Heat oven to 350°F. Grease a 9x13-inch baking dish.
Bring a large pot of salted water to a boil.
Boil macaroni until just shy of al dente. Drain well.
Stir panko with melted butter and Parmesan in a bowl. Set aside.
Melt 5 tablespoons butter in a saucepan over medium heat.
Whisk in flour and cook, whisking, until foamy and blond, about 2 minutes.
Slowly pour in milk and cream, whisking constantly until smooth.
Simmer, stirring, until thick enough to coat a spoon.
Season with salt, pepper, garlic powder, onion powder, mustard, paprika, and cayenne.
Remove from heat. Stir in cheddar, Gruyère, and cream cheese until silky.
Fold cooked pasta into the sauce until evenly coated.
Spread mixture into the prepared dish. Top with buttery panko.
Bake until bubbling and golden on top, 20 to 25 minutes.
Rest 10 minutes. Garnish with parsley and serve warm.