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
A broad spectrum of gram-positive bacteria (including some strains of methicillin-resistant Staphylococcus aureus)
A broad spectrum of gram-negative bacteria
Protozoans Cystoisospora and Cyclospora species
The fungus Pneumocystis jirovecii
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.
Some Indications for TMP/SMX
Indication | Comments |
|---|---|
Bacterial prostatitis | Primary alternative to fluoroquinolones |
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 | Medication of choice |
Intestinal infections due to various bacteria (eg, Shigella species, Vibrio species, Escherichia coli) and the protozoans Cystoisospora and Cyclospora species | Usefulness limited by increasing prevalence of resistance |
Nocardia and Listeria monocytogenes infections | — |
Community-associated methicillin-resistant Staphylococcus aureus infections | Medication of choice for oral treatment of uncomplicated infections caused by community-associated methicillin-resistant S. aureus |
TMP/SMX = | |
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.
