Severe Infection
Conditions
Keywords
ceftazidime/avibactam, continuous infusion, critically ill, ICU, Klebsiella pneumoniae OXA-48, Pseudomonas aeruginosa
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.
Interventions
DRUGContinuos 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
DRUGIntermitent 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.
Sponsors
UHC Zagreb, Zagreb, Croatia
Daniel Lovrić
Mirna Momčilović
Ivan Šitum, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
Patients will not be informed of their group assignment to maintain study integrity. We opted for this study design, which is not fully blinded, for several practical and clinical reasons. First, the dosing regimen of the drug is complex. According to the SmPC, ceftazidime/avibactam is administered as a prolonged infusion over 2 hours every 8 hours. In a placebo-controlled design, all patients would require an additional infusion, either placebo or the active drug, following the initial 2-hour infusion. By not including a placebo, the control group will follow the SmPC dosing regimen (2-hour infusions every 8 hours), while the intervention group will receive the drug as a continuous infusion over 24 hours. Second, the study involves administration in cardiac and cardiac surgery intensive care units, where patients are at a more significant risk of volume overload. The study was designed without a placebo-controlled arm to minimise unnecessary fluid administration.
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| time to weaning from mechanical ventilation | 28 days | time in hours from the start of the trial to the end of mechanical ventilation |
| 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. |
| time to symptoms improvement | 28 day | Patients who achieve clinical cure or clinical improvement |
| 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) |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| the ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC) | 28 day | The ratio of ceftazidime plasma concentration to the pathogen's minimum inhibitory concentration (C/MIC). |
| adverse events | 28 day | Any adverse event that can be attributed to ceftazidime/avibactam |
Contacts
Primary ContactIvan Šitum, MD
Backup ContactDaniel Lovrić, MD, PhD
Outcome results
None listed