Meropenem: Mechanism of Action, Pharmacokinetics, Pharmacodynamics, and Dosing
Mechanism of Action
Meropenem is a carbapenem β-lactam antibiotic that exerts bactericidal activity through inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs). 1, 2 The drug demonstrates concentration-dependent killing against gram-negative bacilli and time-dependent killing characteristics typical of β-lactams, with optimal efficacy when free drug concentrations remain above the organism's minimum inhibitory concentration (MIC) for 40% or more of the dosing interval 3, 4.
- Unlike imipenem, meropenem possesses a 1-β-methyl group that confers stability against human dehydropeptidase-I (DHP-I), eliminating the need for coadministration with a DHP-I inhibitor like cilastatin 5, 2
- Meropenem exhibits a post-antibiotic effect against gram-negative bacilli including Pseudomonas aeruginosa, allowing for sustained bacterial suppression even after drug levels fall below the MIC 3
Pharmacokinetics
Distribution and Metabolism
- Volume of distribution: Approximately 21-29 L in adults, indicating predominantly extracellular distribution 5, 4
- Protein binding: Minimal, allowing for high free drug concentrations at infection sites 5
- CSF penetration: Meropenem distributes into cerebrospinal fluid, making it suitable for meningitis treatment 5, 6
- Elimination half-life: Approximately 1 hour in patients with normal renal function, prolonged to 2.5-6.1 hours with renal impairment, and up to 13.7 hours in anuric patients 7, 5, 4
Excretion
- Primary route: Up to 70% is excreted unchanged in urine; the remainder is metabolized to an inactive ring-opened metabolite (ICI 213689) 5
- Renal replacement therapy clearance: Approximately 50% removed by intermittent hemodialysis, 25-50% by continuous venovenous hemofiltration (CVVHF), and 13-53% by continuous venovenous hemodiafiltration (CVVHDF) 7, 8
Pharmacodynamics
The primary pharmacodynamic target for meropenem is achieving free drug concentrations above the MIC for at least 40% of the dosing interval (fT>MIC ≥40%). 4 For critically ill patients or infections with resistant organisms, extended infusion strategies optimize this parameter 9, 10.
- Peak plasma concentrations (Cmax) reach approximately 30 mg/L after a 1-gram IV dose in healthy volunteers, with linear dose-proportional increases 5
- Monte Carlo simulations demonstrate that standard dosing achieves >90% cumulative fraction of response for enteric pathogens and P. aeruginosa, but only 82-85% for Acinetobacter species 4
- Neurological toxicity risk: Trough concentrations exceeding 64 mg/L are associated with seizures and neurological deterioration, particularly in patients with renal impairment or CNS infections 8, 9
Dosing Recommendations
Adults with Normal Renal Function (CrCl >50 mL/min)
For severe infections including hospital-acquired pneumonia, ventilator-associated pneumonia, and carbapenem-resistant Enterobacterales, administer 1 gram IV every 8 hours by extended infusion over 3 hours. 9, 10
- Complicated skin and skin structure infections: 500 mg IV every 8 hours (15-30 minute infusion); increase to 1 gram every 8 hours for P. aeruginosa 6
- Complicated intra-abdominal infections: 1 gram IV every 8 hours 3, 6
- Healthcare-associated infections in critically ill patients: 1 gram IV every 8 hours 3
- Extended infusion rationale: For organisms with MIC ≥4-8 mg/L, 3-hour infusions optimize time above MIC and improve outcomes 8, 9
Adults with Renal Impairment
Maintain the full 1-gram dose per administration when possible, but extend the dosing interval rather than reducing individual doses, as smaller doses compromise efficacy. 8, 10
| Creatinine Clearance (mL/min) | Dose | Dosing Interval |
|---|---|---|
| >50 | Recommended dose (500 mg or 1 g) | Every 8 hours |
| 26-50 | Recommended dose | Every 12 hours |
| 10-25 | One-half recommended dose | Every 12 hours |
| <10 | One-half recommended dose | Every 24 hours |
Critical pitfall: Doses should be administered after hemodialysis sessions to prevent premature drug removal and subtherapeutic levels 8, 10
Renal Replacement Therapy
- Continuous renal replacement therapy (CRRT): 1 gram every 8-12 hours to compensate for 25-50% drug removal 8, 7
- Sustained low-efficiency dialysis (SLED): 1 gram every 12 hours, administered post-dialysis 8
- Therapeutic drug monitoring: Strongly recommended for patients on renal replacement therapy to ensure adequate exposure while avoiding trough concentrations >64 mg/L 8, 9, 10
Pediatric Dosing (≥3 Months of Age)
| Indication | Dose (mg/kg) | Maximum Dose | Interval |
|---|---|---|---|
| Complicated skin/skin structure infections | 10 | 500 mg | Every 8 hours |
| Complicated intra-abdominal infections | 20 | 1 gram | Every 8 hours |
| Meningitis | 40 | 2 grams | Every 8 hours |
- For P. aeruginosa skin infections: 20 mg/kg (or 1 gram if >50 kg) every 8 hours 6
- Administer as 15-30 minute infusion or 3-5 minute bolus injection 6
Infants <3 Months of Age (Complicated Intra-Abdominal Infections)
| Age Group | Dose (mg/kg) | Interval |
|---|---|---|
| <32 weeks GA and PNA <2 weeks | 20 | Every 12 hours |
| <32 weeks GA and PNA ≥2 weeks | 20 | Every 8 hours |
| ≥32 weeks GA and PNA <2 weeks | 20 | Every 8 hours |
| ≥32 weeks GA and PNA ≥2 weeks | 30 | Every 8 hours |
Administration Considerations
- Standard infusion: 15-30 minutes for most indications 6
- Extended infusion: 3 hours for resistant organisms (MIC ≥4-8 mg/L) or critically ill patients 8, 9
- Bolus injection: 3-5 minutes for 1-gram doses (acceptable alternative to infusion) 6
- Continuous infusion: Possible but requires preparation of new infusion bags every 6 hours due to limited room temperature stability 9
Critical Safety Considerations and Common Pitfalls
Avoid These Errors:
- Never administer meropenem before hemodialysis sessions – this causes premature drug removal and treatment failure 8, 10
- Do not reduce individual doses below 1 gram in adults with serious infections, even with renal impairment – extend the interval instead 8, 10
- Avoid underdosing in ICU patients with normal renal function – these patients have increased clearance and volume of distribution requiring standard or higher doses 9, 10
- Do not co-administer with valproic acid or divalproex sodium – meropenem reduces valproic acid concentrations, increasing breakthrough seizure risk 6
Monitoring Requirements:
- Therapeutic drug monitoring is recommended for critically ill patients, those with renal impairment, and patients on renal replacement therapy 8, 9, 10
- Target trough concentrations <64 mg/L to prevent neurological toxicity, particularly seizures 8, 9
- Monitor renal function throughout treatment, though meropenem itself does not cause clinically significant renal toxicity 8