Sulfamethoxazole and trimethoprim

What it is

Co-trimoxazole is a fixed combination of two synthetic antibacterial drugs in one tablet: sulfamethoxazole, a sulfonamide, and trimethoprim, a diaminopyrimidine, usually in a 5:1 ratio (400 mg plus 80 mg, or 800 mg plus 160 mg in the double-strength tablet). Both are absorbed rapidly by mouth, with serum half-lives of about 10 hours for sulfamethoxazole and 8 to 10 hours for trimethoprim, and both are cleared mainly by the kidneys, so the dose has to be reduced when kidney function is impaired. Sulfamethoxazole inhibits CYP2C9 and trimethoprim inhibits CYP2C8 and the OCT2 transporter, which is the basis of several of its important interactions.

What the research says

It kills bacteria by blocking two consecutive steps in folate synthesis. The best-quantified benefit is preventing Pneumocystis pneumonia: a meta-analysis of 12 randomised trials found a 91% reduction with a number needed to treat of 15. In HIV-infected Zambian children, daily co-trimoxazole cut death from 42% to 28% over a median 19 months even where bacterial resistance was high. In drained skin abscesses it raised cure from 73.6% to 80.5%. Added to cephalexin for uncomplicated cellulitis it added nothing in the per-protocol analysis. Against that sit harms that are unusual for an antibiotic: a near seven-fold increase in hospitalisation for high potassium when combined with an ACE inhibitor or ARB, an associated excess of sudden death in that group, a near four-fold increase in upper gastrointestinal bleeding in people on warfarin, and a strong association with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Evidence grade: Well established.

How it works

Drug class: Sulfonamide plus dihydrofolate reductase inhibitor combination antibacterial (folate-pathway inhibitor)

Bacteria have to make their own folate, and they do it in steps. Sulfamethoxazole imitates para-aminobenzoic acid and blocks the first step, the making of dihydrofolic acid. Trimethoprim blocks the next step by inhibiting dihydrofolate reductase, the enzyme that turns dihydrofolic acid into tetrahydrofolic acid. Blocking two consecutive steps starves the bacterium of the folate it needs to build DNA and protein, and the label notes resistance develops more slowly to the combination than to either drug alone. Trimethoprim also blocks potassium excretion in the kidney's distal tubule, which is why it raises potassium in people. (Source 1)

What it is used for

• An approved indication on the FDA-approved label, version effective 2026-08-07, for infections caused by susceptible organisms. The same label advises that a first episode of uncomplicated urinary infection be treated with a single effective antibacterial rather than the combination. What we hold for this use is the label's position on that date, not evidence of benefit: we reached no placebo-controlled trial and no systematic review of co-trimoxazole for urinary infection. Evidence: unknown. (Source 2)
• A meta-analysis of 12 randomised trials in 1245 immunocompromised people without HIV found a 91% reduction in Pneumocystis pneumonia (relative risk 0.09, 95% CI 0.02-0.32) with a number needed to treat of 15, and a reduction in Pneumocystis-related death, though all-cause mortality did not change significantly. Evidence: established. (Source 3)
• The CHAP trial in 534 HIV-infected Zambian children aged 1 to 14 was stopped early for benefit: 28% died on co-trimoxazole versus 42% on placebo over a median 19 months (hazard ratio 0.57, 95% CI 0.43-0.77), an absolute reduction of 14 percentage points, roughly 8 children treated per death prevented, in a setting with high bacterial resistance to the drug. Evidence: established. (Source 4)
• These are approved indications on the FDA-approved label, version effective 2026-08-07, restricted to susceptible organisms, and for otitis media and bronchitis the label conditions the choice on the prescriber judging there is an advantage over a single agent. The label also says it is not indicated for prophylactic or prolonged administration in otitis media at any age. What we hold is the label's position on that date, not evidence of benefit: we reached no randomised trials for these indications. Evidence: unknown. (Source 2)
• A randomised placebo-controlled trial in 1247 patients in MRSA-prevalent emergency departments found clinical cure in 80.5% on co-trimoxazole versus 73.6% on placebo (difference 6.9 percentage points, 95% CI 2.1-11.7, P=0.005), with fewer repeat drainage procedures and fewer new-site infections. Evidence: established. (Source 5)
• A double-blind randomised trial in 500 patients found cure in 83.5% with cephalexin plus co-trimoxazole versus 85.5% with cephalexin alone in the per-protocol analysis (difference -2.0%, 95% CI -9.7 to 5.7, P=0.50). The trial's authors note the intention-to-treat analysis was imprecise enough to leave some uncertainty. Evidence: not-supported. (Source 6)
• A randomised placebo-controlled trial in 81 patients in remission found 82% still in remission at 24 months on co-trimoxazole versus 60% on placebo (relative risk of relapse 0.40, 95% CI 0.17-0.98), but the drug had to be stopped for side effects in 20% of those assigned to it. Evidence: limited. (Source 7)

Interactions

• Warfarin (case reports): Sulfamethoxazole inhibits CYP2C9, the enzyme that clears warfarin, so the INR rises and bleeding risk goes up. In 134,637 older warfarin users, recent co-trimoxazole was associated with nearly four times the odds of hospitalisation for upper gastrointestinal bleeding. (Source 8)
• Warfarin (label position) (label): The label records the same interaction and directs monitoring of prothrombin time and INR, naming warfarin as a CYP2C9 substrate. (Source 9)
• ACE inhibitors and angiotensin receptor blockers (including irbesartan), and spironolactone (case reports): Trimethoprim blocks potassium excretion, which stacks on top of the potassium retention these drugs cause. Hospitalisation for hyperkalaemia was about seven times more likely, and sudden death was more frequent, in older people on an ACE inhibitor or ARB who were prescribed co-trimoxazole rather than amoxicillin. (Source 10)
• Potassium supplements and any other agent that raises potassium (label): The label states that even recommended doses can cause hyperkalaemia if other drugs known to induce hyperkalaemia are given at the same time, or if the person has disordered potassium metabolism or renal insufficiency. Potassium supplements and potassium-containing salt substitutes fall into that category. (Source 11)
• Folic acid and folinic acid (leucovorin) supplements (label): Co-trimoxazole works by blocking folate synthesis, so folate status cuts both ways. The label records that blood changes indicating folic acid deficiency can appear in older people or those already folate-deficient, and that these are reversible with folinic acid therapy. Folinic acid is also what reverses the haematological toxicity, which is why it is used deliberately in some settings. (Source 12)
• Pyrimethamine (antifolate used for malaria prophylaxis) (case reports): Doses of pyrimethamine above 25 mg weekly with co-trimoxazole have been reported to produce megaloblastic anaemia, the predictable result of stacking two folate blockers. (Source 13)
• Alcohol (chronic heavy use) (label): Chronic heavy drinking is one of the states the label names as a likely cause of folate deficiency, and it tells prescribers to avoid co-trimoxazole in people with possible folate deficiency. We found no study of an acute alcohol-drug reaction with co-trimoxazole in the sources we read; the documented concern is the folate state that heavy drinking produces. (Source 12)
• Sulfonylureas (glipizide, glyburide) and metformin (clinical trial): Co-trimoxazole inhibits CYP2C9, CYP2C8 and the renal OCT2 transporter, so it raises levels of several diabetes drugs. In older sulfonylurea users the odds of hospitalisation or emergency care for hypoglycaemia were about 2.5 times higher after a co-trimoxazole prescription. (Source 14)
• Phenytoin (pharmacokinetic study): Co-trimoxazole slows phenytoin metabolism, lengthening its half-life by 39% and cutting its clearance by 27% at an ordinary clinical dose, so phenytoin toxicity can follow. (Source 9)
• Methotrexate (label): Sulfonamides displace methotrexate from plasma protein and compete with its renal transport, raising free methotrexate levels; the label says to avoid using them together. (Source 13)
• Dofetilide (label): Trimethoprim raises dofetilide levels, which can cause torsades de pointes; the combination is contraindicated on the label. (Source 15)
• Ciclosporin (cyclosporine) (case reports): Marked but reversible kidney toxicity has been reported when the two are given together in kidney transplant recipients; the label says to avoid the combination. (Source 13)
• Thiazide diuretics (case reports): In older people on a thiazide, an increased rate of thrombocytopenia with purpura has been reported with co-trimoxazole; the label advises avoiding concurrent use. (Source 9)
• Food and fluid intake (label): The label does not restrict food, but it does direct adequate fluid intake and urine output during treatment to prevent crystals forming in the urine. (Source 11)

Stopping it

• Co-trimoxazole is given as a fixed, finite course rather than taken indefinitely for most indications: for urinary tract infection the label's stated course is 10 to 14 days, and 5 days for shigellosis. There is no dependence or withdrawal syndrome described for it in the label or in the trials read. (Source 16)
• The one rule about stopping that matters most is to stop at the first sign of a rash, because a rash can be the opening of a severe cutaneous reaction. (Source 17)
• Early warning signs that should prompt stopping are set out on the label and include fever, sore throat, joint pain, cough, breathlessness, pallor, purpura and jaundice as well as rash. (Source 17)
• Stopping for intolerance is common on long courses: in the two-year vasculitis trial 20% of those on co-trimoxazole had to stop it for side effects, while in the Pneumocystis prophylaxis trials discontinuation for adverse events was 3.1% in adults and none in children, and all were reversible. (Source 3)
• Trimethoprim-induced hyperkalaemia is described as reversible, so the potassium rise resolves after the course ends. (Source 11)

What goes wrong

In the CHAP trial, grade 3 or 4 adverse events were no more common on co-trimoxazole than placebo, but low neutrophil counts were about twice as frequent. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 534 children.
• Who: HIV-infected children aged 1 to 14 in Zambia.
• How long: Median 19 months.
• Result: Grade 3 or 4 adverse events 16 (6%) versus 18 (7%); neutrophil count below 0.5x10(9)/L on one occasion in 16 (6%) versus 7 (3%), p=0.06.
• Funding: Not stated in the abstract read.

a neutrophil count on one occasion less than 0.5x10(9)/L (16 [6%] co-trimoxazole vs seven [3%] placebo, p=0.06)

One in five patients given co-trimoxazole for two years in the vasculitis trial had to stop it because of side effects. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 41 patients assigned co-trimoxazole.
• Who: Patients with Wegener's granulomatosis in remission taking 800 mg sulfamethoxazole plus 160 mg trimethoprim twice daily.
• How long: Up to 24 months.
• Result: Drug stopped for side effects in 8 of 41 (20 percent)
• Funding: Not stated in the abstract read.

In 8 of the 41 patients in the co-trimoxazole group (20 percent), the drug had to be stopped because of side effects.

In older people already taking an ACE inhibitor or ARB, a co-trimoxazole prescription was associated with nearly seven times the odds of hospitalisation for high potassium. (Source 10)

• Case-control study, Moderate certainty.
• Size: 4148 hyperkalaemia admissions identified, 371 within 14 days of antibiotic exposure, each case matched to up to 4 controls.
• Who: Ontario residents aged 66 or older on continuous ACE inhibitor or ARB therapy.
• How long: 14-day exposure window, over a 14-year study period.
• Result: Adjusted odds ratio 6.7 (95% CI 4.5-10.0) versus amoxicillin; no such risk with ciprofloxacin, norfloxacin or nitrofurantoin.
• Funding: Not stated in the abstract read (Ontario administrative data)

Compared with amoxicillin, the use of trimethoprim-sulfamethoxazole was associated with a nearly 7-fold increased risk of hyperkalemia-associated hospitalization (adjusted odds ratio, 6.7; 95% confidence interval, 4.5-10.0).

In older people on an ACE inhibitor or ARB, co-trimoxazole was associated with an excess of sudden death amounting to about three deaths per 1000 prescriptions within 14 days. (Source 18)

• Case-control study, Moderate certainty.
• Size: 1027 sudden deaths within seven days of antibiotic exposure, matched to 3733 controls, from 39,879 sudden deaths.
• Who: Ontario residents aged 66 or older treated with an ACE inhibitor or ARB.
• How long: 7 and 14-day exposure windows, 1994 to 2012.
• Result: Adjusted odds ratio versus amoxicillin 1.38 (95% CI 1.09-1.76) at seven days and 1.54 (1.29-1.84) at 14 days; the authors translate this to roughly three sudden deaths per 1000 co-trimoxazole prescriptions within 14 days.
• Funding: Not stated in the abstract read (Ontario administrative data)

Limit of this finding: This is a comparison against amoxicillin, not against taking no antibiotic, and it is a case-control study, which compares how often the drug had recently been taken rather than following people forward. The roughly three deaths per 1000 prescriptions is the authors' own translation of that comparison.

This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions.

In older people taking spironolactone, co-trimoxazole was associated with more than twice the odds of sudden death. (Source 19)

• Case-control study, Moderate certainty.
• Size: 328 sudden deaths within 14 days of antibiotic exposure, from 11,968 sudden deaths in spironolactone users, with up to 4 matched controls each.
• Who: Ontario residents aged 66 or older receiving spironolactone, 1994 to 2011.
• How long: 14-day exposure window.
• Result: Adjusted odds ratio 2.46 (95% CI 1.55-3.90) versus amoxicillin; ciprofloxacin 1.55 (1.02-2.38) and nitrofurantoin 1.70 (1.03-2.79), the latter not robust in sensitivity analysis.
• Funding: Not stated in the abstract read.

Compared with amoxicillin, trimethoprim-sulfamethoxazole was associated with a more than twofold increase in the risk of sudden death (adjusted OR 2.46, 95% confidence interval [CI] 1.55-3.90).

In older people on warfarin, recent co-trimoxazole was associated with nearly four times the odds of hospitalisation for upper gastrointestinal bleeding. (Source 8)

• Case-control study, Moderate certainty.
• Size: 2151 cases of upper gastrointestinal haemorrhage among 134,637 warfarin users, with up to 10 matched controls each.
• Who: Ontario residents aged 66 or older continuously treated with warfarin, 1997 to 2007.
• How long: 14-day exposure window.
• Result: Adjusted odds ratio 3.84 (95% CI 2.33-6.33); compared directly with amoxicillin or ampicillin the ratio of odds ratios was 2.80 (95% CI 1.48-5.32); no significant association for amoxicillin, nitrofurantoin or norfloxacin.
• Funding: Not stated in the abstract read.

Limit of this finding: This is an odds comparison in a case-control study: people admitted with a bleed were almost four times as likely to have recently taken co-trimoxazole as people who were not. It does not mean co-trimoxazole multiplies anyone's own bleeding risk by four, and the study gives no absolute risk.

Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33).

In older people taking glipizide or glyburide, co-trimoxazole was associated with about two and a half times the odds of hospitalisation or emergency care for hypoglycaemia. (Source 20)

• Cohort study, Moderate certainty.
• Size: Texas Medicare claims 2006 to 2009 for patients 66 or older on glipizide or glyburide who also filled one of 16 common antimicrobials.
• Who: Older adults on a sulfonylurea.
• How long: 14 days after antimicrobial exposure.
• Result: Odds ratio 2.56 (95% CI 2.12-3.10) versus non-interacting antimicrobials; number needed to harm across the interacting drugs ranged from 71 (clarithromycin) to 334 (ciprofloxacin); the five interacting drugs accounted for 13.2% of all hypoglycaemia events in sulfonylurea users.
• Funding: Not stated in the article read (Medicare claims analysis)

Limit of this finding: These are adjusted odds ratios from Medicare insurance claims, comparing people who filled an interacting antibiotic with people who filled a non-interacting one. They are observational, not trial results, and cannot rule out that sicker people were given different antibiotics.

sulfamethoxazole-trimethoprim (OR, 2.56 [95% CI, 2.12-3.10])

A European case-control study confirmed a strong association between anti-infective sulfonamides and Stevens-Johnson syndrome or toxic epidermal necrolysis, with risk concentrated in the first weeks of use. (Source 21)

• Case-control study, Moderate certainty.
• Size: 379 validated cases of severe cutaneous adverse reaction and 1505 hospitalised matched controls.
• Who: People in a European hospital network covering more than 100 million inhabitants, 1997 to 2001.
• How long: Risk window the first few weeks of drug intake.
• Result: Strong associations confirmed for anti-infective sulfonamides alongside allopurinol, carbamazepine, phenobarbital, phenytoin and oxicam NSAIDs; the paper gives relative risks for the newly marketed drugs rather than a single figure for sulfonamides.
• Funding: Not stated in the abstract read (EuroSCAR study)

Strong associations were confirmed for anti-infective sulfonamides, allopurinol, carbamazapine, phenobarbital, phenytoin, and oxicam-NSAIDs

The EuroSCAR study found the risk of severe cutaneous reaction was limited to the first few weeks of taking the drug. (Source 21)

• Case-control study, Moderate certainty.
• Size: 379 cases and 1505 controls.
• Who: People hospitalised in Europe with Stevens-Johnson syndrome or toxic epidermal necrolysis.
• How long: First few weeks of drug exposure.
• Result: Risk restricted to the first few weeks of drug intake; a number of widely used drugs showed no risk at all.
• Funding: Not stated in the abstract read.

Risk was restricted to the first few weeks of drug intake.

The FDA label records fatalities and a long list of serious reactions with co-trimoxazole, including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, fulminant hepatic necrosis, agranulocytosis and aplastic anaemia. (Source 22)

• Official position, Low certainty.
• Size: Not applicable (regulatory warning drawing on clinical trials, post-marketing and published reports)
• Who: Anyone taking sulfamethoxazole and trimethoprim.
• How long: Any point in treatment.
• Result: No frequencies given; the label states frequencies cannot reliably be estimated from spontaneous reports.
• Funding: FDA-approved labelling (position of the regulator, label version effective 2026-08-07)

Fatalities and serious adverse reactions including severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis

The commonest adverse effects recorded on the label are gastrointestinal upset and allergic skin reactions. (Source 23)

• Official position, Low certainty.
• Size: Not applicable.
• Who: Anyone taking sulfamethoxazole and trimethoprim.
• How long: Any point in treatment.
• Result: No rates given.
• Funding: FDA-approved labelling (position of the regulator, 2026-08-07)

The most common adverse reactions are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria).

Trimethoprim raises serum potassium in a dose-dependent way and can do so at ordinary doses in people with kidney impairment or on other potassium-raising drugs; the label also records severe symptomatic hyponatraemia. (Source 11)

• Official position, Moderate certainty.
• Size: Not applicable (regulatory warning)
• Who: People on high-dose trimethoprim as used for Pneumocystis pneumonia, and at recommended doses those with disordered potassium metabolism, renal insufficiency, or on other hyperkalaemia-inducing drugs.
• How long: Course of treatment.
• Result: No rate given; a progressive but reversible rise in potassium in a substantial number of patients on high-dose treatment.
• Funding: FDA-approved labelling (position of the regulator, 2026-08-07)

High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients.

Co-trimoxazole can cause hypoglycaemia in people who do not have diabetes at all, usually after a few days of treatment. (Source 12)

• Official position, Low certainty.
• Size: Not applicable (regulatory warning)
• Who: Non-diabetic patients, with extra risk in renal dysfunction, liver disease, malnutrition or on high doses.
• How long: After a few days of therapy.
• Result: Described as seen rarely; no rate given.
• Funding: FDA-approved labelling (position of the regulator, 2026-08-07)

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen rarely, usually occurring after a few days of therapy.

People with glucose-6-phosphate dehydrogenase deficiency can haemolyse on co-trimoxazole, and the reaction is often dose-related. (Source 12)

• Official position, Low certainty.
• Size: Not applicable (regulatory warning)
• Who: People with G6PD deficiency.
• How long: Course of treatment.
• Result: No rate given; described as frequently dose-related.
• Funding: FDA-approved labelling (position of the regulator, 2026-08-07)

Hemolysis In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is frequently dose-related.

What the evidence supports

Co-trimoxazole prophylaxis cut Pneumocystis pneumonia by about 90% in immunocompromised people without HIV, with 15 people needing treatment to prevent one case. (Source 3)

• Meta-analysis, Moderate certainty.
• Size: 1245 patients (50% children) across 12 randomised trials.
• Who: People who had had autologous bone marrow or solid organ transplant, or who had haematological cancer.
• How long: Trial-specific.
• Result: Pneumocystis pneumonia relative risk 0.09 (95% CI 0.02-0.32), number needed to treat 15 (95% CI 13-20), no heterogeneity; Pneumocystis-related mortality relative risk 0.17 (95% CI 0.03-0.94)
• Funding: Not stated in the abstract read.

Limit of this finding: Everyone in these trials was immunocompromised without HIV: people who had had an autologous bone marrow or solid organ transplant, or who had a blood cancer. The 90% reduction and the number needed to treat of 15 belong to that group and should not be carried over to anyone else.

When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity.

Daily co-trimoxazole reduced death in HIV-infected Zambian children by about a third in absolute terms of 14 percentage points, even where resistance to the drug was high. (Source 4)

• Randomized trial, High certainty.
• Size: 534 HIV-infected children analysed (541 randomised, 7 later found HIV negative); per-arm numbers not reported.
• Who: Children aged 1 to 14 with clinical features of HIV infection in Zambia, an area of high bacterial resistance to co-trimoxazole.
• How long: Median 19 months; trial stopped early for benefit.
• Result: Death in 74 (28%) of the co-trimoxazole group and 112 (42%) of the placebo group; hazard ratio 0.57 (95% CI 0.43-0.77, p=0.0002). Absolute risk reduction 14 percentage points, number needed to treat about 8. The paper reports the percentages but not the per-arm denominators; dividing the 534 children analysed between the arms gives roughly 265 per arm, which is our arithmetic and not a figure the paper states.
• Funding: Not stated in the abstract read (CHAP trial, academic collaboration)

Limit of this finding: The per-arm group sizes are not in the paper. The 28% and 42% and the hazard ratio are the published figures; any per-arm denominator you see here is arithmetic from the 534 children analysed, so treat it as approximate.

After median follow-up of 19 months, 74 (28%) children in the co-trimoxazole group and 112 (42%) in the placebo group had died (hazard ratio [HR] 0.57 [95% CI 0.43-0.77], p=0.0002).

After drainage of an uncomplicated skin abscess, co-trimoxazole raised the cure rate by about 7 percentage points over placebo. (Source 5)

• Randomized trial, High certainty.
• Size: 1247 participants in the modified intention-to-treat population (1057 per-protocol)
• Who: Outpatients older than 12 with an uncomplicated drained abscess at five US emergency departments; 45.3% MRSA-positive wound cultures.
• How long: 7 days of treatment, outcome assessed 7 to 14 days later.
• Result: Clinical cure 80.5% versus 73.6% (difference 6.9 percentage points, 95% CI 2.1-11.7, P=0.005), number needed to treat about 15; per-protocol 92.9% versus 85.7% (difference 7.2 points, 95% CI 3.2-11.2, P<0.001); repeat surgical drainage 3.4% versus 8.6%; new-site skin infection 3.1% versus 10.3%.
• Funding: National Institute of Allergy and Infectious Diseases (not industry)

clinical cure of the abscess occurred in 507 of 630 participants (80.5%) in the trimethoprim-sulfamethoxazole group versus 454 of 617 participants (73.6%) in the placebo group (difference, 6.9 percentage points; 95% confidence interval [CI], 2.1 to 11.7; P=0.005)

Co-trimoxazole reduced relapses of granulomatosis with polyangiitis in remission, an off-label use. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 81 patients (41 co-trimoxazole, 40 placebo)
• Who: Patients with Wegener's granulomatosis in remission during or after cyclophosphamide and prednisolone.
• How long: 24 months.
• Result: 82% in remission at 24 months versus 60% on placebo (relative risk of relapse 0.40, 95% CI 0.17-0.98); absolute difference 22 percentage points; fewer respiratory (P=0.005) and non-respiratory (P=0.05) infections.
• Funding: Not stated in the abstract read (Dutch Co-Trimoxazole Wegener Study Group)

According to life-table analysis, 82 percent of the patients remained in remission at 24 months, as compared with 60 percent of the patients in the placebo group (relative risk of relapse, 0.40; 95 percent confidence interval, 0.17 to 0.98).

What the evidence does not support

The same meta-analysis found no significant effect of Pneumocystis prophylaxis on death from any cause. (Source 3)

• Meta-analysis, Low certainty.
• Size: 1245 patients across 12 randomised trials.
• Who: Immunocompromised people without HIV infection.
• How long: Trial-specific.
• Result: All-cause mortality relative risk 0.79 (95% CI 0.18-3.46), a very wide interval.
• Funding: Not stated in the abstract read.

Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46).

Adding co-trimoxazole to cephalexin for uncomplicated cellulitis did not improve cure in the per-protocol analysis. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 500 randomised, 496 in modified intention-to-treat, 411 per-protocol.
• Who: Outpatients older than 12 with cellulitis and no wound, purulent drainage or abscess, abscess excluded by ultrasound, at five US emergency departments.
• How long: 7 days of treatment, follow-up to 7 to 9 weeks.
• Result: Per-protocol cure 83.5% versus 85.5% (difference -2.0%, 95% CI -9.7 to 5.7, P=0.50); modified intention-to-treat 76.2% versus 69.0% (difference 7.3%, 95% CI -1.0 to 15.5, P=0.07); adverse event rates did not differ.
• Funding: Not stated in the abstract read (same NIAID-registered programme as the abscess trial)

Limit of this finding: The trial's authors deliberately do not call this simply 'no benefit'. In the analysis that included everyone randomised, the range of possible results still stretched far enough to include a worthwhile advantage for the combination, so they say further research may be needed.

In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50).

Where the research disagrees

Whether adding co-trimoxazole to a beta-lactam helps in uncomplicated cellulitis

• Moran and colleagues, per-protocol analysis (JAMA 2017), prespecified per-protocol analysis of a double-blind randomised trial in 500 patients: In the per-protocol population, clinical cure occurred in 182 (83.5%) of 218 participants in the cephalexin plus trimethoprim-sulfamethoxazole group vs 165 (85.5%) of 193 in the cephalexin group (difference, -2.0%; 95% CI, -9.7% to 5.7%; P = .50). (Source 6)
• The same authors, on the intention-to-treat result, modified intention-to-treat analysis of the same trial, difference 7.3% with a 95% CI of -1.0 to 15.5: However, because imprecision around the findings in the modified intention-to-treat analysis included a clinically important difference favoring cephalexin plus trimethoprim-sulfamethoxazole, further research may be needed. (Source 24)

Whether Pneumocystis prophylaxis should be given to everyone at risk, given its harms

• Green and colleagues (Mayo Clinic Proceedings 2007 meta-analysis), meta-analysis of 12 randomised trials in 1245 patients, which concluded prophylaxis is warranted when PCP risk exceeds 3.5% in adults: When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. (Source 3)
• The FDA label (version effective 2026-08-07), regulatory position drawing on clinical trial, post-marketing and published reports, with no frequencies attached: Fatalities and serious adverse reactions including severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome, toxic epidermal necrolysis (Source 22)

How much

• Reference intake: There is no dietary reference intake for an antibiotic; the dose and the length of the course are set by the prescriber. As a position, the FDA-approved label (version effective 2026-08-07) gives for urinary tract infection in adults one double-strength tablet (800 mg sulfamethoxazole plus 160 mg trimethoprim) or two single-strength tablets every 12 hours for 10 to 14 days, and 40 mg/kg sulfamethoxazole with 8 mg/kg trimethoprim per 24 hours in two divided doses for children. (Source 16)
• Upper limit: The label does not give a single maximum dose but its highest stated regimen, as a position, is for treating Pneumocystis pneumonia: 75 mg/kg to 100 mg/kg sulfamethoxazole and 15 mg/kg to 20 mg/kg trimethoprim per 24 hours in divided doses every 6 hours for 14 to 21 days. For children on prophylaxis the label caps the total daily dose at 1,600 mg sulfamethoxazole and 320 mg trimethoprim. (Source 25)
• Studied: The skin abscess trial gave 320 mg trimethoprim and 1600 mg sulfamethoxazole twice daily for 7 days. (Source 26)
• Studied: The vasculitis relapse-prevention trial gave 800 mg sulfamethoxazole and 160 mg trimethoprim twice daily for 24 months. (Source 27)
• Studied: The label's stated prophylaxis dose for Pneumocystis pneumonia in adults is one double-strength tablet daily. (Source 25)

A common belief, and what the research shows

The belief: Co-trimoxazole is just a routine antibiotic for bladder infections, so a short course is harmless.

What the research shows: Its harm profile is unlike most antibiotics because the trimethoprim component blocks potassium excretion and the sulfamethoxazole component inhibits CYP2C9. In older people on an ACE inhibitor or ARB, "the use of trimethoprim-sulfamethoxazole was associated with a nearly 7-fold increased risk of hyperkalemia-associated hospitalization (adjusted odds ratio, 6.7; 95% confidence interval, 4.5-10.0)", and the same population showed an excess of sudden death amounting to "approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions." In warfarin users, "Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33-6.33)." The European case-control study of severe skin reactions confirmed anti-infective sulfonamides among the drugs with strong associations, with the risk concentrated in the first weeks.

Questions and answers

What is it?

Co-trimoxazole is a prescription tablet containing two antibacterial drugs together: sulfamethoxazole, a sulfonamide, and trimethoprim. They are combined because they block two consecutive steps in the same biochemical pathway, and the label notes bacterial resistance develops more slowly to the combination than to either drug on its own. It is sold as single-strength and double-strength (800 mg plus 160 mg) tablets. (Source 1)

What does it do in the body?

It starves bacteria of folate. Sulfamethoxazole imitates para-aminobenzoic acid and blocks the making of dihydrofolic acid; trimethoprim then blocks dihydrofolate reductase, the enzyme that converts dihydrofolic acid to tetrahydrofolic acid. With both steps blocked, the bacterium cannot build the nucleic acids and proteins it needs. Human cells get folate from food and use a different enzyme form, which is why the drug is selective, but not perfectly so. (Source 1)

Is it good or bad for you?

Both, and the balance depends on who takes it and what else they take. Preventing Pneumocystis pneumonia it is very effective, with 15 people treated per case prevented, and in HIV-infected Zambian children it cut death from 42% to 28%. For a drained skin abscess it adds about 7 percentage points of cure. But in an older person taking an ACE inhibitor, an ARB, spironolactone or warfarin, a single course carries measurable risk of dangerous potassium rises, sudden death or bleeding, and it is one of the drugs most strongly associated with Stevens-Johnson syndrome. (Source 4)

How do you get more of it?

It is prescription-only and is not found in food or supplements, so there is nothing a person should do to get more of it. The dose and the length of the course are set by a prescriber and must be reduced in kidney impairment: the label states half the usual regimen at a creatinine clearance of 15 to 30 mL/min and advises against use below 15 mL/min. For urinary infection the label's adult course is one double-strength tablet every 12 hours for 10 to 14 days. (Source 16)

If it is harmful, what reduces it?

If it is causing harm, it is stopped, and the label is emphatic that this should happen at the first appearance of a rash or any sign of a serious reaction, because a rash can precede Stevens-Johnson syndrome or toxic epidermal necrolysis. The potassium rise it causes is described as reversible once the drug stops. Folinic acid therapy reverses the blood changes caused by its interference with folate. (Source 17)

Why might someone be low in it or missing it?

Someone may be unable to take it, or may have had it stopped, because of sulfonamide allergy, a past episode of drug-induced immune thrombocytopenia, documented megaloblastic anaemia from folate deficiency, marked liver damage, severe kidney impairment where function cannot be monitored, age under two months, or because they take dofetilide. In practice the commonest reasons for stopping are rash and gastrointestinal upset: on a two-year course for vasculitis, 20% had to stop it. (Source 28)

Which whole foods contain it or feed it?

No whole food contains co-trimoxazole. The food and supplement questions that matter are folate and potassium. Because the drug blocks folate synthesis, people already short of folate, including heavy drinkers and the malnourished, are more likely to develop blood abnormalities on it, and folinic acid reverses those changes. Potassium-rich foods and potassium-containing salt substitutes add to its potassium-raising effect. The label also directs adequate fluid intake during treatment to prevent urinary crystals. (Source 12)

What happens if you do not have it?

The placebo arms answer this. Without co-trimoxazole prophylaxis, Pneumocystis pneumonia occurred about eleven times more often in immunocompromised people (relative risk 0.09 with the drug), and in HIV-infected Zambian children 42% of those on placebo died within a median 19 months compared with 28% on the drug. After drainage of a skin abscess without an antibiotic, 73.6% were cured versus 80.5% with the drug, and repeat drainage was needed in 8.6% versus 3.4%. For most people with no infection and no immune deficiency, not taking it has no consequence at all. (Source 3)

How can you test for it?

Blood levels can be measured but are not part of routine care; the label records a mean steady-state trimethoprim concentration of 1.72 mcg/mL and total sulfamethoxazole of 68 mcg/mL on 800 mg plus 160 mg twice daily, reached after three days. What is actually monitored is harm: serum potassium, sodium, creatinine or eGFR, full blood count, and INR for anyone on warfarin. The label directs close potassium monitoring in people at risk. These are standard, reliable laboratory tests, though a single potassium result can be falsely high if the sample haemolyses. (Source 29)

References

1. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, CLINICAL PHARMACOLOGY (Mechanism of Action). 2026. Read the source
2. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, INDICATIONS AND USAGE (Urinary Tract Infections). 2026. Read the source
3. Mayo Clinic proceedings. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. 2007. PMID 17803871, DOI 10.4065/82.9.1052. Read the source
4. Lancet (London, England). Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. 2004. PMID 15555666, DOI 10.1016/s0140-6736(04)17442-4. Read the source
5. The New England journal of medicine. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. 2016. PMID 26962903, DOI 10.1056/nejmoa1507476. Read the source
6. JAMA. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. 2017. PMID 28535235, DOI 10.1001/jama.2017.5653. Read the source
7. The New England journal of medicine. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. 1996. PMID 8637536, DOI 10.1056/nejm199607043350103. Read the source
8. Archives of internal medicine. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. 2010. PMID 20386005, DOI 10.1001/archinternmed.2010.37. Read the source
9. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS, Drug Interactions, Table 1 (diuretics, warfarin, phenytoin). 2026. Read the source
10. Archives of internal medicine. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. 2010. PMID 20585070, DOI 10.1001/archinternmed.2010.142. Read the source
11. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS (Electrolyte Abnormalities). 2026. Read the source
12. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS (folate deficiency and monitoring). 2026. Read the source
13. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS, Drug Interactions, Table 1 (methotrexate, cyclosporine, digoxin, indomethacin, pyrimethamine, tricyclic antidepressants). 2026. Read the source
14. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS, Drug Interactions, Table 1 (oral hypoglycemics, amantadine, ACE inhibitors). 2026. Read the source
15. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, PRECAUTIONS, Drug Interactions, Table 1 (zidovudine, dofetilide). 2026. Read the source
16. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, DOSAGE AND ADMINISTRATION, Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children. 2026. Read the source
17. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, WARNINGS (Management of Hypersensitivity and Other Serious Reactions). 2026. Read the source
18. BMJ (Clinical research ed.). Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study. 2014. PMID 25359996, DOI 10.1136/bmj.g6196. Read the source
19. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone. 2015. PMID 25646289, DOI 10.1503/cmaj.140816. Read the source
20. JAMA internal medicine. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. 2014. PMID 25179404, DOI 10.1001/jamainternmed.2014.3293. Read the source
21. The Journal of investigative dermatology. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. 2008. PMID 17805350, DOI 10.1038/sj.jid.5701033. Read the source
22. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, WARNINGS. 2026. Read the source
23. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, ADVERSE REACTIONS. 2026. Read the source
24. JAMA. Effect of Cephalexin Plus Trimethoprim-Sulfamethoxazole vs Cephalexin Alone on Clinical Cure of Uncomplicated Cellulitis: A Randomized Clinical Trial. 2017. PMID 28535235, DOI 10.1001/jama.2017.5653. Read the source
25. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, DOSAGE AND ADMINISTRATION, Pneumocystis jirovecii Pneumonia (treatment and prophylaxis). 2026. Read the source
26. The New England journal of medicine. Trimethoprim-Sulfamethoxazole versus Placebo for Uncomplicated Skin Abscess. 2016. PMID 26962903, DOI 10.1056/nejmoa1507476. Read the source
27. The New England journal of medicine. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. 1996. PMID 8637536, DOI 10.1056/nejm199607043350103. Read the source
28. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, CONTRAINDICATIONS. 2026. Read the source
29. DailyMed / Cardinal Health 107, LLC (label version effective 2026-08-07). Sulfamethoxazole and trimethoprim tablet - FDA prescribing information, CLINICAL PHARMACOLOGY (pharmacokinetics: peak levels, half-lives, steady state and renal excretion). 2026. Read the source