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 (TMP) prevents reduction of dihydrofolate to tetrahydrofolate.
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
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
TMP and TMP/SMX are active against
A broad spectrum of gram-positive bacteria (including some strains of methicillin-resistant Staphylococcus aureus Staphylococcal Infections Staphylococci are gram-positive aerobic organisms. Staphylococcus aureus is the most pathogenic; it typically causes skin infections and sometimes pneumonia, endocarditis, and osteomyelitis... read more
)Protozoans Cystoisospora Cystoisosporiasis Cystoisosporiasis is infection with the protozoan Cystoisospora belli (previously known as Isospora belli). Symptoms include watery diarrhea with gastrointestinal and systemic... read more
and Cyclospora Cyclosporiasis Cyclosporiasis is infection with the protozoan Cyclospora cayetanensis. Symptoms include watery diarrhea with gastrointestinal and systemic symptoms. Diagnosis is by detection of characteristic... read more 
species
The combination is inactive against
Enterococci Enterococcal Infections Enterococci are gram-positive, facultative anaerobic organisms. Enterococcus faecalis and E. faecium cause a variety of infections, including endocarditis, urinary tract infections... read more , 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.
Some Indications for TMP/SMX
TMP alone is used less often but may be useful for
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 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
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 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.
TMP can decrease renal tubular potassium excretion, leading to potentially life-threatening hyperkalemia Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more .
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.
