Imipenem-Cilastatin: Clinical Overview
Indications
Imipenem-cilastatin is indicated for moderate-to-severe infections caused by susceptible organisms, particularly in polymicrobial and healthcare-associated infections where broad-spectrum coverage is essential. 1, 2
Specific Clinical Scenarios:
- Healthcare-associated intra-abdominal infections including complicated infections with high severity 1
- Hospital-acquired and ventilator-associated pneumonia when multidrug-resistant pathogens are suspected 1
- Bloodstream infections due to carbapenem-resistant organisms (in combination therapy) 1
- Complicated urinary tract infections caused by carbapenem-resistant Enterobacterales 1
- Neutropenic enterocolitis as monotherapy or combination regimen 1
- Non-tuberculous mycobacterial infections (off-label) 1
- Mixed aerobic-anaerobic infections including obstetric/gynecologic, skin/soft tissue infections 2, 3
Dosing Regimen (Normal Renal Function)
Standard Adult Dosing:
For adults with normal renal function, the recommended dose is 500 mg IV every 6 hours for moderate infections, or 1 g IV every 8 hours for severe infections. 4, 5
- Moderate infections: 500 mg IV every 6 hours 4
- Severe infections: 1 g IV every 8 hours 1, 4, 5
- Life-threatening infections: 1 g IV every 6 hours 4
Weight-Based Dosing:
Special Indication Dosing:
- Drug-resistant tuberculosis: 1 g IV 3-4 times daily (combined with clavulanate) 4
- Carbapenem-resistant Pseudomonas: 500 mg IV every 6 hours (in combination with colistin) 1
Renal Dose Adjustments
Dose reduction is mandatory when creatinine clearance falls below 30 mL/min/1.73 m² to prevent accumulation of cilastatin and imipenem metabolites. 6, 7
Key Pharmacokinetic Considerations:
- Normal renal function: Half-life is 1 hour for both imipenem and cilastatin 6, 7
- Severe renal failure: Half-life extends to >4 hours for imipenem and 16 hours for cilastatin 6
- Hemodialysis: Both drugs are well cleared; administer supplemental 500 mg dose after each dialysis session 6
- Maximum dose in severe renal impairment: Limited to 1 g twice daily or 500 mg four times daily 4
The specific dose adjustments should be guided by periodic renal function assessments, as cilastatin accumulation poses greater risk than imipenem in renal dysfunction 6, 8.
Contraindications and Critical Drug Interactions
Absolute Contraindication:
Avoid concomitant use with valproic acid or divalproex sodium, as imipenem reduces valproate concentrations below therapeutic range, significantly increasing breakthrough seizure risk. 1, 4, 5
Relative Contraindications:
- Known hypersensitivity to carbapenems or beta-lactam antibiotics 8, 2
- Patients predisposed to seizures require careful risk-benefit assessment 8
High-Risk Drug Interaction:
Adverse Effects
Common (Incidence 3-4%):
- Injection site reactions: Phlebitis/thrombophlebitis (3%) 1, 8, 3
- Gastrointestinal: Nausea, vomiting, diarrhea 1, 8, 3
- Hematologic: Eosinophilia (4%) 1
- Hepatic: Transient mild elevations in liver function tests 1, 8
- Renal: Transient increases in urea/creatinine (<2%) 1
Serious Adverse Effects:
Seizures occur in 1-3% of patients, with highest risk in those with renal insufficiency, underlying CNS disease, or receiving higher doses. 4, 8
- Neurologic: Seizures (particularly with doses >25 mg/kg/day or in renal impairment) 1, 4
- Immunologic: Anaphylaxis 1
- Infectious: Clostridium difficile-associated diarrhea and colitis 1
- Hematologic: Pancytopenia, neutropenia, leukopenia, thrombocytopenia, agranulocytosis (rare) 1
- Renal: Acute renal failure, oliguria/anuria (rare) 1
Common Pitfall:
Do not use anticholinergic, antidiarrheal, or opioid agents in neutropenic enterocolitis, as they may aggravate ileus 1.
Monitoring Requirements
Routine drug level monitoring is not required for imipenem-cilastatin. 1, 4, 5
Recommended Monitoring:
- Complete blood count at regular intervals during prolonged therapy 4, 5
- Renal function tests (BUN, creatinine) periodically, especially in renal impairment 4, 5
- Liver function tests intermittently throughout treatment 4, 5
- Clinical assessment for seizure activity, particularly in high-risk patients 4
Alternative Agents
For Carbapenem-Resistant Enterobacterales:
Ceftazidime-avibactam 2.5 g IV every 8 hours is the preferred alternative for CRE infections. 1
- Meropenem-vaborbactam 4 g IV every 8 hours 1
- Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1
For Carbapenem-Resistant Pseudomonas:
- Ceftolozane-tazobactam 1.5-3 g IV every 8 hours 1
- Ceftazidime-avibactam 2.5 g IV every 8 hours 1
- Colistin-based combination therapy 1
For Healthcare-Associated Intra-Abdominal Infections:
- Meropenem 1 g IV every 8 hours 1
- Doripenem (dose per guidelines) 1
- Piperacillin-tazobactam 4.5 g IV every 6 hours 1
- Cefepime 2 g IV every 8-12 hours (plus metronidazole) 1
For Neutropenic Enterocolitis:
Piperacillin-tazobactam is an equally effective alternative monotherapy option. 1
- Cefepime or ceftazidime plus metronidazole 1
Clinical Pearls
Resistance Considerations:
When Pseudomonas aeruginosa is documented or anticipated, always combine imipenem with an aminoglycoside to prevent emergence of resistance during therapy. 8
- Isolates may rapidly acquire resistance or be replaced by resistant strains when imipenem is used as monotherapy for pseudomonal infections 8
- Methicillin-resistant staphylococci should be considered resistant to imipenem 8, 3
- Pseudomonas maltophilia, some Pseudomonas cepacia strains, and Streptococcus faecium are inherently resistant 8, 3