Beta-Lactam/Beta-Lactamase Inhibitor Combinations

Agents: ampicillin/sulbactam, amoxicillin/clavulanate, piperacillin/tazobactam, ticarcillin/clavulanate

Though the aminopenicillins and antipseudomonal penicillins have good intrinsic activity against GNRs, they remain just as susceptible to beta-lactamases as penicillin G. This means that they are not useful against the vast majority of staphylococci or many GNRs and anaerobes, because these organisms have learned to produce beta-lactamase.   In other words, it seemed we learned either how to make a penicillin resistant to beta-lactamase, or how to make it more active against GNRs, but not both. Beta-lactamase inhibitors counter beta-lactamases; these drugs mimic the structure of beta-lactams but have little antimicrobial activity on their own. They bind to beta-lactamases irreversibly, preventing the beta-lactamase from destroying any beta-lactams that are co-administered and enabling the therapeutic beta-lactam to be effective.

When considering the activity of the beta-lactam/beta-lactamase inhibitor combination, re-member that the beta-lactamase inhibitor only frees up the beta-lactam to kill the organism—it doesn’t enhance the activity. Therefore, the combination products are active only against the bacteria that the beta-lactam in the combination has intrinsic activity against. For example, ampicillin/sulbactam is active against beta-lactamase producing  E. coli, because ampicillin alone is active against non-beta-lactamase producing E. coli. However, it has no useful activity against  Pseudomonas aeruginosa, because ampicillin lacks activity against this organism. In contrast, piperacillin/tazobactam is active against  P. aeruginosa because piperacillin alone is useful.  Though these drugs have very broad spectra of activity, there are differences among the agents. Keep in mind the rule that beta-lactamase inhibitors restore activity, not add to it, to set them straight.

Spectrum

Good: MSSA, streptococci, enterococci, many an-aerobes, enteric GNRs,  Pseudomonas aeruginosa (only piperacillin/ tazobactam and ticarcillin/clavulanate)

Moderate: GNRs with advanced beta-lactamases

Poor : MRSA, extended-spectrum beta-lactamase (ESBL) producing GNRs

Adverse Effects

Similar to those of other beta-lactams.

Important Facts

• Unlike the other members of this class, amoxicillin/clavulanate is available orally. Various doses are available, but higher doses are associated with more diarrhea.

• The beta-lactamase inhibitors packaged in these combinations are not active against all beta-lactamases. New beta-lactamases with the ability to destroy many types of beta-lactams are continually being discovered and are becoming more prevalent.

• Except for study purposes, beta-lactamase inhibitors are not available outside of the combination products.

• Sulbactam has good activity against  Acinetobacter baumannii, a highly drug-resistant GNR that causes nosocomial infections. For this reason, high doses of ampicillin/sulbactam can be used in the treatment of infections caused by this organism.

What They’re Good For

Empiric therapy of nosocomial infections, particularly nosocomial pneumonia (not aminopenicillin-based combinations). Because they have activity against aerobes and anaerobes, they are a good empiric choice for mixed infections, such as intra-abdominal infections, diabetic ulcers, and aspiration pneumonia.

 Don’t Forget!

Narrow your coverage once culture results return. These are good choices of empiric therapy, but poor choices of definitive therapy if alternatives are available. Be sure you know which drugs are antipseudomonal and which are not—this is a major difference among these agents that drives their use. Ampicillin/sulbactam is a poor choice for nosocomial pneumonia, and piperacillin/tazobactam is overkill for community-acquired pneumonia.

References

Gallagher ,J.C. and MacDougall ,c. (2012). Antibiotics Simplified. Second Edition. Jones & Bartlett Learning, LLC.