Clinical trial NCT06093269: Pharmacokinetics Study of Cefazolin in Hemodialysis (CEFAZODIAL)
Official title: Pharmacokinetics Study of Cefazolin in Hemodialysis (CEFAZODIAL)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hemodialysis Catheter Infection
Infection, Bacterial
Keywords: Cefazolin
Pharmacology
Nephrology
Hemodialysis
Infectiology
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2023-10-23
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time during which cefazolin plasma concentration exceeds the target concentration of 40 mg/L.
timeFrame: 48 hours after injection
Secondary outcomes:
measure: Occurrence of adverse events
timeFrame: Within 6 weeks of last dose
measure: Early clinical efficacy - Persistence of fever >38°C
timeFrame: At 1 week from start of treatment
measure: Early clinical efficacy - Persistence of positive blood cultures for the same germ(s)
timeFrame: At 1 week from start of treatment
measure: Early clinical efficacy - Death for infectious reasons
timeFrame: At 1 week from start of treatment
measure: Early clinical efficacy - Change of antibiotic therapy due to ineffectiveness
timeFrame: At 1 week from start of treatment
measure: Late clinical efficacy - Persistence of positive blood cultures
timeFrame: At 6 weeks from the start of treatment
measure: Late clinical efficacy - Recurrence of initial infection
timeFrame: At 6 weeks from the start of treatment
measure: Late clinical efficacy - Infectious death
timeFrame: At 6 weeks from the start of treatment
measure: Late clinical efficacy - Change of antibiotic therapy due to ineffectiveness
timeFrame: At 6 weeks from the start of treatment
measure: Persistence of fever >38°C
timeFrame: At 1 week from start of treatment
measure: Persistence of positive blood cultures for the same germ(s)
timeFrame: At 1 week from start of treatment
measure: Death for infectious reasons
timeFrame: At 1 week from start of treatment
measure: Change of antibiotic therapy due to ineffectiveness
timeFrame: At 1 week from start of treatment
measure: Persistence of positive blood cultures
timeFrame: At 6 weeks from the start of treatment
measure: Recurrence of initial infection
timeFrame: At 6 weeks from the start of treatment
measure: Infectious death
timeFrame: At 6 weeks from the start of treatment
measure: Change of antibiotic therapy due to ineffectiveness
timeFrame: At 6 weeks from the start of treatment
measure: Characterizing the pharmacokinetic variability of Cefazolin
timeFrame: 48 hours after injection
Other outcomes:
Locations:
city: Orléans
country: France
facility: Department of hemodialysis, University Hospital of Tours
city: Tours
country: France
facility: Department of hemodialysis, University Hospital of Tours
Study officials:
affiliation: University Hospital, Tours
name: Valentin MAISONS, MD
role: STUDY_DIRECTOR
affiliation: University Hospital, Tours
name: Adrien LEMAIGNEN, MD-PhD
role: STUDY_DIRECTOR
References: