Pharmacokinetics of Ceftriaxone and Its Relation to Concentrations in Extravascular Compartments

Abstract

Two of the 3rd generation cephalosporins, ceftriaxone and cefotaxime, have an almost identical antibacterial spectrum, but completely different pharmacokinetics. After an intravenous dose of 1 g, peak levels of both cephalosporins were > 100 μg/ml. Cefotaxime levels fall rapidly with a T½ of 1.1 h, whereas ceftriaxone persists for 24 h with an unique T½ of 8 h. Cefotaxime is eliminated by the kidneys and metabolized to desacetyl-cefotaxime resulting in a high total clearance. In contrast, ceftriaxone is not metabolized and highly protein bound with a total clearance of only 14 ml/min. Peak concentrations of antibiotics are lower in extravascular compartments than in serum. They depend on the dose administered and the serum T½; they are lower with highly bound drugs. Concentrations of ceftriaxone and cefotaxime were measured by Andrews and Wise in blister fluids, in ascites and pleural fluid by us. We found concentrations of 20–26 μg/ml ceftriaxone up to 12 h in ascites, but only 7–15 μg/ml cefotaxime. The levels persisted for 24 h for ceftriaxone, whereas they fell rapidly for cefotaxime. Because the minimum inhibition concentrations increase in the presence of proteins, and because free, unbound, microbiologically active ceftriaxone is lower than the measured total antibiotic concentrations, we suggest that 2-gram doses should be administered – at least at the beginning of the treatment of an infectious disease – and for prophylaxis.

Disposition of ceftriaxone in rat: Application of a pharmacokinetic-protein binding model and comparison with cefotaxime

“…Furthermore, due to the more extensive (almost three times) binding of ceftriaxone than cefotaxime to plasma protein, the half-life (B phase) of ceftriaxone was twice as long as that of cefotaxime. T h e shorter half-life of cefotaxime may also be due to metabolism of the drug by the liver (Chamberlain et al 1980, Reeves et al 1980, Wise et al 1981, whereas ceftriaxone is not metabolized (Regamey 1985 T h e protein binding constants ( K ) of ceftriaxone and cefotaxime in vim were similar (P> 0.05) following i.v. administration of a high dose of each drug.…”

“…However, a substituent difference in position 3 results in different pharmacokinetic profiles between the two compounds (Regamey 1985), e.g. elimination half-life and protein binding values.…”

Management of Infections Due to Antibiotic-Resistant Streptococcus pneumoniae

“…Since a variety of antimicrobial regimens were used in these patients, it is very difficult to draw any conclusions regarding single-agent therapy. However, most of the antibiotics administered to these patients were shown to achieve concentrations in synovial fluid, peritoneal fluid, or bone in excess of their MICs for penicillin-resistant isolates (21,26,72,98,104,123). In synovial fluid, ceftriaxone reaches a level of up to 66 to 100% of the concomitant levels in serum.…”

Bioavailability and pharmacokinetics of cefotaxime in Muscovy ducks

“…Cefotaxime has an important location in antimicrobial drugs because of its expanded spectrum of antibacterial activity, greater resistance to β-lactamase (Kalager et al, 1982), low renal toxicity (Regamy, 1985), excellent disposition kinetics characteristics and least problem of bacterial resistance as well. It has minimum therapeutic concentration around 0.5 μg/ml for most of the susceptible micro-organisms (Neu, 1982b).…”