Trimethoprim

Pronunciation

Class: Urinary Anti-infectives
VA Class: AM900
CAS Number: 738-70-5
Brands: Primsol, Proloprim

Introduction

Antibacterial; folate-antagonist anti-infective.b Commercially available alone or in fixed combination with sulfamethoxazole.b For information on the fixed combination, see Co-trimoxazole (Systemic).

Uses for Trimethoprim

Acute Otitis Media (AOM)

Treatment of AOM caused by Streptococcus pneumoniae and Haemophilus influenzae.124

Consider use of an alternative anti-infective if Moraxella catarrhalis is suspected; this organism is resistant to trimethoprim.124

Do not use for AOM in adults or in children <6 months of age.124

Do not use for prophylaxis of AOM or for prolonged periods in any age group.124

Urinary Tract Infections (UTIs)

Treatment of initial episodes of acute, uncomplicated UTIs caused by susceptible Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter, or coagulase-negative Staphylococcus (including S. saprophyticus).106 124

Slideshow: The Shocking Truth About Antibiotic Resistance

Has been used for treatment of chronic and recurrent UTIs, but is less effective than other anti-infectives (e.g., co-trimoxazole) for these infections.b

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Used in conjunction with dapsone as an alternative to co-trimoxazole for treatment of initial episodes of mild to moderate Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP) in HIV-infected adults.102 110 115 119 120 121 125

Should not be used alone for treatment of PCP.b

Travelers’ Diarrhea

Has been used for treatment and prevention of travelers’ diarrhea.111 112 113 114 115 116 117

Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin, ofloxacin) usually drugs of choice when anti-infective treatment or prevention of travelers’ diarrhea is indicated; co-trimoxazole is an alternative for treatment when fluoroquinolones cannot be used (e.g., in children).114 123

Trimethoprim Dosage and Administration

Administration

Oral Administration

Administer orally.106 124

Dosage

Pediatric Patients

Acute Otitis Media (AOM)
Oral

Children ≥6 months of age: 10 mg/kg daily in 2 divided doses every 12 hours given for 10 days.124

Adults

Urinary Tract Infections (UTIs)
Acute, Uncomplicated UTIs
Oral

100 mg every 12 hours or 200 mg once daily for 10–14 days.106 124 b

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia
Treatment of PCP
Oral

5 mg/kg 3 times daily for 21 days; used in conjunction with dapsone (100 mg once daily for 21 days).110 115 119 125

Special Populations

Renal Impairment

Urinary Tract Infections (UTIs)
Acute, Uncomplicated UTIs
Oral

Doses and/or frequency of administration must be modified in response to the degree of renal impairment.106 124 b

50 mg every 12 hours in adults with Clcr 15–30 mL/minute.106 124

Manufacturers recommend the drug not be used in patients with Clcr <15 mL/minute;106 124 some clinicians suggest the drug can be used in reduced dosages in these patients.b

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal, hepatic, and/or cardiac function.106 Initiate therapy at the lower end of the dosing range.106 (See Geriatric Precautions under Cautions.)

Cautions for Trimethoprim

Contraindications

  • Hypersensitivity to trimethoprim.106 124

  • Documented megaloblastic anemia secondary to folate deficiency.106 124

Warnings/Precautions

Warnings

Hematologic Effects

Hematologic toxicity (as the result of trimethoprim-induced inhibition of dihydrofolate reductase) has resulted in thrombocytopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.b

Hematologic toxicity occurs most frequently 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 trimethoprim dosage for prolonged periods (e.g., >6 months).b

Clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders.106 124 If such signs occur, perform CBC; discontinue trimethoprim if a clinically important decrease in any formed blood element occurs.106 124

Use caution in patients with possible folate deficiency.106 124

Folic acid may be administered during trimethoprim therapy and will not interfere with the drug’s antibacterial effect.124 b Leucovorin (folinic acid) should be administered if bone marrow depression occurs.b Hematologic abnormalities usually resolve following administration of leucovorin (3–15 mg daily for 3 days or until normal hematopoiesis is restored).b

Sensitivity Reactions

Hypersensitivity Reactions

Most frequent adverse reactions are rash and pruritus.106

Serious hypersensitivity reactions reported rarely, including anaphylaxis,106 exfoliative dermatitis,106 toxic epidermal necrolysis,106 107 108 erythema multiforme,106 and Stevens-Johnson syndrome.106 105 106 107 108

Photosensitivity

Photosensitivity (e.g., erythematous phototoxic eruptions with subsequent hyperpigmentation of sun-exposed skin) has been reported.105 106

General Precautions

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of trimethoprim and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.106

Specific Populations

Pregnancy

Category C.106 124

Because trimethoprim may interfere with folic acid metabolism, use during pregnancy only if potential benefits justify risk to the fetus.106 124

Lactation

Distributed into milk.106 124 Because trimethoprim may interfere with folic acid metabolism, use caution in nursing women.106 124

Pediatric Use

Safety and efficacy not established in infants <2 months of age.106 124

Efficacy for treatment of AOM not established in children <6 months of age.124

It has been suggested that trimethoprim 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.b

Geriatric Use

Experience in those ≥65 years of age insufficient to determine whether they respond differently than younger adults.106

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

Substantially eliminated by kidneys; risk of adverse effects increased in patients with renal impairment.106 Consider monitoring potassium concentrations and renal function (e.g., Clcr) since geriatric patients more likely to have decreased renal function.106

Caution advised; start at the lower end of the dosing range due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.106

Hepatic Impairment

Use with caution.106

Renal Impairment

Use with caution.106

Manufacturers recommend trimethoprim not be used in patients with Clcr <15 mL/minute.106 124

Common Adverse Effects

Hypersensitivity (rash, pruritus), GI effects (epigastric discomfort, nausea, diarrhea, vomiting, glossitis, abnormal taste sensation).106 b 124

Interactions for Trimethoprim

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Phenytoin

May inhibit phenytoin metabolism resulting in increased half-life and decreased clearance of phenytoin104 106 124

Monitor closely for signs of phenytoin toxicity;106 124 reduce phenytoin dosage if necessaryb

Tests for creatinine

Possible interference with Jaffe alkaline picrate assay resulting in falsely elevated creatinine concentrations106 124

Tests for methotrexate

Possible interference with serum methotrexate assays if competitive binding protein technique (CBPA) is used with a bacterial dihydrofolate reductase as the binding protein;106 124 interference does not occur if methotrexate is measured using radioimmunoassay (RIA)106 124

Trimethoprim Pharmacokinetics

Absorption

Bioavailability

Rapidly106 124 b and almost completely absorbed from GI tract.b

Steady-state concentrations attained within 2–3 days.124 Peak serum concentrations attained within 1–4 hours after a dose.106 124 b

Distribution

Extent

Widely distributed into body tissues and fluids, including aqueous humor, middle ear fluid, saliva, lung tissue, sputum, seminal fluid, prostatic tissue and fluid, vaginal secretions, bile, and bone.106 124 b

Distributed into CSF.b In patients with uninflamed meninges receiving oral trimethoprim, CSF concentrations are approximately 13–34% of concurrent serum concentrations.b CSF concentrations somewhat higher if meninges are inflamed.b

Readily crosses the placenta;106 124 b amniotic fluid concentrations are 80% of concurrent maternal serum concentrations.b

Distributed into milk106 124 b in concentrations approximately 125% those of concurrent maternal serum concentrations.b

Plasma Protein Binding

42–46% bound to plasma proteins.106 124 b

Elimination

Metabolism

10–20%106 of a dose is metabolized in the liver to oxide and hydroxylated metabolites.106 124 b

Elimination Route

Eliminated in urine via glomerular filtration and tubular secretion.106 124 b Only small amounts excreted in feces via biliary elimination.b

In adults with normal renal function, approximately 50–60 and 56–70% of an oral dose is excreted in urine within 24 and 72 hours, respectively.106 b Approximately 80% of the amount recovered in urine is unchanged drug.106 124 b

Hemodialysis is only moderately effective in removing trimethoprim; not removed by peritoneal dialysis.106

Half-life

8–11 hours in adults with normal renal function.106 b

7.7 hours in children <1 year of age and 5.5 hours in children 1–10 years of age.b

Special Populations

Half-life is prolonged in patients with renal impairment.124 b Half-life is 15 hours in adults with Clcr 10–30 mL/minute and may increase to >26 hours in those with Clcr ≤10 mL/minute.b

Stability

Storage

Oral

Solution

15–25°C in tight, light-resistant container.124

Tablets

15–25°C in tight, light-resistant container in a dry place.106

Actions and Spectrum

  • A folate antagonist that inhibits formation of tetrahydrofolic acid (the metabolically active form of folic acid) in susceptible bacteria.106 124 b

  • Inhibits reduction of dihydrofolic acid to tetrahydrofolic acid by binding to the enzyme dihydrofolate reductase106 124 and inhibits bacterial thymidine synthesis.b

  • Usually slowly bactericidal.b

  • Spectrum of activity includes some gram-positive aerobes and some gram-negative aerobes, including some Enterobacteriaceae.106 b Inactive against most anaerobes and inactive against Mycobacterium and Chlamydia.b

  • Gram-positive aerobes: Active against coagulase-negative staphylococci (including Staphylococcus saprophyticus)106 124 and Streptococcus pyogenes (group A β-hemolytic streptococci),b and S. pneumoniae (penicillin-susceptible strains).124 May be active against some, but not all, strains of Enterococcus faecalis.b

  • Gram-negative aerobes: Active against Acinetobacter, Citrobacter, Enterobacter,106 124 Escherichia coli,106 124 Haemophilus influenzae (except β-lactamase-negative, ampicillin-resistant strains),124 Klebsiella pneumoniae,106 124 Proteus mirabilis,106 124 Salmonella, and Shigella. Also active against some, but not all, strains of Providencia and Serratia.b Inactive against Moraxella catarrhalis124 and Pseudomonas aeruginosa.106 b

  • Resistant strains of Enterobacteriaceae, especially E. coli, Klebsiella, and Proteus, have developed during trimethoprim therapy.b

Advice to Patients

  • Importance of completing full course of therapy, even if feeling better after a few days.

  • Importance of reporting clinical signs that may be early indications of serious blood disorders (e.g., sore throat, fever, pallor, purpura).106

  • Importance of discontinuing use and contacting clinician if signs or symptoms of sensitization occur.106

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

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

Trimethoprim

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

100 mg*

Proloprim (scored)

Monarch

Trimethoprim Tablets

Teva, Watson

Trimethoprim Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

50 mg (of trimethoprim per 5 mL)

Primsol

FSC

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Trimethoprim 100MG Tablets (WATSON LABS): 30/$20.99 or 90/$40.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 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. [IDIS 183288] [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. [IDIS 184846] [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. [IDIS 217842] [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. [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. [IDIS 215212] [PubMed 2939152]

106. Monarch. Proloprim (trimethoprim) tablets prescribing information. Bristol, TN; 2003 Feb.

107. Nwokolo C, Byrne L, Misch KJ. Toxic epidermal necrolysis occurring during treatment with trimethoprim alone. BMJ. 1988; 296:970. [IDIS 240187] [PubMed 3129113]

108. Das G, Bailey MJ, Wickham JEA. Toxic epidermal necrolysis and trimethoprim. BMJ. 1988; 296:1604-5. [IDIS 242513] [PubMed 3135031]

109. Hedlund J, Aurelius E, Andersson J. Recurrent encephalitis due to trimethoprim intake. Scand J Infect Dis. 1990; 22:109-12. [PubMed 2320959]

110. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chemother. 1998; 42:1309-14. [IDIS 408066] [PubMed 9624465]

111. DuPont HL, Reves RR, Galindo E et al. Treatment of travelers’ diarrhea with trimethoprim/sulfamethoxazole and with trimethoprim alone. N Engl J Med. 1982; 307:841-4. [IDIS 157110] [PubMed 7050714]

112. National Institutes of Health Office of Medical Applications of Research. Consensus conference: travelers’ diarrhea. JAMA. 1985; 253:2700-4. [PubMed 2985834]

113. DuPont HL. Ericsson CD, Johnson PC. Chemotherapy and chemoprophylaxis of travelers’ diarrhea. Ann Intern Med. 1985; 102:260-1. [IDIS 195784] [PubMed 3966763]

114. Centers for Disease Control and Prevention. Health information for international travel, 2003–2004. Atlanta, GA: US Department of Health and Human Services; 2003:184-91. Updates available from CDC website ().

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. [IDIS 364834] [PubMed 8610948]

116. DuPont HL, Ericsson CD, Reves RR et al. Antimicrobial therapy for travelers’ diarrhea. Rev Infect Dis. 1986; 8(Suppl 2):S217-S222. [IDIS 217199] [PubMed 3523718]

117. DuPont HL, Ericsson CD, Galindo E et al. Antimicrobial therapy of travelers’ diarrhea. Scand J Gastroenterol. 1983; 18(Suppl 84):99-105.

118. DuPont HL, Galindo E, Evans DG et al. Prevention of travelers’ diarrhea with trimethoprim-sulfamethoxazole and trimethoprim alone. Gastroenterology. 1983; 84:75-80. [IDIS 164584] [PubMed 6336616]

119. Anon. Drugs for parasitic infections. Med Lett Drugs Ther. Aug 2004. From the Medical Letter website ().

120. Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med. 1994; 154:959-73.

121. National Institutes of Health Combined Clinical Staff Conference. Consensus conference: recent advances in the management of AIDS-related opportunistic infections. Ann Intern Med. 1994; 120:945-55. [IDIS 330618] [PubMed 7909657]

122. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing: eleventh informational supplement. NCCLS document M100-S12. Wayne, PA; NCCLS: 2002 Jan.

123. Anon. Advice for travelers. Med Lett Treat Guid. 2004; 2:33-40.

124. FSC Laboratories. Primsol (trimethoprim) solution prescribing information. Charlotte, NC; 2005 Apr.

125. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Morb Mortal Wkly Rep. 2004; 53(No. RR-15):1-112.

b. AHFS Drug Information 2004. McEvoy GK, ed. Trimethoprim. Bethesda, MD: American Society of Health-System Pharmacists; 2004:872-4.

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