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Trimethoprim and Sulfamethoxazole

By

Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Last full review/revision May 2020
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Trimethoprim is available as a single drug or in combination with sulfamethoxazole (a sulfonamide antibiotic Sulfonamides Sulfonamides are synthetic bacteriostatic antibiotics that competitively inhibit conversion of p-aminobenzoic acid to dihydropteroate, which bacteria need for folate synthesis and ultimately... read more ). The drugs act synergistically to block sequential steps in bacterial folate metabolism:

  • Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.

  • Sulfamethoxazole inhibits conversion of p-aminobenzoic acid to dihydropteroate.

This synergy results in maximal antibacterial activity, which is often bactericidal.

Trimethoprim/sulfamethoxazole (TMP/SMX) is available as a fixed combination consisting of a 1:5 ratio (80 mg TMP plus 400 mg SMX or a double-strength tablet of 160 mg TMP plus 800 mg SMX).

Pharmacokinetics

Both drugs are well absorbed orally and are excreted in the urine. They have a serum half-life of about 11 hours in plasma and penetrate well into tissues and body fluids, including cerebrospinal fluid. TMP is concentrated in prostatic tissue.

Indications for TMP and SMX

The combination is inactive against

Table
icon

TMP alone is especially useful for

Contraindications to TMP and SMX

TMP/SMX is contraindicated in patients who have had an allergic reaction to either drug.

Relative contraindications include folate deficiency, liver dysfunction, and renal insufficiency.

Use During Pregnancy and Breastfeeding

Animal reproduction studies with TMP/SMX show some risk (eg, birth defects). Data related to pregnancy in humans is inadequate. However, use of TMP/SMX should be avoided during the 1st trimester (because neural tube defects are a risk) and near term. If used during pregnancy or in neonates, TMP/SMX increases blood levels of unconjugated bilirubin and increases risk of kernicterus Kernicterus Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei. Normally, bilirubin bound to serum albumin stays in the intravascular space. However... read more in the fetus or neonate. If TMP/SMX cannot be avoided during the 1st trimester, folic acid supplementation (4 mg/day) is necessary.

Sulfonamides enter breast milk, and use during breastfeeding is usually discouraged.

Adverse Effects of TMP and SMX

Adverse effects of TMP/SMX include

Renal failure in patients with underlying renal insufficiency is probably secondary to interstitial nephritis or tubular necrosis. Also, TMP competitively inhibits renal tubular creatinine secretion and may cause an artificial increase in serum creatinine, although glomerular filtration rate remains unchanged. Increases in serum creatinine are more likely in patients with preexisting renal insufficiency and especially in those with diabetes mellitus.

Most adverse effects are the same as those of sulfonamides Adverse Effects Sulfonamides are synthetic bacteriostatic antibiotics that competitively inhibit conversion of p-aminobenzoic acid to dihydropteroate, which bacteria need for folate synthesis and ultimately... read more . TMP has adverse effects identical to those of SMX, but they are less common. Nausea, vomiting, and rash occur most often. AIDS patients have a high incidence of adverse effects, especially fever, rash, and neutropenia.

Folate deficiency (resulting in macrocytic anemia) can also occur. Use of folinic acid can prevent or treat macrocytic anemia, leukopenia, and thrombocytopenia, which sometimes occur with prolonged TMP/SMX use.

Rarely, severe hepatic necrosis occurs. The drug may also cause a syndrome resembling aseptic meningitis.

Dosing Considerations for TMP and SMX

TMP/SMX may increase warfarin activity and levels of phenytoin, methotrexate, and rifampin. SMX can increase the hypoglycemic effects of sulfonylureas.

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