The family just finished our first road trip of the year with the S4. About 600 miles round trip from Monroe, WA to the small town of Pilot Rock, OR. I averaged 30.1 MPG, but I'm sure it would have been better if I was driving the speed limit. It was a packed car with 3 adults and one kid, and still the ride was very good with the Solo-Werks coilovers.
I ran a can of BG 44k fuel system cleaner in the first tank just to keep everything in good shape. I normally run a fuel system treatment once every 6 months when I go on a long drive. EPL recommend this so I figured I give it a try. Honestly, I can't really tell any difference, but it's just preventative maintenance. My wife 2003 Toyota Highlander is having a high idle issue so I'm going to try a can in that car and see if it helps.
Anyway... all is good and looking forward to the Leavenworth Drive on June 15th!