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

Phase 4

Not yet recruiting

• Conditions: Severe Infection
• Interventions: Drug: Continuos ceftazidime/avibactam infusion; Drug: Intermitent dosing as per SMPC

• Registration Number: NCT06811727
• Lead Sponsor: Ivan Šitum, MD

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-01-28
• Study First Submitted QC: 2025-01-31
• Study First Posted: 2025-02-06
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-19
• Last Update Posted: 2025-04-22
• Study Start: 2025-05-01
• Primary Completion: 2027-05-01
• Study Completion: 2027-08-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 140

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Continuos ceftazidime/avibactam infusion	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
Intermitent dosing as per SMPC	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.

Primary Outcome Measures

Name	Time	Method
microbiological success rate	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.

Secondary Outcome Measures

Name	Time	Method
clinical success rate	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.
length of ICU stay	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)
length of hospital stay	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)
time to weaning from mechanical ventilation	28 days	time in hours from the start of the trial to the end of mechanical ventilation
time to symptoms improvement	28 day	Patients who achieve clinical cure or clinical improvement
all-cause 28-day mortality after ceftazidime/avibactam initiation	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.
pathogen recurrence rate on day 28	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.
cumulative vasoactive-inotropic score (VIS)	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.