Tetracycline therapy - chronic Lyme

Discussion in 'Fibromyalgia Main Forum' started by dontlikeliver, Aug 18, 2005.

  1. dontlikeliver

    dontlikeliver New Member

    TETRACYCLINE THERAPY FOR CHRONIC LYME DISEASE Sam T. Donta From Boston University Medical Center and Boston Veterans Affairs Medical Center, Boston, Massachusetts Two hundred seventy-seven patients with chronic Lyme disease were treated with tetracycline for 1 to 11 months (mean, 4 months); the outcomes for these patients were generally good.

    Overall, 20% of the patients were cured; 70% of the patients’ conditions improved, and treatment failed for 10% of the patients.

    Improvement frequently did not take place for several weeks; after 2 months of treatment, 33% of the patients’ conditions were significantly improved (degree of improvement, 75%–100%), and after 3 months of treatment, 61% of the patients’ conditions were significantly improved.

    Treatment outcomes for seronegative patients (20% of all patients) were similar to those for seropositive patients. Western immunoblotting showed reactions to one or more Borrelia burg-dorferi –specific proteins for 65% of the patients for whom enzyme-linked immunosorbent assays were negative.

    Whereas age, sex, and prior erythema migrans were not correlated with better or worse treatment outcomes, a history of longer duration of symptoms or antibiotic treatment was associated with longer treatment times to achieve improvement and cure.

    These results support the use of longer courses of treatment in the management of patients with chronic Lyme disease. Controlled trials need to be conducted to validate these observations.

    Reprints or correspondence: Dr. Sam T. Donta, Boston University Medical Center, 88 East Newton Street, Evans 6th Floor, Boston, Massachusetts 02118. Clinical Infectious Diseases 1997;25(Suppl 1):S52–6 This article is in the public domain.

    The clinical spectrum of illness caused by Borrelia burgdorf eri has been known since the early 1900s, even though the causative organism was not identified until 1982 [1 –3]. In Europe, the disease was described in primarily neurological terms [4], whereas in the United States (where the disease was first described as a cluster of cases of arthritis occurring in young children in Old Lyme, CT), the emphasis initially was placed on the joint manifestations [5].

    Indeed, the case defin-tion of the Centers for Disease Control and Prevention (CDC) includes arthritis but not arthralgias and other neurological symptoms [6].

    It has since become recognized that chronic symptoms consisting of fatigue plus musculoskeletal pains, paresthesias, and other neuropsychiatric dysfunctions are typ cal symptoms of chronic Lyme disease [7 –9]. Laboratory support for the diagnosis of Lyme disease beyond the erythema migrans phase has suffered from a lack of sens tive and definitive tests: ELISAs have been unreliable [10, 11]; western immunoblotting has been more sensitive but more difficult to perform and standardize; and PCR analysis of DNA is insufficiently sensitive [12]. Furthermore, none of the laboratory tests can be used to estimate the extent of infection, its prior duration, or its prognosis.

    The treatment of chronic Lyme disease is also inadequately defined. Although recommendations have been made for 1 month of treatment [13], there have been no trials to test or support this view. Most physicians practicing in this area believe that a longer duration of treatment is needed to effect significant improvement or cure [14].

    Because of our initial positive experience with tetracycline therapy for patients with symptoms compatible with those of chronic Lyme disease [15], many subsequent patients were treated with this antibiotic.

    The results of tetracycline treatment for 277 patients seen between 1988 and 1995 are reported here. Patients and Methods Patients were seen at the University of Connecticut’s Lyme Disease Clinic (Farmington, CT) between 1988 and 1993 and at Boston University Medical Center (Boston) from 1993 to 1995.

    The patients described herein are those whose symptoms existed for œ 3 months with or without a history of tick bite (29% with known bite) or rash (44% with known rash). Inclusion criteria were a combination of at least two of three sets of major symptoms: fatigue, neurological complaints (e.g., paresthesias, cognitive dysfunction, and radicular pains), and musculoskeletal complaints (e.g., arthralgias, myalgias, and weakness).

    Many patients had other symptoms such as visual and auditory disturbances, palpitations, and gastrointestinal and genitourinary dysfunction (the combination of major symptoms and other symptoms has also been noted in other studies [7 –9, 14]).

    All patients were evaluated for alternative diagnoses such as rheumatoid arthritis, systemic lupus erythematosus, and other neurological disorders. Fibromyalgia and/or chronic fatigue had been diagnosed for some patients; if these patients met the clinical inclusion criteria, they were offered a trial of tetracycline therapy.

    Serological evaluations from 1988 to 1993 included ELISA and western immunoblotting conducted at the University of Connecticut Health Center (Farmington, CT); those evaluations from 1993 to 1995 included IgM capture assays and western immunoblotting conducted by BBI/North American Labora- tories (New Britain, CT).

    Both laboratories have rigid quality control programs and have participated in the evaluation of laboratory tests for Lyme disease [10]. Western immunoblot-ting was considered to be positive if there were one or more reactions to proteins specific to B. burgdorferi (i.e., 23 kD, 31 kD, 34 kD, 39 kD, and 83 kD); reactions to several specific proteins were found for most patients, and reactions to at least two proteins (e.g., 23 kD and 41 kD) were found for all patients.

    Patients were treated with tetracycline hydrochloride (500 mg three times daily) before or between meals. The treatment was continued until the patient’s symptoms resolved or the patient’s condition improved. For those patients whose symptoms completely resolved, treatment was generally continued for one more month.

    For those patients whose conditions im-proved but whose symptoms did not resolve, treatment was generally continued for one to two more months before stopping or changing therapy. For those patients for whom treatment failed, therapy was continued for at least 3 months before being judged a failure.

    A treatment cure was defined as the absence of symptoms for 1 year or more following cessation of therapy; significant improvement was defined as having recovered ¤ 75% of previous normal function, as assessed by the patient. The conditions of patients whose symptoms resolved completely by the end of treatment but who subsequently had relapsing symptoms after tetracycline therapy was discontinued were considered significantly improved but not cured; these patients usually relapsed within 2–6 weeks following therapy. Results Serological reactivity and treatment outcome.

    A total of 277 patients were treated with tetracycline for 1 month or more. A comparison of the results of EIA and western immunoblotting for these patients is shown in table 1. Overall, EIA or improve-western immunoblotting was positive for 81% of the patients. EIA was positive for 29% of the patients, and western immu- noblotting was positive for 81% of the patients.

    Whereas EIA was positive for 0.8% of the patients for whom western immu noblotting was negative, EIA was negative for 52% of the patients for whom western immunoblotting was positive. Table 1. Comparison of the results of western immunoblotting and EIA for 254 patients with chronic Lyme disease. Western immunoblotting EIA Positive Negative Positive 72 (28) 2 (0.8) Negative 133 (52) 47 (18.5) NOTE. Data are number (%) of 254 patients for whom the serological test was positive.

    Table 2. Comparison of treatment outcomes of chronic Lyme dis- ease according to serological results. No. (%) of patients with treatment outcome Serological test, result Cure Improvement Failure EIA Positive 10 (14) 51 (74) 8 (12) Negative 34 (22) 105 (70) 12 (8) Western immunoblotting Positive 38 (20) 137 (71) 18 (9) Negative 10 (26) 25 (66) 3 (8) A comparison of treatment outcomes according to seropositivity or seronegativity is shown in table 2.

    There were no significant differences in treatment outcomes between those patients for whom western immunoblotting or EIA was positive and those patients who were seronegative. Age, sex, and treatment outcome. The age of patients treated with tetracycline ranged from 13 to 75 years (mean,-39 years). There were no differences in treatment outcomes according to age (data not shown). Two-thirds of the patients were female; there was a tendency to fewer cures (14% vs. 32%, respectively) and more failures (11% vs. 7%, respec tively) for females than for males (table 3). Duration of prior symptoms and treatment outcome. Pa- tients whose symptoms had been present for > 1 year had fewer cures and more treatment failures than did those patients whose symptoms had been present for < 1 year (table 4).

    Patients with symptoms for > 3 years fared poorer than did those with symptoms for either 1–3 years or < 1 year. The duration of prior symptoms was also directly correlated with the time to onset of any improvement (i.e., the longer the duration of prior symptoms, the longer the time until any signs of improvement were noted; table 5). The mean time to onset of any improvement was 0.9 month. The extent of improvement at 2 and 3 months after the initiation of tetracycline therapy is shown in figure 1. By 2 months of therapy, the mean degree of improvement was 50%–75%, with only one-third of the patients believing that their conditions had significantly improved (degree of improvement, 75%–100%); by 3 months, 61% of the patients believed that their conditions had improved ¤ 75%.

    Table 3. Comparison of treatment outcomes of chronic Lyme dis- ease according to sex. No. (%) of patients with treatment outcome Sex Cure Improvement Failure Male 27 (32) 51 (61) 6 (7) Female 22 (14) 115 (75) 17 (11) Table 4. Comparison of treatment outcomes of chronic Lyme dis- ease according to duration of prior symptoms. No. (%) of patients with treatment outcome Duration (y) of prior symptoms Cure Improvement Failure < 1 33 (28) 78 (67) 6 (5) 1–3 9 (15) 45 (75) 6 (10) > 3 7 (11) 43 (71) 11 (18) Duration of treatment and treatment outcome. Patients were treated for as little as 1 month or as long as 11 months (median, 4 months).

    Most patients were treated for between 3 and 6 months. The duration of treatment was correlated with the duration of prior symptoms (data not shown). Prior treatment and treatment outcome. Patients who were treated with any antibiotics at any time before the onset of tetracycline therapy had fewer cures (16% vs. 31%, respectively) and a generally poorer outcome than did those who were not previously treated (table 6). These poorer outcomes were not dependent on the duration of prior symptoms. Treatment outcome and serological reactivity. The results of western immunoblotting for the first 86 patients studied before and after treatment are shown in table 7.

    Western immu- noblotting was positive for IgM for 94% of the symptomatic patients, and IgM was the only antibody found for 36% of these patients. With successful treatment, the rate of IgM seropositivity decreased to 25%, compared with a rate of 69% for IgG seropositivity; 22% of the patients became seronegative. Retreatment and treatment outcome. Ninety-eight patients who were cured or whose conditions were improved at the end of treatment but who had relapsing symptoms were retreated with antibiotics (table 8). Fifty of these patients were given another course of tetracycline therapy (cure rate, 28%; signifcant improvement rate, 70%).

    Of thirty-five patients treated with a combination of a macrolide and hydroxychloroquine, 74% were cured or believed that their conditions were further improved. Of 13 patients treated with iv ceftriaxone, one was cured, and 10 noted significant improvement in their conditions. Discussion The optimum criteria and methods for the diagnosis and treatment of chronic Lyme disease remain to be defined. Most practitioners use a clinical definition that includes a combination of symptoms and signs with or without positive serological support [14], but there are some who advocate a diagnosis that requires positive serologies [16].

    A recommendation was made at a meeting of territorial public health officers in the fall of 1995 that western blotting be done only to confirm screening EIAs that reveal positive antibody titers [6]. According to our results and a physician survey [14], this approach would not diagnose œ 50% of the cases of chronic Lyme disease. Until better criteria are established, it would seem advisable to recommend that western immunoblotting, especially testing for IgM, be conducted for all patients who meet the clinical criteria.

    IgM reactions may represent reactivation of latent disease or persistent infection and have been noted in other chronic infections (e.g., toxoplasmosis). Seronegative Lyme disease is a recognized entity [17–19] (K. Kezler, R. C. Tilton, M. Manak, and S. T. Donta, unpublished data), and our results demonstrate that patients with similar clinical symptoms who are seronegative have responses to antibiotic treatment that are not distinguishable from those of seropositive patients (including those who meet the current CDC criteria). These findings also suggest that circulating antibody responses are not the most relevant correlates of disease presence or activity. Until better diagnostic tests are available to document the presence and extent of infection, clinical criteria remain the mainstay of diagnosis.

    The optimum treatment for chronic Lyme disease also re mains to be delineated. No controlled clinical trials have been conducted to date, yet there appear to be strong opinions regarding the type and duration of any antibiotic therapy [20]. In contrast, there is a consensus that a 3- to 4-week course of therapy with a tetracycline or b-lactam antibiotic appears to yield a successful outcome of the earliest manifestation of Lyme disease (erythema migrans) [13]. Although it has yet to-be established whether all or most cases of chronic Lyme disease are due to persistent infection, our results support the hypothesis that it is a persistent infection and provide the basis organ-for a reasonable approach to its management.

    The rationale for our use of tetracycline hydrochloride for the treatment of patients with chronic Lyme disease arose from several observations. One observation was that patients being seen in our Lyme disease clinic who had been previously treated with b-lactam antibiotics, including iv ceftriaxone, were not routinely cured or did not believe that their conditions were significantly improved, even after several months of therapy; serological tests for most of these patients were unequivocally positive.

    Another observation was that patients treated with doxycycline (100 mg twice daily) had some improvement in their conditions that was not sustained. When the pharmacologic properties of doxycycline and tetracycline hydrochloride are compared, the absorption of doxycycline is sometimes better at comparable doses, but 500 mg of tetracycline three times daily achieves higher serum levels than does 100 mg of doxycycline twice daily [21]. Because doxycycline is also highly bound to proteins (which accounts for its longer half-life), the amount of free drug available to diffuse into tissues is less than that of tetracycline [21].

    A third observation was the hypothesis that chronic Lyme disease is a persistent intracellular infection. This hypothesis Table 5. Comparison of the onset of improvement of chronic Lyme disease according to the duration of prior symptoms.

    Duration of prior symptoms (Nº patients) Percent of patients with I time to improvement (m) 1 2 3 4 5–6 7–8 9–12 13–16 < 1 y (122) 12 48 12 17 7 2 1 1 1–3 y (73) 5 26 24 24 16 4 1 0 > 3 y (74) 1 28 9 24 23 9 5 1 Table 6. Comparison of treatment outcomes of chronic Lyme dis-ease according to prior antibiotic treatment. Prior treatment (no.(% )of patients) with treatment outcome Cure Improvement Failure Yes 27 (16) 123 (73) 19 (11) No 22 (31) 44 (63) 4 (6) draws support from what is known about other chronic infections, which most, if not all, have an intracellular reservoir (e.g., Chlamydia, Legionella, Leishmania, Rickettsia, and Mycobacterium tuberculosis infections).

    An intracellular location could also explain the difficulties posed for b-lactam antibiotics as treatment of Lyme disease; this location is supported by data from a tissue culture model of B. burgdorferi infection in which ceftriaxone was ineffective against intracellular organisms [22].

    Our results show that a 3- to 6-month course of treatment is associated with cure or significant improvement in 80%–90% of patients with chronic Lyme disease. The most important determinant of treatment duration and outcome appears to be the duration of symptoms before tetracycline therapy (tables 4 and 5). Improvement was noted to begin as early as 1–2 weeks, but in patients with symptoms for >1 year, the onset of any improvement frequently did not occur before 4–6 weeks of therapy had been given. It would not then be surprising if both patients and physicians would conclude that this mode of therapy was ineffective when there was no improvement after 3–4 weeks of therapy.

    This slow rate of improvement may correlate best with organisms for which the rates of multiplication and metabolism are slow, as is known for B. burgdorferi [23].

    We speculate that the frequently noted cycles of improvement and relapse could be consistent with the varying metabolic activities of a heterogeneous population of spirochetes. Our results also show that tetracycline is apparently effective in resolving symptoms associated with CNS function (i.e., cognition and emotions); these symptoms are probably secondary to encephalopathy. Recent studies with nonhuman primates have demonstrated that the CNS, especially sensory functions, is the main target of B. burgdorferi infection [24]. In this setting, tetracycline penetration would not appear to be a major limitation, as it might be in meningitis.

    Our results suggest that the outcome for patients with symptoms compatible with those of chronic Lyme disease is gener- ally good when tetracycline is administered for 3–6 months. Although this approach is relatively simple and inexpensive, it needs to be validated by controlled clinical trials comparing longer terms of therapy with short terms of therapy. Of great interest as well would be trials comparing the outcome of iv b-lactam therapy with that of tetracycline treatment.

    Table 7. Results of western immunoblotting before and after treat- ment of chronic Lyme disease. No. (%) of patients with indicated result Symptomatic Asymptomatic Result (n † 64) (n † 32) IgG 4 (6) 17 (53) IgM 23 (36) 3 (9) IgG and IgM 37 (58) 5 (16) No antibody 0 7 (22) Table 8. Comparison of treatment outcomes of chronic Lyme dis- ease according to retreatment. No. of patients with treatment outcome Retreatment Cure Improvement Failure Tetracycline 14 35 1 Macrolide plus hydroxychloroquine 4 22 9 IV ceftriaxone 1 10 2 References 1. Afzelius A. Erythema chronicum migrans.

    Acta Derm Venereol (Stockh) 1921; 2:120–5. 2. Steere AC, Bartenhagen NH, Craft JE, et al. The early clinical manifesta-1995; tions of Lyme disease. Ann Intern Med 1983; 99:76–82. 3. Burgdorfer W, Barbour AG, Hayes SF, et al. Lyme disease —a tick-borne spirochetosis? Science 1982; 216:1317–9. 4. Bannwarth A. Chronische lymphocytare meningitis entzundliche polyneu-16. ritis and ‘‘rheumatismus.’’ Arch Psychiatr Nervenkr 1941; 113: 284–376. 5. Steere AC, Malawista SE, Hardin JA, Ruddy S, Askenase PW, Andiman WA. Erythema chronicum migrans and Lyme arthritis: the enlarging clinical spectrum. Ann Intern Med 1977; 86:685–98.

    6. Centers for Disease Control. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diag- nosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995; 44: 590–1. 7. Shadick NA, Phillips CB, Logigian EL, et al. The long-term clinical out- comes of Lyme disease. Ann Intern Med 1994; 121:560–7. 8. Asch ES, Bujak DI, Wiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 1994; 21: 454–61. 9. Fallon B, Nields JA. Lyme disease: a neuropsychiatric illness. Am J Psy- chiatry 1994; 141:1571–83.

    10. Fister RD, Weymouth LA, McLaughlin JC, Ryan RW, Tilton RC. Compar- ative evaluation of three products for the detection of Borrelia burgdorf- eri antibody in human serum. J Clin Microbiol 1989; 37:2834–7. 11. Hedberg CW, Osterholm MT. Serologic tests for antibody to Borrelia burgdorferi—another Pandora’s box for medicine? Arch Intern Med 1990; 150:732–3. 12. Luft BJ, Steinman CR, Neimark HC, et al. Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA 1992; 267:1364–7. 13. Luft BJ, Gorevic PD, Halperin JJ, Volkman DJ, Dattwyler RJ. A perspec-tive on the treatment of Lyme borreliosis. Rev Infect Dis 1989; 11(suppl 6):S1518–25. 14. Ziska MH, Donta ST, Demarest F. A survey of physician opinions and preferences in the diagnosis and treatment of Lyme disease. Infection manifesta-1995; 23:1–5. 15. Donta ST. Improvements in the diagnosis and treatment of Lyme disease [abstract no 95]. In: Program and abstracts of the 5th International Conference on Lyme Borreliosis (Arlington, VA). 1992. polyneu- 16.Johnson BJB, Robbins KE, Bailey RE, et al. Serodiagnosis of Lyme dis- ease: accuracy of a two-step approach using a flagella-based ELISA and immunoblotting. J Infect Dis 1996; 174:346–53. 17. Preac-Mursic V, Weber K, Pfister HW, et al. Survival of Borrelia burg- dorferi in antibiotically treated patients with Lyme borreliosis. Infection 1989; 17:6. 18. Preac-Mursic V, Pfister HW, Spiegel H, et al. First isolation of Borrelia burgdorferi from an iris biopsy. J Clin Neuro Ophthalm 1993; 13: 155–61. 19. Mouritsen CL, Wittwer CT, Litwin CM, et al. Polymerase chain reaction detection of Lyme disease: correlation with clinical manifestations and serologic responses. Am J Clin Pathol 1996; 105:647–54. 20. Lightfoot RW, Luft BJ, Rahn DW, et al. Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive sero- logic result for Lyme disease. Ann Intern Med 1993; 119:503–9. 21. Kucers A, Bennett NMcK, eds. The use of antibiotics. 2nd ed. London: William Heinemann Medical Books, 1975:390–2. 22. Georgilis K, Peacocke M, Klempner MS. Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. J Infect Dis 1992; 166:440–4. 23. Barbour AG. Isolation and cultivation of Lyme disease spirochetes. Yale J Biol Med 1984; 57:521–5. 24. Pachner AR, Delaney E, O’Neill T, Major E. Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease. Neurology 1995; 45:165–72.
    [This Message was Edited on 08/18/2005]

    ANNXYZ New Member

    doctors treating chronic lyme with hands on experience .
    This basically says that most people need longer treatment
    than the CDC advises to begin improving or to be cured .

    Good to hear from practitioners whose knowlege of the disease is more complete than a few politically correct
    paragraphs that inaccurately describe a disease that
    is devastating .
  3. Mikie

    Mikie Moderator

    Wish I could read this, but I have to have paragraph breaks. It's all running together and making me disoriented.

    Thanks for posting, though.

    Love, Mikie
  4. dontlikeliver

    dontlikeliver New Member

    have inserted breaks.
  5. Mikie

    Mikie Moderator

    This is a good article and I'm glad I got to read it. I would have put the paragraph breaks in myself, but I got too dizzy just trying to do it.

    I know that for mycoplasma infections, it takes the Doxy 100 mgs twice a day at least six months to work. My symptoms did improve before that time, but they would come back. As you know, it took 2 1/2 years for me to be able to go off the Doxy completely. Even with the probiotics, plain old tetracycline ravages my stomach. I do take it on a short-term basis for other bacterial infections like the bronchitis I had with the flu. It works amazingly well for me.

    I think Lyme and mycoplasma infections are far more widespread than we are being informed. In some cases, 70 percent of those with CFIDS/ME/FMS/GWI tested had a chronic mycoplasma infection. Considering the level of false negative results, the number may be much higher.

    Long-term use of ABX treatment seems to be the only effective treatment at present. I do take the transfer factors now and the TF C targets Lyme. There is one which targets mycoplasmas. It has to be ordered through one's doc here. I do not believe the TF's should be the first choice of treatment. I believe the ABX do a much faster job and give the immune system a chance to rest up. At some point, however, I think it is helpful to switch to the TF's to get one's immune system trained to fight the pathogens. As you also know, I believe in probiotics, undenatured whey, and colostrum to build up one's immune system.

    There are critics of long-term ABX treatment, but there is not much of an alternative which is effective. I believe it is far better to go the ABX route than to sit by and let ones body get sicker and sicker from a horrible chronic stealth infection.

    Love, Mikie