Lyme is a complex organism, with a complex life cycle. It's present in the Americas (one major phenotype group only) and also in Europe and Asia (three major phenotype groups, although usually the two that aren't present in the Americas). It's been recognized as a disease only since the mid-1970s, and research is ongoing.
Here's a good semi-technical description of the organism and infectious process in humans - good photos, maps and interesting technical information. I don't know if the testing protocol in humans described in the article is up to date or not, but in horses (and I believe also in dogs) there is a new ELIZA test from Cornell that is more definitive and identifies antigens A, C and F, the variable levels of which help identify what stage of the disease process the horse is in.
The Lyme disease organism is designed to succeed - it has several mechanisms that help it evade the immune system. Due to its physical structure, it is less identifiable to the immune system that other bacteria - the structures that would typically present as "foreign" to the immune system are not exposed on the surface. Lyme also actively surpresses the host's immune system - this may partly explain why Pie was vulnerable to EPM in the first place and then had sequential infections with different phenotypes. Lyme also can colonize poorly vascularized tissues - like the synovial fluid in joints - which makes it less visible to the immune system and harder to treat. Lyme can even encyst - become dormant and invisible for a period of time. One of the challenges in treating Lyme is that encysting can even occur as a result of treatment with antibiotics - this is one reason for the persistance of Lyme and development of chronic Lyme.
Here's a photo of annular skin lesion in a human caused by the Lyme organism - Pie had several of these - they were ringlike, an inch or so in diameter, had a raised, scaly border and a depressed center. They were on his body, and although I noted them no one had a good explanation for why they were there. They disappeared over the fall of 2011 as the severe symptoms abated. He still has two residual patches of scaly, thickened skin in front of the points of each of his hips just where the hair whorls are - I don't know whether they're associated with his chronic Lyme, but I'm suspicious, as they weren't there before he was sick.
Lyme has been shown to be treatable with doxyclycline (a member of the tetracycline class of drugs). These drugs interfere with the reproduction of the Lyme organism, so are most effective when the organism is reproducing. The objective in treatment is to, over time, affect as much of the bacterial population as possible when it is vulnerable. Many bacteria reproduce rapidly - every 20 minutes or so - whereas Lyme has a much longer reproductive period - 7 to 12 hours or even longer. Therefore short-term antibiotic theraphy - as would be used for a rapidly-reproducing organism like strep - is ineffective in treating Lyme.
The expectations in treating Pie are to knock back the organisms to the extent possible. He hasn't had Lyme for as long as many chronic horses, and his titer levels for chronic Lyme are not at the high end of the range. It is still probable that not all the organisms will be eliminated, due to their ability to hide, but we're expecting significant improvement in symptoms. Apparently follow-on flare ups are possible, but these apparently respond well to another course of antibiotics (this good response to repeated treatment is also true for dogs, according to Cornell, but apparently less so for humans).
My vet is using a revised treatment protocol. Many horses have been treated with doxyclycline pills split into two daily treatments - for the average 1,000 to 1,200 pound horse (Pie is in this range) the treatment has been 50-60 doxy pills twice a day. The revised protocol goes with the total dose - 100-120 pills a day - only once a day. This apparently has something to do with the way the Lyme bacteria operates in the animal - it's apparently more vulnerable to treatment in the late afternoon and early evening, and less vulnerable in the morning. I believe this has something to do with its reproductive behavior. I'm trying to get more information on the science behind this - it's apparently based on ongoing research of what's most effective in treatment - I don't know whether in humans or horses. I haven't been able to find anything yet published about this, and it's quite possible I'm not properly describing the thinking. This protocol allows the peak dose of doxy to be higher, which also may improve the effectiveness of the treatment, while giving the horse a recovery period each day to reduce side effects.
The most significant side effect of doxy in horses is loose manure. To manage this, the other part of the protocol we're using is to very slowly increase the dose, starting with only 10 pills and increasing by 10 per day, and watching carefully for any loose manure. The goal is to build to at least the 100-120 pills per day level, and possibly somewhat higher if Pie tolerates it well, and hold that level for 30 days once reached. Some horses have to back off to the 80 pill per day level, but can still get effective treatment - this was true of one horse at my barn - and some horses can tolerate much higher levels of doxy. The objective is to customize the treatment to the horse and get the highest loading dose possible that doesn't cause loose manure.
The nice thing about the once a day treatment is that it's easier to do - I'll do it myself to be sure every little pill is consumed and not dropped - most horses just eat them without a problem, although I may use a feed bag to make things simpler. The doxy will be fed as whole (tiny) pills together with a small grain meal, to improve gastric comfort, and hay will also be available before and after the treatment. If Pie has any dislike of the pills (the other horse at our barn ate them freely), a bit of cocosoya oil will solve the problem. Once a day treatment also means I can continue to use supplements that contain calcium or magnesium that would otherwise interfere with the absorption of the doxy, if I give them in the mornings. Pie will also get a good dose of probiotics each morning throughout his treatment and for a period thereafter to help maintain healthy gut flora.
I'm hoping the treatment will help Pie out, and also that perhaps I'll get a break - I hope a very long one - from learning about new equine diseases . . .