Meropenem for Severe and Complicated Infections
Meropenem is a broad-spectrum carbapenem antibiotic indicated for complicated skin/soft tissue infections, intra-abdominal infections, and bacterial meningitis, with standard dosing of 1 gram IV every 8 hours for most infections and 2 grams IV every 8 hours for meningitis or severe pneumonia, requiring dose adjustment when creatinine clearance falls below 50 mL/min. 1
FDA-Approved Indications
Meropenem is approved for the following infections 1:
- Complicated skin and skin structure infections (cSSSI): Active against methicillin-susceptible S. aureus, Streptococcus species, E. faecalis (vancomycin-susceptible), P. aeruginosa, E. coli, P. mirabilis, B. fragilis, and Peptostreptococcus species 1
- Complicated intra-abdominal infections: Effective against viridans group streptococci, E. coli, K. pneumoniae, P. aeruginosa, B. fragilis, B. thetaiotaomicron, and Peptostreptococcus species 1
- Bacterial meningitis (pediatric patients ≥3 months): Indicated for H. influenzae, N. meningitidis, and penicillin-susceptible S. pneumoniae 1
Standard Adult Dosing
By Infection Type
For complicated skin/soft tissue infections 1:
- Standard dose: 500 mg IV every 8 hours
- When treating P. aeruginosa: 1 gram IV every 8 hours 1
For complicated intra-abdominal infections 1, 2:
- Standard dose: 1 gram IV every 8 hours
- Provides superior anaerobic coverage compared to ertapenem 2
- Treatment duration typically 5-7 days based on source control and clinical response 2
For hospital-acquired/ventilator-associated pneumonia 2:
- High-dose regimen: 2 grams IV every 8 hours by extended infusion
- Treatment duration at least 7 days 2
For bacterial meningitis 2:
- 2 grams IV every 8 hours for Enterobacteriaceae or suspected ESBL organisms 2
- Duration: 10 days for H. influenzae or pneumococcal meningitis, 21 days for Enterobacteriaceae or Listeria 2
Administration Methods
Meropenem can be administered by 1:
- IV infusion over 15-30 minutes (preferred for most situations)
- IV bolus injection over 3-5 minutes (for 1 gram doses only)
- No loading dose is required for standard administration in patients with normal renal function 2
Extended Infusion Strategy
Extended infusion over 3 hours is recommended for specific high-risk situations to optimize pharmacodynamic targets 2, 3:
Indications for Extended Infusion
- Carbapenem-resistant Enterobacteriaceae (CRE) with meropenem MIC ≤8 mg/L 3, 2
- Carbapenem-resistant Acinetobacter baumannii (CRAB) with meropenem MIC ≤32 mg/L 3
- Critically ill patients with healthcare-associated infections 2
- Any pathogen with MIC ≥8 mg/L 2
Dosing for Extended Infusion
- For CRE infections: 1 gram IV every 8 hours by 3-hour infusion as part of combination therapy 3, 2
- For high MIC KPC-producing K. pneumoniae: 2 grams IV every 8 hours by 3-hour infusion 2
The rationale is that beta-lactam antibiotics should maintain plasma concentrations above the MIC for at least 70% of the dosing interval, with higher targets (Cmin/MIC >4-6) increasing success rates in critically ill patients 2.
Dosing in Renal Impairment
Dose adjustment is mandatory when creatinine clearance falls below 50 mL/min 1:
| Creatinine Clearance | Dose | Interval |
|---|---|---|
| >50 mL/min | Standard dose (500 mg or 1 gram) | Every 8 hours |
| 26-50 mL/min | Standard dose | Every 12 hours |
| 10-25 mL/min | Half the standard dose | Every 12 hours |
| <10 mL/min | Half the standard dose | Every 24 hours |
Renal Replacement Therapy
For continuous venovenous hemodiafiltration (CVVHDF) 4, 5:
- Recommended dose: 1 gram IV every 12 hours 5
- Approximately 13-53% of meropenem is eliminated by CVVHDF 4
- Meropenem clearance during CVVHDF is approximately 129-141 mL/min 5
For intermittent hemodialysis (IHD) 4:
- Approximately 50% of meropenem is removed by IHD 4
- The half-life is prolonged up to 13.7 hours in anuric patients 4
- Inadequate information exists for specific dosing recommendations; the FDA label notes this limitation 1
Critical Pitfall in Renal Function Assessment
Augmented renal clearance and mild renal impairment are both risk factors for target non-attainment 6:
- Standard dosing results in insufficient exposure in 51.6% of patients with MIC 2 mg/L and 79.4% with MIC 8 mg/L 6
- A hyperbolic relationship exists between creatinine clearance (25-255 mL/min) and meropenem concentrations 6
- For MIC 2 mg/L, patients with creatinine clearance from mild impairment up to augmented renal function are at risk 6
- For MIC 8 mg/L, even moderate renal impairment poses risk of inadequate exposure 6
Pediatric Dosing
Children ≥3 Months of Age
Dosing by infection type 1:
| Infection Type | Dose | Maximum | Interval |
|---|---|---|---|
| cSSSI | 10 mg/kg | 500 mg | Every 8 hours |
| cSSSI with P. aeruginosa | 20 mg/kg | 1 gram | Every 8 hours |
| Intra-abdominal | 20 mg/kg | 1 gram | Every 8 hours |
| Meningitis | 40 mg/kg | 2 grams | Every 8 hours |
For children weighing >50 kg, use adult dosing 1.
Infants <3 Months of Age
Dosing based on gestational age (GA) and postnatal age (PNA) 1:
| Age Group | Dose | Interval |
|---|---|---|
| <32 weeks GA and PNA <2 weeks | 20 mg/kg | Every 12 hours |
| <32 weeks GA and PNA ≥2 weeks | 20 mg/kg | Every 8 hours |
| ≥32 weeks GA and PNA <2 weeks | 20 mg/kg | Every 8 hours |
| ≥32 weeks GA and PNA ≥2 weeks | 30 mg/kg | Every 8 hours |
Administer as 30-minute IV infusion 1.
Use in Multidrug-Resistant Gram-Negative Infections
Carbapenem-Resistant Enterobacteriaceae (CRE)
First-line therapy for CRE should be newer beta-lactam/beta-lactamase inhibitor combinations when susceptible 7:
Meropenem monotherapy (without vaborbactam) may be considered for CRE only under specific conditions 3, 7:
- Meropenem MIC ≤8 mg/L 3, 7
- High-dose extended-infusion dosing (2 grams IV every 8 hours over 3 hours) 3
- As part of combination therapy with a second active agent 3
Combination therapy is suggested for severe CRE infections when newer agents are unavailable 7:
- Use two in vitro active drugs from available options (polymyxins, aminoglycosides, tigecycline, fosfomycin) 7
- Monotherapy is appropriate only for non-severe infections 7
Carbapenem-Resistant Pseudomonas aeruginosa (CRPA)
For severe CRPA infections, combination therapy with two active drugs is suggested 3:
- No specific recommendation for or against particular combinations can be provided 3
- For non-severe or low-risk CRPA infections, monotherapy with an active agent is acceptable based on individual assessment 3
Carbapenem-Resistant Acinetobacter baumannii (CRAB)
Meropenem-polymyxin combination therapy has conflicting evidence 3:
- ESCMID guidelines strongly recommend AGAINST polymyxin-meropenem combination therapy for CRAB based on high/moderate quality evidence 3
- However, Asian guidelines suggest this combination may be beneficial for CRAB with meropenem MIC ≤32 mg/L, particularly for pneumonia and bloodstream infections 3
- For CRAB with meropenem MIC ≤8 mg/L, high-dose extended-infusion carbapenem combination therapy is considered good clinical practice 3
This represents a significant divergence in international guidelines, with European societies recommending against this combination while Asian guidelines conditionally support it under specific MIC thresholds.
Spectrum of Activity
Gram-Negative Coverage
Meropenem demonstrates excellent activity against 8, 9:
- Enterobacteriaceae: More active than imipenem 9
- P. aeruginosa: More active than imipenem, though resistance may emerge during therapy 8, 9
- Haemophilus and Neisseria species 8
Important resistance patterns 8:
- Stenotrophomonas maltophilia is typically resistant 8
- Resistance may develop during treatment of P. aeruginosa infections 8
Gram-Positive Coverage
Meropenem is active against 1, 8:
- Methicillin-susceptible S. aureus (MSSA) 1
- Streptococci (including viridans group) 1
- Vancomycin-susceptible E. faecalis 1
Critical limitations 2:
- NOT active against MRSA (methicillin-resistant S. aureus) 2
- NOT active against VRE (vancomycin-resistant enterococci) 2
Anaerobic Coverage
Excellent activity against 1, 8:
- Bacteroides fragilis and B. thetaiotaomicron 1
- Peptostreptococcus species 1
- Most clinically important anaerobes 8
Pharmacokinetics
Key pharmacokinetic parameters in healthy volunteers 4, 9:
- Half-life: Approximately 1 hour 4, 9
- Peak concentration: 53-62 mg/L after 1 gram IV dose 4
- Primary elimination: Renal, with 63% excreted unchanged in urine 4, 5
- Pharmacokinetic profile: Linear and predictable 9
Stability to dehydropeptidase-I (DHP-I) 9:
- Unlike imipenem, meropenem does not require co-administration with a DHP-I inhibitor (cilastatin) 9
- This is due to the 1-beta-methyl group on the carbapenem moiety 9
Safety Profile
Meropenem demonstrates excellent CNS tolerability 9:
- Low propensity to cause seizures compared to imipenem 9
- Infusion-related nausea and vomiting occur no more frequently than with other beta-lactams 8
Common adverse effects 3:
- Diarrhea (increased with colistin-meropenem combination: 27% vs 16% monotherapy) 3
- Mild renal impairment (actually reduced with colistin-meropenem combination: 20% vs 30% monotherapy) 3
Meropenem is not nephrotoxic and can be safely increased to 6 grams daily 8.
Critical Clinical Pitfalls
Avoid Underdosing in Critically Ill Patients
Large inter- and intra-patient variability exists in meropenem concentrations in critically ill patients 6:
- Standard dosing achieves target attainment in less than half of patients 6
- Extended infusion and therapeutic drug monitoring should be strongly considered 2
Inappropriate Carbapenem Use
Indiscriminate use promotes resistance 8:
- Reserve meropenem for mixed bacterial infections and aerobic gram-negative bacteria not susceptible to other beta-lactams 8
- Avoid inappropriate use to reduce selective pressure for carbapenem-resistant Enterobacteriaceae 7
Tigecycline Limitations
Tigecycline should NOT be used for 7:
- Bloodstream infections (poor outcomes) 7
- Hospital-acquired/ventilator-associated pneumonia (poor outcomes) 7
- Infections caused by P. mirabilis (lacks in vitro activity) 2
Susceptibility Testing Essential
Always obtain susceptibility testing before initiating therapy 7: