Cilastatin
| Evidence Level: L3 | Predicted Indications: 9 |
Table of Contents
- Cilastatin
- Pharmacist Assessment Report
- Cilastatin: Dehydropeptidase-I inhibitor (imipenem co-formulant) → Staphylococcus aureus infection
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Canada Market Information
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Cilastatin: Dehydropeptidase-I inhibitor (imipenem co-formulant) → Staphylococcus aureus infection
One-Sentence Summary
Cilastatin is a renal dehydropeptidase-I inhibitor that is combined with the antibiotic imipenem to prevent the carbapenem from being broken down in the kidney. The TxGNN model predicts it may be relevant to Staphylococcus aureus infection, with 1 clinical trial and 20 publications compiled for this direction. However, the trial tests linezolid with or without a carbapenem, and the antibacterial activity in the literature comes from imipenem rather than cilastatin, so the evidence is indirect.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Staphylococcus aureus infection |
| TxGNN Prediction Score | 0.9994 |
| Evidence Level | L3 |
| Canada Market Status | Marketed (marketed DINs: 2 of 2) |
| Number of DINs | 2 (marketed: 2) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data for cilastatin is not available in the data compiled for this report. From the pharmacology data, cilastatin inhibits dehydropeptidase-1 and is given in fixed-dose combination with imipenem to increase imipenem’s effectiveness. Cilastatin itself has no intrinsic antibacterial activity.
Any anti-staphylococcal effect therefore comes from imipenem. The high TxGNN score most likely reflects the imipenem/cilastatin combination and its existing antibacterial uses, not an independent effect of cilastatin. Older clinical studies and case reports describe imipenem/cilastatin in methicillin-sensitive and methicillin-resistant S. aureus infections, including a combination with fosfomycin for refractory MRSA. These support the clinical use of the combination, but they cannot separate cilastatin’s contribution.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01356472 | Phase 4 | Unknown | 60 | Linezolid alone or combined with a carbapenem against MRSA in ventilator-associated pneumonia. The carbapenem is not confirmed to be imipenem/cilastatin, so this is indirect evidence only. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3460521 | 1986 | Clinical study | Antimicrob Agents Chemother | Imipenem-cilastatin evaluated in 23 patients with MSSA or MRSA infections (soft tissue, endovascular, skeletal) |
| 33020155 | 2020 | Case commentary | Antimicrob Agents Chemother | Imipenem/cilastatin plus fosfomycin as a novel combination for refractory MRSA infection |
| 3859210 | 1985 | Clinical study | Am J Med | Imipenem/cilastatin in 17 patients with bacterial endocarditis |
| 3378959 | 1988 | Animal study | J Antimicrob Chemother | Imipenem-cilastatin compared with vancomycin in rabbit MRSA aortic valve endocarditis |
| 8072190 | 1994 | Clinical study | Jpn J Antibiot | Arbekacin plus imipenem/cilastatin against MRSA infections |
| 10588305 | 1999 | Preclinical | J Antimicrob Chemother | Vancomycin plus imipenem showed synergy against MRSA in vitro and in a mouse model |
| 22196394 | 2012 | Review | Int J Antimicrob Agents | Review of MRSA pathogenesis, treatment and resistance |
| 36804370 | 2023 | Review | Int J Antimicrob Agents | Off-label versus recommended antibiotic use for multidrug-resistant bacterial infections |
| 18649613 | 2008 | Review | Am Fam Physician | Diabetic foot infection, where S. aureus is a common pathogen |
| 12878512 | 2003 | Preclinical | Antimicrob Agents Chemother | Imipenem-cilastatin was less active than vancomycin against MRSA in a mouse systemic infection model |
Canada Market Information
| DIN | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 02351706 | TARO-IMIPENEM-CILASTATIN | Not recorded | Not recorded |
| 02358344 | IMIPENEM AND CILASTATIN FOR INJECTION USP | Not recorded | Not recorded |
Safety Considerations
Please refer to the package insert for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The only listed trial does not isolate cilastatin or the imipenem/cilastatin combination, and the supporting studies are mostly older, small or preclinical. Cilastatin has no antibacterial activity of its own, so the model’s score probably reflects imipenem. The evidence level is L3 at most, and the package insert safety data has not yet been obtained.
To proceed, the following is needed:
- Health Canada package insert warnings and contraindications
- Detailed mechanism-of-action data
- Studies that separate the contribution of imipenem from cilastatin in S. aureus infection
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.