Ceftriaxone, sold under the brand name Rocephin, is a third-generation

cephalosporin antibiotic The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...

used for the treatment of a number of bacterial infections. These include

middle ear infections Otitis media is a group of Inflammation, inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling ...

, endocarditis,

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and

pelvic inflammatory disease Pelvic inflammatory disease, also known as pelvic inflammatory disorder (PID), is an infection of the upper part of the female reproductive system, namely the uterus, fallopian tubes, and ovaries, and inside of the pelvis. Often, there may be no ...

. It is also sometimes used before surgery and following a

bite wound Biting is a common zoological behavior involving the active, rapid closing of the jaw around an object. This behavior is found in toothed animals such as mammals, reptiles, amphibians and fish, but can also exist in arthropods. Myocytic contrac ...

to try to prevent infection. Ceftriaxone can be given by injection into a vein or into a muscle. Common side effects include pain at the site of injection and allergic reactions. Other possible side effects include ''C. difficile''-associated diarrhea, hemolytic anemia,

gall bladder disease A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migr ...

, and seizures. It is not recommended in those who have had anaphylaxis to

penicillin Penicillins (P, PCN or PEN) are a group of β-lactam antibiotics originally obtained from ''Penicillium'' moulds, principally '' P. chrysogenum'' and '' P. rubens''. Most penicillins in clinical use are synthesised by P. chrysogenum using ...

but may be used in those who have had milder reactions. The intravenous form should not be given with intravenous calcium. There is tentative evidence that ceftriaxone is relatively safe during pregnancy and breastfeeding. It is a third-generation cephalosporin that works by preventing bacteria from making a

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...

. Ceftriaxone was patented in 1978 and approved for medical use in 1982. It is on the World Health Organization's List of Essential Medicines. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

Medical use

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. Medical uses include: * lower respiratory tract infections * acute bacterial

otitis media Otitis media is a group of inflammatory diseases of the middle ear. One of the two main types is acute otitis media (AOM), an infection of rapid onset that usually presents with ear pain. In young children this may result in pulling at the ear, ...

* skin and skin structure infections * urinary tract infections * uncomplicated gonorrhea *

* bacterial sepsis * intra-abdominal infections *

* surgical prophylaxis * Lyme disease Ceftriaxone is also a choice drug for treatment of

bacterial meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

caused by

pneumococci ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...

, meningococci, '' Haemophilus influenzae'', and "susceptible enteric Gram-negative rods, but not '' Listeria monocytogenes''." In combination with doxycycline or azithromycin, ceftriaxone used to be recommended by the United States Centers for Disease Control and Prevention (CDC) for the treatment of uncomplicated gonorrhea. Due to increased risk of developing azithromycin resistant strains and the high efficacy of higher doses of ceftriaxone the guidance has been updated to mono-antibiotic therapy with a higher dose of ceftriaxone.

Spectrum of activity

Like other third-generation cephalosporins, ceftriaxone is active against ''

Citrobacter ''Citrobacter'' is a genus of Gram-negative coliform bacteria in the family Enterobacteriaceae. The species ''C. amalonaticus'', ''C. koseri'', and ''C. freundii'' can use citrate as a sole carbon source. ''Citrobacter'' species are differentia ...

'' spp., '' Serratia marcescens'', and beta-lactamase-producing strains of '' Haemophilus'' and '' Neisseria''. However, unlike ceftazidime and

cefoperazone Cefoperazone is a third-generation cephalosporin antibiotic, marketed by Pfizer under the name Cefobid. It is one of few cephalosporin antibiotics effective in treating ''Pseudomonas'' bacterial infections which are otherwise resistant to these ...

, 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 (enzymes that hydrolyze cephalosporins and render them inactive).

Available forms

Ceftriaxone is available for administration via the intramuscular or the

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

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.

Specific populations

Pregnancy

Ceftriaxone is pregnancy category B. It has not been observed to cause birth defects in animal studies, but a lack of well-controlled studies done in pregnant women exists.

Breastfeeding

Low concentrations of ceftriaxone are excreted in

breast milk Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by mammary glands located in the breast of a human female. Breast milk is the primary source of nutrition for newborns, containing fat, protein, carbohydrates ( lacto ...

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.

Newborns

Hyperbilirubinemic neonates are contraindicated for the use of ceftriaxone. It can compete with

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

and displace it from binding to albumin, increasing the risk of bilirubin encephalopathy.

Elderly

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."

Adverse effects

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 Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 x 109/ L (i.e. 1,500/μL). The hypereosinophilic syndro ...

(6%) *

Thrombocytosis Thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150x109 to 450x109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750x109/L. ...

(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

, elevations in creatinine, headache and dizziness. Ceftriaxone may precipitate in bile, causing

biliary sludge A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...

biliary pseudolithiasis Biliary pseudolithiasis is an unusual complication of ceftriaxone where the drug complexes with calcium and mimics gallstones. It is reversed when ceftriaxone administration is stopped. It was first described in 1988 by Schaad et al. as "reversibl ...

, and gallstones, especially in children. Hypoprothrombinaemia and bleeding are specific side effects. Haemolysis is reported. It has also been reported to cause post kidney failure in children. Like other antibiotics, ceftriaxone use can result in ''Clostridium difficile''-associated diarrhea ranging from mild diarrhea to fatal colitis.

Contraindications

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 The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...

family of antibiotics. It is within the β-lactam 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.

Pharmacokinetics

Absorption: Ceftriaxone can be administered intravenously and intramuscularly, and the drug is completely absorbed. It is not available orally. Distribution: Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat central nervous system infections. Ceftriaxone is reversibly bound to human plasma proteins and the binding of ceftriaxone decreases with increasing concentration from a value of 95% at plasma concentrations less than 25 mcg/mL to 85% at plasma concentration of 300 mcg/mL. Over a 0.15 to 3 g dose range in healthy adult subjects, the apparent volume of distribution ranged from 5.8 to 13.5 L. 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. Elimination: The average elimination half-life in healthy adults is 5.8–8.7 hours . In people with renal impairment, the average elimination half-life increases to 11.4–15.7 hours.

Chemistry

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 Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...

. The ''syn''-configuration of the methoxy oxime 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 Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

acetyl In organic chemistry, acetyl is a functional group with the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, acetyl is called ethanoyl, ...

group of cefotaxime, ceftriaxone has a metabolically stable thiotriazinedione moiety.

Research

Ceftriaxone has also been investigated for efficacy in preventing relapse to cocaine addiction. Ceftriaxone seems to increase excitatory amino acid transporter-2 pump expression and activity in the central nervous system, so has a potential to reduce glutamatergic toxicity. Ceftriaxone has been shown to have neuroprotective properties in a number of neurological disorders, including

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

and

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(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.

References

External links

* {{portal bar, Medicine Acetaldehyde dehydrogenase inhibitors Cephalosporin antibiotics Hoffmann-La Roche brands Thiazoles Triazines World Health Organization essential medicines Wikipedia medicine articles ready to translate