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In most cases you can simply blast an enemy with a shotgun blast and then hit it until it dies. This works for wheelies and the other medium enemies.
For the large ones you can sometimes get enough hits in to trigger another knockback with the crowbar just as they're getting up again. But if you want to avoid that risk then backstep and equip the nailgun and shoot it 2 more times when they start to rise.
Otherwise a Shotgun blast and 6 nailgun shots is enough to kill the larger enemies.
You get the hints at the final "game complete" screen, But on my speed run of the game (1.27 total) I got it within the first 3 minutes. There's no enemies between you and the weapon.