Medical Pharmacology Chapter 35  Antibacterial Drugs

• Sulfonamides

  • Antimicrobial Spectrum of Activity

    • Gram-Positive Bacteria 

      • Activity includes Staphylococcus aureus, including many community-associated methicillin-resistant S. aureus (CA-MRSA) strains, Streptococcus pneumoniae, and Streptococcus pyogenes.¹ 

        •  However, sulfonamides are clinically ineffective for the treatment of Group A streptococcal pharyngitis because they do not reliably eradicate the organism from the pharynx.²  

    • Gram-Negative Bacteria³ 

      1. The spectrum covers many common enteric and respiratory pathogens, including Escherichia coli, Klebsiella species, Proteus mirabilis, Shigella species, Vibrio species, and Haemophilus influenzae.

      2. Pseudomonas aeruginosa is characteristically resistant.

    • Atypical and Other Organisms

      •  TMP/SMX (Trimethoprim/Sulfamethoxazole) is active against Nocardia species and Listeria monocytogenes. TMP/SMX may be effective against Actinomyces species but is not the agent of first-choice compared to tetracylines and carbapenems.^2,4

      Protozoa and Fungi

      • The combination is highly effective against several non-bacterial pathogens, including the protozoa Toxoplasma gondii (Pyrimethamine is likely the most effective agent against toxoplasmosis, used in combination with other agents such as clindamycin or sulfadiazine), Cystoisospora, and Cyclospora, and is the cornerstone of therapy for the fungus Pneumocystis jirovecii.^2,5

  • Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion (ADME))

    • Absorption

      • Most sulfonamides intended for systemic use are well-absorbed from the GI tract. Oral sulfonamides (e.g. sulfamethoxazole, sulfisoxazole, sulfadiazine) have bioavailability typically in the 70-100% range.⁶

        • Absorption occurs in the stomach and small intestine, and peak plasma levels are reached in 2-4 hours.⁶

          • Peak plasma levels occur about 1-4 hours after oral administration ; C_max at steady state ranges from 57-68 µg/ml. ⁶

      •  Some older sulfonamides with certain substitutions (e.g. sulfathalidine⁸, succinylsulfathiazole⁷) are poorly absorbed by design, so that they remain in the bowel.

        • These drugs were used for intestinal infections or bowel flora suppression.

        • Topical sulfonamides (ophthalmic drops, burn creams) can be absorbed through mucosa or damaged skin and may achieve systemic levels.⁹

    • Distribution

      • Sulfonamides distribute widely into body tissues and fluids.

        • They are relatively small molecules and, in their un-ionized form, cross cell membranes readily.

        • Sulfonamides achieve near-equivalent concentrations in pleural, peritoneal, synovial fluids, etc., compared to plasma.¹⁰ 

        • Sulfonamides also penetrate well into the cerebrospinal fluid (CSF) – levels in CSF can reach ~25-80% of plasma levels for various agents.¹¹ 

          • For example, sulfadiazine is known to attain high enough levels in CSF to treat Toxoplasma encephalitis.

          • Sulfonamides also cross the placenta freely and enter fetal circulation¹², and are excreted into breast milk.¹³ 

            • Sulfadiazine is considered by the manufacturer contraindicated in breast-feeding women.¹³

          • Binding to plasma proteins (primarily albumin) varies by agent and influences distribution and free drug levels.

            • Protein binding also underlies certain drug interactions and the risk of bilirubin displacement in neonates.¹⁴

    • Metabolism

      • Sulfonamides are metabolized chiefly in the liver, primarily by N-acetylation of the N4-amino group, and to a lesser extent by glucuronidation.

        • The acetylated metabolites have no antibacterial activity but may have increased propensity to precipitate in urine (acetyl-sulfonamides are less soluble).¹⁶ 

          • Sulfonamides crystallization in acidic urine was a serious issue, mitigated by using more soluble analogs and advising adequate hydration and urine alkalinization.¹⁷

      • The major modern sulfonamide, sulfamethoxazole, is partly metabolized by the cytochrome P450 system (notably CYP2C9 and CYP3A4).

        • Sulfamethoxazole is also an inhibitor of CYP2C9, which contributes to certain drug interactions (e.g. warfarin).^18,19

    • Excretion

      • Most sulfonamides (and their metabolites) are primarily excreted by the kidneys. They undergo glomerular filtration and also tubular secretion.²¹ 

        • There is also some tubular reabsorption, especially for more lipid-soluble drugs, so half-lives can be prolonged in renal impairment.²⁰

      • Urinary excretion is pH-dependent: alkalinization of urine increases excretion by keeping the drug ionized (and also helps prevent crystal formation).²⁰

      • The plasma half-lives of sulfonamides vary widely from ~6 hours to >100 hours, which forms the basis for classifying them as short-, intermediate-, or long-acting.¹¹ 

        • For instance, sulfisoxazole is eliminated quickly (t½ ~5–6 h), sulfamethoxazole intermediate (~11 h), sulfadiazine (~17 h), whereas sulfadoxine is extremely long-acting (~100–200 h)^11,22

      • Because of renal elimination, doses must be adjusted in patients with renal insufficiency to avoid accumulation.²³ 

        • In the elderly or those with reduced GFR, elimination is slower.

      • Sulfonamides readily cross the placenta and fetal elimination is inefficient (fetal acetylation), so the drug can accumulate in the fetus which has implications for toxicity (kernicterus) in late pregnancy and neonates.²⁴

July, 2025

References

Genc Y Ozkanca R Bekemir Antimicrobial activity of some sulfonamide derivatives in clinical isolates of Staphylococcus aureus. Ann Clin Microbiol Antimicrob. 2008 August 20;7: 17. https://pmc.ncbi.nlm.nih.gov/articles/PMC2546433/ Werth B Trimethoprim and Sulfamethoxazole. Merck manual Professional Version (reviewed/revised May 2024). https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/trimethoprim-and-sulfamethoxazolePhthalylsulfathiazole (a.k.a. sulfathalidine) Ovung A Bhattacharyya J Sulfonamide drugs: structure, antibacterial property, toxicity, and biophysical interactions. Biophys Rev. 2021 March 29;13(2): 259-272. https://pmc.ncbi.nlm.nih.gov/articles/PMC8046889/ Steininger C Willinger B Resistance patterns in clinical isolates of pathogenic Actinomyces species. J. Antimicrob Chemother 2016; 71: 422-427. November 3, 2015. https://pubmed.ncbi.nlm.nih.gov/26538502/ Clinical Care of Toxoplasmosis. CDC. January 22, 2024. https://www.cdc.gov/toxoplasmosis/hcp/clinical-care/index.html Sulfamethoxazole DrugBank. https://go.drugbank.com/drugs/DB01015 Succinylsulfathiazole. https://en.wikipedia.org/wiki/Succinylsulfathiazole Phthalylsulfathiazole. (Also known as sulfathalidine) https://en.wikipedia.org/wiki/Phthalylsulfathiazole Sulfacetamide Ophthalmic. MEDLINEplus. National Library of Medicine. https://medlineplus.gov/druginfo/meds/a601114.html Zinner S Mayer K Chapter 33-Sulfonamides in Trimethoprim in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (8e) Volume 1, 2015, 410-418e2. "The sulfonamides are generally well distributed throughout the body, entering the cerebrospinal fluid and synovial, pleural, and peritoneal fluids with concentrations approaching 80% of serum levels. Blood and tissue levels are related to the degree of protein binding and lipid solubility. Sulfonamides administered in pregnancy readily cross the placenta and are present in the fetal blood and amniotic fluid." Sulfonamides General Statement (Monograph). Drugs.com. https://www.drugs.com/monograph/sulfonamides-general-statement.html Li P Qin X Tao F Huang K Maternal exposure to sulfonamides and adverse pregnancy outcomes: A systematic review and meta-analysis. PLos One. 2020 December 2;15(12): e0242523. https://pmc.ncbi.nlm.nih.gov/articles/PMC7710089/ Sulfadiazine Pregnancy and Breast-feeding Warnings. Drugs.com (last updated May 19, 2025). https://www.drugs.com/pregnancy/sulfadiazine.html Wadsworth S Suh B In vitro Displacement of care bilirubin by Antibiotics and 2-Hydroxybenzoylglycine in Newborns. Antimicrob. Agents Chemother. October 1988, 1571-1575. https://journals.asm.org/doi/pdf/10.1128/aac.32.10.1571 Garcia-Galan M Diaz-Cruz M Barcelo D Identification and determination metabolites and degradation products of sulfonamide antibiotics. Transient Analytical Chemistry, Volume 27, Number 11, 2008. https://www.researchgate.net/publication/223413314 Roedel M Nakada S Penniston K Sulfamethoxazole-induced sulfamethoxazole urolithiasis: a case report .BMC Urol. 2021 September 17;21: 133. https://pmc.ncbi.nlm.nih.gov/articles/PMC8447800/ Shrishrimal K Wessn J Sulfamethoxazole Crystalluria. Am J Kidney Dis. 2011 September;58(3): 492-493. https://pmc.ncbi.nlm.nih.gov/articles/PMC8489184/ Wen X Wang J Backman J Laitla J Neuvonen P Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively. Drug Metab Dispos. 2002 June;30(6): 631-635. https://pubmed.ncbi.nlm.nih.gov/12019187/ Ho J Juurlink D Considerations when prescribing trimethoprim-sulfamethoxazole. CMAG. 2011 November 8;183(16): 1851-1858. https://pmc.ncbi.nlm.nih.gov/articles/PMC3216436/ Werth B Sulfonamides. Merck manual professional version. (Reviewed/revised May 2024). https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-medications/sulfonamides Raghavan R Shawar Tubulointerstitial Disorders in Advances in Chronic Kidney Disease 2017.  https://www.sciencedirect.com/topics/medicine-and-dentistry/sulfonamide Scholar E xPharm:  The Comprehensive Pharmacology Reference 2007 Sulfadozine:  Human Pharmacokinetics  https://www.sciencedirect.com/topics/neuroscience/sulfadoxine Van Roy Z Why should sulfamethoxazole/trimethoprim (Bactrim) be used with caution in patients with renal impairment of those on dialysis? University of Nebraska Medical Center . https://blog.unmc.edu/infectious-disease/2024/06/28/pharmtoexamtable-part-2-why-should-sulfamethoxazole-trimethoprim-bactrim-be-used-with-caution-in-patients-with-renal-impairment-or-those-on-dialysis/ Thyagarajan B Deshpande S Clotrimazole and neonatal kernicterus: a review. Drug Chem Toxicol. 2014 April;37(2): 121-129. https://pubmed.ncbi.nlm.nih.gov/24099411/

 

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