What are recommended dosing strategies for ceftazidime, avycaz, and zerbaxa for VV ECMO assuming normal renal function

Comment by InpharmD Researcher

There is severely limited data specifically assessing VV ECMO. In general, Ex vivo studies demonstrate that ceftazidime shows no significant interaction with ECMO circuits, and case reports indicate that standard doses of ceftolozane/tazobactam (3 g Q8H) are sufficient to achieve therapeutic targets. While data for ceftazidime/avibactam on VV ECMO is more limited, its dosing is typically guided by renal function rather than ECMO presence, with augmented renal clearance being the primary concern for underdosing rather than the circuit itself. Available studies for ceftolozane/tazobactam also suggest that dose adjustments may not be necessary. Therefore, the current evidence does not support routine dose adjustments, although studies in VV ECMO are still needed.

ceftazidime avibactam ceftolozane tazobactam ECMO

Background

A 2022 comprehensive review was conducted which included an analysis to determine dosage considerations for various beta-lactam/beta-lactamase inhibitors in patients receiving extracorporeal membrane oxygenation (ECMO). However, the authors note that the overall data is limited, and what data was available focuses on venoarterial ECMO (VA-ECMO) rather than venovenous ECMO (VV-ECMO). It is possible that VA-ECMO has different physiological effects.There was no data for ceftazidime/avibactam in the author’s search for ECMO, with most findings focused on other forms of renal replacement therapy. For ceftolozane/tazobactam, two case reports/series were found in patients receiving ECMO. The first case used the standard 3 g Q8H dose which was sufficient for achieving aggressive target levels, although lower Cmax and Cmin were seen on the last 2 days of therapy. In the other case report used as part of prophylaxis in cystic fibrosis for a ECMO post-lung transplant, regular manufacturer dosing also achieved target levels and the authors concluded no dosing adjustments were needed. [1], [2], [3]

The 2023 research examined the interactions of ceftazidime and clindamycin with ECMO. The investigation was designed as an ex vivo experiment using blood-primed circuits to evaluate drug disposition under these conditions. Drug recovery percentages over time were assessed to determine interactions with circuit components. ECMO circuits were assembled with various combinations of components such as oxygenators, pumps, and hemofilters, and were tested using expired human blood mixtures. Results highlighted that ceftazidime showed no significant interaction with ECMO components, maintaining similar recovery kinetics compared to controls. By contrast, CRRT rapidly cleared ceftazidime within two hours, suggesting the necessity of dosage adjustments when this therapy is used. These findings underscore the need for careful consideration of dosing strategies for patients on CRRT to optimize therapeutic efficacy and safety. However, in patients on ECMO, dose adjustments may not be necessary with ceftazidime. [4]

A 2017 article investigated the pharmacokinetic impact of ECMO on beta-lactam degradation kinetics using an ex vivo model. The research was meticulously designed to simulate clinical conditions by priming ECMO circuits with whole human blood and administering beta-lactam antibiotics, including cefotaxime, ceftazidime, cefepime, piperacillin, oxacillin, amoxicillin, and ceftriaxone. Serial blood sampling over a 48-hour period enabled a comprehensive evaluation of drug concentration changes using high-performance liquid chromatography, with results benchmarked against controls stored in glass and polyvinyl chloride tubes. For ceftazidime, the degradation rate in ECMO circuits paralleled that observed in controls. After 48 hours, mean drug recoveries from the ECMO circuits was 73% for ceftazidime compared to 69% and 66% from the tubing controls and inert controls, respectively. While ex vivo, the findings suggest that dose adjustments may not be necessary. [5]

A 2021 study investigated ECMO on the pharmacokinetics of ceftolozane/tazobactam (C/T). The investigation aimed to determine the impact of ECMO on the pharmacokinetic behavior of C/T, employing both ex vivo and in vivo models. The ex vivo model involved a closed-loop setup with ECMO circuits primed with human whole blood, where adsorption of the drug was analyzed across multiple dosing intervals. In parallel, an in vivo study using a porcine model measured drug concentrations over an 11-hour period in pigs undergoing ECMO compared to a control group, utilizing non-compartmental analysis and non-linear mixed effects modeling to evaluate pharmacokinetic parameters. The study's findings suggested that ECMO significantly decreased the clearance of tazobactam by 37% without notably altering the pharmacokinetics of ceftolozane, which may have been influenced by the small cohort size. Despite this reduction in tazobactam clearance, variations in concentration from both ex vivo and in vivo models indicated that ECMO's overall effect on C/T pharmacokinetics may not be clinically significant. Therefore, standard dosing of ceftolozane and tazobactam is likely to remain effective for critically ill patients receiving ECMO, although the study emphasized the necessity of further clinical research to validate and refine dosing guidelines in this population. [6]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What are recommended dosing strategies for ceftazidime, avycaz, and zerbaxa for VV ECMO assuming normal renal function

Level of evidence

D - Case reports or unreliable data Read more→

Please see Tables 1-4 for your response.

Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study
Design	Prospective, observational single-center study N= 105
Objective	To evaluate and assess the median serum concentrations of continuously applied antibiotics in intensive care patients being treated with and without ECMO
Study Groups	ECMO (n= 30) Non-ECMO (n= 75)
Inclusion Criteria	All patients aged ≥18 years treated for an acute and severe infectious disease with piperacillin/tazobactam, ceftazidime, meropenem, or linezolid on the ICU during the study period
Exclusion Criteria	Age <18 years, pregnancy, and/or absence of written informed consent
Methods	Patients received antibiotics via continuous infusion. Therapeutic drug monitoring of serum concentrations was conducted using high-performance liquid chromatography. Target concentrations were defined as fourfold above the MIC of susceptible bacterial isolates according to EUCAST breakpoints. The target for ceftazidime was <32 mg/L serum concentrations.
Duration	October 2018 to December 2019
Outcome Measures	Median serum concentrations of ceftazidime, percentage who did not reach pre-specified target concentrations
Baseline Characteristics		All patients (n= 105)	Patients on ECMO support (n= 30)	Patients without ECMO support (n= 75)
	Male sex	66 (62.9%)	20 (66.7%)	46 (61.3%)
	Age (in years)	57.3 ± 13.9	47.7 ± 13.1	61.2 ± 12.3
	Body mass index (BMI)	27.7 ± 8.3	28.8 ± 10.0	27.2 ± 7.5
	Sequential organ failure assessment (SOFA) score (average score and range)	7.0 (4–9)	7.4 (5–8)	6.0 (4–9)
	ICU mortality	35 (33.3%)	18 (60.0%)	17 (22.7%)
	Median ICU stay until death (in days)	23 (13–36)	32 (22.5–50)	14 (6.75–23.5)
	Continuous renal replacement therapy (CRRT)	Patients requiring CRRT	40 (38.1%)	16 (53.3%)
	CRRT blood flow (in ml/min)	101.1 ± 19.6	100.6 ± 18.9	102.8 ± 25.9
	CRRT dialysate flow (in ml/h)	2307.2 ± 536	2486.2 ± 541.6	2101 ± 470.7
Results		Patients with ECMO support	Patients without ECMO support	p-Value
	Ceftazidime	49.3 (42.0–69.0)	63.2 (38.1–71).0	0.69
	Did not reach pre-specified target concentrations	0.0%	0.0%
Adverse Events	Not specifically reported in the study
Study Author Conclusions	ECMO treatment was associated with significantly reduced serum concentrations of specific antibiotics. Future studies are needed to assess the pharmacokinetic characteristics of antibiotics in ICU patients on ECMO support.
Critique	Ceftazidime was ultimately found to not be significantly influenced by ECMO with the authors suggesting it may be safely used in such patients.

References:
[1] [1] Khn D, Metz C, Seiler F, et al. Antibiotic therapeutic drug monitoring in intensive care patients treated with different modalities of extracorporeal membrane oxygenation (ECMO) and renal replacement therapy: a prospective, observational single-center study. Crit Care. 2020;24(1):664. Published 2020 Nov 25. doi:10.1186/s13054-020-03397-1

Ceftazidime/avibactam serum concentration in patients on ECMO
Design	Single-centre, observational, retrospective study N= 14
Objective	To evaluate ceftazidime/avibactam blood levels in ECMO patients and find factors associated with underdosing
Study Groups	All patients (n= 14)
Inclusion Criteria	Patients on ECMO who received ceftazidime/avibactam and had trough blood levels available between October 2020 and October 2021
Exclusion Criteria	Not specified
Methods	Retrospective analysis of ceftazidime/avibactam serum levels in ECMO patients. Dosing was 2000/500 mg q8h over a 2-hour infusion, with adjustments for renal failure. Serum levels were measured just before the next infusion (Cmin).
Duration	October 2020 to October 2021
Outcome Measures	Primary: Number of patients with ceftazidime and avibactam blood levels above predefined cut-off values (8 mg/L for ceftazidime and 4 mg/L for avibactam)
Baseline Characteristics		Patients (N= 14)
	Age, years	49 [41–56]
	Male sex	11 (78.5%)
	Body mass index, kg/m2	32.6 [29.0–37.9]
	Overweight	4 (28.5%)
	Obesity	9 (64%)
	Severity score at ICU admission - SOFA	11.5 [9.0–12.0]
	Severity score at ICU admission - SAPS II	57 [54–59]
	AKI (KDIGO range 1 to 3 during ATB)	5 (35.7%)
	Renal replacement therapy at the time of dosage	4 (28.5%)
	Intermittent haemodialysis	1 (7%)
	CRRT	3 (21.4%)
	Creatinine clearance, mL/min	81 [12–136]
	Creatinine clearance <10 mL/min	4 (29%)
	Creatinine clearance 10–60 mL/min	1 (7%)
	Creatinine clearance 61–130 mL/min	4 (29%)
	Creatinine clearance >130 mL/min	5 (35%)
	Albumin serum level within 48 h before dosage, g/L	23 [16–25]
	Time between ECMO start and ATB, days	26 [22–33]
	Time between ECMO start and TDM, days	32 [28–39]
	Time between ATB start and TDM, days	4.5 [2–5]
	Pathogen type - EBSL Enterobacteriaceae	2 (14.2%)
	Pathogen type - MDR Pseudomonas aeruginosa	11 (78.5%)
	Pathogen type - Class A Carbapenemase Enterobacteriaceae	0
	Pathogen type - Class B Carbapenemase Enterobacteriaceae	5 (35.7%)
	Pathogen type - Class D Carbapenemase Enterobacteriaceae	1 (7.1%)
	Outcomes - Cure of infection	3 (21%)
	Outcomes - Mortality	14 (58%)
Results		Ceftazidime	Avibactam
	Above predefined cut-off	22/23 (96%)	14/23 (61%)
	Below predefined cut-off	1/23 (4%)	9/23 (39%)
	Increased renal clearance associated with below cut-off	1/1	6/9
Adverse Events	Not specified
Study Author Conclusions	Ceftazidime and avibactam serum levels were above EUCAST breakpoints in most cases, justifying the use of normal dosing in ECMO patients. Increased renal clearance may lead to underdosing, highlighting the importance of monitoring trough levels, especially in patients with increased eGFR.
Critique	The study's strengths include its focus on a specific patient population and the identification of increased renal clearance as a factor for underdosing. However, limitations include its retrospective design, small sample size, lack of a control group, and absence of data on tissue antibiotic levels. The study also lacks detailed PK measurements and has limited interpretability regarding MIC and Cmin relationships.

References:
[1] [1] Curtiaud A, Petit M, Chommeloux J, et al. Ceftazidime/avibactam serum concentration in patients on ECMO. J Antimicrob Chemother. 2024;79(5):1182-1186. doi:10.1093/jac/dkae091

Pharmacokinetic/Pharmacodynamic of ceftolozane/tazobactam in critically ill patients receiving extracorporeal membrane oxygenation (ECMO): a retrospective cohort analysis
Design	Single-center, observational, retrospective study N= 42
Objective	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
Study Groups	ECMO patients (n= 39) Weaned ECMO patients (n= 3)
Inclusion Criteria	Patients who received ceftolozane/tazobactam as empirical therapy for ≥ 48 h while undergoing ECMO
Exclusion Criteria	Not explicitly stated
Methods	C/T dosing regimens were adjusted to renal function, with 45% receiving the highest dose (2 g/1 g q8h). PK parameters were measured, including trough, peak, and CT50 concentrations. PK/PD target attainment was calculated using predefined MIC thresholds.
Duration	Not explicitly stated
Outcome Measures	Primary: C/T PK parameters (trough, peak, CT50) Secondary: PK/PD target attainment using predefined MIC thresholds
Baseline Characteristics		All patients (n= 42)
	Sex - Female	9 (21%)
	Sex - Male	33 (79%)
	Age, years	50 [38–58]
	Weight, kg	85 [69–97]
	BMI, kg/m²	27 [23–33]
	SAPS II	56 [45–68]
	McCabe & Jackson score for comorbidity - 0	27 (64%)
	McCabe & Jackson score for comorbidity - 1	6 (14%)
	McCabe & Jackson score for comorbidity - 2	5 (12%)
	McCabe & Jackson score for comorbidity - 3	4 (9.5%)
	SOFA	14.0 [10.0, 16.0]
	Renal replacement therapy at the time of C/T measurement	16 (38%)
	Intermittent hemodialysis	4 (10%)
	Continuous veno-venous hemodiafiltration	12 (29%)
	Creatinine clearance, mL/min > 150	7 (17%)
	Creatinine clearance, mL/min > 80 to ⩽150	8 (19%)
	Creatinine clearance, mL/min > 30 to ⩽80	6 (14%)
	Creatinine clearance, mL/min ⩽30*	21 (50%)
	ECMO type - veno-arterial	27 (64%)
	ECMO type - veno-venous	15 (36%)
	Indication for ECMO support - Cardiogenic shock	25 (59.2%)
	Indication for ECMO support - Acute right heart failure	2 (4.8%)
	Indication for ECMO support - ARDS	15 (36%)
	ECMO status at the time of C/T measurement - On ECMO support	39 (93%)
	ECMO status at the time of C/T measurement - ECMO weaned	3 (7.1%)
	Delay between ICU admission and infection (days)	12 [6–16]
	Delay between ECMO implantation and infection (days)	9 [4–15]
	Oxygenator lifespan at the time of C/T measurement (days)	9 [5–13]
	Indication for antibiotic initiation - Suspected pneumonia	32 (76%)
	Indication for antibiotic initiation - Suspected ECMO-related cannula infections	10 (24%)
	Indication for antibiotic initiation - Bloodstream infection	1 (2.4%)
	Indication for antibiotic initiation - Septic shock	1 (2.4%)
	Prior antibiotic therapy	39 (93%)
	Ceftolozane/tazobactam dosing - 0.5 g/0.25 g q8h	18 (43%)
	Ceftolozane/tazobactam dosing - 1 g/0.5 g q8h	5 (12%)
	Ceftolozane/tazobactam dosing - 2 g/1 g q8h	19 (45%)
	28-day survival rate	29 (69%)
Results		ECMO patients (N= 39)	Weaned patients (N= 3)
	Ceftolozane trough (mg/L)	21.2 [11.4–43.5]	9.9 [9.6–52.8]
	100% f T > MIC	38/38 (100%)	3/3 (100%)
	100% f T > 4 ×MIC	23/38 (61%)	1/3 (33%)
	Ceftolozane peak (mg/L)	68.7 [29.7–95.9]	55.2 [54.1-102.4]
	Ceftolozane CT50 (mg/L)	42.4 [19.3–63.5]	34.2 [32.9–54.5]
	Tazobactam trough (mg/L)	0.6 [0-2.9]	0 [0-3.2]
	100% f T > CT	15/30 (50%)	1/3 (33%)
Adverse Events	Not explicitly stated
Study Author Conclusions	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. IHD was associated with supra-therapeutic ceftolozane levels, while CVVHDF correlated with suboptimal exposure. Augmented renal clearance significantly reduced ceftolozane troughs, whereas severe renal impairment caused accumulation.
Critique	The study's monocentric design and potential survivorship bias limit its generalizability. The small post-ECMO cohort introduces confounding biases, and findings for the IHD subgroup are exploratory due to small numbers and wide confidence intervals.

References:
[1] [1] 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. 2025;29(1):391. Published 2025 Aug 31. doi:10.1186/s13054-025-05641-y

Ceftolozane-Tazobactam Pharmacokinetics during Extracorporeal Membrane Oxygenation in a Lung Transplant Recipient
Design	Case report
Case presentation	A 42-year-old woman with a history of stage IV pulmonary sarcoidosis and alpha-1 antitrypsin deficiency was admitted for acute respiratory failure. After initial empirical antibiotics failed to improve her condition, she was placed on veno-venous ECMO (VV-ECMO) when a tracheal aspirate culture confirmed carbapenem-resistant Pseudomonas aeruginosa. On day 13, she underwent bilateral lung transplantation, during which her support was switched to veno-arterial ECMO (VA-ECMO). Post-operatively, she was started on ceftolozane/tazobactam (C/T) at 2 g/1 g every 8 hours (a 1-hour infusion) combined with ciprofloxacin and vancomycin. Despite being on ECMO, therapeutic drug monitoring over the first 96 hours showed that ceftolozane trough concentrations remained well above the minimum inhibitory concentration (MIC) of 4 µg/mL, with levels initially exceeding 100 µg/mL and later stabilizing above 60 µg/mL. Tazobactam levels also remained consistently above 1.9 µg/mL. VA-ECMO was discontinued on post-operative day 8, and the patient's respiratory status improved. Antibiotics were stopped on day 15, and subsequent tracheal aspirate cultures confirmed clearance of the infection.
Study Author Conclusions	Our findings suggest that optimal ceftolozane-tazobactam C/T PK parameters can be achieved in severely ill patients with normal renal function requiring ECMO, without the need for dose or infusion time adjustment.

References:
[1] [1] Arena F, Marchetti L, Henrici De Angelis L, et al. Ceftolozane-Tazobactam Pharmacokinetics during Extracorporeal Membrane Oxygenation in a Lung Transplant Recipient. Antimicrob Agents Chemother. 2019;63(3):e02131-18. Published 2019 Feb 26. doi:10.1128/AAC.02131-18