# Ceftazidime–Avibactam Pharmacokinetic Comparative In Vivo/In Vitro Study in a Critically Ill Children Under High-Volume Continuous Venovenous Hemodiafiltration

Michael Thy, Alexandre Debs, Gabrielle Lui, Leo Froelicher-Bournaud, Jean-marc Tréluyer, Mehdi Oualha

► To cite this version:

Michael Thy, Alexandre Debs, Gabrielle Lui, Leo Froelicher-Bournaud, Jean-marc Tréluyer, et al. Ceftazidime–Avibactam Pharmacokinetic Comparative In Vivo/In Vitro Study in a Critically Ill Children Under High-Volume Continuous Venovenous Hemodiafiltration. Pharmacology Research & Perspectives, 2025, 13 (4), pp.e70139. 10.1002/prp2.70139. hal-05464275

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# Ceftazidime-Avibactam Pharmacokinetic Comparative *in vivo/in vitro* study in a Critically Ill Children Under High-Volume Continuous Venovenous Haemodiafiltration

Michael Thy<sup>1,2,3</sup>, Alexandre Debs<sup>4</sup>, Gabrielle Lui<sup>2,5</sup>, Leo Froelicher-Bournaud<sup>2,5</sup>, Jean-Marc Tréluyer<sup>2,5,6</sup>, Mehdi Oualha<sup>2,4</sup>

1 Service de Médecine Intensive et Réanimation Infectieuse, Hôpital Bichat Claude-Bernard, AP-HP, Université Paris Cité, 75018, Paris, France.

2 UMR 1343, Evaluation des thérapeutiques et pharmacologie périnatale et pédiatrique, INSERM, Université Paris Cité, 75014, Paris, France

3 UMR 1137, IAME, INSERM, Université Paris Cité, Paris, France

4 Service de réanimation et surveillance continue médicochirurgicales, Hôpital Necker Enfants-Malades, AP-HP, Université Paris Cité, 75015, Paris, France

5 Service de pharmacologie clinique, Hôpital Cochin, AP-HP, Université Paris Cité, 75014, Paris, France

6 Unité de Recherche Clinique-Centre d'Investigation Clinique, CIC1419, Hôpital Cochin-Necker, AP-HP, Université Paris Cité, 75015, Paris, France

Corresponding author: Dr Michaël Thy, michael245thy@gmail.com

Statements and Declarations: None to declare
**Bullet point summary:**

**What is already known about this subject**

* Ceftazidime-avibactam is a novel cephalosporin/B-lactamase inhibitor combination developed to address increasing antimicrobial resistance.

* The pharmacokinetics of ceftazidime-avibactam under continuous renal replacement therapy (CRRT) have been described in few adult studies but not in paediatric patients.

* *In vitro* studies can provide valuable insights into the pharmacokinetic behaviour of drugs under CRRT conditions.

**What this study adds**

* This study provides a comprehensive comparison of the pharmacokinetics of ceftazidime-avibactam in a critically ill children under CRRT with *in vitro* data.

* The results confirm the importance of therapeutic drug monitoring and the need for higher dosing or continuous infusion of ceftazidime-avibactam in critically ill children under CRRT.

* The study underscores the utility of *in vitro* experiments in predicting the pharmacokinetic behaviour of drugs under CRRT conditions.

**ABSTRACT**

Ceftazidime-avibactam is a novel cephalosporin/B-lactamase inhibitor combination developed to address increasing antimicrobial resistance. This report presents a comparative study of the pharmacokinetics of Ceftazidime and Avibactam, utilizing in vitro data derived from two experiments with Continuous Venovenous Haemodiafiltration (CVVHDF) simulation and a comparison with a previous published in vivo case report. The results highlight the importance of therapeutic drug monitoring and the need for higher dosing or continuous infusion of ceftazidime-avibactam in critically ill children under CRRT.
**Introduction**

Ceftazidime-avibactam is a novel cephalosporin/B-lactamase inhibitor combination developed to address the increasing prevalence of multidrug-resistant Gram-negative (MDR-GN) pathogens¹,². Its use in paediatric patients was approved by the US Food and Drug Administration in 2019 for intra-abdominal infections, and recent literature reviews have demonstrated its efficacy and safety in various MDR-GN infections³,⁴. The pharmacokinetics (PK) of ceftazidime-avibactam under continuous renal replacement therapy (CRRT) have been described in a few adult cases, but data in paediatric patients are limited⁵. This study aims to describe the PK of ceftazidime-avibactam with in vitro data derived from two experiments with continuous veno-venous hemodiafiltration (CVVHDF) simulation then compare *in vitro* results with a previous published in vivo case report a critically ill paediatric patient undergoing CRRT.

**Methods**

**In Vivo Study**

The in vivo data were obtained from a case report of a 6-month-old, 8-kg-weighed, female with sepsis due to *Stenotrophomonas maltophilia* infection following stem cell transplantation⁵. The patient was treated with ceftazidime-avibactam every 8 hours with a 2-hour infusion of 30–7.5 mg/kg.

Residual diuresis during CVVHDF remained stable at approximately 0.5 mL/kg/h. CVVHDF was performed using the Prismaflex system machine® (Baxter Int, SE) with an ST 60 set®. Phoxilium was used as both the dialysate and replacement solution. Anticoagulation was avoided due to hemorrhagic risk and liver failure. The blood flow rate was maintained at 80 mL/min (10 mL/kg/min), with a dialysate flow rate of 300 mL/h (37.5 mL/kg/h), replacement flow rate of 600 mL/h (75 mL/kg/h), and net ultrafiltrate flow rate ranging from 30 to 40 mL/h (3.75–5 mL/kg/h). This resulted in a total effluent rate of 930–940 mL/h (116.2–117.5 mL/kg/h), a critical parameter impacting drug clearance.

**In Vitro Study**

In vitro experiments were conducted to simulate the conditions of CRRT⁶. The experiments were performed using the Prismaflex system machine® (Baxter Int, SE) with an ST 60 set®. Dialysate and replacement solutes were Phoxilium. No anticoagulation was administered. The weigh was set to 8kg, the blood flow rate to 80 mL/min (10 mL/kg/min for an 8 kg patient); dialysate flow rate to 300 mL/h (37.5 mL/kg/h); replacement flow rate to 600 mL/h (75 mL/kg/h) and net ultrafiltrate flow rate to 35 mL/h (4.4 mL/kg/h). The total effluent rate was 935 mL/h (117.5 mL/kg/h).

The circuit was primed with 1L of 0.9% NaCl containing heparin to prevent clotting. Ceftazidime-Avibactam were both prepared at a concentration of 50 mg/L by adding 250 mg of each antibiotic to 5L of Phoxilium.

An adsorption and steady state phase of 60 minutes was conducted by running the CVVHDF system with the only antibiotic solution circulating. After this initial phase, sample collections were collected at multiple time points (0 to 360 minutes) to assess drug concentration decay over time from four distinct sites: pre-filter (E), post-filter (S), effluent (F), and the reservoir as a control (T). Each sample underwent analysis to measure the concentrations of
Ceftazidime-Avibactam using validated high-performance liquid chromatography techniques, allowing for accurate monitoring of pharmacokinetic changes over time.

## Results

In vitro data for ceftazidime and avibactam are summarized in Table 1, showing the median and interquartile ranges for the concentrations at different time points.

Blood samples were collected at various time points to evaluate the pharmacokinetics of the administered drugs during CVVHDF. Timepoint 0 represents the baseline sample taken immediately before antibiotic administration. Timepoint 30 was collected 30 minutes after drug administration to assess the initial concentration and potential adsorption by the CVVHDF filter. Timepoint 60 was collected at 60 minutes before initiation of the CRRT by CVVHDF. Timepoints 75 to 360 were obtained at regular intervals (every 15 to 30 minutes) to capture both the distribution and elimination phases of the drug. This sampling strategy provided comprehensive monitoring of the drug's pharmacokinetics over time (Figure 1 and Table 1). A comparison with the in vivo case report is displayed in Table 2.

## Discussion

The *in vitro* data provide valuable insights into the pharmacokinetics of ceftazidime-avibactam under CRRT conditions. The *in vitro* data showed a significant decrease in the concentrations of ceftazidime and avibactam over time, particularly in the pre-filter and post-filter samples. This confirms that the drugs are being effectively removed by the CRRT system, which is consistent with the high clearance rates observed in the *in vivo* study. The effluent samples also showed a significant decrease in the concentrations of both drugs, indicating that the drugs are being eliminated through the CRRT system. The significant decrease in the concentrations of ceftazidime and avibactam over time suggests that higher dosing or continuous infusion may be necessary to maintain therapeutic levels and prevent the development of microbiological resistance. The *in vitro* data also highlight the importance of therapeutic drug monitoring in critically ill patients undergoing CRRT.

The *in vitro* clearances (CLCRRT) for both ceftazidime and avibactam were less variable than the corresponding *in vivo* CRRT clearances. This aligns with the hypothesis that the *in vitro* model corresponds to an ideal PK model due to the absence of complicating factors such as blood, albumin, and clotting, which can hinder filter efficiency *in vivo*.

*In vivo* total clearance (CL) is known to surpass CRRT clearance (CLCRRT) due to residual endogenous elimination pathways such as residual renal function. While *in vitro* models provide valuable experimental control and are instrumental in developing physiologically based pharmacokinetic (PBPK) models, they lack the contribution of these endogenous processes, emphasizing their limitations. Furthermore, *in vitro* models demonstrate lower variability compared to *in vivo* data, reflecting their reproducibility and precision. However, this reduced variability highlights the need to account for the more complex and variable conditions present in clinical settings when interpreting *in vitro* findings.

Thus, while *in vitro* models offer significant advantages for hypothesis testing and parameter estimation, they complement rather than replace *in vivo* studies, which remain essential for capturing the full spectrum of pharmacokinetic variability in patients⁷.
**Conclusion**

The *in vitro* data provide valuable insights into the pharmacokinetics of ceftazidime-
avibactam under CRRT conditions in critically ill children, highlighting the importance of
therapeutic drug monitoring and the need for higher dosing or continuous infusion in this
context. The study underscores the utility of *in vitro* experiments in predicting the clearance
of drugs by CRRT.
**Funding**

Michael Thy received a grant from the "société de reanimation de langue française" (SRLF) supporting research on this topic. The study received a grant from Baxter™.

**Conflicts of Interest/Competing Interests**

The authors declare that they have no conflict of interest.

**Ethics approval and Consent to Participate**

Not applicable as an *in vitro* study, no patient was involved in the study.

**Availability of Data, Material and Code Availability**

All data generated or analyzed during this study are included in this study or its supplementary material files. Further inquiries can be directed to the corresponding author.

**Authors' Contributions and Consent for Publication**

MT and MO conceived the study and the *in vitro* model. MT and AD collected the data.

LF and GL performed the dosages. MT and MO contributed to acquisition, analysis, and interpretation of the results. MT and MO drafted the manuscript and critically revised the manuscript.

All authors critically revised the manuscript and consent for publication.
References

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doi:10.1016/j.cmi.2022.01.030

2. Paul M, Carrara E, Retamar P, et al. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). *Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis.* 2022;28(4):521-547. doi:10.1016/j.cmi.2021.11.025

3. Zavicecka | European Medicines Agency (EMA). 14 July 2016. Accessed January 5, 2025.
https://www.ema.europa.eu/en/medicines/human/EPAR/zavicecka

4. Research C for DE and. Ceftazidime avibactam Injection. FDA. Published online 26 January 2023. Accessed January 5, 2025. https://www.fda.gov/drugs/development-resources/ceftazidime-avibactam-injection

5. Collignon C, Benaboud S, Gana I, et al. Pharmacokinetic of ceftazidime-avibactam in a critically ill patient under high-volume continuous venovenous haemodiafiltration: A first paediatric case report. *Br J Clin Pharmacol*. Published online 4 January 2024.
doi:10.1111/bcp.15993

6. Thy M, Kecili F, Urien S, et al. Impact of pediatric continuous renal replacement therapy parameters on meropenem, piperacillin, and tazobactam pharmacokinetics: an in vitro model. *Expert Opin Drug Metab Toxicol*. Published online 22 December 2024:1-9.
doi:10.1080/17425255.2024.2443754

7. Oualha M, Thy M, Bouazza N, Benaboud S, Béranger A. Drug dosing optimization in critically ill children under continuous renal replacement therapy: from basic concepts to the bedside model informed precision dosing. *Expert Opin Drug Metab Toxicol*. Published online 4 November 2024:1-18. doi:10.1080/17425255.2024.2422875
Summary of Figure and Tables

**Figure 1: Concentration dynamics of Ceftazidime and Avibactam over time under CVVHDF**

Legends: grey line for control sample (T), yellow line for pre-filter sample (E), orange line for post-filter sample (S), blue line for effluent sample (F)

**Table 1: Median concentrations with interquartile range of Ceftazidime and Avibactam in each sample type under CVVHDF**

**Table 2: Comparison of *in vivo* and *in vitro* clearances for Ceftazidime and Avibactam**