Luggage left in car while changing accommodation- tuscany&puglia

First off I’ll say that many of us have taken this risk, I did it all over Puglia despite the warnings, but I’ve seen the accounts enough to know this is a real risk. I’m concerned about the CPAP for obvious reasons. If they’ll take your dirty laundry, they’ll take medical equipment.
1) are you driving after an intl flight? An hour is not that bad in my experience, but making stops can heighten the tiredness. I swore we’d never make stops again after my husband got sleepy when we tried to do too much on arrival. Never had that problem when just driving straight to an accommodation.
However, the easy solution is to just do lunch. Find a countryside place, where your car will be parked right outside, not in a distant lot while you wander.
You’ve got some pretty long drives, but Locorotondo to Otranto is not that long, less than half that.

We will have been in Florence for a few nights before we get the rental.

Okay great, you’d be surprised how many people plan to drive for hours on arrival.
May have strategies they try to employ—back in parking, etc. but it’s just a risk assessment to work around at your comfort level. Annoying to be sure!
I will say I have not been concerned in tiny villages as I would in a city, but I do suppose it can happen anywhere.

SR222
Here are some restaurant suggestions. They are safe locations, but just in case take valuable (including the CPAP) inside the restaurant with you.
Ristorante da Padellina (Strada in Chianti), parking next to it.
Locanda il Gallo (Chiocchio) parking in front across the street.
There are also several in Greve, in Piazza Matteotti, like La Bottega del Moro, but parking may be an issue in the piazza, so you might have to park away, with your car totally out of sight.
La Fattoria di Vignamaggio (Panzano) parking in premises, out of town in the country.
Rosticceria il Re Gallo - This one is in the historical center of Castellina. There are a lot of restaurants within feet from this one, and all of them are good, like Squarcialupi, Sotto le Volte, La Torre, etc.. The only issue with all of these is that you may not be able to park next to them, since it's the historical center closed to car, but only in the parking lot in front of the city hall offices or the parking behind the Coop supermarket. In which case the car will be out of your sight.
Osteria di Fonterutoli in Castellina but a bit out of town in the country, so plenty of parking in premises.
I gave you only some I know, but there are so many.

From Siena to Orvieto are you going by freeway?
If you take the freeway, then I would stop at an autogrill restaurant at a freeway service area.

Like this one.

If not the freeway, where do you intend to go? Take the Via Cassia (SS2)?
I haven't gone there for a very long time, so don't recall restaurants I've tried.

Orvieto to Matera takes all day (7 hours) by freeway. So I would stay on the freeway and stop only at Autogrill, or Sarni, or Chef Express (these are the restaurants chains on the freeway rest stop, or AREA DI SERVIZIO).

Matera to Locorotondo it's less than 1.5 hours. Just get to destination, no reason to stop. Once in Locorotondo and drop the bags you can see Alberobello, Martina Franca, Ostuni, Polignano, Monopoli, etc. on separate day trips.

Locorotondo to Otranto is not 5 hours. It's probably two hours at most. Just get to destination, drop the bags, and use Otranto for your day trip to Lecce, or also Gallipoli. Otranto is a gem, so enjoy the town. If you can't drop the bag until late (is it an AirbnB?), then you could stop in Ostuni along the way, if you haven't visited while in Locorotondo. Or you can swing by Gallipoli. But in both cases you need to park the car outside the historical center (Ostuni at the bottom of the hill, while in Gallipoli at the harbor), so the car won't be within sight. In Ostuni I parked here and there was an attendant, so maybe safer. But Gallipoli it's unguarded lot at the Port of Gallipoli.

Luggage in the car is always a concern. It's one reason we try to use bases for travel and do day trips rather than moving on more frequently. I advise never opening the trunk when you've parked to visit a town. Pull over a mile or two before you arrive and get anything out that you might need. If someone with bad intentions is watching the parking lot and you go to the trunk then you've just shown them a sure thing.

Thank you for all the suggestions for the SR 222 dining, lots to look up. We will definitely not be taking the freeway to Orvieto, so I will look into small places along the way. I forgot to add we plan on stopping at an auto grill on way to Matera from Orvieto. I am very happy we can drop luggage in Locorotondo early, that makes the afternoon much easier to enjoy. I do realize the drive to Otranto will not be that long, we are just stuck with our luggage in the car for 5 hours- first world problems, I know.

We never go into the back, at the parking lot. Well I never do, my spouse doesn't always listen to "directions" during the packing of the car. I know we could have stayed in one spot and done more driving daily, but I really want to experience different places in the early morning and the evening.

if you go in summer, just hang at the beach in Otranto.
Go to this place below and have lunch on the beach until you can check in at your airbnb.
I go here all the time, great beach and their seafood restaurant is not bad at all. I usually park at my hotel walking distance from it, but they have parking here if I remember correctly. I think it's safe, but as a precaution take the valuables with you.

https://maps.app.goo.gl/JU1xQHizHeF2boi17