Introduction
Lyme disease is a complex and systemic illness that is generally very difficult to treat. Many patients do not respond to the initial 28-day treatment course used for acute exposures (1). This results in patients who develop chronic and often debilitating symptoms following antibiotic therapy. Symptoms that persist post-treatment may result from persistent infection or post-infectious immune phenomena (2). Other suggested causes include antigenic changes to the organism, subversion of immune response, infiltration of immune-privileged sites, biofilm aggregates, and persister cells (3). Antimicrobial persistence has been seen in a wide range of chronic relapsing infections (3) and presents a significant problem for treating such infections. The various mechanisms that are used for persistence must be addressed in treatment in order to effectively reach remission.
The biggest barriers for successful treatment include immunologic weakness and the utilization of a variety of bacterial defense mechanisms to cause a persistent infection. As discussed in our article, “The Persistence of Lyme”, we summarized these mechanisms and how they contribute to a chronic, systemic infection. Addressing these defense mechanisms is integral to developing an effective treatment. Treatment needs to target the pleomorphic forms of the bacteria, coinfections, biofilm structures, and persister cell population (3). Additionally, any treatment that enlists antimicrobial agents is inherently somewhat dependent upon the host immune system to control bacteria not killed by antibiotics (1). Any infection that occurs within an immunocompromised host is therefore much more difficult to adequately treat (1). Successful treatment not only works to eradicate the bacteria, but also needs to promote improved immune function.
Developing Antimicrobial Treatment
Many antibiotics commonly used to treat early Lyme disease are administered at a lower dose that actually promotes the development of persister cells (4). In contrast, sometimes higher doses are not possible due to antibiotic side effects making treatment intolerable for patients (5).
Often, sources will say to use monotherapy (aka use only one antibiotic) for treatment, however no single antibiotic can address every form of the Lyme bacteria (4). In a study evaluating the efficacy of monotherapy of doxycycline, amoxicillin, tigecycline, metronidazole, and tinidazole, all antibiotics demonstrated effective eradication of both replicating spirochetes and round body cells, however none managed to kill bacteria in the spirochete persister colonies or biofilm structures (4). In addition, some antibiotics known for being able to kill persister cells in other bacterial species, are unable to kill Borrelia species as well given the variability in persister cell type (ie cysts, round bodies, micro-colonies or biofilms) (4).
When further investigated, it was found that multi-drug therapy managed to eradicate persister cells significantly better, however pulsed administration of multi-drug therapy had the best results (4). Overall, it has been demonstrated that treatment administering pulsed-doses of a combination of two or three antibiotics from a number of different drug classes is the most effective way to eradicate all forms of the bacteria (4). Some herbal agents have also been shown to be effective against persister bacteria and can potentially be utilized alongside antibiotic agents (4). An additional benefit of pulsed treatment is the lessened risk of developing antibiotic resistance (5). Recent studies have suggested pulsed therapy could be a good option for addressing polymicrobial infections and mitigating risk of antibiotic resistance in a variety of settings, not just Lyme disease (7).
Supportive Measures
While antimicrobial therapy is often needed to reach remission, this can be a struggle for patients. Some antibiotic doses can be intolerable due to medication side effects or inflammatory responses (5). Additionally, the efficacy of antimicrobial therapy is somewhat dependent upon a competent and capable immune system (1). Each individual patient’s experience of this disease is highly variable as a result of the differences in each patient’s immune system functioning and individual health factors (3). In turn, this can create variability in the efficacy and tolerance of treatment.
Therefore, successful treatment not only addresses the infection, but also the patient’s overall condition and symptomatic presentation. For patients experiencing neurological symptoms and neuropathic pain, this could mean medications that have demonstrated efficacy in addressing those concerns such as gabapentin or lamotrigine (7). Immune supportive vitamins and nutrients can be utilized to help mitigate oxidative stress and improve immune function (9, 10). For many patients this means incorporating dietary changes and supplement intake throughout the duration of treatment.
Conclusion
Successful treatment of Lyme disease is complex. Treatment regimens have to address the various mechanisms of bacterial persistence in addition to the individual patient’s immune competency and overall health. At Restorative Health & Wellness, we strive to accomplish this through our treatment program to promote successful and long-lasting remission.
Glossary
Immune phenomena – this refers to the activities of the immune system that result in inflammatory responses
Antigenic – of or relating to antigens (a foreign substance, pathogen, or toxin)
Immune-privileged sites – areas of the body that are typically exclusive to immune cells such as lymph nodes.
Biofilm aggregates – polysaccharide complexes that shield bacterial colonies from the immune system and/or antibiotic penetration
Persister cells – bacterial cells that have the ability to persist despite immune activity and antibiotic treatment through various means
Pleomorphic – This word describes bacteria that have the ability to change their appearance and structure.
Immunocompromised – a state in which a person has an immune system that has been compromised or weakened, often resulting in an increased risk of infection or complicated disease
Replicating – within the context of microbiology, this refers to the reproduction of a micro-organism like bacteria or viruses. Continued reproduction or replication indicates bacterial population growth and ongoing infection
Spirochetes – a type of bacteria cell structure that is shaped kind of like a corkscrew
Round body cells – a type of bacteria cell structure that is shaped like a sphere or cyst
Pulsed – this refers to a dosing schedule where doses of medications are taken spaced apart as opposed to consecutive days
Antibiotic resistance – this refers to the development of bacteria that are able to live through antibiotic treatment. This is different from persistence as resistance is acquired specifically through genetic mutations.
Oxidative stress – a condition in which free radicals within the body lead to tissue damage. This can be reduced through anti-oxidants.
References
Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. Borrelia burgdorferi, the Causative Agent of Lyme Disease, Forms Drug-Tolerant Persister Cells. Antimicrob Agents Chemother. 2015;59(8):4616-4624. doi:10.1128/AAC.00864-15
Steere AC, Angelis SM. Therapy for Lyme arthritis: strategies for the treatment of antibiotic-refractory arthritis. Arthritis Rheum. 2006;54(10):3079-3086. doi:10.1002/art.22131
Cabello FC, Embers ME, Newman SA, Godfrey HP. Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes. mBio. 2022;13(3):e0344021. doi:10.1128/mbio.03440-21
Rudenko N, Golovchenko M, Kybicova K, Vancova M. Metamorphoses of Lyme disease spirochetes: phenomenon of Borrelia persisters. Parasit Vectors. 2019;12(1):237. Published 2019 May 16. doi:10.1186/s13071-019-3495-7
Baker CM, Ferrari MJ, Shea K. Beyond dose: Pulsed antibiotic treatment schedules can maintain individual benefit while reducing resistance. Sci Rep. 2018;8(1):5866. Published 2018 Apr 12. doi:10.1038/s41598-018-24006-w
Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010;8(6):423-435. doi:10.1038/nrmicro2333
Horowitz RI, Fallon J, Freeman PR. Combining Double-Dose and High-Dose Pulsed Dapsone Combination Therapy for Chronic Lyme Disease/Post-Treatment Lyme Disease Syndrome and Co-Infections, Including Bartonella: A Report of 3 Cases and a Literature Review. Microorganisms. 2024;12(5):909. Published 2024 Apr 30. doi:10.3390/microorganisms12050909
Backonja M. Neuromodulating drugs for the symptomatic treatment of neuropathic pain. Curr Pain Headache Rep. 2004;8(3):212-216. doi:10.1007/s11916-004-0054-4
Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses. Br J Nutr. 2007;98 Suppl 1:S29-S35. doi:10.1017/S0007114507832971
Iddir M, Brito A, Dingeo G, Fernandez Del Campo SS, Samouda H, La Frano MR, Bohn T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients. 2020; 12(6):1562. https://doi.org/10.3390/nu12061562
Comments