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1
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Huo Y, Wu C, Ma D. Application of metagenomic next-generation sequencing in the diagnosis and treatment of acute pneumonia caused by Tropheryma whipplei. BMC Pulm Med 2025; 25:207. [PMID: 40307822 PMCID: PMC12042330 DOI: 10.1186/s12890-025-03657-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/09/2025] [Indexed: 05/02/2025] Open
Abstract
OBJECTIVE The treatment plan and process for acute pneumonia caused by Tropheryma whipplei have not been clearly defined. The study aimed to conduct a retrospective analysis of the treatment for patients with acute pneumonia, caused by Tropheryma whipplei, diagnosed through metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF). METHODS All patients underwent routine blood examinations and chest CT scans. Electronic fiberoptic bronchoscopy was performed to collect BALF samples from the lesion subsegments. The BALF samples were subjected to mNGS analysis. During hospitalization, all patients were treated with imipenem-cilastatin combined with compound sulfamethoxazole (SMZ-TMP) tablets for anti-infection, and they took SMZ-TMP orally for 3 months after discharge and followed up. RESULTS We identified 7 cases where Tropheryma whipplei was the primary pathogen, with 3 of these cases having it as the sole detected pathogen. The clinical manifestations of acute Tropheryma whipplei pneumonia are atypical. Chest CT scans revealed that 3 cases had exudative lesions in both lungs, 4 cases had unilateral pulmonary exudative lesions, 3 cases had bilateral pulmonary nodules, 2 cases had interstitial changes, and 3 cases had pleural effusion. Following treatment, all follow-up cases showed no recurrence. CONCLUSIONS The mNGS examination of bronchoalveolar lavage fluid can significantly improve the early diagnosis of acute pneumonia caused by Tropheryma whipplei. The treatment involving imipenem-cilastatin combined with SMZ-TMP, followed by oral SMZ-TMP for three months, is effective.
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Affiliation(s)
- Yinping Huo
- Department of Respiratory and Critical Care Medicine, Nanjing Pukou People's Hospital, No.166 Shanghe Street, Jiangpu Street, Pukou District, Nanjing, 211800, Jiangsu, China.
| | - Chao Wu
- Department of Respiratory and Critical Care Medicine, Nanjing Pukou People's Hospital, No.166 Shanghe Street, Jiangpu Street, Pukou District, Nanjing, 211800, Jiangsu, China
| | - Dawen Ma
- Department of Respiratory and Critical Care Medicine, Nanjing Pukou People's Hospital, No.166 Shanghe Street, Jiangpu Street, Pukou District, Nanjing, 211800, Jiangsu, China.
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2
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Puéchal X. Whipple's disease: from in-vitro data to bedside practice via trial results. THE LANCET. INFECTIOUS DISEASES 2025:S1473-3099(25)00016-7. [PMID: 39978371 DOI: 10.1016/s1473-3099(25)00016-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 02/22/2025]
Affiliation(s)
- Xavier Puéchal
- National Referral Centre for Rare Systemic Autoimmune Diseases, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, University Paris Cité, Paris 75014, France.
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3
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Loiseau V, Chopin MC, Antoine P, Landrieux M, Moritz F. [Bilateral panuveitis in Whipple's disease: Case report]. J Fr Ophtalmol 2024; 47:104262. [PMID: 39098166 DOI: 10.1016/j.jfo.2024.104262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Revised: 04/09/2024] [Accepted: 04/29/2024] [Indexed: 08/06/2024]
Abstract
Whipple's disease is a rare disease linked to chronic infection with the intracellular gram-positive bacterium, Tropheryma whipplei. The clinical signs suggestive of this disease are the association of unexplained fever, lymphadenopathy, gastroenterological disorders (malabsorption) and inflammatory joint disorders (arthritis). However, isolated cardiological, neurological or ophthalmological forms have been described. We report the rare case of a 56-year-old patient complaining of floaters and recent visual loss, who presented with bilateral panuveitis in the absence of any systemic disorder. Clinical examination showed inflammation of the anterior segment, vitritis, inflammatory optic disc edema, focal retinitis, and venous vasculitis in both eyes. We describe the clinical characteristics and ancillary findings of the disease (fundus photos, visual field, auto-fluorescence, macular OCT, fluorescein and indocyanine green angiography). The diagnosis was made with the blood (T. whipplei) PCR test and with the help of accessory salivary gland biopsies. We describe the work-up leading to the diagnosis of Whipple's disease, the laboratory tests, and the recommended extended work-up. The patient's course was marked by complete resolution of the symptoms and clinical signs within a few months following corticosteroid therapy (1mg/kg/day) combined with hydroxychloroquine (600mg per day for 1 year) and life-long doxycycline therapy (200mg per day). In conclusion, this is a rare disease which should be discussed when dealing with steroid-resistant and/or steroid-dependent chronic uveitis with a negative work-up (especially in the presence of joint and/or digestive involvement).
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Affiliation(s)
- V Loiseau
- Service d'ophtalmologie, hôpital Claude-Huriez, CHU de Lille, rue Michel-Polonowski, 59000 Lille, France.
| | - M-C Chopin
- Service maladies infectieuses et tropicales, centre hospitalier de Boulogne-Sur-Mer, rue Jacques-Monod, 62200 Boulogne-sur-Mer, France
| | - P Antoine
- Service néphrologie-médecine interne, centre hospitalier de Boulogne-Sur-Mer, rue Jacques-Monod, 62200 Boulogne-sur-Mer, France
| | - M Landrieux
- Service d'ophtalmologie, centre hospitalier de Boulogne-Sur-Mer, rue Jacques-Monod, 62200 Boulogne-sur-Mer, France
| | - F Moritz
- Service d'ophtalmologie, centre hospitalier de Boulogne-Sur-Mer, rue Jacques-Monod, 62200 Boulogne-sur-Mer, France
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4
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Tao Y, Du R, Mao H. Tropheryma whipplei pneumonia revealed by Metagenomic next-generation sequencing: Report of two cases. Diagn Microbiol Infect Dis 2024; 110:116427. [PMID: 39024936 DOI: 10.1016/j.diagmicrobio.2024.116427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/03/2024] [Accepted: 07/05/2024] [Indexed: 07/20/2024]
Abstract
Tropheryma whipplei is the causative agent of Whipple's disease, which is a rare multiorgan systemic disease. We report two cases of Tropheryma whipplei infection, all routine tests were negative and it was finally detected by mNGS. This may help clinicians increase awareness of the diagnosis and treatment of acute severe pneumonia and interstitial pneumonia caused by Tropheryma whipplei.
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Affiliation(s)
- Yuhan Tao
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Rao Du
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Mao
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
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5
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Liu F, Yang X, He Z, OuYang C, Yang X, Yang C. Using Targeted Next-Generation Sequencing to Diagnose Severe Pneumonia Due to Tropheryma Whipplei and Human Metapneumovirus: A Case Report and Literature Review. Infect Drug Resist 2024; 17:1863-1868. [PMID: 38745678 PMCID: PMC11092972 DOI: 10.2147/idr.s451477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 04/17/2024] [Indexed: 05/16/2024] Open
Abstract
Background In addition to the well-known Whipple's disease (WD), Tropheryma Whipplei (TW) can also lead to acute pneumonia. There is no unified consensus on the susceptible population, pathogenesis, clinical manifestations, diagnostic criteria, and treatment options for TW pneumonia. Clinical Presentation and Intervention This is an elderly patient with multiple injuries caused by falling from a building, and was transferred to intensive care unit (ICU) for mechanical ventilation and empirical anti-infection treatment due to severe pneumonia, and then the results of targeted next-generation sequencing (tNGS) in patient's bronchoalveolar lavage fluid (BALF) suggested TW and human metapneumovirus (HMPV) infection, and after switching to anti-infective therapy for TW, the patient was successfully extubated and transferred out of the ICU. Conclusion This is the first case of using tNGS to diagnose severe pneumonia caused by TW and HMPV. We hope that our study can serve as a reference for the diagnosis and treatment of related cases in the future.
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Affiliation(s)
- Fang Liu
- Department of Intensive Care Unit, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, People’s Republic of China
| | - XuYong Yang
- Department of Pediatrics, Gaoxin Hospital of The First Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China
| | - Zhaohui He
- Department of Intensive Care Unit, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, People’s Republic of China
| | - Chenghong OuYang
- Department of Intensive Care Unit, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, People’s Republic of China
| | - Xiaogang Yang
- Department of Intensive Care Unit, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, People’s Republic of China
| | - Chunli Yang
- Department of Intensive Care Unit, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, People’s Republic of China
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6
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Raghav PK, Mann Z, Ahluwalia SK, Rajalingam R. Potential treatments of COVID-19: Drug repurposing and therapeutic interventions. J Pharmacol Sci 2023; 152:1-21. [PMID: 37059487 PMCID: PMC9930377 DOI: 10.1016/j.jphs.2023.02.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 01/31/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is caused when Spike-protein (S-protein) present on the surface of SARS-CoV-2 interacts with human cell surface receptor, Angiotensin-converting enzyme 2 (ACE2). This binding facilitates SARS-CoV-2 genome entry into the human cells, which in turn causes infection. Since the beginning of the pandemic, many different therapies have been developed to combat COVID-19, including treatment and prevention. This review is focused on the currently adapted and certain other potential therapies for COVID-19 treatment, which include drug repurposing, vaccines and drug-free therapies. The efficacy of various treatment options is constantly being tested through clinical trials and in vivo studies before they are made medically available to the public.
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Affiliation(s)
- Pawan Kumar Raghav
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
| | | | - Simran Kaur Ahluwalia
- Amity Institute of Biotechnology, Amity University, Sector-125, Noida, Uttar Pradesh, India
| | - Raja Rajalingam
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, USA
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7
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Stezin A, Pal PK. Treatable Ataxias: How to Find the Needle in the Haystack? J Mov Disord 2022; 15:206-226. [PMID: 36065614 DOI: 10.14802/jmd.22069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 07/05/2022] [Indexed: 11/24/2022] Open
Abstract
Treatable ataxias are a group of ataxic disorders with specific treatments. These disorders include genetic and metabolic disorders, immune-mediated ataxic disorders, and ataxic disorders associated with infectious and parainfectious etiology, vascular causes, toxins and chemicals, and endocrinopathies. This review provides a comprehensive overview of different treatable ataxias. The major metabolic and genetic treatable ataxic disorders include ataxia with vitamin E deficiency, abetalipoproteinemia, cerebrotendinous xanthomatosis, Niemann-Pick disease type C, autosomal recessive cerebellar ataxia due to coenzyme Q10 deficiency, glucose transporter type 1 deficiency, and episodic ataxia type 2. The treatment of these disorders includes the replacement of deficient cofactors and vitamins, dietary modifications, and other specific treatments. Treatable ataxias with immune-mediated etiologies include gluten ataxia, anti-glutamic acid decarboxylase antibody-associated ataxia, steroid-responsive encephalopathy associated with autoimmune thyroiditis, Miller-Fisher syndrome, multiple sclerosis, and paraneoplastic cerebellar degeneration. Although dietary modification with a gluten-free diet is adequate in gluten ataxia, other autoimmune ataxias are managed by short-course steroids, plasma exchange, or immunomodulation. For autoimmune ataxias secondary to malignancy, treatment of tumor can reduce ataxic symptoms. Chronic alcohol consumption, antiepileptics, anticancer drugs, exposure to insecticides, heavy metals, and recreational drugs are potentially avoidable and treatable causes of ataxia. Infective and parainfectious causes of cerebellar ataxias include acute cerebellitis, postinfectious ataxia, Whipple's disease, meningoencephalitis, and progressive multifocal leukoencephalopathy. These disorders are treated with steroids and antibiotics. Recognizing treatable disorders is of paramount importance when dealing with ataxias given that early treatment can prevent permanent neurological sequelae.
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Affiliation(s)
- Albert Stezin
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.,Centre for Brain Research, Indian Institute of Science, Bengaluru, India
| | - Pramod Kumar Pal
- Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India
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8
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Boumaza A, Ben Azzouz E, Arrindell J, Lepidi H, Mezouar S, Desnues B. Whipple's disease and Tropheryma whipplei infections: from bench to bedside. THE LANCET INFECTIOUS DISEASES 2022; 22:e280-e291. [DOI: 10.1016/s1473-3099(22)00128-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/28/2022] [Accepted: 02/02/2022] [Indexed: 12/13/2022]
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9
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Askarian F, Firoozi Z, Ebadollahi-Natanzi A, Bahrami S, Rahimi HR. A review on the pharmacokinetic properties and toxicity considerations for chloroquine and hydroxychloroquine to potentially treat coronavirus patients. Toxicol Res 2021; 38:137-148. [PMID: 34306523 PMCID: PMC8286988 DOI: 10.1007/s43188-021-00101-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/10/2021] [Accepted: 06/07/2021] [Indexed: 02/06/2023] Open
Abstract
The SARS-CoV-2 virus, caused a novel emerged coronavirus disease, is growing rapidly worldwide. Few studies have evaluated the efficacy and safety of Chloroquine (CQ), an old antimalarial drug, and Hydroxychloroquine (HCQ) in the treatment of COVID-19 infection. HCQ is derived from CQ by adding a hydroxyl group into it and is a less toxic derivative of CQ for the treatment of COVID-19 infection because it is more soluble. This article summarizes pharmacokinetic properties and toxicity considerations for CQ and HCQ, drug interactions, and their potential efficacy against COVID-19. The authors also look at the biochemistry changes and clinical uses of CQ and HCQ, and supportive treatments following toxicity occurs. It was believed that CQ and HCQ may provide few benefits to COVID-19 patients. A number of factors should be considered to keep the drug safe, such as dose, in vivo animal toxicological findings, and gathering of metabolites in plasma and/or tissues. The main conclusion of this review is that CQ and HCQ with considered to their ADMET properties has major shortcomings and fully irresponsible.
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Affiliation(s)
- Fatemeh Askarian
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Firoozi
- Department of Medical Genetics, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Ebadollahi-Natanzi
- Medicinal Plants Department, Imam Khomeini Higher Education Center, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Solmaz Bahrami
- Department of Institutional Research, Westcliff University, Irvine, CA 92614 USA
| | - Hamid-Reza Rahimi
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran.,Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
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10
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Guan W, Lan W, Zhang J, Zhao S, Ou J, Wu X, Yan Y, Wu J, Zhang Q. COVID-19: Antiviral Agents, Antibody Development and Traditional Chinese Medicine. Virol Sin 2020; 35:685-698. [PMID: 32997322 PMCID: PMC7524871 DOI: 10.1007/s12250-020-00297-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 08/31/2020] [Indexed: 12/19/2022] Open
Abstract
The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19) is the first pandemic caused by coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, there is no effective anti-SARS-CoV-2 drug approved worldwide for treatment of patients with COVID-19. Therapeutic options in response to the COVID-19 outbreak are urgently needed. To facilitate the better and faster development of therapeutic COVID-19 drugs, we present an overview of the global promising therapeutic drugs, including repurposing existing antiviral agents, network-based pharmacology research, antibody development and traditional Chinese medicine. Among all these drugs, we focus on the most promising drugs (such as favipiravir, tocilizumab, SARS-CoV-2 convalescent plasma, hydroxychloroquine, Lianhua Qingwen, interferon beta-1a, remdesivir, etc.) that have or will enter the final stage of human testing-phase III-IV clinical trials.
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Affiliation(s)
- Wenyi Guan
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Wendong Lan
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Jing Zhang
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Shan Zhao
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Junxian Ou
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Xiaowei Wu
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Yuqian Yan
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China
| | - Jianguo Wu
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Qiwei Zhang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, 510632, Guangdong, China.
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11
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Younis NK, Zareef RO, Al Hassan SN, Bitar F, Eid AH, Arabi M. Hydroxychloroquine in COVID-19 Patients: Pros and Cons. Front Pharmacol 2020; 11:597985. [PMID: 33364965 PMCID: PMC7751757 DOI: 10.3389/fphar.2020.597985] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/13/2020] [Indexed: 01/08/2023] Open
Abstract
The pandemic of COVID-19, caused by SARS-CoV-2, has recently overwhelmed medical centers and paralyzed economies. The unparalleled public distress caused by this pandemic mandated an urgent quest for an effective approach to manage or treat this disease. Due to their well-established anti-infectious and anti-inflammatory properties, quinine derivatives have been sought as potential therapies for COVID-19. Indeed, these molecules were originally employed in the treatment and prophylaxis of malaria, and later in the management of various autoimmune rheumatic and dermatologic diseases. Initially, some promising results for the use of hydroxychloroquine (HCQ) in treating COVID-19 patients were reported by a few in vitro and in vivo studies. However, current evidence is not yet sufficiently solid to warrant its use as a therapy for this disease. Additionally, the therapeutic effects of HCQ are not without many side effects, which range from mild gastrointestinal effects to life-threatening cardiovascular and neurological effects. In this review, we explore the controversy associated with the repurposing of HCQ to manage or treat COVID-19, and we discuss the cellular and molecular mechanisms of action of HCQ.
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Affiliation(s)
- Nour K Younis
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Rana O Zareef
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Sally N Al Hassan
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fadi Bitar
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Pediatric Department, Division of Pediatric Cardiology, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ali H Eid
- Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar.,Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Mariam Arabi
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.,Pediatric Department, Division of Pediatric Cardiology, American University of Beirut Medical Center, Beirut, Lebanon
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12
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Faraone I, Labanca F, Ponticelli M, De Tommasi N, Milella L. Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review. Molecules 2020; 25:E5318. [PMID: 33202656 PMCID: PMC7696151 DOI: 10.3390/molecules25225318] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 10/29/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity.
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MESH Headings
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/physiopathology
- Betacoronavirus/pathogenicity
- COVID-19
- Chikungunya Fever/drug therapy
- Chikungunya Fever/epidemiology
- Chikungunya Fever/physiopathology
- Chikungunya Fever/virology
- Chikungunya virus/pathogenicity
- Coronavirus Infections/drug therapy
- Coronavirus Infections/epidemiology
- Coronavirus Infections/physiopathology
- Coronavirus Infections/virology
- Drug Administration Schedule
- HIV/pathogenicity
- HIV Infections/drug therapy
- HIV Infections/epidemiology
- HIV Infections/physiopathology
- HIV Infections/virology
- Humans
- Hydroxychloroquine/therapeutic use
- Lupus Erythematosus, Systemic/drug therapy
- Lupus Erythematosus, Systemic/immunology
- Lupus Erythematosus, Systemic/physiopathology
- Pandemics
- Pneumonia, Viral/drug therapy
- Pneumonia, Viral/epidemiology
- Pneumonia, Viral/physiopathology
- Pneumonia, Viral/virology
- Severe acute respiratory syndrome-related coronavirus/pathogenicity
- SARS-CoV-2
- Severe Acute Respiratory Syndrome/drug therapy
- Severe Acute Respiratory Syndrome/epidemiology
- Severe Acute Respiratory Syndrome/physiopathology
- Severe Acute Respiratory Syndrome/virology
- Sjogren's Syndrome/drug therapy
- Sjogren's Syndrome/immunology
- Sjogren's Syndrome/physiopathology
- Zika Virus/pathogenicity
- Zika Virus Infection/drug therapy
- Zika Virus Infection/epidemiology
- Zika Virus Infection/physiopathology
- Zika Virus Infection/virology
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Affiliation(s)
- Immacolata Faraone
- Department of Science, University of Basilicata, v.le dell’Ateneo Lucano 10, 85100 Potenza, Italy; (I.F.); (F.L.); (M.P.); (L.M.)
- Spinoff BioActiPlant s.r.l., University of Basilicata, v.le dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Fabiana Labanca
- Department of Science, University of Basilicata, v.le dell’Ateneo Lucano 10, 85100 Potenza, Italy; (I.F.); (F.L.); (M.P.); (L.M.)
| | - Maria Ponticelli
- Department of Science, University of Basilicata, v.le dell’Ateneo Lucano 10, 85100 Potenza, Italy; (I.F.); (F.L.); (M.P.); (L.M.)
| | - Nunziatina De Tommasi
- Department of Pharmacy, Università degli Studi di Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
| | - Luigi Milella
- Department of Science, University of Basilicata, v.le dell’Ateneo Lucano 10, 85100 Potenza, Italy; (I.F.); (F.L.); (M.P.); (L.M.)
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13
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Samaddar A, Grover M, Nag VL. Pathophysiology and Potential Therapeutic Candidates for COVID-19: A Poorly Understood Arena. Front Pharmacol 2020; 11:585888. [PMID: 33041830 PMCID: PMC7527880 DOI: 10.3389/fphar.2020.585888] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/02/2020] [Indexed: 12/13/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), an acute onset pneumonia caused by a novel Betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in the Wuhan City of China in December 2019 and evolved into a global pandemic. To date, there are no proven drugs or vaccines against this virus. Hence, the situation demands an urgent need to explore all potential therapeutic strategies that can be made available to prevent the disease progression and improve patient outcomes. In absence of clinically proven treatment guidelines, several repurposed drugs and investigational agents are currently being evaluated in clinical trials for their probable benefits in the treatment of COVID-19. These include antivirals (remdesivir, lopinavir/ritonavir, umifenovir, and favipiravir), interferon, antimalarials (chloroquine/hydroxychloroquine), antiparasitic drugs (ivermectin and nitazoxanide), biologics (monoclonal antibodies and interleukin receptor antagonist), cellular therapies (mesenchymal stem cells and natural killer cells), convalescent plasma, and cytokine adsorber. Though several observational studies have claimed many of these agents to be effective based on their in vitro activities and extrapolated evidence from SARS and Middle East respiratory syndrome (MERS) epidemics, the currently available data remains inconclusive because of ill-defined patient selection criteria, small sample size, lack of concurrent controls, and use of intermediary outcomes instead of patient-relevant outcomes. Moreover, there is a need to clearly define the patient populations who warrant therapy and also the timing of initiation of treatment. Understanding the disease pathology responsible for the clinical manifestations of COVID-19 is imperative to identify the potential targets for drug development. This review explains the pathophysiology of COVID-19 and summarizes the potential treatment candidates, which can provide guidance in developing effective therapeutic strategies.
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Affiliation(s)
| | | | - Vijaya Lakshmi Nag
- Department of Microbiology, All India Institute of Medical Sciences, Jodhpur, India
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Beck TC, Beck KR, Holloway CB, Hemings RA, Dix TA, Norris RA. The C-C Chemokine Receptor Type 4 Is an Immunomodulatory Target of Hydroxychloroquine. Front Pharmacol 2020; 11:1253. [PMID: 32973504 PMCID: PMC7482581 DOI: 10.3389/fphar.2020.01253] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/30/2020] [Indexed: 12/15/2022] Open
Abstract
The emergence of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) in China, reported to the World Health Organization on December 31, 2019, has led to a large global pandemic and is a major public health issue. As a result, there are more than 200 clinical trials of COVID-19 treatments or vaccines that are either ongoing or recruiting patients. One potential therapy that has garnered international attention is hydroxychloroquine; a potent immunomodulatory agent FDA-approved for the treatment of numerous inflammatory and autoimmune conditions, including malaria, lupus, and rheumatoid arthritis. Hydroxychloroquine has demonstrated promise in vitro and is currently under investigation in clinical trials for the treatment of COVID-19. Despite an abundance of empirical data, the mechanism(s) involved in the immunomodulatory activity of hydroxychloroquine have not been characterized. Using the unbiased chemical similarity ensemble approach (SEA), we identified C-C chemokine receptor type 4 (CCR4) as an immunomodulatory target of hydroxychloroquine. The crystal structure of CCR4 was selected for molecular docking studies using the SwissDock modeling software. In silico, hydroxychloroquine interacts with Thr-189 within the CCR4 active site, presumably blocking endogenous ligand binding. However, the CCR4 antagonists compound 18a and K777 outperformed hydroxychloroquine in silico, demonstrating energetically favorable binding characteristics. Hydroxychloroquine may subject COVID-19 patients to QT-prolongation, increasing the risk of sudden cardiac death. The FDA-approved CCR4 antagonist mogalizumab is not known to increase the risk of QT prolongation and may serve as a viable alternative to hydroxychloroquine. Results from this report introduce additional FDA-approved drugs that warrant investigation for therapeutic use in the treatment of COVID-19.
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Affiliation(s)
- Tyler C. Beck
- Dix Laboratory, Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States,Norris Laboratory, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,College of Medicine, Medical University of South Carolina, Charleston, SC, United States,*Correspondence: Tyler C. Beck, ; Russell A. Norris,
| | - Kyle R. Beck
- College of Pharmacy, The Ohio State University, Columbus, OH, United States
| | - Calvin B. Holloway
- Pritzker School of Medicine, The University of Chicago, Chicago, IL, United States
| | - Richard A. Hemings
- College of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Thomas A. Dix
- Dix Laboratory, Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, United States
| | - Russell A. Norris
- Norris Laboratory, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,*Correspondence: Tyler C. Beck, ; Russell A. Norris,
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15
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Kalra RS, Tomar D, Meena AS, Kandimalla R. SARS-CoV-2, ACE2, and Hydroxychloroquine: Cardiovascular Complications, Therapeutics, and Clinical Readouts in the Current Settings. Pathogens 2020; 9:E546. [PMID: 32645974 PMCID: PMC7400328 DOI: 10.3390/pathogens9070546] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/30/2020] [Accepted: 07/05/2020] [Indexed: 01/08/2023] Open
Abstract
The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome coronavirus 2- SARS-CoV-2), has greatly burdened the global healthcare system and led it into crisis in several countries. Lack of targeted therapeutics led to the idea of repurposing broad-spectrum drugs for viral intervention. In vitro analyses of hydroxychloroquine (HCQ)'s anecdotal benefits prompted its widespread clinical repurposing globally. Reports of emerging cardiovascular complications due to its clinical prescription are revealing the crucial role of angiotensin-converting enzyme 2 (ACE2), which serves as a target receptor for SARS-CoV-2. In the present settings, a clear understanding of these targets, their functional aspects and physiological impact on cardiovascular function are critical. In an up-to-date format, we shed light on HCQ's anecdotal function in stalling SARS-CoV-2 replication and immunomodulatory activities. While starting with the crucial role of ACE2, we here discuss the impact of HCQ on systemic cardiovascular function, its associated risks, and the scope of HCQ-based regimes in current clinical settings. Citing the extent of HCQ efficacy, the key considerations and recommendations for the use of HCQ in clinics are further discussed. Taken together, this review provides crucial insights into the role of ACE2 in SARS-CoV-2-led cardiovascular activity, and concurrently assesses the efficacy of HCQ in contemporary clinical settings.
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Affiliation(s)
- Rajkumar Singh Kalra
- AIST-INDIA DAILAB, DBT-AIST International Center for Translational & Environmental Research (DAICENTER), National Institute of Advanced Industrial Science & Technology (AIST), Higashi 1-1-1, Tsukuba 305 8565, Japan
| | - Dhanendra Tomar
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Avtar Singh Meena
- CSIR-Centre for Cellular and Molecular Biology (CCMB), Habsiguda, Uppal Road, Hyderabad 500 007, Telangana State, India;
| | - Ramesh Kandimalla
- Applied Biology, CSIR-Indian Institute of Chemical Technology (IICT), Uppal Road, Tarnaka, Hyderabad 500007, Telangana State, India;
- Department of Biochemistry, Kakatiya Medical College, Warangal 506007, Telangana State, India
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Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr 2020; 14:241-246. [PMID: 32247211 PMCID: PMC7102587 DOI: 10.1016/j.dsx.2020.03.011] [Citation(s) in RCA: 269] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 03/22/2020] [Accepted: 03/22/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS No drugs are currently approved for Coronavirus Disease-2019 (COVID-19), although some have been tried. In view of recent studies and discussion on chloroquine and hydroxychloroquine (HCQ), we aimed to review existing literature and relevant websites regarding these drugs and COVID-19, adverse effects related to drugs, and related guidelines. AIMS AND METHODS We systematically searched the PubMed database up till March 21, 2020 and retrieved all the articles published on chloroquine and HCQ and COVID-19. RESULTS Two small human studies have been conducted with both these drugs in COVID-19, and have shown significant improvement in some parameters in patients with COVID-19. CONCLUSION Considering minimal risk upon use, a long experience of use in other diseases, cost-effectiveness and easy availability across India, we propose that both these drugs are worthy of fast track clinical trial for treatment, and may be carefully considered for clinical use as experimental drugs. Since HCQ has been approved for treatment of diabetes in India, it should be further researched in diabetes and COVID-19, a subgroup where significant mortality has been shown.
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Affiliation(s)
| | - Akriti Singh
- College of Medicine & JNM Hospital, Kalyani, Nadia, West Bengal, India
| | | | - Ritu Singh
- G. D Hospital & Diabetes Institute, Kolkata, India
| | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Sciences, Chirag Enclave, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India; Diabetes Foundation (India), New Delhi, India
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17
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Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020; 55:105938. [PMID: 32171740 PMCID: PMC7118659 DOI: 10.1016/j.ijantimicag.2020.105938] [Citation(s) in RCA: 672] [Impact Index Per Article: 134.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 02/07/2023]
Abstract
Recently, a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic containment measures, the spread of this virus is ongoing. SARS-CoV-2 is the aetiological agent of coronavirus disease 2019 (COVID-19) characterised by pulmonary infection in humans. The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials. Here we discuss the possible mechanisms of chloroquine interference with the SARS-CoV-2 replication cycle.
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Affiliation(s)
- Christian A Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; CNRS, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France.
| | - Jean-Marc Rolain
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
| | - Philippe Colson
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
| | - Didier Raoult
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
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Andreani J, Le Bideau M, Duflot I, Jardot P, Rolland C, Boxberger M, Wurtz N, Rolain JM, Colson P, La Scola B, Raoult D. In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect. Microb Pathog 2020; 145:104228. [PMID: 32344177 PMCID: PMC7182748 DOI: 10.1016/j.micpath.2020.104228] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 04/17/2020] [Accepted: 04/22/2020] [Indexed: 02/06/2023]
Abstract
Human coronaviruses SARS-CoV-2 appeared at the end of 2019 and led to a pandemic with high morbidity and mortality. As there are currently no effective drugs targeting this virus, drug repurposing represents a short-term strategy to treat millions of infected patients at low costs. Hydroxychloroquine showed an antiviral effect in vitro. In vivo it showed efficacy, especially when combined with azithromycin in a preliminary clinical trial. Here we demonstrate that the combination of hydroxychloroquine and azithromycin has a synergistic effect in vitro on SARS-CoV-2 at concentrations compatible with that obtained in human lung.
SARS-CoV 2 emergence and spreading need to found urgently therapeutics. Drug repurposing is the best strategy for quick therapeutic response. Azithromycin and hydroxychloroquine shows synergistic effect on replication. Concentrations of drugs are more compatible with in vivo concentrations.
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Affiliation(s)
- Julien Andreani
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Marion Le Bideau
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Isabelle Duflot
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Priscilla Jardot
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Clara Rolland
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Manon Boxberger
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Nathalie Wurtz
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Jean-Marc Rolain
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Philippe Colson
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Bernard La Scola
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France.
| | - Didier Raoult
- IHU-Méditerranée Infection, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France.
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19
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Moutaouakkil Y, Tadlaoui Y, Latt EEV, Atbib Y, Cherrah Y, Bennana A, Bousliman Y, Lamsaouri J. Les anti-inflammatoires et SARS-CoV-2 (COVID-19). DOULEURS : ÉVALUATION - DIAGNOSTIC - TRAITEMENT 2020. [PMCID: PMC7252016 DOI: 10.1016/j.douler.2020.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
À ce jour, les options thérapeutiques pour le COVID-19 sévère restent limitées et il n’existe actuellement aucun médicament ni vaccin efficace pour le traitement ou la prévention du SARS-CoV-2 spécifique pour traiter les patients gravement malades. Une nouvelle stratégie de traitement, en plus de la thérapie antivirale seule, est susceptible d’être nécessaire pour avoir un impact significatif sur les résultats cliniques. Un traitement immunomodulateur pour réguler à la baisse de choc cytokinique peut fournir des informations sur le traitement de COVID-19. L’utilisation combinée d’un agent immunomodulateur avec un agent antiviral peut donner aux médecins plus de temps pour fournir un traitement de soutien aux patients atteints de COVID-19. Dans cette revue de la littérature, les rôles de plusieurs médicaments anti-inflammatoires ont été passés en revue pour explorer leur efficacité dans la lutte contre le SARS-CoV-2.
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Affiliation(s)
- Youssef Moutaouakkil
- Pôle pharmacie, hôpital militaire d’instruction Mohamed V, Rabat, Maroc
- Laboratoire de pharmacologie-toxicologie, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
- Auteur correspondant.
| | - Yasmina Tadlaoui
- Pôle pharmacie, hôpital militaire d’instruction Mohamed V, Rabat, Maroc
| | - Esso Eric Valery Latt
- Pôle pharmacie, hôpital militaire d’instruction Mohamed V, Rabat, Maroc
- Laboratoire de pharmacologie-toxicologie, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
| | - Yassine Atbib
- Pôle pharmacie, hôpital militaire d’instruction Mohamed V, Rabat, Maroc
- Laboratoire de chimie thérapeutique, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
| | - Yahia Cherrah
- Laboratoire de pharmacologie-toxicologie, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
| | - Ahmed Bennana
- Laboratoire de chimie thérapeutique, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
| | - Yassir Bousliman
- Laboratoire de pharmacologie-toxicologie, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
| | - Jamal Lamsaouri
- Pôle pharmacie, hôpital militaire d’instruction Mohamed V, Rabat, Maroc
- Laboratoire de chimie thérapeutique, faculté de médecine et de pharmacie, université Mohamed V de Rabat, Rabat, Maroc
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Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020. [PMID: 32171740 DOI: 10.1016/j.ijantimicag.2020.105938.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
Abstract
Recently, a novel coronavirus (2019-nCoV), officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. Despite drastic containment measures, the spread of this virus is ongoing. SARS-CoV-2 is the aetiological agent of coronavirus disease 2019 (COVID-19) characterised by pulmonary infection in humans. The efforts of international health authorities have since focused on rapid diagnosis and isolation of patients as well as the search for therapies able to counter the most severe effects of the disease. In the absence of a known efficient therapy and because of the situation of a public-health emergency, it made sense to investigate the possible effect of chloroquine/hydroxychloroquine against SARS-CoV-2 since this molecule was previously described as a potent inhibitor of most coronaviruses, including SARS-CoV-1. Preliminary trials of chloroquine repurposing in the treatment of COVID-19 in China have been encouraging, leading to several new trials. Here we discuss the possible mechanisms of chloroquine interference with the SARS-CoV-2 replication cycle.
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Affiliation(s)
- Christian A Devaux
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; CNRS, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France.
| | - Jean-Marc Rolain
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
| | - Philippe Colson
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
| | - Didier Raoult
- Aix-Marseille Université, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France; IHU-Méditerranée Infection, 19-21 boulevard Jean Moulin, 13005 Marseille, France
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Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents 2020; 55:105932. [PMID: 32145363 PMCID: PMC7135139 DOI: 10.1016/j.ijantimicag.2020.105932] [Citation(s) in RCA: 544] [Impact Index Per Article: 108.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 02/27/2020] [Indexed: 12/12/2022]
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22
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Tawfik A, Knight P, Duckworth CA, Pritchard DM, Rhodes JM, Campbell BJ. Replication of Crohn's Disease Mucosal E. coli Isolates inside Macrophages Correlates with Resistance to Superoxide and Is Dependent on Macrophage NF-kappa B Activation. Pathogens 2019; 8:pathogens8020074. [PMID: 31181736 PMCID: PMC6630736 DOI: 10.3390/pathogens8020074] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/02/2019] [Accepted: 06/06/2019] [Indexed: 12/19/2022] Open
Abstract
Mucosa-associated Escherichia coli are increased in Crohn’s disease (CD) and colorectal cancer (CRC). CD isolates replicate within macrophages but the specificity of this effect for CD and its mechanism are unclear. Gentamicin exclusion assay was used to assess E. coli replication within J774.A1 murine macrophages. E. coli growth was assessed following acid, low-nutrient, nitrosative, oxidative and superoxide stress, mimicking the phagolysosome. Twelve of 16 CD E. coli isolates replicated >2-fold within J774.A1 macrophages; likewise for isolates from 6/7 urinary tract infection (UTI), 8/9 from healthy subjects, compared with 2/6 ulcerative colitis, 2/7 colorectal cancer and 0/3 laboratory strains. CD mucosal E. coli were tolerant of acidic, low-nutrient, nitrosative and oxidative stress. Replication within macrophages correlated strongly with tolerance to superoxide stress (rho = 0.44, p = 0.0009). Exemplar CD E. coli HM605 and LF82 were unable to survive within Nfκb1-/- murine bone marrow-derived macrophages. In keeping with this, pre-incubation of macrophages with hydrocortisone (0.6 µM for 24 h) caused 70.49 ± 12.11% inhibition of intra-macrophage replication. Thus, CD mucosal E. coli commonly replicate inside macrophages, but so do some UTI and healthy subject strains. Replication correlates with resistance to superoxide and is highly dependent on macrophage NF-κB signalling. This may therefore be a good therapeutic target.
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Affiliation(s)
- Ahmed Tawfik
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
- Gastroenterology Department, Beaumont Hospital, Dublin 9, Ireland.
| | - Paul Knight
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
- Gastroenterology Department, University Hospital of South Manchester, Wythenshawe M23 9LT, UK.
| | - Carrie A Duckworth
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
| | - D Mark Pritchard
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
| | - Jonathan M Rhodes
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
| | - Barry J Campbell
- Gastroenterology Research Unit, Department of Cellular & Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GE, UK.
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Abstract
Whipple's disease is a rare, multisystem infection caused by the Gram-positive Tropheryma whippelii organism. In addition to neurological and rheumatological manifestations, this disease can result in significant gastrointestinal symptoms such as malabsorption, diarrhea, and weight loss. Given the diagnostic challenge and rare occurrence, a high index of suspicion is critical to prevent morbidity and mortality from this otherwise highly infectious disease transmitted via the fecal-oral route. We present a very rare but near-fatal case of hypovolemic shock secondary to protein-losing enteropathy and gastrointestinal bleeding from small bowel T. whippelii infection. Furthermore, the epidemiology, clinical presentation, diagnosis, and management of Whipple's disease is reviewed.
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Abstract
BACKGROUND Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. AIMS To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. METHODS Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. RESULTS Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). CONCLUSIONS TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.
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25
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Affiliation(s)
- Joesph Sellin
- Professor Emeritus, Division of Gastroenterology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Ian L P Beales
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, NR4 7UY, UK.
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Palanisamy N. Identification of putative drug targets and annotation of unknown proteins in Tropheryma whipplei. Comput Biol Chem 2018; 76:130-138. [PMID: 30005292 DOI: 10.1016/j.compbiolchem.2018.05.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 01/02/2018] [Accepted: 05/27/2018] [Indexed: 12/17/2022]
Abstract
Tropheryma whipplei (T. whipplei) is the causative agent of Whipple's disease and blood culture-negative endocarditis. Due to the variability of symptoms, the disease is often poorly diagnosed. Treatment for this bacterial infection is often lengthy, and improper uptake of antibiotics has resulted in relapses in many patients. In the present study, using available bioinformatic tools and databases such as the Cluster Database at High Identity with Tolerance (CD-HIT), the Basic Local Alignment Search Tool for proteins (BLASTp), the Database of Essential Genes (DEG), and the DrugBank database, 13 putative drug targets were identified in T. whipplei by subtractive genome analysis that could be targeted with currently available drugs (experimental or approved). Further, a 3D model was generated for one of these putative drug targets, the T. whipplei DNA ligase, and in silico docking was performed with pyridochromanone and adenosine-derived inhibitors using the AutoDock Vina. Additionally, many of the T. whipplei protein sequences in the National Center for Biotechnology Information (NCBI) protein database were unknown/uncurated. Using available web servers e.g. the KEGG Automatic Annotation Server (KAAS), the BLASTp, the Conserved Domain Architecture Retrieval Tool (CDAT) and the Protein families (Pfam), the function/remote/domain homology for nearly 80% of these uncurated protein sequences were annotated. The data obtained in the present study will aid physicians and researchers alike in curbing this bacterial infection.
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Affiliation(s)
- Navaneethan Palanisamy
- Molecular and Cellular Engineering Group, BioQuant, University of Heidelberg, Heidelberg, Germany; The Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), University of Heidelberg, Heidelberg, Germany.
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Lopes A, Santos AF, Alvarenga MJ, Mello E Silva A. Whipple's disease: a rare case of malabsorption. BMJ Case Rep 2018; 2018:bcr-2017-222955. [PMID: 29507019 DOI: 10.1136/bcr-2017-222955] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Whipple's disease is a chronic, rare, multisystemic, infectious entity, described for the first time in 1907. Its aetiological agent is the Gram-negative rod, Tropheryma whipplei, which was isolated for the first time in 2001 from a cardiac valve of a patient with endocarditis. We present the case of a 71-year-old man, who came into the emergency room complaining of anorexia, weakness, abdominal pain and diarrhoea with haematochezia and presented disseminated palpable purpuric lesions, predominantly in the lower limbs. The upper endoscopy showed a duodenal vasculitis and the biopsy of that location revealed aspects suggestive of Whipple's disease. We started him on antibiotics according to the recent orientations with progressive clinical and analytical improvement, although he developed an immune reconstitution syndrome, which lasted for 2 weeks.
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Affiliation(s)
- Ana Lopes
- Department of Medicina Interna, Hospital Egas Moniz, Lisbon, Portugal
| | - Ana Filipa Santos
- Department of Pneumologia, Hospital Egas Moniz, CHLO, Lisboa, Portugal
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Loiodice A, Losurdo G, Iannone A, Rossi R, Fiore MG, Piscitelli D. Transmission electron microscopy helpfulness in Whipple's disease masked by immunosuppressant therapy for arthritis. APMIS 2017; 126:92-96. [PMID: 29154446 DOI: 10.1111/apm.12782] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 09/17/2017] [Indexed: 12/22/2022]
Abstract
A 61-year-old woman received a diagnosis of undifferentiated non-erosive arthritis in 2010 and assumed methotrexate and steroids in 2014. After 1 year, she experienced watery diarrhea, vomiting, fever, weight loss, and severe hypoalbuminemia, thus being admitted into our Unit. Esophagogastroduodenoscopy showed duodenal lymphangiectasia and duodenal biopsy samples several foamy PAS-positive macrophages and villous subtotal atrophy. Transmission electron microscope demonstrated several extracellular and intracellular rod-shaped bacteria (Tropheryma whipplei). Therefore, we diagnosed Whipple's disease. Our patient assumed doxycycline/hydroxychloroquine with prompt remission of gastrointestinal symptoms. At 1 year of follow-up, she was symptom-free, histological reassessment showed almost complete mucosal healing and transmission electron microscope demonstrated bacteria breaking/disappearance. The present report demonstrates that: (i) rheumatological manifestations are common onset symptoms of Whipple's disease; (ii) immunosuppressive therapy may delay the diagnosis and worsen clinical presentation; (iii) transmission electron microscopy for specific bacteria detection/disappearance is an helpful diagnostic tool, when available.
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Affiliation(s)
- Alessandra Loiodice
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
| | - Giuseppe Losurdo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
| | - Andrea Iannone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
| | - Roberta Rossi
- Section of Pathology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
| | - Maria Grazia Fiore
- Section of Pathology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
| | - Domenico Piscitelli
- Section of Pathology, Department of Emergency and Organ Transplantation, University 'Aldo Moro' of Bari, Bari, Italy
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Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections. Clin Microbiol Rev 2017; 30:529-555. [PMID: 28298472 DOI: 10.1128/cmr.00033-16] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei, a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.
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30
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Whipple's disease. J Neurol Sci 2017; 377:197-206. [DOI: 10.1016/j.jns.2017.01.048] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 12/16/2016] [Accepted: 01/15/2017] [Indexed: 11/24/2022]
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Papakonstantinou D, Riste MJ, Langman G, Moran E. Misdiagnosing Whipple's disease in the young. BMJ Case Rep 2017; 2017:bcr-2016-218866. [PMID: 28325722 DOI: 10.1136/bcr-2016-218866] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Whipple's disease is considered an infection of middle-aged white men of European ancestry. Cases are rare and disproportionately associated with occupational exposure to soil or animals. We report the case of a man aged 22 years with no risk factors, erroneously diagnosed with, and treated for, toxoplasmosis on the basis of consistent lymph node histology. The correct diagnosis was delayed by the dramatic symptomatic improvement resulting from this therapy. Whipple's disease should be considered in cases of granulomatous lymphadenopathy of unknown cause, even if the age of the patient does not fit the classic presentation of the disease.
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Affiliation(s)
- Danai Papakonstantinou
- Department of Infectious Diseases and Tropical Medicine, Birmingham Heartlands Hospital, Heart of England NHS Hospital Trust, Birmingham, UK
| | - Michael J Riste
- Department of Infectious Diseases and Tropical Medicine, Birmingham Heartlands Hospital, Heart of England NHS Hospital Trust, Birmingham, UK
| | - Gerald Langman
- Histopathology Department, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Ed Moran
- Department of Infectious Diseases and Tropical Medicine, Birmingham Heartlands Hospital, Heart of England NHS Hospital Trust, Birmingham, UK
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Hale A, Geerling J, Schmolze D, Pfannl R, Karchmer AW. A 63-Year-Old Man With Rapidly Progressive Dementia. Clin Infect Dis 2016; 63:138-9. [DOI: 10.1093/cid/ciw266] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Deglycosylation of Tropheryma whipplei biofilm and discrepancies between diagnostic results during Whipple's disease progression. Sci Rep 2016; 6:23883. [PMID: 27025850 PMCID: PMC4812295 DOI: 10.1038/srep23883] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 03/15/2016] [Indexed: 12/17/2022] Open
Abstract
Whipple’s disease is a systemic infectious disease associated with the bacterium Tropheryma whipplei. Numerous reports have presented puzzling discrepancies between diagnosis methods. We addressed this confusion using fluorescent in situ hybridization and immunofluorescence assays to evaluate 34 duodenal biopsies and 1 lymph node biopsy from Whipple’s patients. We showed the presence of bacteria in both CK20+ epithelial cells and CD68+ macrophages. Bacteria are found embedded in a biofilm hindering the detection of T. whipplei. Only after treatment of biopsies by glycosidases, co-localization of T. whipplei RNA/DNA with bacterial proteins was restored. Moreover, using 13 bronchoalveolar lavages and 7 duodenal biopsies, we found that hydrolysis of the biofilm weakened the bacteria, facilitated bacterial DNA extraction and improved the sensitivity of qPCR detection by up to 1000x opening new perspectives for diagnostic and scientific approaches.
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Derrick C, Love BL, Sanasi-Bhola K. Successful treatment with ceftriaxone induction and minocycline maintenance for gastrointestinal Whipple's disease. J Antimicrob Chemother 2015; 71:1123-5. [PMID: 26679252 DOI: 10.1093/jac/dkv422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Affiliation(s)
- Caroline Derrick
- University of South Carolina-School of Medicine, 1 Richland Medical Park, Suite 420, Columbia, SC 29203, USA
| | - Bryan L Love
- WJB Dorn Veterans Affairs Medical Center, 6349 Garners Ferry Road, Columbia, SC 29209, USA
| | - Kamla Sanasi-Bhola
- University of South Carolina-School of Medicine, 1 Richland Medical Park, Suite 420, Columbia, SC 29203, USA
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Branquinho DF, Pinto-Gouveia M, Mendes S, Sofia C. From past sailors' eras to the present day: scurvy as a surprising manifestation of an uncommon gastrointestinal disease. BMJ Case Rep 2015; 2015:bcr-2015-210744. [PMID: 26376699 DOI: 10.1136/bcr-2015-210744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
A 45-year-old man presented with follicular exanthema in his lower limbs, alternating bowel habits and significant weight loss. His medical history included seronegative arthritis, bipolar disease and an inconclusive diagnostic laparoscopy. Diagnostic work up revealed microcytic anaemia and multivitamin deficiency. Skin biopsy of the exanthema suggested scurvy. Owing to these signs of malabsorption, upper endoscopy with duodenal biopsies was performed, exhibiting villous atrophy and extensive periodic acid-Schiff-positive material in the lamina propria, therefore diagnosing Whipple's disease (WD). After starting treatment with ceftriaxone and co-trimoxazole, an impressive recovery was noted, as the wide spectrum of malabsorption signs quickly disappeared. After a year of antibiotics, articular and cutaneous manifestations improved, allowing the patient to stop taking corticosteroids and antidepressants. This truly unusual presentation reflects the multisystemic nature of WD, often leading to misdiagnosis of other entities. Scurvy is a rare finding in developed countries, but its presence should raise suspicion for small bowel disease.
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Affiliation(s)
| | | | - Sofia Mendes
- Department of Gastroenterology, Coimbra University Hospital, Coimbra, Portugal
| | - Carlos Sofia
- Department of Gastroenterology, Coimbra University Hospital, Coimbra, Portugal
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Killing of Escherichia coli by Crohn's Disease Monocyte-derived Macrophages and Its Enhancement by Hydroxychloroquine and Vitamin D. Inflamm Bowel Dis 2015; 21:1499-510. [PMID: 25839777 PMCID: PMC4894789 DOI: 10.1097/mib.0000000000000387] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Crohn's disease (CD) is associated with defective innate immunity, including impaired neutrophil chemotaxis, and mucosal invasion by bacteria, particularly adherent and invasive Escherichia coli that replicate inside macrophage phagolysosomes. We compared CD and healthy control (HC) macrophages for their abilities to kill E. coli and generate neutrophil chemoattractants and also assessed the effects of hydroxychloroquine (HCQ) and vitamin D on killing of phagocytosed E. coli. METHODS Peripheral blood monocyte-derived macrophages from CD and HC were compared for bacterial killing and generation of neutrophil chemoattractants in response to CD-derived E. coli. Escherichia coli replication was also assessed in the presence and absence of HCQ, alone and with antibiotics, and vitamin D. RESULTS Monocyte-derived macrophages from patients with CD were similar to HC in allowing replication of phagocytosed CD-derived E. coli: HM605 {CD: N = 10, mean fold replication in 3 hr = 1.08 (95% confidence interval [CI], 0.39-1.78); HC: N = 9, 1.50 (95% CI, 1.02-1.97); P = 0.15} and also in generation of neutrophil chemoattractants in response to E. coli (mean fold chemotaxis relative to control: CD = 2.55 [95% CI, 2.31-2.80]; HC = 2.65 [95% CI, 2.46-2.85], P = 0.42). HCQ and 1,25 OH2-vitamin D3 both caused dose-dependent inhibition of intramacrophage E. coli replication 3-hour postinfection; HCQ: 73.9% inhibition (P < 0.001) at 1 μg/mL, accompanied by raised intraphagosomal pH, and 1,25 OH2-vitamin D3: 80.7% inhibition (P < 0.05) at 80 nM. HCQ had synergistic effects with doxycycline and ciprofloxacin. CONCLUSIONS CD and HC macrophages perform similarly in allowing replication of phagocytosed E. coli and generating neutrophil chemoattractants. Replication of phagocytosed E. coli was substantially decreased by HCQ and vitamin D. These warrant further therapeutic trials in CD in combination with relevant antibiotics.
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37
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The rebirth of culture in microbiology through the example of culturomics to study human gut microbiota. Clin Microbiol Rev 2015; 28:237-64. [PMID: 25567229 DOI: 10.1128/cmr.00014-14] [Citation(s) in RCA: 548] [Impact Index Per Article: 54.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bacterial culture was the first method used to describe the human microbiota, but this method is considered outdated by many researchers. Metagenomics studies have since been applied to clinical microbiology; however, a "dark matter" of prokaryotes, which corresponds to a hole in our knowledge and includes minority bacterial populations, is not elucidated by these studies. By replicating the natural environment, environmental microbiologists were the first to reduce the "great plate count anomaly," which corresponds to the difference between microscopic and culture counts. The revolution in bacterial identification also allowed rapid progress. 16S rRNA bacterial identification allowed the accurate identification of new species. Mass spectrometry allowed the high-throughput identification of rare species and the detection of new species. By using these methods and by increasing the number of culture conditions, culturomics allowed the extension of the known human gut repertoire to levels equivalent to those of pyrosequencing. Finally, taxonogenomics strategies became an emerging method for describing new species, associating the genome sequence of the bacteria systematically. We provide a comprehensive review on these topics, demonstrating that both empirical and hypothesis-driven approaches will enable a rapid increase in the identification of the human prokaryote repertoire.
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38
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Current and past strategies for bacterial culture in clinical microbiology. Clin Microbiol Rev 2015; 28:208-36. [PMID: 25567228 DOI: 10.1128/cmr.00110-14] [Citation(s) in RCA: 327] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
A pure bacterial culture remains essential for the study of its virulence, its antibiotic susceptibility, and its genome sequence in order to facilitate the understanding and treatment of caused diseases. The first culture conditions empirically varied incubation time, nutrients, atmosphere, and temperature; culture was then gradually abandoned in favor of molecular methods. The rebirth of culture in clinical microbiology was prompted by microbiologists specializing in intracellular bacteria. The shell vial procedure allowed the culture of new species of Rickettsia. The design of axenic media for growing fastidious bacteria such as Tropheryma whipplei and Coxiella burnetii and the ability of amoebal coculture to discover new bacteria constituted major advances. Strong efforts associating optimized culture media, detection methods, and a microaerophilic atmosphere allowed a dramatic decrease of the time of Mycobacterium tuberculosis culture. The use of a new versatile medium allowed an extension of the repertoire of archaea. Finally, to optimize the culture of anaerobes in routine bacteriology laboratories, the addition of antioxidants in culture media under an aerobic atmosphere allowed the growth of strictly anaerobic species. Nevertheless, among usual bacterial pathogens, the development of axenic media for the culture of Treponema pallidum or Mycobacterium leprae remains an important challenge that the patience and innovations of cultivators will enable them to overcome.
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Iwata H, Sawada R, Mizutani S, Yamanishi Y. Systematic drug repositioning for a wide range of diseases with integrative analyses of phenotypic and molecular data. J Chem Inf Model 2015; 55:446-59. [PMID: 25602292 DOI: 10.1021/ci500670q] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Drug repositioning, or the application of known drugs to new indications, is a challenging issue in pharmaceutical science. In this study, we developed a new computational method to predict unknown drug indications for systematic drug repositioning in a framework of supervised network inference. We defined a descriptor for each drug-disease pair based on the phenotypic features of drugs (e.g., medicinal effects and side effects) and various molecular features of diseases (e.g., disease-causing genes, diagnostic markers, disease-related pathways, and environmental factors) and constructed a statistical model to predict new drug-disease associations for a wide range of diseases in the International Classification of Diseases. Our results show that the proposed method outperforms previous methods in terms of accuracy and applicability, and its performance does not depend on drug chemical structure similarity. Finally, we performed a comprehensive prediction of a drug-disease association network consisting of 2349 drugs and 858 diseases and described biologically meaningful examples of newly predicted drug indications for several types of cancers and nonhereditary diseases.
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Affiliation(s)
- Hiroaki Iwata
- Division of System Cohort, Multi-Scale Research Center for Medical Science, Medical Institute of Bioregulation, Kyushu University , 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan
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40
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Obma KL, Marx GE, Mauchley D, Seres T, Babu A, Saveli CC, Bartels K. CASE 12--2015: Tropheryma Whipplei Endocarditis. J Cardiothorac Vasc Anesth 2014; 29:1712-6. [PMID: 25675891 DOI: 10.1053/j.jvca.2014.11.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Indexed: 12/12/2022]
Affiliation(s)
| | - Grace E Marx
- Department of Medicine, Division of Infectious Diseases
| | - David Mauchley
- Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado, Denver, Colorado
| | | | - Ashok Babu
- Department of Surgery, Division of Cardiothoracic Surgery, University of Colorado, Denver, Colorado
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41
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Tawfik A, Flanagan PK, Campbell BJ. Escherichia coli-host macrophage interactions in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20:8751-8763. [PMID: 25083050 PMCID: PMC4112894 DOI: 10.3748/wjg.v20.i27.8751] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Revised: 01/07/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Multiple studies have demonstrated alterations in the intestinal microbial community (termed the microbiome) in Crohn’s disease (CD) and several lines of evidence suggest these changes may have a significant role in disease pathogenesis. In active and quiescent disease, both the faecal and mucosa-associated microbiome are discordant with matched controls with reduced biodiversity, changes in dominant organisms and increased temporal variation described. Mucosa-associated adherent, invasive Escherichia coli (E. coli) (AIEC), pro-inflammatory and resistant to killing by mucosal macrophages, appear to be particularly important. AIEC possess several virulence factors which may confer pathogenic potential in CD. Type-1 pili (FimH) allow adherence to intestinal cells via cell-surface carcinoembryonic antigen-related cell adhesion molecules and possession of long polar fimbrae promotes translocation across the intestinal mucosa via microfold (M)-cells of the follicle-associated epithelium. Resistance to stress genes (htrA, dsbA and hfq) and tolerance of an acidic pH may contribute to survival within the phagolysosomal environment. Here we review the current understanding of the role of mucosa-associated E. coli in Crohn’s pathogenesis, the role of the innate immune system, factors which may contribute to prolonged bacterial survival and therapeutic strategies to target intracellular E. coli.
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Sutera V, Caspar Y, Boisset S, Maurin M. A new dye uptake assay to test the activity of antibiotics against intracellular Francisella tularensis. Front Cell Infect Microbiol 2014; 4:36. [PMID: 24672776 PMCID: PMC3957058 DOI: 10.3389/fcimb.2014.00036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 02/24/2014] [Indexed: 11/13/2022] Open
Abstract
Francisella tularensis, a facultative intracellular bacterium, is the aetiological agent of tularaemia. Antibiotic treatment of this zoonosis is based on the administration of a fluoroquinolone or a tetracycline for cases with mild to moderate severity, whereas an aminoglycoside (streptomycin or gentamicin) is advocated for severe cases. However, treatment failures and relapses remain frequent, especially in patients suffering from chronic lymph node suppuration. Therefore, new treatment alternatives are needed. We have developed a dye uptake assay for determination of minimal inhibitory extracellular concentrations (MIECs) of antibiotics against intracellular F. tularensis, and validated the method by comparing the results obtained using a CFU-enumerating method. We also compared MIECs with MICs of the same compounds determined using a CLSI broth microdilution method. We tested the activity of 11 antibiotics against two clinical strains of F. tularensis subsp. holarctica isolated in France. Both strains displayed low MICs (≤1 μg/mL) to fluoroquinolones (ciprofloxacin, levofloxacin and moxifloxacin), gentamicin, doxycycline and rifampicin. Higher MICs (≥8 μg/mL) were found for carbapenems (imipenem and meropenem), daptomycin and linezolid. Erythromycin MICs were 4.0 and 16.0 μg/mL, respectively, for the two clinical strains. MIECs were almost the same with the two methods used. They were concordant with MICs, except for erythromycin and linezolid (respectively, four and eight times more active against intracellular F. tularensis) and gentamicin (four to eight times less active against intracellular F. tularensis). This study validated the dye uptake assay as a new tool for determination of the activity of a large panel of antibiotics against intracellular F. tularensis. This test confirmed the intracellular activity of first-line antibiotics used for tularaemia treatment, but also revealed significant activity of linezolid against intracellular F. tularensis.
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Affiliation(s)
- Vivien Sutera
- Laboratoire de Bactériologie, Département des Agents Infectieux, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire Grenoble Grenoble, France ; Laboratoire Adaptation et Pathogénie des Micro-Organismes, Université Joseph Fourier-Grenoble 1 Grenoble Cedex 9, France ; CNRS, UMR 5163 Grenoble, France
| | - Yvan Caspar
- Laboratoire de Bactériologie, Département des Agents Infectieux, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire Grenoble Grenoble, France ; Laboratoire Adaptation et Pathogénie des Micro-Organismes, Université Joseph Fourier-Grenoble 1 Grenoble Cedex 9, France ; CNRS, UMR 5163 Grenoble, France
| | - Sandrine Boisset
- Laboratoire de Bactériologie, Département des Agents Infectieux, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire Grenoble Grenoble, France ; Laboratoire Adaptation et Pathogénie des Micro-Organismes, Université Joseph Fourier-Grenoble 1 Grenoble Cedex 9, France ; CNRS, UMR 5163 Grenoble, France
| | - Max Maurin
- Laboratoire de Bactériologie, Département des Agents Infectieux, Institut de Biologie et de Pathologie, Centre Hospitalier Universitaire Grenoble Grenoble, France ; Laboratoire Adaptation et Pathogénie des Micro-Organismes, Université Joseph Fourier-Grenoble 1 Grenoble Cedex 9, France ; CNRS, UMR 5163 Grenoble, France
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Compain C, Sacre K, Puéchal X, Klein I, Vital-Durand D, Houeto JL, De Broucker T, Raoult D, Papo T. Central nervous system involvement in Whipple disease: clinical study of 18 patients and long-term follow-up. Medicine (Baltimore) 2013; 92:324-330. [PMID: 24145700 PMCID: PMC4553994 DOI: 10.1097/md.0000000000000010] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Whipple disease (WD) is a rare multisystemic infection with a protean clinical presentation. The central nervous system (CNS) is involved in 3 situations: CNS involvement in classic WD, CNS relapse in previously treated WD, and isolated CNS infection. We retrospectively analyzed clinical features, diagnostic workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data in 18 patients with WD and CNS infection. Ten men and 8 women were included with a median age at diagnosis of 47 years (range, 30-56 yr). The median follow-up duration was 6 years (range, 1-19 yr). As categorized in the 3 subgroups, 11 patients had classic WD with CNS involvement, 4 had an isolated CNS infection, and 3 had a neurologic relapse of previously treated WD. CNS involvement occurred during prolonged trimethoprim-sulfamethoxazole (TMP-SMX) treatment in 1 patient with classic WD. The neurologic symptoms were various and always intermingled, as follows: confusion or coma (17%) related to meningo-encephalitis or status epilepticus; delirium (17%); cognitive impairment (61%) including memory loss and attention defects or typical frontal lobe syndrome; hypersomnia (17%); abnormal movements (myoclonus, choreiform movements, oculomasticatory myorhythmia) (39%); cerebellar ataxia (11%); upper motor neuron (44%) or extrapyramidal symptoms (33%); and ophthalmoplegia (17%) in conjunction or not with progressive supranuclear palsy. No specific pattern was correlated with any subgroup. Brain magnetic resonance imaging (MRI) revealed a unique focal lesion (35%), mostly as a tumorlike brain lesion, or multifocal lesions (23%) involving the medial temporal lobe, midbrain, hypothalamus, and thalamus. Periventricular diffuse leukopathy (6%), diffuse cortical atrophy (18%), and pachymeningitis (12%) were observed. The spinal cord was involved in 2 cases. MRI showed ischemic sequelae at diagnosis or during follow-up in 4 patients. Brain MRI was normal despite neurologic symptoms in 3 cases. CSF cytology was normal in 62% of patients, whereas Tropheryma whipplei polymerase chain reaction (PCR) analysis was positive in 92% of cases with tested CSF. Periodic acid-Schiff (PAS)-positive cells were identified in cerebral biopsies of 4 patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years (range, 1-7 yr) with either oral monotherapy (TMP-SMX, doxycycline, third-generation cephalosporins) or a combination of antibiotics that sometimes followed parenteral treatment with beta-lactams and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow-up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Thirteen patients (72%) had stopped treatment for an average time of 4 years (range, 0.7-14 yr). Four patients had clinical worsening despite antimicrobial therapy; 2 of those died following diffuse encephalitis (n = 1) and lung infection (n = 1). In conclusion, the neurologic manifestations of WD are diverse and may mimic almost any neurologic condition. Brain involvement may occur during or after TMP-SMX treatment. CSF T. whipplei PCR analysis is a major tool for diagnosis and may be positive in the absence of meningitis. Immune reconstitution syndrome may occur in the early months of treatment. Late prognosis may be better than previously reported, as a consequence of earlier diagnosis and a better use of antimicrobial therapy, including hydroxychloroquine and doxycycline combination.
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Affiliation(s)
- Caroline Compain
- From the Service de Médecine Interne (CC, KS, TP) and Service de Radiologie (IK), Université Paris Diderot, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Bichat, Paris; INSERM U699, (KS) Université Paris Diderot, Paris; Centre de Référence National sur les Vascularites Systémiques (XP), Université Paris-Descartes, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris; Service de Médecine Interne (DV-D), Université Lyon-Sud, Lyon; Service de Neurologie (J-LH), Université Poitiers, Poitiers; Service de Neurologie (TDB), Hôpital de Saint-Denis, Saint Denis; Aix Marseille Université (DR), URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, Marseille, France
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Lagier JC, Fenollar F, Lepidi H, Giorgi R, Million M, Raoult D. Treatment of classic Whipple's disease: from in vitro results to clinical outcome. J Antimicrob Chemother 2013; 69:219-27. [PMID: 23946319 DOI: 10.1093/jac/dkt310] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Patients with classic Whipple's disease have a lifetime defect in immunity to Tropheryma whipplei and frequently develop treatment failures, relapses or reinfections. Empirical treatments were tested before culture was possible, but the only in vitro bactericidal treatment consists of a combination of doxycycline and hydroxychloroquine. METHODS Our laboratory has been a reference centre since the first culturing of Tropheryma whipplei, and we have tested 27,000 samples by PCR and diagnosed 250 cases of classic Whipple's disease. We report here the clinical course of patients who were followed by one of our group. RESULTS Of 29 patients, 22 (76%) were previously treated with immunosuppressive drugs, 26 (90%) suffered from arthralgias and 22 (76%) exhibited weight loss. Intravenous initial treatment was paradoxically associated with an increased risk of failure (P = 0.0282). Treatment with doxycycline and hydroxychloroquine (± sulfadiazine or trimethoprim/sulfamethoxazole) was associated with a better outcome (0/13 failures), whereas all 14 patients who were first treated with trimethoprim/sulfamethoxazole and referred to us (P < 0.0001) experienced failure. Among the patients treated with doxycycline and hydroxychloroquine after previous antibiotic treatments, two presented with a reinfection caused by different T. whipplei strains. Finally, serum therapeutic drug monitoring allowed us to detect a lack of compliance in the only patient with failure among the 22 patients treated with lifetime doxycycline. CONCLUSIONS In vitro results were confirmed by clinical outcomes and trimethoprim/sulfamethoxazole was associated with failures. The recommended management is a combination of doxycycline and hydroxychloroquine for 1 year, followed by doxycycline for the patient's lifetime along with stringent therapeutic drug monitoring.
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Affiliation(s)
- Jean-Christophe Lagier
- Aix Marseille Université, URMITE, UM63, CNRS 7278, IRD 198, INSERM 1095, 13005 Marseille, France
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Whipple's Disease: Our Own Experience and Review of the Literature. Gastroenterol Res Pract 2013; 2013:478349. [PMID: 23843784 PMCID: PMC3703430 DOI: 10.1155/2013/478349] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2013] [Accepted: 05/22/2013] [Indexed: 12/17/2022] Open
Abstract
Whipple's disease is a chronic infectious systemic disease caused by the bacterium Tropheryma whipplei. Nondeforming arthritis is frequently an initial complaint. Gastrointestinal and general symptoms include marked diarrhoea (with serious malabsorption), abdominal pain, prominent weight loss, and low-grade fever. Possible neurologic symptoms (up to 20%) might be associated with worse prognosis. Diagnosis is based on the clinical picture and small intestinal histology revealing foamy macrophages containing periodic-acid-Schiff- (PAS-) positive material. Long-term (up to one year) antibiotic therapy provides a favourable outcome in the vast majority of cases. This paper provides review of the literature and an analysis of our 5 patients recorded within a 20-year period at a tertiary gastroenterology centre. Patients were treated using i.v. penicillin G or amoxicillin-clavulanic acid + i.v. gentamicin for two weeks, followed by p.o. doxycycline (100 mg per day) plus p.o. salazopyrine (3 g per day) for 1 year. Full remission was achieved in all our patients.
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Keita AK, Raoult D, Fenollar F. Tropheryma whipplei as a commensal bacterium. Future Microbiol 2013; 8:57-71. [PMID: 23252493 DOI: 10.2217/fmb.12.124] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tropheryma whipplei is the bacterial agent of the well-known and rare Whipple's disease, mainly observed among Caucasians. This bacterium has recently been involved in other chronic and acute infections. For a long time, the only known source of the bacterium was patients with Whipple's disease; however, thanks to the advent of molecular biology, T. whipplei has now been detected in specimens from healthy individuals, mainly in stool and saliva samples. The prevalence of carriage depends on several factors, such as age, exposure and geographical area, reaching 75% in stool specimens from children less than 4 years old in rural Africa. T. whipplei is a commensal bacterium that only causes Whipple's disease in a subset of individuals, probably those with a still-uncharacterized specific immunological defect.
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Affiliation(s)
- Alpha Kabinet Keita
- Aix Marseille Université, Unité des Rickettsies, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, CNRS/INSERM, Marseille, France
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Whipple's disease: Multiple systemic and neurological relapses. NEUROLOGÍA (ENGLISH EDITION) 2013. [DOI: 10.1016/j.nrleng.2011.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Hamasuna R. Identification of treatment strategies for Mycoplasma genitalium-related urethritis in male patients by culturing and antimicrobial susceptibility testing. J Infect Chemother 2012; 19:1-11. [PMID: 23076335 DOI: 10.1007/s10156-012-0487-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Indexed: 11/25/2022]
Abstract
Mycoplasma genitalium was first isolated from urethral swab specimens of male patients with non-gonococcal urethritis. However, the isolation of M. genitalium strains from clinical specimens has been difficult. Co-cultivation with Vero cells is one available technique for the isolation of M. genitalium. The strains that can be used for antimicrobial susceptibility testing by broth dilution or agar dilution methods are limited. Macrolides, such as azithromycin (AZM), have the strongest activity against M. genitalium. However, AZM-resistant strains have emerged and spread. Mutations in the 23S rRNA gene contribute to the organism's macrolide resistance, which is similar to the effects of the mutations in macrolide-resistant Mycoplasma pneumoniae. Of the fluoroquinolones, moxifloxacin (MFLX) and sitafloxacin have the strongest activities against M. genitalium, while levofloxacin and ciprofloxacin are not as effective. Some clinical trials on the treatment of M. genitalium-related urethritis are available in the literature. A doxycycline regimen was microbiologically inferior to an AZM regimen. For cases of treatment failure with AZM regimens, MFLX regimens were effective.
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Affiliation(s)
- Ryoichi Hamasuna
- Department of Urology, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
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Ocular Whipple's Disease: Therapeutic Strategy and Long-Term Follow-Up. Ophthalmology 2012; 119:1465-9. [DOI: 10.1016/j.ophtha.2012.01.024] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2011] [Revised: 01/11/2012] [Accepted: 01/12/2012] [Indexed: 11/23/2022] Open
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Rolain JM, Fenollar F, Raoult D. In vitro activity of pentamidine against Tropheryma whipplei. Int J Antimicrob Agents 2011; 38:545-7. [PMID: 22005072 DOI: 10.1016/j.ijantimicag.2011.07.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Accepted: 07/29/2011] [Indexed: 12/17/2022]
Abstract
Pentamidine is a group I intron splice inhibitor used as a chemotherapeutic agent to treat parasitic infections. It was recently found to be efficient intracellularly against Coxiella burnetii, the bacterial agent of Q fever. This in vitro activity was linked to the presence of self-splicing group I introns that disrupt the 23S rRNA of C. burnetii. However, there are several indications that pentamidine may have a wider range of antibacterial activity. The aim of this study was to determine the in vitro activity of pentamidine against Tropheryma whipplei, the agent of Whipple's disease, a chronic disease for which antibiotic treatment remains challenging. In vitro susceptibility testing of pentamidine and doxycycline was assessed both in axenic medium and in cell culture against three clinical isolates of T. whipplei using a quantitative real-time polymerase chain reaction (PCR) assay as previously described. Both doxycycline and pentamidine were found to be active against T. whipplei strains both in axenic medium and in cell culture, with minimum inhibitory concentration ranges of 0.5-1mg/L and 0.125-0.25mg/L for doxycycline and pentamidine, respectively. Pentamidine was effective in vitro against T. whipplei both intracellularly and in axenic medium. This is the first evidence of the direct efficacy of pentamidine against T. whipplei grown in axenic medium and in cells. Since pentamidine has been widely used in humans, we believe that it could be an alternative drug for the treatment of this chronic disease that should be further studied in clinical trials.
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Affiliation(s)
- Jean-Marc Rolain
- Unité de Recherche sur Maladies Infectieuses et Tropicales Emergents, CNRS-IRD, UMR 6236, Faculté de Médecine et de Pharmacie, Université de Méditerranée Aix-Marseille II, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
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