New antibiotics and antimicrobial combination therapy for the treatment of gram-negative bacterial infections.

Abstract

Increasing rates of life-threatening infections due to multidrug-resistant (MDR) gram-negative bacteria, such as carbapenemase-producer strains, as well as pathogens that are resistant to all current therapeutic options, have been reported. The number of compounds that are currently being developed is still insufficient to control this global threat. We have reviewed the current available options for the treatment of MDR gram-negative infections, including combination regimens employing older antimicrobials and new compounds. A limited number of large trials have assessed the treatment options for commonly encountered resistant pathogens (e.g., Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa). Antimicrobials that were used in the past, such as colistin and fosfomycin, have been recently resumed and used in association with carbapenems, tigecycline, or aminoglycosides, showing a positive impact on clinical outcomes. New compounds belonging to various antimicrobial classes (e.g. beta-lactamase inhibitors, cephalosporins, glycyclines, aminoglycosides) have been investigated. Only few new molecules have an adequate activity against MDR gram-negative pathogens, especially carbapenemase-producer strains. Among these, ceftozolane/tazobactam has been recently approved for clinical use. Other compounds, such as avibactam combinations, plazomicin, and eravacycline, have shown promising activity in phase 2 and 3 clinical trials.