Mechanism of Action and Structural Features
Carbapenems have a unique chemical structure: in their thiazolidine ring, the sulfur atom is replaced by a carbon atom. This key difference from classical penicillins provides them with exceptionally high resistance to degradation by $\beta$-lactamases.
The drug mechanism is bactericidal. It occurs through several sequential steps:
- Due to structural similarity to the D-alanyl-D-alanine terminal of bacterial cell wall peptidoglycan, the antibiotic binds to specific penicillin-binding proteins (PBPs).
- Inhibition of vital enzymes, particularly transpeptidases, occurs.
- Peptidoglycan cross-linking (which forms the structural backbone of the bacterial cell wall) is disrupted.
- Bacterial autolytic enzymes are activated.
- The cell wall suffers irreversible damage, leading to bacterial cell lysis and death.
Clinical Positioning
Carbapenems possess an ultra-broad spectrum of activity. They eradicate Gram-positive and Gram-negative pathogens, including aerobes and anaerobes, as well as strains resistant to 3rd- and 4th-generation cephalosporins.
In clinical practice, these are reserve antibiotics. Their primary indication is the treatment of severe, including healthcare-associated (nosocomial), infections caused by multidrug-resistant strains. However, in life-threatening conditions, carbapenems can be used as first-line agents for empirical therapy.
It is important to remember gaps in their spectrum of activity. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Legionella species possess intrinsic resistance to carbapenems.
Characteristics of Main Agents
- Imipenem: A derivative of thienamycin (produced by Streptomyces cattleya). Its main pharmacokinetic limitation is rapid degradation in renal tubules by the specific enzyme dehydropeptidase I. Because of this, therapeutic concentrations are not achieved in urine, making monotherapy ineffective. The solution is a fixed-dose combination with cilastatin (trade name: Primaxin). Cilastatin has no antibacterial activity itself but inhibits renal dehydropeptidase I, maintaining active imipenem levels in the urinary tract and systemic circulation. It is administered intravenously 3–4 times daily. In the presence of meningeal inflammation, it penetrates the blood-brain barrier (BBB) well.
- Meropenem: Unlike imipenem, it is stable against renal dehydropeptidase I and is therefore administered as monotherapy. It is more active against Gram-negative bacteria but slightly less potent against Gram-positive cocci. It is administered intravenously (infusion or bolus). It is not indicated for bone and joint infections.
- Ertapenem (Invanz): Its main advantage is a long elimination half-life, allowing once-daily administration (IV or IM). However, unlike other carbapenems, it lacks significant activity against non-fermenting Gram-negative bacilli (Pseudomonas aeruginosa and Acinetobacter species).
Safety Profile and Drug Interactions
Carbapenems can cause standard allergic hypersensitivity reactions, nausea, vomiting, and local reactions (phlebitis at the injection site). Hematologic adverse effects include eosinophilia, leukopenia, and neutropenia.
A specific central nervous system (CNS) side effect is seizures. This neurotoxicity/epileptogenic activity is characteristic of imipenem (especially in high doses or renal failure), but is significantly lower with meropenem.
Drug Interactions:
- Probenecid can increase plasma concentrations of meropenem by inhibiting renal tubular secretion.
- All three agents (imipenem, meropenem, ertapenem) significantly decrease serum levels of valproic acid (sodium valproate). This requires caution when prescribing carbapenems to patients with epilepsy due to the risk of breakthrough seizures.