Ineffectiveness of Tigecycline against Persistent Borrelia burgdorferi

Center for Comparative Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 12/2009; 54(2):643-51. DOI: 10.1128/AAC.00788-09
Source: PubMed


The effectiveness of a new first-in-class antibiotic, tigecycline (glycylcycline), was evaluated during the early dissemination (1 week), early immune (3 weeks), or late persistent (4 months) phases of Borrelia burgdorferi infection in C3H mice. Mice were treated with high or low doses of tigecycline, saline (negative-effect controls), or a previously published regimen of ceftriaxone (positive-effect controls). Infection status was assessed at 3 months after treatment by culture, quantitative ospA real-time PCR, and subcutaneous transplantation of joint and heart tissue into SCID mice. Tissues from all saline-treated mice were culture and ospA PCR positive, tissues from all antibiotic-treated mice were culture negative, and some of the tissues from most of the mice treated with antibiotics were ospA PCR positive, although the DNA marker load was markedly decreased compared to that in saline-treated mice. Antibiotic treatment during the early stage of infection appeared to be more effective than treatment that began during later stages of infection. The viability of noncultivable spirochetes in antibiotic-treated mice (demonstrable by PCR) was confirmed by transplantation of tissue allografts from treated mice into SCID mice, with dissemination of spirochetal DNA to multiple recipient tissues, and by xenodiagnosis, including acquisition by ticks, transmission by ticks to SCID mice, and survival through molting into nymphs and then into adults. Furthermore, PCR-positive heart base tissue from antibiotic-treated mice revealed RNA transcription of several B. burgdorferi genes. These results extended previous studies with ceftriaxone, indicating that antibiotic treatment is unable to clear persisting spirochetes, which remain viable and infectious, but are nondividing or slowly dividing.

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Available from: Benjamin Luft, Oct 07, 2015
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    • "Although animals do not experience symptoms that might be judged to be PTLDS, in various animal models (mice, dogs and rhesus macaque monkeys), antibiotic therapy with doxycycline, ceftriaxone or tigecycline has not fully eradicated B. burgdorferi, as determined by methods including xenodiagnosis, although viable organisms have not been able to be cultured in conventional culture media.11,12,13,14 Others have raised concerns about such findings, including the use of high concentration inocula and the use of stationary-phase organisms for infection, insufficient antibiotic dosing and other methodological issues, including concerns that rodents are a natural reservoir of B. burgdorferi and that studies of persistence would not approximate human infections.15,16 "
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    ABSTRACT: Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.
    Emerging Microbes and Infections 07/2014; 3(7):e49. DOI:10.1038/emi.2014.53 · 2.26 Impact Factor
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    • "In contrast, some bacterial species, such as M. tuberculosis, cause a chronic persistent infection that takes at least 6 months to cure while the immune system seems to be less adequate to clear residual persisters left over from chemotherapy. More recently, Borrelia burgdorferi has been demonstrated to have a persistence problem despite antibiotic treatment using mouse and monkey models,53,54 which may provide some explanation for persisting chronic Lyme disease observed in some patients.47 In addition to bacterial factors that vary in persistence, the host susceptibilities that vary among individuals play a role in the degree of persistence during infection as well. "
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    ABSTRACT: Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but can regrow under appropriate conditions. Persisters underlie persistent and latent infections and post-treatment relapse, posing significant challenges for the treatment of many bacterial infections. The current definition of persisters has drawbacks, and a Yin–Yang model is proposed to describe the heterogeneous nature of persisters that have to be defined in highly specific conditions. Despite their discovery more than 70 years ago, the mechanisms of persisters are poorly understood. Recent studies have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. These include toxin–antitoxin modules, stringent response, DNA repair or protection, phosphate metabolism, alternative energy production, efflux, anti-oxidative defense and macromolecule degradation. More sensitive single-cell techniques are required for a better understanding of persister mechanisms. Studies of bacterial persisters have parallels in other microbes (fungi, parasites, viruses) and cancer stem cells in terms of mechanisms and treatment approaches. New drugs and vaccines targeting persisters are critical for improved treatment of persistent infections and perhaps cancers. Novel treatment strategies for persisters and persistent infections are discussed.
    Emerging Microbes and Infections 01/2014; 3(1). DOI:10.1038/emi.2014.3 · 2.26 Impact Factor
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    • "Barthold et al134 demonstrated that neither standard nor more aggressive antibiotic treatments are able to clear persisting Bb from mice, implying that Bb survives antibiotic treatment by shifting into nondividing or slowly dividing forms that retain viability, and possibly infectiousness. Yrjänäinen et al136 demonstrated recalcitrant Bb infection by inducing immune inhibition. "
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    ABSTRACT: Is chronic illness in patients with Lyme disease caused by persistent infection? Three decades of basic and clinical research have yet to produce a definitive answer to this question. This review describes known and suspected mechanisms by which spirochetes of the Borrelia genus evade host immune defenses and survive antibiotic challenge. Accumulating evidence indicates that Lyme disease spirochetes are adapted to persist in immune competent hosts, and that they are able to remain infective despite aggressive antibiotic challenge. Advancing understanding of the survival mechanisms of the Lyme disease spirochete carry noteworthy implications for ongoing research and clinical practice.
    International Journal of General Medicine 04/2013; 6:291-306. DOI:10.2147/IJGM.S44114
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