Trimethoprim-Sulfamethoxazole Revisited
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REVIEW ARTICLE Trimethoprim-Sulfamethoxazole Revisited Philip A. Masters, MD; Thomas A. O’Bryan, MD; John Zurlo, MD; Debra Q. Miller, MD; Nirmal Joshi, MD uring the past 3 decades, the combination of trimethoprim and sulfamethoxazole has occupied a central role in the treatment of various commonly encountered in- fections and has also been particularly useful for several specific clinical conditions. However, changing resistance patterns and the introduction of newer broad- Dspectrum 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 vari- ables 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 anti- biotics used for empirical treatment. In addition, trimethoprim-sulfamethoxazole continues to be the drug of choice for several clinical indications. Arch Intern Med. 2003;163:402-410 Many new antibiotics offer an expanded folic acid and a necessary cofactor in the syn- spectrum of in vitro antimicrobial suscep- thesis of thymidine, purines, and bacterial tibility and an improved toxicity profile DNA (Figure). Sulfamethoxazole, a sul- compared with older agents. However, the fonamide drug, is a structural analogue of threat of development of resistant organ- para-aminobenzoic acid and inhibits syn- isms from selection pressure and the high thesis of the intermediary dihydrofolic acid cost of these drugs raise significant con- from its precursors. Trimethoprim is a struc- cerns about their widespread use. Fur- tural analogue of the pteridine portion of di- thermore, in many instances, less expen- hydrofolic acid that competitively inhibits sive conventional antibiotics may be dihydrofolate reductase and, conse- therapeutically equivalent in clinical prac- quently, the production of tetrahydrofolic tice. With a renewed interest in appropri- acid from dihydrofolic acid. This sequen- ate antibiotic use for common infections1 tial blockade of 2 enzymes in one pathway and the current focus on providing cost- results in an effective bactericidal action. conscious health care, this article exam- The drug was introduced in the late ines the combination of trimethoprim and 1960s based on several potential advan- sulfamethoxazole to redefine its therapeu- tages of the combination of these 2 com- tic role in relation to newer antimicrobial ponents over each one individually. The agents in the face of resistance trends and sequential blockade of the bacterial fo- adverse effect profiles. late synthesis pathway produces in vitro synergism,2-4 and it was postulated that MECHANISM OF ACTION such synergy would occur in vivo. It was also hoped that the use of 2 agents in a The concept of using the fixed combina- single pathway would prevent the devel- tion of trimethoprim and sulfamethoxa- opment of bacterial resistance to either zole resulted from the recognition that bac- component alone.4 teria are obligate folic acid synthesizers, However, the clinical relevance of syn- while humans obtain folate through di- ergy has been questioned by studies5,6 of uri- etary sources. nary tract infections (UTIs) and respira- Trimethoprim and sulfamethoxazole tory tract infections in which trimethoprim inhibit bacterial synthesis of tetrahydrofo- alone seems to be as efficacious as the com- lic acid, the physiologically active form of bination product. In addition, emerging sul- fonamide resistance and the finding that the From the Divisions of General Internal Medicine (Drs Masters, O’Bryan, Miller, and activity of the trimethoprim component is Joshi) and Infectious Diseases (Dr Zurlo), The Pennsylvania State University College the strongest determinant of efficacy of of Medicine, Hershey. the antibiotic7 call into question the pro- (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 WWW.ARCHINTERNMED.COM 402 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tection from resistance provided by Para-aminobenzoic Acid + Pteridine the combination product.8 Despite these concerns, situa- H2N SO2NH Dihydropteroate Synthetase tions exist in which there is variable N CH antimicrobial susceptibility to both O 3 components. In these cases, synergy Sulfamethoxazole and the ability of the combination product to potentially decrease the de- Dihydropteroic Acid velopment of resistance may be im- portant factors in determining the Dihydrofolate Synthetase clinical efficacy of the drug.8 PHARMACOLOGICAL CHARACTERISTICS Dihydrofolic Acid NH2 OCH3 The optimal ratio of the concentra- N H2NCH2 OCH3 Dihydrofolate Reductase tion of the 2 drugs for potential syn- N OCH ergy has been determined to be 20 3 parts of sulfamethoxazole to 1 part Trimethoprim of trimethoprim.3 Thus, available preparations are manufactured in a Tetrahydrofolic Acid 1:5 fixed ratio of trimethoprim to Folate synthesis pathway and sites of action of trimethoprim and sulfamethoxazole. sulfamethoxazole that results in peak serum concentrations of both drugs the kidney, renal insufficiency may However, clinicians need to be aware at levels in the desired synergistic increase the half-lives of both agents of several uncommon, but poten- ratio. up to 30 hours or more. Therefore, tially serious, adverse effects associ- Trimethoprim-sulfamethoxa- the dosage of trimethoprim- ated with trimethoprim and the sulfa- zole is available in oral and intrave- sulfamethoxazole should be ad- containing component of the nous preparations. The standard justed for a creatinine clearance of combination product. single-strength tablet contains 80 mg less than 30 mL/min (Ͻ0.50 mL/s).10 Gastrointestinal and cutane- of trimethoprim and 400 mg of sul- Both components cross the pla- ous symptoms are the most com- famethoxazole, and the more clini- centa and appear in breast milk, with monly encountered adverse effects cally used double-strength tablet detectable concentrations found in and have generally been attributed contains 160 mg of trimethoprim fetal serum in patients undergoing to the sulfonamide portion of the and 800 mg of sulfamethoxazole. therapy.11 Trimethoprim-sulfa- drug.6,32 These reactions tend to be When taken orally, both com- methoxazole is listed in Pregnancy mild, dose related, and reversible, ponents are well absorbed from the Category C by the US Food and Drug and often do not require discontinu- gastrointestinal (GI) tract and may Administration. ation of therapy.7,22,33 Although dif- be administered without regard to ficult to establish, rates of severe food or other medications. How- DRUG INTERACTIONS or life-threatening reactions seem ever, trimethoprim is absorbed more to be low in immunocompetent rapidly than sulfamethoxazole, and Through various mechanisms, both patients.29,34 is more widely distributed through- components of the trimethoprim- A quantitative comparison of out the body.9 Because of this un- sulfamethoxazole combination prod- overall adverse effect rates between equal distribution, a wide range of uct may significantly influence the different antibiotics is difficult; how- concentrations is achieved in differ- metabolism of several drugs fre- ever, multiple studies35-37 suggest that ent tissues and body fluids. High quently used concurrently with the trimethoprim-sulfamethoxazole has concentrations of both drugs are antibiotic, requiring consideration of a 2 to 3 times increased incidence of found in the sputum, cerebrospi- potential risks in treating patients adverse effects relative to newer an- nal fluid, prostatic fluid, and bile. taking these medications. The ma- tibiotics, such as the fluoroquino- Trimethoprim is excreted jor drug interactions noted with tri- lones, for the treatment of similar in- mostly unchanged in the urine, with methoprim-sulfamethoxazole and fections. approximately 10% to 30% metabo- the proposed mechanisms are listed lized to an inactive form. Sulfa- in Table 1. Gastrointestinal methoxazole is primarily metabo- lized in the liver, with approximately TOXICITY AND Gastrointestinal intolerance occurs in 30% excreted unchanged in the ADVERSE EFFECTS approximately3%to8%ofpatients.22,23 urine. In otherwise healthy indi- Symptomscommonlyincludenausea, viduals, the approximate half-lives Trimethoprim-sulfamethoxazole is a vomiting,andanorexia.Diarrhea,glos- of both agents in the 8- to 14-hour generally safe medication with a well- sitis, and stomatitis are much less range require twice-daily dosing. Be- defined adverse effect profile in im- frequent. Hepatotoxicity, a known cause most drug excretion occurs via munocompetent patients (Table 2). but rare complication of sulfonamide (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 WWW.ARCHINTERNMED.COM 403 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 that hyperkalemia may occur in as- Table 1. Major Drug Interactions With Trimethoprim-Sulfamethoxazole sociation with the drug at lower doses used to treat routine infections, even Medication Mechanism (Responsible Component) References in older patients with clinically nor- Warfarin sodium Potentiates an anticoagulant effect 12, 13 mal renal function. Caution, thus, (sulfamethoxazole)