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Trimethoprim / Sulfamethoxazole

Pronunciation
( 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

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

Septra
- Tablets trimethoprim 80 mg/sulfamethoxazole 400 mg

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

Sulfatrim
- Suspension, oral trimethoprim 40 mg/sulfamethoxazole 200 mg per 5 mL

Trimethoprim/Sulfamethoxazole
- Injection, solution trimethoprim 16 mg/sulfamethoxazole 80 mg per 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

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.

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Microbiology

The following organisms are usually susceptible: Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea), Klebsiella species, Enterobacter species, Morganella morganii , Proteus mirabilis , indole-positive Proteus species (including Proteus vulgaris ), Haemophilus influenzae (including ampicillin-resistant strains), Streptococcus pneumoniae , Shigella flexneri , Shigella sonnei , and Pneumocystis carinii .

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, after oral administration. Plasma half-life of sulfamethoxazole and trimethoprim is approximately 13 and 11 h, respectively, after IV administration. Trimethoprim/sulfamethoxazole is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. Urine concentrations are higher than blood concentrations.

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

Total body Cl of trimethoprim was 19% lower in elderly patients.

Indications and Usage

Parenteral

Treatment of enteritis; treatment of P. carinii pneumonia (PCP); 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 PCP; 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; treatment of acute and chronic prostatitis; treatment of skin and soft-tissue infections caused by Staphylococcus aureus .

Contraindications

Hypersensitivity to trimethoprim or sulfonamides; megaloblastic anemia caused by folate deficiency; pregnancy; lactation; infants younger than 2 mo of age; marked hepatic damage or severe renal insufficiency when renal function status cannot be monitored.

Dosage and Administration

UTIs, Enteritis
Adults and Children 2 mo of age and older

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, 60 mL/day (based on trimethoprim).

UTIs, Enteritis, Otitis Media, Chronic Bronchitis
Adults

PO Trimethoprim 160 mg/sulfamethoxazole 800 mg every 12 h for 14 days for chronic bronchitis, 10 to 14 days for UTIs, 5 days for enteritis.

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 for otitis media and UTIs and 5 days for enteritis.

P. carinii pneumonia
Adults and Children 2 mo of age and older (treatment)

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.

Adults Prophylactic

PO Trimethoprim 160 mg/sulfamethoxazole 800 mg every 24 h. Alternative doses recommended by the National Institutes of Health (NIH) and Infectious Diseases Society of America (IDSA) include trimethoprim 80 mg/sulfamethoxazole 400 mg every 24 h or trimethoprim 160 mg/sulfamethoxazole 800 mg 3 times per week.

Treatment

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

Children Prophylactic

PO Trimethoprim 150 mg/m 2 and 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. Alternative doses recommended by the NIH and IDSA include trimethoprim 150 mg/m 2 and sulfamethoxazole 750 mg/m 2 per day in a single daily dose for 3 consecutive days per week; trimethoprim 150 mg/m 2 and sulfamethoxazole 750 mg/m 2 per day in equally divided doses twice a day; or trimethoprim 150 mg/m 2 and sulfamethoxazole 750 mg/m 2 per day in equally divided doses twice a day 3 times per week on alternate days.

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.

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.

Adults

One reference suggests a dosage (based on trimethoprim) of 2.5 to 5 mg/kg IV every 12 h for mild to moderate infections and 10 mg/kg every 12 h for severe infections.

Alternatively, a dosage of 2.5 to 7.5 mg/kg (based on trimethoprim) IV every 12 h is recommended for patients receiving continuous venovenous hemofiltration, continuous venovenous hemodialysis, or continuous venovenous hemodiafiltration. This recommendation assumes ultrafiltration and dialysis flow rates of 1 to 2 L/h.

For severely ill patients infected with PCP who are receiving continuous venovenous hemodiafiltration, a dosage of up to 10 mg/kg IV every 12 h may be necessary.

Off-label dosing
Acute and chronic bacterial prostatitis Adults

PO Trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily up to 12 wk.

Nocardiosis Adults

PO/IV 15 mg/kg/day (based on trimethoprim) in 2 to 4 divided doses for 3 to 4 wk, then decrease dosage to 10 mg/kg/day (based on trimethoprim) in 2 to 4 divided doses for 3 to 6 months.

Prevention of recurrent UTIs in women Adults

PO Trimethoprim 40 mg/sulfamethoxazole 200 mg daily at bedtime, a minimum of 3 times weekly or postcoitally.

Skin and soft-tissue infections Adults

PO Trimethoprim 160 to 320 mg and sulfamethoxazole 800 to 1,600 mg orally twice daily.

Children 2 mo of age and older

IV 8 to 12 mg/kg (based on trimethoprim) in equally divided doses every 6 h.

PO 8 to 12 mg/kg (based on the trimethoprim component) in equally divided doses every 12 hours.

General Advice

  • Administer each dose of injection over 60 to 90 min.
  • Avoid rapid or direct IV injection. Do not inject IM. The following infusion systems have been tested and found satisfactory: unit-dose glass containers, unit-dose polyvinyl chloride, and polyolefin containers.
  • 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.
  • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. If upon visual inspection there is cloudiness or evidence of crystallization after mixing, the solution should be discarded and a fresh solution prepared.
  • Maintain adequate fluid intake to prevent crystalluria and stone formation.
  • Shake suspension well before using.
  • Take each oral dose with a full glass of water.

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. Trimethoprim/sulfamethoxazole and ACE inhibitors may act additively to reduce aldosterone activity, resulting hyperkalemia because of reduced potassium excretion. Serum potassium concentrations should be monitored.

Amantadine

A case of toxic delirium has been reported after coadministration with sulfamethoxazole/trimethoprim. Monitor patients for CNS adverse reactions. If an interaction is suspected, it may be necessary to discontinue one or both drugs.

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. Coadministration of dofetilide and trimethoprim/sulfamethoxazole is contraindicated.

Cyclosporine

May cause decreased therapeutic effect of cyclosporine and increased risk of nephrotoxicity. If coadministration cannot be avoided, monitor cyclosporine blood or plasma concentrations, and serum creatinine concentrations. Monitor for clinical evidence of graft rejection. Adjust the dosage of cyclosporine accordingly, or add additional immunosuppressive agents.

Digoxin

Digoxin plasma concentrations may be elevated, especially in elderly patients. Monitor digoxin concentrations and adjust the digoxin dose as needed.

Diuretics (eg, thiazides)

An increased incidence of thrombocytopenia with purpura has been reported during coadministration. Monitor the platelet count. If an interaction is suspected, it may be necessary to discontinue one or both agents.

Ethanol (alcohol)

Coadministration of alcohol and trimethoprim/sulfamethoxazole may produce an alcohol intolerance reaction. Advise patients receiving trimethoprim/sulfamethoxazole to avoid drinking alcohol and taking alcohol-containing medications.

Indomethacin

Sulfamethoxazole blood levels may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Observe the patient for sulfamethoxazole adverse reactions. If an interaction is suspected, adjust therapy as needed.

Meglitinides (eg, repaglinide)

Trimethoprim may elevate meglitinide plasma concentrations, increasing the risk of hypoglycemia. Closely monitor blood glucose after starting or stopping trimethoprim. Adjust the meglitinide dose as needed.

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, increasing free methotrexate levels. The pharmacologic effects and toxicity of methotrexate may be increased. In addition, trimethoprim may increase the risk of methotrexate-induced bone marrow suppression and megaloblastic anemia. Monitor hematologic status. A lower dose of methotrexate or higher leucovorin rescue dose may be needed during coadministration of trimethoprim-sulfamethoxazole. Methotrexate plasma concentrations may be helpful in making dosage adjustments. Discontinue both drugs if an interaction is suspected.

Phenytoin

Trimethoprim may inhibit metabolism of phenytoin or other hydantoins. Phenytoin plasma concentrations may be elevated and the half-life may be prolonged, increasing the pharmacologic effects and risk of toxicity. Monitor phenytoin concentrations and observe the patient for toxicity. If an interaction is suspected, adjust the phenytoin dose as needed.

Procainamide

Trimethoprim may inhibit renal elimination of procainamide and its metabolite, N-acetylprocainamide (NAPA). Procainamide and NAPA plasma concentrations may be elevated, increasing the pharmacologic and toxic effects of procainamide. Monitor procainamide and NAPA plasma concentrations and cardiac function. Adjust the procainamide dose as needed.

Pyrimethamine

The risk of megaloblastic anemia may be increased in patients receiving more than pyrimethamine 25 mg weekly. Assess the patient for hematologic and neurologic manifestations of megaloblastic anemia. If an interaction is suspected, administer corrective treatment (eg, folic acid if indicated). It may be necessary to discontinue one or both drugs.

Sulfones (eg, dapsone)

The plasma concentration of both drugs may be elevated, increasing the pharmacologic effects and toxicity of both agents. Measure plasma concentrations of both agents and closely monitor patients for sulfone toxicity (eg, methemoglobinemia). Adjust doses or discontinue therapy as necessary.

Sulfonylureas

May increase hypoglycemic response to sulfonylureas because of displacement from protein-binding sites or inhibition of hepatic metabolism. Monitor blood glucose and adjust the sulfonylurea dose as needed.

Thiazolidinediones (eg, pioglitazone)

Trimethoprim may elevate thiazolidinedione plasma concentrations, increasing the risk of hypoglycemia and other adverse reactions. Monitor blood glucose and for other adverse reactions. Adjust the thiazolidinedione dose as needed.

Tretinoin

Phototoxicity may be augmented if tretinoin and sulfamethoxazole are coadministered. Avoid coadministration.

Tricyclic antidepressants (eg, amitriptyline)

Efficacy of tricyclic antidepressants may be decreased. Monitor the response of the patient and adjust the tricyclic antidepressant dose as needed.

Vaccines, live

The effectiveness of live vaccines may be decreased. Concurrent use is not recommended.

Warfarin

Anticoagulant effect of warfarin may be increased. Monitor coagulation parameters. Adjust the warfarin dose as needed.

Laboratory Test Interactions

Trimethoprim can interfere with serum methotrexate assay as determined by competitive binding protein technique when bacterial dihydrofolate reductase is used as binding protein. Trimethoprim/sulfamethoxazole 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.

Dermatologic

Erythema multiforme, exfoliative dermatitis, generalized skin eruptions, Henoch-Schönlein purpura, photosensitivity, pruritus, rash, Stevens-Johnson syndrome, TEN, urticaria.

Endocrine

Diuresis, hypoglycemia.

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.

Hematologic

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

Hypersensitivity

Allergic myocarditis, anaphylaxis, angioedema, generalized allergic reactions.

Local

Local reactions, pain and slight irritation on administration, thrombophlebitis.

Metabolic

Hyperkalemia, hyponatremia.

Musculoskeletal

Arthralgia, myalgia, rhabdomyolysis.

Respiratory

Cough, pulmonary infiltrates, shortness of breath.

Miscellaneous

Chills, conjunctival and scleral injection, drug fever, periarteritis nodosa, serum sickness–like syndrome, SLE, tinnitus.

Precautions

Monitor

Monitor CBC frequently during treatment; obtain urinalysis with microscopic examination and renal function tests; monitor patient for signs and symptoms of skin rash or other adverse reaction.


Pregnancy

Category C .

Lactation

Undetermined. Contraindicated in breast-feeding women.

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, TEN, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.

Renal Function

Contraindicated in severe renal insufficiency when renal function status cannot be monitored. Use drug with caution. Dosage adjustment may be required.

Hepatic Function

Contraindicated in marked hepatic damage. Use with caution.

Special Risk Patients

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

AIDS

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

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.

Clostridium difficile –associated diarrhea

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

Crystalluria

Ensure adequate fluid intake and urinary output to prevent crystalluria.

Hematological effects

Folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or renal failure.

Hyperkalemia

High doses of trimethoprim induce a progressive but reversible increase of serum potassium concentrations. Recommended doses may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, or renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly.

Hypoglycemia

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

Local effects

Local irritation and inflammation have been observed during IV use. If this occurs, discontinue infusion and restart at another site.

Sodium metabisulfite

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

Streptococcal infections

Do not use for the treatment of group A beta-hemolytic streptococcal infections.

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

Anorexia, blood dyscrasias, bone marrow depression, colic, confusion, crystalluria, depression, dizziness, drowsiness, fever, headache, hematuria, jaundice, nausea, unconsciousness, 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 mo after taking their last dose of this medicine.

Copyright © 2009 Wolters Kluwer Health.

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