Cilastatin

證據等級: L5

預測適應症: 10 個

Cilastatin: From Imipenem Protectant (DHP-I Inhibitor) to Staphylococcus Aureus Infection

One-Sentence Summary

Cilastatin is a renal dehydropeptidase-I (DHP-I) inhibitor with no intrinsic antibacterial activity, developed exclusively as a pharmacokinetic protectant co-administered with imipenem to prevent its renal inactivation — it has no approved standalone indication. The TxGNN model predicts it may be effective against Staphylococcus aureus infection, with 3 clinical trials and 20 publications currently supporting this direction — all evidence, however, pertains to the imipenem/cilastatin combination product, not cilastatin alone.

Quick Overview

Item	Content
Original Indication	No registered standalone indication (not marketed as a single agent)
Predicted New Indication	Staphylococcus aureus infection
TxGNN Prediction Score	99.94%
Evidence Level	L1
EU Market Status	Not Marketed
Number of Authorizations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Cilastatin is a specific inhibitor of renal tubular dehydropeptidase-I (DHP-I), an enzyme that hydrolyzes and inactivates imipenem in the kidney before it can reach therapeutic tissue concentrations. By blocking DHP-I, cilastatin preserves imipenem’s pharmacokinetic stability, maintaining effective serum and tissue drug levels that enable broad-spectrum antibacterial activity. Cilastatin itself has no antibacterial properties — its sole clinical purpose is to act as a pharmacokinetic enabler for imipenem. Detailed MOA data from DrugBank is currently unavailable (Data Gap DG002).

The biological rationale for the TxGNN prediction derives from the well-documented antibacterial spectrum of the imipenem/cilastatin combination. Imipenem/cilastatin demonstrates excellent coverage against methicillin-susceptible Staphylococcus aureus (MSSA), with MICs typically far below clinical breakpoints. Against methicillin-resistant S. aureus (MRSA), coverage is significantly reduced — MRSA is intrinsically resistant to all beta-lactams including carbapenems via the mecA-encoded PBP2a — but synergistic combinations of imipenem/cilastatin with vancomycin or fosfomycin have been explored in refractory or bacteremic MRSA cases. Early observational studies (Fan et al., 1986) and more recent case reports (Sakoulas, 2020) document clinical responses across both MSSA and select MRSA contexts.

Critical limitation: All supporting evidence originates from the imipenem/cilastatin combination, not from cilastatin as an isolated agent. Any repurposing trajectory must be attributed to the combination product, with cilastatin explicitly identified as the pharmacokinetic enabler rather than the active antibacterial component. This distinction is essential for regulatory framing and clinical translation.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03583333	Phase 3	Completed	274	Multinational RCT — imipenem/cilastatin/relebactam vs piperacillin/tazobactam for HABP/VABP; non-inferiority in 28-day all-cause mortality demonstrated; covers serious S. aureus-related pneumonia
NCT00707239	Phase 2	Terminated	108	Tigecycline vs imipenem/cilastatin for hospital-acquired pneumonia (≥70% VAP); two dose levels of tigecycline assessed; terminated early with unclear cause — data completeness uncertain
NCT01356472	Phase 4	Unknown	60	Linezolid ± carbapenem for MRSA VAP — imipenem/cilastatin used as adjunct, not primary intervention; status unknown, reliability low

Literature Evidence

PMID	Year	Type	Journal	Key Findings
3460521	1986	Clinical Observational	Antimicrobial Agents and Chemotherapy	Imipenem-cilastatin in 23 patients (11 MRSA, 12 MSSA) — effective for MSSA soft tissue, endovascular, skeletal infections; limited efficacy against MRSA
8072190	1994	Clinical Observational	Japanese Journal of Antibiotics	Arbekacin + imipenem/cilastatin combination showed synergistic MIC reductions against MRSA clinical isolates compared to either agent alone
10588305	1999	In Vitro / In Vivo	Journal of Antimicrobial Chemotherapy	Vancomycin + imipenem showed synergy/additivity in 36 of 36 MRSA isolates in vitro and confirmed efficacy in neutropenic mouse thigh infection model
22196394	2012	Review	International Journal of Antimicrobial Agents	Comprehensive review of MRSA pathogenesis, virulence strategies, and key clinical trials; includes analysis of imipenem-based combination regimens for serious MRSA infections
33020155	2020	Case Report	Antimicrobial Agents and Chemotherapy	Imipenem/cilastatin + fosfomycin novel combination for refractory bacteremic MRSA infection — individualized therapy as a model for challenging cases unlikely to yield RCT data
36804370	2023	Narrative Review	International Journal of Antimicrobial Agents	Off-label antibiotic use for MDR Gram-positive cocci including MRSA and VRE; discusses carbapenem-based combination strategies in treatment-refractory settings
18649613	2008	Review	American Family Physician	Diabetic foot infections — S. aureus and beta-hemolytic streptococci as dominant pathogens; imipenem/cilastatin among options for severe polymicrobial cases
3378959	1988	Animal Model	Journal of Antimicrobial Chemotherapy	Imipenem/cilastatin vs vancomycin in rabbit MRSA aortic valve endocarditis — imipenem bacteriostatic (MIC90 8 mg/L) while vancomycin bactericidal (MIC90 2 mg/L); imipenem showed better vegetal sterilization criteria despite lower in vitro activity
8514648	1993	Animal Model	Journal of Antimicrobial Chemotherapy	Imipenem/cilastatin + cefotiam synergistic activity in mouse bacteremia model — effective against both beta-lactamase-producing and non-producing MRSA strains
12878512	2003	Animal Model	Antimicrobial Agents and Chemotherapy	Imipenem-cilastatin inactive against MRSA in systemic infection model (ED50 >100 mg/kg) vs vancomycin (ED50 ~7 mg/kg) — directly quantifies activity limitation against MRSA

Safety Considerations

Please refer to the SmPC for safety information.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: The imipenem/cilastatin combination carries Phase 3 RCT-level evidence (L1) for serious bacterial infections encompassing susceptible S. aureus, and published combination strategies exist for refractory MRSA contexts, making the TxGNN prediction biologically plausible. However, cilastatin itself is not the antibacterial agent — all clinical benefit derives from imipenem — and no standalone repurposing case for cilastatin can be constructed without acknowledging this fundamental pharmacological dependency.

To proceed, the following is needed:

Reframe the candidate: All downstream analysis should attribute the therapeutic effect to imipenem/cilastatin as a combination; cilastatin should be described as the pharmacokinetic enabler, not the active moiety
Resolve Data Gap DG001 (Blocking): Obtain SmPC/TFDA prescribing information to complete safety profiling — warnings, contraindications, and precautions are currently unavailable
Resolve Data Gap DG002 (High): Query DrugBank API for cilastatin MOA entry to formally document DHP-I inhibition mechanism in the evidence record
Narrow the indication: “Staphylococcus aureus infection” is overly broad; define a specific clinical scenario (e.g., MSSA bacteremia, S. aureus HAP in ICU, refractory MRSA bacteremia with combination therapy) for a focused evidence synthesis
MRSA vs MSSA stratification: Separate evidence streams for MSSA (strong coverage) and MRSA (limited intrinsic activity; requires combination) are needed before any formulary or guideline proposal
Antimicrobial stewardship review: Carbapenem-class agents face stewardship restrictions in most health systems; any proposed expansion of use requires institutional prescribing pathway documentation
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.