Trimethoprim-Sulfamethoxazole Revisited

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 infections 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 antibiotics 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 sulfonamide 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-

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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

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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) needs to be exercised when using tri- Methotrexate Increases the free serum methotrexate fraction 14, 15 (unclear, possibly sulfamethoxazole) methoprim-sulfamethoxazole in pa- Phenytoin Increases the elimination half-life, increasing 16, 17 tients with preexisting renal dysfunc- serum levels (trimethoprim) tion or in those taking concurrent Digoxin Increases the elimination half-life, increasing 17 medications (such as angiotensin- serum levels (trimethoprim) converting enzyme inhibitors and po- Sulfonylureas May mimic or potentiate the effect of 18, 19 sulfonylureas, particularly in high doses, with tassium-sparing diuretics) that may increased insulin output and, rarely, exacerbate this hyperkalemic effect to hypoglycemia (sulfamethoxazole) potentially dangerous levels. Procainamide hydrochloride Decreases renal tubular secretion of procainamide 20 and its active metabolite, N-acetylprocainamide, Hematological increasing serum levels (trimethoprim) Oral contraceptives Induces metabolism of contraceptive agents, 21 leading to decreased effectiveness (unclear) Although trimethoprim inhibits dihydrofolate reductase in bacteria, it is estimated that an approximately 50 000 times increased concentra- Table 2. Adverse Effects With Trimethoprim-Sulfamethoxazole tion of the drug is required to in- in Immunocompetent Patients hibit the human form of this enzyme.43 Consequently, despite the Reaction Estimated Frequency of Occurrence References theoretical potential to do so, tri- Gastrointestinal 3%-8% 7, 22, 23 methoprim does not seem to lead to Dermatological 3%-4% (severe or life-threatening reactions rare) 7, 22-24 megaloblastic changes when used in Renal May cause a mild (∼10%) elevation of the serum 7, 25 creatinine level at standard doses without the treatment of routine infections, decreasing the glomerular filtration rate although patients with known low May lead to hyperkalemia at high doses and at 26-28 folate stores undergoing long-term standard doses in patients with existing renal treatment should be followed up for failure or concurrent use of other medications 8 known to increase the serum potassium level such changes. Hematological Rare, but occasionally severe; comparable to other 7, 29 Sulfonamides have been associ- sulfonamides ated with various other hematologi- Psychiatric Uncommon; delirium and psychosis reported 30, 31 cal disorders, including multiple forms of anemia, granulocytopenia, agranulocytosis, and thrombocyto- penia. These reactions have also treatment, seems uncommon with Renal been reported with trimethoprim- trimethoprim-sulfamethoxazoletreat- sulfamethoxazole, although only ment, and the risk is considered com- Trimethoprim is known to de- rarely and at rates considered simi- parabletootherantimicrobialagents.29 crease the tubular secretion of cre- lar to other sulfonamides.7 atinine and may interfere with cer- Dermatological tain serum creatinine assays, leading Psychiatric to mild elevations of the serum cre- Skin reactions occur in 3% to 4% of atinine level without true diminu- Delirium and psychosis have been the general population treated with tion of the glomerular filtration rarely reported with trimethoprim- trimethoprim-sulfamethoxa- rate.25,40-42 These increases tend to be sulfamethoxazole use, particularly in zole.22-24 Multiple skin reactions have mild (approximately 10%), and re- elderly persons.30,31 been described, including a macu- verse with drug discontinuation. Tri- lopapular rash, urticaria, diffuse ery- methoprim-sulfamethoxazole has Adverse Reactions in Human thema, morbilliform lesions, ery- only rarely been associated with di- Immunodeficiency Virus thema multiforme, purpura, and rect nephrotoxicity.7 (HIV)–Infected Patients photosensitivity. Severe reactions, Recent observations25,26 of hy- including the Stevens-Johnson perkalemia occurring in patients Adverse reactions to trimethoprim- syndrome and toxic epidermal treated with high-dose trimethoprim- sulfamethoxazole seem to be par- necrolysis, have been reported and sulfamethoxazole led to the elucida- ticularly common in HIV-infected fortunately occur only rarely, al- tion of a mechanism whereby trimeth- individuals, occurring in as many as though sulfonamides seem to im- oprim decreases potassium excretion 65% of those receiving the agent.44-46 part a large increase in risk for these by alteration of the transepithelial These effects are seen when the types of reactions relative to other voltage in the distal renal tubule. Sub- medication is used for prophylaxis antibiotics.38,39 sequent studies28 have documented and treatment of Pneumocystis cari-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 nii pneumonia (PCP). Unfortu- ing the development of permeabil- methoprim-sulfamethoxazole for pro- nately, up to 50% of patients may ity barriers, efflux pumps, naturally phylaxis against PCP.65 Further- require discontinuation of trimeth- insensitive target enzymes, and more, a recent study72 of a small oprim-sulfamethoxazole owing to its genetic alterations or dysregula- number of resistant E coli isolates toxicity. tion in the genes encoding target from women with community- Adverse events generally are di- enzymes.59 Resistance to trimetho- acquired UTI in 3 separate US states vided into hypersensitivity reactions prim and sulfamethoxazole is trans- suggested that a single clonal group and all others. Hypersensitivity reac- ferable.59 A plasmid-encoded alter- accounted for nearly half of such tions are most common, and in- ation in dihydrofolate reductase strains. Such findings increase the clude a rash and fever that develop 8 resulting in trimethoprim insensi- concern for widespread transmis- to 12 days after the initiation of tivity against a background of high sion from a contaminated food source, therapy, usually at doses of trimeth- sulfonamide resistance is increas- leading to intestinal colonization.72 oprim-sulfamethoxazole used to treat ingly prevalent among bacterial It is unclear if increased trimeth- acute PCP.47-49 The rash is com- pathogens.60 oprim-sulfamethoxazole resistance monly a generalized maculopapular Certain organisms demon- among uropathogens correlates with eruption that becomes pruritic. Other strate marked geographic variation treatment failure because a high uri- reactions include nausea and vomit- in resistance to trimethoprim- nary drug concentration may over- ing, diarrhea, neutropenia, thrombo- sulfamethoxazole, with a higher in- ride in vitro insensitivity. A few stud- cytopenia, anemia, transaminase el- cidence typically found in develop- ies73 limited by a small sample size evations, cholestatic jaundice, and ing countries. In addition, resistant suggest a higher rate of clinical fail- azotemia.44,46-49 Less common ad- gram-negative organisms are readily ure with trimethoprim-sulfameth- verse reactions include hyperkale- transmitted by person-to-person oxazole among resistant organisms. mia, hyponatremia, resting tremor, contact and spread by travelers.60 The Infectious Diseases Society of aseptic meningitis, rhabdomyolysis, America74 has recommended that tri- the Stevens-Johnson syndrome, and Urinary Tract Infections methoprim-sulfamethoxazole re- toxic epidermal necrolysis.47,50-54 Some main standard therapy for uncompli- adverse reactions seem to be dose re- Trimethoprim-sulfamethoxazole is cated cystitis in women unless the lated (rash, fever, liver enzyme ab- active against many Enterobacteria- prevalence of local resistance to the normalities, and GI disturbances), ceae, including Escherichia coli, Kleb- drug is greater than 10% to 20%. Pa- while others seem to be indepen- siella pneumoniae, and Proteus mi- tient factors favorable to the use of tri- dent of dose (neutropenia, anemia, rabilis, accounting for its widespread methoprim-sulfamethoxazole in- and azotemia).49 use in those with UTIs. In the United clude no recent antimicrobial use, The treatment of HIV-infected States, it has been the drug of choice hospitalization, or recurrent UTI in patients with drug-associated hy- for empirical therapy for uncompli- the past year.73 persensitivity reactions remains con- cated UTIs in women.61 Superior clinical success rates troversial, with symptomatic treat- Unfortunately, the prevalence of with fluoroquinolones have led to ment through the reaction45,55 and resistant coliforms is increas- a preference for their use for acute gradual reintroduction of the drug ing.59,62-70 In the 1980s, trimetho- and chronic prostate infections, al- (desensitization)56,57 proving to be prim resistance in E coli isolates though trimethoprim-sulfamethoxa- successful strategies. from outpatient urine samples often zole retains a role as an effective sec- reached 15% to 20%.71 Trimetho- ond-line treatment.75 ANTIMICROBIAL ACTIVITY prim resistance among enteric organ- AND CLINICAL USE isms is more prevalent in develop- Respiratory Tract Infections IN THE ERA OF ing countries, with reported levels as EMERGING RESISTANCE high as 68% in South America, Asia, Trimethoprim-sulfamethoxazole has and Africa.60 In the United States and been useful in the treatment of com- In the early 1970s, trimethoprim- Europe, recent use of antibiotics, hos- munity-acquired upper and lower sulfamethoxazole demonstrated a pitalization, and immunosuppres- respiratory tract infections because wide spectrum of activity against sion have been implicated as factors of its activity against the major aerobic bacteria.3,58 Its antimicro- contributing to trimethoprim- pathogens Streptococcus pneumo- bial efficacy and inexpensive cost sulfamethoxazole resistance among niae, Haemophilus influenzae, and rapidly garnered global popularity urinary tract isolates.66-68 The San Moraxella catarrhalis. for its use in the treatment of UTIs, Francisco General Hospital, San Fran- Several studies76-78 in the 1980s respiratory tract infections, and GI cisco, Calif, reported a sharp in- showed trimethoprim-sulfamethoxa- tract infections. However, increas- crease of trimethoprim-sulfamethoxazole to be an effective treatment for ing rates of resistance among clini- zole resistance in clinical isolates of otitis media, including infections cally important pathogens have been Staphylococcus aureus and 7 genera of caused by ampicillin-resistant strains reported worldwide during the past Enterobacteriaceae, including E coli, of H influenzae.79 It has also been a few decades. from 1988 to 1995.65 Increases in re- useful agent for acute bacterial sinus- Bacteria may become resistant sistance were most dramatic in iso- itis,80 short-term exacerbations of to trimethoprim and sulfamethoxa- lates from HIV-infected patients and chronic bronchitis,81-85 and prophy- zole by several mechanisms, includ- temporally associated with use of tri- laxis of recurrent otitis media.86,87 Un-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 til recently, trimethoprim-sulfa- susceptible to trimethoprim- resistant coagulase-negative staphy- methoxazole has been considered a sulfamethoxazole in the 1970s. This lococcal isolates were resistant to reasonable alternative to ␤-lactam an- agent was frequently used as suc- trimethoprim-sulfamethoxazole.Strep- tibiotics for the empirical treatment cessful therapy and prophylaxis for tococcus pyogenes is variably suscep- of mild to moderate severity commu- bacterial enteric infections.93 tible.103 Severalantimicrobialagentsare nity-acquired pneumonia.88 Resistant strains of Shigella moreeffectiveandreliableforthetreat- Emerging resistance among res- species rapidly increased in development of skin, soft tissue, and other piratory pathogens has raised seri- ingcountriesandsubsequentlyspread staphylococcal infections. ous concerns regarding the role of tri- worldwide.59,94 Trimethoprim-sulfa- methoprim-sulfamethoxazole in the methoxazole is no longer considered Clinical Use treatment of respiratory tract infec- appropriate treatment of shigellosis in HIV-Infected Patients tions. The drug is not effective against in most parts of the world. Emerging most intermediate- and higher-level resistance among Salmonella isolates Treatment of Active Infections. Be- penicillin-resistant strains of S pneu- has been slower and more geographi- cause it was previously recognized as moniae.89 The SENTRY Antimicro- cally variable than with Shigella spe- an effective agent for the treatment of bial Surveillance Program89 recently cies.60 In the United States, the inci- PCP in immunosuppressed individu- reported a 15% to 20% frequency of dence of infections due to Salmonella als,104 trimethoprim-sulfamethoxa- trimethoprim-sulfamethoxazole re- typhi has been stable since the mid zole became the preferred treatment sistance among S pneumoniae and 1960s; however, the proportion of for PCP as the acquired immunode- H influenzae in the United States, cases acquired abroad has increased ficiency syndrome epidemic un- Canada, and Europe. Higher rates of steadily.95 Multidrug-resistant S typhi folded in the early 1980s. It was sub- resistant respiratory pathogens were isolated in the United States from in- sequently shown to be more effective observed in Latin America and the dividuals with symptomatic typhoid and better tolerated than the other Asian-Pacific region.89 fever was strongly associated with re- major parenterally active agent, pent- Consequently, treatment guide- cent travel to the Indian subcontinent amidine.45 lines by the Sinus and Allergy Health or to Vietnam.95 Most strains from ap- It remains the treatment of Partnership90 recommend trimetho- parentdomesticallyacquiredinfections choice for HIV-infected patients with Ͻ prim-sulfamethoxazole only as an al- remained sensitive to trimethoprim- severe PCP (PO2, 70 mm Hg; or al- ternativein␤-lactam–allergicpatients sulfamethoxazole.95 veolar to arterial gradient of oxygen, for the treatment of mild acute bac- Trimethoprim-sulfamethoxa- Ͼ35 mm Hg [at presentation]). In terial sinusitis in adults and children zole seems to remain efficacious in these patients, the drug is usually ad- who have not received antibiotics in the treatment of enterotoxigenic E ministered intravenously, with pred- the previous 4 to 6 weeks. coli in the interior of Mexico,96 but nisone given as adjunctive therapy. TheAmericanThoracicSociety’s resistance levels are high in other For mild to moderate PCP, recommendations for the empirical parts of the world.97 Yersinia entero- orally administered trimethoprim- treatment of community-acquired colitica,98 Vibrio cholerae,99 and sulfamethoxazole is also consid- pneumonia, released in 1993, consid- Aeromonas hydrophila100 are bacte- ered the agent of choice, although ered trimethoprim-sulfamethoxa- rial causes of diarrheal infections that other oral drug combinations (tri- zole an option for initial outpatient are usually susceptible. methoprim and dapsone and prima- management in adults with a comor- Among travelers to many quine phosphate and clindamycin) bidity or in those 60 years or older. developing countries, fluoroquino- are equally effective.47,105-107 However, the more recent treatment lones have replaced trimethoprim- Approximately 10% to 20% of guidelines for community-acquired sulfamethoxazole as chemoprophy- patients with PCP fail to respond to pneumonia by the American Thoracic laxis.93 The role of trimethoprim- trimethoprim-sulfamethoxazole as a Society91 and the Infectious Diseases sulfamethoxazole in the treatment first-line therapy. Although treat- Society of America92 do not include and prevention of infectious diar- ment failure is likely multifactorial, trimethoprim-sulfamethoxazole rhea in travelers is restricted to cer- drug resistance likely plays a major among recommendations for empiri- tain locations (such as noncoastal role. Mutations in the P carinii dihy- cal therapy. Mexico)96,101 or when treatment is di- dropteroate synthase gene have been Thus, trimethoprim-sulfa- rected at specific pathogens.93 identified more commonly in iso- methoxazole as a treatment for lates from patients who have re- upper and lower respiratory tract in- Skin-Associated Infections ceived trimethoprim-sulfamethoxa- fections requires consideration of lo- zole or dapsone prophylaxis.108 cal resistance patterns and indi- Many isolates of S aureus and Staphy- Trimethoprim-sulfameth- vidual patient factors, such as lococcus epidermidis remain suscep- oxazole is an effective treatment severity of disease, when deciding tible to trimethoprim-sulfamethoxa- for infections due to the coccidian the appropriateness of use. zole. However, resistant strains have protozoal parasites Isospora and Cy- been widely reported among both clospora.109,110 GI Tract Infections species, especially methicillin sodi- The drug has activity in the um–resistant organisms. treatment of cerebral toxoplasmo- Salmonella and Shigella species and In a surveillance102 of inter- sis in patients with the acquired im- enterotoxigenic E coli were widely national strains, most methicillin- munodeficiency syndrome,111,112 al-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 though its use for this infection is not Trimethoprim-sulfamethoxa- which it traditionally had widespread recommended because of the im- zole may have a place in therapy for use. With attention to local, regional, proved efficacy of other regimens. meningitis caused by cephalosporin– and worldwide resistance patterns, resistant nonfermentative gram- trimethoprim-sulfamethoxazole may Prophylaxis. Trimethoprim-sulfa- negative bacilli and for Listeria mono- retain its usefulness as a primary agent methoxazole is the recommended cytogenes infections in patients for selected indications in carefully as- agent for the prevention of first- allergic to penicillin.127-129 sessedpatients(eg,fortheprophylaxis episode and recurrent PCP.113 Indi- Trimethoprim-sulfamethoxa- and treatment of PCP and for the pri- cations for primary prophylaxis in- zole is frequently used to treat No- maryprophylaxisforToxoplasmagon- clude a CD4 cell count of less than cardia infections,130 and is effica- dii in HIV-infected patients). It con- 200/µL or the presence of oropha- cious in the treatment of Whipple tinues to be a second-line or alterna- ryngeal candidiasis.113 Doses as low disease, a multisystem illness caused tive antibiotic for various infections, as 1 double-strength tablet 3 times by the bacillus Tropheryma whip- particularly in penicillin-allergic pa- weekly have been highly effective in pelii.131,132 tients or other situations in which preventing PCP.114 Trimethoprim- Selected patients with Wege- newer antibiotics cannot be used (eg, sulfamethoxazole has been supe- ner granulomatosis may benefit from for uncomplicated UTIs, short-term rior to aerosolized pentamidine for treatment with trimethoprim- exacerbations of chronic bronchitis, the prevention of primary and re- sulfamethoxazole, although the acute otitis media, acute sinusitis, and current episodes of PCP,115,116 and is mechanism of action and degree of acute and chronic prostatitis). equivalent overall when compared clinical efficacy in patients with this A clearly emerging role for the with dapsone-based regimens.116 disorder is uncertain.133 drug seems to be its use as a patho- One double-strength tablet daily gen-directed therapy for organisms has been effective for the primary pro- CONCLUSIONS identified as sensitive to trimetho- phylaxis of toxoplasmosis in pa- prim-sulfamethoxazole (eg, organ- tients with the acquired immunode- Since its introduction more than isms causing community-acquired ficiency syndrome,117 and is the agent 3 decades ago, trimethoprim- and nosocomial pneumonia, GI tract of choice.113 When used prophylac- sulfamethoxazole has played a key infections, staphylococcal infec- tically, trimethoprim-sulfamethoxa- role in the treatment of a wide va- tions, and sexually transmitted zole also has been effective in pre- riety of clinical infections. How- diseases). Increasing resistance may venting other concurrent bacterial ever, worldwide changes in resis- require the use of newer expanded- infections.115,118-120 tance patterns and the introduction spectrum agents and even multiple- of newer agents with different phar- antibiotic regimens for the empiri- Other Uses macological and antimicrobial char- cal treatment of many infections. For acteristics are rapidly changing the those pathogens found to be sensi- Trimethoprim-sulfamethoxazole has manner in which this agent is ap- tive, however, trimethoprim-sulfa- proved beneficial for prophylaxis propriately used. methoxazole remains an effica- against opportunistic infections and Emergingresistancehasrequired cious and cost-effective alternative for reduction in the occurrence of modification of trimethoprim-sulfa- (Table 3) with a well-defined ad- routine infections in patients receiv- methoxazole’sroleasempiricalorfirst- verse effect profile that may help pre- ing immunosuppressive therapy for line therapy for several infections for serve the usefulness of the broader- organ transplantation.121,122 It is also commonly used prophylactically in afebrile neutropenic individuals, al- Table 3. Comparative Cost of Trimethoprim-Sulfamethoxazole vs Selected Antibiotics* though the effectiveness of this prac- 123 tice has been questioned. It is no Antibiotic† Adult Dosing Cost, $‡ longer considered an acceptable empirical treatment for febrile pa- Trimethoprim-sulfamethoxazole 1 double-strength tablet every 12 h 28.57 124 Amoxicillin 500 mg every 12 h 14.84 tients with neutropenia. Amoxicillin-clavulanic acid 500 mg every 8 h 81.63 Nonfermentative gram-nega- 875 mg every 12 h 107.63 tive bacilli are important infectious Azithromycin 500 mg once, then 250 mg/d for 4 d 45.84§ agents among hospitalized and im- Cefuroxime axetil 500 mg twice daily 164.73 munocompromised patients. Cefixime 400 mg/d 89.38 Stenotrophomonas (Xanthomonas) Ciprofloxacin 500 mg twice daily 97.44 Clarithromycin 500 mg every 12 h 82.99 maltophilia is typically resistant to Doxycycline 100 mg twice daily 33.72 several classes of broad-spectrum an- Erythromycin 333 mg every 8 h 15.12 tibiotics, but commonly is inhib- Gatifloxacin 400 mg/d 90.21 ited by trimethoprim-sulfamethoxa- Levofloxacin 500 mg/d 92.75 zole.125,126 Other nonfermentative Moxifloxacin 400 mg/d 94.61 organisms, including Burkholderia 134 (Pseudomonas) cepacia, Acinetobac- *Data from Red Book Updates. †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. susceptible.125 §Denotes a 5-day therapy plan.

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