How can we get rid of Borrelia burgdorferi sensu lato?

Dear Editor! Professor Neubert and his colleagues, in their paper entitled “Borrelia burgdorferi sensu lato – In vitro antibiotic sensitivity,” they have conclusively demonstrated through in vitro studies the effectiveness of ciprofloxacin, which damages the genetic material of Borrelia burgdorferi sensu lato by inhibiting DNA gyrase, and their experiment also confirmed the bactericidal properties of this antibacterial agent (5). However, according to Professor Neubert’s personal communication, ciprofloxacin used in monotherapy was not effective enough in the treatment of Lyme borreliosis.

I was the first to publish data on the role of DNA gyrase in Borrelia burgdorferi sensu lato in my earlier in vitro experiments (1), one to three years ahead of the research groups led by Barbour, Garon and Neubert. The therapeutic effect of ciprofloxacin in combination with other antibiotics can also be explained by DNA gyrase inhibition (2, 3).

The conclusion of the present study by Henneberg and Neubert draws attention to the need for combination therapy. More than a decade ago, I stated: “If the treatment of Lyme borreliosis with a single antibiotic is highly controversial, and all parties to the debate currently agree on this, then – in order to achieve a complete cure – it is necessary to use drug combinations and to support the effect of traditionally used antibiotics with drugs that prevent the pathogen from adapting.” (1, 3).

Based on my hypothesis developed from the results of studies conducted in 1990, I have already stated that effective treatment of Lyme borreliosis requires the prevention of continuous genetic modification while simultaneously damaging cell wall structure or metabolic processes and destroying the pathogen intracellularly.

Borrelia burgdorferi sensu lato is genetically unusual in that it is highly polymorphic and capable of repeated genetic changes during the course of the disease. Therefore, damage to the pathogen’s genetic material is essential for effective treatment. According to my studies, fluoroquinolones that damage the genetic material enhance the effect of other antibiotics with different targets on the pathogens of Lyme borreliosis by one or two orders of magnitude through synergism (1).

My original observation, based on in vitro studies, is that fluoroquinolones acting on the Borrelia burgdorferi sensu lato strain have a post-antibiotic effect. This explains why, in some cases, the initial symptoms may return approximately 10–18 days after the completion of combined treatment with ciprofloxacin. The temporary worsening of the clinical condition may last for a few days. The Spirochaetes with damaged genetic material, which are unable to divide, then disintegrate, and the released components cause recurrent symptoms, confirming the clinical manifestation of the post-antibiotic effect as well as the two- to three-week generation cycle of Borrelia burgdorferi sensu lato. The post-antibiotic effect also confirms in vivo the effect of fluoroquinolones on the sub-strains of Borrelia burgdorferi sensu lato.

A similar periodic change is also confirmed by the cyclical nature of the number of pathogens observed during experimental infection (8). In the clinical history of untreated Lyme borreliosis, the symptoms of Lyme borreliosis also appear and intensify at regular intervals lasting several days (Figure 1). Between symptomatic periods, the patient may even be symptom-free.

Based on our observations and the data in the literature, we can therefore assume that the optimal treatment period is two to three weeks. Effective treatment against facultative intracellular pathogens should last four to six weeks, twice the period specified above.

Lyme borreliosis is a complex disease that affects the entire body, and its diagnosis and treatment – depending on the current clinical symptoms – is the responsibility of several medical specialties. A particular difficulty is that Lyme borreliosis can be associated with any other disease during its chronic course. In such cases, the diagnosis of Lyme borreliosis is a truly consultative, differential diagnostic issue involving all medical specialties.

In evaluating the experience gained in the diagnosis and treatment of Lyme borreliosis, the American College of Physicians concluded that the diagnosis of the disease depends fundamentally on the epidemiological and clinical data reported by the patient, which significantly support the laboratory detection of Lyme borreliosis. Their findings were also accepted by the Board of Reagents (4, 9), thus establishing an objective basis for the consultative diagnosis of Lyme borreliosis.

In my experience, in cases of Lyme borreliosis based on clinical symptoms and examination

– confirmed seropositivity is equivalent to a diagnosis of the disease,

– and the active process indicated by the symptoms indicates treatment.

At the same time as addressing the issue of diagnosis, I would like to emphasise that treatment is only indicated by clinical symptoms indicating an active process. In the case of asymptomatic seropositivity, it is usually only necessary to monitor the patient. However, treatment may be indicated in cases of severe stress or the development of comorbidities. In such cases, we have repeatedly observed recurrence of Lyme borreliosis. In the case of a concomitant bacterial infection, the treatment of Lyme borreliosis should be adjusted so that it is suitable for curing both diseases. In our follow-up examinations to date, we have only been able to confirm the existence of the so-called “serological scar” in three recovered patients: the persistence of asymptomatic seropositivity. In fact, it indicates damage to and insufficiency of the body’s defences. Recovery is characterised by the gradual, slow development of seronegativity. There is currently no targeted antibiotic treatment for Lyme borreliosis.

There is currently no specific antibiotic treatment for Lyme borreliosis. When selecting an antibiotic, in addition to the experience gained from various treatment regimens and in vitro test results, it is also important to consider which antibiotics the patient has taken in recent years. When planning treatment, it is important to find out whether the antibiotics used have caused any changes in the clinical symptoms of Lyme borreliosis. In addition to recording the patient’s antibiotic history, it would be advisable to identify the subspecies or subspecies causing the disease (5), which would provide further guidance for the selection of antibiotics.

Based on our experience to date and data from the literature, it is recommended that effective doses of antibiotics be used in combination to combat this facultative intracellular pathogen, which is genetically polymorphic and known to have a high mutation rate. Drug dosing should be continued on an individual basis, with monitoring by laboratory tests.

Due to prolonged antibiotic treatment, vitamin and trace element supplementation is essential, and patients should be advised to pay increased attention to hygiene rules. At the end of treatment, it is advisable to recultivate the intestinal flora with Lactobacillus, which is also suitable for reducing enteral complaints during treatment. It would also be necessary to support the weakened immune response, but we have not yet found a suitable drug. Lyme borreliosis is a chronic disease that can directly damage the structures that ensure mental functioning, and in other cases, it can lead to dysfunction accompanied by personality changes. Therefore, the diagnosis and treatment of Lyme borreliosis requires time and patience. The only way to monitor the effect of the treatment is through follow-up care, which is also part of the rehabilitation required due to the chronic nature of the disease.

According to observations made since the description of the domestic occurrence of Lyme borreliosis and the follow-up care we have been advocating for years (2), the antibiotics listed in Table 1 have proven to be effective, and based on our experience, a favourable effect can also be expected from parenteral clarithromycin.

Figure 2 summarises the clinical data sent for serological testing during the five-year follow-up and repeated treatment of 250 patients in accordance with the above diagnostic and therapeutic principles. Based on this, it can be safely stated that Lyme borreliosis can be cured with antibiotics. In our experience, there is no single antibiotic that can reliably eradicate the pathogen Borrelia burgdorferi sensu lat from the body in all cases! For this reason, two or three courses of treatment with alternating antibiotics may be necessary for a cure. At least one of these must be administered parenterally. Due to the development of side effects, ciprofloxacin is only recommended for oral use. The pathogenetic basis for repeating treatment is the possibility that several substrains of Borrelia burgdorferi sensu lato, with different antibiotic sensitivities, may simultaneously influence the course of the disease (5). The indication for repeated treatment is the responsibility of follow-up care (2, 6, 8, 10).

REFERENCES

1. Bózsik, B. R: In vitro combination drug effect on Borrelia burgdorferi strains. LAM, 1991, 1, 312-314. — 2. Bózsik, B. P, 71mmer, M., Esztó, K.: Combined Antibiotic Treatment of Lyme Borreliosis. V. Int. Conf. on Lyme Borreliosis, Treatment N° 67. 1992. — 3. Bózsik, B. P.: On the treatment of Lyme borreliosis Orv. Hetil., 2000, 141, 106-111. — 4. Guidelines for laboratory evaluation in the diagnosis of Lyme disease. American College of Physicians Ann. Intern. Med., 1997, 127, 1106-1108. — 5. Henneberg, J. P, Neubert, U.: Antibiotic sensitivity of Borrelia burgdorferi sensu lato — Based on the examination of 24 isolates from three sub-strains. “Anniversary at the turn of the millennium”, International Scientific Congress of the Lyme Borreliosis Foundation, Budapest, 12-13 May 2000. — 6. Horváth, L, Kéri, J.: Insurance and health aspects of zoonoses. “Anniversary at the turn of the millennium”, International Scientific Congress of the Lyme Borreliosis Foundation, Budapest, 12-13 May 2000. — 7. Kéri, J.: Lyme borreliosis In Life Insurance Medicine. Edited by Fehér, J., Horváth, I., Lengyel, G., Fogarasi, I. Medicina, Budapest, 1995, p. 537. — 8. Stanek, G., Burger, L, Hirschl, A. et al.: Borrelia transfer by ticks during their life cycle. Studies on laboratory animals. Zbl. Bakt. Mikrobiol. Hyg. A., 1986, 263, 29-33. — 9. Tugwell, P., Dennis, D. T, Steere, A. C. et al.: Laboratory evaluation in the diagnosis of Lyme disease. Ann. Intern. Med., 1997, 127, 1109-1123. — 10. Vogt, E, Csoma, É., Timmer, M. et al.: Lyme borreliosis. Orv. Hetil., 1993, 134, 271-273.