Pharmacokinetics Study of Cefazolin in Hemodialysis (CEFAZODIAL)
Overview
- Phase
- Phase 4
- Intervention
- Blood samples
- Conditions
- Hemodialysis Catheter Infection
- Sponsor
- University Hospital, Tours
- Enrollment
- 32
- Locations
- 1
- Primary Endpoint
- Time during which cefazolin plasma concentration exceeds the target concentration of 40 mg/L.
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects aged 18 or over
- •On chronic intermittent dialysis
- •With a stated indication for initiation of cefazolin either:
- •For probabilistic treatment of a clinical presentation suggestive of MSSA infection
- •for treatment of Gram-positive cocci bacteremia
- •With the possibility of taking peripheral blood samples or samples from the dialysis machine until the next dialysis session at 48 hours.
- •Included within a maximum of one week after the first cefazolin injection.
- •Affiliated with French social security
- •Having signed an informed consent form
Exclusion Criteria
- •Pregnant or breast-feeding women
- •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.
- •Allergy to cephalosporin and penicillin antibiotics (5-10% risk of cross-reactivity).
- •Non-anuric subjects with inhibitors of tubular creatinine secretion:
- •Curative-dose trimethoprim
- •Ritonavir, Rilpivirine, Dolutegravir, Cobicistat
- •Subjects under guardianship, curatorship or safeguard of justice
Arms & Interventions
Cefazolin
20mg/kg to be administered in the hemodialysis circuit at the end of the 4-hour dialysis period, with no dosage adjustment planned afterwards.
Intervention: Blood samples
Outcomes
Primary Outcomes
Time during which cefazolin plasma concentration exceeds the target concentration of 40 mg/L.
Time Frame: 48 hours after injection
Secondary Outcomes
- Persistence of fever >38°C(At 1 week from start of treatment)
- Late clinical efficacy - Persistence of positive blood cultures(At 6 weeks from the start of treatment)
- Infectious death(At 6 weeks from the start of treatment)
- Occurrence of adverse events(Within 6 weeks of last dose)
- Early clinical efficacy - Persistence of fever >38°C(At 1 week from start of treatment)
- Early clinical efficacy - Persistence of positive blood cultures for the same germ(s)(At 1 week from start of treatment)
- Late clinical efficacy - Recurrence of initial infection(At 6 weeks from the start of treatment)
- Persistence of positive blood cultures for the same germ(s)(At 1 week from start of treatment)
- Late clinical efficacy - Infectious death(At 6 weeks from the start of treatment)
- Change of antibiotic therapy due to ineffectiveness(At 6 weeks from the start of treatment)
- Early clinical efficacy - Death for infectious reasons(At 1 week from start of treatment)
- Early clinical efficacy - Change of antibiotic therapy due to ineffectiveness(At 1 week from start of treatment)
- Death for infectious reasons(At 1 week from start of treatment)
- Recurrence of initial infection(At 6 weeks from the start of treatment)
- Characterizing the pharmacokinetic variability of Cefazolin(48 hours after injection)
- Late clinical efficacy - Change of antibiotic therapy due to ineffectiveness(At 6 weeks from the start of treatment)
- Persistence of positive blood cultures(At 6 weeks from the start of treatment)