β-lactam/β-lactamase inhibitor combinations: from then to now

Abstract

Objective: To review the available evidence regarding the utility of the currently available β-lactam/β-lactamase inhibitor combinations (BLICs) as well as the emerging body of data for the novel agents in the pipeline.

Data sources: A MEDLINE literature search (1960-August 2014) was performed using the search terms β-lactamase, β-lactamase inhibitor, clavulanate, sulbactam, tazobactam, avibactam, NXL104, MK-7655, and RPX7009. Current studies focusing on new agents were obtained from clinicaltrials.gov. Additional references were identified from a review of literature citations and meeting abstracts.

Study selection and data extraction: All English-language studies pertaining to BLICs were evaluated.

Data synthesis: Historical clinical and in vitro data focusing on the characteristics of the conventional BLICs are reviewed. Avibactam, relebactam (formerly MK-7655), and RPX7009 are new β-lactamase inhibitors that are being studied in combination with β-lactams. Clinical and in vitro data that provide support for their use for multidrug-resistant organisms are reviewed. β-Lactam antibiotics are a mainstay for the treatment of many infections. The addition of β-lactamase inhibitors enhances their activity against organisms that produce β-lactamases; however, organisms that produce extended-spectrum β-lactamases, AmpC β-lactamases, and carbapenemases are proliferating. The BLICs (amoxicillin/clavulanate, ticarcillin/clavulanate, ampicillin/sulbactam, and piperacillin/tazobactam) lack activity against some of these enzymes, presenting a critical need for new antibiotics.

Conclusions: The historical BLICs are useful for many infections; however, evolving resistance limits their use. The new BLICs (combinations with avibactam, relebactam, and RPX7009) may be valuable options for patients infected with multidrug-resistant organisms.

Keywords: MK-7655; RPX7009; avibactam; bacterial resistance; carbapenemase; clavulanate; relebactam; sulbactam; tazobactam; β-lactamase; β-lactamase inhibitor.