COTRIM

Sulfamethoxazole is a bacteriostatic sulfonamide antibiotic that interferes with folic acid synthesis in susceptible bacteria.

It is generally given in combination with trimethoprim, which inhibits a sequential step in bacterial folic acid synthesis.

• these agents work synergistically to block two consecutive steps in the biosynthesis of nucleic acids and proteins which are necessary for bacterial growth and division, and using them in conjunction helps to slow the development of bacterial resistance.

In this combination, sulfamethoxazole is useful for the treatment of a variety of bacterial infections, including those of the urinary, respiratory, and gastrointestinal tracts.

Sulfamethoxazole is indicated in combination with trimethoprim, in various formulations, for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and travelers'diarrhea caused by enterotoxigenic E. coli. 9, 11 In Canada, additional indications include the adjunctive treatment of cholera, treatment of bacillary dysentery, nocardiosis, and second-line treatment of brucellosis in combination with gentamicin or rifampicin.

Sulfamethoxazole is a bacteriostatic sulfonamide antibiotic that inhibits a critical step in bacterial folate synthesis.

It is generally given in combination with trimethoprim, a dihydrofolate reductase inhibitor, which inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid.

Studies have shown that bacterial resistance develops more slowly with the combination of the two drugs than with either trimethoprim or sulfamethoxazole alone, as together they inhibit sequential steps in the bacterial folate synthesis pathway.

Sulfonamides, including sulfamethoxazole, have been implicated in hypersensitivity reactions.

• these agents should be discontinued at the first sign of a developing rash, as this may signal the start of a more severe reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis.

Sulfamethoxazole treatment may contribute to folate deficiency and should therefore be used with caution in patients at a higher risk of developing a deficiency.

Hemolysis has been observed in patients with glucose-6-phosphate dehydrogenase deficiency who are using sulfamethoxazole/trimethoprim.

Sulfamethoxazole is rapidly absorbed following oral administration and has a bioavailability of 85-90%.

T max is approximately 1-4 hours following oral administration, and the C max at steady-state is 57.4-68.0 μg/mL.

The volume of distribution sulfamethoxazole following a single oral dose was found to be 13 L.

Sulfamethoxazole distributes into sputum, vaginal fluid, middle ear fluid, breast milk, and the placenta.

Sulfamethoxazole metabolism is mediated primarily by arylamine N-acetyltransferase (NAT) enzymes, which are responsible for acetylation of sulfamethoxazole at its N4 position. 7, 9 Sulfamethoxazole may also undergo oxidation at its C5 and N4 atoms, the latter of which is catalyzed by CYP2C9.

Glucuronidation of the

N4 atom, likely mediated by unspecified UGT enzymes, is an additional minor route of metabolism.

None of the identified metabolites of sulfamethoxazole appear to carry antimicrobial activity.

The hydroxylamine metabolite of sulfamethoxazole, generated via oxidation by CYP2C9, may be further converted to a more reactive nitroso.

Hover over products below to view reaction partners Sulfamethoxazole 5-Hydroxysulfamethoxazole N4-Acetyl-5-OH-sulfamethoxazole N-acetylsulfamethoxazole N4-Acetyl-5-OH-sulfamethoxazole Sulfamethoxazole N4-hydroxylamine Nitroso-sulfamethoxazole Sulfamethoxazole GSH conjugate Sulfamethoxazole N-glucuronide.

Elimination occurs primarily via glomerular filtration and tubular secretion in the kidneys, with urine concentrations generally considerably higher than plasma concentrations.

Approximately 84.5% of a single oral dose of sulfamethoxazole is recovered in the urine within 72 hours, of which ~30% is free sulfamethoxazole and the remainder is the N4-acetylated metabolite.

The average serum half-life of sulfamethoxazole is 10 hours and may be increased in patients with severely impaired renal function.

The oral and renal clearance of sulfamethoxazole have been estimated as 1.2 ± 0.2 and 0.22 ± 0.05 L/h, respectively.

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The oral

LD of sulfamethoxazole in mice and rats is 2300 mg/kg and 6200 mg/kg, respectively.

Signs or symptoms of sulfonamide overdose include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness, and unconsciousness.

Less common symptoms may include pyrexia, hematuria, and crystalluria.

Later manifestations of overdose may include blood dyscrasias and jaundice.

Treatment should be symptomatic and supportive, and may include gastric lavage or forced emesis if applicable.

Monitor patient lab work for evidence of blood dyscrasias or electrolyte imbalances.

Some epidemiologic studies suggest that exposure to sulfamethoxazole and trimethoprim during pregnancy may be associated with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular malformations, urinary tract defects, oral clefts, and club foot.

If sulfamethoxazole and trimethoprim is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazards to the fetus.

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias.

Sulfonamides, including sulfonamide-containing products such as sulfamethoxazole and trimethoprim, should be discontinued at the first appearance of skin rash or any sign of adverse reaction.

In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders.

Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment.

Sulfamethoxazole and trimethoprim-induced thrombocytopenia may be an immune-mediated disorder.

Severe cases of thrombocytopenia that are fatal or life threatening have been reported.

Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole and trimethoprim.

Infections and Rheumatic Fever The sulfonamides should not be used for treatment of group A β-hemolytic streptococcal infections.

In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of

C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibiotic use.

Careful medical history is necessary since

CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Adjunctive Treatment with Leucovorin for Pneumocystis jiroveci Pneumonia Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.

Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.

Sulfamethoxazole and trimethoprim tablets are contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency.

Sulfamethoxazole and trimethoprim tablets are contraindicated in pediatric patients less than 2 months of age.

Sulfamethoxazole and trimethoprim tablets are also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

Sulfamethoxazole and trimethoprim tablets are contraindicated in pediatric patients less than 2 months of age.

Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children Adults The usual adult dosage in the treatment of urinary tract infections is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for to 14 days.

An identical daily dosage is used for 5 days in the treatment of shigellosis.

The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days.

The following table is a guideline for the attainment of this dosage: Children 2 months of age or older: Weight Dose–every 12 hours lb kg Tablets 22 44 66 88 10 20 30 40 – 1 1½ 2 or 1 DS tablet For Patients with Impaired Renal Function When renal function is impaired, a reduced dosage should be employed using the following table: Creatinine Clearance (mL/min) Recommended Dosage Regimen Above 30 15–30 Below 15 Usual standard regimen ½ the usual regimen Use not recommended Acute Exacerbations of Chronic Bronchitis in Adults The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 14 days.

Pneumocystis Jiroveci Pneumonia Treatment Adults and Children The recommended dosage for treatment of patients with documented Pneumocystis jiroveci pneumonia is to 100 mg/kg sulfamethoxazole and to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for to 21 days.

The following table is a guideline for the upper limit of this dosage: Weight Dose–every 6 hours lb kg Tablets 18 35 53 70 88 106 141 176 8 16 24 32 40 48 64 80 – 1 1½ 2 or 1 DS tablet 2½ 3 or 1½ DS tablets 4 or 2 DS tablets 5 or 2½ DS tablets For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table.

The recommended dosage for prophylaxis in adults is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet daily.

For children, the recommended dose is 750 mg/m 2 /day sulfamethoxazole with 150 mg/m 2 /day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week.

The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.

The following table is a guideline for the attainment of this dosage in children: Body Surface Area Dose–every 12 hours (m 2 ) Tablets 0.26 0.53 1.06 – ½ 1 Traveler's Diarrhea in Adults For the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets every 12 hours for 5 days.

USP, 400 mg/80 mg are white to off-white circular, beveled edge uncoated tablets, debossed with “H 48” on one side and deep break line on the other side.

USP, 800 mg/160 mg are white to off-white oval, beveled edge uncoated tablets, debossed with “H 49” on one side and deep break line on other side. 55700-611-10 55700-611-14 55700-611-20 55700-611-28 Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59° to 86°F) .

While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell, 10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim.

The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving sulfamethoxazole and trimethoprim.

There were no abnormalities in the 10 children whose mothers received the drug during the first trimester.

In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.

Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, sulfamethoxazole and trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratogenic Effects Pregnancy Category D Human Data While there are no large prospective, well controlled studies in pregnant women and their babies, some retrospective epidemiologic studies suggest an association between first trimester exposure to sulfamethoxazole and trimethoprim with an increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot.

These studies, however, were limited by the small number of exposed cases and the lack of adjustment for multiple statistical comparisons and confounders.

These studies are further limited by recall, selection, and information biases, and by limited generalizability of their findings.

Lastly, outcome measures varied between studies, limiting cross-study comparisons.

Alternatively, other epidemiologic studies did not detect statistically significant associations between sulfamethoxazole and trimethoprim exposure and specific malformations.

In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratologic effects manifested mainly as cleft palates.

These doses are approximately and 6 times the recommended human total daily dose on a body surface area basis.

In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim.

In some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface area.

CONTRAINDICATIONS section.

Levels of trimethoprim and sulfamethoxazole in breast milk are approximately to 5% of the recommended daily dose for infants over 2 months of age.

Caution should be exercised when sulfamethoxazole and trimethoprim is administered to a nursing woman, especially when breastfeeding, jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and kernicterus.

Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months of age See INDICATIONS and CONTRAINDICATIONS sections.

Clinical studies of sulfamethoxazole and trimethoprim did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, possible folate deficiency, or concomitant use of other drugs.

Severe skin reactions, generalized bone marrow suppression See WARNINGS and ADVERSE REACTIONS sections, a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.

In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.

Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients.

Serum digoxin levels should be monitored.

Hematological changes indicative of folic acid deficiency may occur in elderly patients.

These effects are reversible by folinic acid therapy.

Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions See DOSAGE AND ADMINISTRATION section.

The trimethoprim component of sulfamethoxazole and trimethoprim may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors.

Close monitoring of serum potassium is warranted in these patients.

Discontinuation of sulfamethoxazole and trimethoprim treatment is recommended to help lower potassium serum levels.

Sulfamethoxazole and trimethoprim tablets contain 0.45 mg sodium (0.02 mEq) of sodium per tablet.

Sulfamethoxazole and trimethoprim

DS tablets contain 0.9 mg (0.04 mEq) of sodium per tablet.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects.

The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects.