Continuing Education Activity

Trimethoprim-sulfamethoxazole (TMP-SMX), also known as co-trimoxazole, is a widely used, affordable antimicrobial agent included on the World Health Organization List of Essential Medicines. Since its introduction in 1974, TMP-SMX has been approved by the US Food and Drug Administration for conditions including urinary tract infections, acute exacerbations of chronic bronchitis, otitis media in pediatric patients, traveler’s diarrhea, shigellosis, and treatment and prophylaxis of Pneumocystis jirovecii pneumonia and toxoplasmosis. Off-label applications extend to methicillin-resistant Staphylococcus aureus infections, acne vulgaris, community-acquired pneumonia, tuberculosis, and prophylaxis in individuals with HIV. The combination exerts a synergistic bactericidal effect by sequential inhibition of bacterial folate synthesis. This activity reviews TMP-SMX pharmacology, dosing, administration, adverse effects, contraindications, drug interactions, monitoring, and toxicity management. Participants will enhance skills in patient selection, individualized dosing, recognition of serious adverse reactions, and application of evidence-based monitoring to improve outcomes and minimize preventable complications through effective interprofessional care.

Objectives:

• Identify FDA-approved and off-label indications for trimethoprim-sulfamethoxazole based on patient-specific clinical presentations.
• Differentiate appropriate oral versus intravenous administration based on infection severity and patient status.
• Apply current safety warnings, including recognition of hemophagocytic lymphohistiocytosis, to clinical decision-making.
• Collaborate with the interprofessional healthcare team to individualize dosing plans for pediatric, older, and high-risk patients.

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Indications

Trimethoprim/sulfamethoxazole (TMP-SMX), also known as co-trimoxazole, is commonly abbreviated as SXT, TMP-SMZ, or TMP-sulfa.[1][2] TMP-SMX is a combination antimicrobial medication used to treat and prevent a range of bacterial infections. Since its introduction into clinical practice in 1974, TMP-SMX has become widely used and is included on the World Health Organization's List of Essential Medicines.[3] This drug is very affordable and remains an important treatment option for many illnesses.[4]

FDA-Approved Indications

The US Food and Drug Administration (FDA) has approved TMP-SMX for the following clinical indications:

• Acute exacerbation of chronic bronchitis in adults (susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae)
• Acute otitis media in pediatrics only
• Traveler's diarrhea (treatment and prophylaxis)
• Shigellosis
• Urinary tract infections [5]
• Pneumocystis jirovecii (formerly P carinii) pneumonia (treatment and prophylaxis) [6]
• Toxoplasmosis (treatment and prophylaxis) [7][8]

Off-Label Uses

TMP-SMX is used for the following off-label conditions:

• Prophylaxis in HIV-infected individuals
• Acne vulgaris
• Listeria
• Pertussis (whooping cough)
• Tuberculosis
• Whipple disease
• Isosporiasis
• Malaria
• Community-acquired pneumonia
• Staphylococcus aureus infections, including methicillin-resistant S aureus [9]
• Melioidosis [10][11]
• Nocardiosis [12][13]
• Stenotrophomonas maltophilia  [14] [15]

Mechanism of Action

Sulfamethoxazole is a sulfonamide (an antimicrobial drug class) that acts directly on folate synthesis in microbial organisms (eg, bacteria) by competing with p-aminobenzoic acid for the synthesis of dihydrofolate, thereby inhibiting dihydropteroate synthase. Trimethoprim is a competitive inhibitor of dihydrofolate reductase, thereby inhibiting the enzyme and preventing the formation of tetrahydrofolate, the active form of folate. In combination, sulfamethoxazole and trimethoprim exert a synergistic antifolate effect. Tetrahydrofolate is essential for purine synthesis and, in turn, for DNA and protein production. Individually, each drug is bacteriostatic. Together, TMP-SMX blocks 2 sequential steps in bacterial nucleic acid and protein synthesis, producing bactericidal activity in certain settings (e.g., the urinary tract).[16]

Resistance to TMP-SMX mainly arises from plasmid-borne genes encoding resistant variants of target enzymes such as dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) (see Image. Mechanism of Action of Trimethoprim-Sulfamethoxazole). Additional mechanisms include active efflux pumps and reduced membrane permeability.[17][18]

Pharmacokinetics

Absorption: Peak blood levels of both components occur within 1 to 4 hours after oral dosing, with steady-state levels reached in approximately 3 days.

Distribution: Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. Both drugs distribute into sputum, vaginal fluid, and middle ear fluid. They cross the placenta and are excreted in breast milk. Trimethoprim is also distributed to bronchial secretions.

Metabolism: Sulfamethoxazole inhibits CYP2C9 and undergoes hepatic metabolism via the cytochrome P450 (CYP450) system. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1, and OCT2.[19] 

Excretion: Sulfamethoxazole and trimethoprim are primarily excreted by the kidneys through both glomerular filtration and tubular secretion. The half-life of sulfamethoxazole is 6 to 12 hours and may increase to 20 to 50 hours in patients with renal impairment. Trimethoprim has a half-life of 8 to 10 hours, undergoes minimal hepatic metabolism, and is excreted primarily in the urine, largely unchanged.

Administration

Available Dosage Forms and Strengths

TMP-SMX may be administered orally without regard to meals; however, patients should take each dose with at least 8 ounces of water. TMP-SMX is also available in an intravenous (IV) formulation. The choice between oral and IV administration depends on the type of infection or the need for prophylaxis. Intramuscular administration is not recommended. TMP-SMX is formulated as tablets in a 1:5 ratio of trimethoprim to sulfamethoxazole. After absorption and distribution throughout the blood and tissues, this ratio yields plasma and tissue concentrations of approximately 1:20, which corresponds to the peak synergistic effect of the 2 agents.[20]

TMP-SMX is available as an intravenous formulation containing 800 mg of sulfamethoxazole and 160 mg of trimethoprim in 10 mL multiple-dose vials (80 mg/mL and 16 mg/mL, respectively). TMP-SMX is also available in a 30 mL vial containing 2,400 mg of sulfamethoxazole and 480 mg of trimethoprim (80 mg/mL and 16 mg/mL, respectively). The solution should be administered by IV infusion over 60 to 90 minutes. Bolus injection or rapid infusion should be avoided. Do not administer TMP-SMX injection intramuscularly.

An oral suspension is available containing sulfamethoxazole 200 mg and trimethoprim 40 mg per 5 mL. Common tablet formulations include a standard tablet (400 mg sulfamethoxazole/80 mg trimethoprim) and a double-strength tablet (800 mg sulfamethoxazole/160 mg trimethoprim). For all indications, local antibiograms and resistance patterns should be reviewed before prescribing, given the increasing antimicrobial resistance.

Indications and Dosages (FDA-Approved)

• Bacterial infections: Adults and children with a body weight of 40 kg (88 lbs) or more should take 1 tablet (800 mg sulfamethoxazole/160 mg trimethoprim) orally every 12 hours for 10 to 14 days. Weight-based dosing is recommended for children aged 2 months or older.
• P jirovecii pneumonia (treatment): Adults and children aged 2 months or older should receive weight-based dosing. The usual dosage is sulfamethoxazole 75 to 100 mg/kg/d and trimethoprim 15 to 20 mg/kg/d, administered for 14 to 21 days.[20]
• P jirovecii pneumonia (prevention): In adults, 800 mg sulfamethoxazole and 160 mg trimethoprim are administered daily. In children aged 2 months or older, dosages are determined by body weight.[20]
• Traveler's diarrhea: In adults, 800 mg sulfamethoxazole and 160 mg trimethoprim are administered every 12 hours for 5 days. For children aged 2 months or older, use and dosage vary.
• Chronic bronchitis: For acute exacerbations caused by S pneumoniae or H influenzae, the recommended dosage is 1 tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim every 12 hours for 10 to 14 days.[21]
• Shigellosis: For enteritis caused by Shigella flexneri and S sonnei, the recommended dosage is 1 tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim every 12 hours for 5 days. Antimicrobial resistance is a growing concern in the treatment of this infection.[22]
• Urinary tract infections: TMP-SMX may be used to treat select infections, as outlined below.

  • Pyelonephritis: One tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim is administered every 12 hours for 14 days.
  • Prostatitis: One tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim is administered every 12 hours for 14 days, or for 2 to 3 months in cases of chronic infection.[23]

Indications and Dosages (Off-Label Use)

• Acne vulgaris: One tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim is administered every 12 hours for 18 days.
• Community-acquired pneumonia: One tablet containing 800 mg sulfamethoxazole and 160 mg trimethoprim is administered every 12 hours for 10 to 14 days.

Specific Patient Populations

Hepatic impairment: TMP-SMX–induced hepatotoxicity ranges from mild, self-limited enzyme elevations to acute hepatitis and liver failure. Most cases are self-limited and resolve rapidly after discontinuation of the drug. Trimethoprim alone can also cause acute liver injury, and recurrence has been reported when patients were switched from TMP-SMX to trimethoprim. In most cases, the sulfonamide component is implicated. Use with caution in patients with hepatic impairment.[24]

Renal impairment: The trimethoprim component of co-trimoxazole may cause hyperkalemia in patients with renal impairment or when coadministered with drugs that can induce hyperkalemia, such as angiotensin-converting enzyme inhibitors. Periodic monitoring of serum potassium is required in these patients. 

Dosing adjustments based on renal function are as follows:

• If creatinine clearance (CrCl) is greater than 30 mL/min, no dosage adjustment is required.
• If CrCl is 15 to 30 mL/min, the dose should be reduced by 50%.
• If CrCl is less than 15 mL/min, co-trimoxazole is not recommended.

Pregnancy considerations: First-trimester co-trimoxazole exposure increases the risk of congenital malformations, including cardiac defects, cleft lip/palate, and neural tube defects.[25][26] Use during pregnancy may also increase the risk of multiple abnormalities, particularly urinary tract and cardiovascular defects.[27] Because sulfamethoxazole and trimethoprim can interfere with folic acid metabolism, co-trimoxazole should be prescribed during pregnancy only if the potential benefit outweighs the potential risk to the fetus. The risk of major malformations is reduced with folic acid supplementation. In patients with first-trimester exposure to TMP-SMX, ultrasonography should be performed at 18 to 20 weeks of gestation.[28]

Breastfeeding considerations: Trimethoprim and sulfamethoxazole levels in breast milk are less than 5% of the infant dose in infants older than 2 months. In healthy, full-term infants, the use of sulfamethoxazole and trimethoprim during breastfeeding appears acceptable after the neonatal period. The period of highest risk for hemolysis in full-term newborns without glucose-6-phosphate dehydrogenase (G6PD) deficiency may be as short as 8 days postpartum. Until more data are available, alternative medications should likely be considered in jaundiced, critically ill, or premature infants due to the risk of bilirubin displacement and kernicterus. Sulfamethoxazole and trimethoprim should be avoided when breastfeeding G6PD-deficient infants.[29]

Pediatric patients: TMP-SMX is not recommended for use in infants younger than 2 months. Serious adverse reactions, including fatal outcomes and gasping syndrome, have been reported in premature and low-birth-weight neonates in neonatal intensive care units who received parenteral solutions containing benzyl alcohol as a preservative.

Older patients: In older adults, particularly those with chronic kidney disease or concurrent use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or potassium-sparing diuretics, TMP-SMX increases the risk of hyperkalemia and acute kidney injury. According to the 2023 American Geriatrics Society Beers Criteria, clinicians should use this agent cautiously in older adults and monitor renal function and serum potassium closely.[30]

Adverse Effects

The primary adverse effects of TMP-SMX include rash, photosensitivity, and folate deficiency.[31][32] The more common adverse effects include:

• Loss of appetite
• Nausea/vomiting/dyspepsia
• Painful or swollen tongue
• Dizziness
• Tinnitus
• Fatigue
• Insomnia
• Rash/urticaria
• Anorexia
• Photosensitivity

More serious adverse reactions include Stevens-Johnson syndrome, various anemias, agranulocytosis, Clostridioides difficile–associated diarrhea, myelosuppression, renal failure or interstitial nephritis, pancreatitis, and hepatotoxicity. Hemolytic anemia may occur with sulfonamides such as sulfamethoxazole in patients with a G6PD deficiency.[33]

Patients with an unrecognized sulfonamide allergy treated with TMP-SMX may develop anaphylaxis or severe reactions, including hives, itchy eyes, swelling of the mouth or throat, and abdominal cramping.[34] Hepatotoxicity may be more frequent in patients of African ancestry in whom the HLA-B*35:01 seems to be a risk factor.[24] In 2025, the FDA updated the warnings and precautions for sulfamethoxazole and trimethoprim to include hemophagocytic lymphohistiocytosis as a potential adverse reaction, based on reported cases in the literature.[35]

Drug-Drug Interactions

TMP-SMX should be used with caution when coadministered with the following drugs:

• Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Concomitant use may result in clinically significant hyperkalemia, particularly in older adults or patients with renal impairment; serum potassium levels should be monitored closely.
• Amantadine and memantine: Delirium has been reported with concomitant use. Trimethoprim inhibits the renal organic cation transporter 2 (OCT2), which may increase plasma concentrations of OCT2 substrates.[36][37]
• Antiarrhythmics (eg, dofetilide, amiodarone): Concomitant use with QT-prolonging interval increases the risk of ventricular arrhythmias. Dofetilide is specifically contraindicated due to increased plasma levels and risk of Torsades de Pointes.
• Warfarin: Sulfamethoxazole inhibits S-warfarin metabolism via CYP2C9, which may significantly increase prothrombin time; patients should be monitored for signs of bleeding and prothrombin time/international normalized ratio.
• Methotrexate: Concomitant use increases the risk of methotrexate toxicity and megaloblastic anemia due to displacement from protein-binding sites, inhibition of renal tubular secretion, and additive inhibition of dihydrofolate reductase.
• Antiretrovirals (eg, zidovudine, lamivudine, zalcitabine): Zidovudine increases the risk of hematologic toxicity and neutropenia. Trimethoprim also raises serum concentrations of these agents by inhibiting their renal tubular secretion.
• Ciclosporin: Concomitant use may cause reversible renal dysfunction and increased nephrotoxicity, especially in transplant recipients.
• Clozapine: Concomitant use increases the risk of idiosyncratic drug-induced neutropenia and agranulocytosis; this combination should be avoided, or absolute neutrophil counts should be monitored frequently.[38] 
• Dapsone: A bidirectional interaction exists in which plasma concentrations of both dapsone and trimethoprim may increase, potentially increasing the risk of methemoglobinemia and hemolytic anemia.
• Digoxin: Trimethoprim may decrease the renal clearance of digoxin, leading to increased serum levels and potential toxicity, especially in older adults.[39]
• Thiazides: Concomitant use may increase the risk of thrombocytopenia with purpura in older adults.
• Indomethacin: Concomitant use may increase plasma concentrations of sulfamethoxazole, potentially increasing the risk of sulfonamide-related adverse effects.
• Methenamine: Combined use is not recommended because sulfonamides may form insoluble precipitates with methenamine in acidic urine, increasing the risk of crystalluria.
• Para-aminobenzoic acid and derivatives: These agents (eg, some local anesthetics) may competitively antagonize the antibacterial effect of sulfonamides.
• Phenytoin: Sulfamethoxazole inhibits CYP2C9-mediated metabolism of phenytoin, increasing its half-life by approximately 39% and increasing the risk of toxicity; serum phenytoin levels should be monitored.
• Prilocaine: Concomitant use of these drugs increases the risk of methemoglobinemia.
• Procainamide: Trimethoprim increases plasma concentrations of procainamide and its active metabolite, N-acetylprocainamide, increasing the risk of QTc interval prolongation.
• Pyrimethamine: Doses greater than 25 mg weekly may cause megaloblastic anemia when combined with TMP-SMX.
• Rifampin: Concomitant use may reduce plasma concentrations of trimethoprim and sulfamethoxazole, potentially decreasing clinical efficacy.
• Spironolactone: Concomitant use increases the risk of severe, potentially fatal hyperkalemia; close monitoring of serum potassium is required.
• Sulfonylureas and oral hypoglycemics: TMP-SMX enhances the effects of agents metabolized by CYP2C8 (eg, repaglinide, rosiglitazone, pioglitazone) and CYP2C9 (eg, glyburide, glipizide); blood glucose levels should be monitored.

Drug-Laboratory interactions

• Methotrexate levels: In co-trimoxazole, trimethoprim may interfere with serum methotrexate measurement when the competitive binding protein assay uses bacterial dihydrofolate reductase as the binding protein. No interference occurs when methotrexate is measured by radioimmunoassay.
• Serum creatinine: Co-trimoxazole may interfere with the Jaffé alkaline picrate assay, leading to an overestimation of serum creatinine by approximately 10% within the normal range.

Contraindications

Trimethoprim-Sulfamethoxazole Contraindications

TMP-SMX is contraindicated in patients with the following conditions:

• known hypersensitivity to trimethoprim, sulfamethoxazole, or a history of sulfonamide allergy
• hepatic impairment, including liver parenchymal damage, jaundice, and hepatic failure
• megaloblastic anemia due to folate deficiency
• renal insufficiency 
• neonates younger than 6 weeks
• concurrent administration with dofetilide [40]
• history of drug-induced immune thrombocytopenia [41]

Warnings and Precautions

• Embryofetal toxicity: TMP-SMX use in early pregnancy has been linked to congenital malformations and maternal folate deficiency, resulting in neural tube defects (eg, spina bifida), urinary tract defects, oral clefts, and clubfoot. Use of TMP-SMX during late pregnancy has been associated with an increased risk of preterm labor; the use should be avoided, but it is not contraindicated in some conditions, such as Q fever (caused by Coxiella burnetii), which may require its use according to the CDC guidance.[42] [Clinical Guidance for Q fever]. As TMP-SMX is also excreted in breast milk, its use should be avoided during breastfeeding.
• Streptococcal infection: Sulfonamides should not be used to treat group A β-hemolytic streptococcal infections. In established cases, co-trimoxazole does not eliminate Streptococcus and thus cannot prevent rheumatic fever.
• Sodium metabisulfite (IV formulation): Co-trimoxazole IV may contain sodium metabisulfite, which can trigger allergic reactions, including anaphylaxis and asthma exacerbations, in susceptible individuals. Sulfite sensitivity occurs more frequently in patients with asthma.
• Sulfa allergy labeling: Sulfite sensitivity and sulfonamide allergy are medically unrelated and do not cross-react. Sulfites are inorganic preservatives that may cause bronchospasm in up to 10% of patients with asthma, whereas sulfonamides such as TMP-SMX are antibiotics that can cause immunoglobulin E–mediated anaphylaxis or T-cell–mediated cutaneous reactions.[43]

• Propylene glycol toxicity (IV formulation): Co-trimoxazole IV formulation contains propylene glycol as a solvent. High-dose administration in P jirovecii pneumonia may cause hyperosmolarity and anion-gap metabolic acidosis. Propylene glycol toxicity can lead to lactic acidosis, central nervous system toxicity, acute kidney injury,  and multiorgan failure. Patients should be monitored for total daily propylene glycol intake from all sources. Discontinue  IV co-trimoxazole injection if propylene glycol toxicity is suspected.[44]

• Crystalluria: Patients should ensure adequate fluid intake and urinary output to prevent crystalluria and subsequent kidney stone formation or acute kidney injury.[45][46][47]

• Renal tubular acidosis: Co-trimoxazole may rarely cause renal tubular acidosis.[48][49]

Monitoring

When initiating therapy with TMP-SMX, some patients may require baseline blood urea nitrogen and serum creatinine measurements. Periodic complete blood counts and electrolyte measurements are recommended for patients with renal impairment or for those receiving concomitant medications that affect potassium levels.[50][51][52]

Toxicity

Signs and Symptoms of Overdose

Overdosing on TMP-SMX is possible, and potential signs of toxicity include:

• Nausea or vomiting
• Dizziness
• Headache
• Depression
• Confusion
• Thrombocytopenia
• Uremia
• Loss of appetite
• Colic
• Drowsiness
• Bone marrow depression

Management of Overdose

If TMP-SMX toxicity is suspected, treatment consists of supportive care. Activated charcoal may be administered if ingestion is recent, along with gastric lavage and IV or oral fluid resuscitation. In severe cases, treatment may include hemodialysis and urinary alkalinization.[16] If methotrexate has been co-administered, leucovorin (folinic acid) rescue therapy is the mainstay.[53] If bone marrow suppression is present, administer leucovorin at 5 to 15 mg daily until hematopoietic function normalizes.

Enhancing Healthcare Team Outcomes

TMP-SMX is a widely used antimicrobial agent indicated for multiple bacterial infections, including urinary tract infections, acute exacerbations of chronic bronchitis, P jirovecii pneumonia, and select off-label uses such as methicillin-resistant S aureus infections and prophylaxis in HIV-infected patients. TMP-SMX acts by inhibiting bacterial folate synthesis, producing a synergistic bactericidal effect. Healthcare providers must consider patient-specific factors, including age, weight, renal and hepatic function, potential drug interactions, pregnancy, and risks of adverse effects such as hematologic abnormalities, Stevens-Johnson syndrome, and hemophagocytic lymphohistiocytosis.[54] Baseline and follow-up laboratory monitoring is essential for patients with renal impairment or those receiving interacting medications.

Optimal patient-centered care with TMP-SMX requires coordinated interprofessional collaboration. Physicians, nurse practitioners, and physician assistants are responsible for appropriate prescribing and monitoring, while nurses ensure safe administration and early detection of adverse effects. Pharmacists verify dosing, perform medication reconciliation, and consult with infectious disease specialists as needed. In cases of overdose, consultation with a critical care physician and a medical toxicologist is recommended. Collaboration among the interprofessional healthcare team ensures individualized dosing, minimizes risks, facilitates patient education, and improves outcomes through shared decision-making, effective communication, and adherence to evidence-based practices.

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Disclosure: Tyler Kemnic declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Samar Nicolas declares no relevant financial relationships with ineligible companies.