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Trimethoprim and Sulfamethoxazole

By Hans P. Schlecht, MD, MSc; Christopher Bruno, MD

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Trimethoprim is available as a single drug or in combination with sulfamethoxazole (a sulfonamide antibiotic—see Sulfonamides). 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).


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


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

  • A broad spectrum of gram-positive bacteria (including some methicillin-resistant Staphylococcus aureus)

  • A broad spectrum of gram-negative bacteria

  • Protozoans Cystoisospora and Cyclospora spp

  • The fungus Pneumocystis jirovecii

The combination is inactive against

  • Anaerobes

  • Treponema pallidum

  • Mycobacterium tuberculosis

  • Mycoplasma sp

  • Pseudomonas aeruginosa

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

Some Indications for TMP/SMX



Chronic bacterial prostatitis

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

Uncomplicated cystitis in women

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

Prophylaxis for recurrent UTI in women and children

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 sp, Vibrio sp, Escherichia coli) and the protozoans Cystoisospora and Cyclospora spp

Usefulness limited by increasing prevalence of resistance

Nocardia and Listeria monocytogenes infections

Acute exacerbations of chronic bronchitis

Methicillin-resistant Staphylococcus aureus infections

Used if patients cannot tolerate vancomycin

TMP/SMX =trimethoprim/sulfamethoxazole.

TMP alone is especially useful for

  • Chronic bacterial prostatitis

  • Prophylaxis and treatment of UTI in patients allergic to sulfonamides


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

TMP/SMX is in pregnancy category C (animal studies show some risk, evidence in human studies is inadequate, but clinical benefit sometimes outweighs risk). However, use near term is contraindicated; 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.

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

Adverse Effects

Adverse effects include

  • Those associated with sulfonamide (see Rifaximin : Adverse Effects)

  • Folate deficiency

  • Hyperkalemia (TMP can decrease renal tubular K excretion, leading to 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 GFR 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 for 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.

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.

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