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      Combinations of registered drugs reduce treatment times required to deplete Wolbachia in the Litomosoides sigmodontis mouse model

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          Abstract

          Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4–6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no more than 7–10 days of treatment.

          Author summary

          Over the past years, more attention has been brought to neglected tropical diseases including lymphatic filariasis and onchocerciasis. The latter are caused by helminthic parasites and lead to chronic and debilitating symptoms and present a major health burden that also affects the economy of endemic countries. It has been suggested that disease elimination may be possible but an accelerated implementation of proven and cost-effective interventions are needed if the targets for elimination are to be achieved. Recently, an indirect mode of action has been identified, targeting bacterial Wolbachia endosymbionts within the filariae, which also kills the adult parasites, an advantage over the drug currently used for mass drug administration, i.e. ivermectin. Doxycycline has been successfully used in clinical trials, however due to its long regimen as well as restrictions of use in children and pregnant women new drugs or drug combinations are required that overcome these obstacles. Here, we present the filarial parasite Litomosoides sigmodontis as suitable model for the preclinical testing of anti-wolbachial drugs against filariae and show that combinations of already registered drugs with anti-wolbachial efficacy are able to reduce the treatment time dramatically.

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          Most cited references37

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          Pharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines.

          The pharmacokinetics of tetracyclines and glycylcyclines are described in three groups. Group 1, the oldest group, represented by tetracycline, oxytetracycline, chlortetracycline, demeclocycline, lymecycline, methacycline and rolitetracycline is characterized by poor absorption after food. Group 2, represented by doxycycline and minocycline, is more reliably absorbed orally, while group 3, represented by the glycylcycline tigecycline, is injectable only, with an improved antibacterial spectrum compared with the tetracyclines. Though incompletely understood, the pharmacodynamic properties of the tetracyclines and glycylcyclines are summarized.
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            Tetracycline therapy targets intracellular bacteria in the filarial nematode Litomosoides sigmodontis and results in filarial infertility.

            Intracellular bacteria have been described in several species of filarial nematodes, but their relationships with, and effects on, their nematode hosts have not previously been elucidated. In this study, intracellular bacteria were observed in tissues of the rodent parasite Litomosoides sigmodontis by transmission electron microscopy and by immunohistochemistry using antiendobacterial heat shock protein-60 antisera. Molecular phylogenetic analysis of the bacterial 16S ribosomal RNA gene, isolated by PCR, showed a close relationship to the rickettsial Wolbachia endobacteria of arthropods and to other filarial intracellular bacteria. The impact of tetracycline therapy of infected rodents on L. sigmodontis development was analyzed in order to understand the role(s) these bacteria might play in filarial biology. Tetracycline therapy, when initiated with L. sigmodontis infection, eliminated the bacteria and resulted in filarial growth retardation and infertility. If initiated after microfilarial development, treatment reduced filarial fertility. Treatment with antibiotics not affecting rickettsial bacteria did not inhibit filarial development. Acanthocheilonema viteae filariae were shown to lack intracellular bacteria and to be insensitive to tetracycline. These results suggest a mutualistic interaction between the intracellular bacteria and the filarial nematode. Investigation of such a mutualism in endobacteria-containing human filariae is warranted for a potential chemotherapeutic exploitation.
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              Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study

              In a randomized, placebo-controlled trial in Ghana, 67 onchocerciasis patients received 200-mg/day doxycycline for 4–6 weeks, followed by ivermectin (IVM) after 6 months. After 6–27 months, efficacy was evaluated by onchocercoma histology, PCR and microfilariae determination. Administration of doxycycline resulted in endobacteria depletion and female worm sterilization. The 6-week treatment was macrofilaricidal, with >60% of the female worms found dead, despite the presence of new, Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline may be developed as second-line drug for onchocerciasis, to be administered in areas without transmission, in foci with IVM resistance and in areas with Loa co-infections.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Funding acquisitionRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: VisualizationRole: Writing – review & editing
                Role: Funding acquisitionRole: Methodology
                Role: Data curationRole: InvestigationRole: MethodologyRole: Visualization
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Writing – review & editing
                Role: Funding acquisitionRole: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                4 January 2018
                January 2018
                : 12
                : 1
                : e0006116
                Affiliations
                [1 ] Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany
                [2 ] Institute for Laboratory Animal Science, Vetsuisse Faculty, University of Zurich, Switzerland
                [3 ] German Centre for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany
                [4 ] UMR 7245 MCAM MNHN CNRS, Museum National d`Histoire Naturelle, Paris, France
                [5 ] Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom
                University of California San Diego School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3096-2465
                http://orcid.org/0000-0001-7919-2866
                Article
                PNTD-D-17-01370
                10.1371/journal.pntd.0006116
                5771630
                29300732
                38eae272-ca98-47b1-b21a-56188bfe4388
                © 2018 Specht et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 August 2017
                : 15 November 2017
                Page count
                Figures: 10, Tables: 0, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: This work was funded through a grant from the Liverpool School of Tropical Medicine as part of the A-WOL Consortium funded by the Bill and Melinda Gates Foundation. The funders had no role in study design, data collection and analysis,
                This work was funded through a grant from the Liverpool School of Tropical Medicine as part of the A-WOL Consortium funded by the Bill and Melinda Gates Foundation. The funders had no role in study design, data collection and analysis.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Bacteria
                Wolbachia
                Medicine and Health Sciences
                Parasitic Diseases
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibiotics
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Antibiotics
                Tetracyclines
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Antibiotics
                Tetracyclines
                Medicine and Health Sciences
                Pharmacology
                Routes of Administration
                Oral Administration
                Research and analysis methods
                Extraction techniques
                DNA extraction
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Drug Administration
                Custom metadata
                vor-update-to-uncorrected-proof
                2018-01-17
                All relevant data are within the paper and its Supporting Information files.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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