Otherwise a very standard run, the challenge comes from every enemy and boss placed naturally in rooms (as opposed to being spawned later) being doubled. Due to the high enemy density, damage may prove difficult to avoid in some rooms. It is recommended for oneself to be already familiar with the gameplay of Jacob and Esau prior to attempting this challenge.
It may be wise to keep Silver Dollar if found, as the Shops it will spawn in Chapter 4 can be incredibly useful.
Eraser is an extremely powerful item for this challenge that can be found in Shops, as permanently erasing common enemies can help tremendously.
Mapping effects such as The Compass or The Mind can help quickly navigate through levels and avoid unnecessary risks.
Teleportation items such as 0 - The Fool, Teleport!, or Telepills can be used to quickly escape dangerous situations or skip rooms altogether. Glowing Hour Glass may also be used to return to the previous room and revert any possible health loss.
Room clearing effects are particularly powerful in this challenge: