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      Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines

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          Abstract

          Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.

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          Most cited references61

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          Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.

          Neisseria gonorrhoeae is evolving into a superbug with resistance to previously and currently recommended antimicrobials for treatment of gonorrhea, which is a major public health concern globally. Given the global nature of gonorrhea, the high rate of usage of antimicrobials, suboptimal control and monitoring of antimicrobial resistance (AMR) and treatment failures, slow update of treatment guidelines in most geographical settings, and the extraordinary capacity of the gonococci to develop and retain AMR, it is likely that the global problem of gonococcal AMR will worsen in the foreseeable future and that the severe complications of gonorrhea will emerge as a silent epidemic. By understanding the evolution, emergence, and spread of AMR in N. gonorrhoeae, including its molecular and phenotypic mechanisms, resistance to antimicrobials used clinically can be anticipated, future methods for genetic testing for AMR might permit region-specific and tailor-made antimicrobial therapy, and the design of novel antimicrobials to circumvent the resistance problems can be undertaken more rationally. This review focuses on the history and evolution of gonorrhea treatment regimens and emerging resistance to them, on genetic and phenotypic determinants of gonococcal resistance to previously and currently recommended antimicrobials, including biological costs or benefits; and on crucial actions and future advances necessary to detect and treat resistant gonococcal strains and, ultimately, retain gonorrhea as a treatable infection. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
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            Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action

            In a Policy Forum, Teodora Wi and colleagues discuss the challenges of antimicrobial resistance in gonococci.
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              Is Neisseria gonorrhoeae initiating a future era of untreatable gonorrhea?: detailed characterization of the first strain with high-level resistance to ceftriaxone.

              Recently, the first Neisseria gonorrhoeae strain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (penA, mtrR, penB, ponA, and pilQ). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 μg/ml, which is 4- to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A new penA mosaic allele caused the ceftriaxone resistance. In conclusion, N. gonorrhoeae has now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance in N. gonorrhoeae remains unknown, N. gonorrhoeae may soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.

                Author and article information

                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                26 July 2017
                July 2017
                : 14
                : 7
                : e1002366
                Affiliations
                [1 ] Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative, (DNDi, ), Geneva, Switzerland
                [2 ] World Health Organization (WHO), Geneva, Switzerland
                [3 ] Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India
                [4 ] Federal University of Santa Catarina, Florianópolis, Brazil
                [5 ] National Center for STD Control, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Dermatology, Nanjing, China
                [6 ] STD Branch, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), Rockville, Maryland, United States of America
                [7 ] University of Saskatchewan, Saskatoon, Saskatchewan, Canada
                [8 ] Centre for HIV & Sexually Transmitted Infections, National Institute for Communicable Diseases, Johannesburg, South Africa
                [9 ] University of Alabama, Birmingham, Alabama, United States of America
                [10 ] World Health Organization Collaborating Centre for Sexually Transmitted Diseases, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Sydney, Australia
                [11 ] Western Sydney Sexual Health Centre, Parramatta, NSW, Australia, and Marie Bashir Institute for Infectious Diseases and Biosecurity & Sydney Medical School-Westmead, University of Sydney, Westmead, Australia
                [12 ] Skin & GU Medicine Clinic, Harare, Zimbabwe
                [13 ] Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America, and Laboratories of Bacterial Pathogenesis, VA Medical Center, Decatur, Georgia, United States of America
                [14 ] Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, Georgia, United States of America
                [15 ] World Health Organization Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden
                Author notes

                We have read the journal's policy and the authors of this manuscript have the following competing interests: EWH has received grant support/research materials from US Centers for Disease Control and Prevention, National Institutes of Health, Hologic, Becton Dickinson, Cepheid, Roche Molecular, and Cempra; and has acted as a consultant for Astra Zeneca (Entasis), and GlaxoSmithKline. DAL has provided an external consultancy service for GlaxoSmithKline with respect to gonorrhoea management. KW has received research funds from Melinta and GlaxoSmithKline.

                Author information
                http://orcid.org/0000-0001-8691-3991
                http://orcid.org/0000-0002-7640-9166
                http://orcid.org/0000-0002-2261-9424
                http://orcid.org/0000-0001-7533-613X
                http://orcid.org/0000-0002-9918-9493
                http://orcid.org/0000-0002-2091-6660
                Article
                PMEDICINE-D-17-01131
                10.1371/journal.pmed.1002366
                5528252
                28746372
                73fc0943-19a7-4913-99b6-78fef5fd73ed

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                Page count
                Figures: 0, Tables: 1, Pages: 12
                Funding
                The authors received no specific funding for this work.
                Categories
                Essay
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                Genitourinary Infections
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