jones%20rationale%20for%20LT%20tx.pdf

Rationale for Prolonged Antibiotic Therapy in Treating

Lyme Disease

By Charles Ray Jones, M.D .

In my opinion and in my experience in treating over ten thousand young people with Lyme

disease, decisions on duration of treatment in many cases where there is central nervous system

involvement and chronic persistent infection, are best determined by clinical response, as would

be the case with any other illness or infectious disease and not by any arbitrary limit of days

given. There is very ample documentation in the peer reviewed medical literature of the ability of

the Lyme organism to survive intensive and prolonged antibiotic treatment, including intravenous

antibiotics. A recent report in Infection by Steven Phillips, et al. (1998 Nov-Dec 26 (6): 364-367)

indicates that Borrelia burgdorferi spirochetes can be reliably cultured from the blood of patients

with Lyme disease, even from those previously aggressively treated with antibiotics. In my

experience, patients with chronic central nervous system infection can benefit from many months

of intravenous antibiotic treatment. Although such durations of treatment are controversial within

the medical community, at the 1991 NIH State-of-the-Art Conference on Lyme disease, there was

general agreement that optimal regimens of antibiotic therapy for central nervous system Lyme

disease remained to be defined. Thus, it is not sustainable to adopt a doctrinaire position about

what constitutes “sufficient” therapy in individual cases.

Much has been made of the risks and expenses of prolonged oral, intramuscular and intravenous

antibiotic therapy. Without such treatment, however, patients are likely to remain very

compromised, may become unable to finish their education, earn a living, and run the risk of

pursuing a course of progressive deterioration. The following evidence, supporting the rationale

for prolonged antibiotic therapy for Lyme disease, can be used to evaluate and determine the

therapy for anyone with this infection.

Lyme disease is a chronic, persisting, difficult disease to treat, which is caused by Borrelia

burgdorferi spirochetes. There has never been a study in the history of Lyme disease that, even in

the simplest way, proves that a short course, 2-6 weeks, therapy results in bacteriologic cure.

There is no double blind study to determine the optimal duration of antibiotic treatment for Lyme

disease. There is evidence, however, that if antibiotic treatment therapy is stopped before

symptoms resolve, then the patient will relapse and Lyme disease will progress. 1,2,3,4,5

Lyme disease can respond favorably to antibiotic treatment in all stages, but it is far from clear

whether currently available methods of treatment achieve genuine bacteriologic cure. Many other

patients with Lyme disease remain well following oral, IM, or IV antibiotic therapy. Many other

patients with Lyme disease, however, improve while on antibiotic therapy but deteriorate or

relapse when the antibiotic therapy is stopped. The relief of symptoms when taking another round

of antibiotics is consistent with persistent infection. Patients with Lyme disease on antibiotic

therapy experience a worsening of symptoms during the first days of antibiotic therapy and

periodically as the therapy continues. This worsening of symptoms is consistent with a Jarisch-

Herxheimer reaction which is an immune response to the destruction of Borrelia burgdorferi

spirochetes, the bacteria that cause Lyme disease. A Jarisch-Herxheimer reaction indicates an

active Borrelia burgdorferi infection. Despite the fact that Borrelia burgdorferi spirochetes are

almost impossible to culture from any infected host, 6,7,8 there are well-documented culture

confirmations of persisting Borrelia burgdorferi infection in antibiotic-treated patients. 1,9

Borrelia burgdorferi spirochetes have been cultured from patients who have been given intensive

(21 days to one year) antibiotic therapy with IV third generation cephalosporins. 3,4,9,10,11,12

There are many ways by which Borrelia burgdorferi spirochetes resist antibiotic and immune

destruction. The Lyme spirochetes can attain in vivo antibiotic resistance by their ability to live

intracelluarly in fibroblasts, endothelial and glial cells, as well as other cells. 13,14,15,16 Another was

in which Borrelia burgdorferi can escape destruction by antibiotics is by virtue of its slow rate of

division. Since many antibiotics, such as beta-lactams, only kill actively dividing organisms, the

fact that some cultures of Borrelia burgdorferi have taken up to 10.5 months to grow, suggests

that certain treatment length guidelines are too short. 17

L-forms of many bacteria have long been shown to be pivotal in setting up chronic infection. 18,19

The discovery of L-forms of Borrelia burgdorferi implies that antibiotics would likely to result in

treatment failures. 20 These mutant forms of Borrelia burgdorferi develop resistance to antibiotics

in several ways. One is by loss of their cell wall, thereby circumventing cell wall-acting

antibiotics such as beta-lactam, and taking this step even further, many L-forms actually lose their

ability to replicate, easily sidestepping replication-dependent antibiotics. 20 Borrelia burgdorferi

spirochetes can evade immune surveillance by releasing blebs which bind free antibodies,

forming immune complexes. 21,22 These immune complexes are not detected by Lyme ELISA and

Lyme western blot assays, which only detect free antibodies. Borrelia burgdorferi spirochetes can

also escape immune detection by altering surface protein antigens. 23

Considering the difficulty in eradicating the organism that causes Lyme disease, it is realistic to

use two antibiotics simultaneously, one antibiotic that acts on the surface of the organism and the

other internally.

Antibiotic therapy should be continued for at least two months after any Jarisch-Herxheimer

reaction has occurred, at least two months after there is no recurrence of Lyme symptoms in

response to other infections or menstruation, and after all Lyme symptoms are resolved or

stabilized. If antibiotic therapy is stopped prematurely, the patient’s Lyme disease will relapse

and result in more Borrelia burgdorferi brain and body injury by a more resilient and difficult-to-

treat Lyme organism.

References:

1. Preac-Mursic V, Weber K, Pfister W, Wilske B, Gross B, Baumann A, Prokop J. 1989.

Survival of Borrelia burgdorferi in Antibiotically Treated Patients with Lyme Borreliosis.

Infection 17:335-339.

2. Logigian EL, Kaplan RF, Steere AC. Chronic neurologic manifestations of Lyme disease. N

Engl J Med. 1990;323:1438-1444.

3. Liegner K. Culture-confirmed Treatment Failure of Cefotaxime and Minocycline in a Case of

Lyme Meningoencephalomyelitis in the US. V Int Conf Lb, 1992. Abstr #42.

4. Krupp LB, Masur D, Schwartz J, Coyle PK, et al. Cognitive functioning in late Lyme

borreliosis. Arch Neurol 1991; 48:1125-29.

5. Liegner KB, Shapiro JR, Ramsay D, Halperin AJ, Hogrefe W, Kong L. 1993. Recurrent

erythema migrans despite extended antibiotic treatment with minocycline in a patient with

persisting Borrelia burgdorferi infection. J Am Acad Dermatol.1993. 28:312-314.

6. Demiroz P, Serbes S, Keskin K, Irmak H, Kocabalican F. Lyme Disease. Microbio Bul.

1989;23 (1) 80-84.

7. Preac-Mursic V. et. al. First isolation of B burgdorferi from an iris biopsy. J Clin Neuro-

opthalmol (1993)13:155-161.

8. Satz N. Immunology and diagnostic test results in Lyme borreliosis. Schweiz Med

Wochenschr. 1992; 122 (47): 1779-1791.

9. Schmidli J, Hunzicker T, Moesli P, et al. Cultivation of Borrelia burgdorferi from joint fluid

three months after treatment of facial palsy due to Lyme borreliosis. J Infect Dis

1988;158:905-6.

10. Haupl, T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR, Burmester

GR. Persistence of B. burgdorferi in Ligamentous Tissue from a Patient with Chronic Lyme

Borreliosis. Arthritis Rheum 1993; 36:1621-6.

11. Pfister HW, Preac-Mursic V, Wilske B, Schielke E, Sorgel F, Einhaupl KM. Randomized

comparison of ceftriaxone and cephotaxime in Lyme neuroborreliosis. J Infect Dis. 1991; 163

(2): 311-318.

12. Hassler D, Riedel K, Zorn J, Preac-Mursic V. Pulsed High Dose Cefotaxime Therapy in

Refractory Lyme Borreliosis (Letter) Lancet; 338:193.

13. Klempner MS, Noring R, Rogers RA. Invasion of Human Skin Fibroblasts by the Lyme

Disease Spirochete, Borrelia burgdorferi . J Infect Diseases 1993;67:1074-81.

14. Ma Y, Sturrock A, Weis JJ. Intracellular localization of Borrelia burgdorferi within human

endothelial cells. Infect Immun 1991;59:671-78.

15. Duray PH, Johnson RC. The histopathology of experimentally infected hamsters with the

Lyme disease spirochete, Borrelia burgdorferi . Proc Soc Exp Biol Med. 1986: 263-269.

16. Georgilis K, Peacocke M, and Klempner MS. Fibroblasts Protect the Lyme Spirochete,

Borrelia burgdorferi , from Ceftriaxone in vitro. J. Infec. Dis. 1992:166:440-4.

17. MacDonald AB, Berger BW, Schwan TG. Clinical implications of delayed growth of the

Lyme borreliosis spirochete, Borrelia burgdorferi . Acta Tropica 1991;48:89-94.

18. Beaman BL, Scates SM. Role of L-Forms of Nocadia caviae in the development of chronic

mycetomas in normal and immunodeficient murine models. Infect Immun. 1981: 33 (3): 893-

907.

19. Cook J, et al. Chronic arthritis produced by streptococcal L-forms. J Pathol. 1969; 99 (4):

283-297.

20. Preac-Mursic V, et al. Formation and Cultivation of Borrelia burgdorferi Spheroblast-L Form

Variants. Infection 24(1996);3.

21. Coyle PK, Schutzer SE, Deng Z, Krupp LB, Belman AL, Benach JL, Luft BJ. Detection of

Borrelia burgdorferi antigens in antibody negative cerebrospinal fluid in neurologic Lyme

disease. Neurology 1995;45(11):2010-2015.

22. Lawrence C, Lipton RB, Lowy RD, Coyle PK. Seronegative Chronic Relapsing

Neuroborreliosis. Eur Neurol. 1995;35:113-117.

23. Simon MM, Wallich R, Kramer MD. Borrelia burgdorferi infection of inbred strains of mice

provides insights into cellular and molecular parameters of pathogenesis and protection of

Lyme disease: A viewpoint. J Spirochetal & Tickborne Dis 1996; 3:45-52.

Dr. Jones practices medicine at 111 Park Street, New Haven, Connecticut 06511, Tel. 203-772-

1123.

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