As Isaac is blindfolded, Isaac cannot use tears, and must rely entirely on Distant Admiration, Forever Alone, and bombs to deal damage.
Because Isaac starts with 3 Fly items, he will also begin the challenge as Beelzebub. This allows Isaac to amass a large number of friendly flies on the Basement floors.
The orbiting attack flies can be quite powerful, especially Distant Admiration when used properly. This will require optimization of Isaac's movement to maneuver into position to deal damage, as the flies are constantly moving, and avoid damage simultaneously.
Duct Tape can fix the position of the flies around Isaac, somewhat alleviating this.
Enemies that explode on death should only be targeted with Forever Alone, as destroying them with Distant Admiration will result in Isaac getting caught in their explosions.
Shops can carry BFFS! and Hive Mind, the former of which affects the damage of the orbiting attack flies and the latter of which affects the damage of the blue flies spawned from Beelzebub as well as the size of the orbiting attack flies.
Obtaining Gnawed Leaf makes the challenge trivial as Isaac's orbiting flies still deal damage while Isaac is invulnerable. Obtaining it is highly unlikely, however, since there is no treasure room present.