BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID, SULBACTAM, & TAZOBACTAM)
These substances resemble β-lactam molecules (Figure 43–7), but they have very weak antibacterial action. They are potent inhibitors of many but not all bacterial β lactamases and can protect hydrolyz-able penicillins from inactivation by these enzymes. Beta-lactamase inhibitors are most active against Ambler class A β lactamases (plasmid-encoded transposable element [TEM] β lactamases in particular), such as those produced by staphylococci, H influenzae, N gonorrhoeae, salmonella, shigella, E coli, and K pneumoniae. They are not good inhibitors of class C β lactamases, which typically are chromosomally encoded and inducible, produced by Enterobacter sp, Citrobacter sp, S marcescens, and P aeruginosa, but they do inhibit chromosomal β lactamases of B fragilis and M catarrhalis.
The three inhibitors differ slightly with respect to pharmacol-ogy, stability, potency, and activity, but these differences usually are of little therapeutic significance. Beta-lactamase inhibitors are available only in fixed combinations with specific penicillins. The antibacterial spectrum of the combination is determined by the companion penicillin, not the β-lactamase inhibitor. (The fixed combinations available in the USA are listed in Preparations Available.) An inhibitor extends the spectrum of a penicillin pro-vided that the inactivity of the penicillin is due to destruction by
lactamase and that the inhibitor is active against the β lactamase that is produced. Thus, ampicillin-sulbactam is active against β-lactamase-producingS aureusandH influenzaebut not againstserratia, which produces a β lactamase that is not inhibited by sulbactam. Similarly, if a strain of P aeruginosa is resistant to piperacillin, it is also resistant to piperacillin-tazobactam because tazobactam does not inhibit the chromosomal β lactamase pro-duced by P aeruginosa.
The indications for penicillin-β-lactamase inhibitor combina-tions are empirical therapy for infections caused by a wide range of potential pathogens in both immunocompromised and immu-nocompetent patients and treatment of mixed aerobic and anaero-bic infections, such as intra-abdominal infections. Doses are the same as those used for the single agents except that the recom-mended dosage of piperacillin in the piperacillin-tazobactam combination is 3–4 g every 6 hours. Adjustments for renal insuf-ficiency are made based on the penicillin component.