A Clinical Pharmacokinetic Study: Is Three Times Weekly Temocillin Appropriate for the Treatment of Severe Gram-negative Infections in Patients With ESRD Treated With Intermittent Hemodialysis?

Background: Temocillin is a renally cleared penicillin with long serum half-live and potent activity against most gram-negative bacteria, making it an ideal candidate for treatment given on dialysis days only of severe gram-negative infections in patients with ESRD treated with haemodialysis.

Endpoints:

Primary: The current study aimed to demonstrated by measurement of AUC whether or not the pharmacodynamics target of a time above a MIC of 8 and 16 mg/L of more than 40 and 60 % of the dosing interval could be obtained with a dosing schedule of 1 gram/24 hours, 2 gram/48 hours and 3 gram/72 hours, all of these doses given after haemodialysis sessions only.

Secondary: Key pharmacokinetic and dialytic parameters were determined as previously described16. The following parameters were recorded: the volume of distribution Vd (determined as Vd = dose / (Tempeak - Temtrough) in liter); the Vd/Wt (in liter/kg body weight); the non-dialysis clearance of temocillin (Ke(non-dialysis) = [ln(Tempeak) - ln(Tempre)] / time between peak level and start of next dialysis); the non-dialysis half-life (T1/2(non-dialysis) = 0.693 / Ke(non-dialysis) in hours); the dialysis clearance of temocillin (Ke(dialysis) = [ln(Tempre) - ln(Tempost)] / dialysis duration); the dialysis half-life (T1/2(dialysis) = 0.693 / Ke(dialysis) in hours); the Urea Reduction Ratio (URR = (BUNpre - BUNpost) / BUNpre); the Temocillin Reduction Ratio TRR = (Tempre - Tempost) / Tempre); the Temocillin Removal Ratio (the total amount of temocillin recovered in the dialysate, based on the area under the curve of the temocillin removal rate and the treatment time); and the AUC of temocillin. For all PK/PD analysis, the non-compartmental method using RStudio 0.98.501 with R 3.0.2 software was used.

Methods: Pharmacokinetic study measuring total and free temocillin concentrations in patients treated with intermittent haemodialysis and temocillin. Blood samples were drawn just before, and at 0.5, 3, 6, 12, 20 (before dialysis) and 24 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 1-day interval; just before and at 0.5, 3, 6, 12, 24, 36, 44 (before dialysis) and 48 (at the end of dialysis) hours after start of the infusion when patients were dialysed with a 2-day interval, and just before and at 0.5, 3, 6, 12, 24, 36, 48, 68 (before dialysis) and 72 (at the end of dialysis) hours after start of the infusion if patients were dialysed with a 3-day interval. Patients were followed for 1 to 6 subsequent AUC. Dialysate samples were taken 1, 2, 3 and 4 h after the start of dialysis. All samples were taken from an arterial or venous catheter, after thorough rinsing. Serum (obtained by centrifugation after blood clotting) and dialysate was frozen (-80 C) immediately after sampling until analysis.