Ceftriaxone displays nonlinear pharmacokinetics. All pharmacokinetic parameters, with the exception of the elimination half-life, are dose dependent if they refer to the overall concentration (free- and protein-bound ceftriaxone).
After an IM injection of ceftriaxone 1 g, a maximum plasma concentration of 81 mg/L was achieved after 2-3 hrs. After a single IV infusion of 1 g, a concentration of 168.1±28.2 mg/L was achieved after 30 min. After a single IV infusion of 2 g, a concentration of 256.9±16.8 mg/L was achieved after 30 min.
The areas under the plasma concentration-time curves after IV and IM administration are identical. This means that the bioavailability of ceftriaxone administered IM is 100%.
The distribution volume lies between 7 and 12 L.
With IV administration, ceftriaxone rapidly penetrates interstitial body fluids, where bactericidal concentrations remain active against sensitive pathogens for 24 hrs.
After a dose of 1-2 g, ceftriaxone shows good penetration into tissue and body fluids; concentrations above the minimal inhibitory concentration for most pathogens were measured for >24 hrs in over 60 tissues and body fluids, including lungs, heart, biliary tract, liver, middle ear, nasal mucous membrane and bones
as well as cerebrospinal, pleural, synovial and prostate fluid.
Ceftriaxone is reversibly bound to plasma albumin, and the binding decreases with the increase in the concentration eg, 95% binding at plasma concentrations of <100 mg/L to 85% binding at a plasma concentration of 300 mg/L. Owing to the lower albumin content, the proportion of free ceftriaxone in the interstitial fluid is correspondingly higher than in plasma.
Ceftriaxone penetrates the inflamed meninges of infants and children. An average maximal concentration of 18 mg/L in the CSF is reached approximately 4 hrs after IV application of ceftriaxone 50-100 mg/kg. The average extent of diffusion into the CSF in bacterial meningitis is about 17% of the plasma concentration; in aseptic meningitis, 4%. Twenty-four hours after injection of ceftriaxone in doses of 50-100 mg/kg body weight, concentrations of >1.4 mg ceftriaxone/L have been found in the CSF. In adult patients with meningitis, administration of 50 mg/kg leads within 2-24 hrs to CSF concentrations which are several times higher than the required minimal inhibitory concentration against the most common causative organisms in meningitis.
Ceftriaxone penetrates the placental barrier. Ceftriaxone is excreted into breast milk in low concentrations (3-4% of the mother's plasma concentration after 4-6 hrs).
Ceftriaxone is not metabolized in the organism itself. Bowel flora converts the active agent into inactive metabolites after biliary excretion into the lumen of the bowel.
Plasma clearance is 10-22 mL/min. Renal clearance is 5-12 mL/min. In adults, 50-60% of ceftriaxone is excreted in the urine as unchanged drug while 40-50% is excreted unchanged in the bile. The serum elimination half-life in healthy subjects is about 8 hrs.
Special Clinical Situations:
In neonates, renal elimination accounts for about 70% of the dose. In infants <8 days and subjects >75 years, the average elimination half-life is about 2-3 times as long. The pharmacokinetics of ceftriaxone are only minimally altered in patients with renal impairment
or hepatic dysfunction, and the elimination half-life is only slightly increased. If kidney function alone is impaired, biliary elimination of ceftriaxone is increased; hepatic dysfunction alone leads to increased renal excretion.
Long-acting, broad-spectrum bactericidal antibiotic.
The bactericidal activity of ceftriaxone results from inhibition of cell wall synthesis. Ceftriaxone exerts in vitro
activity against a wide range of gram-negative and gram-positive microorganisms. It is highly stable to most β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Ceftriaxone is usually active against the following microorganisms in vitro
and in clinical infections: See Table 1.
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Susceptibility to ceftriaxone can be determined by the disk diffusion test or by the agar or broth dilution test using standardised techniques for susceptibility testing eg, those recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The NCLLS issued the following interpretative breakpoints for ceftriaxone: See Table 2.
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Microorganisms should be tested with the ceftriaxone disk since it has been shown by in vitro
tests to be active against certain strains resistant to cephalosporin class disks.
Where NCLLS recommendations are not in daily use, alternative, well standardised, susceptibility interpretative guidelines eg, those issued by DIN, ICS and others may be substituted.
Some isolates of this species are resistant to ceftriaxone because of the dereprimation of the chromosomal β-lactamase; some isolates of Klebsiella pneumoniae
are resistant to ceftriaxone because of the plasmid-dependent β-lactamase production; some isolates of Bacteroides
sp are resistant to ceftriaxone.
Many strains of the β-lactamase-producing Bacteroides
sp (specifically B. fragilis
) are resistant.
sp are resistant to cephalosporins including ceftriaxone. Enterococcus faecalis
and Enterococcus faecium
as well as Listeria monocytogenes
are resistant as a rule.
Many strains of gram-negative aerobes demonstrating multiple resistance to other antibiotics eg, amino- and ureido-penicillins, older cephalosporins and aminoglycosides are sensitive to ceftriaxone. Treponema pallidum
is sensitive in vitro
and in animal experiments. Clinical trials have shown that primary and secondary syphilis responds well to treatment with ceftriaxone.
With few exceptions, clinical isolates of Pseudomonas aeruginosa
are resistant to ceftriaxone.