What are dose adjustment recommendations for fluconazole, voriconazole, and linezolid for patients with normal renal function on ECMO

Comment by InpharmD Researcher

Reviews and results from individual studies suggest dose adjustment recommendations for patients with normal renal function on ECMO focus on individualized strategies rather than uniform changes due to variable pharmacokinetics. For fluconazole, a loading dose has ranged from 15-35 mg/kg, but available data was limited to a pediatric population. Voriconazole exposure is variable and influenced by ECMO configuration, making routine therapeutic drug monitoring (TDM) essential to achieve target concentrations, while a maintenance dose of 6 mg/kg twice daily may be required. For linezolid, standard dosing of 600 mg every 12 hours may be insufficient for pathogens with an MIC ≥2 mg/L, and while increased frequency (600 mg every 8 hours) improves target attainment, it significantly elevates the risk of thrombocytopenia, necessitating TDM to guide dosing adjustments.

fluconazole voriconazole linezolid renal function ECMO

Literature Review

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

What are dose adjustment recommendations for fluconazole, voriconazole, and linezolid for patients with normal renal function on ECMO

Level of evidence

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


Please see Tables 1-7 for your response.

 

 

Underexposure of linezolid in critically ill patients with extracorporeal membrane oxygenation (ECMO): results from a monocentric study including blood samples from 52 patients
Design

Retrospective observational study

N= 52
Objective To evaluate whether linezolid trough concentrations are within the therapeutic range and to assess whether clinical or demographic characteristics influence drug concentrations in critically ill extracorporeal membrane oxygenation (ECMO) patients
Study Groups All patients (n= 52)
Inclusion Criteria Adult ICU patients on ECMO treated with linezolid with available plasma trough concentrations
Exclusion Criteria Not specified
Methods A total of 156 linezolid trough plasma concentrations from 52 adult ICU patients receiving ECMO were analyzed retrospectively. Trough concentrations were defined as samples drawn 30 minutes before or immediately before the next dose. Linezolid concentrations were quantified using liquid chromatography with tandem mass spectrometry. Concentrations were evaluated against EUCAST minimum target thresholds of 2 mg/L and 4 mg/L. Associations between trough levels and clinical/demographic variables including age, sex, BMI, daily dose, creatinine clearance (CrCl), and renal replacement therapy (RRT) were assessed using statistical modeling.
Duration Study period: March 2016 to October 2021
Intervention duration: Not standardized; multiple measurements per patient during therapy
Outcome Measures

Linezolid trough plasma concentrations, correlation of trough levels with clinical and demographic characteristics
Baseline Characteristics   All patients (n= 52)
Male 29 (55.8%)
Age, mean (IQR) 49.5 years (39.5–61.8)
Body Mass Index (BMI), mean (IQR) 29.2 kg/m2 (22.7–33)
Renal Replacement Therapy (RRT) n= 18 (34.6%)
Creatinine clearance (CrCl), mean (IQR) 123.9 mL/min (68.3–162.8)
Augmented renal clearance 25 patients (48.1%)
Daily dose of linezolid, mean (IQR) 1440 mg (1200–1800)
Standard dosing: 1200 mg/day 21 patients (40.4%)
Adjusted dosing 31 patients (59.6%)
Results Sub-cohort Cmin (mg/L) (median and IQR) Percentage of levels below 2 mg/L Percentage of levels below 4 mg/L P-value
All 1.55 (0.61–3.07) 62.2 84 -
Standard dosing (1200 mg/day) 1.84 (0.84–3.13) 58 84.1 0.058
Escalated dosing (1800 mg/day) 1.09 (0.39–2.43) 69.4 85.5 -
Women 1.15 (0.50–2.43) 69.4 89 -
Men 1.80 (0.80–3.26) 56 78.8 -
RRT no 1.65 (0.76–3.18) 59.1 81.8 -
RRT yes 1.12 (0.50–2.29) 72.7 90.9 -
Adverse Events Not specified
Study Author Conclusions Both standard and increased dosing regimens of linezolid showed potentially inadequate linezolid plasma levels in the large majority of critically ill ECMO patients. Future TDM studies with optimized dosing and application regimens in ECMO patients are warranted
Critique This study provides strong ECMO-specific pharmacokinetic data and demonstrates that standard linezolid dosing frequently results in subtherapeutic exposure, particularly in patients with higher creatinine clearance. However, the retrospective design, inclusion of patients with varying renal function (including RRT), and lack of standardized sampling limit its ability to define a specific dose adjustment for ECMO patients with normal renal function, supporting the need for individualized dosing guided by TDM.

 

References:
[1] [1] Hhl R, Rasshofer F, Kinzig M, et al. Underexposure of linezolid in critically ill patients with extracorporeal membrane oxygenation (ECMO): results from a monocentric study including blood samples from 52 patients. Infection. 2026;54(1):401-407. doi:10.1007/s15010-025-02679-6
Pharmacokinetics and Safety of Fluconazole in Young Infants Supported with Extracorporeal Membrane Oxygenation
Design

Prospective, single-center, open-label PK and safety trial

N= 10
Objective To determine the pharmacokinetics of fluconazole in infants on ECMO and evaluate surrogate pharmacodynamic targets for efficacy
Study Groups All infants (n= 10)
Inclusion Criteria Infants <120 postnatal days supported with ECMO
Exclusion Criteria History of hypersensitivity or severe vasomotor reaction to any triazole; previous participation in the study
Methods Infants received either prophylactic fluconazole (25 mg/kg weekly) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Duration August 2010 to July 2011
Outcome Measures

Primary: Fluconazole PK indices (clearance, volume of distribution), number of infants achieving PD target for fungal prophylaxis

Secondary: Fluconazole extraction by the ECMO circuit
Baseline Characteristics   All patients (n= 10)
Median age, days (range) 19 (1-113)
Female 30%
White 60%
Hispanic 10%
Pre-term 3 infants
Results   First dose Multiple doses
Median clearance, mL/kg/h 17 22
Median volume of distribution, L/kg 1.5 1.9
Median AUC0–24, h*mg/L 322 352
Prophylaxis target achieved 78% 71%
Therapeutic target achieved 11% 0%
Adverse Events There were no adverse events related to fluconazole. Three infants had elevated AST or ALT levels prior to initiation of study fluconazole, which declined to normal levels while on study drug. Three deaths occurred, none related to the study drug
Study Author Conclusions

Infants on ECMO had higher volume of distribution but similar clearance compared with historical controls not on ECMO. A fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections, but higher doses may be needed for treatment.
Critique

The study provides valuable insights into the pharmacokinetics of fluconazole in infants on ECMO, highlighting the need for adjusted dosing. However, the small sample size and single-center design may limit the generalizability of the findings. Additionally, the study did not evaluate long-term outcomes or compare with other antifungal agents.

 

References:
[1] Watt KM, Benjamin DK Jr, Cheifetz IM, et al. Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2012;31(10):1042-1047. doi:10.1097/INF.0b013e31825d3091
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 ECMO and CRRT and to identify dosing strategies that provide maximal exposures for clinical efficacy
Study Groups All patients (n= 8)
Inclusion Criteria Patients between 18 and 90 years, hospitalized in 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, ongoing massive blood transfusion (>50% blood volume) in the previous 8 hours, or therapeutic plasma exchange in the previous 24 hours
Methods

Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. Dosing regimens were evaluated for achieving fluconazole AUC0-24/MIC >100.
Duration November 2012 to November 2019
Outcome Measures

Primary: Probability of target attainment (PTA) for fluconazole AUC0-24/MIC >100

Secondary: Evaluation of different fluconazole dosing regimens for target exposure
Baseline Characteristics   All patients (n= 8)
Male 6 (75%)
Age (years) 43
Total body weight (kg) at admission 95
Body mass index (kg/m2) 27.2
Results   All patients (n= 8)
Mean clearance (L/h) 2.87 ± 0.63
Volume of distribution (L) 15.90 ± 13.29
PTA for MIC ≤ 1 mg/L >90%
PTA for MIC > 2 mg/L <90%
Adverse Events No specific adverse events reported in the study
Study Author Conclusions

The current fluconazole dosing regimen of 12 mg/kg as an initial loading dose followed by 6 mg/kg q24h provides a high probability of efficacy only against Candida spp. with an MIC ≤1 mg/L. Total body weight should be considered for fluconazole dose calculations.
Critique

The study provides valuable insights into the PK of fluconazole in a specific patient population, but the small sample size and lack of ECMO- or CRRT-related variables as significant predictors of fluconazole clearance limit the generalizability of the findings. Additionally, the study did not collect data on patient outcomes or specific infection types, which could have provided more comprehensive insights into the clinical implications of the dosing regimens.

 

References:
[1] [1] 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
Impact of extracorporeal membrane oxygenation modes on voriconazole exposure in critically ill patients
Design

Retrospective observational cohort study

N= 166
Objective To evaluate the impact of ECMO support and specific ECMO modes on voriconazole exposure, and to identify patient- and treatment-related factors associated with voriconazole trough concentrations
Study Groups

ECMO group (n= 33)

Non-ECMO group (n= 133)
Inclusion Criteria All patients admitted to the ICU from January 2018 to May 2025 who were treated with intravenous or oral voriconazole for suspected fungal infections
Exclusion Criteria Absence of any available voriconazole trough concentration measurements during the treatment course; insufficient dosing information or essential clinical data
Methods

Voriconazole trough concentrations were measured using high-performance liquid chromatography. Patients received a loading dose of 400 mg every 12 h for the first two doses, followed by a maintenance dose of 200 mg every 12 h. Data were collected from electronic medical records, including demographic and clinical data, laboratory parameters, and ECMO status and mode.
Duration January 2018 to May 2025
Outcome Measures

Primary: Voriconazole trough concentrations

Secondary: Impact of ECMO mode on voriconazole exposure, factors associated with voriconazole Cmin
Baseline Characteristics   ECMO (n= 33) Non-ECMO (n= 133)
Age, years (IQR) 58.0 (50.5–67.0) 67.0 (58.0–72.0)
BMI, kg/m2 (IQR) 24.21 (23.00–27.62) 23.37 (20.64–25.66)
CRRT (%) 18 (54.5%) 26 (19.5%)
Direct bilirubin (µmol/L, IQR) 7.50 (5.20–12.80) 4.50 (2.60–8.96)
Aspartate transferase (U/L, IQR) 41.00 (29.50–55.50) 29.00 (22.00–41.00)
Results   ECMO (n= 111) Non-ECMO (n= 381) p-value
Cmin (mg/L, IQR) 2.46 (1.58–4.16) 2.35 (1.52–3.74) 0.586
Infra-therapeutic samples (%) 15 (13.5%) 45 (11.8%) 0.630
Therapeutic samples (%) 84 (75.7%) 304 (79.8%) 0.350
Supra-therapeutic samples (%) 12 (10.8%) 32 (8.4%) 0.433
Adverse Events Not specifically reported in the study
Study Author Conclusions

ECMO support did not significantly reduce voriconazole Cmin compared with the non-ECMO group. However, VAV-ECMO is associated with reduced voriconazole exposure, suggesting a configuration-specific rather than uniform ECMO effect. Routine therapeutic drug monitoring remains essential.
Critique

The study provides valuable insights into the impact of ECMO on voriconazole exposure, particularly highlighting the configuration-specific effects of VAV-ECMO. However, the retrospective design and limited sample size in the ECMO subgroup may limit the generalizability of the findings. Additionally, the lack of CYP2C19 genotype information could introduce residual confounding by genetic variability.

 

References:
[1] [1] Wang X, Zhang H, Song S, et al. Impact of extracorporeal membrane oxygenation modes on voriconazole exposure in critically ill patients. J Antimicrob Chemother. 2026;81(2):dkaf501. doi:10.1093/jac/dkaf501
Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study
Design

Retrospective comparative case-control study

N= 24
Objective To compare voriconazole pharmacokinetics in patients receiving ECMO support versus those who do not and determine the optimal voriconazole dosage required to achieve and maintain the pharmacokinetic target in a timely manner
Study Groups

Non-ECMO group (n= 15)

ECMO group (n= 9)
Inclusion Criteria All adult patients admitted to the ICU and treated with voriconazole, who had at least one Cmin determination as part of routine clinical practice, regardless of the type of treatment indication or the route of administration
Exclusion Criteria Post-dose plasma voriconazole concentrations were excluded from the analysis
Methods

Retrospective analysis of voriconazole Cmin in critically ill patients with and without ECMO support. Voriconazole Cmin was measured using HPLC. Patients were divided into ECMO and non-ECMO groups. Voriconazole dosage was standardised according to actual body weight or adjusted body weight for patients with BMI ≥30 kg/m2. TDM was used to optimise dosing.
Duration November 2012 to February 2022
Outcome Measures

Primary: Voriconazole Cmin values

Secondary: Voriconazole dosage required to achieve therapeutic Cmin, impact of ECMO support and albumin levels on Cmin
Baseline Characteristics   Non-ECMO Group (n= 15) ECMO Group (n= 9)
Age, years 65 (18) 58 (2)
Gender (women) 5 (33.3%) 4 (44.4%)
BMI (kg/m2) 25.3 (5.1) 30 (1.8)
Actual weight (kg) 70 (15) 75 (12)
Adjusted weight (kg) 62.6 (14.4) 66.6 (9.4)
Days of treatment 11 (12) 38 (24)
Number of Cmin determinations per patient 1 (1) 4 (2)
CAPA diagnosis 1 (7%) 7 (78%)
Results   Non-ECMO Group (n= 15) ECMO Group (n= 9) p-Value
Cmin (mg/L) 3.62 (3.88) 0.38 (2.98) <0.001
Standardised doses (mg/kg/12 h) 3.53 (1.04) 4.50 (3.10) 0.007
Cmin/daily dose/kg ((mg/L)/(kg/day)) 0.98 (1.12) 0.12 (0.33) <0.001
Number of infra-therapeutic samples (Cmin < 1) 1 (3.8%) 16 (59.3%) <0.001
Adverse Events No specific adverse events related to voriconazole dosing were reported in the study
Study Author Conclusions

Therapeutic drug monitoring of voriconazole is essential in patients receiving ECMO support to ensure effective plasma levels. A maintenance dose of 6 mg/kg BID is needed to achieve the optimal pharmacokinetic target. ECMO support and plasma albumin concentrations are independent variables influencing voriconazole Cmin values.
Critique

The study provides valuable insights into the pharmacokinetics of voriconazole in ECMO patients, highlighting the need for higher dosing and therapeutic drug monitoring. However, the retrospective design and small sample size may limit the generalizability of the findings. The lack of CYP2C19 genotyping and matching between ECMO and non-ECMO groups could introduce bias.

 

References:
[1] Ronda M, Llop-Talaveron JM, Fuset M, et al. Voriconazole Pharmacokinetics in Critically Ill Patients and Extracorporeal Membrane Oxygenation Support: A Retrospective Comparative Case-Control Study. Antibiotics (Basel). 2023;12(7):1100. Published 2023 Jun 25. doi:10.3390/antibiotics12071100
Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study
Design

Retrospective, observational cohort study

N= 132
Objective To assess the impact of extracorporeal membrane oxygenation (ECMO) on voriconazole exposure
Study Groups

ECMO group (n= 66)

Non-ECMO group (n= 66)
Inclusion Criteria Adult critically ill patients (≥18 years old) hospitalized in the ICU from August 2017 to December 2021, treated with intravenous voriconazole for possible, probable or proven Aspergillus infection, and had at least one voriconazole Cmin available during treatment
Exclusion Criteria Not explicitly stated
Methods

Retrospective analysis of voriconazole trough concentrations (Cmin) in patients with and without ECMO support. Voriconazole was administered as an initial loading dose of 6 mg/kg i.v., every 12 h on day 1, followed by 4 mg/kg i.v., every 12 h for maintenance. TDM was performed 5–7 days after administration. Data were collected from electronic medical records.
Duration August 2017 to December 2021
Outcome Measures

Primary: Voriconazole trough concentrations (Cmin) in ECMO and non-ECMO patients

Secondary: Prevalence of subtherapeutic concentrations (<2 mg/L), factors affecting voriconazole exposure
Baseline Characteristics   Total (n= 132) ECMO (n= 66) Non-ECMO (n= 66) p-value
Age (years) 58.1 ± 17.0 52.0 ± 17.2 64.1 ± 14.5 0.000
Female 39 (29.5%) 18 (27.3%) 21 (31.8%) 0.567
Total body weight (kg) 66.3 ± 15.6 68.9 ± 16.9 63.8 ± 13.9 0.060
APACHE II 22.9 ± 5.3 22.2 ± 4.6 23.7 ± 5.9 0.111
SOFA 9.4 ± 3.7 10.3 ± 3.4 8.4 ± 3.8 0.003
ALB (g/L) 35.5 ± 6.0 38.4 ± 6.5 32.9 ± 4.2 0.000
Cmin (mg/L) 3.6 (1.8–5.3) 1.9 (1.4–4.4) 4.4 (3.2–6.9) 0.000
Results   ECMO (n= 66) Non-ECMO (n= 66) p-value
Median Cmin (mg/L) 1.9 (1.4–4.4) 4.4 (3.2–6.9) 0.000
Subtherapeutic Cmin (<2 mg/L) 51.5% 7.6% 0.000
Adverse Events Not explicitly stated
Study Author Conclusions

ECMO is a significant covariable affecting voriconazole exposure, leading to subtherapeutic concentrations. SOFA score was also associated with increased voriconazole concentration. Therapeutic drug monitoring remains important, especially in ECMO patients.
Critique

The study provides valuable insights into the impact of ECMO on voriconazole exposure, highlighting the need for careful monitoring. However, the retrospective design and single-center setting may limit the generalizability of the findings. The lack of CYP2C19 genotype data is a limitation, as it could influence voriconazole metabolism. Further prospective studies are needed to confirm these findings and optimize dosing regimens for ECMO patients.
References:
[1] [1] Ye Q, Yu X, Chen W, et al. Impact of extracorporeal membrane oxygenation on voriconazole plasma concentrations: A retrospective study. Front Pharmacol. 2022;13:972585. Published 2022 Aug 17. doi:10.3389/fphar.2022.972585
A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation
Design

Retrospective, multicenter study

N= 69
Objective To assess the effect of ECMO on voriconazole exposure in a large patient population
Study Groups ECMO (n= 69)
Inclusion Criteria All adult patients hospitalized in the ICU, treated with voriconazole and simultaneously received ECMO-support during at least a part of this antifungal treatment, with at least one voriconazole trough concentration available during ECMO-support
Exclusion Criteria None specified
Methods

Voriconazole concentrations were collected during ECMO and before/after ECMO treatment. Multivariate analyses were performed to evaluate the effect of ECMO on voriconazole exposure and to assess the impact of possible saturation of the circuit’s binding sites over time. Data were collected from eight centers in four countries.
Duration January 2009 to July 2020
Outcome Measures

Primary: Voriconazole trough concentration

Secondary: Subtherapeutic concentrations (<2 mg/L), therapeutic concentrations (2-5.5 mg/L), supratherapeutic concentrations (>5.5 mg/L)
Baseline Characteristics   ECMO (n= 69)
Age, median years (IQR) 54 (42–60)
Male 67%
Weight, kg (IQR) 77 (65–95)
Length of ICU stay, days (range) 8 to 228 (median 40)
APACHE II score, median (IQR) 18 (14–23)
Results   ECMO Non-ECMO p-Value
Trough concentration (mg/L), median (IQR) 2.4 (1.2–4.7) 2.5 (1.4–3.9) 0.58
Subtherapeutic Cmin (<2 mg/L), n (%) 106 (56%) 57 (39%) 0.80
Therapeutic Cmin (2–5.5 mg/L), n (%) 55 (29%) 76 (52%) 0.37
Supratherapeutic Cmin (>5.5 mg/L), n (%) 29 (15%) 14 (10%) 0.40
Adverse Events Not specified
Study Author Conclusions

No significant ECMO-effect was observed on voriconazole exposure. A large proportion of patients had voriconazole subtherapeutic concentrations.
Critique

The study's retrospective design and the limited number of samples collected during the first three days of ECMO initiation may limit the ability to detect the full impact of ECMO on voriconazole exposure. Additionally, the use of the same patient cohort for control may not account for all patient-specific characteristics. Despite these limitations, the study provides valuable insights into the variability of voriconazole exposure in critically ill patients on ECMO.

 

References:
[1] [1] Van Daele R, Bekkers B, Lindfors M, et al. A Large Retrospective Assessment of Voriconazole Exposure in Patients Treated with Extracorporeal Membrane Oxygenation. Microorganisms. 2021;9(7):1543. Published 2021 Jul 20. doi:10.3390/microorganisms9071543