|Systematic (IUPAC) name|
|Trade names||Rocephin, Epicephin, Arixon, Elcefrin|
|Biological half-life||5.8–8.7 hours|
|Excretion||33–67% renal, 35–45% biliary|
|Molar mass||554.58 g/mol|
Ceftriaxone, sold under the trade name Rocephin, is an antibiotic useful for the treatment of a number of bacterial infections. This includes pneumonia, ear infections, skin infections, urinary tract infections, gonorrhea, pelvic inflammatory disease, septisis, bone and joint infections, intra-abdominal infections, and meningitis. It is also used preoperatively to reduce the risk of postoperative infections. It is administered by intravenous or intramuscular injection.
The most common side effects are related to route of drug administration, including pain at the site of intramuscular injection and thrombophlebitis in intravenous administration. Gastrointestinal upset is also common. Due to precipitation of ceftriaxone in bile, biliary sludging, gallstones, and cholecystitis are also possible, if less common. It should not be used in newborns due to the risks of bilirubin encephalopathy and ceftriaxone-calcium precipitation. Dosage adjustment is usually required in people with kidney failure. Caution should be used in those who have had serious allergic reactions to penicillin.
It is a third-generation cephalosporin. Like other third-generation cephalosporins, it has broad-spectrum activity against Gram-positive bacteria and expanded Gram-negative coverage compared to second-generation agents. In most cases, it is considered to be equivalent to cefotaxime in terms of spectrum of antibacterial activity.
Ceftriaxone sodium is marketed by Hoffmann-La Roche. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
Ceftriaxone and other third-generation antibiotics are used to treat organisms that tend to be resistant to many other antibiotics. Due to emergent resistance, ceftriaxone should not be used for the treatment of Enterobacter infections. Before using ceftriaxone, it is important to determine the susceptibility of the bacteria. If sepsis is being considered, empiric therapy may be initiated prior to susceptibility testing in immunocompromised and Immunocompetent patients.
According to the package insert, clinical indications for ceftriaxone include:
- lower respiratory tract infections
- acute bacterial otitis media
- skin and skin structure infections
- urinary tract infections
- uncomplicated gonorrhea
- pelvic inflammatory disease
- bacterial septicemia
- intra-abdominal infections
- surgical prophylaxis
It is also a choice drug for treatment of bacterial meningitis caused by pneumococci, meningococci, Haemophilus influenzae, and "susceptible enteric Gram-negative rods, but not Listeria monocytogenes."
In combination with doxycycline or azithromycin, ceftriaxone is recommended by the United States Centers for Disease Control for the treatment of gonorrhea. By itself, it is not recommended due to the potential for resistance development.
Spectrum of activity
Like other third-generation cephalosporins, ceftriaxone is active against Citrobacter spp., Serratia marcescens, and beta-lactamase-producing strains of Haemophilus and Neisseria. However, unlike ceftazidime and cefoperazone, ceftriaxone does not have useful activity against Pseudomonas aeruginosa. It is generally not active against Enterobacter species, and its use should be avoided in the treatment of Enterobacter infections, even if the isolate appears susceptible, because of the emergence of resistance. Some organisms, such as Citrobacter, Providencia, and Serratia, have the ability to become resistant through the development of cephalosporinases (these enzymes hydrolyze cephalosporins and render them inactive).
Ceftriaxone is available for administration via the intramuscular or the intravenous routes. Diluents containing calcium should not be used to reconstitute ceftriaxone and it must not be administered in intravenous lines containing other calcium-containing solutions, as a ceftriaxone-calcium precipitate could form.
Low concentrations of ceftriaxone are excreted in breast milk that are "not expected to cause adverse effects in breastfed infants." The manufacturer recommends that caution be exercised when administering ceftriaxone to women who breastfeed.
Hyperbilirubinemic neonates are contraindicated for the use of ceftriaxone. It can compete with bilirubin and displace it from binding to albumin, increasing the risk of bilirubin encephalopathy.
According to the package insert, clinical studies did not show differences in efficacy and safety of ceftriaxone in geriatrics compared to younger patients but "greater sensitivity of some older individuals cannot be ruled out."
Although generally well tolerated, the most common adverse reactions associated with ceftriaxone are changes in white blood cell counts, local reactions at site of administration, rash, and diarrhea.
Incidence of adverse effects greater than 1%:
- Eosinophilia (6%)
- Thrombocytosis (5.1%)
- Elevations in liver enzymes (3.1 - 3.3%)
- Diarrhea (2.7%)
- Leukopenia (2.1%)
- Elevation in BUN (1.2%)
- Local reactions—pain, tenderness, irritation (1%)
- Rash (1.7%)
Some less frequently reported adverse events (incidence < 1%) include phlebitis, itchiness, fever, chills, nausea, vomiting, elevations of bilirubin, elevations in creatinine, headache and dizziness.
Ceftriaxone may precipitate in bile, causing biliary sludge, biliary pseudolithiasis, and gallstones, especially in children. Hypoprothrombinaemia and bleeding are specific side effects. Haemolysis is reported. It has also been reported to cause post renal failure in children. Like other antibiotics, ceftriaxone use can result in Clostridium difficile-associated diarrhea ranging from mild diarrhea to fatal colitis.
Ceftriaxone should not be used in those with an allergy to ceftriaxone or any component of the formulation. Although there is negligible cross-reactivity between penicillins and third-generation cephalosporins, caution should still be used when using ceftriaxone in penicillin-sensitive patients. Caution should be used in people who have had previous severe penicillin allergies. It should not be used in hyperbilirubinemic neonates, particularly those who are premature because ceftriaxone is reported to displace bilirubin from albumin binding sites, potentially causing bilirubin encephalopathy. Concomitant use with intravenous calcium-containing solutions/products in neonates (≤28 days) is contraindicated  even if administered through different infusion lines due to rare fatal cases of calcium-ceftriaxone precipitations in neonatal lungs and kidneys.
Mechanism of action
Ceftriaxone is a third-generation antibiotic from the cephalosporin family of antibiotics. Ceftriaxone selectively and irreversibly inhibits bacterial cell wall synthesis by binding to transpeptidases, also called transamidases, which are penicillin-binding proteins (PBPs) that catalyze the cross-linking of the peptidoglycan polymers forming the bacterial cell wall. The peptidoglycan cell wall is made up of pentapeptide units attached to a polysaccharide backbone with alternating units of N-acetylglucosamine and N-acetylmuramic acid. PBPs act on a terminal D-alanyl-D-alanine moiety on a pentapeptide unit and catalyze the formation of a peptide bond between the penultimate D-alanine and a glycine unit on an adjacent peptidoglycan strand, releasing the terminal D-alanine unit in the process. The structure of ceftriaxone mimics the D-alanyl-D-alanine moiety, and the PBP attacks the beta-lactam ring in ceftriaxone as if it were its normal D-alanyl-D-alanine substrate. The peptidoglycan cross-linking activity of PBPs is a construction and repair mechanism that normally helps to maintain bacterial cell wall integrity, so the inhibition of PBPs leads to damage and destruction of the cell wall and eventually to cell lysis.
Metabolism: 33-67% of ceftriaxone is renally excreted as unchanged drug, but no dose adjustments are required in renal impairment with dosages up to 2 grams per day. The rest is excreted in the bile as inactive compounds from hepatic and gut flora metabolism.
Distribution: Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat central nervous system infections. The average volume of distribution in adults is 5.8-13.5 liters.
Ceftriaxone is commercially available as a white to yellowish-orange crystalline powder for reconstitution. Reconstituted ceftriaxone injection solutions are light yellow- to amber-colored depending on how long the solution had been reconstituted, the concentration of ceftriaxone in the solution, and the diluent used. To reduce pain with intramuscular injections, ceftriaxone may be reconstituted with lidocaine.
The syn-configuration of the methoxyoxime moiety confers resistance to beta-lactamase enzymes produced by many Gram-negative bacteria. The stability of this configuration results in increased activity of ceftriaxone against otherwise resistant Gram-negative bacteria. In place of the easily hydrolyzed acetyl group of cefotaxime, ceftriaxone has a metabolically stable thiotriazinedione moiety.
Ceftriaxone has also been investigated for efficacy in preventing relapse to cocaine addiction.
Ceftriaxone has been shown to have neuroprotective properties in a number of neurological disorders, including spinal muscular atrophy and amyotrophic lateral sclerosis (ALS). Despite earlier negative results in the 1990s, a large clinical trial was undertaken in 2006 to test ceftriaxone in ALS patients, but was stopped early after it became clear that the results would not meet the predetermined criteria for efficacy.
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