What is the appropriate dosing of imipenem‑cilastatin, including renal dose adjustments, and what alternatives should be used for patients with β‑lactam allergy or carbapenem resistance?

Imipenem-Cilastatin Dosing and Management

For standard dosing in patients with normal renal function, administer imipenem-cilastatin 1 g IV every 8 hours for critically ill patients with healthcare-associated or community-acquired intra-abdominal infections, or 500 mg IV every 6-8 hours for less severe infections. 1

Standard Dosing Regimens

Critically Ill Patients

• Imipenem-cilastatin 1 g IV every 8 hours is the recommended dose for critically ill patients with community-acquired intra-abdominal infections at risk for ESBL-producing Enterobacteriaceae 1
• For healthcare-associated intra-abdominal infections in critically ill patients, the same dose of 1 g IV every 8 hours applies 1
• This regimen provides coverage against ampicillin-susceptible enterococci, eliminating the need for additional ampicillin 1

Non-Critically Ill Patients

• For healthcare-associated infections in non-critically ill patients at higher risk for multidrug-resistant organisms (recent antibiotic exposure, nursing home residence with indwelling catheter, or post-operative infection), use imipenem-cilastatin 1 g IV every 8 hours 1

Drug-Resistant Tuberculosis

• For multidrug-resistant tuberculosis, the dose is 1,000 mg IV 3-4 times daily (based on the imipenem component) 1
• In children with drug-resistant TB, dosing is 15-25 mg/kg/dose of the imipenem component, 1,000 mg three times daily 1

Renal Dose Adjustments

Moderate to Severe Renal Impairment

• Dosage reduction is essential when creatinine clearance falls below 30 mL/min to prevent accumulation of cilastatin and imipenem metabolites 2, 3
• The elimination half-life extends to slightly greater than 4 hours for imipenem and 16 hours for cilastatin in functionally anephric patients 2
• For drug-resistant tuberculosis patients with reduced renal function, reduce the dosing frequency while maintaining therapeutic imipenem concentrations 1

Hemodialysis Patients

• Both imipenem and cilastatin are well cleared by hemodialysis 2
• Administer a supplemental 500 mg dose after each dialysis session to maintain therapeutic levels 2
• This post-dialysis dosing prevents premature drug removal and ensures adequate antimicrobial coverage 2

Pharmacokinetic Considerations

• Cilastatin eliminates more slowly than imipenem in renal impairment, necessitating dose adjustments to prevent cilastatin accumulation 4, 2
• Renal clearance occurs via glomerular filtration and active tubular secretion for both components 2
• With declining renal function, imipenem elimination becomes controlled by a metabolic clearance pathway unaffected by cilastatin 2

Alternatives for β-Lactam Allergy

Intra-Abdominal Infections

For patients with documented β-lactam allergy:

• Amikacin 15-20 mg/kg IV every 24 hours in combination regimens is recommended for both non-critically ill and critically ill patients with healthcare-associated infections 1
• This aminoglycoside-based approach provides coverage when carbapenems cannot be used 1

Important Caveat

• The guidelines emphasize using "antibiotic combinations with amikacin" rather than monotherapy, indicating that additional agents targeting anaerobes and gram-positive organisms should be added based on the clinical scenario 1

Alternatives for Carbapenem Resistance

Carbapenem-Resistant Enterobacteriaceae (CRE)

Ceftazidime-avibactam 2.5 g IV every 8 hours infused over 3 hours is the preferred agent for CRE bloodstream infections 1

Alternative newer β-lactam/β-lactamase inhibitor combinations include:

• Meropenem-vaborbactam 4 g IV every 8 hours infused over 3 hours 1
• Imipenem-cilastatin-relebactam 1.25 g IV every 6 hours 1

Carbapenem-Sparing Regimens

For healthcare-associated infections when carbapenem resistance is not confirmed but carbapenem-sparing is desired:

• Ceftolozane-tazobactam 1.5 g IV every 8 hours + metronidazole 500 mg every 6 hours 1
• Ceftazidime-avibactam 2.5 g IV every 8 hours + metronidazole 500 mg every 6 hours 1
• Piperacillin-tazobactam 4.5 g IV every 6 hours + tigecycline 100 mg loading dose, then 50 mg every 12 hours 1

Polymyxin-Based Therapy for CRE

When newer agents are unavailable:

• Colistin-based combination therapy (loading dose 300 mg colistimethate sodium [9 MU] infused over 0.5-1 hour, maintenance 300-360 mg [9-10.9 MU] divided in two doses) reduces 28-day mortality compared to monotherapy (35.7% vs 55.5%) 1
• Combination therapy is particularly beneficial in patients with high INCREMENT-CPE mortality scores 1

Critical Safety Considerations

Seizure Risk

• Patients predisposed to seizures or receiving anticonvulsant medication require close monitoring and strict adherence to dosage schedules, particularly with renal impairment 5
• Dose reductions appropriate for renal function should be guided by periodic renal function assessments 5

Resistance Development

• When Pseudomonas aeruginosa recovery is anticipated or documented, combine imipenem-cilastatin with an aminoglycoside to prevent emergence of resistant organisms during therapy 5
• Isolates may rapidly acquire resistance or be replaced by resistant strains when imipenem is used as monotherapy for serious pseudomonal infections 5

Rationale for Fixed Combination

• Cilastatin inhibits renal dehydropeptidase I, increasing urinary recovery of active imipenem from 5.5-42.5% (when given alone) to approximately 70% (when combined 1:1 with cilastatin) 4, 3
• The combination eliminates nephrotoxic potential associated with very high doses of imipenem alone 4
• Both compounds have elimination half-lives of 1 hour in normal renal function, with linear pharmacokinetics across therapeutic dose ranges 3