CONTinuous Infusion Versus Intermittent Dosing of ceftaZidime/AVIbactam in Critically Ill Patients (ZAVICONT)

April 19, 2025 updated by: Ivan Šitum, MD

CONTinuous Infusion Versus Intermittent Dosing of ceftaZidime/AVIbactam in Critically Ill Patients With Klebsiella Pneumoniae OXA-48 or Pseudomonas Aeruginosa Infections: A Single-centre Randomized Open-label Trial (ZAVICONT)

Ceftazidime/avibactam (CZA) is an essential treatment option for managing infections caused by multidrug-resistant (MDR) gram-negative (G-) bacteria, including Klebsiella pneumoniae OXA-48 and carbapenem-resistant Pseudomonas aeruginosa. Critically ill intensive care unit (ICU) patients frequently exhibit altered pharmacokinetics (PK) of CZA, potentially compromising optimal PK/pharmacodynamic (PD) target attainment with standard dosing regimens. This study compares the efficacy of continuous infusion (CI) versus conventional intermittent dosing (ID) of CZA in critically ill ICU patients with severe infections caused by K. pneumoniae OXA-48 or P. aeruginosa.

This single-centre, randomized, open-label trial will be conducted at a tertiary care hospital within the University Hospital Centre in Zagreb, Croatia, with a 1:1 allocation ratio. One hundred forty critically ill ICU patients requiring CZA treatment will be randomized to receive either ID (2 g/0.5 g every 8 hours over 2 hours) or an equivalent dose in CI (6 g/1.5 g continuously over 24 hours).

The primary outcome is the microbiological success rate. Secondary outcomes include clinical success rate, time to symptom improvement, length of ICU and hospital stay, 28-day all-cause mortality, pathogen recurrence rate, time to weaning from mechanical ventilation, cumulative vasoactive-inotropic score, adverse events, and the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC).

This trial seeks to provide evidence on the optimal administration strategy for CZA in critically ill ICU patients with severe infections due to MDR G- pathogens.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

140

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. General

    1. Age above or equal to 18 years of age.
    2. Able to provide informed consent personally or by his/her next of kin, as requested by the Ethics Committee.

  2. Disease-specific

    1. Critically ill patients requiring admission to the intensive care unit (medical or surgical).
    2. Diagnosed with severe infections.
    3. At least one microbiological sample positive for Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa.
    4. Requiring a prescription for ceftazidime/avibactam, by clinical judgement

Exclusion Criteria:

  1. General

    1. Known or suspected hypersensitivity to ceftazidime/avibactam, excipients, or any other cephalosporin antibacterial agent. Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).
    2. Withdrawal of informed consent.
    3. Age above 85 years of age.
    4. Female who is pregnant or breast-feeding.
    5. Participation (i.e. signed informed consent) in any other interventional clinical trial of an approved or non-approved antibacterial agent within 30 days before screening.
    6. Any disorder which, in the investigator's opinion, might jeopardize the participant's safety or compliance with the protocol.

  2. Laboratory values

    1. Severe neutropenia before or during ceftazidime/avibactam administration.

  3. Medical conditions

    1. Death within 48 hours following randomization.
    2. Concomitant acquired immunodeficiency syndrome.
    3. Presence or history of malignant neoplasms or in situ carcinomas.
    4. Duration of ceftazidime/avibactam administration is shorter than 72 hours.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Continuos ceftazidime/avibactam infusion
Continuous infusion will include a loading dose of 2 g/0.5 g administered over 2 hours, followed by continuous infusion of 6 g/1.5 g over 24 hours, equivalent to 0.25 g of ceftazidime per hour. The drug reconstitution and dilution process are shown in Figure 2. The final volume of a solution of CZA will be 50 mL, which gives the concentration of ceftazidime 40 mg/mL, with a 4:1 concentration ratio for avibactam (10 mg/mL). The solution will be administered via an infusion syringe with an infusion rate of 6.25 mL/h. Dose adjustments will be applied according to renal function, calculated using the Cockroft-Gault formula
Drug: Continuos ceftazidime/avibactam infusion
Continuous infusion will include a loading dose of 2 g/0.5 g administered over 2 hours, followed by continuous infusion of 6 g/1.5 g over 24 hours, equivalent to 0.25 g of ceftazidime per hour. The drug reconstitution and dilution process are shown in Figure 2. The final volume of solution of CZA will be 50 mL, which gives concentration of ceftazidime of 40 mg/mL, with 4:1 concentration ratio for avibactam (10 mg/mL). The solution will be administered via an infusion syringe, with an infusion rate of 6.25 mL/h. Dose adjustments will be applied according to renal function, calculated using Cockroft-Gault formula
Active Comparator: Intermitent dosing as per SMPC
Intermittent dosing, as outlined in the SmPC, consists of 2 g/0.5 g administered by prolonged infusion over 2 hours every 8 hours. Dose adjustments will be applied according to renal function, calculated using the Cockroft-Gault formula.
Drug: Intermitent dosing as per SMPC
Intermittent dosing, as outlined in the SmPC, consists of 2 g/0.5 g administered by prolonged infusion over 2 hours every 8 hours. Dose adjustments will be applied according to renal function, calculated using Cockroft-Gault formula.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
microbiological success rate
Time Frame: 28 days
The aim of this study is to investigate efficacy of continuous infusion of ceftazidime/avibactam compared to conventional intermittent dosing, in treating critically ill ICU patients with severe infections caused by Klebsiella pneumoniae OXA-48 or Pseudomonas aeruginosa. The primary outcome of the study is microbiological success rate, defined by proportion of patients in whom the causative pathogen is absent from specimen at the site of infection.
28 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
clinical success rate
Time Frame: 28 day

The clinical success rate is the proportion of patients who achieve clinical cure or clinical improvement evaluated at the end of therapy.

Clinical cure is the complete resolution of all signs and symptoms, with no evidence of ongoing infection. Clinical improvement is a significant reduction in infection-related signs and symptoms such that the patient demonstrates considerable progress towards recovery.
28 day
time to symptoms improvement
Time Frame: 28 day
Patients who achieve clinical cure or clinical improvement
28 day
length of ICU stay
Time Frame: 28 day

Length of ICU stay is defined as the total number of days from the day of the first CZA administration (study day on 0) until either:

Discharge from the ICU (if the patient is transferred out of the ICU before day 28) Day 28 (for patients who remain in the ICU beyond this time)
28 day
length of hospital stay
Time Frame: 28 day

Length of hospital stay is defined as the total number of days from the day of the first CZA administration (study day on 0) until either:

Discharge from the hospital (if the patient is discharged before day 28) Day 28 (for patients who remain hospitalized beyond this time)
28 day
all-cause 28-day mortality after ceftazidime/avibactam initiation
Time Frame: 28 day
All-cause 28-day mortality is defined as death at any point up to and including study day 28. The 28-day mortality rate will be calculated as the number of deaths divided by the total number of patients in the group, expressed as a percentage.
28 day
pathogen recurrence rate on day 28
Time Frame: 28 day
The pathogen recurrence rate on day 28 is defined as the proportion of patients who have a recurrence of the initial causative pathogen from clinical or surveillance microbiological samples taken by study day 28 after completion of CZA therapy.
28 day
time to weaning from mechanical ventilation
Time Frame: 28 days
time in hours from the start of the trial to the end of mechanical ventilation
28 days
cumulative vasoactive-inotropic score (VIS)
Time Frame: 28 day

The vasoactive-inotropic score is a quantitative measure that evaluates the cumulative effect of vasoactive and inotropic medications. It is calculated using the following formula:

VIS = dobutamine dose (μg/kg/min) + adrenaline dose (μg/kg/min) x 100 + noradrenaline dose (μg/kg/min) x 100 + vasopressin dose (IU/kg/min) x 10 + angiotensin II dose (ng/kg/min) x 10000 24-hour VIS quantifies the overall cardiovascular support required over 24 hours. The average daily VIS score will be calculated using the following formula: Daily VIS=∑ (VIS for each interval × interval duration (hours)/24 An interval is defined as the period where drug doses remain constant.
28 day

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
adverse events
Time Frame: 28 day
Any adverse event that can be attributed to ceftazidime/avibactam
28 day
the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC)
Time Frame: 28 day
The ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC).
28 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ivan Šitum, MD

Collaborators

UHC Zagreb, Zagreb, Croatia
Daniel Lovrić
Mirna Momčilović

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2025

Primary Completion (Estimated)

May 1, 2027

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

January 28, 2025

First Submitted That Met QC Criteria

January 31, 2025

First Posted (Actual)

February 6, 2025

Study Record Updates

Last Update Posted (Actual)

April 22, 2025

Last Update Submitted That Met QC Criteria

April 19, 2025

Last Verified

April 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ZAVICONT01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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