co-trimoxazole (trimethoprim-sulfamethoxazole)
Apo-Sulfatrim ◆, Bactrim, Bactrim DS, Bactrim I.V., Cotrim, Cotrim D.S., Novo-Trimel ◆, Roubac ◆, Septra, Septra DS, Septra I.V., SMZ-TMP, Sulfatrim

Available forms
Available by prescription only
Injection: trimethoprim 16 mg/ml and sulfamethoxazole 80 mg/ml
Suspension: trimethoprim 40 mg and sulfamethoxazole 200 mg/5 ml
Tablets: trimethoprim 80 mg and sulfamethoxazole 400 mg; trimethoprim 160 mg and sulfamethoxazole 800 mg

Indications and dosages
 Urinary tract infections and shigellosis. Adults: One double-strength or two regular-strength tablets P.O. q 12 hours for 10 to 14 days or 5 days for shigellosis. Or, 8 to 10 mg/kg (based on trimethoprim) I.V. daily given in two to four equally divided doses for up to 14 days (5 days for shigellosis). Maximum daily dose is 960 mg.
Children older than age 2 months: 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole P.O. daily in two divided doses q 12 hours (10 days for urinary tract infections; 5 days for shigellosis).
 Primary prophylaxis against toxoplasmosis in HIV-infected patients. Adults and adolescents: 160 mg (based on trimethoprim) P.O. daily.
Children: 150 mg/m² (based on trimethoprim) P.O. daily in two divided doses.
 Otitis media. Children older than age 2 months: 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole P.O. daily, in two divided doses q 12 hours for 10 days.
 Pneumocystis carinii pneumonitis. Adults and children older than age 2 months: 15 to 20 mg/kg trimethoprim and 100 mg/kg sulfamethoxazole P.O. daily, in equally divided doses, q 6 hours for 14 to 21 days.
 Prophylaxis of P. carinii pneumonia. Adults: 160 mg (based on trimethoprim) daily.
Children: 150 mg/m² (based on trimethoprim) daily in two divided doses for 3 consecutive days each week.
 Chronic bronchitis. Adults: One double-strength or two regular-strength tablets P.O. q 12 hours for 14 days.
 Traveler’s diarrhea. Adults: One double-strength or two regular-strength tablets P.O. q 12 hours for 5 days.
 Note: For the following unlabeled uses, dosages refer to oral trimethoprim (as co-trimoxazole).
 Septic agranulocytosis ◇. Adults: 2.5 mg/kg I.V. q.i.d.; for prophylaxis, 80 to 160 mg b.i.d.
 Norcardia infection ◇. Adults: 640 mg P.O. daily for 7 months.
 Pharyngeal gonococcal infections ◇. Prepubertal children age 1 month and older: 720 mg P.O. daily for 5 days.
 Chancroid ◇. Adults: 160 mg P.O. b.i.d. for 7 days.
 Pertussis ◇. Adults: 320 mg P.O. daily in two divided doses.
Children: 40 mg/kg P.O. daily in two divided doses.
 Cholera ◇. Adults: 160 mg P.O. b.i.d. for 3 days.
Children: 4 to 5 mg/kg P.O. b.i.d. for 3 days.
 Isosporiasis ◇. Adults: 160 mg P.O. q.i.d. for 10 days, followed by 160 mg b.i.d. for 3 weeks.
≡ Dosage adjustment. For patients with impaired renal function, adjust dose or frequency of administration of parenteral form according to degree of renal impairment, severity of infection, and susceptibility of organism.

Creatinine clearance (ml/min) Adult dosage 15-30 1/2 the usual regimen < 15 Use isn’t recommended

Pharmacodynamics
Antibacterial action: Co-trimoxazole is generally bactericidal; it acts by sequential blockade of folic acid enzymes in the synthesis pathway. The sulfamethoxazole component inhibits formation of dihydrofolic acid from para-aminobenzoic (PABA), whereas trimethoprim inhibits dihydrofolate reductase. Both drugs block folic acid synthesis, preventing bacterial cell synthesis of essential nucleic acids.
 Co-trimoxazole is effective against Escherichia coli, Klebsiella, Enterobacter, Proteus mirabilis,Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Acinetobacter, Salmonella, Shigella, and P. carinii.

Pharmacokinetics
Absorption: Well absorbed from the GI tract after oral administration.
Distribution: Distributed widely into body tissues and fluids, including middle ear fluid, prostatic fluid, bile, aqueous humor, and CSF. Protein binding is 44% for trimethoprim, 70% for sulfamethoxazole. Drug crosses the placental barrier. Metabolism: Metabolized by the liver.
Excretion: Both components of co-trimoxazole are excreted primarily in urine by glomerular filtration and renal tubular secretion; some appears in breast milk. Trimethoprim’s plasma half-life in patients with normal renal function is 8 to 11 hours, extended to 26 hours in patients with severe renal dysfunction; sulfamethoxazole’s plasma half-life is 10 to 13 hours, extended to 30 to 40 hours in patients with severe renal dysfunction. Hemodialysis removes some co-trimoxazole.

Contraindications and precautions
Contraindicated in patients hypersensitive to trimethoprim or sulfonamides, those with severe renal impairment (creatinine clearance of less than 15 ml/minute) or porphyria, those with megaloblastic anemia caused by folate deficiency, pregnant women at term, breast-feeding women, and children younger than age 2 months.
  Use cautiously in patients with impaired renal or hepatic function, severe allergies, severe bronchial asthma, chronic alcoholics, G6PD deficiency, or blood dyscrasia.

Interactions
Drug-drug. Cyclosporine: Increases risk of nephrotoxicity. Avoid use together.
Digoxin: Increases digoxin levels. Monitor serum levels closely.
Indomethacin: May increase sulfamethoxazole levels. Dosage adjustment may be needed.
Methotrexate: Increases methotrexate levels. Use together cautiously.
Oral anticoagulants: Co-trimoxazole may inhibit hepatic metabolism, enhancing anticoagulant effects. Observe patient for signs of bleeding.
Oral sulfonylureas: Enhances hypoglycemic effects. Monitor blood glucose levels.
Para-aminobenzoic acid: Antagonizes sulfonamide effects. Monitor patient closely.
Phenytoin: Inhibits phenytoin metabolism. Dosage adjustment may be needed.
Pyrimethamine: May cause megaloblastic anemia with pyrimethamine doses greater than 25 mg weekly. Avoid use together.
Tricyclic antidepressants: Decreases antidepressant effect. Monitor patient closely.
Zidovudine: May increase serum zidovudine level. Monitor patient carefully.
Drug-herb. Dong quai, St. John’s wort: Causes additive photosensitivity risk. Advise patient to take precautions against sunburn.
Drug-lifestyle. Sun exposure: Photosensitivity reaction may occur. Advise patient to take precautions.

Adverse reactions
CNS: headache, mental depression, aseptic meningitis, apathy, seizures, hallucinations, ataxia, nervousness, fatigue, vertigo, insomnia.
CV: thrombophlebitis.
EENT: tinnitus.
GI: nausea, vomiting, diarrhea, abdominal pain, anorexia, stomatitis, pancreatitis, pseudomembranous colitis.
GU: toxic nephrosis with oliguria and anuria, crystalluria, hematuria, interstitial nephritis.
Hematologic: agranulocytosis, aplastic anemia, megaloblastic anemia, thrombocytopenia, leukopenia, hemolytic anemia, pancytopenia.
Hepatic: jaundice, hepatic necrosis.
Musculoskeletal: arthralgia, myalgia, muscle weakness.
Respiratory: pulmonary infiltrates.
Skin: erythema multiforme (Stevens-Johnson syndrome), generalized skin eruptions, epidermal necrolysis, exfoliative dermatitis, photosensitivity, urticaria, pruritus.
Other: hypersensitivity reactions (serum sickness, drug fever, anaphylaxis), rhabdomyolysis.

Effects on lab test results
• May increase BUN, creatinine, aminotransferase, and bilirubin levels.
• May decrease hemoglobin, hematocrit, and granulocyte, platelet, and WBC counts.

Overdose and treatment
Signs and symptoms of overdose include mental depression, drowsiness, anorexia, jaundice, confusion, headache, nausea, vomiting, diarrhea, facial swelling, slight elevations in liver function test results, and bone marrow depression.
 Treat by emesis or gastric lavage, followed by supportive care (correction of acidosis, forced oral fluids, and I.V. fluids). Treatment of renal failure may be required; transfuse appropriate blood products in severe hematologic toxicity; use folinic acid to rescue bone marrow. Hemodialysis has limited ability to remove co-trimoxazole. Peritoneal dialysis isn’t effective.

Special considerations
 ALERT Note that DS means double-strength.
 ALERT Don’t write dosage as trimethoprim component.
 ALERT Drug isn’t for I.M. use.
• Co-trimoxazole has been used effectively to treat chronic bacterial prostatitis and as prophylaxis against recurrent urinary tract infection in women and traveler’s diarrhea.
• For I.V. use, dilute infusion in D₅W. Don’t mix with other drugs. Don’t administer by rapid infusion or bolus injection. Infuse slowly over 60 to 90 minutes.
• I.V. infusion must be diluted before use. Each 5 ml should be added to 125 ml D₅W. Don’t refrigerate solution; diluted solutions must be used within 6 hours. A dilution of 5 ml per 75 ml D₅W may be prepared for patients requiring fluid restriction, but these solutions should be used within 2 hours.
• Check solution carefully for precipitate before starting infusion. Don’t use solution containing a precipitate.
• Shake oral suspension thoroughly before administering.
• Trimethoprim can interfere with serum methotrexate assay as determined by the competitive binding protein technique. No interference occurs if radioimmunoassay is used.
• Assess I.V. site for signs of phlebitis or infiltration.
• Monitor renal and liver function test results.
Pregnant patients
• Use only when crucial in pregnant women.
Breast-feeding patients
• Drug isn’t recommended for breast-feeding women.
Pediatric patients
• Drug isn’t recommended for infants younger than age 2 months.
Geriatric patients
• In elderly patients, diminished renal function may prolong half-life. Such patients also have an increased risk of adverse reactions.

Patient education
• Inform patient of potential adverse reactions.
• Tell patient to take drug as prescribed, even if he feels better.
• Instruct patient to take oral dose with 8 oz (240 ml) of water on an empty stomach.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use