Ceftriaxone

Ceftriaxone
Names
Pronunciation/ˌsɛftraɪˈæksoʊn/
Trade namesRocephin, Epicephin, Wintriaxone, others
IUPAC name
  • (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)->2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Clinical data
Drug classAntibiotic (3rd-generation cephalosporin)
Side effectsPain at the site of injection, allergic reactions[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B1[2]
  • US: B (No risk in non-human studies)[2]
    Routes of
    use    		Intravenous, intramuscular
    Defined daily dose2 gm[3]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa685032
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    Pharmacokinetics
    Bioavailabilityn/a
    MetabolismNegligible
    Elimination half-life5.8–8.7 hours
    Excretion33–67% kidney, 35–45% biliary
    Chemical and physical data
    FormulaC18H18N8O7S3
    Molar mass554.57 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C2N1/C(=C(\CS[C@@H]1[C@@H]2NC(=O)C(=N\OC)/c3nc(sc3)N)CS\C4=N\C(=O)C(=O)NN4C)C(=O)O
    InChI
    • InChI=1S/C18H18N8O7S3/c1-25-18(22-12(28)13(29)23-25)36-4-6-3-34-15-9(14(30)26(15)10(6)16(31)32)21-11(27)8(24-33-2)7-5-35-17(19)20-7/h5,9,15H,3-4H2,1-2H3,(H2,19,20)(H,21,27)(H,23,29)(H,31,32)/b24-8-/t9-,15-/m1/s1 checkY
    • Key:VAAUVRVFOQPIGI-SPQHTLEESA-N checkY

    Ceftriaxone, sold under the brand name Rocephin, is an antibiotic used for the treatment of a number of bacterial infections.[1] 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.[1] It is also sometimes used before surgery and following a bite wound to try to prevent infection.[1] Ceftriaxone can be given by injection into a vein or into a muscle.[1]

    Common side effects include pain at the site of injection and allergic reactions.[1] Other possible side effects include C. difficile associated diarrhea, hemolytic anemia, gall bladder disease, and seizures.[1] It is not recommended in those who have had anaphylaxis to penicillin but may be used in those who have had milder reactions.[1] The intravenous form should not be given with intravenous calcium.[1] There is tentative evidence that ceftriaxone is relatively safe during pregnancy and breastfeeding.[2] It is a third-generation cephalosporin that works by preventing bacteria from making a cell wall.[1] It can cross the blood-brain barrier.[4]

    Ceftriaxone was patented in 1978, and approved for medical use in 1982.[5] It is on the World Health Organization's List of Essential Medicines.[6] It is available as a generic medication.[1] In the developing world the wholesale cost per one-gram vial is about US$0.20 to US$5.80 as of 2015.[7] In the United States a course of treatment is typically less than US$25.[8]

    Medical use

    A vial of ceftriaxone, manufactured and sold in Russia

    It is in the 'watch' group of the WHO AWaRe Classification.[9]

    Ceftriaxone and other third-generation antibiotics are used to treat organisms that tend to be resistant to many other antibiotics.[10] Due to emergent resistance, ceftriaxone should not be used for the treatment of Enterobacter infections.[10] Before using ceftriaxone, it is important to determine the susceptibility of the bacteria.[11] If sepsis is being considered, empiric therapy may be initiated prior to susceptibility testing.[10]

    Medical uses include:[11]

    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."[12]

    In combination with doxycycline or azithromycin, ceftriaxone is recommended by the United States Centers for Disease Control and Prevention (CDC) for the treatment of gonorrhea. By itself, it is not recommended due to the potential for resistance development.[13]

    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."[11]

    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.[10] However, unlike ceftazidime and cefoperazone, ceftriaxone does not have useful activity against Pseudomonas aeruginosa.[10] 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.[10] 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).[10]

    Dosage

    The defined daily dose is 2 grams by injection.[3] For severe bacterial infections in adults 1 to 2 grams once per day or 20 to 100 mg/kg in children over a month of age is generally used.[14]

    For gonorrhea in those over 45 kg 250 mg by injection into a muscle or for those under 45 kg 125 mg injected into a muscle is recommended by MSF.[14] In 2020 the US CDC increased the recommended dose for gonorrhea to 500 mg and 1,000 mg for those over 150 kg.[15] For conjunctivitis due to gonorrhea the dose is 50 mg/kg or 1 gram as a single injection into a muscle.[14]

    Ceftriaxone is available for the intramuscular or intravenous routes.[11] Diluents containing calcium should not be used to reconstitute ceftriaxone and it should not be administered in intravenous lines containing other calcium-containing solutions, as a ceftriaxone-calcium precipitate could form.[11]

    Side effects

    Urticarial and maculopapular rash

    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.[16]

    Incidence of adverse effects greater than 1%:

    Some less frequently reported adverse events (incidence < 1%) include phlebitis, itchiness, fever, chills, nausea, vomiting, elevations of bilirubin, elevations in creatinine, headache and dizziness.[16]

    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.[17][18][19] It has also been reported to cause post kidney failure in children.[20] Like other antibiotics, ceftriaxone use can result in Clostridium difficile-associated diarrhea ranging from mild diarrhea to fatal colitis.[16]

    Pregnancy and breastfeeding

    Ceftriaxone is pregnancy category B.[11][2] It has not been observed to cause birth defects in animal studies, but there are a lack of well-controlled studies in pregnant women.[11]

    Low concentrations of ceftriaxone are excreted in breast milk that are "not expected to cause adverse effects in breastfed infants."[21][14] The manufacturer recommends that caution be exercised when administering ceftriaxone to women who breastfeed.[11]

    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,[12][22] caution should still be used when using ceftriaxone in penicillin-sensitive patients.[16] Caution should be used in people who have had previous severe penicillin allergies.[16] 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 [23] even if administered through different infusion lines due to rare fatal cases of calcium-ceftriaxone precipitations in neonatal lungs and kidneys.[16][24]

    Hyperbilirubinemic neonates are contraindicated for the use of ceftriaxone.[11] It can compete with bilirubin and displace it from binding to albumin, increasing the risk of bilirubin encephalopathy.[11]

    Mechanism of action

    Ceftriaxone is a third-generation antibiotic from the cephalosporin family of antibiotics.[10] 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.[25] 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.[26][27] 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.[25][27] 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.[25] 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.[25]

    Pharmacokinetics

    Absorption: Ceftriaxone can be administered intravenously and intramuscularly, and the drug is completely absorbed.[11][28] It is not available orally.[29][30]

    Distribution: Ceftriaxone penetrates tissues and body fluids well, including cerebrospinal fluid to treat central nervous system infections.[11][31] The average volume of distribution in adults is 5.8–13.5 liters.[11]

    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.[11] The rest is excreted in the bile as inactive compounds from hepatic and gut flora metabolism.[11][32][33]

    Elimination: The average elimination half-life in healthy adults is 5.8–8.7 hours.[11] In people with renal impairment, the average elimination half-life increases to 11.4–15.7 hours.[11]

    Chemistry

    Ceftriaxone is commercially available as a white to yellowish-orange crystalline powder for reconstitution.[11] 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.[11] To reduce pain with intramuscular injections, ceftriaxone may be reconstituted with lidocaine.[34]

    The syn-configuration of the methoxyoxime moiety confers resistance to beta-lactamase enzymes produced by many Gram-negative bacteria.[25] The stability of this configuration results in increased activity of ceftriaxone against otherwise resistant Gram-negative bacteria.[25] In place of the easily hydrolyzed acetyl group of cefotaxime, ceftriaxone has a metabolically stable thiotriazinedione moiety.[25]

    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 2 3 4 5 6 7 8 9 10 11 12 "Ceftriaxone Sodium Monograph for Professionals". Drugs.com. Archived from the original on 31 May 2016. Retrieved 27 August 2016.
    2. 1 2 3 4 "Ceftriaxone (Rocephin) Use During Pregnancy". Drugs.com. 12 December 2019. Archived from the original on 23 August 2016. Retrieved 24 December 2019.
    3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 20 September 2020. Retrieved 1 September 2020.
    4. ↑ Ritter, James M.; Flower, Rod; Henderson, Graeme; Loke, Yoon Kong; Rang, Humphrey P. (2020). "52. Antibacterial drugs". Rang & Dale's Pharmacology (9th ed.). Elsevier. pp. 665–666. ISBN 978-0-7020-7448-6. Archived from the original on 28 August 2021. Retrieved 1 December 2021.
    5. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 495. ISBN 9783527607495. Archived from the original on 20 December 2016. Retrieved 5 June 2020.
    6. ↑ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    7. ↑ "Single Drug Information – International Medical Products Price Guide". Archived from the original on 28 August 2021. Retrieved 28 May 2020.
    8. ↑ Facep, Hamilton (2013). Tarascon Pocket Pharmacopoeia 2014 Deluxe Lab-Coat Edition. Jones & Bartlett Publishers. p. 75. ISBN 9781284053999. Archived from the original on 8 September 2017.
    9. ↑ Zanichelli, Veronica; Sharland, Michael; Cappello, Bernadette; Moja, Lorenzo; Getahun, Haileyesus; Pessoa-Silva, Carmem; Sati, Hatim; van Weezenbeek, Catharina; Balkhy, Hanan; Simão, Mariângela; Gandra, Sumanth; Huttner, Benedikt (1 April 2023). "The WHO AWaRe (Access, Watch, Reserve) antibiotic book and prevention of antimicrobial resistance". Bulletin of the World Health Organization. 101 (4): 290–296. doi:10.2471/BLT.22.288614. ISSN 0042-9686. Archived from the original on 7 May 2023. Retrieved 17 November 2023.
    10. 1 2 3 4 5 6 7 8 Katzung, Bertram; Masters, Susan; Trevor, Anthony (2012). Basic and Clinical Pharmacology. McGraw-Hill. pp. 797–801. ISBN 978-0-07-176402-5.
    11. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 "Ceftriaxone- ceftriaxone sodium injection, powder, for solution". DailyMed. 31 December 2019. Archived from the original on 17 November 2015. Retrieved 1 February 2020.
    12. 1 2 Katzung, Bertram (2009). Basic and Clinical Pharmacology, Eleventh Edition. New York: McGraw-Hill. pp. 783–784. ISBN 978-0-07-160405-5.
    13. ↑ Centers for Disease Control Prevention (CDC) (August 2012). "Update to CDC's Sexually transmitted diseases treatment guidelines, 2010: oral cephalosporins no longer a recommended treatment for gonococcal infections" (PDF). MMWR. Morbidity and Mortality Weekly Report. 61 (31): 590–4. PMID 22874837. Archived (PDF) from the original on 27 June 2020. Retrieved 2 February 2020.
    14. 1 2 3 4 "CEFTRIAXONE injectable - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 1 September 2020.
    15. ↑ St. Cyr, Sancta; Barbee, Lindley; Workowski, Kimberly A.; Bachmann, Laura H.; Pham, Cau; Schlanger, Karen; Torrone, Elizabeth; Weinstock, Hillard; Kersh, Ellen N.; Thorpe, Phoebe (18 December 2020). "Update to CDC's Treatment Guidelines for Gonococcal Infection, 2020". MMWR. Morbidity and Mortality Weekly Report. 69 (50): 1911–1916. doi:10.15585/mmwr.mm6950a6. {{cite journal}}: Check |doi= value (help)
    16. 1 2 3 4 5 6 7 "Rocephin Prescribing Information" (PDF). Roche. Archived (PDF) from the original on 4 March 2016. Retrieved 1 November 2015.
    17. ↑ Shiffman ML, Keith FB, Moore EW (December 1990). "Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility". Gastroenterology. 99 (6): 1772–8. doi:10.1016/0016-5085(90)90486-K. PMID 2227290.
    18. ↑ Shrimali JD, Patel HV, Gumber MR, Kute VB, Shah PR, Vanikar AV, Trivedi HL (November 2013). "Ceftriaxone induced immune hemolytic anemia with disseminated intravascular coagulation". Indian Journal of Critical Care Medicine. 17 (6): 394–5. doi:10.4103/0972-5229.123465. PMC 3902580. PMID 24501497.
    19. ↑ Guleria VS, Sharma N, Amitabh S, Nair V (September–October 2013). "Ceftriaxone-induced hemolysis". Indian Journal of Pharmacology. 45 (5): 530–1. doi:10.4103/0253-7613.117758. PMC 3793531. PMID 24130395.
    20. ↑ Li N, Zhou X, Yuan J, Chen G, Jiang H, Zhang W (April 2014). "Ceftriaxone and acute renal failure in children". Pediatrics. 133 (4): e917-22. doi:10.1542/peds.2013-2103. PMID 24664092. S2CID 2854637.
    21. ↑ "TOXNET". toxnet.nlm.nih.gov. Archived from the original on 8 September 2017. Retrieved 4 November 2015.
    22. ↑ "The Use of Cephalosporins in Penicillin-allergic Patients". www.medscape.com. Archived from the original on 14 November 2015. Retrieved 10 November 2015.
    23. ↑ "FDA Updates warning on Ceftriaxone-Calcium injection". Archived from the original on 28 November 2009.
    24. ↑ Bradley JS, Wassel RT, Lee L, Nambiar S (April 2009). "Intravenous ceftriaxone and calcium in the neonate: assessing the risk for cardiopulmonary adverse events". Pediatrics. 123 (4): e609-13. doi:10.1542/peds.2008-3080. PMID 19289450.
    25. 1 2 3 4 5 6 7 Lemke, Thomas L.; Williams, David A., eds. (2013). Foye's Principles of Medicinal Chemistry (Seventh ed.). Philadelphia, PA: Lippincott Williams & Wilkins. pp. 1093–1094, 1099–1100. ISBN 9781609133450.
    26. ↑ van Heijenoort J (March 2001). "Formation of the glycan chains in the synthesis of bacterial peptidoglycan". Glycobiology. 11 (3): 25R–36R. doi:10.1093/glycob/11.3.25r. PMID 11320055. S2CID 46066256.
    27. 1 2 Scheffers DJ, Pinho MG (December 2005). "Bacterial cell wall synthesis: new insights from localization studies". Microbiology and Molecular Biology Reviews. 69 (4): 585–607. doi:10.1128/MMBR.69.4.585-607.2005. PMC 1306805. PMID 16339737.
    28. ↑ Patel IH, Kaplan SA (October 1984). "Pharmacokinetic profile of ceftriaxone in man". The American Journal of Medicine. 77 (4C): 17–25. PMID 6093513.
    29. ↑ Red Book: Pharmacy's Fundamental Reference (114th ed.). PDR Network, LLC. 2010. ISBN 9781563637513.
    30. ↑ "DailyMed – Search Results for ceftriaxone". dailymed.nlm.nih.gov. Archived from the original on 6 March 2016. Retrieved 4 November 2015.
    31. ↑ Nau R, Sörgel F, Eiffert H (October 2010). "Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections". Clinical Microbiology Reviews. 23 (4): 858–83. doi:10.1128/CMR.00007-10. PMC 2952976. PMID 20930076.
    32. ↑ Balant L, Dayer P, Auckenthaler R (1 April 1985). "Clinical pharmacokinetics of the third generation cephalosporins". Clinical Pharmacokinetics. 10 (2): 101–43. doi:10.2165/00003088-198510020-00001. PMID 3888488. S2CID 23478077.
    33. ↑ Wilkins, Lippincott Williams & (7 March 2012). Nursing Pharmacology Made Incredibly Easy!. Lippincott Williams & Wilkins. p. 496. ISBN 9781451146240. Archived from the original on 3 June 2016.
    34. ↑ Schichor A, Bernstein B, Weinerman H, Fitzgerald J, Yordan E, Schechter N (January 1994). "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): 72–5. doi:10.1001/archpedi.1994.02170010074017. PMID 8143016.
    35. ↑ Knackstedt LA, Melendez RI, Kalivas PW (January 2010). "Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking". Biological Psychiatry. 67 (1): 81–4. doi:10.1016/j.biopsych.2009.07.018. PMC 2795043. PMID 19717140.
    36. ↑ Verma R, Mishra V, Sasmal D, Raghubir R (July 2010). "Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury". European Journal of Pharmacology. 638 (1–3): 65–71. doi:10.1016/j.ejphar.2010.04.021. PMID 20423712.
    37. ↑ Lee SG, Su ZZ, Emdad L, Gupta P, Sarkar D, Borjabad A, et al. (May 2008). "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): 13116–23. doi:10.1074/jbc.M707697200. PMC 2442320. PMID 18326497.
    38. ↑ Hedlund E (September 2011). "The protective effects of β-lactam antibiotics in motor neuron disorders". Experimental Neurology. 231 (1): 14–8. doi:10.1016/j.expneurol.2011.06.002. PMID 21693120. S2CID 26353910.
    39. ↑ Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. (January 2005). "Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression". Nature. 433 (7021): 73–7. Bibcode:2005Natur.433...73R. doi:10.1038/nature03180. PMID 15635412. S2CID 4301666.
    40. ↑ "Statement on the Clinical Trial of Ceftriaxone". The Northeast ALS Consortium (NEALS). 8 August 2012. Archived from the original on 28 May 2013. Retrieved 10 May 2013.


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