Folate synthesis pathway and sites of action of trimethoprim and sulfamethoxazole.
Masters PA, O'Bryan TA, Zurlo J, Miller DQ, Joshi N. Trimethoprim-Sulfamethoxazole Revisited. Arch Intern Med. 2003;163(4):402-410. doi:10.1001/archinte.163.4.402
During the past 3 decades, the combination of trimethoprim and sulfamethoxazole has occupied a central role in the treatment of various commonly encountered infections and has also been particularly useful for several specific clinical conditions. However, changing resistance patterns and the introduction of newer broad-spectrum antibiotics have led to the need to carefully redefine the appropriate use of this agent in clinical practice. While trimethoprim-sulfamethoxazole's traditional role as empirical therapy for several infections has been modified by increasing resistance, it remains a highly useful alternative to the new generation of expanded-spectrum agents if resistance patterns and other clinical variables are carefully considered. It also seems to have an increasing role as a cost-effective pathogen-directed therapy with the potential to decrease or delay development of resistance to newer antibiotics used for empirical treatment. In addition, trimethoprim-sulfamethoxazole continues to be the drug of choice for several clinical indications.
Many new antibiotics offer an expanded spectrum of in vitro antimicrobial susceptibility and an improved toxicity profile compared with older agents. However, the threat of development of resistant organisms from selection pressure and the high cost of these drugs raise significant concerns about their widespread use. Furthermore, in many instances, less expensive conventional antibiotics may be therapeutically equivalent in clinical practice. With a renewed interest in appropriate antibiotic use for common infections1 and the current focus on providing cost-conscious health care, this article examines the combination of trimethoprim and sulfamethoxazole to redefine its therapeutic role in relation to newer antimicrobial agents in the face of resistance trends and adverse effect profiles.
The concept of using the fixed combination of trimethoprim and sulfamethoxazole resulted from the recognition that bacteria are obligate folic acid synthesizers, while humans obtain folate through dietary sources.
Trimethoprim and sulfamethoxazole inhibit bacterial synthesis of tetrahydrofolic acid, the physiologically active form of folic acid and a necessary cofactor in the synthesis of thymidine, purines, and bacterial DNA (Figure 1). Sulfamethoxazole, a sulfonamide drug, is a structural analogue of para-aminobenzoic acid and inhibits synthesis of the intermediary dihydrofolic acid from its precursors. Trimethoprim is a structural analogue of the pteridine portion of dihydrofolic acid that competitively inhibits dihydrofolate reductase and, consequently, the production of tetrahydrofolic acid from dihydrofolic acid. This sequential blockade of 2 enzymes in one pathway results in an effective bactericidal action.
The drug was introduced in the late 1960s based on several potential advantages of the combination of these 2 components over each one individually. The sequential blockade of the bacterial folate synthesis pathway produces in vitro synergism,2- 4 and it was postulated that such synergy would occur in vivo. It was also hoped that the use of 2 agents in a single pathway would prevent the development of bacterial resistance to either component alone.4
However, the clinical relevance of synergy has been questioned by studies5,6 of urinary tract infections (UTIs) and respiratory tract infections in which trimethoprim alone seems to be as efficacious as the combination product. In addition, emerging sulfonamide resistance and the finding that the activity of the trimethoprim component is the strongest determinant of efficacy of the antibiotic7 call into question the protection from resistance provided by the combination product.8
Despite these concerns, situations exist in which there is variable antimicrobial susceptibility to both components. In these cases, synergy and the ability of the combination product to potentially decrease the development of resistance may be important factors in determining the clinical efficacy of the drug.8
The optimal ratio of the concentration of the 2 drugs for potential synergy has been determined to be 20 parts of sulfamethoxazole to 1 part of trimethoprim.3 Thus, available preparations are manufactured in a 1:5 fixed ratio of trimethoprim to sulfamethoxazole that results in peak serum concentrations of both drugs at levels in the desired synergistic ratio.
Trimethoprim-sulfamethoxazole is available in oral and intravenous preparations. The standard single-strength tablet contains 80 mg of trimethoprim and 400 mg of sulfamethoxazole, and the more clinically used double-strength tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole.
When taken orally, both components are well absorbed from the gastrointestinal (GI) tract and may be administered without regard to food or other medications. However, trimethoprim is absorbed more rapidly than sulfamethoxazole, and is more widely distributed throughout the body.9 Because of this unequal distribution, a wide range of concentrations is achieved in different tissues and body fluids. High concentrations of both drugs are found in the sputum, cerebrospinal fluid, prostatic fluid, and bile.
Trimethoprim is excreted mostly unchanged in the urine, with approximately 10% to 30% metabolized to an inactive form. Sulfamethoxazole is primarily metabolized in the liver, with approximately 30% excreted unchanged in the urine. In otherwise healthy individuals, the approximate half-lives of both agents in the 8- to 14-hour range require twice-daily dosing. Because most drug excretion occurs via the kidney, renal insufficiency may increase the half-lives of both agents up to 30 hours or more. Therefore, the dosage of trimethoprim-sulfamethoxazole should be adjusted for a creatinine clearance of less than 30 mL/min (<0.50 mL/s).10
Both components cross the placenta and appear in breast milk, with detectable concentrations found in fetal serum in patients undergoing therapy.11 Trimethoprim-sulfamethoxazole is listed in Pregnancy Category C by the US Food and Drug Administration.
Through various mechanisms, both components of the trimethoprim-sulfamethoxazole combination product may significantly influence the metabolism of several drugs frequently used concurrently with the antibiotic, requiring consideration of potential risks in treating patients taking these medications. The major drug interactions noted with trimethoprim-sulfamethoxazole and the proposed mechanisms are listed in Table 1.
Trimethoprim-sulfamethoxazole is a generally safe medication with a well-defined adverse effect profile in immunocompetent patients (Table 2). However, clinicians need to be aware of several uncommon, but potentially serious, adverse effects associated with trimethoprim and the sulfa-containing component of the combination product.
Gastrointestinal and cutaneous symptoms are the most commonly encountered adverse effects and have generally been attributed to the sulfonamide portion of the drug.6,32 These reactions tend to be mild, dose related, and reversible, and often do not require discontinuation of therapy.7,22,33 Although difficult to establish, rates of severe or life-threatening reactions seem to be low in immunocompetent patients.29,34
A quantitative comparison of overall adverse effect rates between different antibiotics is difficult; however, multiple studies35- 37 suggest that trimethoprim-sulfamethoxazole has a 2 to 3 times increased incidence of adverse effects relative to newer antibiotics, such as the fluoroquinolones, for the treatment of similar infections.
Gastrointestinal intolerance occurs in approximately 3% to 8% of patients.22,23 Symptoms commonly include nausea, vomiting, and anorexia. Diarrhea, glossitis, and stomatitis are much less frequent. Hepatotoxicity, a known but rare complication of sulfonamide treatment, seems uncommon with trimethoprim-sulfamethoxazole treatment, and the risk is considered comparable to other antimicrobial agents.29
Skin reactions occur in 3% to 4% of the general population treated with trimethoprim-sulfamethoxazole.22- 24 Multiple skin reactions have been described, including a maculopapular rash, urticaria, diffuse erythema, morbilliform lesions, erythema multiforme, purpura, and photosensitivity. Severe reactions, including the Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported and fortunately occur only rarely, although sulfonamides seem to impart a large increase in risk for these types of reactions relative to other antibiotics.38,39
Trimethoprim is known to decrease the tubular secretion of creatinine and may interfere with certain serum creatinine assays, leading to mild elevations of the serum creatinine level without true diminution of the glomerular filtration rate.25,40- 42 These increases tend to be mild (approximately 10%), and reverse with drug discontinuation. Trimethoprim-sulfamethoxazole has only rarely been associated with direct nephrotoxicity.7
Recent observations25,26 of hyperkalemia occurring in patients treated with high-dose trimethoprim-sulfamethoxazole led to the elucidation of a mechanism whereby trimethoprim decreases potassium excretion by alteration of the transepithelial voltage in the distal renal tubule. Subsequent studies28 have documented that hyperkalemia may occur in association with the drug at lower doses used to treat routine infections, even in older patients with clinically normal renal function. Caution, thus, needs to be exercised when using trimethoprim-sulfamethoxazole in patients with preexisting renal dysfunction or in those taking concurrent medications (such as angiotensin-converting enzyme inhibitors and potassium-sparing diuretics) that may exacerbate this hyperkalemic effect to potentially dangerous levels.
Although trimethoprim inhibits dihydrofolate reductase in bacteria, it is estimated that an approximately 50 000 times increased concentration of the drug is required to inhibit the human form of this enzyme.43 Consequently, despite the theoretical potential to do so, trimethoprim does not seem to lead to megaloblastic changes when used in the treatment of routine infections, although patients with known low folate stores undergoing long-term treatment should be followed up for such changes.8
Sulfonamides have been associated with various other hematological disorders, including multiple forms of anemia, granulocytopenia, agranulocytosis, and thrombocytopenia. These reactions have also been reported with trimethoprim-sulfamethoxazole, although only rarely and at rates considered similar to other sulfonamides.7
Delirium and psychosis have been rarely reported with trimethoprim-sulfamethoxazole use, particularly in elderly persons.30,31
Adverse reactions to trimethoprim-sulfamethoxazole seem to be particularly common in HIV-infected individuals, occurring in as many as 65% of those receiving the agent.44- 46 These effects are seen when the medication is used for prophylaxis and treatment of Pneumocystis carinii pneumonia (PCP). Unfortunately, up to 50% of patients may require discontinuation of trimethoprim-sulfamethoxazole owing to its toxicity.
Adverse events generally are divided into hypersensitivity reactions and all others. Hypersensitivity reactions are most common, and include a rash and fever that develop 8 to 12 days after the initiation of therapy, usually at doses of trimethoprim-sulfamethoxazole used to treat acute PCP.47- 49 The rash is commonly a generalized maculopapular eruption that becomes pruritic. Other reactions include nausea and vomiting, diarrhea, neutropenia, thrombocytopenia, anemia, transaminase elevations, cholestatic jaundice, and azotemia.44,46- 49 Less common adverse reactions include hyperkalemia, hyponatremia, resting tremor, aseptic meningitis, rhabdomyolysis, the Stevens-Johnson syndrome, and toxic epidermal necrolysis.47,50- 54 Some adverse reactions seem to be dose related (rash, fever, liver enzyme abnormalities, and GI disturbances), while others seem to be independent of dose (neutropenia, anemia, and azotemia).49
The treatment of HIV-infected patients with drug-associated hypersensitivity reactions remains controversial, with symptomatic treatment through the reaction45,55 and gradual reintroduction of the drug (desensitization)56,57 proving to be successful strategies.
In the early 1970s, trimethoprim-sulfamethoxazole demonstrated a wide spectrum of activity against aerobic bacteria.3,58 Its antimicrobial efficacy and inexpensive cost rapidly garnered global popularity for its use in the treatment of UTIs, respiratory tract infections, and GI tract infections. However, increasing rates of resistance among clinically important pathogens have been reported worldwide during the past few decades.
Bacteria may become resistant to trimethoprim and sulfamethoxazole by several mechanisms, including the development of permeability barriers, efflux pumps, naturally insensitive target enzymes, and genetic alterations or dysregulation in the genes encoding target enzymes.59 Resistance to trimethoprim and sulfamethoxazole is transferable.59 A plasmid-encoded alteration in dihydrofolate reductase resulting in trimethoprim insensitivity against a background of high sulfonamide resistance is increasingly prevalent among bacterial pathogens.60
Certain organisms demonstrate marked geographic variation in resistance to trimethoprim-sulfamethoxazole, with a higher incidence typically found in developing countries. In addition, resistant gram-negative organisms are readily transmitted by person-to-person contact and spread by travelers.60
Trimethoprim-sulfamethoxazole is active against many Enterobacteriaceae, including Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, accounting for its widespread use in those with UTIs. In the United States, it has been the drug of choice for empirical therapy for uncomplicated UTIs in women.61
Unfortunately, the prevalence of resistant coliforms is increasing.59,62- 70 In the 1980s, trimethoprim resistance in E coli isolates from outpatient urine samples often reached 15% to 20%.71 Trimethoprim resistance among enteric organisms is more prevalent in developing countries, with reported levels as high as 68% in South America, Asia, and Africa.60 In the United States and Europe, recent use of antibiotics, hospitalization, and immunosuppression have been implicated as factors contributing to trimethoprim-sulfamethoxazole resistance among urinary tract isolates.66- 68 The San Francisco General Hospital, San Francisco, Calif, reported a sharp increase of trimethoprim-sulfamethoxazole resistance in clinical isolates of Staphylococcus aureus and 7 genera of Enterobacteriaceae, including E coli, from 1988 to 1995.65 Increases in resistance were most dramatic in isolates from HIV-infected patients and temporally associated with use of trimethoprim-sulfamethoxazole for prophylaxis against PCP.65 Furthermore, a recent study72 of a small number of resistant E coli isolates from women with community-acquired UTI in 3 separate US states suggested that a single clonal group accounted for nearly half of such strains. Such findings increase the concern for widespread transmission from a contaminated food source, leading to intestinal colonization.72
It is unclear if increased trimethoprim-sulfamethoxazole resistance among uropathogens correlates with treatment failure because a high urinary drug concentration may override in vitro insensitivity. A few studies73 limited by a small sample size suggest a higher rate of clinical failure with trimethoprim-sulfamethoxazole among resistant organisms. The Infectious Diseases Society of America74 has recommended that trimethoprim-sulfamethoxazole remain standard therapy for uncomplicated cystitis in women unless the prevalence of local resistance to the drug is greater than 10% to 20%. Patient factors favorable to the use of trimethoprim-sulfamethoxazole include no recent antimicrobial use, hospitalization, or recurrent UTI in the past year.73
Superior clinical success rates with fluoroquinolones have led to a preference for their use for acute and chronic prostate infections, although trimethoprim-sulfamethoxazole retains a role as an effective second-line treatment.75
Trimethoprim-sulfamethoxazole has been useful in the treatment of community-acquired upper and lower respiratory tract infections because of its activity against the major pathogens Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
Several studies76- 78 in the 1980s showed trimethoprim-sulfamethoxazole to be an effective treatment for otitis media, including infections caused by ampicillin-resistant strains of H influenzae.79 It has also been a useful agent for acute bacterial sinusitis,80 short-term exacerbations of chronic bronchitis,81- 85 and prophylaxis of recurrent otitis media.86,87 Until recently, trimethoprim-sulfamethoxazole has been considered a reasonable alternative to β-lactam antibiotics for the empirical treatment of mild to moderate severity community-acquired pneumonia.88
Emerging resistance among respiratory pathogens has raised serious concerns regarding the role of trimethoprim-sulfamethoxazole in the treatment of respiratory tract infections. The drug is not effective against most intermediate- and higher-level penicillin-resistant strains of S pneumoniae.89 The SENTRY Antimicrobial Surveillance Program89 recently reported a 15% to 20% frequency of trimethoprim-sulfamethoxazole resistance among S pneumoniae and H influenzae in the United States, Canada, and Europe. Higher rates of resistant respiratory pathogens were observed in Latin America and the Asian-Pacific region.89
Consequently, treatment guidelines by the Sinus and Allergy Health Partnership90 recommend trimethoprim-sulfamethoxazole only as an alternative in β-lactam–allergic patients for the treatment of mild acute bacterial sinusitis in adults and children who have not received antibiotics in the previous 4 to 6 weeks.
The American Thoracic Society's recommendations for the empirical treatment of community-acquired pneumonia, released in 1993, considered trimethoprim-sulfamethoxazole an option for initial outpatient management in adults with a comorbidity or in those 60 years or older. However, the more recent treatment guidelines for community-acquired pneumonia by the American Thoracic Society91 and the Infectious Diseases Society of America92 do not include trimethoprim-sulfamethoxazole among recommendations for empirical therapy.
Thus, trimethoprim-sulfamethoxazole as a treatment for upper and lower respiratory tract infections requires consideration of local resistance patterns and individual patient factors, such as severity of disease, when deciding the appropriateness of use.
Salmonella and Shigella species and enterotoxigenic E coli were widely susceptible to trimethoprim-sulfamethoxazole in the 1970s. This agent was frequently used as successful therapy and prophylaxis for bacterial enteric infections.93
Resistant strains of Shigella species rapidly increased in developing countries and subsequently spread worldwide.59,94 Trimethoprim-sulfamethoxazole is no longer considered appropriate treatment of shigellosis in most parts of the world. Emerging resistance among Salmonella isolates has been slower and more geographically variable than with Shigella species.60 In the United States, the incidence of infections due to Salmonella typhi has been stable since the mid 1960s; however, the proportion of cases acquired abroad has increased steadily.95 Multidrug-resistant S typhi isolated in the United States from individuals with symptomatic typhoid fever was strongly associated with recent travel to the Indian subcontinent or to Vietnam.95 Most strains from apparent domestically acquired infections remained sensitive to trimethoprim-sulfamethoxazole.95
Trimethoprim-sulfamethoxazole seems to remain efficacious in the treatment of enterotoxigenic E coli in the interior of Mexico,96 but resistance levels are high in other parts of the world.97Yersinia enterocolitica,98Vibrio cholerae,99 and Aeromonas hydrophila100 are bacterial causes of diarrheal infections that are usually susceptible.
Among travelers to many developing countries, fluoroquinolones have replaced trimethoprim-sulfamethoxazole as chemoprophylaxis.93 The role of trimethoprim-sulfamethoxazole in the treatment and prevention of infectious diarrhea in travelers is restricted to certain locations (such as noncoastal Mexico)96,101 or when treatment is directed at specific pathogens.93
Many isolates of S aureus and Staphylococcus epidermidis remain susceptible to trimethoprim-sulfamethoxazole. However, resistant strains have been widely reported among both species, especially methicillin sodium–resistant organisms.
In a surveillance102 of international strains, most methicillin-resistant coagulase-negative staphylococcal isolates were resistant to trimethoprim-sulfamethoxazole. Streptococcus pyogenes is variably susceptible.103 Several antimicrobial agents are more effective and reliable for the treatment of skin, soft tissue, and other staphylococcal infections.
Treatment of Active Infections. Because it was previously recognized as an effective agent for the treatment of PCP in immunosuppressed individuals,104 trimethoprim-sulfamethoxazole became the preferred treatment for PCP as the acquired immunodeficiency syndrome epidemic unfolded in the early 1980s. It was subsequently shown to be more effective and better tolerated than the other major parenterally active agent, pentamidine.45
It remains the treatment of choice for HIV-infected patients with severe PCP (PO2, <70 mm Hg; or alveolar to arterial gradient of oxygen, >35 mm Hg [at presentation]). In these patients, the drug is usually administered intravenously, with prednisone given as adjunctive therapy.
For mild to moderate PCP, orally administered trimethoprim-sulfamethoxazole is also considered the agent of choice, although other oral drug combinations (trimethoprim and dapsone and primaquine phosphate and clindamycin) are equally effective.47,105- 107
Approximately 10% to 20% of patients with PCP fail to respond to trimethoprim-sulfamethoxazole as a first-line therapy. Although treatment failure is likely multifactorial, drug resistance likely plays a major role. Mutations in the P carinii dihydropteroate synthase gene have been identified more commonly in isolates from patients who have received trimethoprim-sulfamethoxazole or dapsone prophylaxis.108
Trimethoprim-sulfamethoxazole is an effective treatment for infections due to the coccidian protozoal parasites Isospora and Cyclospora.109,110
The drug has activity in the treatment of cerebral toxoplasmosis in patients with the acquired immunodeficiency syndrome,111,112 although its use for this infection is not recommended because of the improved efficacy of other regimens.
Prophylaxis. Trimethoprim-sulfamethoxazole is the recommended agent for the prevention of first-episode and recurrent PCP.113 Indications for primary prophylaxis include a CD4 cell count of less than 200/µL or the presence of oropharyngeal candidiasis.113 Doses as low as 1 double-strength tablet 3 times weekly have been highly effective in preventing PCP.114 Trimethoprim sulfamethoxazole has been superior to aerosolized pentamidine for the prevention of primary and recurrent episodes of PCP,115,116 and is equivalent overall when compared with dapsone-based regimens.116
One double-strength tablet daily has been effective for the primary prophylaxis of toxoplasmosis in patients with the acquired immunodeficiency syndrome,117 and is the agent of choice.113 When used prophylactically, trimethoprim-sulfamethoxazole also has been effective in preventing other concurrent bacterial infections.115,118- 120
Trimethoprim-sulfamethoxazole has proved beneficial for prophylaxis against opportunistic infections and for reduction in the occurrence of routine infections in patients receiving immunosuppressive therapy for organ transplantation.121,122 It is also commonly used prophylactically in afebrile neutropenic individuals, although the effectiveness of this practice has been questioned.123 It is no longer considered an acceptable empirical treatment for febrile patients with neutropenia.124
Nonfermentative gram-negative bacilli are important infectious agents among hospitalized and immunocompromised patients. Stenotrophomonas (Xanthomonas) maltophilia is typically resistant to several classes of broad-spectrum antibiotics, but commonly is inhibited by trimethoprim-sulfamethoxazole.125,126 Other nonfermentative organisms, including Burkholderia (Pseudomonas) cepacia, Acinetobacter, and Alcaligenes, are frequently susceptible.125
Trimethoprim-sulfamethoxazole may have a place in therapy for meningitis caused by cephalosporin–resistant nonfermentative gram-negative bacilli and for Listeria monocytogenes infections in patients allergic to penicillin.127- 129
Trimethoprim-sulfamethoxazole is frequently used to treat Nocardia infections,130 and is efficacious in the treatment of Whipple disease, a multisystem illness caused by the bacillus Tropheryma whippelii.131,132
Selected patients with Wegener granulomatosis may benefit from treatment with trimethoprim-sulfamethoxazole, although the mechanism of action and degree of clinical efficacy in patients with this disorder is uncertain.133
Since its introduction more than 3 decades ago, trimethoprim-sulfamethoxazole has played a key role in the treatment of a wide variety of clinical infections. However, worldwide changes in resistance patterns and the introduction of newer agents with different pharmacological and antimicrobial characteristics are rapidly changing the manner in which this agent is appropriately used.
Emerging resistance has required modification of trimethoprim-sulfamethoxazole's role as empirical or first-line therapy for several infections for which it traditionally had widespread use. With attention to local, regional, and worldwide resistance patterns, trimethoprim-sulfamethoxazole may retain its usefulness as a primary agent for selected indications in carefully assessed patients (eg, for the prophylaxis and treatment of PCP and for the primary prophylaxis for Toxoplasma gondii in HIV-infected patients). It continues to be a second-line or alternative antibiotic for various infections, particularly in penicillin-allergic patients or other situations in which newer antibiotics cannot be used (eg, for uncomplicated UTIs, short-term exacerbations of chronic bronchitis, acute otitis media, acute sinusitis, and acute and chronic prostatitis).
A clearly emerging role for the drug seems to be its use as a pathogen-directed therapy for organisms identified as sensitive to trimethoprim-sulfamethoxazole (eg, organisms causing community-acquired and nosocomial pneumonia, GI tract infections, staphylococcal infections, and sexually transmitted diseases). Increasing resistance may require the use of newer expanded-spectrum agents and even multiple-antibiotic regimens for the empirical treatment of many infections. For those pathogens found to be sensitive, however, trimethoprim-sulfamethoxazole remains an efficacious and cost-effective alternative (Table 3) with a well-defined adverse effect profile that may help preserve the usefulness of the broader-spectrum drugs used for empirical therapy. Proper use in this manner requires greater diligence by the clinician in seeking a microbial diagnosis and a concerted effort at focusing treatment once a diagnosis has been made.
Trimethoprim-sulfamethoxazole certainly retains a special role in the prophylaxis and treatment of certain HIV-associated infections, and as first-line therapy for various less common infections (organisms affected include P carinii, S [X] maltophilia and other nonfermentative gram-negative bacilli, Isospora, Cyclospora, Nocardia, and T whippelii).
The judicious use of trimethoprim-sulfamethoxazole may ultimately serve as a model for the future appropriate use of broad-spectrum antibiotics in the setting of increasing antimicrobial resistance pressure and cost-conscious medical practice.
Corresponding author and reprints: Philip A. Masters, MD, Division of General Internal Medicine, The Pennsylvania State University College of Medicine, 500 University Dr, Suite 4100, Hershey, PA 17033 (e-mail: firstname.lastname@example.org).
Accepted for publication June 13, 2002.