section name header

Introduction

VA Class:AM900

AHFS Class:

Generic Name(s):

Trimethoprim, a dihydrofolate reductase inhibitor, is an antibacterial agent.106,124 (For information on the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.)

Uses

[Section Outline]

Acute Otitis Media !!navigator!!

Trimethoprim has been used for treatment of acute otitis media (AOM) caused by Streptococcus pneumoniae and Haemophilus influenzae .124 Because Moraxella catarrhalis is resistant to trimethoprim, the drug should not be used if M. catarrhalis is suspected.124

The manufacturer states that trimethoprim is not indicated for treatment of AOM in adults or in children younger than 6 months of age.124 In addition, the drug should not be used for prophylaxis of AOM and should not be given for prolonged periods for treatment of AOM in any age group.124

When anti-infective therapy is indicated for treatment of AOM, the American Academy of Pediatrics (AAP) recommends high-dose amoxicillin or amoxicillin and clavulanate potassium as the drugs of first choice for initial treatment and certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients who do not have a history of severe and/or recent penicillin-allergic reactions.321 Although the fixed combination containing trimethoprim and sulfamethoxazole (see Co-trimoxazole 8:12.20) has been used for treatment of AOM,186,321 substantial resistance to the drug has been reported in S. pneumoniae and AAP states that it should not be used as an alternative in patients who do not respond to amoxicillin.321

Urinary Tract Infections !!navigator!!

Trimethoprim is used for treatment of initial episodes of acute, uncomplicated urinary tract infections caused by susceptible Escherichia coli , Proteus mirabilis , Klebsiella pneumoniae , Enterobacter , or coagulase-negative Staphylococcus (including S. saprophyticus ).106,124

Although trimethoprim has been used for treatment of acute, uncomplicated cystitis,163 the value of trimethoprim alone for treatment of acute, uncomplicated urinary tract infections has been questioned because of emergence of an increasing number of trimethoprim-resistant organisms. The fixed combination containing trimethoprim and sulfamethoxazole (see Co-trimoxazole 8:12.20) is used for treatment of urinary tract infections,135,186 and has been recommended as a good choice for empiric treatment of acute, uncomplicated cystitis.163 However, uropathogens with resistance to trimethoprim (with or without sulfamethoxazole) have been reported with increasing frequency.163

Prior to initiation of trimethoprim for treatment of acute, uncomplicated urinary tract infections, specimens should be collected for culture and in vitro susceptibility tests; the drug may be initiated before obtaining results.106,124 Some clinicians also recommend obtaining follow-up urine cultures after discontinuance of anti-infective therapy to determine whether the bacteria have been eliminated.

Pneumocystis jirovecii Pneumonia !!navigator!!

Treatment of Pneumocystis jirovecii Pneumonia

Trimethoprim is used in conjunction with dapsone as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP).102,110,115,134,155,156 Animal studies suggest that trimethoprim alone is ineffective for treatment of PCP.103

The fixed combination containing trimethoprim and sulfamethoxazole (see Co-trimoxazole 8:12.20) is the drug of choice for treatment of mild, moderate, or severe PCP, including PCP in adults, adolescents, and children with human immunodeficiency virus (HIV) infection.134,155,156

The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternative regimens for treatment of mild to moderate PCP in HIV-infected adults and adolescents when co-trimoxazole cannot be used are dapsone in conjunction with trimethoprim, primaquine in conjunction with clindamycin, or atovaquone alone.155 These experts state that dapsone in conjunction with trimethoprim may be as effective as co-trimoxazole for treatment of mild to moderate PCP and has fewer adverse effects, but is less convenient because of higher pill burden.155 Although efficacy and safety data are limited regarding use of dapsone in conjunction with trimethoprim for treatment of PCP in children,156 some clinicians also recommend the regimen as an alternative for treatment of mild to moderate PCP in children when co-trimoxazole cannot be used.134 The dapsone and trimethoprim regimen is not included in recommendations for treatment of severe PCP.134,155,156

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Trimethoprim is administered orally.106,124 Trimethoprim also is administered orally or IV as a fixed-combination preparation with sulfamethoxazole.135,186 (For information on the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.)

Dosage !!navigator!!

Acute Otitis Media

For treatment of acute otitis media (AOM) in children 6 months of age or older, the manufacturer recommends that the oral solution containing 50 mg of trimethoprim per 5 mL be given in a dosage of 10 mg/kg daily in 2 divided doses every 12 hours for 10 days.124

Urinary Tract Infections

For treatment of acute, uncomplicated urinary tract infections, the usual adult dosage of trimethoprim is 100 mg every 12 hours or 200 mg once daily for 10 days.106,124

Pneumocystis jirovecii Pneumonia

When used as an alternative for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP) in adults and adolescents 13 years of age or older, including those with human immunodeficiency virus (HIV) infection, trimethoprim is given in a dosage of 5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (100 mg once daily for 21 days).134,155

Although efficacy and safety data are limited in children,156 some clinicians state that trimethoprim can be given in a dosage of 5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (2 mg/kg [up to 100 mg] once daily for 21 days) as an alternative for treatment of mild to moderate PCP in children younger than 13 years of age.134,156

Dosage in Renal Impairment !!navigator!!

If trimethoprim is used for treatment of acute, uncomplicated urinary tract infections in adults with creatinine clearances of 15-30 mL/minute, dosage of the drug should be reduced to 50 mg every 12 hours.106 The drug is not recommended in patients with creatinine clearances less than 15 mL/minute.106

For information on dosage of the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.

Cautions

[Section Outline]

Dermatologic and Sensitivity Reactions !!navigator!!

The most frequent adverse effects of trimethoprim are rash and pruritus.106 Rash generally is maculopapular, morbilliform, and pruritic.106,124 Mild to moderate rash appearing 7-14 days after initiation of trimethoprim has occurred in 2.9-6.7% of patients receiving a dosage of 200 mg daily.106,124 Rash has been reported to occur in up to 24% of patients receiving a dosage of 400 mg or more for 14 days. Photosensitivity (e.g., erythematous phototoxic eruptions with subsequent hyperpigmentation of sun-exposed skin) also has occurred.105,106

Serious hypersensitivity reactions have been reported rarely in patients receiving trimethoprim.106 Exfoliative dermatitis,106 toxic epidermal necrolysis (Lyell's syndrome),106,107,108 erythema multiforme,106 and Stevens-Johnson syndrome106 have been reported.105,106,107,108 Anaphylaxis also has occurred rarely.106

GI Effects !!navigator!!

Adverse GI reactions reported in patients receiving trimethoprim include epigastric discomfort,106,124 nausea,106,124 diarrhea,124 vomiting,106,124 glossitis,106,124 and abnormal taste sensation.

Hepatic Effects !!navigator!!

Elevated serum aminotransferase and bilirubin concentrations have been reported in patients receiving trimethoprim,106,124 but the clinical importance is not known.106 Cholestatic jaundice has been reported rarely.106

Hematologic Effects !!navigator!!

Hematologic toxicity, resulting from trimethoprim-induced inhibition of dihydrofolate reductase, has resulted rarely in thrombocytopenia,106,124 leukopenia,124 neutropenia,106,124 megaloblastic anemia,106,124 and methemoglobinemia.106,124 Mild, reversible hematologic toxicity, including thrombocytopenia, megaloblastic anemia, and leukopenia has occurred with a trimethoprim dosage of 1 g daily for 1 month.

Hematologic toxicity may occur with increased frequency in folate-depleted patients including geriatric, malnourished, alcoholic, pregnant, or debilitated patients; in patients receiving folate antimetabolites (e.g., phenytoin); in patients with hemolysis or impaired renal function; and in patients receiving high doses of trimethoprim for prolonged periods (e.g., longer than 6 months). Hematologic abnormalities usually resolve following administration of leucovorin (folinic acid).

Other Adverse Effects !!navigator!!

Other adverse effects of trimethoprim occurring rarely include fever,106,124 aseptic meningitis,106 elevated BUN and serum creatinine concentrations,106,124 hyperkalemia,106,124 and hyponatremia.106,124

Precautions and Contraindications !!navigator!!

Trimethoprim is contraindicated in patients with known hypersensitivity to the drug or with documented megaloblastic anemia secondary to folate deficiency.106,124

Trimethoprim should be used with caution in patients with impaired renal or hepatic function.106,124 The drug is not recommended in patients with creatinine clearances less than 15 mL/minute.106,124

Trimethoprim should be used with caution in patients with possible folate deficiency.106,124 Folates, such as leucovorin, may be administered during trimethoprim therapy and will not interfere with the drug's antibacterial effect.106,124

If signs of bone marrow depression occur, trimethoprim should be discontinued and leucovorin administered as required to restore normal hematopoiesis.106,124

Clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders.106,124 A complete blood count (CBC) should be obtained if these signs and symptoms occur in a patient receiving trimethoprim, and the drug should be discontinued if any clinically important reduction in formed blood elements is noted.106,124

Pediatric Precautions !!navigator!!

Safety and efficacy of trimethoprim oral solution or tablets have not been established in infants younger than 2 months of age.106,124

Safety and efficacy of trimethoprim oral solution have not been established for treatment of acute otitis media (AOM) in infants younger than 6 months of age.124

Efficacy of trimethoprim tablets when used as a single agent have not been established for treatment of acute, uncomplicated urinary tract infections in children younger than 12 years of age.106

It has been suggested that trimethoprim should be used with caution in children who have the fragile X chromosome associated with mental retardation, because folate depletion may worsen the psychomotor regression associated with the disorder.

Geriatric Precautions !!navigator!!

Clinical studies of trimethoprim did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.106 While other clinical experience has not revealed age-related differences in response, dosage of the drug for geriatric patients generally should be selected carefully, usually initiating therapy at the low end of the dosage range.106 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.106

Hyperkalemia has been reported in geriatric patients receiving the fixed combination of trimethoprim and sulfamethoxazole (co-trimoxazole).106

Trimethoprim is substantially eliminated by the kidneys, and the risk of adverse effects is increased in patients with renal impairment.106 Because geriatric patients are more likely to have decreased renal function, consideration should be given to monitoring potassium concentrations and renal function in this age group.106

Mutagenicity and Carcinogenicity !!navigator!!

Trimethoprim did not exhibit mutagenic activity in the Ames test, and no chromosomal damage was observed in human leukocytes cultured in vitro with trimethoprim concentrations exceeding those attained in blood during therapy with the drug.106,124 Long-term animal studies to determine carcinogenic potential of the drug have not been performed to date.106,124

Pregnancy, Fertility, and Lactation !!navigator!!

Pregnancy

Trimethoprim has been shown to be teratogenic in rats when given in doses 40 times the usual human dose; in rabbits, an overall increase in fetal loss was associated with trimethoprim doses 6 times the usual human dose.106,124 Although there are no adequate and controlled studies to date using trimethoprim in humans, a retrospective study that reported the outcome of 186 pregnancies suggested that the incidence of congenital abnormalities in those who received the fixed combination containing trimethoprim and sulfamethoxazole (co-trimoxazole) was similar to that in those who received a placebo.106,124 Because trimethoprim may interfere with folic acid metabolism, the drug should be used during pregnancy only when potential benefits justify possible risks to the fetus.106,124

Fertility

Reproduction studies in rats using oral trimethoprim dosages up to 70 mg/kg daily in males and 14 mg/kg daily in females have not revealed evidence of impaired fertility.106,124

Lactation

Trimethoprim is distributed into milk.106,124 Because trimethoprim may interfere with folic acid metabolism, the drug should be used with caution in nursing women.106,124

Drug Interactions

[Section Outline]

Dapsone !!navigator!!

Concomitant use of dapsone and trimethoprim may increase serum dapsone concentrations and potentially increase the risk of adverse effects associated with dapsone.161,162 In a study in adults with acquired immunodeficiency syndrome (AIDS) who received oral dapsone (100 mg once daily) alone or in conjunction with oral trimethoprim (20 mg/kg daily) for treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP), plasma dapsone concentrations were 40% higher with the combined regimen than with dapsone alone and methemoglobinemia occurred more frequently with the combined regimen (67%) than with dapsone alone (11%).162 There also is some evidence that dapsone may increase plasma trimethoprim concentrations,161,162 but an increased risk of trimethoprim-associated adverse effects was not identified in this study.162

Periodic monitoring for potential toxicity (e.g., methemoglobinemia) is recommended in patients receiving dapsone in conjunction with trimethoprim.160,162

Phenytoin !!navigator!!

Trimethoprim appears to inhibit hepatic metabolism of phenytoin.104,106,124 When the drugs are administered concomitantly, the metabolic clearance of phenytoin is substantially decreased and its elimination half-life is substantially increased.104,106,124 If trimethoprim is administered concomitantly with phenytoin, the patient should be observed closely for signs of phenytoin toxicity106,124 and dosage of phenytoin reduced if necessary.

Other Information

[Section Outline]

Laboratory Test Interferences

Methotrexate Assays !!navigator!!

Trimethoprim interferes with serum methotrexate assays that use a competitive binding protein technique (CBPA) with a bacterial dihydrofolate reductase as the binding protein.106,124 Trimethoprim does not interfere with radioimmunoassay (RIA) methods for determining methotrexate concentrations.106,124

Tests for Creatinine !!navigator!!

Trimethoprim may cause falsely elevated creatinine values when the Jaffe reaction is used.106,124

Acute Toxicity

Manifestations !!navigator!!

Overdosage with 1 g or more of trimethoprim may produce nausea, vomiting, dizziness, mental depression, confusion, headache, and bone marrow depression.106,124

Treatment !!navigator!!

In acute overdosage, the stomach should be emptied by gastric lavage and supportive and symptomatic treatment should be initiated.106,124 Acidification of the urine may enhance elimination of the drug.106,124 Hemodialysis may remove only moderate amounts of trimethoprim from serum; peritoneal dialysis is not effective for enhancing elimination of the drug.106,124

Mechanism of Action

Trimethoprim usually is slowly bactericidal. The drug acts on the folic acid pathway to inhibit the reduction of dihydrofolic acid to tetrahydrofolic acid by the enzyme dihydrofolate reductase.106 By inhibiting synthesis of tetrahydrofolic acid, the metabolically active form of folic acid, trimethoprim inhibits bacterial thymidine synthesis.106

Trimethoprim binds several thousand times more readily to bacterial than to human dihydrofolate reductase.

Spectrum

In Vitro Susceptibility Testing !!navigator!!

For most organisms, inoculum size may influence the results of in vitro trimethoprim susceptibility tests, particularly when the organisms are grown in media containing thymidine. Accurate in vitro sensitivity testing requires that thymidine not be present in the growth medium or that the medium be supplemented with thymidine phosphorylase to inactivate any thymidine that might be present.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to trimethoprim, the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]) recommends that a disk containing 5 mcg of trimethoprim be used.122 When disk-diffusion procedures are performed according to CLSI standardized procedures, urinary isolates of Enterobacteriaceae with growth inhibition zones of 16 mm or greater are susceptible to trimethoprim, those with zones of 11-15 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to trimethoprim.122

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures, urinary isolates of Enterobacteriaceae with MICs of 8 mcg/mL or less are susceptible to trimethoprim and those with MICs of 16 mcg/mL or greater are resistant to the drug.122

Gram-positive Aerobic Bacteria !!navigator!!

In vitro, trimethoprim concentrations of 5 mcg/mL or less inhibit most strains of Streptococcus pneumoniae , group A β-hemolytic streptococci ( S. pyogenes ), and coagulase-negative staphylococci. Some strains of enterococci, including some E. faecalis (formerly S. faecalis ), are resistant to the drug; to accurately determine the susceptibility of enterococci to trimethoprim, the growth medium must be free of thymidine and other sources of exogenous folate.

Gram-negative Aerobic Bacteria !!navigator!!

Trimethoprim is active in vitro against common gram-negative bacteria associated with urinary tract infections, including most Enterobacteriaceae. The drug is inactive against Pseudomonas aeruginosa.

Generally, trimethoprim is active in vitro against most of the following Enterobacteriaceae: Acinetobacter , Citrobacter , Enterobacter , Escherichia coli , Klebsiella pneumoniae , Proteus mirabilis , Salmonella , and Shigella . The MIC of trimethoprim for most of these gram-negative bacilli is 5 mcg/mL or less. Some strains (approximately 50% of those tested) of Providencia , Serratia , and Proteus species other than P. mirabilis are susceptible to trimethoprim.

Trimethoprim is active against most strains of Haemophilus influenzae , including many ampicillin-resistant strains. Neisseria gonorrhoeae , N. meningitidis , Nocardia , Mycobacterium , and Chlamydia .

Anaerobic Bacteria !!navigator!!

Trimethoprim generally is considered inactive against Bacteroides, and appears to have no activity against strict anaerobes such as Clostridium , Fusobacterium , and Lactobacillus.

Resistance

Resistance to trimethoprim has been shown to occur by several mechanisms, but is most often chromosomally mediated. Resistance may also rarely be the result of mutation of bacteria to thymidine-dependent strains or plasmid-mediated resistance involving altered production or sensitivity of bacterial dihydrofolate reductase. Plasmid-mediated resistance to trimethoprim has been shown to be transferable among some bacterial strains. Thymidine-dependent strains account for less than 1% of trimethoprim resistance, and chromosomal- and plasmid-mediated resistance accounts for approximately 90% and 10% of reported resistant strains, respectively.

Moraxella catarrhalis is resistant to trimethoprim.124 Resistant strains of Enterobacteriaceae, especially Escherichia coli , Klebsiella , and Proteus , have occurred during therapy with trimethoprim. Strains of Klebsiella and Proteus that are only moderately susceptible to trimethoprim in vitro at the beginning of therapy appear especially likely to develop resistance during therapy. The incidence of resistance among Enterobacteriaceae associated with urinary tract infections has been reported to range from 8-38% in some hospitals and to range from 15-100% among fecal Enterobacteriaceae following 2 weeks of trimethoprim therapy. Strains of Enterobacteriaceae and S. pneumonia resistant to trimethoprim, but susceptible to sulfonamides and penicillin, respectively, have been reported. Resistant strains of Shigella dysenteriae , Sh. flexneri , Sh. boydii ,100 and Salmonella typhi 101 also have been reported.

Resistance may develop more rapidly when trimethoprim is used alone than when it is used in combination with a sulfonamide (e.g., sulfamethoxazole), but this has not been demonstrated conclusively.

Pharmacokinetics

Absorption !!navigator!!

Trimethoprim is readily and almost completely absorbed from the GI tract. Peak serum concentrations of approximately 1, 1.6, and 2 mcg/mL are reached in 1-4 hours after single 100-, 160-, and 200-mg oral doses of trimethoprim. Following multiple-dose oral administration, steady-state peak serum concentrations of trimethoprim usually are 50% greater than those obtained after single-dose administration of the drug. Steady-state trough serum concentrations range from 1.2-3.2 mcg/mL following oral administration of 160 mg of trimethoprim every 12 hours in adults with normal renal function.

Distribution !!navigator!!

Trimethoprim is widely distributed into body tissues and fluids including the aqueous humor, middle ear fluid, saliva, lung tissue, sputum, seminal fluid, prostatic tissue and fluid, vaginal secretions, bile, bone, and CSF. The apparent volume of distribution of trimethoprim in adults with normal renal function ranges from 100-120 L. In patients with uninflamed meninges, trimethoprim concentrations in CSF are approximately 20-44 and 13-34% of concurrent trimethoprim serum concentrations following IV and oral administration of the drug, respectively. If the meninges are inflamed, a somewhat higher concentration of the antibiotic is found in CSF. Trimethoprim concentrations in middle ear fluid, prostatic fluid, and vaginal secretions are approximately 75, 200, and 160%, respectively, of concurrent trimethoprim serum concentrations.

Trimethoprim is 42-46% bound to plasma proteins.

Trimethoprim readily crosses the placenta,106,124 and amniotic fluid concentrations are reported to be 80% of concurrent maternal serum concentrations.

Trimethoprim is distributed into milk106,124 in concentrations approximately 125% those of concurrent maternal serum concentrations.

Elimination !!navigator!!

Trimethoprim has a serum half-life of approximately 8-11 hours in adults with normal renal function. In adults with creatinine clearances of 10-30 or 0-10 mL/minute, serum half-life of the drug may increase to 15 hours or greater than 26 hours, respectively. Trimethoprim serum half-lives of about 7.7 and 5.5 hours have been reported in children less than 1 year of age and between 1 and 10 years of age, respectively.

Trimethoprim is metabolized in the liver to oxide and hydroxylated metabolites. The drug is rapidly excreted in urine via glomerular filtration and tubular secretion. In adults with normal renal function, approximately 50-60 and 56-70% of an oral dose of trimethoprim is excreted in urine within 24 and 72 hours, respectively. Approximately 80% of the amount recovered in urine is unchanged drug. In adults with normal renal function, urinary concentrations of trimethoprim range from 30-160 and 18-91 mcg/mL at 0-4 and 8-24 hours, respectively, after administration of a single 100-mg dose of the drug. Urinary concentrations of the drug are decreased in patients with impaired renal function.

Only small amounts of trimethoprim are excreted in feces via biliary elimination. Trimethoprim is only moderately removed by hemodialysis,106,124 and is not removed by peritoneal dialysis.106,124

Chemistry and Stability

Chemistry !!navigator!!

Trimethoprim, a dihydrofolate reductase inhibitor, is an antibacterial agent.106,124 Trimethoprim is commercially available alone106,124 or in fixed combination with sulfamethoxazole.135,186 (For information on the fixed combination containing trimethoprim and sulfamethoxazole, see Co-trimoxazole 8:12.20.) Trimethoprim occurs as white to cream-colored, bitter-tasting, odorless crystals or crystalline powder. The drug is very slightly soluble in water and slightly soluble in alcohol.

Stability !!navigator!!

Trimethoprim hydrochloride oral solution should be stored at 15-25°C in tight, light-resistant containers.124

Trimethoprim tablets should be stored at 20-25°C in tight, light-resistant containers in a dry place.106

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Trimethoprim

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg*

Trimethoprim Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Trimethoprim Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

50 mg (of trimethoprim) per 5 mL

Primsol®

FSC

Copyright

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 5, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Gross RJ, Threlfall EJ, Ward LR et al. Drug resistance in Shigella dysenteriae, S. flexneri and S. boydii in England and Wales: increasing incidence of resistance to trimethoprim. BMJ . 1984; 288:784-6. [PubMedCentral][PubMed 6423079]

101. Ling J, Chin PY. Plasmids mediating resistance to chloramphenicol, trimethoprim, and ampicillin in Salmonella typhi strains isolated in the Southeast Asian region. J Infect Dis . 1984; 149:652. [PubMed 6725997]

102. Leoung GS, Mills J, Hopewell PC et al. Dapsone-trimethoprim for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med . 1986; 105:45-8. [PubMed 2940954]

103. Hughes WT, Smith BL. Efficacy of diaminodiphenylsulfone and other drugs in murine Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother . 1984; 26:436-40. [PubMedCentral][PubMed 6335017]

104. Hansen JM, Kampmann JP, Siersbaek-Nielsen K et al. The effect of different sulfonamides on phenytoin metabolism in man. Acta Med Scand Suppl . 1979; 624:106-10. [PubMed 284708]

105. Chandler MJ. Recurrence of phototoxic skin eruptions due to trimethoprim. J Infect Dis . 1986; 153:1001. [PubMed 2939152]

106. Watson Pharma, Inc. Trimethoprim tablet prescribing information. Corona, CA; 2009 Jun.

107. Nwokolo C, Byrne L, Misch KJ. Toxic epidermal necrolysis occurring during treatment with trimethoprim alone. BMJ . 1988; 296:970. [PubMedCentral][PubMed 3129113]

108. Das G, Bailey MJ, Wickham JEA. Toxic epidermal necrolysis and trimethoprim. BMJ . 1988; 296:1604-5. [PubMed 3135031]

110. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chemother . 1998; 42:1309-14. [PubMedCentral][PubMed 9624465]

115. Safrin S, Finkelstein DM, Feinberg J et al. Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS: a double-blind, randomized trial of oral trimethoprim—sulfamethoxazole, dapsone—trimethoprim, and clindamycin-primaquine. Ann Intern Med . 1996; 124:792-802. [PubMed 8610948]

122. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: Twenty-first informational supplement. CLSI document M100-S21. Wayne, PA; 2011.

124. FSC Laboratories, Inc. Primsol® (trimethoprim) solution prescribing information. Charlotte, NC; 2008 Aug.

134. Anon. Drugs for parasitic infections. Treat Guidel Med Lett . 2010; 8:e1-16. [Web]

135. Teva Pharmaceuticals USA. Sulfamethoxazole and trimethoprim injection solution prescribing information. Sellersville, PA; 2014 Apr.

155. Panel on Opportunistic Infections in HIV-infected Adults and Adolescents. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (May 7, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

156. Panel on Opportunistic Infection in HIV-exposed and HIV-infected children, US Department of Health and Human Services (HHS). Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-infected children: recommendations from the National Institutes of Health, Centers for Disease Control and Prevention, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics (Nov 6, 2013). Updates may be available at HHS AIDS Information (AIDSinfo) website. [Web]

160. Reviewers' comments (personal observations) on Dapsone 8:16.92.

161. Medina I, Mills J, Leoung G et al. Oral therapy for Pneumocystis carinii pneumonia in acquired immunodeficiency syndrome: a controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med . 1990; 323:776-82. [PubMed 2392131]

162. Lee BL, Medina I, Benowitz NL et al. Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS): evidence of drug interactions. Ann Intern Med . 1989; 110:606-11. [PubMed 2784648]

163. Gupta K, Hooton TM, Naber KG et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis . 2011; 52:e103-20. [PubMed 21292654]

186. AR Scientific Inc. Bactrim® (sulfamethoxazole and trimethoprim DS [double strength]) tablets and tablets USP prescribing information. Philadelphia, PA; 2013 Jun.

321. Lieberthal AS, Carroll AE, Chonmaitree T et al. The diagnosis and management of acute otitis media. Pediatrics . 2013; 131:e964-99. [PubMed 23439909]