What is Cilastatin?
Cilastatin is a renal dehydropeptidase-I inhibitor that prevents the breakdown of certain antibiotics (particularly imipenem) in the kidneys, thereby increasing their urinary concentrations and effectiveness. 1
Primary Clinical Role
Cilastatin itself has no antibacterial activity. Its primary FDA-approved use is as a co-formulation with imipenem (a carbapenem antibiotic) to prevent imipenem's rapid renal metabolism by dehydropeptidase-I enzyme in the proximal renal tubules 1. Without cilastatin, imipenem would be metabolized before achieving adequate urinary concentrations.
Key Pharmacologic Properties:
- Protein binding: Approximately 40% 1
- Half-life: Approximately 1 hour 1
- Excretion: ~70% recovered in urine within 10 hours 1
- Hemodialyzable: Yes 1
Clinical Applications in Guidelines
The imipenem/cilastatin combination appears extensively in treatment guidelines for serious infections:
Intra-Abdominal Infections
- Critically ill patients with community-acquired IAI: Imipenem/Cilastatin 1 g every 8 hours 2
- Healthcare-associated IAI: Imipenem/Cilastatin 1 g every 8 hours (both critically ill and non-critically ill patients) 2
- Active against ampicillin-susceptible enterococci, eliminating need for additional enterococcal coverage 2
Multidrug-Resistant Organisms
The newer formulation imipenem-cilastatin-relebactam (adding a β-lactamase inhibitor) is recommended for:
- Carbapenem-resistant Enterobacterales (CRE) bloodstream infections: 1.25 g IV every 6 hours 3
- CRE urinary tract infections: 1.25 g IV every 6 hours 3
- Difficult-to-treat resistant Pseudomonas aeruginosa (DTR-PA): May be considered when susceptibility confirmed 3, 4
The susceptibility rate of CRE to imipenem-cilastatin-relebactam was 83.8% in Taiwan surveillance data 3
Necrotizing Soft Tissue Infections
- Polymicrobial necrotizing fasciitis: Imipenem-cilastatin 500 mg every 6 hours IV as single-drug regimen 5
Emerging Nephroprotective Role
Beyond its traditional use, cilastatin demonstrates significant nephroprotective properties through multiple mechanisms:
Mechanisms of Protection:
- Reduces reactive oxygen species (ROS) production 6
- Decreases apoptosis in proximal tubular cells 6, 7
- Suppresses P-glycoprotein activity 6
- Prevents morphological changes in renal cells 6
Evidence for Nephroprotection:
A 2024 meta-analysis of 10 studies (531 patients in RCTs, 6,321 in observational studies) showed:
- 52% reduction in AKI risk with imipenem-cilastatin versus comparators (RR 0.52,95% CI 0.40-0.67) 8
- Lower serum creatinine by 0.14 mg/dL (95% CI -0.21 to -0.07) 8
- Consistent benefits in both RCTs and observational studies 8
Specific Nephrotoxicity Prevention:
- Tacrolimus-induced nephrotoxicity: Improved renal function, reduced interstitial fibrosis and inflammation through anti-oxidative and anti-apoptotic effects 7
- Cisplatin-induced nephrotoxicity: Protected kidney function without compromising anticancer efficacy in cancer cell lines 9
- Crush syndrome: Increased measured GFR, reduced creatinine, decreased histopathologic kidney damage, and enhanced myoglobin excretion in large animal models 10
Important Clinical Considerations
Dosing Adjustments:
- Renal impairment: Dosage adjustment mandatory for creatinine clearance ≤30 mL/min 1
- Hemodialysis patients: Imipenem/cilastatin is dialyzable; timing considerations necessary 1
- Seizure risk: Higher in patients with CrCl ≤30 mL/min; close monitoring required 1
Sodium Content:
Common Pitfall:
Do not confuse the traditional imipenem/cilastatin formulation with the newer imipenem-cilastatin-relebactam combination, which adds relebactam (a β-lactamase inhibitor active against class A carbapenemase and class C cephalosporinase) for enhanced activity against resistant organisms 3.