A resurgence of β-lactamase inhibitor combinations effective against multidrug-resistant Gram-negative pathogens.
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.
Indiana University, Bloomington, IN, USA. Electronic address: karbush@indiana.edu.
Karen
K
Bush
D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000639:trends; D004359:Drug Therapy, Combination / Q000379:methods; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000201:enzymology*; D016905:Gram-Negative Bacterial Infections / Q000453:epidemiology / Q000382:microbiology*; D006801:Humans; D065093:beta-Lactamase Inhibitors / Q000627:therapeutic use*; D047090:beta-Lactams / Q000627:therapeutic use
D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
Carbapenemase; ESBL; Gram-negative; MBL; β-Lactam; β-Lactamase inhibitor