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 Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or the ...

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 Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severity ...

, 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 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 ...

or into a muscle. Common side effects include pain at the site of injection and

allergic reaction Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

s. Other possible side effects include ''C. difficile''-associated diarrhea, hemolytic anemia, gall bladder disease, and

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

. It is not recommended in those who have had

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

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 Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

. There is tentative evidence that ceftriaxone is relatively safe during pregnancy and breastfeeding. It is a

third-generation 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 ...

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 ''Enterobacter'' is a genus of common Gram-negative, facultatively anaerobic, rod-shaped, non-spore-forming bacteria of the family Enterobacteriaceae. It is the type genus of the order Enterobacterales. Several strains of these bacteria are pat ...

'' 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 infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

s * uncomplicated gonorrhea *

* bacterial

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

* intra-abdominal infections *

* surgical prophylaxis *

Lyme disease Lyme disease, also known as Lyme borreliosis, is a vector-borne disease caused by the ''Borrelia'' bacterium, which is spread by ticks in the genus ''Ixodes''. The most common sign of infection is an expanding red rash, known as erythema migran ...

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 ''Neisseria meningitidis'', often referred to as meningococcus, is a Gram-negative bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life-threatening sepsis. The bacterium is referred to as a ...

, ''

Haemophilus influenzae ''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bacteria ...

'', 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 The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...

(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 ''Serratia marcescens'' () is a species of rod-shaped, Gram-negative bacteria in the family Yersiniaceae. It is a facultative anaerobe and an opportunistic pathogen in humans. It was discovered in 1819 by Bartolomeo Bizio in Padua, Italy.Serrati ...

'', and beta-lactamase-producing strains of ''

Haemophilus ''Haemophilus'' is a genus of Gram-negative, pleomorphic, coccobacilli bacteria belonging to the family Pasteurellaceae. While ''Haemophilus'' bacteria are typically small coccobacilli, they are categorized as pleomorphic bacteria because of ...

'' 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 ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

''. It is generally not active against ''

'' 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 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 ...

cephalosporins and render them inactive).

Available forms

Ceftriaxone is available for administration via the

intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles have l ...

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 Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...

, 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 Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

(2.1%) * Elevation in

BUN A bun is a type of bread roll, typically filled with savory fillings (for example hamburger). A bun may also refer to a sweet cake in certain parts of the world. Though they come in many shapes and sizes, buns are most commonly round, and are ...

(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, 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 Penicillin-binding proteins (PBPs) are a group of proteins that are characterized by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discove ...

(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 Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

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 In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

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

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