• Sulfonamides

  • Sulfonamides: Comparative Pharmacokinetics

• Drug	Route of Administration	Oral Bioavailability	Primary Site of Action	Protein Binding	Key Metabolic pathways	Elimination Half-life	Primary Excretion Route	Note
  Sulfamethoxazole	Oral	85%-90%1	Systemic	About 70%1	Hepatic:N-acetylation, Oxidation (CYP2C9)1	About 10 hours1	Renal2	Systemic component of TMP/SMX for wide range of infections
  Sulfasalazine	Oral	Less than 15% parent drug; about 60% as metabolite3	Colon	>99% (parent drug); about 70% as sulfapyridine metabolite3	Intestinal cleavage of active components; hepatic acetylation of sulfapyridine3	About 7.6 hours for parent drug; 10-15 hours for metabolite3	Fecal (5-ASA); renal (sulfapyridine)3	Prodrug: targeted anti-inflammatory colon action for IBD
  Sulfadiazine	Oral, topical, as silver sulfadiazine	Well absorbed4	Systemic	38-48%5	Hepatic acetylation5	7-17 hours5	Renal5	Elevated risk of crystalluria because of low drug and metabolite urinary solubility

• Table References

  • (1) Sulfamethoxazole. DrugBank. https://go.drugbank.com/drugs/DB01015

  • (2) Bactrim: sulfamethoxazole and trimethoprim FDA drug label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/017377s084lbl.pdf

  • (3) Azulfidine Clinical Pharmacology (sulfasalazine). Pfizer Medical. https://www.pfizermedical.com/azulfidine/clinical-pharmacology

  • (4) Sulfadiazine https://www.glowm.com/resources/glowm/cd/pages/drugs/s030.html

  • (5) Sulfadiazine. https://en.wikipedia.org/wiki/Sulfadiazine

   

   

• Profiles of Some Key Sulfonamides

  • Sulfamethoxazole (SMX) is particularly important given that it is used in the important combination product (TMP/SMX).

    Sulfamethoxzole Audio Overview

    • Absorption

      • It is rapidly absorbed orally with a high bioavailability of 85-90%. Peak plasma concentrations (T_max) are reached within 1 to 4 hours.⁷

    • Distribution

      • SMX has a volume of distribution of approximately 13 L.

        • Sulfamethoxazole distributes into various tissues and fluids, including sputum, vaginal fluid, and middle ear fluid. and is approximately 70% bound to plasma proteins.⁷

    • Metabolism

      • SMX is extensively metabolized in the liver.^7,8

        • The primary pathway is N4-acetylation, mediated by N-acetyltransferase (NAT) enzymes.

        • A clinically significant secondary pathway is oxidation by the cytochrome P450 enzyme CYP2C9.

        • This oxidation can form a reactive hydroxylamine metabolite, which is thought to play a role in idiosyncratic hypersensitivity reactions.

    • Excretion^7,8,9

      • The elimination half-life is approximately 10 hours.

        • Sulfamethoxazole is excreted renally, with about 30% as the free, active drug and the remainder as the inactive N4-acetylated metabolite.

        • Dose adjustments are necessary for patients with significant renal impairment.

        • Sulfamethoxazole induced crystalluria Isaac concern because of the amount of acetylated, relatively insoluble form of the drug concentrated in urine.³

  • Sulfasalazine

    Sulfasalazine Audio Overview

    • Sulfasalazine is a prodrug designed for targeted delivery to the colon.

      • Absorption^10,11

        • Less than 15% of an oral dose is absorbed as the intact parent drug in the small intestine.

          • The majority of the dose transits to the colon, where intestinal bacteria cleave its azo bond, releasing the two active components: sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA).

      • Distribution & Action^11,12

        • This differential absorption and metabolism is the key to its therapeutic effect.

          • The sulfapyridine moiety is well-absorbed from the colon (bioavailability ~60%) and is thought to be responsible for the systemic anti-inflammatory and immunomodulatory effects in conditions like rheumatoid arthritis.

          • In contrast, the 5-ASA moiety is poorly absorbed (~10-30%) and exerts its anti-inflammatory effects locally on the colonic mucosa, making it effective for ulcerative colitis.

      • Metabolism & Excretion

        • Absorbed sulfapyridine (SP) is metabolized in the liver, primarily via acetylation.

          • The rate of this metabolism is dependent on the patient's genetically determined NAT2 acetylator phenotype (i.e., "fast" or "slow" acetylators), which influences the half-life of SP.

          •  The unabsorbed 5-ASA and its metabolites are largely excreted in the feces.^11,12

    • Sulfadiazine (Oral and Tropical)

      Sulfadiazine Audio Overview

      • Absorption

        • Sulfadiazine is readily absorbed from the GI tract when given orally. When used topically as silver sulfadiazine cream on large burn areas, some systemic absorption of sulfadiazine can occur.¹⁴

      • Distribution

        • It is widely distributed in the body and is 38-48% bound to plasma proteins.

      • Metabolism & Excretion

        • It is partially metabolized in the liver via acetylation and has an elimination half-life of 7 to 17 hours.¹³  

          • It is excreted renally, but its relatively poor solubility and the even lower solubility of its acetylated metabolite in acidic urine confer a significant risk of crystalluria and renal obstruction.¹³  

          • The topical formulation, silver sulfadiazine, has a distinct dual mechanism where the silver ion also exerts a broad-spectrum bactericidal effect by binding to bacterial DNA and cell wall proteins. ¹⁵

• Therapeutics in Clinical Medicine

  • Sulfonamide Antibiotics | Bacterial Targets, Mechanism of Action, Adverse Effects

    Attribution Flutamide Antibiotics | Bacterial Targets, Mechanism of Action, Adverse Effects. JJ Medicine https://www.youtube.com/watch?v=7CHX_c4Xu3c (February 22, 2019)

  • A combination of trimethoprim sulfamethoxazole is an appropriate and effective choice to treat a variety of infections such as: Pneumocystis jiroveci pneumonia, prostatitis, urinary tract infections as well as certain infections due to susceptible strains of Shigella, Salmonella and nontuberculosis mycobacteria.

    • This combination (TMP-SMZ) retains activity against most Staphylococcus aureus strains (methicillin-susceptible and-resistant) as well as against respiratory tract bacteria such as Haemophilus species, Moraxella catarrhalis and Klebsiella pneumoniae.²⁴

  • Urinary Tract Infections (UTIs):

    Urinary Tract Infections Audio Overview

    • TMP-SMX is an effective and important oral treatment for uncomplicated UTIs (cystitis) and an option for pyelonephritis, provided local E. coli resistance rates are not too high.

      • Strains of the following bacteria are responsible for urinary tract infections and include: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis, and Proteus vulgaris.

        • For initial, uncomplicated urinary tract infections, a single, effective agent is preferred compared to combinations (Bactrim a.k.a. trimethoprim/sulfamethoxazole in this case is considered a single agent).⁸

      • Guidelines recommend a 3-day course of TMP-SMX for acute uncomplicated cystitis in women when the local resistance prevalence of uropathogens to TMP-SMX is < ~20%.

      • For treating urinary tract infections, trimethoprim/sulfamethoxazole (TMP-SMX) is highly effective for susceptible bacteria.

        • Increasing resistance among E. coli, however, presents treatment challenges.

        • Prescribing based on empiric (experience) for UTIs probably may not be appropriate if local resistance among E. coli is greater than 20%.⁴  The same guidance would apply if the patient has recently received TMP-SMX.³

          • In this case, alternative first-line agents (like nitrofurantoin or fosfomycin) are preferred.^4,6 

          • Due to increasing E. coli resistance (often via sul and dfr genes), clinicians should use local antibiograms to guide empiric therapy.⁵

        • TMP-SMX is also effective in prophylaxis of recurrent UTIs:

    • Respiratory tract Infections

      • Sulfonamides are not first-line for common community-acquired pneumonia or sinusitis due to resistance of S. pneumoniae and H. influenzae in many regions.¹⁶ 

        • However, TMP-SMX can be used in acute exacerbations of chronic bronchitis in COPD (where H. influenzae or Moraxella may be targets). ¹⁷

      • Sulfonamides is also an alternative (though not preferred) for acute otitis media in children or sinusitis, particularly if the patient cannot take beta-lactams, as long as regional pneumococcal resistance is low.¹⁸

      • Pneumocystis pneumonia (PCP) in immunocompromised patients (HIV/AIDS, transplant, etc.) is optimally treated with high-dose TMP-SMX.

        Pneumocystis jirovecii Pneumonia (PjP) Audio Overview

        • It is the first-line treatment and prophylaxis for Pneumocystis jirovecii pneumonia (PjP) as no other drug has proven more effective.¹⁹

          • Trimethoprim/sulfamethoxazole is the drug of choice for both the treatment and prophylaxis of PjP.^8,9,19

            • This opportunistic fungal infection is a major cause of morbidity and mortality in immunocompromised individuals, particularly those with HIV/AIDS, organ transplant recipients, and patients on chronic high-dose corticosteroids.

              • For this indication, TMP/SMX is life-saving.^8,9,19

        • Dosing for PCP is higher and intravenous therapy is used for moderate-severe cases. ²⁰

          • TMP-SMX for PCP prophylaxis is standard in AIDS patients with CD4 count <200, in transplant patients, etc.²¹

          • Sulfamethoxazole exhibits good  penetration into lung tissue.²² 

      • Otolaryngologic infections

        • TMP-SMX is an option for chronic sinusitis or otitis media when first-line agents fail or cannot be used.²³ 

          • It is ineffective for streptococcal pharyngitis as  it does not eradicate Group A strep and thus cannot prevent rheumatic fever.¹⁹

        • For acute otitis media in children and for acute maxillary sinusitis in adults (as the result of infection by susceptible Haemophilus influenzae and Streptococcus pneumoniae strains) trimethoprim-sulfamethoxazole would be a reasonable, effective treatment.³

    • Skin and Soft Tissue Infections

      Skin and Soft Tissue Infection Audio Overview

      • Oral TMP-SMX has emerged as an important drug for community-acquired MRSA (CA-MRSA, Community-Associated Methicillin-Resistant Staphylococcus Aureus) skin and soft tissue infections, such as:

        • Cellulitis

        • Abscesses, and

        • Wound infections.^25,9  

      • CA-MRSA isolates are often susceptible to TMP-SMX (even if resistant to beta-lactams), making it a recommended oral agent for outpatient therapy of uncomplicated MRSA infections.¹⁹

      • The IDSA MRSA guidelines list TMP-SMX as a first-line option for purulent skin infections caused by MRSA, in addition to clindamycin or doxycycline.²⁶ 

        • Dosing is typically 1-2 DS tablets BID for 7–10 days, depending on severity.²⁷

    • Gastrointestinal Infections

      • TMP-SMX can be used for some bacterial diarrheal illnesses.

        • It is effective against traveler’s diarrhea caused by enterotoxigenic E. coli and is an option (though fluoroquinolones are more commonly used, resistance patterns permitting)^28,29  

        • TMP-SMX is effective for treating shigellosis (caused by Shigella) but only in regions where the organism is still susceptible.

          • There is widespread resistance to trimethoprim-sulfamethoxazole as well as many other antibiotics. So other agents including ß-lactams, quinolones, azithromycin are more likely to be effective.³⁰

        • For cholera (Vibrio cholerae), TMP-SMX is an alternative to tetracyclines.³¹

        • In cyclosporiasis and isosporiasis (protozoal diarrheal infections), TMP-SMX is the recommended treatment and prophylaxis.^32,33

    • Nocardiosis

      Nocardiosis Audio Overview

      • Infection with Nocardia (a Gram-positive branching filamentous bacterium) is traditionally treated with sulfonamides.³⁴

        • TMP-SMX is first-line therapy for Nocardia infections (e.g. Nocardia pneumonia or brain abscess), given its effectiveness against most Nocardia species.^34,35  

          • Relatively slow response requires higher than usual doses for extended time (many months).³⁵

          • Nocardiosis- Gram Stain

            "Numerous long, thin, Gram-positive filaments are present. "Although the appearance of the filaments is similar to that of Actinomyces, Nocardia do not form colonies in tissue they are are usually seen within abscesses. Sometimes the filaments of Nocardia stain positive with acid-fast stains." Attribution: Yale Rosen from USA, CC BY-SA 2.0 <https://creativecommons.org/licenses/by-sa/2.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Nocardiosis_-_Gram_stain_Case_149_(5286067518).jpg

    • Parasitic and Fungal Infections

      • Toxoplasmosis

        Toxoplasmosis Audio Overview

        • Toxoplasmosis of the brain (toxoplasmic encephalitis) in immunosuppressed patients is treated with sulfadiazine + pyrimethamine plus leucovorin rescue.³⁶

        • If a patient with toxoplasmosis has a sulfonamide allergy, clindamycin + pyrimethamine is used as an alternative, or high-dose TMP-SMX has also shown efficacy.³⁶

          • Toxoplasma gonii tachy

            Attribution: DPDx Image Library, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Toxoplasma_gondii_tachy.jpg

      • Pneumocystis jirovecii pneumonia:

        • TMP-SMX is first-line for both treatment and prophylaxis.¹⁹

      • Malaria: sulfadoxine-pyrimethamine (Fansidar) was a key therapy for Plasmodium falciparum (especially chloroquine-resistant strains) and is still used intermittently for prevention in pregnant women in Africa. ^37,38

        • Chloroquine is the preferred malaria treatment providing the parasite is sensitive to the drug.³⁹ 

          • Resistance to chloroquine is widespread and typically alternative medications must be used.

            • Examples of alternative drugs include the combination of artemether-lumefantrine and artesunate-mefloquine.³⁹ 

      • Brucellosis

        • Brucellosis, a bacterial zoonosis, can be treated with a combination that includes TMP-SMX (e.g. TMP-SMX + rifampin) as a second-line regimen.⁴⁰

          • Doxycycline, gentamicin, streptomycin and rifampin may also be used.⁴⁰

      • Isosporiasis and cyclosporiasis

        • This infection due to intestinal coccidian parasites are effectively treated with TMP-SMX.^32,33

    • Burn wound prophylaxis and other topical uses

      • Silver sulfadiazine cream is widely used in burn units and emergency settings to prevent burn wound infections.⁴¹

        • Effectiveness against many Gram-positive and Gram-negative bacteria (and some Candida) is due to released silver ions.

        • Burn patients often receive daily topical silver sulfadiazine as standard care, with reapplication if needed to prevent wound sepsis.⁴¹

July, 2025