Neglected class A carbapenemases: Systematic review of IMI/NmcA and FRI from a One Health perspective.

Carbapenemase-producing Enterobacterales are pathogens classified as a critical priority by the World Health Organization and a burden on human health worldwide. IMI, NmcA, and FRI are under-detected class A carbapenemases that have been reported in the human, animal and environmental compartments, particularly these last 5 years. Bacteria producing these carbapenemases have been mostly identified in digestive carriage screenings, but they are also involved in severe infections, such as bacteremia. Their increasing detection in wild fauna and natural environments confirms their ubiquitous nature. Indeed, they have been especially found in aquatic ecosystems and in many animals living in close association with them. Therefore, the hydric compartment is suspected to be the main reservoir of IMI carbapenemases. Although they are almost confined to Enterobacter cloacae complex species, some variants are plasmid-encoded and may diffuse to other bacterial species that are more virulent or more adapted to humans. Furthermore, their association with other resistance mechanisms, such as Extended Spectrum Beta-Lactamases, leaves only few therapeutic options and raises concerns about the environmental spread of Multi-Drug-Resistant bacteria. These carbapenemase might be responsible of "mixed" outbreaks of CPE with a community origin and a possible secondary nosocomial spread. Therefore, more studies from a One Health perspective are needed to identify as many primary environmental (aquatic) reservoirs as possible, as well as secondary distribution routes (directly from the environment, via the food chain or animals…) which may also become secondary reservoirs for these carbapenemases, in order to implement measures to combat this potential emerging threat to humans. This review summarizes the main characteristics of the IMI, NmcA, and FRI carbapenemases, covering their detection, epidemiology, genetic environment, and associated resistance genes using a One Health approach.