If you can get an overnight direct flight out to your first City it really give you a full or nearly full day there - if you can sleep on a plane. We are not venturesome drivers, and I have heard from friends who did drive in Italy that they found the parking hard to find in places. I would opt for trains in Italy.
Totally agree about the driving in Italy. I lived in Europe and did drive to Venice and Florence (Venice more than once), but the train is really better unless you want to explore the countryside. In Venice, obviously, you park outside the city and leave your car, but we did this in Florence, as well. It's been many, many years ago and the parking was terrible then. I suggest trains. If you want to see the countryside, rent a car for a day on the outskirts.