Early Optimization of Ceftazidime Regimen in Critical Care

Not Applicable

Not yet recruiting

• Conditions: Infection in ICU; Sepsis; Septic Shock; Pseudomonas Aeruginosa Infection
• Interventions: Drug: ceftazidime; Biological: plasma ceftazidime dosage

• Registration Number: NCT07085624
• Lead Sponsor: Centre Hospitalier Universitaire de Saint Etienne

Brief Summary

Hospital-acquired infections, most of which are caused by Gram-negative bacteria, are common in intensive care units and have a major impact on patient prognosis. Patient survival in severe sepsis and septic shock depends on the early administration of appropriate antibiotic therapy, with mortality increasing by 7.6% for each hour of delay, justifying the probabilistic use of broad-spectrum antibiotics such as ceftazidime, an essential betalactamine, particularly used for its activity against Pseudomonas aeruginosa, a frequent pathogen in nosocomial infections.

It is currently recommended that ceftazidime should initially be administered as a 2g loading dose, followed by maintenance treatment by continuous infusion, at a dose adapted to renal function.

The recommended dosage regimen, with its 2g loading dose, was developed using the median value of parameters from a pharmacokinetic model. This explains the findings of many critical care studies, which have found that 40-60% of patients initially have concentrations below target with the recommended dosing regimen.

In the context of critical care, maintaining concentrations within the target therapeutic range is difficult due to variations in the elimination clearance of ceftazidime. Ceftazidime is mainly eliminated by the kidneys. Critical patients may have increased glomerular filtration rate, or, conversely, impaired renal function, with rapid variations in the event of severe infection. This leads to high intra- and inter-individual variability, and increases the risk of antibiotic under- or overdose when the maintenance dose is administered at a fixed dose (6g/d continuously). This high variability can also be observed in the volume of distribution (capillary leakage, oedema, perfusion volumes, effusions ...).

In order to propose an individualised dosing regimen, we therefore propose an iterative randomised study to :

* Step 1: FORTOPTIM_1 Evaluation of an optimised dosage regimen based on literature data compared with the standard psological regimen.

* Step 2: FORTOPTIM_2 Build a pharmacokinetic model from the prospective data obtained in step 1. Based on this model, an individualised dosage regimen (loading dose and maintenance dose) will be obtained for step 3.

* Step 3: FORTOPTIM_3 Prospectively evaluate in a randomised trial the individualised dosing regimen previously defined (Step 2) by comparing it to the best dosing regimen determined in Step 1 or to the standard dosing regimen if there is no significant difference in Step 1.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2025-03-25
• Status Verified: 2025-07
• Study First Submitted QC: 2025-07-24
• Last Update Submitted: 2025-07-24
• Study First Posted: 2025-07-25
• Last Update Posted: 2025-07-25
• Study Start: 2025-09-01
• Primary Completion: 2026-11
• Study Completion: 2026-11-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 128

Inclusion Criteria

Not provided

Exclusion Criteria

• Pregnant woman, parturient, nursing mother;
• Person deprived of liberty, hospitalized without consent,
• Adults under legal protection (guardianship-curatorship)
• Patients undergoing extra-renal purification or whose CKD-EPI at the start of treatment is less than 15 ml/min.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
ceftazidime standard dosage regimen	ceftazidime	Loading dose 2g Maintenance dose : 6g/d if GFR (Glomerular Filtration Rate) ≥ 60 3g/d if GFR between 30 and 60 1.5g/d if GFR between 15 and 30
ceftazidime standard dosage regimen	plasma ceftazidime dosage	Loading dose 2g Maintenance dose : 6g/d if GFR (Glomerular Filtration Rate) ≥ 60 3g/d if GFR between 30 and 60 1.5g/d if GFR between 15 and 30
ceftazidime optimised dosage regimen	ceftazidime	Loading dose 4g Maintenance dose : 6g/d if GFR (Glomerular Filtration Rate) ≥ 60 3g/d if GFR between 30 and 60 1.5g/d if GFR between 15 and 30
ceftazidime optimised dosage regimen	plasma ceftazidime dosage	Loading dose 4g Maintenance dose : 6g/d if GFR (Glomerular Filtration Rate) ≥ 60 3g/d if GFR between 30 and 60 1.5g/d if GFR between 15 and 30

Primary Outcome Measures

Name	Time	Method
Percentage of subjects with a ceftazidime concentration equal to or above the target concentration threshold (35 mg/L) at both 3h and 24h after the first administration, and below the toxicity threshold of 100 mg/L.	24 hours

Secondary Outcome Measures

Name	Time	Method
Patient severity assessed using the SOFA (Sequential Organ Failure Assessment Score)	day 7	SOFA score from 0 to 24 The higher the score (24), the greater the incidence of organ failure
death	day 28
Occurrence of neurological adverse events defined as: seizure, myoclonus, encephalopathy or delirium, altered consciousness (Glasgow score)	day 28
Occurrence of an overdose defined as a concentration greater than 100 mg/L.	day 28
Renal function assessment	day 28	creatinine clearance (mL/mn) with the CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration) equation
Time to reach PK/PD (pharmacokinetics/pharmacodynamics) targets	24 hours

Trial Locations

Locations (8)

CHU GRENOBLE, Médecine intensive; 🇫🇷 Grenoble, France

HCL Croix Rousse, Médecine intensive réanimation; 🇫🇷 Lyon, France

HCL Hôpital Edouard Herriot, Médecine intensive et réanimation; 🇫🇷 Lyon, France

CHU Nord, Médecine intensive et réanimation; 🇫🇷 Marseille, France

HCL Hôpital Lyon Sud, Médecine intensive réanimation; 🇫🇷 Pierre Benite, France

CHU ST-ETIENNE - Médeine Intensive Réanimation; 🇫🇷 St-etienne, France

CHU ST-ETIENNE, Médecine intensive Réanimation B; 🇫🇷 St-etienne, France

CHU ST-ETIENNE, Réanimation Néphrologie; 🇫🇷 St-etienne, France