Trimethoprim/Sulfamethoxazole

After completing this article, readers should be able to: Throughout the past 30 years, TMP/SMX has been used to treat infections caused by both gram-positive and gram-negative bacteria as well as mycobacteria, parasites, and fungi. SMX was derived from an industrial dye that was found to have antimicrobial activity. SMX was used to treat infections in humans in the 1930s, making it one of the earliest antimicrobial agents. TMP, a diaminopyrimidine, was used initially in humans in 1962. Sequentially inhibiting the production of folinic acid, TMP and SMX were combined for their synergistic bactericidal effects. In 1968, TMP/SMX became one of the few commercially available combination antimicrobials. TMP/SMX has been used widely throughout the world, but changing resistance patterns and the development of new antimicrobials have led to changes in its use.Many bacteria are obligate folic acid synthesizers, and humans use folic acid from their diets. Inhibiting folic acid production in bacteria blocks production of nucleotides and, in turn, bacterial DNA. SMX is a structural analog of para-aminobenzoic acid (PABA) that binds to the enzyme dihydropteroate synthetase competitively, inhibiting the conversion of PABA to dihydrofolic acid (FigureF1). TMP acts on the next step in the pathway. A dihydrofolic acid analog, TMP binds to the enzyme dihydrofolate reductase and hinders the production of tetrahydrofolic acid. The sequential blockade of two enzymes in the pathway of bacterial DNA production retards bacterial growth.TMP/SMX follows first-order kinetics for absorption, distribution, metabolism, and excretion. After oral administration, 85% of the drug is absorbed readily regardless of food or other medications and reaches peak serum concentrations within 2 to 4 hours. Equilibrium is reached on the third day of therapy. Peak serum concentrations are reached 1 to 2 hours sooner after intravenous administration. TMP/SMX is distributed throughout all body tissues, including cerebrospinal, middle ear, vaginal, and synovial fluids; lung parenchyma; placenta; and breast milk. TMP is more lipophilic than SMX, leading to slightly wider distribution. Tissue concentrations of TMP and SMX are 30% to 50% and 20%, respectively, of serum concentrations. Optimal synergy of the two agents against susceptible bacteria in vivo is achieved with a TMP:SMX serum concentration ratio of 1:20. Administration of TMP/SMX at a fixed combination of 1:5 in oral and intravenous preparations results in serum concentrations of approximately 1:20 because of increased tissue distribution of TMP compared with SMX.TMP/SMX tablets are available in three strengths: single strength (80 mg TMP/400 mg SMX), double strength (160 mg TMP/800 mg SMX), and a pediatric preparation (20 mg TMP/100 mg SMX). An oral suspension containing 40 mg TMP/200 mg SMX per 5 mL is available. Intravenous preparations contain 80 mg TMP/400 mg SMX per 5 mL. The recommended pediatric dose is 8 mg/kg TMP and 40 mg/kg SMX in two divided doses every 12 hours for 10 days for urinary tract infections.Sixty percent of TMP and 20% to 30% of SMX is excreted unchanged in the urine. Metabolites of TMP/SMX are bacteriologically inactive but may have toxic properties if not excreted. Because renal excretion occurs via glomerular filtration and tubular secretion, renal insufficiency increases drug half-life. If creatinine clearance is below 15 to 30 mL/min (0.25 to 0.50 mL/sec), a standard loading dose should be followed by half-standard dosing. If creatinine clearance is below 15 mL/min (0.25 mL/sec), TMP/SMX concentrations should be monitored and the dose adjusted to a percentage of the loading dose that is equal to the percentage of renal function. It may be preferable to use another antimicrobial agent in the presence of impaired renal function.During the 1970s and early 1980s, TMP/SMX was used widely to treat infections caused by aerobic bacteria. The agent was inexpensive and effective for the treatment of urinary tract infections, gastrointestinal infections, genital infections, and upper and lower respiratory tract infections (Table 1). With increasing bacterial resistance, the role of TMP/SMX has changed. Resistance occurs by several mechanisms, including changes in permeability barriers, efflux pumps, naturally insensitive target enzymes, and genetic alterations or dysregulation in the genes encoding target enzymes. These mechanisms are coded for by easily transferable plasmids that propagate the spread of resistance among bacteria. Resistance rates vary dramatically from one part of the world to another. In developing countries, where TMP/SMX is used widely, resistance to Escherichia coli is close to 70% compared with only 20% in other areas of the world. Although not of the same magnitude, increases in resistance also are being noted for Shigella sp, Salmonella sp, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.Historically, E coli, Klebsiella sp, and Enterobacter sp were highly susceptible to TMP/SMX, and uncomplicated lower urinary tract infections caused by these organisms were treated easily. Resistance to TMP/SMX has decreased its usefulness for this indication. The risk of having a TMP/SMX-resistant urinary tract infection increases if the patient has diabetes, has been hospitalized recently, currently is receiving antimicrobial therapy, or recently has received TMP/SMX. TMP/SMX is recommended as first-line therapy for urinary tract infections as long as the resistance rates for local pathogens are not greater than 20% and the patient has not been hospitalized recently or treated with other antimicrobials (Table 2). Cost analysis has shown that treatment with TMP/SMX is cost-effective only when resistance is less than 20%. TMP/SMX is especially useful in children because fluoroquinolones are not recommended for this population. Additionally, TMP/SMX remains the first-line therapy for prophylaxis in patients who have frequent urinary tract infections at doses of one double-strength tablet every day for adults and 2 to 4 mg/kg per day TMP/10 to 12 mg/kg per day SMX suspension for children once a day.The use of conjugate Haemophilus influenzae type b and S pneumoniae vaccines has resulted in a sharp decline in serious infections caused by these organisms. When H influenzae and S pneumoniae infections do occur, the organisms are likely resistant to TMP/SMX. H influenzae and S pneumoniae resistance to TMP/SMX is at a rate of 15% to 20% in the United States and Canada and even higher in Latin America and the Asian-Pacific regions. Penicillin-resistant S pneumoniae isolated from patients who have acute otitis media also are resistant to TMP/SMX in more than 40% of cases. TMP/SMX is an alternative choice for beta-lactam-allergic adults and children who have mild acute sinusitis or otitis media and have not been treated with another antimicrobial in the last 4 to 6 weeks. TMP/SMX is not included in the current treatment guidelines for adult community-acquired pneumonia. In the past, TMP/SMX was used to treat various sexually transmitted diseases, but it no longer is included in therapeutic regimens.Thirty years ago, TMP/SMX was used widely to treat bacterial gastroenteritis. Resistance rates of Shigella sp to TMP/SMX are rising rapidly in developing countries, as are resistance rates of Salmonella sp and enterotoxigenic E coli. S typhi resistance has been reported to be as high as 17% in the United States. In addition to the limited efficacy of TMP/SMX in treating active gastroenteritis, fluoroquinolones have replaced TMP/SMX as early therapy for traveler’s diarrhea in adults.Intravenous TMP/SMX remains the treatment of choice for severe Pneumocystis carinii pneumonia (PCP) in patients receiving immunosuppressive therapy and in human immunodeficiency virus (HIV)-infected patients. Oral TMP/SMX is preferred for mild-to-moderate PCP. Unfortunately, resistance is developing in strains of P carinii, with 10% to 20% of patients failing to respond to TMP/SMX therapy. TMP/SMX continues to be used for PCP prophylaxis in HIV-infected patients who have CD4 counts of less than 200 cells/mcL or who have oral candidiasis as well as for prophylaxis against PCP and other opportunistic infections in patients receiving immunosuppressive therapy.Other infections in which TMP/SMX may be effective include long-term (6 wk) therapy for brucellosis, biliary tract infections, and nocardiosis. TMP/SMX is the best alternative to ampicillin in penicillin-allergic patients who have Listeria monocytogenes meningitis. Recent studies indicate that therapy with TMP/SMX should be based on susceptibility testing of bacterial isolates. TMP/SMX is extremely cost-effective when used to treat infections caused by susceptible organisms.Generally well tolerated, TMP/SMX has several distinct and well-documented adverse effects. Although usually mild, various gastrointestinal symptoms, including nausea, vomiting, anorexia, diarrhea, glossitis, and stomatitis, can be seen in 3% to 8% of patients receiving TMP/SMX. Dermatologic conditions are the most common adverse events experienced with TMP/SMX treatment. Approximately 3% to 4% of patients experience various skin lesions, including a maculopapular eruption, urticaria, pruritus, erythema multiforme, exfoliative dermatitis, photodermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome.TMP/SMX very rarely has been associated with direct nephrotoxicity, but decreased drug clearance can develop when there is existing renal insufficiency, and dosing should be adjusted. Rare occurrences of acute interstitial nephritis, crystalluria, or renal stone formation can be avoided with adequate fluid intake.Bone marrow suppression can occur with prolonged use of TMP/SMX and can result in pancytopenia, agranulocytosis, anemia, or thrombocytopenia. Hyperkalemia, headache, confusion, psychosis, and hepatitis are other rarely reported adverse effects. All adverse reactions are seen more frequently in HIV-infected patients, with 25% to 50% experiencing a dermatologic reaction during TMP/SMX therapy.TMP/SMX crosses the placenta and is present in human milk. The American Academy of Pediatrics has stated that breastfeeding while receiving TMP/SMX is believed to be safe for most term infants but should be avoided in preterm neonates, neonates who have hyperbilirubinemia, and those who have glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. TMP/SMX competes with bilirubin for plasma protein binding sites, thereby increasing the risk of kernicterus, particularly in preterm or already jaundiced neonates. TMP/SMX is not recommended for children younger than 2 months of age. Individuals who have G-6-PD deficiency, as well as fetuses and preterm neonates (who have a relative G-6-PD deficiency), may develop dose-related acute hemolytic anemia if treated with TMP/SMX. Any individual who has had a previous reaction to any sulfonamide or possible folate deficiency should avoid TMP/SMX. Although there are no well-controlled prospective human studies, animal studies have shown teratogenic effects with rat and rabbit fetuses. TMP/SMX is listed as Pregnancy Category C by the United States Food and Drug Administration and, therefore, should not be used in pregnancy.TMP/SMX can interact with a number of commonly used medications, leading to toxicity or adverse reactions. The effects of warfarin, phenytoin, and oral hypoglycemics are potentiated by TMP/SMX, causing excessive anticoagulation, phenytoin toxicity, and hypoglycemia, respectively. TMP/SMX can increase the concentrations of free serum methotrexate and azathioprine, potentially causing severe pancytopenia. The half-life of digoxin is increased, resulting in elevated serum concentrations of digoxin. Oral contraceptive metabolism is increased by simultaneous TMP/SMX therapy and can result in ineffective contraception.With rising rates of resistance to TMP/SMX and the introduction of new broad-spectrum antimicrobials, the indications for TMP/SMX therapy have narrowed. Acute, uncomplicated urinary tract infections, urinary tract prophylaxis, selected bacterial gastrointestinal infections, and PCP treatment and prophylaxis are the primary recommended uses. Because TMP/SMX is one of the most inexpensive antimicrobials available, it remains a drug of choice in the treatment of many infections. However, increased resistance requires caution, and therapy should be based on results of susceptibility tests.