How should meropenem be dosed and monitored in patients with impaired renal function, including those on hemodialysis or continuous renal replacement therapy?

Meropenem Dosing in Renal Failure

Administer a full loading dose of meropenem (500 mg or 1 gram depending on infection type) regardless of renal function, then adjust maintenance dosing based on creatinine clearance, with doses given every 12 hours for CrCl 26-50 mL/min, every 12 hours at half-dose for CrCl 10-25 mL/min, and every 24 hours at half-dose for CrCl <10 mL/min. 1, 2

Loading Dose Strategy

The loading dose must never be reduced based on renal function. 1

• Administer the full standard dose (500 mg for complicated skin/soft tissue infections or 1 gram for intra-abdominal infections) as the initial loading dose in all patients, including those with severe renal dysfunction 1, 2
• This loading dose is essential for achieving rapid therapeutic concentrations needed for concentration-dependent bactericidal activity 1
• Reducing the loading dose leads to subtherapeutic initial concentrations and potential treatment failure 1

Maintenance Dosing Based on Creatinine Clearance

The FDA-approved dosing adjustments are: 2

• CrCl >50 mL/min: Standard dose (500 mg or 1 gram) every 8 hours 2
• CrCl 26-50 mL/min: Standard dose (500 mg or 1 gram) every 12 hours 2
• CrCl 10-25 mL/min: Half the standard dose (250 mg or 500 mg) every 12 hours 2
• CrCl <10 mL/min: Half the standard dose (250 mg or 500 mg) every 24 hours 2

Pharmacokinetic Rationale

• Meropenem's terminal half-life increases from approximately 1 hour in normal renal function to 9.7-13.7 hours in anuric patients 3, 4
• Total body clearance correlates linearly with creatinine clearance, necessitating dose adjustments 3
• Peak plasma concentrations (28-40 mcg/mL) remain unaffected by renal impairment, but drug accumulation occurs without dosing adjustments 3
• Even with recommended dose reductions, drug exposure in renal impairment patients is 158-286% higher than in patients with normal renal function, but this is generally well-tolerated given meropenem's excellent safety profile 5

Hemodialysis Patients

For patients on intermittent hemodialysis, administer the dose immediately after each dialysis session. 6, 7

• Hemodialysis removes approximately 50% of meropenem over a 4-hour session, shortening the elimination half-life from 9.7 hours to 1.4 hours during dialysis 3, 4
• Post-dialysis dosing prevents premature drug removal and ensures the full therapeutic dose is retained 6, 7
• The FDA label notes inadequate information for specific hemodialysis dosing recommendations, but the principle of post-dialysis administration applies 2
• Maintain the milligram dose per administration rather than reducing it, as smaller doses may compromise efficacy 6

Continuous Renal Replacement Therapy (CRRT)

For patients on CRRT, increase the standard dose by 100% to avoid underdosing. 8

• CRRT significantly contributes to meropenem elimination, with 25-50% removed by continuous venovenous hemofiltration (CVVHF) and 13-53% by continuous venovenous hemodiafiltration (CVVHDF) 4, 8
• In critically ill anuric patients receiving CVVHF, hemofiltration clearance averages 22 mL/min, accounting for 47% of total drug clearance 8
• The recommended dosing for CVVHF is 500 mg every 8 hours or 1 gram every 12 hours, depending on infection severity 8
• Peak and trough concentrations with 500 mg every 12 hours are 38.9 mg/L and 7.3 mg/L respectively, which may be subtherapeutic for resistant organisms 8

Pharmacodynamic Target Attainment

Meropenem exhibits time-dependent bactericidal activity, requiring the free-drug concentration to remain above the MIC for approximately 40% of the dosing interval (%T>MIC). 9

• For optimal bactericidal effect, maintain plasma concentrations above the pathogen's MIC for at least 40% of the dosing interval 9
• Extended infusion times (3-4 hours) may be considered for organisms with higher MICs, particularly in critically ill patients with augmented renal clearance 9
• The standard 15-30 minute infusion is adequate for most susceptible organisms with MICs ≤2 mcg/mL 2, 9

Monitoring Requirements

• Therapeutic drug monitoring should be considered in patients with severe renal impairment to ensure adequate drug exposure without excessive accumulation 1, 5
• Monitor renal function regularly, as changes in creatinine clearance necessitate dosing adjustments 2, 3
• For patients on CRRT, monitor for signs of underdosing (clinical failure, persistent fever) given the significant drug removal by hemofiltration 8

Critical Pitfalls to Avoid

• Never reduce the loading dose based on renal function—this is the most common error leading to treatment failure 1
• Do not underdose patients on CRRT—the standard renal impairment dosing is insufficient due to significant drug removal by hemofiltration 8
• Avoid pre-dialysis dosing in hemodialysis patients, as this results in premature drug removal and subtherapeutic levels 6, 7
• Do not rely solely on standard dosing tables for critically ill patients—consider therapeutic drug monitoring given the high variability in pharmacokinetics 5, 8