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Carbapenems: special properties contributing to their activity
Abstract:
Imipenem is a beta-lactam antibiotic that inhibits most clinical isolates of staphylococci, Enterobacteriaceae, and streptococci, excluding enterococci, at 1 microgram/ml or less. Resistance can develop in methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens, albeit infrequently. Pseudomonas maltophilia is intrinsically resistant to imipenem. Many strains of Enterobacter cloacae, Clostridium freundii, and S. marcescens resistant to the aminothiazolyl cephalosporins are susceptible to imipenem, but tend to have higher minimal inhibitory concentrations. In general, imipenem inhibits organisms resistant to other beta-lactams and aminoglycosides. Imipenem binds to PBP-2 and rapidly kills most bacteria which it inhibits. Imipenem is highly stable against attack by beta-lactamases of both plasmid and chromosomal origin, and is more stable by several thousand-fold than earlier beta-lactamase stable compounds. It acts as a suicide inhibitor of beta-lactamases. Imipenem does induce beta-lactamases, but the activity of imipenem against isolates containing induced beta-lactamases is not decreased and it appears not to be susceptible to the trapping that occurs with some of the cephalosporins. Imipenem acts synergistically with aminoglycosides against a wide variety of bacteria, but this is most readily demonstrated for Streptococcus faecalis, S. aureus, and P. aeruginosa organisms which show a difference between inhibition and killing. Overall, the excellent activity of imipenem is the result of (1) the lack of a permeability barrier; (2) high affinity for PBP-2, a critical protein in cell wall synthesis in gram-negative bacteria, and for critical penicillin-binding proteins of gram-positive species; and, above all, (3) its great beta-lactamase stability.
Insights
Imipenem, a potent beta-lactam antibiotic, effectively inhibits many bacteria, including resistant strains. Its stability against beta-lactamases and high affinity for essential bacterial proteins contribute to its broad-spectrum efficacy.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Imipenem is a broad-spectrum beta-lactam antibiotic.
- It exhibits activity against a wide range of bacteria, including Gram-positive and Gram-negative pathogens.
- Understanding its mechanism of action and resistance patterns is crucial for effective clinical use.
Purpose of the Study:
- To evaluate the in vitro activity of imipenem against various bacterial isolates.
- To investigate the mechanisms underlying imipenem's efficacy and potential resistance.
- To assess the synergistic effects of imipenem with other antibiotics.
Main Methods:
- In vitro susceptibility testing against clinical isolates of staphylococci, Enterobacteriaceae, streptococci, and Pseudomonas species.
- Determination of minimal inhibitory concentrations (MICs).
- Assessment of beta-lactamase stability and interaction with bacterial penicillin-binding proteins (PBPs).
Main Results:
- Imipenem inhibited most staphylococci, Enterobacteriaceae, and streptococci at low concentrations (≤1 µg/ml), excluding enterococci.
- Resistance was infrequently observed in methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens.
- Pseudomonas maltophilia demonstrated intrinsic resistance.
- Many cephalosporin-resistant strains were susceptible to imipenem, albeit with higher MICs.
- Imipenem exhibited high stability against plasmid and chromosomal beta-lactamases, acting as a suicide inhibitor.
- Synergistic activity was observed with aminoglycosides against certain bacteria, notably Streptococcus faecalis, S. aureus, and P. aeruginosa.
Conclusions:
- Imipenem possesses excellent broad-spectrum antibacterial activity due to its lack of a permeability barrier, high affinity for PBPs, and significant beta-lactamase stability.
- It remains effective against many organisms resistant to other beta-lactams and aminoglycosides.
- Imipenem's stability and unique mechanism make it a valuable therapeutic option, though resistance can emerge in specific pathogens.