Sulfonamides

The first drugs to cure a wide range of bacterial infections inside the body, which starve bacteria of folate. A sulfonamide and trimethoprim block two steps of one pathway, together, as co-trimoxazole, the first choice against Pneumocystis, and trimethoprim alone treats cystitis.

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Checked 26 Oct 2026

Contents8 sections

At a glance

Sulfonamides and trimethoprim block two steps of the pathway by which bacteria make their own folate. Sulfonamides look like PABA, one of folate's building blocks, and block dihydropteroate synthase, an enzyme we don't have; trimethoprim blocks dihydrofolate reductase, binding the bacterial enzyme tens of thousands of times more tightly than ours.
Alone, each stops bacteria growing. Together, as co-trimoxazole, sulfamethoxazole and trimethoprim in a 5 to 1 dose, they are synergistic and often bactericidal.
Co-trimoxazole is the first choice to treat and prevent Pneumocystis pneumonia, and treats nocardiosis and Stenotrophomonas. Trimethoprim alone treats cystitis where few E. coli resist it; in the UK co-trimoxazole is kept for urinary infections shown to be susceptible.
Watch for severe skin reactions (Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS), marrow suppression, haemolysis in G6PD deficiency, and, with trimethoprim, a raised potassium and a creatinine that rises without the kidneys failing.
They interact with methotrexate, which together with trimethoprim can suppress the marrow, with warfarin and phenytoin, and with anything else that raises potassium.
Trimethoprim is avoided in the first trimester, a folate antagonist linked to neural tube defects, and its EU licence now rules it out then; sulfonamides are avoided near term and in the first weeks of life, for the newborn's bilirubin. Breastfeeding a healthy baby born at term is compatible.

Drug classification

In 1932 Gerhard Domagk found that Prontosil, a red dye, cured streptococcal infections in mice; in the body it releases sulfanilamide, the part that acts. The sulfonamides that followed were the first drugs to cure a wide range of bacterial infections inside the body, years before penicillin was in use; only Salvarsan, Paul Ehrlich's arsenical against syphilis, had come before. Trimethoprim came in the 1960s, and in 1968 it was paired with sulfamethoxazole as co-trimoxazole. Together they are the antifolate drugs.

Sulfonamides

Look-alikes of PABA that block dihydropteroate synthase, bacteriostatic alone. Of the many once made, few are still used: with trimethoprim, against toxoplasmosis, or on the skin and eye.

Sulfamethoxazoleby mouth or into a vein, only with trimethoprim
Sulfadiazineby mouth, with pyrimethamine for toxoplasmosis
Silver sulfadiazinecream, for burns, leg ulcers and pressure sores
Sulfacetamideeye drops

Trimethoprim

A diaminopyrimidine that blocks dihydrofolate reductase, bacteriostatic alone.

Trimethoprimby mouth, for cystitis and to prevent it

Trimethoprim with sulfamethoxazole

Co-trimoxazole, called TMP-SMX in American usage: two blocks of one pathway, synergistic and often bactericidal.

Co-trimoxazoleby mouth or into a vein

Antifolates and sulfonamides elsewhere

Other antifolates are pyrimethamine against toxoplasmosis, dapsone, a sulfone, against leprosy (Antituberculosis drugs), and methotrexate in cancer and inflammatory disease. Sulfasalazine, for ulcerative colitis and rheumatoid arthritis, releases a sulfonamide, sulfapyridine. Furosemide, the thiazides, acetazolamide and the sulfonylureas carry a sulfonamide group too but aren't antibiotics, and they lack the arylamine group that most allergic reactions to the antibiotics are directed at. A patient allergic to a sulfonamide antibiotic is somewhat likelier to react to them, about 10% against 2% in one large study, but likelier still to react to a penicillin, so the link is a general proneness to allergy rather than cross-reactivity. Some of their licences still list the allergy as a reason not to give them.

Pharmacokinetics

Sulfamethoxazole and trimethoprim are almost completely absorbed by mouth and spread widely, into the cerebrospinal fluid among other places, so a tablet can do the work of a drip. Trimethoprim is a weak base, so it is trapped in fluids more acid than plasma, in the prostate and the vagina, where it reaches high levels.

Given as 5 parts sulfamethoxazole to 1 of trimethoprim, they reach about 20 to 1 in the blood, the ratio at which they work best together, because trimethoprim spreads more widely into the tissues. Their half-lives are alike, so they stay in step.

Drug	Half-life	How it leaves
Sulfamethoxazole	about 10 hours	acetylated in the liver, then in the urine; the acetylated drug dissolves less well and can crystallise in an acid, concentrated urine, so patients drink plenty
Trimethoprim	about 10 hours	largely unchanged in the urine, where it is concentrated
Co-trimoxazole	about 10 hours	in the urine; the dose is halved when the creatinine clearance is 15 to 30 ml/minute; below 15 it isn't recommended, and it is ruled out when its blood levels can't be measured

From silver sulfadiazine cream, some sulfadiazine is absorbed through the broken skin, on large burns enough to matter in a newborn.

Pharmacodynamics

Two steps of one pathway

Most bacteria can't take up folate, so they make their own; we take it ready-made from food. Its active form, tetrahydrofolate, carries the single carbons that build thymidine and purines, so without it no new DNA is made.

1
PABA joins a pteridine
Dihydropteroate synthase joins para-aminobenzoic acid (PABA) to a pteridine. Sulfonamides, look-alikes of PABA, compete for the enzyme. Human cells don't have it.
2
Glutamate is added
The product, dihydropteroate, gains a glutamate and becomes dihydrofolate.
3
Dihydrofolate is reduced
Dihydrofolate reductase makes tetrahydrofolate. Trimethoprim blocks it; our own reductase, which we need too, binds it far more weakly.
4
Carbons for DNA
Tetrahydrofolate hands on single carbons to make thymidine and purines. Without it the bacterium can't copy its DNA.

How sulfonamides and trimethoprim starve a bacterium of folate

Step 1 of 6PABA is joined to a pteridine. Dihydropteroate synthase holds a pteridine and PABA side by side and joins them, making dihydropteroate. Our cells can’t make folate at all; we take it from food.

Point at a name or a part to light it.

Bacteria make their own folate. We can’t make it and take ours from food, so sulfonamides spare our cells. We do have a dihydrofolate reductase, but trimethoprim binds the bacterial one about 100,000 times more tightly. Each drug alone only stops bacteria growing; together, as co-trimoxazole, blocking two steps of one pathway, they can kill them.

Simplified: the enzymes’ shapes simplified, each drawn as one rounded body with its site in a groove along the top; the molecules drawn flat and their hydrogens left out; each drug drawn lying exactly where the piece it mimics lay; in the enzymes they overlap only roughly; the pteridine’s two phosphates, which leave as PABA joins it, left out; the enzyme that adds the glutamate left out; the NADPH that gives the reductase its hydrogens left out; where tetrahydrofolate gets its carbons left out, and the carbon drawn in the one form thymidine takes, though the purines take theirs in another; the DNA drawn growing on its own, the nucleotides the carbons go into and the enzymes that make and join them left out; a sulfonamide can also be joined to the pteridine in PABA’s place, a dead end, drawn only filling PABA’s place.

13 sources

Stevens CW. Brenner and Stevens’ Pharmacology, 6th ed. Elsevier, 2023. Chapter 40, Other antimicrobial agents.
Stevens CW. Brenner and Stevens’ Pharmacology, 6th ed. Elsevier, 2023. Chapter 17, Hematopoietic drugs.
Stevens CW. Brenner and Stevens’ Pharmacology, 6th ed. Elsevier, 2023. Chapter 45, Antineoplastic agents.
Yun MK et al. Catalysis and sulfa drug resistance in dihydropteroate synthase. Science 2012;335:1110–4.
Cao H et al. The crystal structure of a tetrahydrofolate-bound dihydrofolate reductase reveals the origin of slow product release. Commun Biol 2018;1:226.
Sittikornpaiboon P, Toochinda P. Structural and dynamics perspectives on the binding of substrate and inhibitors in Mycobacterium tuberculosis DHFR. Sci Pharm 2017;85:31.
OpenStax Microbiology, 14.3 Mechanisms of antibacterial drugs.
PubChem. 4-Aminobenzoic acid (CID 978).
PubChem. Sulfamethoxazole (CID 5329).
PubChem. Trimethoprim (CID 5578).
PubChem. 6-Hydroxymethyl-7,8-dihydropterin diphosphate (CID 135398612).
PubChem. Dihydrofolic acid (CID 98792).
PubChem. L-Glutamic acid (CID 33032).

Alone, each drug only stops bacteria growing. Blocking the same pathway twice, co-trimoxazole is synergistic and often bactericidal, and can work against bacteria that resist one of its parts. Sulfonamides work poorly in pus, which is full of the thymidine and PABA that dead cells release.

What they reach

Co-trimoxazole: many Enterobacterales (E. coli, Klebsiella, Proteus, Enterobacter), Staphylococcus aureus, many MRSA among them, Stenotrophomonas maltophilia, Burkholderia cepacia, Listeria, Nocardia, Haemophilus influenzae and Moraxella.
Beyond bacteria: Pneumocystis jirovecii, a fungus, Toxoplasma gondii, and the intestinal parasites Cyclospora and Cystoisospora.
Not: Pseudomonas aeruginosa and the anaerobes. Enterococci can take up folate made elsewhere, so co-trimoxazole can fail against them in the body even when the laboratory finds them susceptible, and it clears streptococcal sore throat less well than penicillin.

How bacteria resist

A second enzyme the drug can't block. Genes for a resistant dihydropteroate synthase (sul1, sul2, sul3) or dihydrofolate reductase (the dfr genes) travel on plasmids and integrons, often with genes for resistance to other antibiotics, so using one antibiotic can select resistance to several.
Changes to their own enzymes, and making more PABA.

Decades of use have made resistance common in urinary E. coli. Trimethoprim and co-trimoxazole are first choices for cystitis only where under 20% of E. coli resist them.

Clinical indications

Infection	The usual choice
Pneumocystis pneumonia	co-trimoxazole, first choice to treat and to prevent
Toxoplasmosis	co-trimoxazole to prevent it in HIV; to treat it, pyrimethamine with sulfadiazine and folinic acid, or co-trimoxazole
Nocardiosis	co-trimoxazole, for months
Stenotrophomonas maltophilia	co-trimoxazole, often the first choice
Cystitis	trimethoprim where resistance is unlikely; co-trimoxazole in the UK only with proven susceptibility
Recurrent cystitis	trimethoprim at night, or as a single dose after a trigger such as sex
Acute prostatitis	trimethoprim for 14 days when a fluoroquinolone isn't suitable; co-trimoxazole with specialist advice
Listeria meningitis	co-trimoxazole in place of amoxicillin in penicillin allergy
Some MRSA infections of the skin	co-trimoxazole, by susceptibility
Infected burns, leg ulcers and pressure sores	silver sulfadiazine cream, though on clean burns modern dressings did better in trials, with fewer infections and faster healing

Clinical link

Pneumocystis. In people with HIV whose CD4 count is under 200 per microlitre, after transplants, in leukaemia treatment and on long courses of high-dose steroids, Pneumocystis jirovecii can cause a pneumonia that kills. Co-trimoxazole prevents it, 960 mg a day or three times a week, and in HIV prevents toxoplasmosis too; it is stopped once the CD4 count is over 100 and the virus has been undetectable for three months, and dapsone, atovaquone or inhaled pentamidine replace it when it can't be taken. It treats it at a high dose, 90 to 120 mg/kg a day in divided doses for two to three weeks, with prednisolone when the patient with HIV is short of oxygen. At these doses rashes, fever, low white cells and platelets, a raised potassium and a low sodium are frequent, so the blood is checked often.

Cystitis. In the UK, non-pregnant women are given nitrofurantoin, or trimethoprim when resistance is unlikely, 200 mg twice a day for 3 days; men take trimethoprim or nitrofurantoin for 7 days. A recent course of trimethoprim and older age in a care home make resistance likelier. Across Europe fosfomycin, pivmecillinam, nitrofurantoin or nitroxoline are preferred, and trimethoprim and co-trimoxazole are kept for places where under 20% of E. coli resist them. Both are avoided in the first trimester of pregnancy.

Potassium and creatinine. Trimethoprim blocks the epithelial sodium channel of the collecting duct, as amiloride does, so less potassium is excreted. The potassium is checked in older people, in kidney disease, at the high doses for Pneumocystis, and with ACE inhibitors, angiotensin receptor blockers or spironolactone. Trimethoprim also blocks the tubules' secretion of creatinine, so the creatinine rises a little while the filtration rate stays the same.

sulfamethoxazole to trimethoprim, about 20 to 1 in the blood: 5 to 1by dose
of co-trimoxazole to treat Pneumocystis pneumonia: 90 to 120mg/kg a day
of trimethoprim for 3 days treats cystitis in women in the UK: 200mg twice a day
above which trimethoprim isn't a first choice for cystitis: 20%of E. coli resistant

Adverse drug reactions

Life-threatening
Stevens–Johnson syndrome, toxic epidermal necrolysis and DRESS, most often in the first weeks. Co-trimoxazole is stopped at the first blistering rash, sore mouth or eyes, or a rash with fever, and never given again. Severe rashes are far commoner in people with HIV.
Life-threatening
Blood disorders: agranulocytosis, aplastic anaemia and an immune thrombocytopenia, rarely, but sometimes fatally.
Serious
Megaloblastic anaemia and low counts from too little folate, in older people, the malnourished, and on long or high-dose courses. Blood counts are checked monthly on long treatment; folinic acid helps, but in Pneumocystis it makes co-trimoxazole work less well.
Serious
A raised potassium, from trimethoprim, which can reach levels that disturb the heart. It is checked in older people, in kidney disease, at high doses and with other drugs that raise potassium.
Serious
Haemolysis in G6PD deficiency.
Serious
Liver injury, mostly cholestatic.
Life-threatening
Fulminant liver necrosis, very rarely, which has killed.
Serious
Kidney injury: crystals of the acetylated sulfonamide in an acid, concentrated urine, and interstitial nephritis.
Serious
A low sodium, a low blood sugar, aseptic meningitis and muscle breakdown, rarely, though a low sodium and muscle breakdown are commoner at the doses for Pneumocystis.
Life-threatening
Anaphylaxis and other severe allergic reactions, rarely: among them a reaction in the lungs, with cough, breathlessness and infiltrates, that has been fatal, and shock, mostly in immunocompromised patients.

Side effects

Mild
Nausea, vomiting, diarrhoea and loss of appetite, the commonest.
Mild
An itchy rash, common, and a common reason co-trimoxazole is stopped. A rash with blisters, a sore mouth or a fever is the start of a severe reaction (above).
Mild
A creatinine that rises a little on trimethoprim, without any fall in the filtration rate, and falls back when it is stopped.
Mild
Headache.
Mild
Thrush, in the mouth or vagina.

Contraindications

Contraindicated
An allergy to the drug: to any sulfonamide, for co-trimoxazole and the sulfonamides, and to trimethoprim, for trimethoprim and co-trimoxazole, and above all a severe skin reaction before.
Contraindicated
Newborns. Co-trimoxazole isn't given in the first six weeks of life, for the newborn's bilirubin, and trimethoprim's licence rules it out in premature babies and under six weeks. Silver sulfadiazine isn't put on premature babies or on newborns in their first three months.
Contraindicated
Severe liver disease, for co-trimoxazole, trimethoprim and sulfadiazine, and severe kidney failure, for sulfadiazine, and for co-trimoxazole when its blood levels can't be measured.
Contraindicated
Blood disorders: megaloblastic anaemia or other blood dyscrasias with trimethoprim, jaundice or blood disorders with sulfadiazine, and a past immune thrombocytopenia from trimethoprim or a sulfonamide.
Contraindicated
Acute porphyria, for co-trimoxazole and sulfadiazine, which can provoke it; trimethoprim alone is avoided.
Contraindicated
Clozapine. Its licence rules out sulfonamides, co-trimoxazole among them, as drugs that can suppress the marrow.
Avoid
Methotrexate. Both block folate, co-trimoxazole raises methotrexate's free level, and together they have caused fatal marrow suppression. Another antibiotic is chosen.
Caution
Drugs that raise potassium: ACE inhibitors, angiotensin receptor blockers, spironolactone and amiloride. The potassium is checked.
Caution
Warfarin, phenytoin and sulfonylureas, whose effects co-trimoxazole raises, so the INR, the phenytoin level and the blood sugar are watched.
Caution
G6PD deficiency, folate deficiency and older age, in which blood counts are watched, and severe atopy or asthma.

Pregnancy and lactation

Avoid
Trimethoprim and co-trimoxazole in the first trimester. Trimethoprim is a folate antagonist, and its use then has been linked to neural tube defects, oral clefts, heart defects and miscarriage. If it is needed, it is given with high-dose folic acid. After a 2025 European review, its licence now rules it out in the first trimester.
Avoid
Trimethoprim later in pregnancy, given when tests show it is the best antibiotic or another has failed. The UK licence is stricter: it asks that it be avoided then unless clinically necessary, and elsewhere still calls it contraindicated in pregnancy.
Avoid
Sulfonamides near term: co-trimoxazole, sulfadiazine and silver sulfadiazine on large areas. The drug left in the newborn could displace bilirubin, a risk of kernicterus thought largely theoretical, and cause haemolysis in a baby with G6PD deficiency. Co-trimoxazole is not given in the last trimester.
Compatible
Breastfeeding a healthy baby born at term, with trimethoprim or co-trimoxazole: little passes into the milk, and no harm has been seen. The licences are stricter: trimethoprim's rules it out while the baby is under four months, and co-trimoxazole's advises against it while the baby is under eight weeks.
Caution
Breastfeeding a baby who is premature, jaundiced or in the first month, with a sulfonamide, watching the baby for jaundice, and avoiding it then if possible.
Avoid
Breastfeeding a baby with G6PD deficiency, with a sulfonamide, for the risk of haemolysis.
Caution
Silver sulfadiazine while breastfeeding, on small areas, never on the breast. Its Irish licence rules out breastfeeding.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1Why are sulfamethoxazole and trimethoprim given together, as co-trimoxazole?

2A man of 78 on ramipril and spironolactone is given co-trimoxazole. Three days later his potassium is 6.4 mmol/L. What has raised it?

3A woman 8 weeks pregnant has cystitis. Why is trimethoprim not the antibiotic chosen?

4A man with HIV has a CD4 count of 120 cells per microlitre. What prevents Pneumocystis pneumonia?

5A woman on weekly methotrexate for rheumatoid arthritis is prescribed trimethoprim for cystitis. What is the danger?

6Why is co-trimoxazole not given to babies in their first six weeks?

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Pneumonia

Co-trimoxazole treats Pneumocystis pneumonia in immunocompromised patients.

Antibiotics: classification; mechanisms, type and spectrum of action. Principles of the rational antibiotic therapy and prophylaxisAntimicrobials and chemotherapeuticsTreat first by the likely germ, then narrow once it is known.
PenicillinsAntimicrobials and chemotherapeuticsAmoxicillin for most pneumonia caught in the community.
Macrolides and ketolides (50S inhibitors)Antimicrobials and chemotherapeuticsClarithromycin or azithromycin add cover for atypical bacteria.
QuinolonesAntimicrobials and chemotherapeuticsLevofloxacin and moxifloxacin, the respiratory quinolones, are kept for when first choices can’t be used.
Antiviral drugsAntimicrobials and chemotherapeuticsNot written yetOseltamivir for influenza.
Bacterial community – acquired pneumoniaInternal medicineStreptococcus pneumoniae is the commonest cause.
Nonbacterial community – acquired pneumoniaInternal medicineViruses such as influenza and SARS-CoV-2.
Hospital – acquired pneumonia and pneumonia in immunocompromised patientsInternal medicineStarts 48 hours or more after admission; gram-negatives and S. aureus are common causes, some resistant.
Treatment of pneumoniasInternal medicineChoosing the antibiotic by severity and setting.

Folate and vitamin B12

Sulfonamides stop bacteria making folate, which we take from food; trimethoprim blocks a later step.

DNA replicationBiologyThymidine, one of DNA’s building blocks, is made with folate’s help.
Vitamins: clinical applicationsGastrointestinal, metabolic and hormonal drugsNot written yetVitamin B12 and folic acid as treatments.
Haematopoietic drugsHematologic drugsNot written yetHydroxocobalamin and folic acid restore normal blood formation.
Antitumor chemotherapeuticalsAntimicrobials and chemotherapeuticsNot written yetMethotrexate blocks dihydrofolate reductase.
Macrocytic and megaloblastic anemiasInternal medicineA lack of B12 or folate gives large red cells, from megaloblasts in the marrow; lack of B12 can also damage nerves.
Rheumatoid arthritisInternal medicineFolic acid is given with methotrexate to cut its side effects.

01Drug classification

02Pharmacokinetics

03Pharmacodynamics