Cilastatin

證據等級: L5

預測適應症: 10 個

Cilastatin: From Imipenem/Cilastatin Combination Component to Staphylococcus Aureus Infection

One-Sentence Summary

Cilastatin is a renal dehydropeptidase-I (DHP-I) inhibitor with no standalone antibacterial activity, used exclusively as a fixed-dose combination partner with Imipenem to prevent its renal degradation and protect against nephrotoxicity. The TxGNN model predicts it may be effective for Staphylococcus aureus infection (encompassing both MSSA and MRSA), with 3 clinical trials and 20 publications currently indexed — though most evidence reflects the Imipenem/Cilastatin combination as a whole, rather than Cilastatin's independent contribution.

Quick Overview

Item	Content
Original Indication	No independent registered indication; used exclusively as part of the Imipenem/Cilastatin fixed-dose combination for broad-spectrum bacterial infections
Predicted New Indication	Staphylococcus aureus infection
TxGNN Prediction Score	99.94%
Evidence Level	L2
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data for Cilastatin is not available from the Evidence Pack. Based on known pharmacological information, Cilastatin is the indispensable companion component of the Imipenem/Cilastatin fixed-dose combination (brand name: Tienam®). Its sole function is to competitively and reversibly inhibit the renal brush-border enzyme dehydropeptidase-I (DHP-I), which would otherwise rapidly metabolize and inactivate Imipenem in the proximal renal tubule. By protecting Imipenem from this degradation, Cilastatin enables the antibiotic to sustain effective concentrations in blood and tissues, while simultaneously reducing Imipenem-associated nephrotoxicity.

The mechanistic rationale linking this combination to Staphylococcus aureus infection rests on Imipenem's β-lactam activity: Imipenem binds with high affinity to penicillin-binding proteins (PBPs) and disrupts bacterial cell wall synthesis, conferring broad-spectrum bactericidal activity that includes methicillin-susceptible S. aureus (MSSA). Cilastatin's pharmacokinetic "enabling" role allows Imipenem to reach adequate tissue concentrations needed to sustain time-dependent killing (T>MIC). However, a critical biological caveat limits this prediction: methicillin-resistant S. aureus (MRSA) carries the mecA gene encoding PBP2a, a low-affinity PBP that confers intrinsic resistance to all β-lactams including carbapenems. For MRSA, Imipenem/Cilastatin is ineffective as monotherapy, and any clinical utility requires synergistic combinations (e.g., with Arbekacin, Fosfomycin, or Cefotiam, as described in several case reports and in vitro studies).

The TxGNN model's high prediction score (99.94%, global rank #1,315) likely reflects the Imipenem/Cilastatin combination's well-documented activity across diverse bacterial pathogens captured as co-occurring nodes in the underlying knowledge graph, rather than a truly novel repurposing signal for Cilastatin specifically against S. aureus. The repurposing hypothesis requires further mechanistic disambiguation: MSSA infections represent an established (not novel) use of the combination, while MRSA represents an experimental niche requiring combination strategies.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT03583333	Phase 3	Completed	274	IMI/Cilastatin/Relebactam vs. Piperacillin/Tazobactam for hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP); non-inferiority design with Imipenem/Cilastatin as the carbapenem backbone — not S. aureus-specific
NCT00707239	Phase 2	Terminated	108	Two doses of Tigecycline vs. Imipenem/Cilastatin for hospital-acquired pneumonia (≥70% VAP); Imipenem/Cilastatin served as the active comparator arm; early termination limits conclusions, and S. aureus was not the primary target organism
NCT01356472	Phase 4	Unknown	60	Linezolid alone or combined with Carbapenem (including Imipenem/Cilastatin) against MRSA in ventilator-associated pneumonia patients; small scale and unknown status substantially limit evidence quality; investigates synergy relevant to the MRSA repurposing hypothesis

Literature Evidence

PMID	Year	Type	Journal	Key Findings
3460521	1986	Comparative Clinical Study	Antimicrobial Agents and Chemotherapy	Imipenem-cilastatin evaluated in 23 patients (11 MRSA, 12 MSSA) with soft tissue, endovascular, and skeletal infections; demonstrated efficacy for MSSA; limited activity against MRSA confirmed in vitro (MIC90 6.25 mg/L)
8072190	1994	Clinical Trial	The Japanese Journal of Antibiotics	Arbekacin (ABK) + Imipenem/Cilastatin combination showed synergistic MIC reductions against MRSA clinical isolates; combination superior to either agent alone, supporting a salvage combination strategy
3378959	1988	Animal Model	Journal of Antimicrobial Chemotherapy	Rabbit model of MRSA aortic valve endocarditis: Imipenem bacteriostatic in vitro (MIC90/MBC90: 8/32 mg/L) vs vancomycin bactericidal; Imipenem-cilastatin showed comparable or superior efficacy to vancomycin by several in vivo criteria
10588305	1999	In Vitro / In Vivo Study	Journal of Antimicrobial Chemotherapy	Vancomycin + Imipenem demonstrated synergistic or additive effects in 36 of 36 MRSA clinical isolates in vitro, with confirmation in a neutropenic mouse thigh infection model
8514648	1993	Animal Model	Journal of Antimicrobial Chemotherapy	Imipenem/Cilastatin + Cefotiam synergistic against MRSA in mouse bacteremia model, effective against both β-lactamase-producing and non-producing MRSA strains at ratios of 1:5 to 1:160
33020155	2020	Case Commentary	Antimicrobial Agents and Chemotherapy	Commentary on use of Imipenem/Cilastatin + Fosfomycin for refractory MRSA bacteremia; argues that individualized combination selection is essential given the near-impossibility of conducting RCTs in this patient population
22196394	2012	Narrative Review	International Journal of Antimicrobial Agents	Comprehensive review of MRSA pathogenesis and treatment; discusses carbapenems in the context of combination regimens for serious healthcare-associated MRSA infections
36804370	2023	Narrative Review	International Journal of Antimicrobial Agents	Off-label antibiotic use for multidrug-resistant bacteria; includes discussion of carbapenem combinations for resistant Gram-positive pathogens, contextualizing the role of Imipenem/Cilastatin in MDR scenarios
12878512	2003	In Vivo Preclinical Study	Antimicrobial Agents and Chemotherapy	Comparative in vivo study: Imipenem-cilastatin less active against MRSA (ED50 >100 mg/kg) compared to vancomycin and the experimental cephalosporin S-3578; reinforces carbapenem limitations as MRSA monotherapy
18649613	2008	Clinical Review	American Family Physician	Diabetic foot infection review: S. aureus and β-hemolytic streptococci predominate in mild-to-moderate infections; severe or polymicrobial diabetic foot infections may require broad-spectrum coverage including carbapenems as second-line agents

Singapore Market Information

Cilastatin currently has no registered products in Singapore. It is not available as a standalone agent; it is always co-formulated with Imipenem. There are no Health Sciences Authority (HSA) product authorizations on record for this compound.

Safety Considerations

Please refer to the package insert for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: The clinical trials and literature in this Evidence Pack address the Imipenem/Cilastatin combination against broad nosocomial infections — none is specifically designed to evaluate Cilastatin's contribution to S. aureus outcomes. More critically, Cilastatin carries no independent antibacterial activity; it is a pharmacokinetic enhancer. For MSSA, Imipenem/Cilastatin is already an established treatment option (not a repurposing opportunity), while MRSA is intrinsically carbapenem-resistant, making straightforward repurposing biologically untenable without a defined combination strategy and specific patient population.

To proceed, the following is needed:

Clarify the repurposing hypothesis: Is the target MSSA (established use, low novelty) or MRSA in a defined combination regimen (experimental, requires dedicated study design)?
Fill the MOA data gap: Query the DrugBank API (DB01597) to retrieve full pharmacological data and support mechanistic analysis
Resolve the safety data gap: Download and parse the TFDA/FDA package insert PDF to complete safety and contraindication assessment before any regulatory pathway can be evaluated
Define a specific clinical niche: A narrowly scoped question — such as "Imipenem/Cilastatin + Fosfomycin for MRSA bacteremia in patients failing vancomycin" — is more tractable than the broad indication "S. aureus infection"
Clarify whether Cilastatin is the true repurposing candidate: If the clinical signal belongs to the Imipenem/Cilastatin combination, the repurposing unit of analysis should be the combination drug (DB00691 + DB01597), not Cilastatin alone
Note on a higher-evidence opportunity: The pneumonia indication (TxGNN rank #6 in this pack) carries L1 evidence supported by multiple completed Phase 3 RCTs — if the goal is to identify the most actionable repurposing candidate for this drug, pneumonia warrants prioritized evaluation over 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.