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Trimethoprim and Sulfamethoxazole

By

Brian J. Werth

, PharmD, University of Washington School of Pharmacy

Last full review/revision May 2020| Content last modified May 2020
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NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version
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Trimethoprim is available as a single drug or in combination with sulfamethoxazole (a sulfonamide antibiotic). 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

TMP and TMP/SMX (see table Some Indications for TMP/SMX) are active against

The combination is inactive against

Enterococci, many Enterobacteriaceae, and Streptococcus pneumoniae strains are resistant. TMP/SMX is not clinically effective for group A streptococcal pharyngitis.

Table
icon

Some Indications for TMP/SMX

Indication

Comments

Chronic bacterial prostatitis

One of the few effective drugs, but cures < 1/2 of patients, even after 12 weeks

Uncomplicated cystitis in women

As effective as fluoroquinolones for empiric short-course (3-day) therapy if the rate of TMP/SMX resistance is < 15%

Use of 1/2 to 1 double-strength tablet every night or every other night or, for women with previous recurrences after coitus, after coitus

Treatment of Pneumocystis jirovecii pneumonia and prophylaxis of this infection in patients with AIDS or cancer

Drug of choice

Intestinal infections due to various bacteria (eg, Shigella species, Vibrio species, Escherichia coli) and the protozoans Cystoisospora and Cyclosporaspecies

Usefulness limited by increasing prevalence of resistance

Acute exacerbations of chronic bronchitis

Community-associated methicillin-resistant Staphylococcus aureus infections

Drug of choice for oral treatment of community-associated methicillin-resistant S. aureus

TMP/SMX = trimethoprim/sulfamethoxazole.

TMP alone is especially useful for

  • Chronic bacterial prostatitis

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

Contraindications

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 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

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. 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.

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

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

Dosing Considerations

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

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
OTREXUP
DILANTIN
COUMADIN
RIFADIN, RIMACTANE
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