What ECMO dosing strategies exist for aztreonam, cefazolin, and cefepime? (assuming normal renal function)?

Comment by InpharmD Researcher

Extracorporeal membrane oxygenation (ECMO) dosing strategies for aztreonam, cefazolin, and cefepime are not well defined, and the available literature consists primarily of case reports, case series, and pharmacokinetic (PK) studies without corresponding clinical outcomes. Antibiotic PK and pharmacodynamics (PD) may be significantly altered during ECMO due to increased volume of distribution, altered clearance, and drug adsorption to circuit components. Data describing aztreonam dosing in ECMO are extremely limited; one observational study reports use of aztreonam 2 grams every 8 hours administered over 30 minutes in a patient on ECMO with a creatinine clearance (CrCl) of 33 mL/min. Reports of cefazolin describe dosing of 2 grams every 8 hours in patients on ECMO, with one study administering the total daily dose as a continuous 24-hour infusion. Cefepime dosing varies across PK/PD studies, many of which include patients with renal impairment or receiving renal replacement therapy (RRT), with reported regimens generally ranging from 1 to 2 grams every 8 hours administered as either 30-minute or extended (e.g., 3-hour) infusions; one study also reports improved PD target attainment with a 3 gram loading dose infused over 30 minutes. Overall, ECMO-specific dosing data for these agents remain limited, and reported regimens largely mirror those used in non-ECMO patients, with several studies and expert guidance recommending consideration of extended infusions and therapeutic drug monitoring (TDM) to optimize target attainment.

Background

A 2020 review aimed to examine how the use of extracorporeal membrane oxygenation (ECMO) impacts antibiotic pharmacokinetics and consequently influences dosing requirements in critically ill adult ECMO patients. The use of ECMO is associated with a high frequency of antibiotic use due to its complications, such as the risk of infection due to invasive cannulation and immunosuppression from critical illness and mechanical support devices. Antibiotic pharmacokinetics and pharmacodynamics are significantly altered in ECMO due to factors like increased volume of distribution, altered clearance, and adsorption into circuit components. These changes complicate the selection, management, and dosing of antibiotics. While literature on this topic is limited, recent research has shed light on antibiotic pharmacokinetics during ECMO support. Key findings include the influence of antibiotic properties on drug loss in the ECMO circuit, the need for separate dosing considerations for adults compared to neonatal and pediatric populations, minimal impact of modern ECMO circuits on antibiotic pharmacokinetics, and pharmacokinetic changes primarily reflecting critical illness rather than the ECMO therapy itself. Overall, understanding these pharmacokinetic alterations is crucial for optimizing antibiotic dosing in critically ill ECMO patients, with recommendations generally aligning with dosing strategies for critically ill patients not on ECMO support. Therapeutic drug monitoring is also suggested as a potentially useful approach for guiding antibiotic dosing in this population. Notably, the authors provide general dosing recommendations for specific antibiotics in critically ill patients receiving ECMO (see Table 1) [1], [2]

A 2022 comprehensive review examines the challenges and practical considerations of antibiotic use in adult patients receiving extracorporeal membrane oxygenation (ECMO). With respect to cefazolin, in vitro studies have demonstrated substantial sequestration within ECMO circuits, with reports of up to 84% drug loss depending on circuit characteristics. However, clinical data are inconsistent. A case series (Table 2) reported higher cefazolin clearance and increased unbound concentrations, likely reflecting pharmacokinetic variability and changes in volume of distribution, whereas another case report (Table 3) found no significant alteration in pharmacokinetics. Given the high interindividual variability observed, the available evidence suggests that routine cefazolin dose adjustment solely due to ECMO support is not required. [2]

A 2025 retrospective observational single-center study conducted at Clínica Universidad de Navarra in Pamplona, Spain, evaluated clinical outcomes with combination ceftazidime-avibactam and aztreonam for the treatment of infections caused by VIM-producing Pseudomonas aeruginosa. Eight patients treated between 2019 and 2024 who received the dual regimen for at least 72 hours were included. Ceftazidime-avibactam was administered at 2.5 g every 8 hours infused over 2 hours, and aztreonam was administered at 2 g every 8 hours infused over 30 minutes. One patient was a 68-year-old male receiving ECMO for cardiogenic shock secondary to acute myocardial infarction; he received ceftazidime-avibactam plus aztreonam for 3 days and had a creatinine clearance of 33 mL/min. Clinical success, defined as clinical cure or survival at day 28, was achieved in seven of eight patients, including the patient on ECMO, with clinical cure documented in five infections across three distinct P. aeruginosa clones. Two patients died from all causes by day 28. No treatment-related adverse events or infection relapses were reported, although microbiological recurrence occurred in two patients. All isolates were susceptible to aztreonam and aztreonam-avibactam, and one isolate demonstrated overexpression of the MexAB-OprM efflux pump. [3]

A 2025 report outlines the DOSEBL study protocol, a national initiative to define dosing strategies and establish a consensus framework for beta-lactam use in critically ill patients with multidrug-resistant gram-negative bacilli (MDR-GNB) infections receiving extracorporeal life-support therapies, including ECMO. The protocol addresses pharmacokinetic alterations in this population and emphasizes optimized dosing and therapeutic drug monitoring (TDM) to mitigate subtherapeutic exposure. Antimicrobials included are meropenem, ceftazidime/avibactam, ceftolozane/tazobactam, cefiderocol, meropenem/vaborbactam, imipenem/relebactam, and aztreonam. The study consists of a national survey assessing current dosing and TDM practices, followed by development of a consensus-based dosing document. Notably, this report does not provide the dosing regimens that will be studied. Results are currently pending. [4]

According to the 2024 Antimicrobial ECMO Dosing Guidance from Northwestern Medicine, aztreonam, cefazolin, and cefepime are categorized as “Potentially Requires Dose Adjustment.” The guidance recommends dosing on the aggressive end of the therapeutic range for aztreonam and cefazolin, without specifying exact regimens, and notes minimal to moderate circuit sequestration for both agents. Cefepime is described as having minimal sequestration, and standard dosing with consideration of therapeutic drug monitoring (TDM) is recommended; however, specific dosing protocols are not provided. [5]

References: [1] Abdul-Aziz MH, Roberts JA. Antibiotic dosing during extracorporeal membrane oxygenation: does the system matter?. Curr Opin Anaesthesiol. 2020;33(1):71-82. doi:10.1097/ACO.0000000000000810
[2] Gomez F, Veita J, Laudanski K. Antibiotics and ECMO in the Adult Population-Persistent Challenges and Practical Guides. Antibiotics (Basel). 2022;11(3):338. Published 2022 Mar 4. doi:10.3390/antibiotics11030338
[3] Pina-Sánchez M, Rua M, López-Causapé C, et al. Ceftazidime-avibactam plus aztreonam cocktail for the treatment of VIM-producing Pseudomonas aeruginosa infections: good enough to have another?. J Antimicrob Chemother. 2025;80(5):1371-1376. doi:10.1093/jac/dkaf083
[4] Pau-Parra A, Núñez-Núñez M, Sadyrbaeva-Dolgova S, et al. [Translated article] National survey and consensus document on dosing strategies for beta-lactam antibiotics against multidrug-resistant gram-negative bacilli (MDR-GNB) in critically ill patients undergoing extracorporeal life-support techniques: The DOSEBL study protocol. Farm Hosp. 2025;49(3):T179-T183. doi:10.1016/j.farma.2024.11.005
[5] Northwestern Medicine. Northwestern Medicine Antimicrobial ECMO Dosing Guidance.; 2024. https://adsp.nm.org/uploads/1/4/3/0/143064172/nm_antimicrobial_ecmo_dosing.pdf. Accessed February 26, 2026.
Literature Review

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

What ECMO dosing strategies exist for aztreonam, cefazolin, and cefepime? (assuming normal renal function)?

Level of evidence

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


Please see Tables 1-7 for your response.

Suggested antibiotic dosing regimen in critically ill patients receiving extracorporeal membrane oxygenation

Aminoglycosides

General dosing recommendations:

  • Dosing should align with the recommended dosing strategies for critically ill patients without ECMO support
  • Higher than recommended aminoglycoside dosing, with an extended-interval dosing regimen should be used
  • Regular dosing review with the aid of TDM is essential

Practical and specific recommendations:

  • Amikacin 30 mg/kg i.v. and dosing interval is determined by renal function and TDM
  • Gentamicin/tobramycin 7–10 mg/kg i.v. and dosing interval is determined by renal function and TDM

Beta-lactams

General dosing recommendations:

  • Dosing should align with the recommended dosing strategies for critically ill patients without ECMO support
  • High initial loading doses followed by prolonged infusion should be considered
  • Regular dosing review with the aid of TDM is essential

Practical and specific dosing recommendations:

  • Meropenem 1 g i.v. LD (over 0.5 h) followed by 1 g i.v. every 8 h (as EI or CI)
  • Piperacillin-tazobactam 4.5 g i.v. LD (over 0.5 h) followed by 4.5 g i.v. every 6 h (as EI or CI)

Fluoroquinolones

General dosing recommendations

  • Dosing should align with the recommended dosing strategies for critically ill patients without ECMO support
  • Use loading and higher daily doses
  • Regular dosing review with the aid of TDM should be considered

Practical and specific dosing recommendations:

  • Ciprofloxacin 800 mg i.v. LD (over 1 h) followed by 400–600 mg i.v. every 8 h

Glycopeptides

General dosing recommendations:

  • Dosing should align with the recommended dosing strategies for critically ill patients without ECMO support
  • Use loading and higher daily doses
  • Regular dosing review with the aid of TDM is essential

Practical and specific dosing recommendations:

  • Teicoplanin 12 mg/kg i.v. LD every 12 h (for three to five doses) followed by 12 mg/kg every 24 h
  • Vancomycin 25–30 mg/kg i.v. LD followed by 15–20 mg/kg every 8–12 h

Linezolid

General dosing recommendations:

  • Dosing should align with the recommended dosing strategies for critically ill patients without ECMO support
  • Use higher daily doses and altered dosing approaches
  • Front-loaded dosing regimen and CI can be considered
  • Regular dosing review with the aid of TDM should be considered

Practical and specific dosing recommendations:

  • Linezolid 600 mg i.v. every 8–12 h
Abbreviations: CI= continuous infusion; ECMO= extracorporeal membrane oxygenation; EI= extended infusion; i.v.= intravenous; LD= loading dose; TDM= therapeutic drug monitoring
References:
[1] [1] Abdul-Aziz MH, Roberts JA. Antibiotic dosing during extracorporeal membrane oxygenation: does the system matter?. Curr Opin Anaesthesiol. 2020;33(1):71-82. doi:10.1097/ACO.0000000000000810
Excessive unbound cefazolin concentrations in critically ill patients receiving veno-arterial extracorporeal membrane oxygenation (vaECMO): an observational study
Design

Prospective, observational study

N= 6
Objective To evaluate the pharmacokinetics of cefazolin in patients undergoing ECMO treatment and determine whether a dosing software enables ECMO patients to achieve target cefazolin exposures
Study Groups All patients (n= 6)
Inclusion Criteria Critically ill patients receiving ECMO and cefazolin admitted to the ICU 
Exclusion Criteria Age <18, mass transfusion, and pregnancy
Methods Patients received 6000 mg cefazolin over 24 hours, administered as three single doses of 2000 mg every 8 hours. Each dose was administered over 8 hours. Blood sampling occurred at steady state, daily on day one, two, three, and day six after inclusion. Total and unbound cefazolin concentrations were determined using HPLC assay
Duration October 2019 to October 2020
Outcome Measures

Primary: Pharmacokinetics of cefazolin in ECMO patients

Secondary: Effectiveness of dosing software in achieving target cefazolin exposures
Baseline Characteristics   All patients (n= 6)
Age, years 66 ± 6.6
Male sex 5 (83%)
Bodyweight, kg 91.0 ± 34.3
BMI, kg/m2 32.1 ± 10.6
SAPS II 54 ± 17
Patients on CRRT 4 (66%)
Dialytic flow, ml/h 2500 ± 341
Daily balance, ml −155 ± 1683
Albumin concentration, g/dl 2.1 ± 0.3
Cefazolin clearance, L/h 4.3 ± 3.9
Cefazolin clearance in patients with CRRT, L/h 2.0 ± 0.4
Cefazolin clearance in patients without CRRT, L/h 8.5 ± 3.8
Cefazolin free fraction, % 49 ± 9
Abbreviations: BMI, body mass index; CRRT, continuous renal replacement therapy; SAPS II, Simplified Acute Physiology Score II
Results   All patients (n= 6)
Total cefazolin concentration, mg/L 98.1 ± 52.6
Unbound cefazolin concentration, mg/L 51.1 ± 33.8
Mean cefazolin clearance, L/h 4.3 ± 3.9
Unbound cefazolin >8x ECOFF (>16 mg/L) 71% (n= 12) samples
Abbreviations: ECOFF, EUCAST epidemiological cut-off values
Adverse Events No specific adverse events were reported in the study
Study Author Conclusions Excessive unbound cefazolin concentrations were observed in patients receiving ECMO. The use of dosing software could optimize cefazolin dosing, and therapeutic drug monitoring could further improve dosing and minimize side effects. The distinction between unbound and bound cefazolin is recommended as only the unbound fraction is biologically active.
Critique The study highlights the variability in cefazolin pharmacokinetics in ECMO patients and the potential benefits of dosing software. However, the small sample size and the inability to complete the full observation period for all patients limit the generalizability of the findings. The study's observational nature also limits the ability to establish causality.
References:
[1] [1] Booke H, Frey OR, Rhr AC, et al. Excessive unbound cefazolin concentrations in critically ill patients receiving veno-arterial extracorporeal membrane oxygenation (vaECMO): an observational study. Sci Rep. 2021;11(1):16981. Published 2021 Aug 20. doi:10.1038/s41598-021-96654-4

Pharmacokinetics of Total and Unbound Cefazolin during Veno-Arterial Extracorporeal Membrane Oxygenation: A Case Report

Design

 Case report

Case presentation

 A 25-year-old woman (estimated weight 85 kg) presented with cardiac arrest and refractory ventricular fibrillation, with bedside echocardiography demonstrating right ventricular dilation suggestive of massive pulmonary embolism; oral contraceptive use was her only identified risk factor. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated using a 23-Fr femoral venous cannula and 15-Fr femoral arterial cannula (blood flow 3 L/min; gas flow 4 L/min), and thrombolysis with alteplase 100 mg was administered. Following partial surgical cutdown for venous cannulation, cefazolin prophylaxis was started at 2 g intravenously every 8 hours. Baseline laboratory values included serum creatinine 114 µmol/L, estimated glomerular filtration rate 58 mL/min/1.73 m², and albumin 32 g/L. Pre- and post-oxygenator blood samples were collected at 0, 1, 4, and 8 hours after a 2-g cefazolin infusion administered over 1 hour. Total and unbound plasma cefazolin concentrations were quantified using a validated HPLC-MS/MS assay, and non-compartmental pharmacokinetic analysis was performed. Maximum and minimum plasma concentrations (Cmax and Cmin) were obtained directly from observed data, area under the concentration–time curve over the 8-hour dosing interval (AUC0–8) was calculated using the linear trapezoidal method, total clearance was estimated as dose/AUC0–8, and apparent volume of distribution at steady state was derived from clearance and mean residence time. Pre- and post-oxygenator pharmacokinetic parameters, including Cmax, Cmin, and AUC0–8, were comparable for both total and unbound cefazolin, and median protein binding ranged from 52% to 60% at 1, 4, and 8 hours post-infusion.

Study Author Conclusions

 This case study highlights that there is no effect of ECMO on the PK of cefazolin suggesting that the dose of cefazolin may not need adjustment. Prospective studies are required to confirm these findings and to inform clinical management.  
References:
[1] [1] Dhanani JA, Lipman J, Pincus J, et al. Pharmacokinetics of Total and Unbound Cefazolin during Veno-Arterial Extracorporeal Membrane Oxygenation: A Case Report. Chemotherapy. 2019;64(3):115-118. doi:10.1159/000502474
Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study)
Design

Prospective, open-labelled, multi-centre pharmacokinetic study

N= 6
Objective To describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy
Study Groups All patients (n= 6)
Inclusion Criteria Patients aged between 18–90 years, hospitalised in ICU and receiving cefepime whilst undergoing ECMO for respiratory and/or cardiac dysfunction
Exclusion Criteria Known allergy to cefepime, pregnant, bilirubin > 150 μmol/L, ongoing massive blood transfusion (> 50% blood volume) in the preceding 8 hours, or therapeutic plasma exchange in the preceding 24 hours
Methods Serial cefepime plasma concentrations were measured in patients on ECMO, analyzed using a population PK approach with Pmetrics®. Dosing simulations were used to identify optimal dosing strategy achieving target trough concentrations (Cmin) of 8–20 mg/L. Cefepime was described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters
Duration November 2012 to November 2019
Outcome Measures Primary: Population pharmacokinetics of cefepime Secondary: Optimal dosing strategy for efficacy and safety
Baseline Characteristics   All patients (n= 6)
Male 5 (83%)
Age, years 55 (50–61)
Weight, kg 89 (75–90)
Height, cm 183 (172–185)
Indication for ECMO Cardiogenic shock, Lung transplant, TRALI, Aspiration pneumonia, Heart transplant
APACHE II on admission 25 (19–29)
SOFA score on sampling day 10 (7–11)
CrCL, mL/min 75 (64–84)
Albumin, g/L 26 (24–28)
Bilirubin, μmol/L 53 (26–56)
Total protein, g/L 49 (47–52)
Urea, mmol/L 16 (13–25)
Dosing regimen administered 1 g 8-hourly, 2 g 8-hourly
ECMO mode 50% VA, 50% VV
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II score; CrCl, creatinine clearance; ECMO, extracorporeal membrane oxygenation; SOFA, Sequential Organ Failure Assessment; TRALI, transfusion-related acute lung injury
Results   Mean Standard deviation Coefficient of variation (%) Median Shrink (%)
CL, L/h 2.43 1.55 63.73 1.50 0.001
Vc, L 15.09 3.33 22.10 14.06 0.004
kPC, h−1 0.36 0.28 76.36 0.24 0.034
kCP, h−1  1.74 0.90 51.96 2.03 0.21
Adverse Events Cefepime neurotoxicity may present as encephalopathy, myoclonus, and seizures. Higher probabilities of achieving toxic concentrations (Cmin > 20 mg/L) were observed in patients with CrCL of 30–65 mL/min.
Study Author Conclusions Reduced cefepime clearance in patients receiving ECMO increases the risk of cefepime toxicity. Modified dosing regimens should be used in critically ill patients on ECMO to avoid drug accumulation. Therapeutic drug monitoring is recommended when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.
Critique The study provides valuable insights into cefepime pharmacokinetics in ECMO patients, highlighting the need for modified dosing regimens. However, the small sample size and the inability to measure free drug concentrations limit the generalizability of the findings. The study's reliance on total drug concentrations and the derived neurotoxic threshold may not fully capture the clinical scenario, necessitating further research with larger cohorts and direct measurement of free drug levels.
References:
[1] [1] Cheng V, Abdul-Aziz MH, Burrows F, et al. Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study). Int J Antimicrob Agents. 2021;58(6):106466. doi:10.1016/j.ijantimicag.2021.106466
Individual target pharmacokinetic/pharmacodynamic attainment rates among cefepime-treated patients admitted to the ICU with hospital-acquired pneumonia with and without ECMO
Design

Single-center, prospective study

N= 70
Objective To evaluate patient-specific and population pharmacokinetic (PK)/pharmacodynamic (PD) attainment in critically ill patients treated with cefepime, with and without extracorporeal membrane oxygenation (ECMO), and not requiring renal replacement therapy (RRT)
Study Groups

ECMO (n= 9)

Non-ECMO (n= 61)
Inclusion Criteria Mechanically ventilated patients with suspected pneumonia, excluding those on renal replacement therapy
Exclusion Criteria Patients requiring concurrent hemodialysis, peritoneal dialysis, or continuous renal replacement therapy
Methods Cefepime dosing followed institutional renal function-based protocols. Plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry. A two-compartment PK model was developed using Pmetrics for R, with Vd scaled to body weight and ECMO status, and clearance (CL) scaled to renal function. Target attainment was calculated from Bayesian posterior predictions, and Monte Carlo simulations evaluated the cumulative fraction of response (CFR) for regimens of 2 grams IV every 8 hours, administered as either 0.5 hour intermittent or 4 hour extended infusion with or without a 2 or 3 gram loading dose (LD) (0.5 hours).
Duration June 2018 to March 2024
Outcome Measures

Primary: Individual PK/PD target attainment rates

Secondary: Cumulative fraction of response (CFR) for different dosing regimens
Baseline Characteristics   All patients (N = 70)
Age, years 62.1 ± 14.4
Total body weight, kg 83.3 ± 26.5
Body surface area, m2 1.96 ± 0.33
Serum creatinine, mg/dL 1.12 ± 0.66
Creatinine clearance, mL/min 115.8 ± 88.6
ECMO 9 (12.9%)
Samples per patient - ECMO 2 (1–6)
Samples per patient - Non-ECMO 2 (1–3)
Male 42 (60%)
Results   ECMO (n= 9) Non-ECMO (n= 61)
CL, L/h 4.6 (3.6–6.7) 3.12 (2.0–4.1)
Vd, L 23 (15.4–50.4) 17.1 (2.9–23.1)
Adverse Events Not specifically reported
Study Author Conclusions ECMO significantly increased cefepime volume of distribution in ICU patients, suggesting sub-optimal target attainment at higher minimum inhibitory concentrations. A 3 gram loading dose appears essential for target attainment, underscoring the need for revised dosing strategies in ECMO.
Critique The study provides valuable insights into the pharmacokinetics of cefepime in ECMO patients, highlighting the need for adjusted dosing strategies. However, the single-center design and small ECMO sample size may limit generalizability. The study did not evaluate clinical outcomes, which could provide further context for the PK/PD findings.
References:
[1] [1] Valadez A, Zurawska M, Harlan E, et al. Individual target pharmacokinetic/pharmacodynamic attainment rates among cefepime-treated patients admitted to the ICU with hospital-acquired pneumonia with and without ECMO. Antimicrob Agents Chemother. 2025;69(6):e0010225. doi:10.1128/aac.00102-25
Pharmacokinetics and Time above the MIC Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)
Design

Single-center, observational pharmacokinetic study

N= 6
Objective To determine the pharmacokinetics of cefepime in patients requiring ECMO support to guide dosage selection
Study Groups All patients (n= 6)
Inclusion Criteria Patients ≥18 years old, receiving veno-arterial (VA) or veno-venous (VV) ECMO, and receiving cefepime as part of their standard-of-care antibiotic regimen
Exclusion Criteria Not specified
Methods Cefepime was administered as 2 grams every 8 hours (q8h) as a 3-hour infusion. Blood samples were collected pre-oxygenator over a single dosing interval at steady-state after at least 72 hours of ECMO support. Pharmacokinetic analyses were conducted using Pmetrics for R, and simulations were employed to determine f T > MIC and total trough concentration of varying regimens
Duration September 2020 to March 2021
Outcome Measures

Primary: Pharmacokinetics of cefepime in ECMO patients

Secondary: Ability to achieve optimal pharmacodynamic exposure and thresholds for cefepime-associated neurotoxicity
Baseline Characteristics   All patients (n= 6)
Age, years 31 to 62
Sex 4 Male, 2 Female
CrCL, ml/min 92 to 199
Weight, kg 75 to 173
APACHE II score 12 to 19
ECMO Indication COVID-19, ARDS/VABP, Heart failure/cardiogenic shock
ECMO Modality 4 VV, 2 VA
ECMO Flow Rate, L/min 3.1 to 6.2

Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ARDS, acute respiratory distress syndrome; CL, total body clearance; CrCL, creatinine clearance; ECMO, extracorporeal membrane oxygenation; VABP, ventilator associated pneumonia; VA, veno-arterial; VV, veno-venous.
Results   2g q8h (3h infusion) 2g q12h (0.5h infusion) 1g q12h
% f T > MIC at 4 μg/mL 100% 83% 50%
% f T > MIC at 8 μg/mL 100% 83% 50%
% f T > MIC at 16 μg/mL 100% 17% 0%
Trough concentration > 21.6 μg/mL 50% 0% 0%
Adverse Events No patient demonstrated signs or symptoms of neurotoxicity during treatment.
Study Author Conclusions For ECMO patients with normal to augmented renal clearance or those receiving CVVHDF, dosing regimens of 2 grams q8h (3-hour infusions) are supported to empirically target MICs up to 16 μg/mL. Larger studies are needed to determine how ECMO affects cefepime pharmacokinetics.
Critique The study provides valuable insights into cefepime pharmacokinetics in ECMO patients, but is limited by its small sample size and lack of post-ECMO pharmacokinetic data. The findings may not be generalizable to all ECMO patients due to the specific renal function profiles of the participants.
References:
[1] [1] Kois AK, Gluck JA, Nicolau DP, Kuti JL. Pharmacokinetics and Time above the MIC Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO). Int J Antimicrob Agents. 2022;60(1):106603. doi:10.1016/j.ijantimicag.2022.106603
Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation
Design

Prospective, open-labeled, pharmacokinetic study

N= 85
Objective To describe the pharmacokinetics (PK) of antimicrobials in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and to determine whether current antimicrobial dosing regimens achieve effective and safe exposure
Study Groups All patients (n= 85)
Inclusion Criteria Adult ECMO recipients from six participating ICUs; age >18 years and <90 years; currently undergoing ECMO for respiratory and/or cardiac dysfunction; cinical indication for the study sedatives/analgesics and/or antimicrobials
Exclusion Criteria Missing consent; known allergy to study drug; pregnancy; serum bilirubin >150 µmol/L; ongoing massive blood transfusion requirement (>50% blood volume) transfused in the previous 8 hours; therapeutic plasma exchange in the preceding 24 hours
Methods Serial blood samples were collected over a single dosing interval during ECMO for 11 antimicrobials. PK parameters were estimated using noncompartmental methods. Antimicrobials included caspofungin, cefepime, ceftriaxone, ciprofloxacin, fluconazole, linezolid, meropenem, oseltamivir, piperacillin, vancomycin, and voriconazole. Dosing regimens and ECMO configurations were determined by the treating clinician. Cefepime doses ranged from 3 grams to 6 grams daily. Additional dosing details not provided
Duration November 2012 through November 2019
Outcome Measures

Primary: Pharmacokinetics of antimicrobials

Secondary: Achievement of target concentration exposures
Baseline Characteristics   All patients (n= 85)
Age, years 44.7 ± 14.4
Weight, kg 82.0 (70.0–95.0)
Body mass index, kg/m2 26.6 (24.0–31.6)
Male 52 (61.2%)
APACHE II on admission 17.0 (14.0–24.0)
SOFA score on sampling day 9.0 ± 3.8
Serum creatinine, μmol/L 98.5 (66.5–171.5)
Estimated creatinine clearance, ml/min 70.0 (49.0–119.3)
Blood urea nitrogen, mmol/L 10.2 (6.3–14.7)
Serum albumin, g/L 27.0 ± 7.2
Total protein, g/L 53.0 (49.0–59.0)
Total bilirubin, μmol/L 17.5 (10.0–47.3)

ECMO indication 

          Acute respiratory distress syndrome

          Cardiogenic shock

 

37 (43.5%)

14 (16.5%)

ECMO mode 

          Venoarterial

          Venovenous

 

36 (42.4%)

47 (55.3%)
Renal replacement therapy 38 (44.7%)
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ECMO, extracorporeal membrane oxygenation; SOFA,  Sequential Organ Failure Assessment.
Results   Target Attainment
Oseltamivir 33.3%
Piperacillin 44.4%
Vancomycin 27.3%
Cefepime 20.0%
Ciprofloxacin 37.5%
Adverse Events Not specified in the provided text
Study Author Conclusions Antimicrobial pharmacokinetics were highly variable in critically ill patients receiving ECMO, leading to poor target attainment rates. Antimicrobial dosing in ECMO recipients should align with strategies for critically ill patients without ECMO support, and therapeutic drug monitoring is recommended to ensure optimal dosing.
Critique The study is significant as it is the first multinational and largest PK study in critically ill adult patients receiving ECMO, providing valuable insights into antimicrobial dosing challenges. However, the study is limited by its small sample sizes for some antimicrobials, lack of clinical outcome data, and absence of non-ECMO controls for comparison. The variability in PK parameters highlights the need for individualized dosing and therapeutic drug monitoring in this population.
References:
[1] [1] Shekar K, Abdul-Aziz MH, Cheng V, et al. Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation. Am J Respir Crit Care Med. 2023;207(6):704-720. doi:10.1164/rccm.202207-1393OC