I also use Akismet but rarely does a spam comment get past my defenses.
This is what i do.
1. If you remove the website url field from your comment form, you'll find this will reduce both automated and manual spam comments as most are only interested in leaving links. You can do this by installing a plugin or using code.
2. I also removed the comment form allowed tags because they include the word email which spam bots are programmed to look for. You can do this by installing a plugin or using code.
3. Configure Discussion settings correctly. I would disable trackbacks and also set comment author must have at least one approved comments. All comments must be approved by an administrator.
You can also configure your settings so only one link is allowed however its better to not allow any unless manually approved.
Comment spam has never been a problem for me except when Akismet stopped working sometimes which isn't very often and doesn't last long but you will know about it when it happens.