It is hard to defend against, unless you want a system that constantly prompts you for your password everytime you want to do something. Frequent password prompts is not really good for security either. Current mitigations really just slow down the attacks and gives you time to respond. If they are left alone they will manage to gather credentials over time.
https://github.com/gentilkiwi/mimikatz https://www.sans.org/reading-room/whitepapers/detection/mimi...