Pharmacokinetics and protein binding of ceftriaxone during pregnancy

Abstract

The purpose of the present work was to study the pharmacokinetics and the protein binding (free fraction of the drug) of ceftriaxone (CTX) during pregnancy. Nine pregnant women (ages, 20 to 34 years) whose gestational ages ranged from 28 4/7 to 40 5/7 weeks were included. The diagnosis of infection was established in all cases; i.e., four women had chorioamnionitis and five women had pyelonephritis. The following triple antibiotic therapy was infused with the aim of achieving cure: CTX, 2 g once every 24 h (constant rate over 60 min); tobramycin, 3 mg/kg of body weight once every 24 h; and ornidazole, 1 g/day. Two series of blood samples were collected, i.e., during the first day of treatment (on day 1), to establish the primary pharmacokinetic profile of CTX, and at the plateau (on day 7), to evaluate a possible accumulation of the drug.This was an open, noncompartmental study, with each patient serving as her own control. Concentrations of total and unbound CTX in serum were measured by a high-performance liquid chromatographic method. Pharmacokinetic analysis was done by a noncompartmental method. Data were compared by a Wilcoxon t test (a P value of .0.05 was considered significant). Data were also compared with those obtained for healthy subjects who received similar treatments. (i) The tolerance to treatment was excellent, and in all cases patients had a complete remission without premature delivery. (ii) No accumulation of CTX was noted during the treatment, and the profiles of the drug determined at days 1 and 7 were not significantly different. (iii) The pharmacokinetic parameters measured in pregnant patients during the third trimester of pregnancy were similar to those measured in healthy subjects. (iv) Residual concentrations of total and unbound CTX measured at 24 h were greater than the MICs for allegedly susceptible organisms, both on day 1 and at steady state. (v) During the final 3 months of pregnancy, the dosage schedule of CTX (2-g infusion per day) required no particular adjustment (i.e., neither a loading dose nor any increase in the maintenance dose).Ceftriaxone (CTX) is the first broad-spectrum cephalosporin prescribed on a single-daily-administration basis (24). This dosage schedule, which is unusual for a beta-lactam antibiotic, has been validated by a number of clinical studies since CTX came onto the market (11, 31). A pharmacodynamic and bacteriological approach taken together with the specific pharmacokinetics of the compound have formed the theoretical basis of a simplified administration schedule compared with those for other beta-lactams with shorter half-lives (9). The dosage recommended by the manufacturer (a single injection of 1 to 2 g every 24 h) is the consequence of an essential peculiarity of CTX: its prolonged terminal half-life (between 6.5 and 8.5 h) (21). The antibacterial spectrum of CTX is similar to that of other broad-spectrum cephalosporins. However, in comparison with other members of the group, it is less active against anaerobic organisms such as Bacteroides fr...

Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis

“…Overall, 54% of variability in CSF concentration was explained by plasma concentration. It is likely that the incomplete CSF uptake of ceftriaxone is explained by plasma protein binding, with free fraction previously reported to be in the range of 4% of the total plasma concentration . Since CSF ordinarily contains low concentration of protein, protein‐binding of ceftriaxone in CSF is likely to be negligible.…”

“…Preclinical studies highlight ceftriaxone as a potential anti‐excitoxicity therapy for patients with ALS . § Ceftriaxone has a relatively long half‐life (6–9 hours in blood and 17 hours in CSF), excellent penetration into extracellular fluid, and extensive serum protein binding which is reported to be saturable . The actual CNS/CSF concentration necessary to be neuroprotective in human brain or to induce human excitatory amino acid transporter 2 (EAAT2) in vivo is not clearly established, and it is not known how CSF concentrations reflect concentrations in brain tissue.…”

“…4,6,7,9-11 § Ceftriaxone has a relatively long half-life (6-9 hours in blood [12][13][14][15][16] and 17 hours in CSF 17,18 ), excellent penetration into extracellular fluid, [17][18][19][20][21][22][23][24][25][26][27][28] and extensive serum protein binding which is reported to be saturable. [29][30][31] The actual CNS/ CSF concentration necessary to be neuroprotective in human brain or to induce human excitatory amino acid transporter 2 (EAAT2) in vivo is not clearly established, and it is not known how CSF concentrations reflect concentrations in brain tissue. In any case, in vitro models suggest that ceftriaxone concentrations of at least 1 mM are effective in increasing expression of glutamate transporter 1, and in preventing toxicity caused by threo-hydroxyaspartate.…”

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“…The drug acts through inhibition of transpeptidase enzymes responsible for the final step in bacterial cell wall synthesis and has broad stability against beta-hydrolysis 2 . In human medicine, ceftriaxone is widely used, because of its prolonged terminal half-life (5.4-8.2 h) that allows its prescription on a single administration per day basis 3,4 . So expanded informations concerning the pharmacodynamic effects of ceftriaxone will be of benefits to physicians and their patients.…”

Protective effect of Matricaria Chamomilla extract on hepatic-renal toxicity of ceftriaxone in rats

“…Ceftriaxone is wide distribution in tissues and has rapid absorption as well as body fluids; it is extremely useful in a variety of infectious diseases including meningitis, septicemia, urinary tract, respiratory tract and joints infections (Gohil et al 2009). Ceftriaxone is widely used in human medicine because of it has prolonged terminal half-life (5.4-8.2h) which allows its prescription on a single administration per day (Bourget et al 1993). Ceftriaxone undergoes hydrolysis to form active metabolite ceftizoxime in goat (Sar et al 2006).…”