Trimethoprim and Sulfamethoxazole

ByBrian J. Werth, PharmD, University of Washington School of Pharmacy
Reviewed/Revised May 2024
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sulfonamide antibiotic). The antibiotics act synergistically to block sequential steps in bacterial folate metabolism:

  • Sulfamethoxazole (SMX) 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 of TMP and SMX

Both antibiotics 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

TMP and TMP/SMX are active against

The TMP/SMX combination is inactive against

Enterococci, many Enterobacterales (formerly Enterobacteriaceae), and many Streptococcus pneumoniae strains are resistant. TMP/SMX is not clinically effective for group A streptococcal pharyngitis and does not prevent sequelae such as rheumatic fever.

Table

TMP alone is used less often but may be useful for

  • Chronic bacterial prostatitis

  • Prophylaxis and treatment of urinary tract infection in patients allergic to sulfonamides

Contraindications to TMP and SMX

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

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

Use of TMP and SMX 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 first 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

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

Adverse Effects of TMP and SMX

Adverse effects of TMP/SMX include

  • Those associated with sulfonamides

  • Folate deficiency

  • Hyperkalemia

  • Renal insufficiency

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. TMP has adverse effects identical to those of SMX, but they are less common. Nausea, vomiting, and rash occur most often. Patients with AIDS 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.

TMP can decrease renal tubular potassium excretion, leading to potentially life-threatening hyperkalemia.

Rarely, severe hepatic necrosis occurs. TMP 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.

Dose of TMP/SMX should be adjusted in patients with renal insufficiency. These antibiotics should we be used with caution in patients with renal impairment, and alternative agents should be considered.

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