β-Lactamase inhibitors (BLIs) have played an important role in combatting β-
lactam resistance in Gram-negative bacteria, but their effectiveness has diminished with the evolution of diverse and deleterious varieties of β-lactamases. In this review, a new generation of BLIs and inhibitor combinations is presented, describing epidemiological information, pharmacodynamic studies, resistance identification and current clinical status. Novel
serine BLIs of major interest include the non-β-
lactams of the diazabicyclo[3.2.1]octanone (DBO) series. The DBOs
avibactam,
relebactam and
RG6080 inhibit most class A and class C β-lactamases, with selected inhibition of class D
enzymes by
avibactam. The novel
boronic acid inhibitor
RPX7009 has a similar inhibitory profile. All of these inhibitors are being developed in combinations that are targeting primarily
carbapenemase-producing Gram-negative pathogens. Two BLI combinations (
ceftolozane/tazobactam and
ceftazidime/avibactam) were recently approved by the US Food and Drug Administration (FDA) under the designation of a Qualified
Infectious Disease Product (QIDP). Other inhibitor combinations that have at least completed phase 1 clinical trials are
ceftaroline fosamil/
avibactam,
aztreonam/
avibactam,
imipenem/
relebactam,
meropenem/
RPX7009 and
cefepime/
AAI101. Although effective inhibitor combinations are in development for the treatment of
infections caused by Gram-negative bacteria with
serine carbapenemases, better options are still necessary for pathogens that produce metallo-β-lactamases (MBLs). The
aztreonam/
avibactam combination demonstrates inhibitory activity against MBL-producing enteric bacteria owing to the stability of the
monobactam to these
enzymes, but resistance is still an issue for MBL-producing non-fermentative bacteria. Because all of the inhibitor combinations are being developed as parenteral drugs, an orally bioavailable combination would also be of interest.