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La Presse Médicale
Volume 44, n° 7-8
pages 828-831 (juillet 2015)
Doi : 10.1016/j.lpm.2015.06.002
Critical review of studies trying to evaluate the treatment of chronic Lyme disease
Revue critique des études essayant d’évaluer le traitement de la maladie de Lyme chronique

Christian Perronne
 AP–HP, hôpitaux universitaires Paris–Île-de-France Ouest, University of Versailles Saint-Quentin, département d’infectiologie, 92380 Garches, France 

Although antibiotic treatment for Lyme disease is effective in some patients, especially during the early phase of the disease, many patients suffer from chronic disease with persisting and evolving signs and symptoms. The role of persistent microorganisms in the pathophysiology of chronic syndromes following Lyme disease treated according to the current recommendations is still being debated [1, 2, 3]. The clinician has no diagnostic test to use in routine practice to check for the persistence of live Borreliae . Several publications show contradictory results regarding the treatment of chronic Lyme disease.

Efficacy of prolonged antibiotic treatment for chronic Lyme disease

The efficacy of long-term antibiotic treatment in patients with chronic Lyme disease or chronic syndromes following tick-bites is still controversial [2]. Several open-label studies have shown that a large proportion of patients with chronic Lyme disease improve after prolonged courses of antibiotic treatment [4, 5, 6]. For their condition to improve, patients with a long history of the disease required longer antibiotic treatments. Several randomized studies tried to evaluate the efficacy of antibiotic treatment versus placebo in chronic Lyme disease. In one study, no difference was shown [7]. In the two following studies, a significant albeit limited beneficial effect of antibiotic therapy was demonstrated. In the study by Krupp et al., a four-week course of treatment with ceftriaxone improved the fatigue syndrome as reassessed at 6 months, with a significant improvement of 64% in the ceftriaxone group versus 18.5% in the placebo group (P <0.001) [8]. In the study by Fallon et al. that included patients with memory impairment persisting after an initial three-week course of treatment with ceftriaxone, a 10-week long retreatment with ceftriaxone was successful, versus placebo, in improving their cognitive functioning (P <0.01). However, this beneficial effect was transient and the difference between the retreated and the non-retreated groups disappeared after 6 months [9]. This transient effect of antibiotics could be due to bacterial persistence.

B. burgdorferi is highly adaptable and able to persist within tissues

B. burgdorferi has a complex genetic structure. It has more than 132 function genes. In contrast, Treponema pallidum , another spirochete, only has 22 function genes. B. burgdorferi has one linear chromosome and 21 plasmids. Chlamydophila only has 7 plasmids. This genetic complexity suggests that B. burgdorferi is a highly adaptable organism capable of evading the human immune response. It can do so through different processes such as immunosuppression, antigenic variation, mutation and gene recombination. It can survive extracellularly as well as intracellularly; it releases factors for cell adherence and some studies have shown that it can persist in atypical dormant state forms through cyst formation. The cyclic conversion of cystic forms into free spirochetes releases new Borreliae in tissues. Animal models in mice, dogs and monkeys clearly demonstrate that B. burgdorferi may persist in tissues even after several months of treatment with antibiotics that are effective in vitro [2, 10]. Persistence of B. burgdorferi after antibiotic treatment has also been reported in some studies done on humans [11, 12, 13]. Dormant persister cells of bacteria from different genera can escape the bactericidal effect of antibiotics and be responsible for latent infections [11, 12, 13, 14]. Persisters are quiescent bacterial cells that are able to survive antibiotics or stresses and that are able to resume growth under favorable conditions [15]. Clinicians have no diagnostic tests to check for the persistence of live Borreliae . Changes seen in the serologic profile are not contributive. The antibiotic susceptibility profile of the growing forms of B. burgdorferi differs from that of the persistent forms of the bacterium [16]. The cystic forms of B. burgdorferi are able to escape the antibactericidal effect of antibiotics. Moreover, the persistence of other species of Borreliae has not yet been well studied.

Several species of Borreliae are pathogenic for humans

Borreliae were initially reported by Charles Nicolle as microbial agents responsible for relapsing fever (Borrelia recurrentis ). Relapsing fever due to another species of Borrelia (B. crocidurae ) is endemic in some parts of Africa [17]. While Lyme disease is usually described as an infection due to B. burgdorferi sensu stricto, to B. afzelii and to B. garinii , Lyme-like diseases may be due to other species of Borrelia. They are rarely considered or tested for, and their antibiotic susceptibility profile is poorly studied [3, 14, 18]. Borrelia miyamotoi , phylogenetically close to relapsing fever borreliae, is now recognized as a cause of Lyme-like disease and relapsing fever in Asia, Europe and North America [14, 18]. Another novel isolate of Borrelia has been identified by PCR in a post-treatment serum from a patient with neurologic Lyme disease, showing the capacity of this new species to persist despite antibiotic treatment [14]. Few studies have looked at drugs capable of killing persistent B. burgdorferi or other species of Borrelia .

Activity of drugs against Borrelia persisters

Metronidazole and tinidazole, which have a high in vitro activity against B. burgdorferi , are also effective against cystic forms of the bacterium [19]. Tigecycline is effective against round-body propagules of B. burgdorferi [20]. Some drugs, which are not antibiotics, can play a role against persistent bacteria. It has been suggested in an open-label study that the combination of hydroxychloroquine with antibiotics improves the efficacy of antibiotic treatment against chronic Lyme disease [5]. Hydroxychloroquine and chloroquine are able to enhance the bactericidal activity of antibiotics in the phagolysosome within leucocytes, as shown for Mycobacterium tuberculosis or Coxiella burnetii [21, 22]. Q fever is a good example of the antibacterial use of hydroxychloroquine. When combinations of three antibiotics of different classes were given daily for as long as three years, live forms of Coxiella burnetii could still be isolated from the cardiac valves of patients suffering from a chronic form of the disease. The systematic addition of hydroxychloroquine to the antibiotic treatment, consisting of a single antibiotic, doxycycline, for at least 18 months, results in the cure of the majority of chronic Q fever cases. Furthermore, it has been shown that hydroxychloroquine has a direct inhibitory effect against B. burgdorferi [23]. In addition to this antibacterial effect, hydroxychloroquine and chloroquine are mainly known as anti-parasitic drugs and their clinical efficacy could be due in part to their activity against parasites responsible for coinfections, such as Babesiae . In fact, alternative treatments to antibiotics have rarely been studied [16, 24, 25]. In these studies, melittin, grapefruit seed extract, clofazimine (already used for leprosy or mycobacteria), bismuth (currently used for Helicobacter pylori ), amphotericin B (an antifunfal drug), amodiaquin and quinine hydrobromide (effective against Plasmodium sp.) should be further studied against persistent forms of B. burgdorferi . The study of effective non-antibiotic drugs should be included in the clinical research programs. It could be a partial response to the fear of developing antibiotic resistance when treating cases of chronic Lyme disease.

Role of coinfections in the persistence of signs and symptoms

The limited efficacy of antibiotic treatments observed in some patients could also be due to coinfections with other microorganisms. Acute or chronic syndromes occurring after tick bite may be due, in part or in total, to pathogens other than Borrelia sp., some of them tick-transmitted, others transmitted through different mechanisms [3]. Other well-known tick-transmitted infections are human granulocytic anaplasmosis and babesiosis, a frequent parasitic infection of animals. Other bacterial species are also able to persist: Chlamydophila , Mycoplasma , Bartonella , Coxiella burnetii , and a new tick-borne bacterial pathogen, Candidatus Neoehrlichia mikurensis [26, 27]. In addition to bacteria and parasites, viruses such as HHV-6, or fungi such as Leishmania , could be involved. Some of these infections may have an impact on the neuropsychiatric status of patients. For example, Toxoplasma gondii infection can increase the risk of suicidal behavior [28, 29]. As described above, the anti-parasitic effect of hydroxychloroquine could partly explain its clinical efficacy in some patients through its activity against Babesiae . The anti-fungal drug, fluconazole may improve some patients [30]. It is not known if this clinical benefit is due to the activity against a fungal coinfection or if it is due to the presence of receptors to fluconazole on persistent microorganisms.

Critical analysis of studies trying to evaluate the treatment of chronic Lyme disease

Exacerbation of signs and symptoms is a frequent event during antibiotic treatment of Lyme disease. The acute exacerbations at the beginning of treatment, known as the Jarish-Herxheimer reaction, have been well described. Exacerbations occurring during prolonged antibiotic treatment of chronic Lyme disease may occur later in the course of treatment and may have a cyclic course for weeks or months before progressively disappearing (personal clinical observation). The evaluation of antibiotic efficacy, versus placebo, after several weeks of treatment may be biased. The first cause of bias is the cyclic nature of the disease, compounded with the intermittent exacerbations due to antibiotics in the treated group. Some patients in the treated arm who will eventually be cured may experience an exacerbation at the time-point of evaluation. The second bias is when the tool used for evaluation is too general, such as a quality of life score, which does not analyze the different categories of signs and symptoms (general, articular, neurologic, cardiac, etc.). At a given point in time, a certain category of signs or symptoms may have disappeared and improvement may be long term, while another category of signs and symptoms may appear to be transient worsening, leading to the false conclusion of global failure. So, in fact, the two randomized studies, which evaluated specific objective end-points, showed a benefit of antibiotic treatment, whilst the randomized study that used a general quality of life score did not. The design of future randomized studies should take into account these potential pitfalls.


Fundamental and clinical research is needed to move forward in the management of patients suffering from chronic Lyme disease or associated diseases. New PCR methods and new genomic techniques, such as high throughput sequencing, should be used to identify the microorganisms that could be involved in a particular patient [14]. New strategies should be designed in order to determine the best treatments against Borrelia sp. and the possible coinfections. The addition of a maintenance phase treatment to the induction phase treatment is probably needed in some patients. As well as drugs that are well-known to be effective against bacteria in their growth phase, other drugs, which can be effective against persistent bacteria, should be evaluated for their efficacy in the maintenance phase of treatment.

Disclosure of interest

the author declares that he has no conflicts of interest concerning this article.


The author thanks Nelly Pointis for her review of the English text.

 See the related editorial by Hansmann et al. published in the same issue,


Wormser G.P., Dattwyler R.J., Shapiro E.D., Halperin J.J., Steere A.C., Klempner M.S., and al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America Clin Infect Dis 2006 ;  43 : 1089-1134[IDSA Guidelines].  [cross-ref]
Stricker R.B. Counterpoint: long term antibiotic therapy improves persistent symptoms associated with Lyme disease Clin Infect Dis 2007 ;  45 : 149-157 [cross-ref]
Perronne C. Lyme and associated tick-borne diseases: global challenges in the context of a public health threat Front Cell Infect Microbiol 2014 ; 10.3389/fcimb.2014.00074
Donta S.T. Tetracycline therapy for chronic Lyme disease Clin Infect Dis 1997 ;  25 : S52-S56
Donta S.T. Macrolide therapy of chronic Lyme disease Med Sci Monit 2003 ;  9 : 136-142
Clarissou J., Song A., Bernede C., Guillemot D., Dinh A., Ader F., and al. Efficacy of a long-term antibiotic treatment in patients with a chronic tick associated poly-organic syndrome (TAPOS) Med Mal Infect 2009 ;  39 : 108-115
Klempner M.S., Hu L.T., Evans J., Schmid C.H., Johnson G.M., Trevino R.P., and al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease N Engl J Med 2001 ;  345 : 85-92 [cross-ref]
Krupp L.B., Hyman L.G., Grimson R., Coyle P.K., Melville P., Ahnn S., and al. Study and treatment of post-Lyme disease (STOP-LD). A randomized double masked clinical trial Neurology 2003 ;  60 : 1923-1930 [cross-ref]
Fallon B.A., Keilp J.G., Cordera K.M., Petkova E., Britton C.B., Dwyer E., and al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy Neurology 2008 ;  70 : 992-1003 [cross-ref]
Embers M.E., Barthold S.W., Borda J.T., Bowers L., Doyle L., Hodzic E., and al. Persistence of Borrelia burgdorferi in Rhesus macaques following antibiotic treatment of disseminated infection PLOS One 2012 ;  7 : e29914[Erratum PLOS One 2012; 7. doi: 10.1371.].
Phillips S.E., Mattman L.H., Hulinska D., Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated Infection 1998 ;  26 : 364-367 [cross-ref]
Hunfeld K.P., Ruzic-Sabljic E., Norris D.E., Kraiczy P., Strl F. In vitro susceptibility testing of Borrelia burgdorferi sensu lato isolates cultured from patients with erythema migrans before and after antimicrobial chemotherapy Antimicrob Agents Chemother 2005 ;  49 : 1294-1301 [cross-ref]
Masters E., Lynxwiler P., Rawlings J. Spirochetemia after continuous high-dose oral amoxicillin therapy Infect Dis Clin Pract 1994 ;  3 : 207-208 [cross-ref]
Lee S.H., Vigliotti J.S., Vigliotti V.S., Jones W., Shearer D.M. Detection of Borreliae in archived sera from patients with clinically suspect Lyme disease Int J Mol Sci 2014 ;  15 : 4284-4298 [cross-ref]
Zhang Y. Persisters, persistent infections and the Yin-Yang model Emerg Microbes Infect 2014 ; [doi: 10.1038/emi.2014.3].
Feng J., Wang T., Shi W., Zhang S., Sullivan D., Auwaerter P.G., and al. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library Emerg Microbes Infect 2014 ; 10.1038/emi.2014.53
Schwan T.G., Anderson J.M., Lopez J.E., Fischer R.J., Raffel S.J., McCoy B.N., and al. Endemic foci of the tick-borne relapsing fever spirochete Borrelia crocidurae in Mali, West Africa, and the potential for human infection PLOS Negl Trop Dis 2012 ;  2012 : [doi: 10.1371].
Branda J.A., Rosenberg E.S. Borrelia miyamotoi : a lesson in disease discovery Ann Intern Med 2013 ;  159 : 61-62 [cross-ref]
Brorson O., Brorson S.H. An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole APMIS 1999 ;  107 : 566-576 [cross-ref]
Brorson O., Brorson S.H., Scythes J., Mac Allister J., Wier A., Margulis L. Destruction of spirochete Borrelia burgdorferi round-body propagules (RBs) by the antibiotic tigecycline Proc Natl Acad Sci U S A 2009 ;  106 : 1865-1961
Crowle A.J., May M.H. Inhibition of tubercle bacilli in cultured human macrophages by chloroquine used alone and in combination with streptomycin, isoniazid, pyrazimamide, and two metabolites of vitamin D Antimicrob Agents Chemother 1990 ;  34 : 2217-2222 [cross-ref]
Rolain J.M., Colson P., Raoult D. Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century Int J Antimicrob Agents 2007 ;  30 : 297-308 [cross-ref]
Brorson O., Brorson S.H. An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine Int Microbiol 2002 ;  5 : 25-31 [cross-ref]
Lubke L.L., Garon C.F. The antimicrobial agent melittin exhibits powerful in vitro inhibitory effects on the Lyme disease spirochete Clin Infect Dis 1997 ;  25 : S48-S51
Brorson O., Brorson S.H. Grapefruit seed extract is a powerful in vitro agent against motile and cystic forms of Borrelia burgdorferi sensu lato Infection 2007 ; 35-206
Fehr J.S., Bloemberg G.V., Ritter C., Hombach M., Lüscher T.F., Weber R., and al. Septicemia caused by tick-borne bacterial pathogen Candidatus Neoehrlichia mikurensis Emerg Infect Dis 2010 ;  16 : 1127-1129 [cross-ref]
Grankvist A., Andersson P.O., Mattsson M., Sender M., Vaht K., Höper L., and al. Infections with the tick-borne bacterium “Candidatus Neoerlichia mikurensis” mimic noninfectious conditions in patients with B cell malignancies or auto-immune diseases Clin Infect Dis 2014 ;  58 : 1716-1722 [cross-ref]
Zhang Y., Träskman-Bendz L., Janelidze S., Langeberg P., Saleh A., Constantine N., and al. Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence J Clin Psychiatry 2012 ;  73 : 1069-1076 [cross-ref]
Pedersen M.G., Mortensen P.B., Norgaard-Pedersen B., Postolache T.T. Toxoplasma gondii infection and self-directed violence in mothers Arch Gen Psychiatry 2012 ;  69 : 1123-1130
Schardt F.W. Clinical effects of fluconazole in patients with neuroborreliosis Eur J Med Res 2004 ;  9 : 334-336

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