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:
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
Indications
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 species
-
The fungus Pneumocystis jirovecii
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.
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% |
|
Prophylaxis for recurrent urinary tract infections in women and recurrent urinary tract infections in 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 species, Vibrio species, Escherichia coli) and the protozoans Cystoisospora and Cyclosporaspecies |
Usefulness limited by increasing prevalence of resistance |
|
Nocardia and Listeria monocytogenes infections |
— |
|
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
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
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
Trimethoprim |
No US brand name |
methotrexate |
OTREXUP |
phenytoin |
DILANTIN |
warfarin |
COUMADIN |
rifampin |
RIFADIN, RIMACTANE |
