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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
140
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
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.
microbiological success rate
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.
Time frame: 28 days
clinical success rate
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.
Time frame: 28 day
time to symptoms improvement
Patients who achieve clinical cure or clinical improvement
Time frame: 28 day
length of ICU stay
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)
Time frame: 28 day
length of hospital stay
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 frame: 28 day
all-cause 28-day mortality after ceftazidime/avibactam initiation
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.
Time frame: 28 day
pathogen recurrence rate on day 28
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.
Time frame: 28 day
time to weaning from mechanical ventilation
time in hours from the start of the trial to the end of mechanical ventilation
Time frame: 28 days
cumulative vasoactive-inotropic score (VIS)
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.
Time frame: 28 day
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