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

Ivan Šitum, MD

Status and phase: Not yet enrolling; Phase 4

Conditions: Severe Infection

Treatments: Drug: Intermitent dosing as per SMPC; Drug: Continuos ceftazidime/avibactam infusion

Study type: Interventional

Funder types: Other

Identifiers

NCT06811727

ZAVICONT01

Details and patient eligibility

About

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.

Enrollment: 140 estimated patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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140 participants in 2 patient groups

Continuos ceftazidime/avibactam infusion

Experimental group

Description:

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

Treatment:

Drug: Continuos ceftazidime/avibactam infusion

Intermitent dosing as per SMPC

Active Comparator group

Description:

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.

Treatment:

Drug: Intermitent dosing as per SMPC