Chemistry:Ceftriaxone

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Short description: Antibiotic medication
Ceftriaxone
Ceftriaxone-skeletal.svg
Ceftriaxone-from-PDB-6XQV-3D-bs-17.png
Clinical data
Pronunciation/ˌsɛftraɪˈæksoʊn/
Trade namesRocephin, Epicephin, Wintriaxone, others
AHFS/Drugs.comMonograph
MedlinePlusa685032
License data
Pregnancy
category
  • AU: B1[1]
  • US: B (No risk in non-human studies)[1]
Routes of
administration		Intravenous, intramuscular
Drug classThird-generation cephalosporin
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityn/a
MetabolismNegligible
Elimination half-life5.8–8.7 hours[2]
Excretion33–67% kidney, 35–45% biliary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H18N8O7S3
Molar mass554.57 g·mol−1
3D model (JSmol)
  (verify)

Ceftriaxone, sold under the brand name Rocephin, is a third-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections.[3] These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease.[3] It is also sometimes used before surgery and following a bite wound to try to prevent infection.[3] Ceftriaxone can be given by injection into a vein or into a muscle.[3]

Common side effects include pain at the site of injection and allergic reactions.[3] Other possible side effects include C. difficile-associated diarrhea, hemolytic anemia, gall bladder disease, and seizures.[3] It is not recommended in those who have had anaphylaxis to penicillin but may be used in those who have had milder reactions.[3] The intravenous form should not be given with intravenous calcium.[3] There is tentative evidence that ceftriaxone is relatively safe during pregnancy and breastfeeding.[1] It is a third-generation cephalosporin that works by preventing bacteria from making a cell wall.[3]

Ceftriaxone was patented in 1978 and approved for medical use in 1982.[4] It is on the World Health Organization's List of Essential Medicines.[5] It is available as a generic medication.[3]

Medical use

A vial of ceftriaxone, manufactured and sold in Russia

Ceftriaxone and other third-generation cephalosporin antibiotics are used to treat organisms that tend to be resistant to many other antibiotics.[6] Due to emergent resistance, ceftriaxone should not be used for the treatment of Enterobacter infections.[6] Before using ceftriaxone, it is important to determine the susceptibility of the bacteria.[7] If sepsis is being considered, empiric therapy may be initiated prior to susceptibility testing.[6]

Medical uses include:[7]

Ceftriaxone 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."[8]

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.[9]

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.[6] However, unlike ceftazidime and cefoperazone, ceftriaxone does not have useful activity against Pseudomonas aeruginosa.[6] 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.[6] 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).[6] Although not being used as first line therapy against Staphylococcus aures, ceftriaxone retains activity against isolates of methicillin-susceptible S. aureus and is used in clinic for infections sustained by this bacterium. In this case the dose should be doubled (e.g. 2 g intravenously every 12 hours).[10]

Available forms

Ceftriaxone is available for administration via the intramuscular or the intravenous routes.[7] 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.[7]

Specific populations

Pregnancy

Ceftriaxone is pregnancy category B.[7][1] It has not been observed to cause birth defects in animal studies, but a lack of well-controlled studies done in pregnant women exists.[7]

Breastfeeding

Low concentrations of ceftriaxone are excreted in breast milk that are "not expected to cause adverse effects in breastfed infants."[11][failed verification] The manufacturer recommends that caution be exercised when administering ceftriaxone to women who breastfeed.[7]

Newborns

Hyperbilirubinemic neonates are contraindicated for the use of ceftriaxone.[7] It can compete with bilirubin and displace it from binding to albumin, increasing the risk of bilirubin encephalopathy.[7]

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."[7]

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.[12]

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%)[12]

Some less frequently reported adverse events (incidence < 1%) include phlebitis, itchiness, fever, chills, nausea, vomiting, elevations of bilirubin, elevations in creatinine, headache and dizziness.[12]

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.[13][14][15] It has also been reported to cause post kidney failure in children.[16] Like other antibiotics, ceftriaxone use can result in Clostridioides difficile-associated diarrhea ranging from mild diarrhea to fatal colitis.[12] In this regard it has been reported that shifting from ceftriaxone to cefotaxime would have a lower impact on C. difficile infection rates, since cefotaxime is almost entirely excreted by the kidneys [17] while ceftriaxone has a 45% biliary excretion [18]

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,[8][19] caution should still be used when using ceftriaxone in penicillin-sensitive patients.[12] Caution should be used in people who have had previous severe penicillin allergies.[12] 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 [20] even if administered through different infusion lines due to rare fatal cases of calcium-ceftriaxone precipitations in neonatal lungs and kidneys.[12][21]

Mechanism of action

Ceftriaxone is a third-generation antibiotic from the cephalosporin family of antibiotics.[6] 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.[22] 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.[23][24] 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.[22][24] 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.[22] 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.[22]

Pharmacokinetics

Absorption: Ceftriaxone can be administered intravenously and intramuscularly, and the drug is completely absorbed.[7][25] It is not available orally.[26][27]

Distribution: Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat central nervous system infections.[7][28] 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.[7]

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.[7] The rest[29] is excreted in the bile as unchanged drug[30] which is ultimately excreted in feces as inactive compounds from hepatic and gut flora metabolism.[7][31][32]

Elimination: The average elimination half-life in healthy adults is 5.8–8.7 (mean 6.5) hours,[2] with some reviews estimated half-life up to 10 hours.[33] In people with renal impairment, the average elimination half-life increases to 11.4–15.7 hours.[7]

Chemistry

Ceftriaxone is commercially available as a white to yellowish-orange crystalline powder for reconstitution.[7] 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.[7] To reduce pain with intramuscular injections, ceftriaxone may be reconstituted with lidocaine.[34]

The syn-configuration of the methoxy oxime moiety confers resistance to beta-lactamase enzymes produced by many Gram-negative bacteria.[22] The stability of this configuration results in increased activity of ceftriaxone against otherwise resistant Gram-negative bacteria.[22] In place of the easily hydrolyzed acetyl group of cefotaxime, ceftriaxone has a metabolically stable thiotriazinedione moiety.[22]

Research

Ceftriaxone has also been investigated for efficacy in preventing relapse to cocaine addiction.[35]

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.[36][37]

Ceftriaxone has been shown to have neuroprotective properties in a number of neurological disorders, including spinal muscular atrophy[38] and amyotrophic lateral sclerosis (ALS).[39] 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.[40]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Ceftriaxone (Rocephin) Use During Pregnancy". 12 December 2019. https://www.drugs.com/pregnancy/ceftriaxone.html. 
  2. ↑ 2.0 2.1 "Ceftriaxone: a beta-lactamase-stable, broad-spectrum cephalosporin with an extended half-life". Pharmacotherapy 5 (5): 237–253. 1985. doi:10.1002/j.1875-9114.1985.tb03423.x. PMID 3906584. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 "Ceftriaxone Sodium Monograph for Professionals". Drugs.com. https://www.drugs.com/monograph/ceftriaxone-sodium.html. 
  4. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 495. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA495. 
  5. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Basic and Clinical Pharmacology. McGraw-Hill. 2012. pp. 797–801. ISBN 978-0-07-176402-5. 
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 "Ceftriaxone- ceftriaxone sodium injection, powder, for solution". 31 December 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5cd2d96f-83e5-4326-ae87-d0ede4ba493a. 
  8. ↑ 8.0 8.1 Basic and Clinical Pharmacology, Eleventh Edition. New York: McGraw-Hill. 2009. pp. 783–784. ISBN 978-0-07-160405-5. 
  9. ↑ "Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020". MMWR. Morbidity and Mortality Weekly Report 69 (50): 1911–1916. December 2020. doi:10.15585/mmwr.mm6950a6. PMID 33332296. 
  10. ↑ "Ceftriaxone for methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia: a matter of dosages?" (in en). European Journal of Clinical Microbiology & Infectious Diseases 42 (7): 917–918. 2023-04-29. doi:10.1007/s10096-023-04612-x. ISSN 1435-4373. PMID 37119346. 
  11. ↑ "TOXNET". http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/r?dbs+lactmed:@term+@DOCNO+57. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 "Rocephin Prescribing Information". Roche. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050585s061lbl.pdf. 
  13. ↑ "Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility". Gastroenterology 99 (6): 1772–1778. December 1990. doi:10.1016/0016-5085(90)90486-K. PMID 2227290. 
  14. ↑ "Ceftriaxone induced immune hemolytic anemia with disseminated intravascular coagulation". Indian Journal of Critical Care Medicine 17 (6): 394–395. November 2013. doi:10.4103/0972-5229.123465. PMID 24501497. 
  15. ↑ "Ceftriaxone-induced hemolysis". Indian Journal of Pharmacology 45 (5): 530–531. Sep–Oct 2013. doi:10.4103/0253-7613.117758. PMID 24130395. 
  16. ↑ "Ceftriaxone and acute renal failure in children". Pediatrics 133 (4): e917–e922. April 2014. doi:10.1542/peds.2013-2103. PMID 24664092. 
  17. ↑ "Pharmacokinetics of cefotaxime in healthy volunteers and patients". Diagnostic Microbiology and Infectious Disease 22 (1–2): 49–55. May 1995. doi:10.1016/0732-8893(95)00072-I. PMID 7587050. 
  18. ↑ "Influence of cephalosporines III generation with varying biliary excretion on fecal flora and emergence of resistant bacteria during and after cessation of therapy". Padiatrie und Padologie 21 (4): 335–342. 1986. PMID 3562044. https://pubmed.ncbi.nlm.nih.gov/3562044/. Retrieved 29 April 2023. 
  19. ↑ "The Use of Cephalosporins in Penicillin-allergic Patients". http://www.medscape.com/viewarticle/764042. 
  20. ↑ "FDA Updates warning on Ceftriaxone-Calcium injection". http://healthcare.utah.edu/pharmacy/alerts/243.htm. 
  21. ↑ "Intravenous ceftriaxone and calcium in the neonate: assessing the risk for cardiopulmonary adverse events". Pediatrics 123 (4): e609–e613. April 2009. doi:10.1542/peds.2008-3080. PMID 19289450. 
  22. ↑ 22.0 22.1 22.2 22.3 22.4 22.5 22.6 Foye's Principles of Medicinal Chemistry (Seventh ed.). Philadelphia, PA: Lippincott Williams & Wilkins. 2013. pp. 1093–1094, 1099–1100. ISBN 9781609133450. 
  23. ↑ "Formation of the glycan chains in the synthesis of bacterial peptidoglycan". Glycobiology 11 (3): 25R–36R. March 2001. doi:10.1093/glycob/11.3.25r. PMID 11320055. 
  24. ↑ 24.0 24.1 "Bacterial cell wall synthesis: new insights from localization studies". Microbiology and Molecular Biology Reviews 69 (4): 585–607. December 2005. doi:10.1128/MMBR.69.4.585-607.2005. PMID 16339737. 
  25. ↑ "Pharmacokinetic profile of ceftriaxone in man". The American Journal of Medicine 77 (4C): 17–25. October 1984. PMID 6093513. 
  26. ↑ Red Book: Pharmacy's Fundamental Reference (114th ed.). PDR Network, LLC.. 2010. ISBN 9781563637513. 
  27. ↑ "DailyMed – Search Results for ceftriaxone". http://dailymed.nlm.nih.gov/dailymed/search.cfm?query=ceftriaxone&searchdb=all&labeltype=all&sortby=rel&audience=professional&page=1&pagesize=100. 
  28. ↑ "Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections". Clinical Microbiology Reviews 23 (4): 858–883. October 2010. doi:10.1128/CMR.00007-10. PMID 20930076. 
  29. ↑ "Ceftriaxone: renal and biliary excretion and effect on the colon microflora". The Journal of Antimicrobial Chemotherapy 10 (3): 207–215. September 1982. doi:10.1093/jac/10.3.207. PMID 6292158. 
  30. ↑ "Pharmacokinetics of ceftriaxone". Hospital Practice 26 (Suppl 5): 7–13; discussion 52–4. September 1991. doi:10.1080/21548331.1991.11707737. PMID 1918224. 
  31. ↑ "Clinical pharmacokinetics of the third generation cephalosporins". Clinical Pharmacokinetics 10 (2): 101–143. 1985-04-01. doi:10.2165/00003088-198510020-00001. PMID 3888488. 
  32. ↑ Nursing Pharmacology Made Incredibly Easy!. Lippincott Williams & Wilkins. 2012-03-07. p. 496. ISBN 9781451146240. https://books.google.com/books?id=NA41OnSGFWEC. 
  33. ↑ "Third-generation cephalosporins". The Medical Clinics of North America 79 (4): 705–719. July 1995. doi:10.1016/s0025-7125(16)30034-7. PMID 7791418. 
  34. ↑ "Lidocaine as a diluent for ceftriaxone in the treatment of gonorrhea. Does it reduce the pain of the injection?". Archives of Pediatrics & Adolescent Medicine 148 (1): 72–75. January 1994. doi:10.1001/archpedi.1994.02170010074017. PMID 8143016. 
  35. ↑ "Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking". Biological Psychiatry 67 (1): 81–84. January 2010. doi:10.1016/j.biopsych.2009.07.018. PMID 19717140. 
  36. ↑ "Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury". European Journal of Pharmacology 638 (1–3): 65–71. July 2010. doi:10.1016/j.ejphar.2010.04.021. PMID 20423712. 
  37. ↑ "Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes". The Journal of Biological Chemistry 283 (19): 13116–13123. May 2008. doi:10.1074/jbc.M707697200. PMID 18326497. 
  38. ↑ "The protective effects of β-lactam antibiotics in motor neuron disorders". Experimental Neurology 231 (1): 14–18. September 2011. doi:10.1016/j.expneurol.2011.06.002. PMID 21693120. 
  39. ↑ "Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression". Nature 433 (7021): 73–77. January 2005. doi:10.1038/nature03180. PMID 15635412. Bibcode: 2005Natur.433...73R. 
  40. ↑ "Statement on the Clinical Trial of Ceftriaxone". The Northeast ALS Consortium (NEALS). 8 August 2012. http://www.alsconsortium.org/news_ceftriaxone_announcement.php. 

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