Clavulanic Acid
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Clavulanic Acid: From Bacterial Infections to Gonococcal Urethritis
One-Sentence Summary
Clavulanic acid is a beta-lactamase inhibitor, used in combination with amoxicillin, originally for urinary tract infections, bacterial pneumonia and staphylococcal, streptococcal, E. coli and Klebsiella infections. The TxGNN model predicts it may be effective for gonococcal urethritis, with no registered clinical trials but 9 publications (mostly 1980s clinical studies) currently supporting this direction. The top-ranked prediction by score, Ureaplasma urethritis, is not mechanistically credible; gonococcal urethritis is the best-supported candidate.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Urinary tract infection, bacterial pneumonia, staphylococcal infection, and related bacterial infections |
| Predicted New Indication | Gonococcal urethritis (best-supported candidate; the highest-scoring prediction is Ureaplasma urethritis) |
| TxGNN Prediction Score | 0.9993 |
| Evidence Level | L5 |
| Canada Market Status | Marketed (marketed DINs on record: at least 20) |
| Number of DINs | at least 20 |
| Recommended Decision | Hold (research question) |
Note: Ureaplasma urethritis ranks first (score 0.9993, evidence level L5), but the data compiled for this report show no mechanistic support for it. Gonococcal urethritis has the same score and the strongest evidence of the ten predictions, so this report focuses on it.
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the compiled data. Based on known information, clavulanic acid is a beta-lactamase inhibitor that is given with amoxicillin. Its efficacy in bacterial infections such as urinary tract infection and pneumonia is established.
Many strains of Neisseria gonorrhoeae produce penicillinase (a beta-lactamase) that destroys penicillins. Clavulanic acid inhibits this enzyme and restores amoxicillin activity against penicillinase-producing strains. The original indications (urinary tract and respiratory bacterial infections) and the predicted indication are both bacterial infections that this antibacterial combination can treat, so the prediction is mechanistically plausible.
Several other predictions are not credible. Ureaplasma lacks a cell wall and is inherently resistant to beta-lactams. Abdominal cystic lymphangioma, celiac trunk compression syndrome, abdominal ectopic pregnancy and lymph node palisaded myofibroblastoma have no plausible link to a beta-lactamase inhibitor and are likely TxGNN model (deep learning) artifacts.
Clinical Trial Evidence
Currently no related clinical trials registered. The evidence for gonococcal urethritis comes from published clinical studies, listed below.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3533755 | 1986 | Randomised comparative trial | Genitourin Med | Cefuroxime axetil vs amoxicillin 3 g + clavulanic acid 0.25 g (with probenecid) in 500 patients with uncomplicated urogenital and rectal gonorrhoea |
| 6365235 | 1984 | Comparative trial | Br J Vener Dis | In 121 men, amoxicillin/clavulanate left 9.4% culture-positive at 7 days vs 26.3% with intramuscular procaine penicillin |
| 6428699 | 1984 | Clinical study | Br J Vener Dis | Two-dose Augmentin cured 95.9% vs 87.4% with kanamycin in 192 men |
| 4007860 | 1985 | Dose-comparison trial | Genitourin Med | Single-dose amoxicillin 3 g + clavulanic acid 125 mg plus probenecid cured 97 of 100 assessable patients; 85% of penicillinase-producing strains cured |
| 3004176 | 1985 | Clinical study | Afr J Med Med Sci | Single-dose Augmentin in Ibadan, Nigeria, where about 80% of gonococcal strains produce penicillinase |
| 6757686 | 1982 | Clinical study (uncontrolled) | Med J Malaysia | Single-dose oral amoxicillin/clavulanic acid in males with gonococcal urethritis |
| 3147528 | 1988 | Clinical review | Sex Transm Dis | Clavulanic acid added to penicillin G or amoxicillin is among the options for beta-lactamase-producing gonorrhoea |
| 3132029 | 1988 | Microbiological study | Hinyokika Kiyo | Penicillinase production and antibiotic susceptibility in isolates from 89 male urethritis patients |
| 21947096 | 2011 | Review | Rev Esp Quimioter | Best empirical treatment of urethritis |
For the other predictions, evidence is indirect or absent. Uterine inflammatory disease has one human guideline on postpartum endometritis plus veterinary and animal-model studies. Urogenital tuberculosis has a single case report. Xanthogranulomatous pyelonephritis and the remaining predictions have no literature.
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02238831 | CLAVULIN 200 | Not available | Not available |
| 02238830 | CLAVULIN 400 | Not available | Not available |
| 01916874 | CLAVULIN 250 F ORAL SUS | Not available | Not available |
| 02243351 | APO-AMOXI CLAV | Not available | Not available |
| 02482576 | SANDOZ AMOXI-CLAV TABLET | Not available | Not available |
A total of 20 valid single-ingredient licences are listed in Canada. They include amoxicillin/clavulanate injection products and generic oral products.
Safety Considerations
- Disease-level contraindication signals (knowledge graph, not label text): kidney disease, liver disease, gallbladder disease, cholestasis (including benign recurrent and familial intrahepatic cholestasis), Clostridium difficile colitis, perinatal necrotizing enterocolitis, pyoureter, infectious mononucleosis, and chronic Epstein-Barr virus infection syndrome.
- Drug interactions: 16 interactions were identified.
- Major: leflunomide and teriflunomide.
- Moderate (14 drugs): methotrexate, naltrexone, balsalazide, epirubicin, clofarabine, tioguanine, trabectedin, brentuximab vedotin, idelalisib, asparaginase Escherichia coli, pegaspargase, interferon beta-1a, interferon beta-1b and peginterferon beta-1a.
Please refer to the package insert for label warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (research question)
Rationale: Gonococcal urethritis has a plausible mechanism and several 1980s clinical studies showing high cure rates. However, these studies are old, small and mostly non-randomised. Current gonococcal resistance patterns and guideline-recommended regimens limit their relevance today. The highest-scoring prediction (Ureaplasma urethritis) lacks mechanistic support, and the remaining predictions are unsupported.
To proceed, the following is needed:
- Health Canada package insert warnings and contraindications (a blocking gap for safety screening)
- Mechanism of action data from DrugBank
- Review of current gonococcal resistance data and treatment guidelines to judge contemporary relevance
- Approved indication text for the Canadian licences, to confirm whether urethritis or gonorrhoea is already covered
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.