Patients who have previously been diagnosed as having Lyme disease who have relapsing symptoms are often given the diagnosis of post-treatment Lyme disease, the implication being that they no longer have the infection, but this assumption is not based on any specific diagnostic criteria. The assumption is primarily based on the lack of improvement in a treatment trial that used a regimen consisting of one month of intravenous ceftriaxone followed by two months of oral doxycyline [21
]. That regimen did indeed seem to be ineffective, but the reasons for the lack of efficacy were not adequately addressed, especially the lack of consideration that there may be other regimens that might be effective. B. burgdorferi
is sensitive in vitro
to various antibiotics, including the penicillins, tetracyclines, and macrolides, but there are a number of mitigating factors that affect the clinical efficacy of these antibiotics. Not all antibiotics are equally effective in treating various infections, so it should not be surprising that there might be other successful regimens. Indeed, based on pharmacologic considerations, there appear to be highly effective regimens consisting of either tetracycline itself, or the combination of a macrolide anitibiotic (eg erythromycin, clarithromycin, azithromycin) with a lysosomotropic agent such as hydroxychloroquine [10
There continue to be various recommendations regarding antibiotic treatment of patients with relapsing or persisting symptoms. While there have not been agreed upon uniform regimens, there has been agreement amongst practitioners involved in treating such patients that more prolonged treatment is needed for more successful outcomes. With the exception of the study that involved a month of intravenous ceftriaxone followed by two months of oral doxycycline, and subsequent studies of either one month or ten weeks of intravenous ceftriaxone [22
], there have been no randomized, placebo-controlled trials of longer duration, using other antibiotic regimens. It should not be surprising that longer regimens would be required to treat a chronic infection, especially if the causative organism is not rapidly replicating and is in a protective niche such as an intracellular locus. Such is the case with a number of other infections, including tuberculosis, Q fever, various parasitic and fungal infections, and viral infections such as hepatitis B, hepatitis C, and HIV. In the case of hepatitis B and C, initial recommendations were for 6 weeks of treatment, but with further studies, the recommendation for the duration of treatment was then extended to 12 weeks, then to 24 weeks, and perhaps longer to resolve the infection.
In assessing whether treatment of patients with Lyme disease who have chronic symptoms are responding to the treatment, the lack of objective manifestations and more definitive means to determine whether the infection is being resolved, makes it more difficult to prove that the infection is being successfully treated. Nonetheless, it is the patient’s assessment of whether there is any improvement, just as in treatment of any other medical condition, that is the determinant of progress and success. There are also potential confounding factors, such as whether a given antibiotic is exerting a specific or non-specific effect. In the case of beta-lactam antibiotics such as penicillin and cephalosporins, especially ceftriaxone, recent evidence shows that these antibiotics can affect glutamate transport in the nervous system [23
], and that their clinical effects on patients’ symptoms might not be anti-bacterial in nature, but symptomatic. Patients and physicians have often concluded, perhaps erroneously, that additional treatments with these antibiotics are needed, and in our experience, treatment with this class of antibiotics, including several months of intravenous ceftriaxone, is not curative in patients with chronic symptoms.
Doxycycline is effective treatment for early Lyme disease, but does not appear to be curative in relapsing, persisting Lyme disease. This likely is because of two factors, ie dose, and protein-binding. Most of absorbed doxycycline remains highly protein-bound in the circulation, meaning that the amount of free drug to diffuse into cells is limited. This may be the explanation as to why the original parent compound tetracycline appears to be more effective [10
]. The dose of tetracycline used in our published observations that was found to be effective was 1500mg/day; in contrast, doxycycline dosage is 200mg/day, and tetracycline is not highly protein-bound, allowing more free tetracycline to diffuse into cells. In treating patients with tetracycline, a minimum of three months is needed to demonstrate progress, and in patients who have been ill for more than one or two years, 18 months of treatment may be needed to resolve the illness. Whether increasing the dose of doxycycline to 300-400mg/day would be more effective remains uncertain.
The use of a macrolide antibiotic such as clarithromycin or erythromycin, when combined with a lysosomotropic agent such as hydroxychloroquine, has been a very tolerable and successful regimen in treating patients with chronic, persisting symptoms [11
]. The use of either antibiotic or hydroxychloroquine alone does not result in any obvious improvement, supporting the hypothesis that the Lyme spirochetes reside in an intracellular acidic endosome. A controlled clinical trial would however be needed to prove this hypothesis. Further to that point, tetracycline, which is active in an acid milieu, is not benefited by the addition of hydroxychloroquine to the regimen. As with tetracycline, treatment with this regimen may also require a number of months to resolve most, if not all symptoms. As a practical approach, courses of treatment are alternated between tetracycline and the macrolide/hydroxychloroquine regimen, consisting of 6 months for each course, until symptoms are resolved (Table
). Patients who have been ill for shorter periods of time can resolve their symptoms in shorter periods of time than those who have had illness for a few years or more. In patients with longer standing illness, it also takes longer to begin to see any progress, often needing 4-6 months; nonetheless, sustained improvement can be seen in most of these patients over a prolonged period of time.
Recommended Reatment Regimens for Chronic Lyme Disease