The pharmacokinetics of ticarcillin/clavulanate acid in neonates

Abstract

The pharmacokinetics of a 25:1 combination of ticarcillin and clavulanate were studied in nine pre-term and seven full-term neonates. Pre-term neonates with a gestational age ranging from 30 to 36 weeks received 83.3 mg of ticarcillin and 3.3 mg of clavulanate per kg bw and full-term neonates with a gestational age from 39 to 43 weeks received 100 mg of ticarcillin and 4 mg of clavulanate per kg bw 8-hourly, each by a slow infusion over 10 min. Serum was sampled 15, 30, 60, 120, 240 and 480 min after the first dose and trough samples were additionally obtained on the fourth day of treatment. The patients were allocated to Groups 1-3 on the basis of the pharmacokinetic characteristics obtained. Group 1 comprised seven full-term babies. Group 2 contained seven pre-term neonates with a birth weight between 1915 and 2650 g and Group 3 consisted of two pre-term neonates of low birth weight (1400 g and 1640 g). Mean (+/- S.E.) pharmacokinetic characteristics of Group 1 patients for ticarcillin were: Cmax = 404.9 mg/l (36.0); T = 2.68 h (0.23); AUC = 1287 h.mg/l (69); Vd = 266 ml/kg (28) and for clavulanate: Cmax = 15.0 mg/l (1.2); T = 1.39 h (0.12); AUC = 30.1 h.mg/l (1.7); Vd = 263 ml/kg (22). Corresponding parameters for Group 2 patients for ticarcillin were: Cmax 278.7 mg/l (30.4); T = 4.20 h (0.49); AUC = 1107 h.mg/l (57); Vd = 338 ml/kg (35) and for clavulanate: Cmax = 8.4 mg/l (0.56); T = 2.56 h (0.18); AUC = 27.1 h.mg/l (2.0); Vd = 414 ml/kg (29). Drug accumulation was not observed in patients of Groups 1 and 2. Each of the two patients of Group 3 presented a pharmacokinetic profile which was considerably different from those observed in Groups 1 and 2. While in patients of the latter group the peak serum concentrations were achieved at 15-30 min after the end of infusion, these concentrations occurred between 120 and 240 min in one of the Group 3 patients. In the other Group 3 patient a remarkable drug accumulation was noted but was not associated with clinical or laboratory evidence of toxicity. These data show that ticarcillin and clavulanic acid in these dose ranges achieved adequate peak and trough concentrations in pre-term and full-term neonates.

Ticarcillin-clavulanic acid pharmacokinetics in preterm neonates with presumed sepsis

“…Retrospective analysis by optimal sampling theory (5, 6,8) The pharmacokinetic parameters that we determined were consistent with those reported by other investigators (9,12) in infants closer to full term than ours,, Fayed et al (9) reported a mean ± standard deviation t1,2 for ticarcillin of 4.5 ± 3.4 h and for clavulanic acid of 2 ± 1.6 h. Their sample consisted of 24 newborn infants with a mean gestational age of 30.7 weeks (range, 25 to 39 weeks) and a mean birth weight of 1,700 g (ranige, 895 to 3,900 g) (9). Fricke et al (12), in their sample of seven preterm infants with a mean birth weight of 2,377 g (range, 1,915 to 2,650 g) and a mean gestational age of 35 weeks (range, 34 to 36 weeks), found a mean ± standard deviation Vs, and t12 for ticarcillin of 0.338 ± 0.35 liter/kg and 4.20 ± 0.50 h, respectively and for clavulanic acid of 0.414 + 0.29 liter/kg and 2.56 + 0.18 h, respectively. Additionally, the pharmacokinetics of ticarcillin and clavulanic acid were available for one patient with a gestational age of 30 weeks and a birth weight of 1,400 g. The Vss and t1l2 for ticarcillin were 0.515 liter/kg and 16 h, respectively, and those for clavulanic acid were 0.441 liter/kg and 2.5 h, respectively, in that subject (12).…”

“…Fricke et al (12), in their sample of seven preterm infants with a mean birth weight of 2,377 g (range, 1,915 to 2,650 g) and a mean gestational age of 35 weeks (range, 34 to 36 weeks), found a mean ± standard deviation Vs, and t12 for ticarcillin of 0.338 ± 0.35 liter/kg and 4.20 ± 0.50 h, respectively and for clavulanic acid of 0.414 + 0.29 liter/kg and 2.56 + 0.18 h, respectively. Additionally, the pharmacokinetics of ticarcillin and clavulanic acid were available for one patient with a gestational age of 30 weeks and a birth weight of 1,400 g. The Vss and t1l2 for ticarcillin were 0.515 liter/kg and 16 h, respectively, and those for clavulanic acid were 0.441 liter/kg and 2.5 h, respectively, in that subject (12).…”

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

“…Those studies that have been carried out show that both GA and PNA have an impact on clearance and hence plasma t ½ [5,11,12,15,17,20,27,29]. Most of these PK studies have been classical PK studies where several blood samples were taken from each infant.…”

“…There have been three PK studies of ticarcillin in neonates where it has been given in combination with clavulanic acid Values are given as the mean or range Values are given as the mean or range a Patients on cardiopulmonary bypass [26][27][28] (Table 7). The first study looked at the use of prophylactic ticarcillin and clavulanic acid (ratio 15:1) in neonates from 25 to 39 weeks GA. As well as studying the PK of ticarcillin, these researchers also looked at the PK of clavulanic acid [26].…”

“…The first study looked at the use of prophylactic ticarcillin and clavulanic acid (ratio 15:1) in neonates from 25 to 39 weeks GA. As well as studying the PK of ticarcillin, these researchers also looked at the PK of clavulanic acid [26]. A subsequent study looked at a 25:1 combination of ticarcillin and clavulanic acid and showed that term neonates had a shorter t ½ (2.7 h) than preterm infants (4.2 h) [27]. The third study looked at a different ratio (30:1 ticarcillin-clavulanic acid) [28] and found a similar t ½ to that of previous studies but also calculated Cl.…”