I've started experiencing long save times and increased save file size after using destroyallnpcs and destroyalltownies repeatedly. The file size suddenly went up from approximately 30 MB to over 60 MB. I tried clearing inventories and wishes, but it didn't help.
Tired of waiting ten minutes for each save, I saved all households to the bin and inserted them into a new, identical neighbourhood, after using therapture so I wouldn't have any duplicate sims (I had some of the townies and npcs married to my sims). In 5 sim days, I've played each family a bit, and the save file size is a reasonable 31 MB and takes 15-20 seconds to save. All this without changing my mod configuration.
Also, I've noticed that when playing the borked neighbourhood, the game doesn't run nearly as smooth as when playing the new one, especially on the higher speeds (ultra speed is actually slower than double speed). Additionally, if use dresser or plan outfit more than once before quitting and restarting the game, I get error code 12 for sure every time I try to save. This doesn't happen in the new neighbourhood, though.