What is trimethoprim (TMP)?

What is Trimethoprim (TMP)?

Trimethoprim is a synthetic antifolate antimicrobial agent that blocks bacterial dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate (the active form of folic acid), thereby inhibiting bacterial DNA synthesis and cell division. 1, 2

Mechanism of Action

• Trimethoprim arrests bacterial purine synthesis by competitively inhibiting dihydrofolate reductase, an enzyme essential for bacterial folate metabolism 1, 2
• When combined with sulfonamides (which block an earlier step in folate synthesis), the two agents act synergistically and bactericidally, creating sequential blockade of the bacterial folate pathway 1, 3
• This dual mechanism explains why trimethoprim-sulfamethoxazole (TMP-SMX, also known as Bactrim or Septra) is more effective than either agent alone 4, 3

Antimicrobial Spectrum

• Trimethoprim demonstrates inhibitory activity against most gram-positive aerobic cocci and many gram-negative aerobic bacilli 2, 5
• The drug is particularly effective against Escherichia coli, common respiratory pathogens, and certain opportunistic organisms 2, 5
• Notably, TMP-SMX does not cover Pseudomonas aeruginosa, which is a critical limitation in neutropenic patients 4
• TMP-SMX is the antimicrobial agent of choice for Pneumocystis jirovecii pneumonia (PCP) and most Nocardia asteroides infections 4, 5

Clinical Formulations and Dosing

• The FDA-approved combination contains trimethoprim and sulfamethoxazole in a 1:5 ratio 6
• Double-strength (DS) tablets contain 160 mg trimethoprim and 800 mg sulfamethoxazole 6
• Regular-strength tablets contain 80 mg trimethoprim and 400 mg sulfamethoxazole 6
• Available in both oral and intravenous formulations for flexible administration based on disease severity 5

Pharmacokinetics

• Both trimethoprim and sulfamethoxazole are excreted primarily through the kidneys 5
• Dosage adjustment is mandatory when creatinine clearance falls below 30 mL/min 5
• The American Geriatrics Society recommends checking creatinine clearance before initiating therapy in frail elderly patients, as they frequently have reduced kidney function 7

Primary Clinical Indications

Urinary Tract Infections

• Trimethoprim constitutes very effective therapy for acute symptomatic urinary tract infections caused by E. coli, comparing favorably with ampicillin and cephalexin 2, 8

Respiratory Infections

• Effective for acute exacerbations of chronic bronchitis, bacterial pneumonia, and acute otitis media 8, 3

Opportunistic Infection Prophylaxis

• TMP-SMX is highly effective for preventing Pneumocystis jirovecii pneumonia in neutropenic and immunocompromised patients, including those with HIV/AIDS 4
• For PCP treatment in HIV-infected children, the recommended dose is 15-20 mg/kg/day of the TMP component (75-100 mg/kg of SMX component) administered intravenously in 3-4 divided doses for 21 days 4

Other Infections

• Prostatitis, bacterial septicemia, enteric fever, brucellosis, skin and soft-tissue infections, and certain cases of bacterial endocarditis 3, 8
• Alternative agent for pertussis when macrolides are contraindicated (TMP 8 mg/kg/day, SMX 40 mg/kg/day in 2 divided doses for 14 days in children; TMP 320 mg/day, SMX 1,600 mg/day in adults) 4

Bacterial Resistance Patterns

• Resistance to trimethoprim may be intrinsic or acquired 2
• Acquired resistance most commonly results from chromosomal mutations producing a dihydrofolate reductase enzyme less vulnerable to trimethoprim inhibition 2
• The emergence of quinolone-resistant gram-negative bacilli has been demonstrated in patients given quinolone prophylaxis, making TMP-SMX an important alternative in some settings 4
• Indiscriminate use of trimethoprim could foster resistance emergence, negating the value of both trimethoprim and TMP-SMX, so prescribe only for well-defined indications 2

Adverse Effects Profile

Common Reactions

• Gastrointestinal intolerance (epigastric distress, abdominal cramps, nausea, vomiting, diarrhea) and skin eruptions are the most common adverse reactions 2, 4
• The drug is relatively nontoxic in patients without AIDS, but HIV-infected patients experience substantially higher rates of adverse effects 5

Serious Adverse Events

• The American Geriatrics Society and CDC note higher incidence of severe adverse events in older adults, including Stevens-Johnson syndrome, toxic epidermal necrolysis, blood dyscrasias (neutropenia, thrombocytopenia, megaloblastic anemia, aplastic anemia), and hepatic necrosis 7, 4
• Myelosuppression can occur, which is particularly problematic in neutropenic patients 4

Metabolic Complications

• Trimethoprim blocks epithelial sodium channels in the distal nephron, causing hyperkalemia and hyponatremia, with hyponatremia occurring in approximately 72% of hospitalized patients receiving high-dose therapy 7
• The 2019 AGS Beers Criteria lists TMP-SMX as requiring caution based on kidney function due to concerns of worsening renal function and hyperkalemia 7

Critical Drug Interactions and Contraindications

Absolute Contraindications

• Known hypersensitivity to trimethoprim or sulfonamides 4
• Concurrent methotrexate, cyclosporine, or dofetilide use, as sulfonamides displace methotrexate from protein binding and compete with renal transport, increasing toxicity risk 7
• Infants aged <2 months due to kernicterus risk 4

High-Risk Combinations

• Avoid concurrent use of ACE inhibitors or ARBs with TMP-SMX, as this combination increases hyperkalemia risk nearly 7-fold (adjusted OR 6.7,95% CI 4.5-10.0) 7
• Caution with oral anticoagulants, antidiabetic agents, thiazide diuretics, anticonvulsants, and antiretroviral drugs 4

Monitoring Requirements

• The CDC recommends monitoring electrolytes every 3-5 days during treatment, especially in the first week when hyponatremia and hyperkalemia typically develop 7
• Increase monitoring frequency in elderly patients, those with renal impairment, patients on interacting medications, or diabetics on hypoglycemics 7
• Complete blood counts should be monitored if long-term therapy is used, as trimethoprim can cause folate deficiency and bone marrow suppression 9

Special Population Considerations

Pregnancy

• Trimethoprim is classified as FDA Pregnancy Category C 4
• The safety of trimethoprim in pregnant women has not been established 2
• Should not be administered to pregnant women due to kernicterus risk in the newborn 4

Neutropenic Patients

• In neutropenic cancer patients, TMP-SMX reduces infection rates compared to placebo, but experts differ on routine use due to lack of mortality benefit, potential for prolonged granulocytopenia, and increased fungal colonization 4
• For patients with cyclic neutropenia, Bactrim DS should be strictly avoided when ANC is <500 cells/mm³ or during predictable neutropenic nadirs, and fluoroquinolones are strongly preferred for prophylaxis 10

Elderly Patients

• The Infectious Diseases Society of America makes strong recommendations against treating asymptomatic bacteriuria in elderly patients, as high-quality evidence demonstrates no mortality or sepsis benefit while confirming frequent adverse effects including Clostridioides difficile infection and antimicrobial resistance 7