Avibactam-based combinations for the treatment of multidrug resistant Gram-negative bacilli infections

The approach to multidrug-resistant (MDR) Gram-negative bacilli (GNB) infections has changed following the introduction of avibactam-based β-lactam/β-lactamase inhibitor combinations. Ceftazidime/avibactam has become a cornerstone for the treatment of infections caused by KPC-producing Enterobacterales, whereas the recent availability of aztreonam/avibactam has provided the first targeted option against metallo-β-lactamase (MBL)-producing Enterobacterales. At the same time, the emergence of KPC variants, the increasing dissemination of MBLs and the growing complexity of resistance mechanisms have made both empirical and targeted therapeutic decisions increasingly challenging. This narrative review summarizes the current evidence regarding the microbiological activity, clinical efficacy and optimal place in therapy of avibactam-based combinations. Ceftazidime/avibactam is a cornerstore for the treatment of KPC infections, and significantly modified the outcome of patients with KPC infections during the last decade. Robust observational studies demonstrated its clinical efficacy and safety. It may also represent a carbapenem-sparing option for treating infections due to difficult-to-treat ESBL- and OXA-48-producing Enterobacterales. Moreover, its activity against MDR Pseudomonas aeruginosa makes it an attractive option for empirical therapy in patients with risk factors for this non-fermenting GNB. Aztreonam/avibactam represents the first-line option for the treatment of MBL-producing Enterobacterales and plays a pivotal role in the current era of increasing dissemination of multiple carbapenemases. Their optimal clinical positioning should rely on optimal use in empirical therapy in patients with rectal colonization with carbapenem-resistant Enterobacterales who develop sepsis or septic shock, antimicrobial stewardship principles and integration of local epidemiology, microbiological data and patient characteristics to maximize efficacy while preserving their long-term activity.