What are the typical doses of carbapenems (meropenem and imipenem/cilastatin) for a patient with impaired renal function requiring carbapenem therapy for various infections?

Carbapenem Dosing in Renal Impairment

Standard Dosing in Normal Renal Function

For patients with normal renal function, meropenem should be dosed at 1 gram IV every 8 hours for most serious infections, with extended 3-hour infusions recommended for critically ill patients or when treating organisms with elevated MICs ≥8 mg/L 1.

Meropenem Standard Regimens

• Standard dose: 1 gram IV every 8 hours for complicated intra-abdominal infections, urinary tract infections, and bloodstream infections 1, 2
• High-dose regimen: 2 grams IV every 8 hours for severe infections, pneumonia, or CNS infections (meningitis) 1
• Extended infusion: Administer over 3 hours when MIC ≥8 mg/L or for carbapenem-resistant Enterobacteriaceae (CRE) infections 1, 2
• No loading dose required for standard administration 1

Imipenem/Cilastatin Standard Regimens

• Standard dose: 500 mg to 1 gram IV every 6-8 hours 3, 4
• Critically ill patients: 1 gram every 8 hours for healthcare-associated intra-abdominal infections 5
• The half-life is approximately 1 hour in patients with normal renal function 6, 7

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Dosing Adjustments in Renal Impairment

Meropenem in Renal Dysfunction

Meropenem requires dosage adjustments in renal impairment because approximately 70% is excreted unchanged via the kidneys 8, 9.

• The half-life increases from 1 hour in healthy volunteers to up to 13.7 hours in anuric patients with end-stage renal disease 9
• Peak plasma concentrations after 1 gram IV reach 18-45 mg/L during continuous renal replacement therapy (CRRT) in critically ill patients 9
• Dosage reductions are necessary to prevent drug accumulation while maintaining therapeutic concentrations 8

Imipenem/Cilastatin in Renal Dysfunction

Imipenem requires more aggressive dose adjustments than meropenem because renal clearance accounts for 60-70% of plasma clearance when co-administered with cilastatin 6.

• The half-life increases to slightly greater than 4 hours for imipenem and 16 hours for cilastatin in functionally anephric patients 6
• Dose and schedule alterations prevent accumulation of cilastatin and circulating metabolites of imipenem while maintaining therapeutic imipenem concentrations 6
• Renal clearance occurs via both glomerular filtration and active tubular secretion 6

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Hemodialysis Considerations

Meropenem During Hemodialysis

• Approximately 50% of meropenem is eliminated by intermittent hemodialysis (IHD) 9
• Peak concentrations reach up to 53 mg/L after 0.5 gram dose in hemodialysis patients 9
• Supplemental dosing is required after dialysis sessions 9

Imipenem During Hemodialysis

• Both imipenem and cilastatin are well cleared by hemodialysis 6
• Supplemental 500 mg doses are recommended after each dialysis session 6
• This prevents subtherapeutic levels while avoiding accumulation of cilastatin 6

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Continuous Renal Replacement Therapy (CRRT)

Meropenem elimination varies significantly based on the specific CRRT modality used 9:

• Continuous venovenous hemofiltration (CVVHF): 25-50% elimination 9
• Continuous venovenous hemodiafiltration (CVVHDF): 13-53% elimination 9
• These differences demonstrate the substantial influence of treatment modality on drug elimination 9
• Physicians risk underdosing due to varying recommendations in the literature 9

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Critical Pitfalls to Avoid

Underdosing Risks

• Do not use standard dosing for high-MIC organisms—extended infusion is mandatory when MIC ≥8 mg/L to achieve adequate time above MIC 2
• The quite different recommendations in literature for CRRT patients create risk of underadministration 9
• Given meropenem's excellent tolerability profile, such underadministration should be avoided 9

Cilastatin Accumulation

• In severe renal failure, cilastatin accumulates more than imipenem (half-life 16 hours vs. 4 hours) 6
• Dose adjustments must account for both components to prevent cilastatin toxicity 6

Nephrotoxicity Considerations

• Unlike imipenem, meropenem does not require a dehydropeptidase inhibitor and achieves consistently high urinary concentrations without nephrotoxic effects 8
• Imipenem is hydrolyzed by renal dehydropeptidase-I and must be co-administered with cilastatin to prevent this degradation 6, 7

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Comparative Pharmacokinetics

The pharmacokinetic parameters for meropenem are similar to imipenem/cilastatin, except meropenem has a smaller volume of distribution 8:

• Meropenem achieves urinary recovery as high as imipenem combined with cilastatin 8
• Both drugs have plasma clearances averaging 220 ml/min for imipenem in normal volunteers 6
• Meropenem is eliminated by both excretion (70%) and metabolism (30%) 8