Trimethoprim-Sulfamethoxazole Revisited
Philip A. Masters, MD; Thomas A. O’Bryan, MD; John Zurlo, MD; Debra Q. Miller, MD; Nirmal Joshi, MD Duringthepast3decades,thecombinationoftrimethoprimandsulfamethoxazole
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- spectrum antibiotics have led to the need to carefully redefine the appropriate use of this agent inclinical practice. While trimethoprim-sulfamethoxazole’s traditional role as empirical therapy forseveral infections has been modified by increasing resistance, it remains a highly useful alternativeto 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 bethe drug of choice for several clinical indications.
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-
fonamide drug, is a structural analogue of threat of development of resistant organ- 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- tural analogue of the pteridine portion of di- hydrofolic acid that competitively inhibits 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 results in an effective bactericidal action.
conscious health care, this article exam- sulfamethoxazole to redefine its therapeu- tic role in relation to newer antimicrobial agents in the face of resistance trends and late synthesis pathway produces in vitrosynergism,2-4 and it was postulated that MECHANISM OF ACTION
such synergy would occur in vivo. It wasalso hoped that the use of 2 agents in a zole resulted from the recognition that bac- teria are obligate folic acid synthesizers, ergy has been questioned by studies5,6 of uri- nary tract infections (UTIs) and respira- 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 theactivity of the trimethoprim component is From the Divisions of General Internal Medicine (Drs Masters, O’Bryan, Miller, andJoshi) and Infectious Diseases (Dr Zurlo), The Pennsylvania State University College the antibiotic7 call into question the pro- (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
and the ability of the combinationproduct to potentially decrease the de- velopment of resistance may be im-portant factors in determining the PHARMACOLOGICAL
preparations are manufactured in a1:5 fixed ratio of trimethoprim to Folate synthesis pathway and sites of action of trimethoprim and sulfamethoxazole.
sulfamethoxazole that results in peakserum concentrations of both drugs t h e d o s a g e o f t r i m e t h o p r i m - DRUG INTERACTIONS
nal fluid, prostatic fluid, and bile.
in Table 1.
methoxazole is primarily metabo-lized in the liver, with approximately TOXICITY AND
munocompetent patients (Table 2).
(REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
Table 1. Major Drug Interactions With Trimethoprim-Sulfamethoxazole
sociation with the drug at lower dosesused to treat routine infections, even Medication
Mechanism (Responsible Component)
Increases the free serum methotrexate fraction Increases the elimination half-life, increasing Increases the elimination half-life, increasing sulfonylureas, particularly in high doses, withincreased insulin output and, rarely, Decreases renal tubular secretion of procainamide and its active metabolite, N-acetylprocainamide, Hematological
Induces metabolism of contraceptive agents, leading to decreased effectiveness (unclear) Although trimethoprim inhibits di-hydrofolate reductase in bacteria, itis estimated that an approximately50 000 times increased concentra- Table 2. Adverse Effects With Trimethoprim-Sulfamethoxazole
in Immunocompetent Patients
hibit the human form of this en-zyme.43 Consequently, despite the Reaction
Estimated Frequency of Occurrence
3%-4% (severe or life-threatening reactions rare) May cause a mild (∼10%) elevation of the serum creatinine level at standard doses withoutdecreasing the glomerular filtration rate May lead to hyperkalemia at high doses and at standard doses in patients with existing renal failure or concurrent use of other medications known to increase the serum potassium level Rare, but occasionally severe; comparable to other Uncommon; delirium and psychosis reported cal disorders, including multipleforms of anemia, granulocytopenia,agranulocytosis, and thrombocyto-penia. These reactions have also Dermatological
t r i m e t h o p r i m - s u l f a m e t h o x a - Adverse Reactions in Human
Immunodeficiency Virus
(HIV)–Infected Patients
and treatment of Pneumocystis cari- (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
number of resistant E coli isolates Urinary Tract Infections
ceae, including Escherichia coli, Kleb- siella pneumoniae, and Proteus mi- tient factors favorable to the use of tri- rabilis, accounting for its widespread prim resistance in E coli isolates ANTIMICROBIAL ACTIVITY
Respiratory Tract Infections
Staphylococcus aureus and 7 genera of Enterobacteriaceae, including E coli, of H influenzae.79 It has also been a laxis of recurrent otitis media.86,87 Un- (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
trimethoprim-sulfamethoxazole.Strep- tococcus pyogenes is variably suscep- Clinical Use
in HIV-Infected Patients
resistance among Salmonella isolates Treatment of Active Infections. Be-
penicillin-resistant strains of S pneu- cally variable than with Shigella spe- dence of infections due to Salmonella typhi has been stable since the mid H influenzae in the United States, steadily.95 Multidrug-resistant S typhi ternative in ␤-lactam–allergicpatients the treatment of enterotoxigenic E coli in the interior of Mexico,96 but parts of the world.97 Yersinia entero- colitica,98 Vibrio cholerae,99 and Aeromonas hydrophila100 are bacte- bidity or in those 60 years or older.
role. Mutations in the P carinii dihy- Skin-Associated Infections
Many isolates of S aureus and Staphy- lococcus epidermidis remain suscep- protozoal parasites Isospora and Cy- GI Tract Infections
Salmonella and Shigella species and enterotoxigenic E coli were widely (REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
Prophylaxis. Trimethoprim-sulfa-
negative bacilli and for Listeria mono- for selected indications in carefully as- zole is frequently used to treat No- mary prophylaxis for Toxoplasma gon- cardia infections,130 and is effica- dii in HIV-infected patients). It con- CONCLUSIONS
Other Uses
(Table 3) with a well-defined ad-
organ transplantation.121,122 It is alsocommonly used prophylactically inafebrile neutropenic individuals, al- Table 3. Comparative Cost of Trimethoprim-Sulfamethoxazole
vs Selected Antibiotics
though the effectiveness of this prac-tice has been questioned.123 It is no Antibiotic†
Adult Dosing
Cost, $‡
longer considered an acceptable em-pirical treatment for febrile pa- m u n o c o m p r o m i s e d p a t i e n t s .
Stenotrophomonas (Xanthomonas) maltophilia is typically resistant to organisms, including Burkholderia(Pseudomonas) cepacia, Acinetobac- *Data from Red Book Updates.134†Generic drugs were used for comparison, if available.
ter, and Alcaligenes, are frequently ‡Given for a 10-day course of therapy, based on the average wholesale price plus a $4 dispensing fee.
(REPRINTED) ARCH INTERN MED/ VOL 163, FEB 24, 2003 2003 American Medical Association. All rights reserved.
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Mental health medications used for adolescents

740 15th Street, NW Washington, DC 20005 • 202.662.1506 • [email protected] • Mental Health Medications Used for Adolescents The medications below are among those most commonly used to treat mental health disorders in children and adolescents. Though not intendedto be a comprehensive guide or to replace the advice of a doctor, this information may prove


Clinical Rehabilitation 2009; 23: 771–781Vibration therapy in multiple sclerosis: a pilot studyexploring its effects on tone, muscle force, sensationand functional performanceF Schyns Revive MS Support, MS Therapy Centre, Glasgow, L Paul Nursing and Health Care–Faculty of Medicine, University ofGlasgow, K Finlay Wishaw General Hospital, NHS Lanarkshire, C Ferguson Department of Statistics, U

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