Trimethoprim
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Trimethoprim: From Urinary Tract Infection to Punctate Epithelial Keratoconjunctivitis
One-Sentence Summary
Trimethoprim is an antibacterial originally used for urinary tract infections and several other infections, including otitis media, pneumocystosis, shigellosis and conjunctivitis. The TxGNN model predicts it may be effective for punctate epithelial keratoconjunctivitis with a very high score, but at present no clinical trials and no publications support this specific prediction. The top-ranked prediction is therefore a model signal only. Among the other predictions, "conjunctivitis" has the most literature, but it is already a labelled use of the drug.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Urinary tract infection (other labelled uses: infectious otitis media, pneumocystosis, shigellosis, conjunctivitis, blepharoconjunctivitis). The Singapore licence records list no indication text. |
| Predicted New Indication | Punctate epithelial keratoconjunctivitis |
| TxGNN Prediction Score | 99.57% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 12 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Trimethoprim is generally known as an antibacterial that inhibits bacterial dihydrofolate reductase (a folate pathway enzyme). Its efficacy in bacterial eye and urinary infections is established, and mechanistically it may be applicable to infectious surface eye disease.
Trimethoprim is already used topically (combined with polymyxin B) for bacterial conjunctivitis, so a link to ocular surface disease is plausible. However, punctate epithelial keratoconjunctivitis is often viral or toxic/inflammatory in origin, and trimethoprim has no antiviral activity. The high score (0.996) is a graph-based prediction only, and nothing in the compiled data supports it.
Clinical Trial Evidence
Currently no related clinical trials registered for punctate epithelial keratoconjunctivitis.
For context, trials were found for other lower-ranked predictions, but all involve trimethoprim-sulfamethoxazole rather than trimethoprim alone and address infection prevention or treatment in general. They do not test the top prediction.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02096159 | NA | Active, not recruiting | 93 | Double-blind, placebo-controlled test of TMP-SMX prophylaxis after hypospadias repair (predicted label: post-bacterial disorder) |
| NCT02024867 | NA | Completed | 249 | 3 vs 10 days of TMP-SMX after drainage of skin abscesses (non-inferiority) |
| NCT07619027 | Phase 4 | Not yet recruiting | 1084 | Low- vs standard-dose TMP-SMX to prevent Pneumocystis pneumonia after kidney transplant |
| NCT05106803 | N/A | Completed | 24 | Observational antibiotic-susceptibility profile of bacteria from surgical site infections |
| NCT01101412 | Phase 1/2 | Withdrawn | 0 | Antimicrobial catheter lock solution containing TMP-SMX; withdrawn with no participants |
Literature Evidence
No literature was found for punctate epithelial keratoconjunctivitis. The most relevant publications relate to conjunctivitis, which is already a labelled indication and not a true repurposing case.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 19043945 | 2008 | Multicenter comparative study | J Pediatr Ophthalmol Strabismus | Polymyxin B/trimethoprim eye drops compared with moxifloxacin for speed of clinical efficacy in bacterial conjunctivitis |
| 30007329 | 2018 | Systematic review/Meta-analysis | J Pediatric Infect Dis Soc | Antibiotic treatments, including oral trimethoprim, for neonatal chlamydial conjunctivitis |
| 6204534 | 1984 | Clinical evaluation | Am J Ophthalmol | Efficacy and safety of trimethoprim-containing eye drops in bacterial conjunctivitis or blepharitis |
| 2418736 | 1985 | Clinical comparison | Ann Ophthalmol | Trimethoprim-polymyxin B eye drops in surface ocular bacterial infections; clinically and bacteriologically effective |
| 8595639 | 1995 | Survey | Clin Ther | Children with acute bacterial conjunctivitis treated with trimethoprim-polymyxin B eye drops |
| 20084257 | 2001 | Review | Paediatr Child Health | Causes, features and management of acute infectious conjunctivitis in children |
| 16491721 | 2006 | Review | J Pediatr Ophthalmol Strabismus | Controlling contagious bacterial conjunctivitis and limiting transmission |
Singapore Market Information
All 12 licences are valid single-ingredient registrations. The compiled data contain no approved-indication text for them. The first five are listed below.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN00508P | APO-SULFATRIM PEDIATRIC TABLET | Tablet | Not available |
| SIN00435P | APO-SULFATRIM TABLET | Tablet | Not available |
| SIN00526P | B.S. SUSPENSION | Suspension | Not available |
| SIN02183P | DBL SULFAMETHOXAZOLE 400MG AND TRIMETHOPRIM 80MG CONCENTRATE INJECTION BP | Injection | Not available |
| SIN00583P | CO-TRIMEXAZOLE SUSPENSION | Suspension | Not available |
Available routes are oral (tablet), injectable and suspension. No topical ophthalmic product appears among the Singapore registrations, which matters for an eye indication.
Safety Considerations
Package insert warnings and contraindications were not available. Please refer to the package insert for safety information.
- Disease associations from the knowledge graph (not label text): inherited porphyria, porphyria and porphyrin metabolism disease, kidney disease, liver disease, gallbladder disease, thrombocytopenia, neutropenia, agranulocytosis, Clostridium difficile colitis, perinatal necrotizing enterocolitis, G6PD deficiency, glycogen storage disease, cystinuria, galactosemia, and folic acid deficiency anemia.
- Drug interactions: 100 interactions were found. The major ones are with potassium salts (potassium citrate, potassium bicarbonate, potassium chloride, potassium gluconate), which relates to the risk of raised potassium. Moderate interactions include metformin, pioglitazone, rosiglitazone, repaglinide, balsalazide, picosulfuric acid and sapropterin.
Conclusion and Next Steps
Decision: Hold
Rationale: The top prediction, punctate epithelial keratoconjunctivitis, rests only on a model score. It has no trials or literature. The condition is often viral or toxic, and trimethoprim has no antiviral action. The one prediction with real supporting literature, conjunctivitis (L3, Proceed with Guardrails), is already a labelled use and is not a new repurposing finding.
To proceed, the following is needed:
- Evidence that punctate epithelial keratoconjunctivitis cases with a bacterial component respond to trimethoprim, or a clear mechanistic rationale
- Mechanism of action data and the package insert warnings and contraindications from the HSA website
- Confirmation of whether a topical ophthalmic formulation can be supplied in Singapore, since none of the 12 registrations is an eye product
- A review of the safety associations above (blood disorders, kidney and liver disease, G6PD deficiency) and of the potassium-related interactions
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.