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In the process of integrating the available information on Bb biology and what is known about the effect, or lack of effect, of various antimicrobial programs, the Jemsek Specialty Clinic developed a treatment protocol for LD in late 2001. When advanced CNS involvement or neurological disease is present, both intravenous and oral antimicrobial agents may be used to treat Bb in combination; otherwise, cyclic oral therapeutic programs are employed. Our cycles on oral antibiotic are designed to run for four months. Our experience suggests that, if a patient is ultimately going to improve on oral therapy, positive results with clear symptom relief are evident by the third or fourth cycle. If a patient fails to progress, i.e. no clinical improvement in any parameter, absence of Herxheimer effect, and so forth, we are not hesitant to change the antimicrobial program, especially in view of what is known about strain variability and antibiotic response.
Our treatment approach is designed for a Bb organism that is recognized as polymorphic and microaerophilic. Other important features of Bb biological traits are the capacity to exist in either an intracellular or extracellular state. Finally, Bb has a tendency for latency and for slow replication (125), a fact that has profound implications of the length of antibiotic therapy required for eradication. In summarizing all of these considerations, we have concluded that a treatment protocol employing long-term cyclic, pulse therapy with drugs effective against all forms of the organism might be effective, particularly if given in sequence with agents active against the cyst active form administered late in the cycle.
When IV or oral therapy is employed, the idea of a “drug holiday” after pulsing seems attractive for several reasons., Early in therapy, most patients will relapse, or experience the recurrence of symptoms, within one or two weeks of therapeutic interruption. This pattern of relapsing provides useful clinical information for future treatment (see below). In theory, our treatment and the subsequent Bb “die-off” and then relapse off therapy is an approach that might stimulate immune recognition and activation, thereby improving immune surveillance/eradication of Bb. This idea bears similarities to the auto-immunization theory that has received attention in HIV therapeutic strategies. That is, if one suppresses HIV with drug treatment, the CD8 cytotoxic/suppressor cell level wanes (127) (these are lymphocytes responsible for activity against cellular pathogens, including HIV). As treatment is withdrawn, the reappearance of the virus causes an augmented or boosted CD8 response that, if repeated cyclically, might build the response to the point that the pathogen could be controlled or eliminated by the immune system. Realistically though, this is a grossly oversimplified theory and a considerable amount of scientific work will be required to answer these questions. Regrettably, given the current medical and political circumstances for LD, meaningful clinical, epidemiological, and immunologic research are but a faint hope.
In the figurative sense, if there were a race to cure HIV and Bb (no judgmental view intended here), the HIV researchers would have a 20-year and a several billion-dollar head start, with the Bb folks falling further and further behind each year for the foreseeable future. Perhaps the silver lining in all this is that all of the wonderful scientific information that has come from the HIV pandemic will benefit our understanding of many other diseases, including neuroborreliosis.
Obviously, our ultimate goal is Bb eradication, if possible, or at least a state of competent immune surveillance resulting in lasting relief from disease. As successful treatment progresses, return of symptoms off therapy becomes more delayed and symptoms tend to be milder. During the first week or two on holiday, our patients invariably remark that they feel the best they have since becoming ill. Obviously, when a patient ceases to relapse on holiday, it is taken as a positive indication. It is even more encouraging at that point if the patient fails to exhibit any sign of Herxheimer reaction (see below) during the ensuing treatment cycle, suggesting that Bb die-off is clinically non-detectable. In general, we have informed patients that therapy may extend for two or three years before they may reach an asymptomatic state. At this point in therapy, we would consider performing a “test of suppression”, probably by utilizing newly available urinary antigen detection testing procedures such as the urinary Dot-Blot test through Igenex laboratory (128), in a protocol that employs an antibiotic challenge to enhance Bb shedding in the genitourinary tract. Pre and post therapeutic trials with more sensitive laboratory markers are needed.
The use of IV clindamycin has now become routine in our treatment protocol for advanced neuroborreliosis. This change came about after we began using oral clindamycin (with mepron) empirically for suspected cases of babesiosis coinfection in our most recalcitrant, unresponsive patients. We immediately noted some new and positive developments, e.g. absence of fever and night sweats for the first time in months/years, increased mental acuity, and so forth. Other patients had Herxheimer reactions that they had not experienced for weeks on prior therapy, even though we were treating aggressively with both intravenous and oral antibiotics. Since our most debilitated patients were already on IV therapy, we decided to try short courses of IV clindamycin and the effect has been consistently impressive, even more so than with the oral formulation. We have now gone back and retreated those patients who have had an incomplete response to prolonged IV therapy, and in 11/12 of these cases, improvement on IV Clindamycin has been dramatic. We are currently in the process of evaluating the optimal use of clindamycin, as we continually do with all of the therapies we employ. Our hope is that these more intensive therapeutic programs still provided in such a way that they are tolerated, will allow us to shorten the IV program by hastening the time to clinical improvement.
In order to address the pleomorphic nature of Bb in cyst formation, we routinely cycle metronidazole during the treatment period, thereby achieving three separate active modes of treatment (extracellular, intracellular, and cystic). Since it is very difficult to maintain a patient on such intensive therapy for a prolonged period, the rotation of oral antimicrobials through the IV treatment period has been quite helpful in term of program tolerance. In fact, out of tolerance concerns, metronidazole is typically given intermittently and on a short term basis because of its propensity to cause severe Herxheimer reactions, especially in patients with advanced illness. Because of the complex drug issues in patients who invariably risk great morbidity, we accommodate each individual with a treatment plan that is best suited for them. While we have developed a protocol for general guidance, we understand that it is the exception to the rule that creates new insights about the treatment of Bb. This is how our protocol evolved and continues to evolve; by careful observation and documentation of the clinical presentation using well established scientific data in order to craft sophisticated empiric therapy. Prior to any treatment, IV or oral (or both), our patients are educated in the use of probiotics and schooled to observe for potential side effects. Safety labs are performed weekly or biweekly. Specific considerations in IV therapy include the addition of Actigall (ursediol), which seems to reduce the incidence of ceftriaxone-induced cholelithiasis (personal reference) and is well tolerated. When using imipenem, we add probenecid in order to boost drug levels during twice daily dosing.
In administering these treatment programs, the Jemsek Specialty Clinic is cognizant of criticism concerning outside perceptions and opinions of excessive or unguided antibiotic use by our clinic. Certainly, we do not now and never will condone indiscriminate use of these important and valuable drugs. In view of our training and experience, we are completely confident in our use of these medications. In response to any real or potential criticism, we would reply by pointing out that we are treating seriously ill and/or impaired individuals who have not responded to conventional medical therapies. As mentioned previously, we are encouraged that a significant percentage of our patients are responding to our care, including several individuals who had been totally incapacitated for appreciable periods of time. We acknowledge that the understanding of neuroborreliosis is incomplete and so we continue to study the entire process of diagnosis and treatment for Bb infections. We look forward to the day when funding and scientific support for Bb research is available.
During our discussions, we have routinely mentioned the risk and possibility of co-infection with Babesia, Ehrlichlia, and Bartonella. Regrettably, at present, a thorough discussion of these important tick borne infections is beyond the scope of this presentation. However, the importance of these other pathogens cannot be underestimated. In future times, we hope to expand our scope and include these very important discussions to our presentation.