Trimethoprim

Pronunciation

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

Introduction

Antibacterial; dihydrofolate reductase inhibitor.106 124 Commercially available alone106 124 or in fixed combination with sulfamethoxazole.135 186 For information on the fixed combination, see Co-trimoxazole (Systemic).

Uses for Trimethoprim

Acute Otitis Media (AOM)

Has been used for treatment of AOM caused by Streptococcus pneumoniae and Haemophilus influenzae.124

Do not use if Moraxella catarrhalis is suspected; this organism is resistant to trimethoprim.124

Not indicated 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

When anti-infectives indicated, AAP recommends high-dose amoxicillin or amoxicillin and clavulanate as drugs of first choice for initial treatment of AOM and certain cephalosporins (cefdinir, cefpodoxime, cefuroxime, ceftriaxone) as alternatives for initial treatment in penicillin-allergic patients without a history of severe and/or recent penicillin-allergic reactions.321 Although fixed combination containing trimethoprim and sulfamethoxazole (co-trimoxazole) has been used for treatment of AOM,186 321 substantial resistance to the drug reported in S. pneumoniae and AAP states do not use as an alternative to amoxicillin.321

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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

Has been used alone for treatment of acute, uncomplicated cystitis;163 however, value of trimethoprim alone for treatment of acute, uncomplicated UTIs has been questioned.b Fixed combination containing trimethoprim and sulfamethoxazole (co-trimoxazole) is used for treatment of UTIs,135 186 and has been recommended as a good choice for empiric treatment of acute, uncomplicated cystitis.163

Consider that uropathogens with resistance to trimethoprim (with or without sulfamethoxazole) reported with increasing frequency.163

If using for treatment of acute, uncomplicated UTI, collect specimen for culture and in vitro susceptibility tests prior to initiating the drug.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.b

Pneumocystis jirovecii Pneumonia

Treatment of mild to moderate Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP); used in conjunction with dapsone.102 110 115 134 155 156

Co-trimoxazole is drug of choice for treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.134 155 156

Dapsone in conjunction with trimethoprim is one of several alternatives recommended by CDC, NIH, and IDSA for treatment of mild or moderate PCP in HIV-infected adults and adolescents when co-trimoxazole cannot be used.155 Although efficacy and safety data limited regarding use for treatment of PCP in children,156 some clinicians also recommend dapsone in conjunction with trimethoprim as an alternative for treatment of mild to moderate PCP in children.134 Not included in recommendations for treatment of more severe PCP infections.134 155 156

Animal studies suggest trimethoprim alone is ineffective for treatment of PCP.103

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

Pneumocystis jirovecii Pneumonia (PCP)
Treatment of Mild to Moderate PCP
Oral

Children: 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).134 156

Adolescents ≥13 years of age: 5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (100 mg once daily for 21 days).134 155

Adults

Urinary Tract Infections (UTIs)
Acute, Uncomplicated UTIs
Oral

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

Pneumocystis jirovecii Pneumonia (PCP)
Treatment of Mild to Moderate PCP
Oral

5 mg/kg 3 times daily for 21 days in conjunction with oral dapsone (100 mg once daily for 21 days).134 155

Special Populations

Renal Impairment

Urinary Tract Infections (UTIs)
Acute, Uncomplicated UTIs
Oral

Adults with Clcr 15–30 mL/minute: 50 mg every 12 hours.106

Adults with Clcr <15 mL/minute: Not recommended.106

Geriatric Patients

Cautious dosage selection because of age-related decreases in renal, hepatic, and/or cardiac function.106 Initiate at lower end of 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, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.106 124

Hematologic toxicity occurs more 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 clinically important decrease in any formed blood element occurs.106 124

Use with caution in patients with possible folate deficiency.106 124

Folates, such as leucovorin (folinic acid), may be administered during trimethoprim therapy and will not interfere with the drug’s antibacterial effect.106 124 Hematologic abnormalities usually resolve following administration of leucovorin.b

If signs of bone marrow depression occur, discontinue trimethoprim and administer leucovorin as required to restore normal hematopoiesis.106 124

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.106

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 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 of oral solution and tablets not established in infants <2 months of age.106 124

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

Efficacy of tablets when used as a single agent for treatment of acute, uncomplicated UTIs not established in children <12 years of age.106

It has been suggested that trimethoprim be used with caution in children who have fragile X chromosome associated with mental retardation, because folate depletion may worsen 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 lower end of 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.106 124

Renal Impairment

Use with caution.106 124

Not recommended in patients with Clcr <15 mL/minute;106 124 decrease dosage in those with Clcr 15–30 mL/minute.106 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

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

Interactions for Trimethoprim

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Dapsone

Increased dapsone concentrations and increased risk of dapsone-associated adverse effects (e.g., methemoglobinemia);161 162 possible increased trimethoprim concentrations, but no evidence of increased risk of trimethoprim-associated adverse effects162

Monitor periodically for potential toxicity (e.g., methemoglobinemia) 160 162

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

Rapidly absorbed from GI tract.106 124

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 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 amount recovered in urine is unchanged drug.106 124 b

Hemodialysis is only moderately effective in removing trimethoprim;106 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

20–25°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

  • Moraxella catarrhalis is resistant to trimethoprim.124 Resistant strains of Enterobacteriaceae, especially E. coli, Klebsiella, and Proteus, have developed during trimethoprim therapy.b

Advice to Patients

  • 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.106

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.106

  • Importance of informing patients of other important precautionary information.106 (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*

Trimethoprim Tablets

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 08/2014. 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 August 5, 2014. 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. 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. [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]

110. Fishman JA. Treatment of infection due to Pneumocystis carinii. Antimicrob Agents Chemother. 1998; 42:1309-14. [IDIS 408066] [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. [IDIS 364834] [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.

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.

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.

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. [IDIS 270540] [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. [IDIS 253259] [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]

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

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