https://www.frontiersin.org/articles/10.3389/fmed.2023.1183344/full
Lyme disease and the pursuit of a clinical cure
- Division of Immunology, Tulane National Primate Research Center, Tulane University Health Sciences, Covington, LA, United States
Lyme disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne illness in the United States. Many aspects of the disease are still topics of controversy within the scientific and medical communities. One particular point of debate is the etiology behind antibiotic treatment failure of a significant portion (10–30%) of Lyme disease patients. The condition in which patients with Lyme disease continue to experience a variety of symptoms months to years after the recommended antibiotic treatment is most recently referred to in the literature as post treatment Lyme disease syndrome (PTLDS) or just simply post treatment Lyme disease (PTLD). The most commonly proposed mechanisms behind treatment failure include host autoimmune responses, long-term sequelae from the initial Borrelia infection, and persistence of the spirochete. The aims of this review will focus on the in vitro, in vivo, and clinical evidence that either validates or challenges these mechanisms, particularly with regard to the role of the immune response in disease and resolution of the infection. Next generation treatments and research into identifying biomarkers to predict treatment responses and outcomes for Lyme disease patients are also discussed. It is essential that definitions and guidelines for Lyme disease evolve with the research to translate diagnostic and therapeutic advances to patient care.
Translation: TIME FOR CHANGE!
- Without intervention, Bb establishes a persistent/chronic infection in both its reservoir and non-reservoir hosts.
- Controversy regarding chronic infection revolves around whether Bb can persist after antibiotics and whether they are capable of causing the symptoms patients experience.
- There are many bacterial species associated with persistent infections in humans including: Mycobacterium tuberculosis, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and B. burgdorferi (109).
- Bacterial tolerance is different from resistance in that bacteria are not actively growing in the presence of the antibiotic and there is no heritable genetic change in the persistent bacteria’s genome (110, 111).
- The stress response and other mechanisms allow bacteria, including Borrelia, to survive lethal conditions such as limited nutrients, extreme pH levels, and the presence of certain antibiotics.
- Drug-induced bacterial persisters show a biphasic killing curve and the regrown persister cells have the same minimum inhibitory concentration (MIC) to the administered antibiotic as the original population but a higher minimum bactericidal concentration (MBC) (112).
- Several independent studies have demonstrated that Bb can form drug-tolerant persister cell in vitro.
- In vivo studies of Bb antibiotic persistence often use different parameters that can make comparisons between two or more studies difficult.
- It is likely that lack of consensus of definitions and diagnosis lead to the treatment controversy.
- Despite treatment controversy, a biostatistical review of the literature found that retreatment of LD with antibiotics may be beneficial in certain cases (163).
- Since research for PTLD revolves around autoimmunity, immune-mediated factors, and/or persistent infection, most drugs fit into one of three categories: immune therapies, pathogen specific inhibitors, or antibiotics.
- Studies screening drug libraries have revealed:
- disulfiram has demonstrated borreliacidal activity both in vitro and in vivo (174–176)
- vancomycin may have efficacy against stationary Bb based upon cultures and evaluation in SCID mice (177)
- hygromycin A has shown efficacy against Bb, without disturbing the gut microbiome like so many broad-spectrum antibiotics, in vitro and in an in vivo mouse assay, but it’s use in preventing persistent infections was not determined (178)
- drug combinations such as daptomycin or artemisinin, cefoperazone, and doxycycline as well as the combination sulfachlorpyridazine, daptomycin, and doxycycline have shown evidence of in vitro activity against Bb persisters and round bodied forms (117, 172). Azlocillin and cefotaxime are effective in in vitro killing against Bb persisters induced by doxycycline, which appear to be more tolerant to other antibiotics (179).
- daptomycin or daunomycin, doxycycline, and cefuroxime have had success in sterilizing in vitro Bb biofilm-like microcolonies (180, 181).
- dapsone, used in treatment of leprosy, has had success when combined with other antibiotics in killing biofilm-like Bb (182), and dapsone has had positive effects in a small PTLD and co-infection clinical study (183).
- oregano, cinnamon bark, clove, and various flowers, grasses, and berries, as well as natural compounds such as those found in bee venom and its component melittin have demonstrated potential in vitro growth inhibition against Bb and its various forms (184–188) but need further research to determine the safety and efficacy of, and the composition and activity of the exact compounds found.
- Curative treatment during early LD stages is a key to solving the current PTLD public health problem.
- It is likely that more than one mechanism is involved in antibiotic treatment failure that leads to PTLD.
- The current treatment guidelines are dependent upon the immune system’s ability to clear persistent spirochetes and conditional to the surviving spirochetes being non-viable and not enough to sustain a prolonged immune response.
- In order to make PTLD a thing of the past, personalized medicine is required as well as the need to evolve and progress with scientific discoveries and innovations.
