Cilastatin
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Cilastatin: From Bacterial Pneumonia to Staphylococcus aureus Infection
One-Sentence Summary
Cilastatin is a renal dehydropeptidase-I inhibitor. It is used with the carbapenem imipenem to protect it from breakdown in the kidney, and the combination is used for bacterial infections such as pneumonia, peritonitis and endocarditis. The TxGNN model predicts it may be useful for Staphylococcus aureus infection, supported by 1 clinical trial (Phase 4, small, status unknown) and 20 publications, none of them RCTs. Cilastatin has no antibacterial activity of its own, so any benefit would come from the imipenem/cilastatin combination, not from cilastatin alone.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Bacterial pneumonia, peritonitis, endocarditis and other bacterial infections (the Singapore registry entries do not state an indication text) |
| Predicted New Indication | Staphylococcus aureus infection |
| TxGNN Prediction Score | 99.94% |
| Evidence Level | L3 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available for this report. From the literature, cilastatin inhibits dehydropeptidase-I in the renal tubules. This prevents imipenem from being degraded and raises its urinary and tissue exposure. Cilastatin itself is not an antibiotic.
The link to S. aureus therefore runs through imipenem. Imipenem is a broad-spectrum carbapenem with activity against methicillin-susceptible S. aureus (MSSA). Its original indications (pneumonia, endocarditis, bone and joint infections, peritonitis) already include infections in which S. aureus is a common pathogen. This makes the prediction biologically plausible.
There are important limits. Imipenem is generally unreliable against methicillin-resistant S. aureus (MRSA), so the MRSA literature mostly describes combination or salvage regimens, for example with fosfomycin, linezolid, arbekacin or vancomycin. The evidence supports the imipenem/cilastatin combination in selected cases, not cilastatin as an independent agent.
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, and the small size and unknown status limit its weight. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 3460521 | 1986 | Clinical study | Antimicrob Agents Chemother | Imipenem-cilastatin was evaluated in 23 patients (11 MRSA, 12 MSSA) with soft tissue, endovascular and skeletal infections. |
| 3859210 | 1985 | Clinical study | Am J Med | 17 patients with bacterial endocarditis (mostly intravenous drug users) were treated with imipenem/cilastatin 500 mg every 6 hours for a mean of 29 days. |
| 33020155 | 2020 | Case commentary | Antimicrob Agents Chemother | Imipenem/cilastatin plus fosfomycin was used as a novel combination for refractory MRSA bacteremia. |
| 8072190 | 1994 | Clinical study | Jpn J Antibiot | Arbekacin plus imipenem/cilastatin showed lower MICs than either drug alone against MRSA. |
| 3378959 | 1988 | Animal study | J Antimicrob Chemother | In a rabbit model of MRSA aortic valve endocarditis, imipenem-cilastatin had better efficacy than vancomycin by the study's criteria. In vitro, imipenem was only bacteriostatic against MRSA isolates. |
| 10588305 | 1999 | In vitro / animal study | J Antimicrob Chemother | Vancomycin plus imipenem showed synergy against 34 of 36 MRSA isolates and in a neutropenic mouse thigh infection model. |
| 12878512 | 2003 | Animal study | Antimicrob Agents Chemother | In mouse systemic MRSA infection, imipenem-cilastatin was less active than vancomycin. |
| 22196394 | 2012 | Review | Int J Antimicrob Agents | Review of MRSA pathogenesis, treatment trials and resistance. |
| 36804370 | 2023 | Review | Int J Antimicrob Agents | Off-label use versus formal recommendations for antibiotics against multidrug-resistant bacteria, including MRSA. |
| 3890533 | 1985 | Review | Am J Med | Pathogenesis and treatment of endocarditis, including the rationale for imipenem as a rapidly bactericidal agent. |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16280P | IMCIL Powder for Solution for Injection or Infusion 500mg/500mg per vial | Injection, powder, for solution | Not specified in registry data |
| SIN14765P | Imipenem/Cilastatin Kabi Powder for Solution for Infusion 500mg/500mg | Injection, powder, for solution | Not specified in registry data |
Both authorizations are currently valid, and both are injectable products.
Safety Considerations
- Disease associations flagged in the knowledge graph (these come from a knowledge graph, not from package insert text): epilepsy, kidney disease, pyoureter, Clostridium difficile colitis and perinatal necrotizing enterocolitis.
- Drug Interactions: The only recorded interaction is pharmacological, with its target dipeptidase-1. This is the intended mechanism, not a drug-drug interaction. No clinically relevant drug-drug interactions were reported in the data compiled for this report.
Please refer to the package insert for full warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: Evidence for S. aureus infection is limited to one small Phase 4 trial of unknown status, older small clinical series, case reports and animal or in vitro work, with no RCTs. The activity comes from imipenem, not cilastatin, and imipenem is unreliable against MRSA. The better-supported use of the combination is hospital-acquired and ventilator-associated pneumonia, which has several Phase 3 trials, including RESTORE-IMI 2 with imipenem/cilastatin/relebactam. However, pneumonia is already a labeled original indication, so that evidence confirms an existing use and is not new repurposing.
To proceed, the following is needed:
- Controlled clinical data on imipenem/cilastatin specifically in MSSA infections, with MRSA addressed separately.
- Confirmation of which carbapenem was used in NCT01356472.
- The approved indication text and the package insert warnings and contraindications from the Singapore regulator, which are currently missing.
- Mechanism of action data for cilastatin.
- Review of the knowledge-graph disease associations (seizure risk, renal impairment, C. difficile colitis) against the package insert, plus an antimicrobial stewardship assessment.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.