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 together with amoxicillin to treat bacterial infections such as urinary tract infection and bacterial pneumonia. The TxGNN model's top-ranked prediction is Ureaplasma urethritis, but this has no clinical trials and only indirect literature. A better-supported alternative among the predictions is gonococcal urethritis, with 9 publications, several of them 1980s clinical studies.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Urinary tract infection, bacterial pneumonia, Staphylococcus aureus infection, Escherichia coli infection, Klebsiella pneumonia (approved indication text is not available from the New Zealand licence records) |
| Predicted New Indication | Ureaplasma urethritis (rank 1); gonococcal urethritis is the best-supported prediction (rank 2) |
| TxGNN Prediction Score | 99.93% (Ureaplasma urethritis); 99.93% (gonococcal urethritis) |
| Evidence Level | L5 (Ureaplasma urethritis); L3 (gonococcal urethritis) |
| New Zealand Market Status | Cancelled only |
| Number of Authorizations | 3 (all cancelled) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the data compiled for this report. Based on known pharmacology, clavulanic acid is a beta-lactamase inhibitor with no meaningful antibacterial activity of its own. It is combined with amoxicillin to restore amoxicillin's activity against beta-lactamase-producing bacteria.
Ureaplasma urethritis (rank 1): The mechanistic case is weak. Ureaplasma has no cell wall, so beta-lactam antibiotics are not expected to work, and a beta-lactamase inhibitor would not change that. The high score most likely reflects a general association with urogenital infections rather than a true biological link. The retrieved literature covers urethritis in general (Pasteurella bettyae, empirical treatment, anaerobes in prostatitis) and contains nothing specific to Ureaplasma and clavulanic acid.
Gonococcal urethritis (rank 2): Here the mechanism is plausible. Clavulanic acid inhibits the penicillinase produced by Neisseria gonorrhoeae, which restores amoxicillin activity against penicillinase-producing strains. This is a historical use, however. Current gonorrhoea management is driven by widespread resistance and ceftriaxone-based guideline regimens, so this is not a novel repurposing opportunity.
Other predictions: Uterine inflammatory disease (rank 3) has a theoretical rationale, since amoxicillin/clavulanate covers polymicrobial genital tract infection. Xanthogranulomatous pyelonephritis (rank 4) and urogenital tuberculosis (rank 5) have only weak rationale. Ranks 6-10 (celiac trunk compression syndrome, abdominal ectopic pregnancy, abdominal cystic lymphangioma, lymph node palisaded myofibroblastoma, disease of uterine broad ligament) are largely non-infectious and likely model artifacts.
Clinical Trial Evidence
Currently no related clinical trials are registered for Ureaplasma urethritis or any other predicted indication in the data compiled for this report.
Literature Evidence
Literature for the top-ranked prediction (Ureaplasma urethritis) is indirect and low-tier. The table below therefore also lists the most relevant publications for gonococcal urethritis, the best-supported prediction.
Ureaplasma urethritis (rank 1)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 34366085 | 2021 | Case report/Series | Infectious Diseases Now | Urethritis and balanitis caused by Pasteurella bettyae in men who have sex with men; no clavulanic acid evaluation |
| 19544099 | 2009 | Review | Rev Esp Quimioter | Prevalence of organisms causing urethritis in men in Madrid |
| 21947096 | 2011 | Review | Rev Esp Quimioter | Best empirical treatment for urethritis in Madrid |
| 9669200 | 1998 | Review | Int J Androl | Possible role of anaerobic bacteria in chronic prostatitis |
Gonococcal urethritis (rank 2)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3533755 | 1986 | Randomised comparative trial | Genitourin Med | Single-dose cefuroxime axetil vs amoxicillin 3 g + clavulanic acid 0.25 g (with probenecid) in 500 patients with uncomplicated gonorrhoea |
| 6365235 | 1984 | Comparative clinical trial | Br J Vener Dis | In 121 men, amoxicillin + clavulanate had a 9.4% culture-positive rate at 7 days vs 26.3% with intramuscular procaine penicillin |
| 6428699 | 1984 | Clinical study | Br J Vener Dis | Two-dose Augmentin cured 95.9% of 192 men's group vs 87.4% with kanamycin |
| 4007860 | 1985 | Clinical study | Genitourin Med | Single-dose amoxicillin 3 g + clavulanic acid 125 mg plus probenecid cured 97 of 100 assessable patients, including 11 of 13 with penicillinase-producing strains |
| 3004176 | 1985 | Clinical study | Afr J Med Med Sci | Single-dose Augmentin for gonococcal urethritis in Ibadan, where about 80% of strains produce penicillinase |
| 6757686 | 1982 | Clinical study | Med J Malaysia | Single-dose oral amoxycillin + clavulanic acid in males (no abstract available) |
| 3147528 | 1988 | Clinical study/Review | Sex Transm Dis | Therapy options for antibiotic-resistant gonorrhoea, including clavulanic acid added to amoxicillin or penicillin G |
| 3132029 | 1988 | Laboratory study | Hinyokika Kiyo | Penicillinase production and susceptibility of gonococcal isolates, including amoxicillin/clavulanate |
| 21947096 | 2011 | Review | Rev Esp Quimioter | Best empirical treatment for urethritis |
Evidence for the other predictions is minimal. Uterine inflammatory disease has a postpartum endometritis guideline, veterinary studies, a murine Chlamydia model and an IUD-associated actinomycosis case. Urogenital tuberculosis has a single case report, and xanthogranulomatous pyelonephritis and ranks 6-10 have no literature.
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2602121 | Curam Duo 500/125 | Tablet 500 mg (amoxicillin) with clavulanic acid 125 mg | Not available (cancelled) |
| 2684748 | Amoxiclav Devatis Forte | Granules for oral liquid, amoxicillin 50 mg with clavulanic acid 12.5 mg per ml | Not available (cancelled) |
| 319473 | Augmentin | Granules for oral liquid, amoxicillin 25 mg with clavulanic acid 6.25 mg per ml | Not available (cancelled) |
All three authorizations are cancelled, so no valid product is currently listed.
Safety Considerations
- Disease-level contraindication signals (from the knowledge graph, not label text): kidney disease, pyoureter, liver disease, gallbladder disease, cholestasis (including benign recurrent and familial intrahepatic forms), Clostridium difficile colitis, perinatal necrotizing enterocolitis, infectious mononucleosis, and chronic Epstein-Barr virus infection syndrome.
- Drug Interactions: 16 interactions were identified.
- Major: leflunomide and teriflunomide.
- Moderate: methotrexate, naltrexone, balsalazide, asparaginase (E. coli), pegaspargase, brentuximab vedotin, clofarabine, epirubicin, idelalisib, interferon beta-1a, interferon beta-1b, peginterferon beta-1a, tioguanine, and trabectedin.
Package insert warnings and contraindications have not been retrieved. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold
Rationale:
- The top-ranked prediction, Ureaplasma urethritis, has no trials and a mechanistic argument against it, because Ureaplasma lacks a cell wall.
- Gonococcal urethritis is the only prediction with clinical studies and a sound mechanism, but the studies date from the 1980s and the use is historical rather than new. All New Zealand licences are cancelled, and current practice favours ceftriaxone-based regimens.
- The remaining predictions are supported only by computation or indirect evidence.
To proceed, the following is needed:
- Medsafe package insert warnings and contraindications (a blocking gap for safety screening).
- Mechanism-of-action data from DrugBank.
- Current gonococcal resistance and guideline data to judge whether the historical use has any contemporary relevance.
- If uterine or pelvic infection is pursued, human clinical studies of amoxicillin/clavulanate in that setting.
- Clarification of whether any active New Zealand amoxicillin/clavulanate product is available.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.