A-Z Drug Facts > Trimethoprim/Sulfamethoxazole (Co-trimoxazole)

Trimethoprim / Sulfamethoxazole

( Co-Trimoxazole ) Pronunciation: (trye-METH-oh-prim/SUL-fa-meth-OX-a-zole)
Class: Antibiotic combination

Trade Names:
Bactrim
- Tablets, trimethoprim 80 mg/sulfamethoxazole 400 mg

Trade Names:
Bactrim DS
- Tablets, double-strength trimethoprim 160 mg/sulfamethoxazole 800 mg

Trade Names:
Cotrim Pediatric
- Oral suspension, trimethoprim 40 mg/sulfamethoxazole 200 mg per 5 mL

Trade Names:
Septra
- Tablets, trimethoprim 80 mg/sulfamethoxazole 400 mg

Trade Names:
Septra DS
- Tablets, double-strength trimethoprim 160 mg/sulfamethoxazole 800 mg

Trade Names:
Sulfatrim
- Oral suspension, trimethoprim 40 mg/sulfamethoxazole 200 mg per 5 mL

Trade Names:
Trimethoprim/Sulfamethoxazole
- Injection, trimethoprim 80 mg/sulfamethoxazole 400 mg per 5 mL

Apo-Sulfatrim (Canada)
Apo-Sulfatrim DS (Canada)
Apo-Sulfatrim Pediatric (Canada)
Novo-Trimel (Canada)
Novo-Trimel DS (Canada)
Nu-Cotrimox (Canada)
Septra Injection (Canada)

Pharmacology

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Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with PABA. Trimethoprim blocks production of tetrahydrofolic acid by inhibiting the enzyme dihydrofolate reductase. This combination blocks 2 consecutive steps in bacterial biosynthesis of essential nucleic acids and proteins and is usually bactericidal.

Pharmacokinetics

Absorption

Trimethoprim/sulfamethoxazole is rapidly absorbed following oral administration. T _max is 1 to 4 h. Steady state is achieved after 3 days.

Distribution

70% of sulfamethoxazole and 44% of trimethoprim is protein bound. Trimethoprim/sulfamethoxazole is distributed to sputum, vaginal fluid, and middle ear fluid. Trimethoprim also distributes into bronchial secretions. Trimethoprim/sulfamethoxazole passes the placental barrier and is excreted in human milk.

Metabolism

Metabolism of sulfamethoxazole is primarily by N ₄ -acetylation. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms are considered therapeutically active.

Elimination

Serum half-life of sulfamethoxazole and trimethoprim is 10 h and 8 to 10 h, respectively. Trimethoprim/sulfamethoxazole is primarily eliminated by kidneys through glomerular filtration and tubular secretion. Urine concentrations are higher than blood concentrations.

Onset

Onset of action is 24 h after administration.

Special Populations

Renal Function Impairment

Patients with severely impaired renal function exhibit an increase in the half lives of both components, requiring dosage adjustments.

Elderly

Renal Cl of trimethoprim was significantly lower in the elderly.

Indications and Usage

Parenteral

Treatment of enteritis; treatment of Pneumocystis carinii pneumonia; treatment of severe or complicated UTIs caused by susceptible strains of bacteria.

PO

Treatment of acute otitis media and acute exacerbations of chronic bronchitis; treatment of traveler's diarrhea; treatment and prophylaxis of P. carinii pneumonia; Shigella enteritis; UTIs caused by susceptible strains of bacteria.

Unlabeled Uses

Treatment of cholera, salmonella-type infections, and nocardiosis; prevention of recurrent UTIs in women; prophylaxis of bacterial infections in susceptible patients; treatment of prostatitis; treatment of skin and soft-tissue infections caused by Staphylococcus aureus .

Contraindications

Hypersensitivity to sulfonamides; megaloblastic anemia caused by folate deficiency; pregnancy at term; lactation; infants younger than 2 mo of age.

Dosage and Administration

UTIs, Shigella Enteritis, Acute Otitis Media (oral only)
Adults

PO Trimethoprim 160 mg/sulfamethoxazole 800 mg every 12 h for 10 to 14 days and 5 days for Shigella enteritis. IV 8 to 10 mg/kg/day (based on trimethoprim) in 2 to 4 divided doses every 6, 8, or 12 h for up to 14 days for severe UTIs and 5 days for Shigella enteritis. Max dosages 60 mL/day (based on trimethoprim).

Children 2 mo of age and older

PO Trimethoprim 8 mg/kg and sulfamethoxazole 40 mg/kg daily in 2 divided doses every 12 h for 10 days and 5 days for Shigella enteritis.

P. carinii pneumonia
Adults Prophylactic

PO Trimethoprim 160 mg/sulfamethoxazole 800 mg every 24 h.

Treatment

PO Trimethoprim 15 to 20 mg/kg and sulfamethoxazole 75 to 100 mg/kg/day in equally divided doses every 6 to 8 h for 14 to 21 days.

Adults

IV 15 to 20 mg/kg/day (based on trimethoprim) in 3 to 4 equally divided doses every 6 to 8 h for up to 14 days by IV infusion.

Children Prophylactic

PO Trimethoprim 150 mg/m ² with sulfamethoxazole 750 mg/m ² per day in equally divided doses twice a day, on 3 consecutive days per week. Max total daily dose is trimethoprim 320 mg/sulfamethoxazole 1,600 mg.

Treatment

PO Trimethoprim 15 to 20 mg/kg and sulfamethoxazole 75 to 100 mg/kg per day in divided doses every 6 h for 14 to 21 days.

Traveler's Diarrhea
Adults

PO trimethoprim 160 mg/sulfamethoxazole 800 mg every 12 h for 5 days.

Exacerbation of Chronic Bronchitis
Adults

PO trimethoprim 160 mg/sulfamethoxazole 800 mg every 12 h for 14 days.

Renal Function Impairment
CrCl 15 to 30 mL/min

One-half the usual regimen.

CrCl less than 15 mL/min

Not recommended.

Hemodialysis

One-half of the normal dose as a supplement after dialysis.

Alternative dosing regimen
CrCl 30 to 50 mL/min

Trimethoprim 5 to 7.5 mg/kg per dose every 8 h.

CrCl 10 to 29 mL/min

Trimethoprim 5 to 10 mg/kg per dose every 12 h

CrCl less than 10 mL/min

Not recommended, but if used: trimethoprim 5 to 10 mg/kg per dose every 24 h.

Hemodialysis

Not recommended, but if used: trimethoprim 5 to 10 mg/kg per dose every 24 h. Alternatively, 5 to 20 mg/kg IV 3 times per week in adults following dialysis. These recommendations assume the patient is receiving standard intermittent hemodialysis 3 times per week and completes the full dialysis sessions.

Peritoneal dialysis

Not recommended, but if used: trimethoprim 5 to 10 mg/kg per dose every 24 h.

Continuous renal replacement therapy

Trimethoprim 5 to 7.5 mg/kg per dose every 8 h.

General Advice

Injection

• Administer each dose over 60 to 90 min. Flush IV line after infusion. Do not use IV solution if cloudy or precipitates are noted.
• If local irritation or inflammation because of extravascular infiltration occurs, discontinue infusion and restart at another site.
• Avoid rapid or direct IV injection. Do not inject IM.
• Do not mix injection with other drugs or solutions other than dextrose 5% in water.
• Injection solution must be diluted; add the contents of each 5 mL ampule to 125 mL of dextrose 5% in water
• Do not refrigerate; use within 6 h. If a dilution of 5 mL per 100 mL of dextrose 5% in water is desired, use within 4 h.
• When fluid restriction is desirable, add each 5 mL ampule to 75 mL of dextrose 5% in water. Mix solution just prior to use and administer within 2 h.
• Maintain adequate fluid intake to prevent crystalluria and stone formation.

Oral suspension

• Shake suspension well before using.

Storage/Stability

Store tablets and oral suspension at 59° to 77°F. Protect from light. Store vials at 59° to 86°F. Do not refrigerate. Protect from light. After initial entry into the multidose vial, use the remaining contents within 48 h.

Drug Interactions

ACE inhibitors

Hyperkalemia, possibly with cardiac arrhythmias or cardiac arrest, may occur during coadministration.

Amantadine

A case of toxic delirium has been reported after coadministration with sulfamethoxazole/trimethoprim.

Antiarrhythmic agents (eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, quinidine, sotalol), arsenic trioxide, chlorpromazine, cisapride, dolasetron, droperidol, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, tacrolimus, thioridazine, ziprasidone

An additive effect of trimethoprim/sulfamethoxazole with other drugs that prolong the QT interval cannot be excluded.

Cyclosporine

May cause decreased therapeutic effect of cyclosporine and increased risk of nephrotoxicity.

Digoxin

Increased digoxin levels may occur.

Diuretics (eg, thiazides)

An increased incidence of thrombocytopenia with purpura has been reported during coadministration.

Indomethacin

Sulfamethoxazole blood levels may be increased.

Methenamine

Methenamine is contraindicated for use with sulfonamides because of the potential of formation of insoluble precipitates in the urine.

Methotrexate

May displace methotrexate from protein-binding sites, thus increasing free methotrexate levels.

Phenytoin

Trimethoprim may inhibit metabolism of phenytoin or other hydantoins.

Procainamide

Trimethoprim may inhibit renal elimination of procainamide and its metabolites.

Sulfones (eg, dapsone)

The plasma concentration of both drugs may be increased.

Sulfonylureas

May increase hypoglycemic response to sulfonylureas because of displacement from protein-binding sites or inhibition of hepatic metabolism.

Tricyclic antidepressants

Efficacy may be decreased.

Vaccine, live

The effectiveness of live vaccines may be decreased.

Warfarin

May cause prolonged PT.

Laboratory Test Interactions

Can interfere with serum methotrexate assay as determined by competitive binding protein technique when bacterial dihydrofolate reductase is used as binding protein. May interfere with Jaffe alkaline picrate reaction assay for creatinine, resulting in overestimations.

Adverse Reactions

CNS

Apathy, aseptic meningitis, ataxia, convulsions, depression, fatigue, hallucinations, headache, insomnia, nervousness, peripheral neuritis, vertigo, weakness.

EENT

Tinnitus.

Endocrine

Diuresis, hypoglycemia.

Hematologic

Agranulocytosis, aplastic anemia, eosinophilia, hemolytic anemia, hypoprothrombinemia, leukopenia, megaloblastic anemia, methemoglobinemia, neutropenia, thrombocytopenia.

Hypersensitivity

Allergic myocarditis, anaphylaxis, angioedema, chills, conjunctival and scleral injection, drug fever, erythema multiforme, exfoliative dermatitis, generalized allergic reactions, generalized skin eruptions, Henoch-Schoenlein purpura, periarteritis nodosa, photosensitivity, pruritus, rash, serum sickness–like syndrome, Stevens-Johnson syndrome, systemic lupus erythematosus, toxic epidermal necrolysis, urticaria.

GI

Abdominal pain, anorexia, diarrhea, elevation of serum transaminase and bilirubin, emesis, glossitis, hepatitis (including cholestatic jaundice and hepatic necrosis), nausea, pancreatitis, pseudomembranous enterocolitis, stomatitis, vomiting.

Genitourinary

BUN and serum creatinine elevation, crystalluria and nephrotoxicity in association with cyclosporine, interstitial nephritis, renal failure, toxic nephrosis with oliguria and anuria.

Metabolic

Hyperkalemia.

Musculoskeletal

Arthralgia, myalgia, rhabdomyolysis.

Respiratory

Cough, shortness of breath, pulmonary infiltrates.

Precautions

Monitor Monitor CBC frequently during treatment, obtain urinalysis with microscopic examination and renal function tests.

Pregnancy

Category C . Do not use at term because of risk of neonatal kernicterus.

Lactation

Undetermined. Not recommended during breast-feeding because sulfonamides are excreted in breast milk and may cause kernicterus. Premature infants and infants with hyperbilirubinemia or G-6-PD deficiency are also at risk for adverse reactions.

Children

Not recommended for infants younger than 2 mo of age.

Elderly

Increased risk of severe adverse reactions in elderly patients.

Hypersensitivity

Sulfonamide-associated deaths, although rare, have occurred from hypersensitivity of respiratory tract, Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Both components can interfere with hematopoiesis. IV use at high doses for extended periods of time may cause bone marrow depression.

Renal Function

Use drug with caution. Dosage adjustment may be required.

Hepatic Function

Use drug with caution. Dosage adjustment may be required.

Special Risk Patients

Use drug with caution in patients with possible folate deficiency (eg, patients who are elderly or chronic alcoholic, patients undergoing anticonvulsant therapy, patients with malabsorption syndromes or malnutrition), patients with porphyria, thyroid dysfunction, severe allergy or bronchial asthma, patients who have sulfite sensitivity, and G-6-PD–deficient patients.

Clostridium difficile–associated diarrhea

Has been reported and may range in severity from mild diarrhea to fatal colitis.

Ulceration

Take tablets with water or food to prevent lodging in esophagus and subsequent ulceration.

Hypoglycemia

Cases of hypoglycemia in nondiabetic patients are seen rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease, malnutrition, or those receiving high doses are particularly at risk.

Benzyl alcohol

Injection solution may contain benzyl alcohol. In newborn infants, benzyl alcohol has been associated with an increased incidence of neurological and other complications, which are sometimes fatal.

Sodium metabisulfite

Injection solution may contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms.

Patients With AIDS

Incidence of adverse reactions, especially rash, fever, elevated aminotransferase values, and leukopenia, is greatly increased.

Streptococcal pharyngitis

Do not use for streptococcal pharyngitis.

Sulfonamides

Sulfonamides are chemically similar to some diuretics (acetazolamide and the thiazides), goitrogens, and oral hypoglycemic agents. Goiter production, diuresis, and hypoglycemia occur rarely in patients receiving sulfonamides. Cross-sensitivity may occur.

Overdosage

Symptoms

Altered mental status, anorexia, blood dyscrasias, bone marrow depression, colic, confusion, crystalluria, depression, dizziness, drowsiness, fever, headache, hematuria, jaundice, nausea, pyrexia, vomiting.

Patient Information

• Advise patient to complete full course of therapy.
• Encourage patient to maintain adequate fluid intake.
• Advise patient to take tablet with full glass of water.
• Educate patient and family to report any signs of superinfection, such as fever, vaginitis, oral candidiasis, and fatigue.
• Instruct patient to report the following symptoms to health care provider: fever, skin rash, sore throat, unusual bruising or bleeding.
• Caution patient to avoid exposure to sunlight and to use sunscreen or wear protective clothing to avoid photosensitivity reaction.
• Instruct patients to contact their health care provider as soon as possible if they develop watery and bloody stools, with or without stomach cramps and fever, even as late as 2 months after taking their last dose of this medicine.

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