Pharmacokinetics Study of Cefazolin in Hemodialysis (CEFAZODIAL)

Infection, Bacterial Clinical Trial

— CEFAZODIAL  

Official title:

Pharmacokinetics Study of Cefazolin in Hemodialysis (CEFAZODIAL)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06093269
• Other study ID #: DR220268
• Secondary ID: EuCT number
• Status: Recruiting
• Phase: Phase 4
• Start date: November 20, 2023
• Est. completion date: July 2025

Study information

• Verified date: November 2023
• Source: University Hospital, Tours
• Contact: Valentin MAISONS, MD
• Phone: 0247473746
• Email: valentin.maisons[@]univ-tours.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In chronic hemodialysis patients, bacteremia is most commonly caused by dialysis catheter infections. It is estimated that the vast majority (52-84%) of these infections are due to Gram-positive cocci, particularly Staphylococcus aureus (21-43%). Penicillin M (oxacillin and cloxacillin in France) is the reference beta-lactam for the treatment of invasive methicillin-sensitive S. aureus (MSSA) infections, but has not shown a prognostic benefit in large retrospective cohorts comparing penicillin M and cefazolin, at the expense of more frequent adverse events. Dosage in the chronic hemodialysis population is unclear because it is based on old studies.

Description:

In chronic hemodialysis patients, bacteremia is most commonly caused by dialysis catheter infections. It is estimated that the vast majority (52-84%) of these infections are due to Gram-positive cocci, particularly Staphylococcus aureus (21-43%). The uremia associated with kidney replacement therapy affects the immune system as a whole and is associated with an increased risk of infection. Bacterial infections are a major cause of mortality and morbidity in these patients. They are a major cause of hospitalization and the third leading cause of death after cardiovascular disease and treatment discontinuation.

Penicillin M (oxacillin and cloxacillin in France) is the reference beta-lactam for the treatment of invasive methicillin-sensitive S. aureus (MSSA) infections, but large retrospective cohorts comparing penicillin M and cefazolin have shown no prognostic benefit at the expense of more frequent adverse events. What's more, its short half-life means that it requires a more time-consuming hemodialysis protocol. Cefazolin is therefore the preferred treatment for invasive MSSA infections in the target population. This is because its clearance is slow in chronic renal failure patients during the replacement phase, and it can be administered as a single dose during hemodialysis sessions. The most recent French recommendations for cefazolin plasma concentration targets are to maintain the free form concentration at more than 4 times the minimum inhibitory concentration (MIC) for documented invasive MSSA infections or 40 - 80 mg/L (total form) for probabilistic treatment.

However, the pharmacokinetics of cefazolin at these high doses have been little studied in renal failure and dialysis patients, and dosing recommendations are mainly based on the doses recommended in the Summary of Product Characteristics (500mg at each hemodialysis session) up to 2-3g according to later pharmacokinetic and efficacy studies, or a fairly similar dosage but adapted to the weight of each patient (20mg/kg).

To our knowledge, there are no pharmacokinetic studies in infected chronic hemodialysis patients using modern assessment tools. Given the high interest in this drug in the target population, it seems essential to conduct such a study. In a second phase, a larger study could be conducted to validate the doses proposed in this study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subjects aged 18 or over

2. On chronic intermittent dialysis

3. With a stated indication for initiation of cefazolin either:

1. For probabilistic treatment of a clinical presentation suggestive of MSSA infection

2. for treatment of Gram-positive cocci bacteremia

4. With the possibility of taking peripheral blood samples or samples from the dialysis machine until the next dialysis session at 48 hours.

5. Included within a maximum of one week after the first cefazolin injection.

6. Affiliated with French social security

7. Having signed an informed consent form

Exclusion Criteria:

1. Pregnant or breast-feeding women

2. Dialysis lasting less than 3 hours, which most often corresponds to "acute" dialysis or the start of chronic dialysis, which fundamentally changes the elimination profile.

3. Allergy to cephalosporin and penicillin antibiotics (5-10% risk of cross-reactivity).

4. Non-anuric subjects with inhibitors of tubular creatinine secretion:

1. Curative-dose trimethoprim

2. Cimetidine

3. Ritonavir, Rilpivirine, Dolutegravir, Cobicistat

5. Subjects under guardianship, curatorship or safeguard of justice

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Diseases
• Hemodialysis Catheter Infection
• Infection, Bacterial
• Infections

Intervention

Biological:
• Blood samples
For all subjects (short kinetics): Pre-injection of cefazolin Start of next dialysis Two hours after start of subsequent dialysis End of next dialysis, before cefazolin administration Only in hospitalized subjects (rich kinetics): 30 minutes, 1h and 2h after cefazolin injection, to describe the cefazolin peak and possible post-dialysis rebound 12h, 24h and 36h after cefazolin injection, to better describe cefazolin elimination and distribution

Locations

Country	Name	City	State
France	Department of hemodialysis, University Hospital of Tours	Orléans
France	Department of hemodialysis, University Hospital of Tours	Tours

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Tours

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time during which cefazolin plasma concentration exceeds the target concentration of 40 mg/L.		48 hours after injection
Secondary	Occurrence of adverse events		Within 6 weeks of last dose
Secondary	Early clinical efficacy - Persistence of fever >38°C	Early clinical efficacy (at 1 week from start of treatment) in cefazolin-susceptible patients, defined as absence of failure, composite endpoint including: Persistence of fever >38°C; Persistence of positive blood cultures for the same germ(s); Death for infectious reasons; Change of antibiotic therapy due to ineffectiveness	At 1 week from start of treatment
Secondary	Early clinical efficacy - Persistence of positive blood cultures for the same germ(s)	Early clinical efficacy (at 1 week from start of treatment) in cefazolin-susceptible patients, defined as absence of failure, composite endpoint including: Persistence of fever >38°C; Persistence of positive blood cultures for the same germ(s); Death for infectious reasons; Change of antibiotic therapy due to ineffectiveness	At 1 week from start of treatment
Secondary	Early clinical efficacy - Death for infectious reasons	Early clinical efficacy (at 1 week from start of treatment) in cefazolin-susceptible patients, defined as absence of failure, composite endpoint including: Persistence of fever >38°C; Persistence of positive blood cultures for the same germ(s); Death for infectious reasons; Change of antibiotic therapy due to ineffectiveness	At 1 week from start of treatment
Secondary	Early clinical efficacy - Change of antibiotic therapy due to ineffectiveness	Early clinical efficacy (at 1 week from start of treatment) in cefazolin-susceptible patients, defined as absence of failure, composite endpoint including: Persistence of fever >38°C; Persistence of positive blood cultures for the same germ(s); Death for infectious reasons; Change of antibiotic therapy due to ineffectiveness	At 1 week from start of treatment
Secondary	Late clinical efficacy - Persistence of positive blood cultures	Late clinical efficacy (at 6 weeks from the start of treatment) in patients with cefazolin-susceptible organisms, defined as absence of failure, composite endpoint including : Persistence of positive blood cultures; Recurrence of initial infection; Infectious death; Change of antibiotic therapy due to ineffectiveness	At 6 weeks from the start of treatment
Secondary	Late clinical efficacy - Recurrence of initial infection	Late clinical efficacy (at 6 weeks from the start of treatment) in patients with cefazolin-susceptible organisms, defined as absence of failure, composite endpoint including : Persistence of positive blood cultures; Recurrence of initial infection; Infectious death; Change of antibiotic therapy due to ineffectiveness	At 6 weeks from the start of treatment
Secondary	Late clinical efficacy - Infectious death	Late clinical efficacy (at 6 weeks from the start of treatment) in patients with cefazolin-susceptible organisms, defined as absence of failure, composite endpoint including : Persistence of positive blood cultures; Recurrence of initial infection; Infectious death; Change of antibiotic therapy due to ineffectiveness	At 6 weeks from the start of treatment
Secondary	Late clinical efficacy - Change of antibiotic therapy due to ineffectiveness	Late clinical efficacy (at 6 weeks from the start of treatment) in patients with cefazolin-susceptible organisms, defined as absence of failure, composite endpoint including : Persistence of positive blood cultures; Recurrence of initial infection; Infectious death; Change of antibiotic therapy due to ineffectiveness	At 6 weeks from the start of treatment
Secondary	Persistence of fever >38°C	All components of the composite endpoint "Early clinical efficacy" will be assessed separately.	At 1 week from start of treatment
Secondary	Persistence of positive blood cultures for the same germ(s)	All components of the composite endpoint "Early clinical efficacy" will be assessed separately.	At 1 week from start of treatment
Secondary	Death for infectious reasons	All components of the composite endpoint "Early clinical efficacy" will be assessed separately.	At 1 week from start of treatment
Secondary	Change of antibiotic therapy due to ineffectiveness	All components of the composite endpoint "Early clinical efficacy" will be assessed separately.	At 1 week from start of treatment
Secondary	Persistence of positive blood cultures	All components of the composite endpoint "Late clinical efficacy" will be assessed separately.	At 6 weeks from the start of treatment
Secondary	Recurrence of initial infection	All components of the composite endpoint "Late clinical efficacy" will be assessed separately.	At 6 weeks from the start of treatment
Secondary	Infectious death	All components of the composite endpoint "Late clinical efficacy" will be assessed separately.	At 6 weeks from the start of treatment
Secondary	Change of antibiotic therapy due to ineffectiveness	All components of the composite endpoint "Late clinical efficacy" will be assessed separately.	At 6 weeks from the start of treatment
Secondary	Characterizing the pharmacokinetic variability of Cefazolin	Characterizing the pharmacokinetic variability of Cefazolin with the occurrence of under- or over-exposure (concentration below 40 mg/L or above 80mg/L)	48 hours after injection