Pharmacokinetics of the combination of ticarcillin with clavulanic acid in renal insufficiency

Abstract

The pharmacokinetics of ticarcillin and clavulanic acid were studied by blood and urine assay methods in 25 patients divided into five groups with varying degrees of renal insufficiency i.e. mild, moderate and severe renal insufficiency, almost anuric patients and those requiring haemodialysis (groups A to E). A single dose of 5.2 g Timentin (5.0 g ticarcillin and 200 mg clavulanic acid) was administered intravenously by infusion over 30 min. The average elimination half-life (T1/2) of ticarcillin increased from 0.95 h in patients with creatinine clearance (Clcr) of 80 ml/min to 1.8, 4.4, 6.9 and 11.2 h respectively in mild, moderate and severe renal insufficiency and in almost anuric patients. The T1/2 values for clavulanic acid were 0.75, 0.9, 2.0, 2.5 and 4.8 h in the same groups. The area under concentration-time curve (AUC) for ticarcillin increased from 787 to 2839 mg/l/h and for clavulanic acid from 12.8 to 29 mg/l/h when group mean values from patients with mild and severe renal insufficiency were compared. The plasma clearance (Clpl) of clavulanic acid was in all groups greater than that of ticarcillin i.e. 166 and 100 ml/min vs. 79.2 and 25.0 ml/min when comparing mean values from groups with mild and severe renal insufficiency respectively. The plasma clearance ratio clavulanic acid/ticarcillin increased proportionally to the degree of renal insufficiency from a value of 1.5 in normal subjects to between 3.3 and 3.8 in more advanced cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Pharmacokinetics of Enzyme Inhibitors in Antimicrobial Chemotherapy

“…Renal failure results in accumulation of amoxycillin, clavulanic acid and ticarcillin, due to progressive impairment of renal excretion (Boelaert et al 1985;Dalet et al 1983Dalet et al , 1984Dalet et al , 1985Horber et al 1986;Jungbluth et al 1986;Koeppe et al 1987;Watson & Boulton-Jones 1985;Watson et al 1987). The greater the renal impairment severity the less the clearance, although an increase in clavu1anic acid non-renal clearance was not manifested in severe renal failure (creatinine clearance < 10 mlj min), but was noted in anephric patients (Watson et al 1987).…”

“…Although penicillins have a high therapeutic index and the adverse reactions attributable to c1a-vulanic acid are minor, several authors have designed dosage regimens to: (a) avoid periods of inadequate drug concentration; and (b) minimise excessive serum concentrations (Boelaert et al 1985;Dalet et al 1983Dalet et al , 1984Dalet et al , 1985Horber et al 1986;Jungbluth et al 1986;Koeppe et al 1987;Watson et al 1987).…”

“…amoxycillin + clavulanic acid 500: 125mg orally or 1000: 200mg intravenously; ticarcillin + clavulanic acid 3000 :lOOmg, 3000: 200mg, 5000 : 2oomg. For both amoxycillin + clavulanic acid and ticarcillin + clavulanic dosage regimens, using the standard dose with decreased frequency has been advocated (Dalet et al 1984(Dalet et al , 1985Horber et al 1986;Jungbluth et al 1986). Others have used a combination of dosage reduction and decreased dosing frequency (Boelaert et al 1985;Koeppe et al 1987;Watson & Boulton-Jones 1985;Watson et al 1987).…”

“…The effects of haemodialysis on amoxycillin + clavulanic acid and ticarcillin + clavulanic acid have been considered (Dalet et al 1983(Dalet et al , 1984(Dalet et al , 1985Horber et al 1986;Slaughter et al 1984;Watson et al 1987). Clearance during haemodialysis is particularly affected by blood flow rate through the dialyser, membrane type and surface area, thus results between studies are not strictly comparable.…”

“…Volumes of distribution were unaffected by haemodialysis (Dalet et al 1984(Dalet et al , 1985, but redistribution of both clavulanic acid and ticarcillin to the central compartment has been noted on cessation of dialysis (Watson et al 1987). Due to the efficient elimination of both drug components, a post-dialysis loading dose and an 'anephric' dosing schedule has been proposed (Watson et al 1987).…”