Imipenem-Cilastatin: Composition and Dosing
Composition
Imipenem-cilastatin is a fixed-combination antibiotic consisting of equal parts imipenem (a carbapenem) and cilastatin (a renal dehydropeptidase-I inhibitor). 1
- Imipenem is a broad-spectrum carbapenem antibiotic with activity against gram-positive, gram-negative, aerobic, and anaerobic organisms 2, 3
- Cilastatin has no antibacterial activity but prevents renal metabolism of imipenem by inhibiting dehydropeptidase-I in the renal tubular brush border, increasing urinary concentrations of active imipenem from 6-38% (when given alone) to 70% (when combined with cilastatin) 4, 5
- Available formulations contain 250 mg imipenem + 250 mg cilastatin OR 500 mg imipenem + 500 mg cilastatin per vial 1
Standard Dosing Regimens
For critically ill patients with healthcare-associated intra-abdominal infections, administer 500 mg IV every 6 hours by extended infusion. 6
Adult Dosing by Weight:
Alternative Dosing for Severe Infections:
- 1 g IV every 8 hours for critically ill patients with healthcare-associated infections 7
- 500 mg IV every 6 hours by extended infusion is recommended for septic shock or severe intra-abdominal infections 6
Extended Infusion Strategy
Extended infusion administration is recommended to optimize pharmacodynamic targets, particularly in critically ill patients. 6
- Imipenem requires plasma concentrations above the MIC for at least 70% of the dosing interval for optimal efficacy 8
- Extended infusion (over 3 hours) should be considered when treating resistant organisms or in patients with deep infection foci 8
Treatment Duration by Infection Type
- Complicated urinary tract infections: 5-7 days 7
- Complicated intra-abdominal infections: 5-7 days 7
- Bacteremia: 7-14 days 7
- Hospital-acquired or ventilator-associated pneumonia: 10-14 days 7
Pharmacokinetic Properties
- Half-life: 1 hour for both imipenem and cilastatin in patients with normal renal function 4, 5
- Renal excretion: 70-80% of cilastatin and 60-70% of imipenem excreted unchanged in urine when co-administered 4, 5
- Plasma clearance: Approximately 220 ml/min for imipenem 5
- No loading dose required for standard administration 7
Renal Dose Adjustment
Dosage reduction is required when creatinine clearance falls below 30 ml/min per 1.73 m² 4
- In severe renal failure (functionally anephric), terminal half-life extends to >4 hours for imipenem and 16 hours for cilastatin 5
- Both drugs are cleared by hemodialysis; administer supplemental 500 mg dose after dialysis 5
Critical Monitoring Parameters
- Seizure risk: Close adherence to dosage schedules is essential, particularly in patients predisposed to seizures or receiving anticonvulsant medication 2
- Drug interactions: Avoid concomitant use with valproate (decreases valproate concentrations); increased seizure risk with ganciclovir 7
- Routine monitoring: Periodic assessment of renal, hepatic, and hematologic function for long-term treatment 7
- No routine drug level monitoring required 7
Antimicrobial Spectrum and Resistance Considerations
- Excellent activity against most gram-positive and gram-negative aerobes and anaerobes, including beta-lactamase producers 2, 3
- Resistant organisms: Stenotrophomonas maltophilia, some Burkholderia cepacia strains, Enterococcus faecium, and methicillin-resistant staphylococci 2
- For documented or anticipated Pseudomonas aeruginosa infections, combine with an aminoglycoside to prevent emergence of resistance during therapy 2
Newer Formulation: Imipenem-Cilastatin-Relebactam
Imipenem-cilastatin-relebactam (1.25 g IV every 6 hours by extended infusion) is recommended for carbapenem-resistant Enterobacteriaceae infections. 6
- Relebactam is a novel β-lactamase inhibitor active against class A carbapenemases (including KPC) and class C cephalosporinases 6
- Inactive against class B (metallo-β-lactamases) and class D (OXA-type) carbapenemases 6
- FDA-approved in July 2019 for complicated urinary tract infections and complicated intra-abdominal infections 6