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Clinical data
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • AU: C
Routes of
administration		Oral, IV
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding70%
MetabolismHepatic acetylation and glucuronidation
Elimination half-life10 hours
ExcretionRenal
Identifiers
  • 4-Amino-N-(5-methylisoxazol-3-yl)-benzenesulfonamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
Chemical and physical data
FormulaC10H11N3O3S
Molar mass253.279 g/mol g·mol−1
3D model (JSmol)
Melting point169 °C (336 °F)
  • O=S(=O)(Nc1noc(c1)C)c2ccc(N)cc2
  • InChI=1S/C10H11N3O3S/c1-7-6-10(12-16-7)13-17(14,15)9-4-2-8(11)3-5-9/h2-6H,11H2,1H3,(H,12,13) checkY
  • Key:JLKIGFTWXXRPMT-UHFFFAOYSA-N checkY
  (verify)

Sulfamethoxazole (abbreviated SMZ and SMX)[1][2][3], also known as Gantanol (trade name), is a sulfonamide bacteriostatic antibiotic introduced to the United States in 1961[4] that is discontinued.[5][6] It is now commonly used as part of a synergistic combination with trimethoprim (abbreviated SMZ-TMP and SMX-TMP,[7] or TMP-SMZ and TMP-SMX), also known under trade names such as Bactrim, Bactrim DS, Septra DS, or Sulfatrim.[8]

It was used for bacterial infections such as urinary tract infections, bronchitis, and prostatitis and is affective against both gram negative and positive bacteria such as Listeria monocytogenes and E. coli.[6]

Other names include: sulfamethalazole, sulfisomezole,[9][10] and sulfamethazole.[11]

Side effects

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The most common side effects of sulfamethoxazole are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). [12]. There have been rare instances where severe adverse reactions have resulted in fatalities. These include Stevene-Johnson Syndrome (SJS), toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias[12].

Allergic reactions to Sulfonamides have been shown to include the entire Gel-Coombs spectrum of hyperactivity reactions [13]. Type 1 reactions include immunoglobulin E (IgE)-mediated reactions such as urticaria, angioedema, and anaphylaxis. In contrast, non-type 1 hypersensitivities are believed to be caused by metabolites of sulfonamides[14]. Therefor, the liver and kidney are the determining factors of these other hypersensitivity reactions; [14] alterations in kidney or liver functions may increase or decrease the frequencies of these reactions. One study has shown the allergic reaction rate to be about 3.0% over 359 courses of therapy[15]. Of the allergic reactions, skin rashes, eosinophilia and drug fever were the most common, while serious reactions were less common.

Sulfamethoxazole is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides[13].

Mechanism of action

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Sulfamethoxazole, a sulfonamide, is a structural analog of para-aminobenzoic acid (PABA). They compete with PABA to bind to dihydropteroate synthetase and inhibit conversion of PABA and dihydropteroate diphosphate to dihydrofolic acid, or dihydrofolate. [16] Inhibiting the production of dihydrofolate intermediate interferes with the normal bacterial synthesis of folic acid (folate). Folate is an essential metabolite for bacterial growth and replication because it is used in DNA synthesis, primarily at thymidylate and purine biosynthesis, and amino acids synthesis, including serine, glycine and methionine. [17] Hence, blockage of folate production inhibits the folate-dependent metabolic processes for bacterial growth and makes sulfamethoxazole a bacteriostatic antibiotic.[18]

Tetrahydrofolate synthesis pathway

Sulfonamides are selective against bacteria because it interferes with the synthesis of folate, a process which does not occur in humans. [19]

Pharmacokinetics

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Absorption

Sulfamethoxazole is well-absorbed when administered topically. It is rapidly absorbed when it is orally administered[6].

Distribution

Sulfamethoxazole distributes into most body tissues as well as into sputum, vaginal fluid, and middle ear fluid [15][12]. It also crosses the placenta. About 70% of the drug is bound to plasma proteins. Its Tmax (or time to reach maximum drug concentration in plasma) occurs 1 to 4 hours after oral administration. The mean serum half-life of sulfamethoxazole is 10 hours[12]. However, the half-life of the drug noticeably increases in patients with creatinine clearance rates equal to or less than 30 mL/minute. A half-life of 22-50 hours has been reported for patients with creatinine clearances of less than 10 mL/minute[15].

Metabolism

Sulfamethoxazole is metabolized in the human liver to at least 5 metabolites. These metabolites are the N4-acetyl-, N4-hydroxy-, 5-methylhydroxy-, N4-acetyl-5-methylhydroxy-sulfamethoxazole metabolites, and an N-glucuronide conjugate. The CYP2C9 enzyme is responsible for the formation of the N4-hydroxy metabolite. In vitro studies suggest sulfamethoxazole is not a substrate of the P-glycoprotein transporter[12].

Excretion

Sulfamethoxazole is primarily renally excreted via glomerular filtration and tubular secretion[12]. About 20% of the sulfamethoxazole in urine is the unchanged drug, about 15-20% is the N-glucuronide conjugate, and about 50-70 % is the acetylated metabolite[15]. Sulfamethoxazole is also excreted in human milk[12].

See also

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Notes

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  1. ^ Ma, M.; Cheng, Y.; Xu, Z.; Xu, P.; Qu, H.; Fang, Y.; Xu, T.; Wen, L. (2007). "Evaluation of polyamidoamine (PAMAM) dendrimers as drug carriers of anti-bacterial drugs using sulfamethoxazole (SMZ) as a model drug". European Journal of Medicinal Chemistry. 42 (1): 93–8. doi:10.1016/j.ejmech.2006.07.015. PMID 17095123.
  2. ^ Garg, S.K.; Ghosh, S.S.; Mathur, V.S. (1986). "Comparative pharmacokinetic study of four different sulfonamides in combination with trimethoprim in human volunteers". International Journal of Clinical Pharmacology, Therapy, and Toxicology. 24 (1): 23–5. PMID 3485584.
  3. ^ SMZ in Abstract of "Rat model of concurrent Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium complex (MAC) infections for assessment of multiple prophylaxis" at ncbi.nlm.nih.gov
  4. ^ Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. William Andrew Publishing. 22 October 2013. ISBN 9780815518563.
  5. ^ "Sulfamethoxazole". Drugs@FDA. Retrieved 5 November 2015.
  6. ^ a b c "Sulfamethoxazole". DrugBank. Retrieved 5 November 2015.
  7. ^ SMZ-TMP in Abstract of "Cutaneous hypersensitivity to sulfamethoxazole-trimethoprim (SMZ TMP) in HIV infected patients" at nlm.nih.gov
  8. ^ Williams, Eni. "sulfamethoxazole and trimethoprim, Bactrim, Septra". MedicineNet.com. Retrieved 5 November 2015.
  9. ^ PubChem. "Sulfamethoxazole - Substance Summary", PubChem, National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), National Institutes of Health (NIH)
  10. ^ ChemDB. "Sulfamethoxazole", ChemDB, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)
  11. ^ Sulfamethazole in "Clinical Diabetes: Case Study: A 90-Year-Old Man With Confusion and Night Sweats", and "Chronic Granulomatous Disease"
  12. ^ a b c d e f g "Bactrim USPI" (PDF). FDA. Cite error: The named reference "USPI" was defined multiple times with different content (see the help page).
  13. ^ a b Wulf, Matuszewski (2013). "Sulfonamide cross-reactivity: Is there evidence to support broad cross-allergenicity?". Clinical Consultations. 70.
  14. ^ a b Choquet-Kastylevsky, Vial, Descotes (2002). "Allergic Adverse Reactions to Sulfonamides". Allergy and Asthma Reports. 2 (1): 16–25. doi:10.1007/s11882-002-0033-y. PMID 11895621. S2CID 19624750.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ a b c d "Toxnet: Sulfamethoxazole".
  16. ^ Cite error: The named reference :0 was invoked but never defined (see the help page).
  17. ^ "Sulfonamides and Sulfonamide Combinations: Antibacterial Agents: Merck Veterinary Manual". www.merckvetmanual.com. Retrieved 2015-11-05.
  18. ^ "Sulfamethoxazole". {{cite journal}}: Cite journal requires |journal= (help)
  19. ^ "Sulfonamides - Infectious Diseases". Merck Manuals Professional Edition. Retrieved 2015-11-05.
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Category:Anilines Category:Aromatic amines Category:Isoxazoles Category:Sulfonamide antibiotics Category:Dihydropteroate synthetase inhibitors Category:Equine medications

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