title: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  All English-language studies pertaining to BLICs were evaluated.
  
  
  RESULTS
  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.
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA toussaka@temple.edu.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Toussaint
authors.affiliation: Temple University School of Pharmacy, Philadelphia, PA, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gallagher
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000378:metabolism; D004359:Drug Therapy, Combination; D006801:Humans; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000627:therapeutic use*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C048795:AmpC beta-lactamases; D001618:beta-Lactamases; C063912:carbapenemase
keywords: MK-7655; RPX7009; avibactam; bacterial resistance; carbapenemase; clavulanate; relebactam; sulbactam; tazobactam; β-lactamase; β-lactamase inhibitor