Thienamycin: development of imipenen-cilastatin

Area of Science:

• Microbiology
• Pharmacology
• Medicinal Chemistry

Background:

• Thienamycin, a carbapenem antibiotic, showed potent activity but suffered from instability.
• Development of N-formimidoyl thienamycin (imipenem) addressed stability issues, creating a potent broad-spectrum antibiotic.
• Imipenem exhibits high activity against Gram-positive and Gram-negative bacteria, including resistant strains like Pseudomonas aeruginosa.

Purpose of the Study:

• To introduce imipenem as a stable carbapenem antibiotic with superior properties to thienamycin.
• To investigate the broad antimicrobial spectrum and potency of imipenem.
• To address the renal metabolism of imipenem and introduce cilastatin as a solution.

Main Methods:

• Synthesis of N-formimidoyl thienamycin (imipenem) from thienamycin.
• Evaluation of imipenem's antibacterial spectrum and activity against various bacterial species.
• Identification of dehydropeptidase-I as the enzyme responsible for imipenem's renal metabolism.
• Development and pharmacokinetic evaluation of cilastatin (MK0791) as a dehydropeptidase inhibitor.

Main Results:

• Imipenem demonstrated significantly improved stability and a broader antibacterial spectrum than thienamycin.
• Imipenem showed high bactericidal activity against resistant pathogens and was refractory to bacterial beta-lactamases.
• Renal metabolism of imipenem was identified, leading to low urinary recovery.
• Cilastatin effectively inhibited dehydropeptidase-I, preventing imipenem metabolism and enhancing urinary concentrations.
• The imipenem/cilastatin combination eliminated imipenem-induced tubular necrosis in animal models.

Conclusions:

• The imipenem/cilastatin combination provides a stable, potent, and safe therapeutic option for difficult-to-treat infections.
• Cilastatin's co-administration optimizes imipenem's pharmacokinetic profile and safety, overcoming its metabolic liabilities.
• This combination represents a significant advancement in utilizing carbapenem antibiotics against a wide range of bacterial pathogens.