Urinary Infections
Conditions
Keywords
antibiotic, cephalosporin, therapeutic target, pharmacokinetics
Brief summary
Urinary tract infections (UTIs) are the leading cause of community-acquired bacterial infections in adults. They are a common reason for admission to the Emergency Department (ED), particularly when pyelonephritis is suspected. The main bacteria responsible for UTIs are Enterobacteriaceae, with Escherichia coli being the main cause, found in more than 90% of cases. The French guidelines of the SPLIF (French-Speaking Infectious Pathology Society) recommend the probabilistic use of a 3rd generation cephalosporin or a fluoroquinolone. Ceftriaxone is often chosen over cefotaxime because it can be injected only once a day, which simplifies its administration in overcrowded emergency departments. There are currently no SPLIF recommendations regarding the dosage of ceftriaxone to be administered. The IDSA (Infectious Diseases Society of America) suggests a single dosage of 1 gram/day. Ceftriaxone is a 3rd generation cephalosporin antibiotic in the β-lactam class. Its mechanism of action is based on the inhibition of bacterial cell wall synthesis. Due to its broad spectrum against Gram-positive and Gram-negative aerobic bacteria and also some anaerobic germs, ceftriaxone is a commonly prescribed antibiotic in emergency departments (Therapeutic Guidelines Limited, Melbourne, 2014; Kumar et al., 2009) because of its broad indications: neuromeningeal infections, intra-abdominal infections and urinary tract infections (UTIs). Since most UTIs requiring hospitalization do not require intensive care, the optimal dosage of ceftriaxone in this context remains to be determined. Indeed, patients in emergency departments are on average less serious, without sepsis or septic shock, and therefore with probably different pharmacokinetic parameters.
Detailed description
While PK data in healthy volunteers support a single dose of ceftriaxone 1 gram/day, those from intensive care patients support 2 or even 4 grams/day. Febrile UTIs are a heterogeneous group of patients ranging from simple acute pyelonephritis in young women with no history to complex urinary tract infection in malnourished elderly patients and male urinary tract infection in elderly patients with benign prostatic hyperplasia. The present project therefore aims to evaluate whether a single dose of 1 g of ceftriaxone is sufficient to achieve the therapeutic target in all patients suffering from febrile UTI without septic shock or whether certain situations would justify a dosage adjustment. To this end, patients presenting a clinical and biological picture of UTI and having received ceftriaxone administration will be offered inclusion in this protocol. A 4 mL dry tube and a 4 mL heparinized tube will be collected for the determination of total and free ceftriaxone, albumin, and bilirubin concentrations. These samples will be added to the assessment performed as part of routine care within 24 hours of the first ceftriaxone injection. This study will calculate the probability of reaching the therapeutic target in patients treated with ceftriaxone for UTI without septic shock. Depending on the results, this study could allow the proposal of a personalized dosage of ceftriaxone for each patient suffering from urinary tract infection based on their clinical and biological parameters.
Interventions
BIOLOGICALfree ceftriaxone concentration dosage
The proportion of patients with UTI for whom the time spent with a free ceftriaxone concentration above 1x MIC is 100% will be determined by calculating the ratio of the total number of patients meeting this criterion to the total number of patients included. Plasma ceftriaxone dosages will be integrated into a structural model from the scientific literature using the MonolixSuite 2023R1® package (Lixoft - Saclay) including a modeling module (Monolix) and a simulation module (Simulx). T. Individual pharmacokinetic parameters will be determined by Bayesian estimation by integrating the dosage performed in the protocol.
Sponsors
University Hospital, Rouen
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult patient over 18 years of age * Requiring hospitalization at Rouen University Hospital * Clinical diagnosis of urinary tract infection requiring ceftriaxone antibiotic therapy * Prescription of 1g IV ceftriaxone * Venipuncture for laboratory testing as part of the prescribed treatment within 24 hours of the first ceftriaxone injection * Patient has read and understood the information letter and given oral consent to participate in the study
Exclusion criteria
* Minor patient * Patient hospitalized in an intensive care unit * Patient with septic shock * Chronic dialysis or indication for emergency renal replacement therapy (ERP) * Prescription of a dosage other than 1g intravenously per 24 hours * Patient having received more than one injection of 1g ceftriaxone * Pregnant, parturient, or breastfeeding woman * Person deprived of liberty by an administrative or judicial decision * Person placed under judicial protection, guardianship, or curatorship
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with urinary tract infection (UTI) for whom the time spent with a free ceftriaxone concentration | within 24 hours after enrollment visit | To determine the proportion of patients with UTI for whom the time spent with a free ceftriaxone concentration above 1x MIC is 100% (fT \> 1x MIC = 100%). The primary objective will be evaluated by simulation using a two-compartment population pharmacokinetic model whose initial parameters will be set in accordance with the scientific literature. The residual concentration of free ceftriaxone will be used and compared to the critical concentration threshold of ceftriaxone for each pathogen defined by EUCAST (European Committee on Antimicrobial Susceptibility Testing). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine the probability of reaching the efficiency threshold fT > 1x MIC = 100% for MICs varying from 0.25 to 32 mg/L | within 24 hours after enrollment visit | For beta-lactams (BL) such as ceftriaxone, this is the fraction of time, fT, (expressed as a percentage between doses) where the free concentration of the antibiotic is above the minimum inhibitory concentration or MIC (%ƒT\>MIC). - The probability of reaching the efficacy threshold fT \> 1x MIC = 100% will be assessed using PTA (probability of target attainment) curves. Simulations will be performed using the pharmacokinetic model with different dosages and according to different MICs (from 0 to 32 mg/L). |
| Determine a mathematical function allowing the free plasma fraction of ceftriaxone to be extrapolated from the total ceftriaxone concentration | within 24 hours after enrollment visit | The relationship between the free and total form of plasma ceftriaxone will be studied according to a linear binding model |
| Describe the microbial epidemiology of UTIs in the Emergency Department (ED) | within 24 hours after enrollment visit | The microbial epidemiology of UTIs in the ED will be assessed by microbiological analysis of the ECBU of included patients collected retrospectively. |
| Determine the impact of clinical-biological variables on the pharmacokinetic profile of ceftriaxone (weight) | within 24 hours after enrollment visit | The weight will be that measured from the patient. This variable will be analyzed centered on the mean with and without logarithmic conversion. |
| Determine the impact of clinical-biological variables on the pharmacokinetic profile of ceftriaxone (albuminemia) | within 24 hours after enrollment visit | The dosages of albuminemia will be carried out using samples taken as part of the study. The variable will be analyzed centered on the mean with and without logarithmic conversion. |
| Determine the impact of clinical-biological variables on the pharmacokinetic profile of ceftriaxone (bilirubinemia) | within 24 hours after enrollment visit | The dosages of bilirubinemia will be carried out using samples taken as part of the study. The variable will be analyzed centered on the mean with and without logarithmic conversion. |
| Determine the impact of clinical-biological variables on the pharmacokinetic profile of ceftriaxone (creatinineemia) | within 24 hours after enrollment visit | The dosages of creatinineemia will be carried out using samples taken as part of the study. The variable will be analyzed centered on the mean with and without logarithmic conversion. |
Countries
France
Outcome results
None listed