What is the recommended dosage of cilastatin (Cilastin) for patients with impaired renal function when used in combination with imipenem?

Cilastatin Renal Dosage Adjustment

Direct Recommendation

For patients with severe renal impairment (creatinine clearance <15 mL/min), limit imipenem/cilastatin to a maximum of either 500/500 mg four times daily or 1000/1000 mg twice daily, and do not initiate therapy unless hemodialysis will be instituted within 48 hours. 1, 2

Dosage Adjustment Algorithm by Renal Function

Normal Renal Function (CrCl ≥90 mL/min)

• Standard dosing: 500 mg every 6 hours, 1000 mg every 8 hours, or 1000 mg every 6 hours 1
• No adjustment needed for cilastatin component 1

Moderate to Severe Renal Impairment (CrCl <90 mL/min)

• Dose reduction is mandatory for all patients with creatinine clearance below 90 mL/min 1
• The specific reduction depends on the degree of impairment, with more aggressive reductions needed as CrCl decreases 2, 3

Severe Renal Failure (CrCl <15 mL/min)

• Maximum dose: 500/500 mg four times daily OR 1000/1000 mg twice daily 2
• This dosing limitation is primarily driven by cilastatin accumulation rather than imipenem 2, 4
• Therapy should not be initiated unless hemodialysis will begin within 48 hours 1

Pharmacokinetic Rationale

Differential Elimination Patterns

• Imipenem and cilastatin have markedly different elimination profiles in renal failure 2, 3, 5
• Imipenem half-life increases from 52 minutes (normal function) to 173 minutes (end-stage renal disease), but maintains significant non-renal metabolic clearance 2, 3
• Cilastatin half-life increases dramatically from 54 minutes (normal) to 798 minutes (end-stage renal disease), representing a 15-fold increase 2
• In severe renal failure, cilastatin half-life reaches approximately 16 hours compared to imipenem's 4 hours 3

Clinical Implications of Dissociation

• The dissociation in pharmacokinetic profiles means cilastatin accumulates substantially more than imipenem in renal failure 4, 5
• Despite this accumulation, twice-daily dosing of 500/500 mg has been shown to be well-tolerated with stable trough levels after the third injection 4
• Therapeutic imipenem plasma levels (≥4 mg/L) are maintained for 8-10 hours after administration even in severe renal impairment 4

Hemodialysis Considerations

During Dialysis

• Both imipenem and cilastatin are efficiently removed by hemodialysis 2, 3
• Approximately 30% of cilastatin dose is removed during a 4-hour hemodialysis session 5
• Imipenem removal is lower at approximately 7% of the dose 5

Post-Dialysis Supplementation

• Administer a supplemental 500/500 mg dose after each hemodialysis session 2, 3
• Give the dose after dialysis to facilitate directly observed therapy and avoid premature drug removal 6

Continuous Renal Replacement Therapy (CRRT)

Dosing Principles

• Dose modification should be based on residual renal function rather than CRRT elimination 5
• CAVH removes only 7% of imipenem dose and approximately 30% of cilastatin dose 5
• The pharmacokinetic dissociation between imipenem and cilastatin persists during CRRT and is not corrected by hemofiltration 5

Monitoring Recommendations

• Therapeutic drug monitoring should be performed 24-48 hours after treatment initiation in all ICU patients with renal impairment or on renal replacement therapy 7
• Measure creatinine clearance using the U × V/P formula at treatment onset and recalculate whenever clinical condition changes 7
• Plasma concentrations can vary 100-fold between ICU patients receiving identical doses, making empiric dosing unreliable without TDM 7

Critical Pitfalls to Avoid

Do Not Reduce Dose Below Therapeutic Threshold

• Avoid reducing the milligram dose amount when possible, as this may compromise bactericidal effect 6
• The dose limitation in severe renal failure (500/500 mg QID or 1000/1000 mg BID) represents the maximum safe dose, not a starting point for further reduction 2

Do Not Ignore Cilastatin Accumulation

• The primary reason for dose limitation in severe renal failure is cilastatin accumulation, not imipenem toxicity 2, 4
• Cilastatin accumulation stabilizes after the third injection but requires dose limitation to prevent excessive buildup 4

Do Not Initiate in Severe Renal Failure Without Dialysis Plan

• Patients with CrCl <15 mL/min should not receive imipenem/cilastatin unless hemodialysis will be instituted within 48 hours 1
• This restriction prevents dangerous accumulation of both drugs, particularly cilastatin 2