concomitant ECMO and CRRT cohort (n= 8)
Inclusion Criteria	Patients between 18 and 90 years, hospitalized in intensive care unit (ICU), and receiving fluconazole whilst undergoing ECMO for respiratory and/or cardiac dysfunction
Exclusion Criteria	Known allergy to the study drug, pregnant, bilirubin >150 µmol/L, received ongoing massive blood transfusion (>50% blood volume) in the previous 8 hours or received therapeutic plasma exchange in the previous 24 hours
Methods	Fluconazole was administered intravenously according to local protocols, and serial plasma samples were collected over 480 minutes after infusion initiation. Population pharmacokinetic modeling and 1,000-patient Monte Carlo simulations evaluated four weight-based dosing regimens across body weights and MICs using an AUC₀–₂₄/MIC >100 target. CRRT modalities included continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and predominantly continuous venovenous hemodiafiltration (CVVHDF).
Duration	November 2012 to November 2019
Outcome Measures	Fluconazole plasma concentration-time data and population pharmacokinetic parameters; effects of demographic, ECMO, and CRRT covariates on pharmacokinetic parameters; probability of target attainment (PTA) for AUC₀–₂₄/MIC >100 on days 1 and 7 across fluconazole regimens, body weights, and MICs; empirical and directed FTA against the EUCAST C albicans MIC distribution
Baseline Characteristics		All patients (n= 8)
	Median age, years (IQR)	43 (41–49)
	Male	6 (75%)
	Age, years	43 (41-49)
	Total body weight, kg	95 (75-102)
	Median body mass index, kg/m² (IQR)	27.2 (23.4–31.6)
	APACHE II score at admission, median (IQR)	18 (13–22)
	SOFA score on sampling day, median (IQR)	8 (7–16)
	VA ECMO	4 (50%)
	VV ECMO	3 (38%)
	VA and VV ECMO	1 (12%)
	Days receiving ECMO before sampling, median (IQR)	9 (6–12%)
	CVVH	1 (12.5%)
	CVVHD	1 (12.5%)
	CVVHDF	5 (reported as 75% in the study table)
	Abbreviations: IQR, interquartile range; VA, venous arterial; VV, venovenous.
Results	Among 8 critically ill adults receiving concomitant ECMO and CRRT, 67 plasma samples were collected, and fluconazole pharmacokinetics were best described by a two-compartment model with total body weight as a covariate on clearance. Mean clearance and central volume of distribution were 2.87 ± 0.63 L/hour and 15.90 ± 13.29 L, respectively; neither ECMO- nor CRRT-related variables significantly improved the model. All simulated regimens achieved 100% probability of target attainment (PTA) for an AUC₀–₂₄/MIC >100 at MICs ≤1 mg/L; at an MIC of 2 mg/L, >90% PTA required an 18-mg/kg loading dose on day 1 and either 12 mg/kg every 24 hours or 6 mg/kg every 12 hours on day 7. No evaluated regimen achieved ≥90% PTA at MICs >2 mg/L.
Adverse Events	No specific adverse events related to fluconazole dosing regimens were reported in the study
Study Author Conclusions	This is the first study to describe the PK of fluconazole in critically ill adult patients on ECMO and CRRT. The current dosing regimen of fluconazole (a loading dose of 12 mg/kg followed by 6 mg/kg q24h) in patients on ECMO and RRT provides a high PTA against Candida spp. with an MIC of up to 1 mg/L. Based on our model and simulations, TBW should be considered and used to calculate fluconazole doses.
Critique	This prospective multicenter study provides directly relevant fluconazole pharmacokinetic and dosing-simulation data in patients receiving concomitant ECMO and CRRT, predominantly CVVHDF. However, the small cohort, incomplete CRRT data, concurrent ECMO exposure, absence of clinical or microbiologic outcomes, and lack of modality-specific simulations limit application of the proposed regimens to CRRT patients generally or to an individual CRRT modality.

Table 4 References:
[6] Novy E, Abdul-Aziz MH, Cheng V, et al. Population pharmacokinetics of fluconazole in critically ill patients receiving extracorporeal membrane oxygenation and continuous renal replacement therapy: an ASAP ECMO study. Antimicrob Agents Chemother. 2024;68(1):e0120123. doi:10.1128/aac.01201-23

Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy
Design	Prospective observational study N= 7
Objective	To characterize cefepime pharmacokinetics in critically ill pediatric patients on continuous kidney replacement therapy (CKRT)
Study Groups	All patients (N= 7)
Inclusion Criteria	Patients who had at least 24 hours on CKRT, received at least two doses of cefepime while on CKRT, and had at least two opportunistic blood samples available during CKRT
Exclusion Criteria	Samples collected within 30 min of recorded cefepime start time were excluded
Methods	Patients were part of an ongoing PK/PD study of beta-lactam antibiotics. Blood samples were obtained using scavenged residual blood. PK parameters were estimated using MwPharm++ with Bayesian estimation and a pediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC)
Duration	2018 to 2021
Outcome Measures	Time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC)
Baseline Characteristics		All patients (n= 7)
	Age, years	2 to 20
	Mean age, years	9.8
	Indications for CKRT Renal failure Fluid overload Liver failure	4 2 1
Results		All patients (N= 7)
	Total effluent flow rate, mL/1.73 m2/h Mean	1833 to 3115 2603
	Clearance, L/h/70 kg Mean	2.11 to 3.70 3.0
	100% fT > MIC	7/7
	100% fT > 4× MIC	1/7
Adverse Events	N/A
Study Author Conclusions	Model-informed precision dosing may benefit critically ill pediatric patients on CKRT, as most patients failed to attain stringent targets of 100% fT > 4× MIC.
Critique	The study provides valuable insights into cefepime pharmacokinetics in pediatric CKRT patients, highlighting variability in drug exposure and the potential need for precision dosing. However, the small sample size and retrospective nature limit the generalizability of the findings. Additionally, the study's opportunistic design precluded testing different dosing regimens or CKRT flows.

Table 5 References:
[7] Pavia K, Hambrick HR, Paice K, et al. Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy. J Antimicrob Chemother. 2023;78(9):2140-2147. doi:10.1093/jac/dkad192

Aminoglycoside Pharmacokinetics in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy
Design	Retrospective observational pharmacokinetic study N= 80
Objective	To characterize the effect of CRRT on aminoglycoside clearance and volume of distribution (Vd)
Study Groups	SLED (n= 49) CVVHD (n= 19) CVVH (n= 12)
Inclusion Criteria	Aged ≥ 18 years; admitted to an ICU; received intravenous amikacin or tobramycin between February 1, 2012, and February 28, 2017, while undergoing CRRT; had 2 postdistributional aminoglycoside serum levels obtained following the first dose
Exclusion Criteria	Dose given prior to CRRT initiation; interruption in CRRT between aminoglycoside administration and second level; dose administered in the previous 7 days; already enrolled; pregnant
Methods	Retrospective analysis of adult critically ill oncologic patients receiving amikacin or tobramycin during CRRT. Doses were amikacin 15 to 20 mg/kg and tobramycin 7 mg/kg, with serum levels drawn at 4 and 10 hours post-infusion. Pharmacokinetic parameters calculated using the Sawchuk-Zaske method.
Duration	February 2012 to May 2017
Outcome Measures	Primary: Aminoglycoside clearance, volume of distribution (Vd) Secondary: Attainment of target peak: MIC ratio
Baseline Characteristics		SLED (n= 49)	CVVHD (n= 19)	CVVH (n= 12)	Total (n= 80)
	Age (years)	57.2 (23.1-85.8)	57.9 (31.8-78.3)	65.7 (37.4-74.3)	58.3 (23.1-85.8)
	Male sex, n (%)	33 (67.4)	10 (52.6)	8 (66.7)	51 (63.8)
	Actual weight, kg	96.4 (59.0-164.3)	92.1 (69.8-138.0)	100.0 (56.2-127.7)	96.5 (56.2-164.3)
	BMI, kg/m2	28.7 (18.6-61.9)	30.3 (19.1-47.8)	28.5 (20.6-38.7)	29.6 (18.6-61.9)
	APACHE II Score	30 (16-42)	32 (23-42)	32.5 (15-40)	31 (15-42)
	Vasopressor use, n (%)	43 (87.8)	19 (100.0)	12 (100.0)	74 (92.5)
	Mechanically ventilated, n (%)	37 (75.5)	15 (79.0)	9 (75.0)	61 (76.3)
	ICU mortality, n (%)	35 (71.4)	15 (78.9)	10 (83.3)	60 (75)
	Hospital mortality, n (%)	6 (12.2)	2 (10.5)	1 (8.3)	9 (11.3)
	ICU LOS (days)	10 (2-64)	12 (3-125)	11.5 (1-61)	10.5 (1-125)
	Hospital LOS (days)	35 (2-174)	41 (8-140)	27.5 (4-77)	35 (2-174)
Results		SLED (n = 49)	CVVHD (n = 19)	CVVH (n = 12)	P	Total (n = 80)
	Amikacin, n (%)	30 (61.2)	14 (73.7)	7 (58.3)	0.58	51 (63.8)
	Tobramycin, n (%)	19 (38.8)	5 (26.3)	5 (41.7)		29 (36.3)
	Amikacin dose, mg/kg	13.5 (7.2-19.9)	15.0 (11.5-20.5)	16.0 (11.9-19.9)	0.33	14.5 (7.2-20.5)
	Tobramycin dose, mg/kg	6.5 (3.6-9.5)	6.2 (5.6-7.0)	6.5 (2.8-8.5)	0.66	6.5 (2.8-9.5)
	Clearance, mL/min	62.1 (12.8-120.6)	64.6 (30.4-103.6)	62.1 (35.1-99.7)	0.97	63.1 (12.8-120.6)
	Volume of distribution, L/kg	0.43 (0.18-1.35)	0.49 (0.27-0.74)	0.56 (0.38-0.77)	0.02	0.47 (0.18-1.35)
	Elimination rate constant, h	0.09 (0.02-0.16)	0.09 (0.04-0.12)	0.08 (0.05-0.09)	0.07	0.09 (0.02-0.16)
	Half-life, hour	7.4 (4.3-28.7)	7.7 (5.7-17.6)	8.9 (7.4-12.7)	0.56	7.8 (4.3-28.7)
	Amikacin C_peak, mg/L	26.5 (13.0-46.5)	27.9 (18.0-40.7)	26.4 (04.9-34.4)	0.70	26.7 (13.0-46.5)
	Tobramycin C_peak, mg/L	10.8 (3.7-20.3)	9.3 (8.2-12.8)	7.7 (4.2-16.7)	0.52	10.3 (3.7-20.3)
	Patients with positive cultures, n (%)	21 (42.9)	11 (57.9)	10 (83.3)	0.04	42 (52.5)
	Isolates tested for aminoglycoside susceptibility, n	23	10	8		41
	Patients with isolates tested for aminoglycoside susceptibility, n	12	6	5		23
	Empiric peak (per patient), n (%)	16 (32.7)	4 (21.1)	3 (25.0)	0.49	23 (28.8)
	MIC-based peak (per patient), n (%)	5 (41.7)	4 (66.7)	1 (20.0)	0.13	10 (43.5)
Adverse Events	N/A
Study Author Conclusions	Critically ill oncology patients undergoing CRRT exhibited reduced clearance and expanded Vd that was not significantly different between CRRT modalities. Current dosing regimens led to low peak concentrations and poor attainment of pharmacokinetic targets
Critique	The study is limited by its retrospective design and single-center setting, which may affect the generalizability of the findings. The use of 24-hour SLED and high dialysate rates may not reflect practices at other institutions. Additionally, the study did not correlate pharmacokinetic targets with clinical outcomes, and the high ICU mortality rate limits the assessment of clinical response. Further studies are needed to explore the relationship between aminoglycoside pharmacokinetics and clinical outcomes.

Table 6 References:
[8] Krueger CK, Bruno JJ, Tverdek FP, Hernandez M, Abudayyeh A. Aminoglycoside Pharmacokinetics in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy. Ann Pharmacother. 2023;57(6):629-636. doi:10.1177/10600280221120600

Population Pharmacokinetics of Vancomycin in Intensive Care Patients with the Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy
Design	Single-center prospective PK study N= 25
Objective	To characterize the population pharmacokinetics of vancomycin in patients treated with and without continuous renal replacement therapy (CRRT) or temporary mechanical circulatory support (tMCS) and to provide dosing recommendations based on the probability of target attainment (PTA)
Study Groups	All patients (n= 25)
Inclusion Criteria	Adult patients (age ≥18) admitted to the cardiac intensive care unit (ICU) receiving vancomycin, with or without tMCS or CRRT, and without a history of adverse drug effects from vancomycin
Exclusion Criteria	Patients with a history of adverse drug effects from vancomycin
Methods	Clinical and laboratory information was recorded in a time-varying structure from the first vancomycin dose through the index dose preceding pharmacokinetic sampling. Vancomycin dosing and infusion duration were determined clinically. Blood was collected before infusion and at 0.5, 1, 2, 3, 6, 9, and 12 hours after infusion, and plasma concentrations were measured using high-performance liquid chromatography. One-, two-, and three-compartment models were evaluated, with clinical characteristics, renal function, dialysis status, and tMCS status tested as covariates. The final model was externally validated using retrospective vancomycin concentrations. Monte Carlo simulations evaluated loading doses of 0–50 mg/kg and maintenance doses of 10 to 80 mg/kg/day administered every 6, 8, 12, or 24 hours. Each regimen was simulated in 10,000 subjects and assessed for attainment of an AUC₍₂₄ₕ₎/MIC of 400 to 600 mg·h/L, assuming an MIC of 1 mg/L.
Duration	January 2018 to March 2022
Outcome Measures	Pharmacokinetic/model outcomes: Vancomycin clearance, central and peripheral volumes of distribution, intercompartmental clearance, and the effects of CRRT, serum creatinine, body weight, and tMCS status on these parameters. Dosing-simulation outcomes: Probability of attaining an AUC₍₂₄ₕ₎/MIC of 400–600 mg·h/L, probability of AUC₍₂₄ₕ₎ >400 mg·h/L, trough concentration at 48 hours corresponding to the target AUC, and probability of a 48-hour trough of 15–20 mg/L.
Baseline Characteristics		All patients (n= 25)
	Age, years (IQR)	61.0 (49.0 to 66.0)
	Male	24 (96.0%)
	Weight, kg (IQR)	68.8 (61.0 to 82.1)
	Apache II score (IQR)	24.0 (20.5 to 29.0)
	Median serum creatinine, mg/dL (IQR)	1.1 (0.8–1.7)
	Median creatinine clearance, mL/min (IQR)	67.0 (42.0–90.0)
	CRRT at index dose	6 (24.0%)
	CVVH at index dose	4 (16.0%)
	CVVHDF at index dose	2 (8.0%)
	Median CRRT effluent flow, mL/kg/h (IQR)	29.7 (28.4–31.1)
	Any tMCS at index dose	14 (56.0%)
	Abbreviations: IQR, interquartile range; CVVH, continuous venovenous hemofiltration; CVVHDF, continuous venovenous hemodiafiltration.
Results	In a prospective population pharmacokinetic study of 25 critically ill adults with 184 vancomycin concentrations, 6 patients received CRRT at the index dose, including CVVH (n= 4) and CVVHDF (n= 2), with a median effluent flow rate of 29.7 mL/kg/h. The final two-compartment model estimated a vancomycin clearance of 2.30 L/h during CRRT in a 70-kg patient, and CRRT was associated with an increase in the central volume of distribution from 13.49 L to approximately 23.1 L. Monte Carlo simulations identified a loading dose of 20–25 mg/kg followed by 15 mg/kg/day as the optimal CRRT regimen, producing probabilities of attaining an AUC₍₂₄ₕ₎ of 400–600 mg·h/L of 63.8% to 67.6% with temporary mechanical circulatory support and 65.5% to 68.5% without support across simulated body weights of 60 to 80 kg. Because CVVH and CVVHDF data were pooled, these findings provide a general CRRT dosing recommendation rather than modality-specific dosing.
Adverse Events	Not specifically reported in the study
Study Author Conclusions	The dosing strategy of vancomycin for critically ill patients can be based on the body weight or renal function status regardless of the presence of tMCS. Intercompartmental clearance is reduced under tMCS, which can mislead dose adjustment based on trough level. Therapeutic dose monitoring after the first 48 h of vancomycin to achieve target AUC24h is highly recommended because the probability of target attainment is generally unsatisfactory in these patients.
Critique	This study incorporated time-varying CRRT and tMCS status, intensive pharmacokinetic sampling, external model validation, and dosing simulations based on an AUC₍₂₄ₕ₎ target. However, the modeling cohort was small, only 6 patients were receiving CRRT at the index dose, and incomplete information regarding CRRT intensity and modality required CVVH and CVVHDF data to be pooled; therefore, the recommended regimen represents general CRRT dosing rather than a modality-specific recommendation.

Table 7 References:
[9] Tsai MT, Wang WC, Roan JN, Luo CY, Chou CH. Population Pharmacokinetics of Vancomycin in Intensive Care Patients with the Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy. Infect Dis Ther. 2024;13(12):2617-2635. doi:10.1007/s40121-024-01071-5