What is the mechanism, indication, and potential complications of meropenem (carbapenem antibiotic)?

Meropenem: Mechanism, Indications, and Complications

Meropenem is a broad-spectrum carbapenem antibiotic that exerts its bactericidal activity through inhibition of bacterial cell wall synthesis by binding to penicillin-binding proteins, and is indicated for serious bacterial infections including complicated intra-abdominal infections, complicated skin and skin structure infections, bacterial meningitis, and as empirical therapy for multidrug-resistant organisms. 1

Mechanism of Action

• Meropenem's bactericidal activity results from inhibition of bacterial cell wall synthesis by penetrating the cell wall of most gram-positive and gram-negative bacteria to bind penicillin-binding protein (PBP) targets 1
• Specifically, meropenem binds to PBPs 2,3, and 4 of Escherichia coli and Pseudomonas aeruginosa, and PBPs 1,2, and 4 of Staphylococcus aureus 1
• Bactericidal concentrations are typically 1-2 times the bacteriostatic concentrations, achieving a 3 log10 reduction in bacterial counts within 12-24 hours 1
• Unlike other β-lactam antibiotics, carbapenems including meropenem have shown activity against extended-spectrum β-lactamase (ESBL)-producing and AmpC chromosomal β-lactamase-producing bacteria 2

Clinical Indications

• FDA-approved indications in the United States include:

  • Complicated intra-abdominal infections 3
  • Complicated skin and skin structure infections 1
  • Bacterial meningitis in pediatric patients ≥3 months of age 4

• Additional indications in other countries include:

  • Nosocomial pneumonia 4
  • Septicemia/bloodstream infections 4
  • Febrile neutropenia 4
  • Complicated urinary tract infections 4
  • Severe community-acquired pneumonia 4
  • Pulmonary exacerbations in cystic fibrosis patients 4

• Meropenem is particularly valuable for infections caused by carbapenem-resistant organisms:

  • Meropenem-vaborbactam is recommended for carbapenem-resistant Enterobacteriaceae (CRE) bloodstream infections 5
  • In combination with colistin for carbapenem-resistant Acinetobacter baumannii (CRAB) infections 5

Dosing Considerations

• Standard dosing is 1 gram IV every 8 hours for most serious infections 3
• For carbapenem-resistant Enterobacteriaceae (CRE) infections:
  • Extended infusion (3 hours) of 1 gram IV every 8 hours is recommended 3
  • For high MIC value (≥16 mg/L) KPC-producing K. pneumoniae infections, 2 grams IV every 8 hours with 3-hour prolonged infusion may be used 3
• Dosage adjustment is necessary in patients with creatinine clearance ≤50 mL/min 1
• Pediatric dosing varies by age and weight 1

Antimicrobial Spectrum

• Gram-positive bacteria (susceptible isolates):

  • Enterococcus faecalis (vancomycin-susceptible isolates only)
  • Staphylococcus aureus (methicillin-susceptible isolates only)
  • Streptococcus species including S. pneumoniae (penicillin-susceptible) 1

• Gram-negative bacteria:

  • Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae
  • Neisseria meningitidis, Proteus mirabilis, Pseudomonas aeruginosa 1
  • More active against Pseudomonas aeruginosa and Enterobacteriaceae compared to imipenem 6

• Anaerobic bacteria:

  • Bacteroides fragilis, Bacteroides thetaiotaomicron, Peptostreptococcus species 1

• Notable resistant organisms:

  • No activity against methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant Staphylococcus epidermidis (MRSE) 1
  • Limited activity against Enterococcus faecium 6

Complications and Adverse Effects

• Most common adverse events:

  • Diarrhea (2.5%)
  • Rash (1.4%)
  • Nausea/vomiting (1.2%) 7

• Neurological complications:

  • Low incidence of seizures (0.07%) in non-meningitis infections 7
  • Lower propensity for seizures compared to imipenem, making it suitable for treating bacterial meningitis 4

• Potential for development of resistance:

  • Mechanisms include decreased outer membrane permeability, reduced affinity of target PBPs, increased efflux pump expression, and production of carbapenemases or metallo-β-lactamases 1
  • Inappropriate use can lead to selection of carbapenem-resistant organisms 8

• Special populations:

  • No dosage adjustment needed for hepatic impairment 1
  • Dosage adjustment required for renal impairment 1
  • Elderly patients may require dose adjustment due to age-associated reduction in creatinine clearance 1

Clinical Pearls and Pitfalls

• Meropenem is hemodialyzable, but there is limited information on the usefulness of hemodialysis to treat overdosage 1
• Extended or continuous infusions are recommended for critically ill patients with healthcare-associated infections to optimize pharmacodynamic targets 3
• For carbapenem-resistant infections, combination therapy (e.g., with colistin) may be beneficial in severely ill patients 5
• Probenecid competes with meropenem for active tubular secretion, increasing systemic exposure by 56% and elimination half-life by 38% 1
• In vitro tests show meropenem may act synergistically with aminoglycosides against some isolates of Pseudomonas aeruginosa 1
• Meropenem does not require co-administration with a renal dehydropeptidase inhibitor (unlike imipenem) due to its stability to human dehydropeptidase-I 9