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      Peripheral neuropathy in a diabetic child treated with linezolid for multidrug-resistant tuberculosis: a case report and review of the literature

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          Abstract

          Background

          Extensively drug-resistant (XDR) tuberculosis (TB) and multidrug resistant (MDR)-TB with additional resistance to injectable agents or fluoroquinolones are challenging to treat due to lack of available, effective drugs. Linezolid is one of the few drugs that has shown promise in treating these conditions. Long-term linezolid use is associated with toxicities such as peripheral and optic neuropathies. Diabetes mellitus (DM), especially when uncontrolled, can also result in peripheral neuropathy. The global burden of DM is increasing, and DM has been associated with a three-fold increased risk of developing TB disease. TB and DM can be a challenging combination to treat. DM can inhibit the host immune response to tuberculosis infection; and TB and some anti-TB drugs can worsen glycaemic control. A child experiencing neuropathy that is a possible complication of both DM and linezolid used to treat TB has not been reported previously. We report peripheral neuropathy in a 15-year-old boy with type 1 DM, diagnosed with MDR-TB and additional resistance to injectable TB medications.

          Case presentation

          The boy was treated with a linezolid-based regimen, but after 8 months developed peripheral neuropathy. It was unclear whether the neuropathy was caused by the DM or the linezolid therapy. He had clinical improvement following cessation of linezolid and was declared cured following 21 months of treatment. Following completion of treatment, nerve conduction studies demonstrated significant improvement in neuropathy.

          Conclusions

          To the best of our knowledge, this is the first case of peripheral neuropathy reported in a diabetic child on long-term linezolid therapy for tuberculosis. This case study underlines the importance of stringent follow-up for side effects of linezolid, especially when associated with co-morbidity such as DM that increases the chances of adverse effects. The presence of both DM and TB should alert a physician to strive for optimal glycaemic control to minimize the risk of complications as well as optimizing the chances of recovery from TB. Our case report shows the need for close and frequent monitoring for neuropathy to enable early intervention and thereby a favourable outcome in children who may otherwise suffer a long-lasting, debilitating, and painful neuropathy.

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          Most cited references14

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          Diabetic peripheral neuropathy: current perspective and future directions.

          Diabetic neuropathy is a heterogeneous group of disorders with extremely complex pathophysiology and affects both somatic and autonomic components of the nervous system. Neuropathy is the most common chronic complication of diabetes mellitus. Metabolic disruptions in the peripheral nervous system, including altered protein kinase C activity, and increased polyol pathway activity in neurons and Schwann cells resulting from hyperglycemia plays a key role in the development of diabetic neuropathy. These pathways are related to the metabolic and/or redox state of the cell and are the major source of damage. Activation of these metabolic pathways leads to oxidative stress, which is a mediator of hyperglycemia induced cell injury and a unifying theme for all mechanisms of diabetic neuropathy. The therapeutic intervention of these metabolic pathways is capable of ameliorating diabetic neuropathy but therapeutics which target one particular mechanism may have a limited success. Available therapeutic approaches are based upon the agents that modulate pathogenetic mechanisms (glycemic control) and relieve the symptoms of diabetic neuropathy. This review emphasizes the pathogenesis, presently available therapeutic approaches and future directions for the management of diabetic neuropathy. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Linezolid-induced inhibition of mitochondrial protein synthesis.

            Linezolid is an oxazolidinone antibiotic that is increasingly used to treat drug-resistant, gram-positive pathogens. The mechanism of action is inhibition of bacterial protein synthesis. Optic and/or peripheral neuropathy and lactic acidosis are reported side effects, but the underlying pathophysiological mechanism has not been unravelled. We studied mitochondrial ultrastructure, mitochondrial respiratory chain enzyme activity, and mitochondrial DNA (mtDNA) in muscle, liver, and kidney samples obtained from a patient who developed optic neuropathy, encephalopathy, skeletal myopathy, lactic acidosis, and renal failure after prolonged use of linezolid. In addition, we evaluated mtDNA, respiratory chain enzyme activity, and protein amount in muscle and liver samples obtained from experimental animals that received linezolid or placebo. In the patient, mitochondrial respiratory chain enzyme activity was decreased in affected tissues, without ultrastructural mitochondrial abnormalities and without mutations or depletion of mtDNA. In the experimental animals, linezolid induced a dose- and time-dependent decrease of the activity of respiratory chain complexes containing mtDNA-encoded subunits and a decreased amount of protein of these complexes, whereas the amount of mtDNA was normal. These results provide direct evidence that linezolid inhibits mitochondrial protein synthesis with potentially severe clinical consequences. Prolonged courses of linezolid should be avoided if alternative treatment options are available.
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              Diabetes and tuberculosis: a review of the role of optimal glycemic control

              Developing countries shoulder most of the burden of diabetes and tuberculosis. These diseases often coexist. Suboptimal control of diabetes predisposes the patient to tuberculosis, and is one of the common causes of poor response to anti-tubercular treatment. Tuberculosis also affects diabetes by causing hyperglycemia and causing impaired glucose tolerance. Impaired glucose tolerance is one of the major risk factors for developing diabetes. The drugs used to treat tuberculosis (especially rifampicin and isoniazid) interact with oral anti-diabetic drugs and may lead to suboptimal glycemic control. Similarly some of the newer oral anti-diabetic drugs may interact with anti-tuberculosis drugs and lower their efficacy. Therefore diabetes and tuberculosis interact with each other at multiple levels – each exacerbating the other. Management of patients with concomitant tuberculosis and diabetes differs from that of either disease alone. This article reviews the association between diabetes and tuberculosis and suggests appropriate management for these conditions.
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                Author and article information

                Contributors
                draravind08@gmail.com
                philipp.ducros@london.msf.org
                james.seddon@imperial.ac.uk
                shamsiya-5aug@mail.ru
                rajabovsafar@gmail.com
                zdusmatova@gmail.com
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                12 June 2017
                12 June 2017
                2017
                : 17
                : 417
                Affiliations
                [1 ]Médecins Sans Frontières (MSF), Dushanbe, Tajikistan
                [2 ]ISNI 0000 0004 0439 3876, GRID grid.452573.2, , Médecins Sans Frontières (MSF), Manson Unit, ; London, UK
                [3 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, , Imperial College London, ; London, UK
                [4 ]National Tuberculosis Programme, Ministry of Health and Social Protection of the Republic of Tajikistan, Dushanbe, Tajikistan
                [5 ]Department of Paediatrics, Saveetha Medical College and Hospital, Thandalam, Kancheepuram, Tamil Nadu India
                Author information
                http://orcid.org/0000-0001-7519-9585
                Article
                2499
                10.1186/s12879-017-2499-1
                5469058
                28606115
                b9dd1d88-a70d-437d-9352-bcbf139fc750
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 8 August 2016
                : 28 May 2017
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2017

                Infectious disease & Microbiology
                case report,multi drug resistant tuberculosis,linezolid,neuropathy,diabetes mellitus

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