Chemical and Microbiologic Aspects of Penems, a Distinct Class of β-Lactams: Focus on Faropenem

Jeremy M. T. Hamilton-Miller, D.Sc., FRCPath

Disclosures

Pharmacotherapy. 2003;23(11) 

In This Article

Mechanism of Action

The β-lactam ring interacts with the bacterial target proteins and is responsible for the antimicrobial activity of these molecules. The side chains and fused heterocyclic rings define the stereochemical and physicochemical differences between different β-lactams. These properties combine to contribute to the ability of the drug molecules to cross bacterial cell membranes (affecting access to bacterial targets, and hence spectra of activity), bind to serum proteins (affecting pharmacokinetics), bind to β-lactamase enzymes (affecting sensitivity to bacterial drug-resistance mechanisms and in vivo stability), and enter different body compartments.

Penems, like all β-lactams, enter the bacterial cell and bind to PBPs, preventing bacterial cell wall synthesis. Penems have a higher affinity for many PBPs than do many other β-lactams.[3] This is particularly noted for PBP2b, which may partly explain the good activity of penems against Streptococcus pneumoniae isolates with reduced sensitivity to penicillin G.[3] Penems tend to have a broader spectrum than do penicillins and cephalosporins[13]; this is due to their smaller size (typically around 300 daltons) and favorable ionization characteristics.[3,14] These factors allow them access to PBPs of both gram-positive and gram-negative bacteria.[3] Penems, like other β-lactams, can cause morphologic changes to susceptible bacteria and bactericidal effects.

An important property of penems is their resistance to the actions of β-lactamases of both bacterial and mammalian origin (the latter are known as dehydropeptidases [DHPs]). Bacterial production of β-lactamases constitutes their main mechanism of resistance to β-lactams and has limited the utility of some β-lactams, or necessitated coadministration with a β-lactamase inhibitor such as clavulanic acid to restore efficacy. Although such use of β-lactamase inhibitors has overcome resistance problems in some cases, some specific adverse effects have been noted for these agents (e.g., the cholestatic jaundice associated with amoxicillin plus clavulanic acid), and not all β-lactamase enzymes are inhibited. Agents that have inherent resistance to the action of β-lactamases without adverse effects would be of benefit. Although some penems, such as BRL 42715, are solely β-lactamase inhibitors, with no bactericidal effects, others, such as faropenem, offer dual bactericidal and β-lactamase inhibitory effects.

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