Pharmacokinetic/Pharmacodynamic of ceftolozane/tazobactam in critically ill patients receiving extracorporeal membrane oxygenation (ECMO): a retrospective cohort analysis

Abstract

Ceftolozane/tazobactam (C/T), a β-lactam/β-lactamase inhibitor combination, demonstrates potent activity against difficult-to-treat resistance Gram-negative pathogens, including Pseudomonas aeruginosa and ESBL-producing Enterobacterales. Pharmacokinetic (PK) alterations in ECMO patients—due to drug adsorption, increased volume of distribution, and altered clearance—raise concerns about antibiotic underdosing [1]. While an ex vivo study reported minimal C/T adsorption on ECMO circuits (≤ 12.95% concentration loss over 8 h), PK evaluation in a porcine ECMO model found no significant effect on ceftolozane exposure, whereas ECMO was associated with reduced renal clearance of tazobactam by 37%, potentially affecting its plasma concentrations [2]. This study aimed to characterize C/T PK parameters—including trough (Cmin), peak (Cmax), and concentration at 50% of the dosing interval (CT50)—in patients who received C/T as empirical therapy for ≥ 48 h undergoing ECMO, post‑decannulation data were included only as exploratory, secondary observations. PK/PD target attainment was calculated using predefined MIC thresholds for ceftolozane and tazobactam, as detailed in the Online Supplement.

This was a single-center, observational, retrospective study conducted at Pitié-Salpêtrière University Hospital (Paris, France). The study was approved by the SRLF ethics committee (CE SRLF 19–70). 42 patients were included in the study, including 39 patients on ECMO support and 3 recently weaned ECMO patients. Baseline characteristics and C/T PK parameters are summarized in Table 1. C/T dosing regimens were adjusted to renal function (Supplementary file), with 45% receiving the highest dose (2 g/1 g q8h).

Table 1 Demographic, clinical characteristics and pharmacokinetics data of patients

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In ECMO patients, median ceftolozane trough concentration was 21.2 mg/L [11.4–43.5], with 100% of patients achieving concentrations above the MIC (100% fT > MIC) and 61% (23/38) reaching 4×MIC (16 mg/L). Median peak concentration was 68.7 mg/L [29.7–95.9]. Tazobactam trough concentrations had a median of 0.6 mg/L [0–2.9], with 50% (15/30) achieving 100% fT > 1 mg/L and 76% (28/37) reaching CT50 > 1 mg/L.

Among the three patients recently weaned from ECMO, median ceftolozane trough was 9.9 mg/L [9.6–52.8], with 33% (1/3) reaching 4×MIC. Median tazobactam trough was 0 mg/L [0–3.2], with 67% (2/3) maintaining CT50 > 1 mg/L.

Ceftolozane trough concentrations varied with renal function (Fig. 1): severe impairment (CrCl ≤ 30 mL/min) 93.6 mg/L [85.1–108.4], intermittent hemodialysis 55.3 mg/L [47.3–98.1], continuous venovenous hemodiafiltration 12.2 mg/L [10.1–15.8], augmented renal clearance (CrCl > 150 mL/min) 9.9 mg/L [7.3–20.3], and normal renal function (CrCl 80–150 mL/min) 22.4 mg/L [10.3–31.1].

Fig. 1

Results of ceftolozane trough blood levels depending on creatinine clearance (mL/min) or renal replacement therapy. The dashed lines indicate the EUCAST breakpoint MIC of 4 mg/mL for Pseudomonas aeruginosa and 4 times this MIC. Creatinine clearance estimated by UV/P formula. The box plots report: the internal horizontal line is the median; the lower and upper box limits are the quartile 1 and quartile 3, respectively; and bars represent the 95% CI * Dosage data available for 5/6 patients in this CrCl category. HD: Intermittent Hemodialysis. CVVHDF: Continuous Veno-Venous Hemodiafiltration. MIC : minimum inhibitory concentration

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Univariate logistic regression analyses identified albumin level (OR 1.20, 95% CI 1.03–1.48, p = 0.018) as a significant predictor of achieving ceftolozane trough concentrations > 4×MIC (16 mg/L). CVVHDF was strongly associated with reduced odds of target attainment (OR 0.08, 95% CI 0.01–0.35, p = 0.0005). Patients with severe renal impairment (CrCl ≤ 30 mL/min) or moderate impairment (CrCl 30–80 mL/min) showed a trend toward increased odds of target attainment (OR 9.87, 95% CI 1.00–1331.19), but this was not statistically significant (p = 0.050). Augmented renal clearance (CrCl > 130 mL/min) trended toward reduced likelihood of supratherapeutic exposure (OR 0.25, 95% CI 0.04–1.22, p = 0.088), while IHD showed a non-significant positive association (OR 7.68, 95% CI 0.74–1045.14, p = 0.096). ECMO support, oxygenator duration, disease severity (SAPS II), and clinical outcomes (28-day survival, infection recurrence) demonstrated no significant associations.

The main findings of this study can be summarized as follows (1) C/T PK were satisfactory, with 100% of troughs ≥ 4 mg/L and 61% of ECMO patients achieving > 16 mg/L (4×MIC) for ceftolozane, while tazobactam trough concentrations were frequently below the β-lactamase inhibition threshold of 1 mg/L. (2) IHD was associated with supra-therapeutic ceftolozane levels, while CVVHDF correlated with suboptimal exposure. (3) Augmented renal clearance (CrCl > 130 mL/min) significantly reduced ceftolozane troughs, whereas severe renal impairment (CrCl ≤ 30 mL/min) caused accumulation. Univariate analysis identified high albumin level as a predictor of achieving ceftolozane trough > 16 mg/L.

The finding that 100% of patients achieved ceftolozane trough concentrations above the Pseudomonas aeruginosa critical MIC (4 mg/L) aligns with prior studies in ECMO populations. Our findings further validate ex vivo data that showed minimal ceftolozane adsorption (< 13%) in ECMO circuits, supporting its reliability in this setting [2]. The pharmacodynamic target for tazobactam lacks consensus and may vary by pathogen β-lactamase expression; Kalaria et al. [3] highlight that trough concentrations above the MIC, critical for high-enzyme-producing resistant bacteria, are seldom achieved in critically ill patients. The divergent ceftolozane exposure between IHD and CVVHDF mirrors trends observed with cephalosporins. Ceftobiprole troughs has been shown to be 65% lower under CVVHDF than IHD [4]. Augmented renal clearance (CrCl > 130 mL/min) is a risk factor for β-lactam underdosing in critically ill patient [5]. Our findings extend this phenomenon to C/T. Conversely, severe renal impairment (CrCl ≤ 30 mL/min) led to ceftolozane accumulation.

The association between higher albumin levels and elevated ceftolozane troughs—despite its low protein binding (16–21%)—may reflect augmented volume of distribution, as hypoalbuminemia is often linked to capillary leak and fluid overload in critical illness.

This study has limitations, including its monocentric design, potential survivorship bias (as drug levels were measured only in surviving patients), and a small post-ECMO cohort, whose clinical improvement and successful ECMO weaning likely introduce confounding biases, limiting the interpretability of comparisons with ECMO patients. Similarly, findings for the IHD subgroup (n = 4) are exploratory due to very small numbers and wide confidence intervals.

The datasets generated during the current study are available from the corresponding author on reasonable request.

ARC:

Augmented renal clearance

CI:

Confidence interval

CrCl:

Creatinine clearance

C/T:

Ceftolozane/Tazobactam

CVVHDF:

Continuous venovenous hemodiafiltration

ECMO:

Extracorporeal membrane oxygenation

ESBL:

Extended-spectrum beta-lactamase

HABP:

Hospital-acquired bacterial pneumonia

ICU:

Intensive care unit

IHD:

Intermittent hemodialysis

IQR:

Interquartile range

MIC:

Minimum inhibitory concentration

OR:

Odds ratio

PD:

Pharmacodynamic

PK:

Pharmacokinetic

RRT:

Renal replacement therapy

SAPS II:

Simplified acute physiology score II

SOFA:

Sequential organ failure assessment

TDM:

Therapeutic drug monitoring

VABP:

Ventilator-associated bacterial pneumonia

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Authors and Affiliations

1. Service de Médecine Intensive Réanimation, Institut de Cardiologie, ICAN, Groupe Hospitalier Pitié–Salpêtrière, 47–83, boulevard de l’Hôpital, Paris Cedex 13, 75651, France

   Alexandre Coppens, Melchior Gautier, David Levy, Ouriel Saura, Juliette Chommeloux, Guillaume Hekimian, Matthieu Schmidt, Alain Combes & Charles-Edouard Luyt

2. Department of Pharmacology, Pharmacokinetics and Therapeutic Drug Monitoring Unit, AP-HP. Sorbonne Université, Pitié-Salpêtrière Hospital, UMR-S 1166, Paris, CIC-1901, F-75013, France

   Noël Zahr

3. Service de pharmacie, Groupe Hospitalier Pitié–Salpêtrière, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié–Salpêtrière, Sorbonne-Université, Paris, France

   Helga Junot

4. Service des Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié– Salpêtrière, Assistance Publique–Hôpitaux de Paris, Sorbonne-Université, Hôpital Pitié–Salpêtrière, INSERM U1135 EDIRA CIMI Sorbonne University, Paris, France

   Alexandre Bleibtreu

5. DMU BioGem, APHP.Sorbonne Université, Bactériologie-Hygiène, Hôpital Pitié–Salpêtrière, CIMI-Paris, Inserm U1135, Sorbonne- Université, Paris, F-75013, France

   Brigitte Rached

6. Sorbonne Université, INSERM, UMRS_1166-ICAN Institute of Cardiometabolism and Nutrition, Paris, France

   Matthieu Schmidt, Alain Combes & Charles-Edouard Luyt

Authors

1. Alexandre CoppensView author publications

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2. Melchior GautierView author publications

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3. Noël ZahrView author publications

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4. Helga JunotView author publications

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5. Brigitte RachedView author publications

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7. Ouriel SauraView author publications

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8. Juliette ChommelouxView author publications

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9. Guillaume HekimianView author publications

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11. Alain CombesView author publications

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12. Alexandre BleibtreuView author publications

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13. Charles-Edouard LuytView author publications

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Contributions

ACoppens, MG and CEL designed the study, collected, compiled, analyzed and interpreted the data and wrote the manuscript. DL, OS, JC, GH, MS, ACombes and AB collected data. NZ performed the ceftolozane tazobactam dosages and collected data. BR was responsible for bacteriological analyses and collected data. ACoppens and CEL performed statistical analysis. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Charles-Edouard Luyt.

Ethics approval

In accordance with current French law, informed written consent for demographic, physiologic and hospital-outcome data analyses was not obtained because this observational study did not modify existing diagnostic or therapeutic strategies. Nonetheless, patients and/or relatives were informed about the anonymous data collection and told that they could decline inclusion. The study was approved by the SRLF ethics committee (CE SRLF 19–70). The database is registered with the Commission Nationale l’Informatique et des Libertés (CNIL, registration no. 1950673).

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Not applicable.

Competing interests

CEL received lecture fees Merck, the manufacturer of ceftolozane/tazobactam; and lecture fees from AdvanzPharma, Shionoghi, travel grant from Pfizer and grant from Eumedica, all outside the submitted work. AB received lecture fees from Merck, the manufacturer of ceftolozane/tazobactam. The other authors have no conflicts of interest to declare in relationship to this manuscript.

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Coppens, A., Gautier, M., Zahr, N. et al. Pharmacokinetic/Pharmacodynamic of ceftolozane/tazobactam in critically ill patients receiving extracorporeal membrane oxygenation (ECMO): a retrospective cohort analysis. Crit Care 29, 391 (2025). https://doi.org/10.1186/s13054-025-05641-y

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• Received: 17 July 2025

• Accepted: 27 August 2025

• Published: 31 August 2025

• DOI: https://doi.org/10.1186/s13054-025-05641-y

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Keywords

• Ceftolozane/tazobactam
• Pharmacokinetic
• ECMO