What is the recommended dosing regimen for meropenem in the treatment of bacterial infections, considering pharmacokinetics (PK) and pharmacodynamics (PD)?

Meropenem Pharmacokinetics and Pharmacodynamics: Dosing Recommendations

For optimal PK/PD target attainment, administer meropenem 1 gram IV every 8 hours as a standard regimen for serious infections in adults with normal renal function, with extended infusion (over 3 hours) strongly recommended when treating organisms with elevated MICs ≥8 mg/L. 1, 2

Standard Dosing Regimens

Adults with Normal Renal Function

• Complicated intra-abdominal infections: 1 gram IV every 8 hours 1, 3
• Complicated skin and soft tissue infections: 500 mg IV every 8 hours (or 1 gram every 8 hours for Pseudomonas aeruginosa) 1
• Carbapenem-resistant Enterobacterales (when susceptible): 1 gram IV every 8 hours by extended infusion over 3 hours 2

Infusion Strategy for PK/PD Optimization

• Standard infusion: 15-30 minutes for routine administration 1
• Extended infusion: 3 hours when MIC ≥8 mg/L to maximize time above MIC (T>MIC), the critical PK/PD parameter for carbapenems 2, 3
• Bolus injection: 3-5 minutes acceptable for doses up to 1 gram, though extended infusion preferred for resistant organisms 1

The rationale for extended infusion stems from meropenem's time-dependent killing, where efficacy correlates with the percentage of the dosing interval that free drug concentrations remain above the MIC (fT>MIC target: 40-50% for bacteriostatic effect, >60% for maximal bactericidal activity) 4, 5.

Renal Dose Adjustments

Meropenem requires mandatory dose reduction in renal impairment due to primary renal elimination (half-life ~1 hour in normal function, prolonged significantly with decreased clearance). 1, 6

Adult Dosing by Creatinine Clearance

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

Continuous Renal Replacement Therapy

For patients on continuous venovenous hemofiltration (CVVH), pharmacokinetic data demonstrates significant drug removal with a post-to-pre hemofiltration ratio of 0.24, requiring 1 gram every 8 hours to maintain therapeutic levels (peak ~28 mcg/mL, trough ~6.6 mcg/mL at 6 hours) 7.

Pediatric Dosing

Children ≥3 Months with Normal Renal Function

• Complicated skin/soft tissue infections: 10 mg/kg every 8 hours (maximum 500 mg/dose) 1, 2
• Complicated intra-abdominal infections: 20 mg/kg every 8 hours (maximum 1 gram/dose) 1, 2
• Meningitis: 40 mg/kg every 8 hours (maximum 2 grams/dose) 1, 2
• P. aeruginosa infections: 20 mg/kg every 8 hours regardless of site 1

Infants <3 Months with Normal Renal Function

Dosing based on gestational age (GA) and postnatal age (PNA) for complicated intra-abdominal infections, administered as 30-minute infusion 1:

• GA <32 weeks, PNA <2 weeks: 20 mg/kg every 12 hours 1, 2
• GA <32 weeks, PNA ≥2 weeks: 20 mg/kg every 8 hours 1, 2
• GA ≥32 weeks, PNA <2 weeks: 20 mg/kg every 8 hours 1, 2
• GA ≥32 weeks, PNA ≥2 weeks: 30 mg/kg every 8 hours 1, 2

Treatment Duration

Limit therapy to 5-7 days for complicated intra-abdominal infections and complicated urinary tract infections when adequate source control is achieved. 3, 2

• Bloodstream infections: 7-14 days 2
• Complicated intra-abdominal infections: 5-7 days 3, 2
• Complicated urinary tract infections: 5-7 days 2
• Meningitis: At least 7 days (pediatric data) 2

Duration should be shortened rather than prolonged when clinical response is favorable and source control adequate, as unnecessarily prolonged carbapenem exposure drives resistance 2.

Microbiological Spectrum and PD Considerations

Meropenem demonstrates concentration-independent, time-dependent bactericidal activity with an ultra-broad spectrum 5, 6:

• Gram-positive coverage: Streptococci, methicillin-susceptible S. aureus, Enterococcus faecalis (vancomycin-susceptible) 1, 5
• Gram-negative coverage: Enterobacterales, P. aeruginosa, H. influenzae, N. meningitidis 1, 5
• Anaerobic coverage: Bacteroides fragilis, Peptostreptococcus species 1, 5

Meropenem is more active than imipenem against Enterobacterales and P. aeruginosa but slightly less active against staphylococci and enterococci 5, 6. It demonstrates stability to most β-lactamases, though resistance can emerge during P. aeruginosa treatment 4, 5.

Critical Pitfalls

• Do not use standard dosing for high-MIC organisms: Extended infusion is essential when MIC ≥8 mg/L to achieve adequate fT>MIC 2, 3
• Avoid in MRSA or E. faecium infections: Uniformly resistant 5
• Adjust for renal function: Failure to reduce dose in renal impairment increases seizure risk, though meropenem has lower CNS toxicity than imipenem 1, 6
• Monitor for resistance emergence: Particularly with P. aeruginosa and Stenotrophomonas maltophilia (intrinsically resistant) 4, 5
• Inadequate source control negates antibiotic efficacy: Surgical intervention or drainage mandatory for intra-abdominal infections 2