Early Optimization of Ceftazidime Regimen in Critical Care

Overview

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.

Interventions

• Drug ceftazidime
  ceftazidime loading dose and maintenance dose
• Biological plasma ceftazidime dosage
  plasma ceftazidime dosage kinetics will be performed according to an optimal D- sampling plan (4 measurements per subject: T0+5min, T0+3h, T0+6h, T0+24h, PFIM software). T0 corresponds to the time to administer the ceftazidime loading dose.

Primary outcome measures

• 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. [Time frame: 24 hours]

Secondary outcome measures (6)

• Patient severity assessed using the SOFA (Sequential Organ Failure Assessment Score) [Time frame: day 7]
• death [Time frame: day 28]
• Occurrence of neurological adverse events defined as: seizure, myoclonus, encephalopathy or delirium, altered consciousness (Glasgow score) [Time frame: day 28]
• Occurrence of an overdose defined as a concentration greater than 100 mg/L. [Time frame: day 28]
• Renal function assessment [Time frame: day 28]
• Time to reach PK/PD (pharmacokinetics/pharmacodynamics) targets [Time frame: 24 hours]

Eligibility criteria

Inclusionn criteria:

• Patient hospitalized in intensive care unit for an expected duration of at least 72 hours, with an infection for which initiation of ceftazidime therapy is being considered.
• Patient with an arterial catheter for blood sampling.
• Patients affiliated to or entitled under a social security scheme.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

France · 8 centers

• CHU GRENOBLE, Médecine intensive — Grenoble
• HCL Croix Rousse, Médecine intensive réanimation — Lyon
• HCL Hôpital Edouard Herriot, Médecine intensive et réanimation — Lyon
• CHU Nord, Médecine intensive et réanimation — Marseille
• HCL Hôpital Lyon Sud, Médecine intensive réanimation — Pierre-Bénite
• CHU ST-ETIENNE - Médeine Intensive Réanimation — Saint-Etienne
• CHU ST-ETIENNE, Médecine intensive Réanimation B — Saint-Etienne
• CHU ST-ETIENNE, Réanimation Néphrologie — Saint-Etienne

Identifiers

NCT: NCT07085624 · 24PH176_1 · 2024-519783-41-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗