Beta-lactamase inhibitors

General information

Beta-lactamases are genetically and structurally closely related to penicillin-binding proteins. Their production by bacteria is a major mechanism of resistance to the action of beta-lactam antibiotics. Drugs have therefore been developed that inhibit beta-lactamase, as a way of overcoming this resistance [ ]. They are beta-lactam compounds with particularly high affinities for beta-lactamases [ , ], which therefore act as competitive inhibitors of beta-lactamases. Beta-lactamase inhibitors have no important antimicrobial activity and are only given in combination with an antimicrobial beta-lactam.

The following beta-lactamase inhibitors are in use:

• clavulanic acid (rINN), produced naturally by Streptomyces clavuligerus , used in combination with amoxicillin or ticarcillin; the combination clavulanic acid + amoxicillin is also called co-amoxiclav (BAN);

• sulbactam (rINN), a halogenated derivative of penicillanic acid, used in combination with ampicillin or cefoperazone;

• tazobactam (rINN), a halogenated derivative of penicillanic acid, used in combination with piperacillin.

In order to improve absorption, sulbactam has also been bound to ampicillin in the single molecule sultamicillin, which is hydrolysed to the active components after absorption.

An inherent obstacle in evaluating the adverse effects of beta-lactamase inhibitors is that they are only co-administered with antimicrobial beta-lactams, the doses of which are usually several times higher. For the most part, combinations of beta-lactam antibiotics with beta-lactamase inhibitors produce the adverse effects of the individual drugs. However, it is not always possible to say whether an adverse effect is due to one drug alone or to the combination. For example, cholestatic hepatitis occurs more often with co-amoxiclav than with ampicillin alone; however, this could be because it is primarily due to clavulanic acid or because the combination somehow increases the risk.

Organs and systems