New β-lactam-β-lactamase inhibitor combinations in clinical development

Tazobactam was the most recent β‐lactamase inhibitor to be approved in 1993. Since the approval of piperacillin–tazobactam, the complexity of β‐lactamase–mediated resistance among Gram‐negative bacilli has increased enormously. After more than 20 years since the first such combination, amoxicillin–clavulanic acid, was approved, several new β‐lactam–β‐lactamase inhibitor combinations have reached late‐stage (phase II and beyond) clinical trials. These include ceftolozane–tazobactam (2:1, ratios of β‐lactam to β‐lactamase inhibitor in parentheses), ceftazidime–avibactam (4:1), ceftaroline–avibactam (1:1), and imipenem–cilastatin–MK‐7655 (2:2:1 and 4:4:1). Avibactam and MK‐7655 are diazabicyclooctane (DABCO) inhibitors and thus not β‐lactams themselves; they include class A carbapenemases and class C enzymes within their spectra of activity. Ceftolozane is an antipseudomonal cephalosporin, and tazobactam is used to protect it against extended spectrum β‐lactamases to which it is labile. Additional novel combinations are in preclinical development. This review will focus on the biochemistry, antimicrobial activity, pharmacodynamics, and clinical development of these novel combinations.