Dr. Weeks’ Comment: You have Lyme and it was treated but you still feel terrible. Why? Because you have Post Treatment Lyme Disease Syndrome (PTLDS). Is that treatable? Yes. Dr. Ying Zhang, (Johns Hopkins University), has worked on an effective Post Treatment Lyme Disease Syndrome (PTLDS) and reports that “current Lyme disease treatments may not clear bacterial debris or ‘persisters,’ which may be one of the possible causes of PTLDS.”
Dr. Zhang has identified an old leprosy drug Clofazamine, as beneficial. Tuberculosis (TB) is his primary focus but he researched drugs which can help Lyme.
In his 2014 study which he co-authored in the Journal of Emerging Microbes and Infections, (read this article but see excerpts below), he writes: “We identified 165 [drugs] approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters.”
The study pointed out that clofazimine, originally developed for the treatment of tuberculosis, and commonly used for treating leprosy, was one of the most effective agents against the Borrelia burgdorferi bacterium, when used in combination with currently prescribed drugs like doxycycline.
Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library
- Emerging Microbes & Infections volume3, pagee49 (2014)
ABSTRACT
Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.
SUMMARY
In summary, this study represents the first high throughput screen against B. burgdorferi in vitro persisters and identified a number of interesting FDA-approved drugs that have excellent anti-persister activity. Further studies are needed to evaluate these drug candidates in animal models of B. burgdorferi persistence and determine whether they can break the persistence phenomenon the current Lyme disease antibiotics failed to eliminate. Although the question of B. burgdorferipersistence in humans has been raised, there is no high-quality evidence to support this concept or the idea that additional antibiotic therapy is helpful for patients for PTLDS. Whether earlier resolution of B. burgdorferi infection, either alone or in combination with current Lyme disease antibiotics, will decrease long term symptoms of fatigue or PTLDS is unknown and will require further study.
Consider with your doctor what Dr. Zhang writes:
- Amphotericin B
Amphotericin B is a powerful antifungal drug that targets sterols in fungal cell membranes, forming a transmembrane channel that leads to ion leakage.38 Because sterol mainly exists in the membranes of eukaryotes, amphotericin B is not a good agent to control prokaryotes. Because B. burgdorferi is one of the rare prokaryotes that possesses cholesterol and cholesterol glycolipids in its membranes,39 it is not surprising that amphotericin B had some activity against stationary-phase B. burgdorferi persisters (Table 1). Its activity was comparable to colistin, but it was less active than daptomycin (Table 1). Amphotericin B may also target the sterol lipid rafts in the membrane of B. burgdorferi.
2) Clofazamine
Clofazimine was originally developed for the treatment of tuberculosis and currently is commonly used for the treatment of leprosy.36Additionally, with the increasing drug-resistant TB problem, it has been used for the treatment of MDR-TB.37 Clofazimine is thought to act through different mechanisms on mycobacteria, including membrane destabilization, the production of reactive oxygen species and the inhibition of membrane energy production.37 Here, we observed that clofazimine was highly active against stationary-phase B. burgdorferipersisters (Figure 3F), although the MIC of clofazimine was relatively high (6.25 µg/mL). The preferential activity of clofazimine against B. burgdorferi persisters may be due to its high lipophilicity and its effects on the membrane. It is of interest to note that clofazimine is known to accumulate in host tissues,37 and this property may allow clofazimine to accumulate to high concentrations and act preferentially against B. burgdorferi persisters if they occur in human tissues. Future studies are needed to test this possibility.
3) Daptomycin
Daptomycin is a lipopeptide antibiotic that has been used in the treatment of severe infections caused by antibiotic resistant gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus(MRSA) and vancomycin-resistant enterococci (VRE). Daptomycin can disrupt bacterial cell membrane function, including insertion into the membrane, creating pores that allow cells to leak ions, which results in rapid membrane depolarization, loss of membrane potential and bacterial cell death.33 We determined that daptomycin had the highest activity against B. burgdorferi persisters among all the active hits (Table 1, Figure 3D) but had a high MIC (12.5–25 µg/mL) against log-phase organisms (Table 2). The B. burgdorferi stationary-phase cells treated by daptomycin had almost all red fluorescence as spirochetes (Figure 3D). This result indicated the daptomycin could similarly disrupt the cell membrane of B. burgdorferi, causing PI dye to permeate the cell, leading to cell death. Microscope examination revealed spirochetal shaped remnants after daptomycin treatment (Figure 3A), suggesting that the cells were dead and did not change form to coccoid shape, which occurred following cefoperazone and tetracycline treatment (Figures 3E and 3I).
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