Answer: Very carefully. Sorry, I couldn't help myself.
Seriously - What I've learned from punishing my arse...
1 - Shorts which are too big are much worse than too small. I'm often in the middle of S and M sizing for shorts and now tend to just buy Small. A tight trampoline over your skin is better than loose fabric which can wrinkle.
2 - A good saddle is important, but it's probably 50-50 with the shorts. I don't like saddles with cutaways and deep ridges/valleys. It seems you want to minimize the force per unit area, so why remove material from the saddle? You want the force to be evenly distributed across what little area the saddle provides. Smooth top works best for me, but saddle shape can be both personal and an adaptive thing. I wouldn't experiment with a new shape without first having put in many miles on it. Too much padding is bad. Too little is also bad. But the 'right' saddle can be surprisingly firm and thinly padded.
3 - Another yes to all the above posting on good hygiene, for those equatorial regions of the body. If you're doing a multi-day event and choose to sleep at night, get out of the shorts and dry them. Apply something like A & D ointment to the high friction/pressure areas of your arse proactively. This comment will probably be controversial, but my experience shows that something dirt-cheap, like A & D or Desitin, seems to work just as well as the big-buck stuff. The thicker, the better. A high concentration of lanolin is good. The trick it to put it on before you have a raw ass.
4 - But in case you do get an infection, carry some triple-biotic. However, using it all the time might result in you having some type of resistant infection if you do get an infection.
5 - Unfortunately, a lot of saddle/shorts issues can only be avoided by more TITS - time in the saddle.
-Barry
PS Edit - Another vote for Fizik, but I'm using Aliante Gamma XM. If only Fizik could come up with simpler names, right. I can't afford Fiziks retail, so I snatch up the white ones when they go on sale. BTW, I'm 6'2" and ~165#.
...Or how do you wear 2 pair of shorts?...