Carbapenem

Structure of the carbapenem backbone

Carbapenems are a class of β-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally derived product of Streptomyces cattleya.

Carbapenems are one of the antibiotics of last resort for many bacterial infections, such as Escherichia coli (E. coli) and Klebsiella pneumoniae. Recently, alarm has been raised over the spread of drug resistance to carbapenem antibiotics among these coliforms, due to production of the New Delhi metallo-β-lactamase, NDM-1. There are currently no new antibiotics in the pipeline to combat bacteria resistant to carbapenems, and worldwide spread of the resistance gene is considered a potential nightmare scenario.

Examples

The following drugs belong to the carbapenem class:

• Imipenem, generally given as part of Imipenem/cilastatin (FDA approval 1985)
  • Imipenem can be hydrolysed in the mammalian kidney by a dehydropeptidase enzyme to a nephrotoxic metabolite, and so is given with a dehydropeptidase inhibitor, cilastatin
• Meropenem (FDA approval 1996)
• Ertapenem (FDA approval 2001, since approved for multiple indications, )
• Doripenem (FDA Approval 2007)
• Panipenem/betamipron (Japanese approval 1993)
• Biapenem (Japanese approval 2001)

Unapproved/experimental

• Razupenem (PZ-601)
  • PZ-601 is a carbapenem antibiotic currently being tested as having a broad spectrum of activity including strains resistant to other carbapenems. Despite early PII promise, Novartis (who acquired PZ-601 in a merger deal with Protez Pharmaceuticals) recently dropped PZ-601, citing a high rate of adverse events in testing.

• Tebipenem

Uses

These agents have the broadest antibacterial spectrum compared to other β-lactam classes such as penicillins and cephalosporins. In addition, they are generally resistant to the typical bacterial enzyme, β-lactamase, which is one of the principal β-lactam resistance mechanisms of bacteria. However, in the United States and United Kingdom, strains of carbapenem-resistant enteric bacteria have been isolated from patients having received recent medical care in Pakistan, Bangladesh, and India. These strains carry a gene called New Delhi metallo-β-lactamase (shortened NDM-1) that is responsible for the production of a metallo-β-lactamase enzyme that hydrolyses carbapenem.

Carbapenems are active against both Gram-positive and Gram-negative bacteria, and anaerobes, with the exception of intracellular bacteria (atypicals), such as the Chlamydiae. Carbapenems also are thus far the only β-lactams capable of inhibiting l,d-transpeptidases

Structure

In terms of structure, the carbapenems are very similar to the penicillins (penams), but the sulfur atom in position 1 of the structure has been replaced with a carbon atom, and an unsaturation has been introduced—hence the name of the group, the carbapenems.

Biosynthesis

The carbapenems are thought to share their early biosynthetic steps in which the core ring system is formed. Malonyl-CoA is condensed with glutamate-5-semialdehyde with concurrent formation of the five-membered ring. Next, a β-lactam synthetase uses ATP to form the β-lactam and the saturated carbapenam core. Further oxidation and ring inversion provides the basic carbapenem.

Administration

Due to their expanded spectra, the desire to avoid generation of resistance and the fact that, in general, they have poor oral bioavailability, they are administered intravenously in hospital settings for more serious infections. However, research is underway to develop an effective oral carbapenem.

See also

• Faropenem is closely related, but it is a penem, not a carbapenem.

External links

• Structure Activity Relationships "Antibacterial Agents; Structure Activity Relationships," André Bryskier MD; beginning at pp131
• Page 2: Ertapenem vs. Meropenem: Equivalency of Clinical and Microbiological Outcomes. 2010