Things to remember, lots of people come on forums just to post about problems, think of the large number of cars that never have any issues. Most of the issues could be the fact that they're not getting the oil burning lump hot on short trips.
They have issues but are easy to spot, if its got a full history lexus will warranty the engine till 140k or 7 years, so you could say they're a better buy as you've got a level of factory cover.
MPG wise, I seem to average about 45mpg on the motorway and 39ish around town. Last tank did 550 miles, that was all motorway and about 2.5hours central london, 44mpg. They've not got a big tank(should be 80ltrs really).
6th is fine at 70 unless you've got big hills etc, I tend to do 75 in 5th where there's no vibration/noise. A lot more midrange stomp than a is250 but not as smooth at lower speeds.
For what its worth I had a is250 on test and got 31mpg over a 200mile journey(which I thought was good for a 2.5 auto), the 220d did 42mpg on the same journey the following day.
If you're doing the miles the 220d is the best bet, if you're not the cheaper is250 would be the better bet.