β‐Lactamase Inhibitor Combinations with Extended‐Spectrum Penicillins: Factors Influencing Antibacterial Activity against Enterobacteriaceae and Pseudomonas aeruginosa

Production of β‐lactamases is the most common mechanism by which gram‐negative bacteria express resistance to β‐lactam antibiotics. One successful method of circumventing the threat of plasmid‐encoded β‐lactamases is to combine inhibitors of these enzymes with a penicillin. Currently, four inhibitor‐penicillin combinations are in clinical use: ampicillin‐sulbactam, amoxicillin‐clavulanate, ticarcillin‐clavulanate, and piperacillin‐tazobactam. Of these, ticarcillin‐clavulanate and piperacillin‐tazobactam have the broadest spectra of activity that includes Pseudomonas aeruginosa. Many factors influence the activity and pharmacodynamics of these combinations, including potency of both agents, pharmacokinetics of the inhibitor, type and quantity of β‐lactamase produced by the target bacterium, and potential for the inhibitor to induce expression of chromosomal cephalosporinases in the target bacterium. Although ticarcillin‐clavulanate and piperacillin‐tazobactam have similar spectra of activity, they have many differences. Most notable are increased potency of piperacillin against Enterobacteriaceae and P. aeruginosa , increased activity of piperacillin‐tazobactam against gram‐negative pathogens producing penicillin‐sensitive enzyme (PSE)‐class β‐lactamase or hyperproducing other plasmid‐encoded β‐lactamases, and the more favorable pharmacokinetics of tazobactam. In the treatment of P. aeruginosa infections, the potential for clavulanate to induce expression of chromosomal cephalosporinase and antagonize antibacterial activity of ticarcillin is a concern, especially in patients who lack protective host defenses. These are not concerns with piperacillin‐tazobactam.