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      Antimicrobial resistance in Neisseria gonorrhoeae: Global surveillance and a call for international collaborative action

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          Abstract

          In a Policy Forum, Teodora Wi and colleagues discuss the challenges of antimicrobial resistance in gonococci.

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          Most cited references54

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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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            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.
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              High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure.

              Recently, the first Neisseria gonorrhoeae strain (H041) highly resistant to the expanded-spectrum cephalosporins (ESCs) ceftriaxone and cefixime, which are the last remaining options for first-line gonorrhea treatment, was isolated in Japan. Here, we confirm and characterize a second strain (F89) with high-level cefixime and ceftriaxone resistance which was isolated in France and most likely caused a treatment failure with cefixime. F89 was examined using six species-confirmatory tests, antibiograms (33 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of known gonococcal resistance determinants (penA, mtrR, penB, ponA, and pilQ). F89 was assigned to MLST sequence type 1901 (ST1901) and NG-MAST ST1407, which is a successful gonococcal clone that has spread globally. F89 has high-level resistance to cefixime (MIC = 4 μg/ml) and ceftriaxone (MIC = 1 to 2 μg/ml) and resistance to most other antimicrobials examined. A novel penA mosaic allele (penA-CI), which was penA-XXXIV with an additional A501P alteration in penicillin-binding protein 2, was the primary determinant for high-level ESC resistance, as determined by transformation into a set of recipient strains. N. gonorrhoeae appears to be emerging as a superbug, and in certain circumstances and settings, gonorrhea may become untreatable. Investigations of the biological fitness and enhanced understanding and monitoring of the ESC-resistant clones and their international transmission are required. Enhanced disease control activities, antimicrobial resistance control and surveillance worldwide, and public health response plans for global (and national) perspectives are also crucial. Nevertheless, new treatment strategies and/or drugs and, ideally, a vaccine are essential to develop for efficacious gonorrhea management.
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                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
                7 July 2017
                July 2017
                : 14
                : 7
                : e1002344
                Affiliations
                [1 ]Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland
                [2 ]World Health Organization Collaborating Centre for Sexually Transmitted Diseases, New South Wales Health Pathology, Sydney, Australia
                [3 ]School of Medical Sciences, The University of New South Wales, Sydney, Australia
                [4 ]Skin and Genitourinary Medicine Clinic, Harare, Zimbabwe
                [5 ]Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India
                [6 ]University of Saskatchewan, Saskatoon, Saskatchewan, Canada
                [7 ]Communicable Disease Analysis, World Health Organization, Washington, D.C., United States of America
                [8 ]Antimicrobial Resistance Secretariat, World Health Organization, Geneva, Switzerland
                [9 ]Division of STD Prevention, Centers for Disease Control and Prevention, Georgia, Atlanta, United States of America
                [10 ]World Health Organization Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-7640-9166
                http://orcid.org/0000-0002-4351-666X
                http://orcid.org/0000-0002-4862-2568
                http://orcid.org/0000-0002-0486-3255
                http://orcid.org/0000-0003-1710-2081
                Article
                PMEDICINE-D-17-00886
                10.1371/journal.pmed.1002344
                5501266
                28686231
                f5a75ac7-aa3c-475f-b1de-a93105374268
                © 2017 World Health Organization

                Licensee Public Library of Science. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/3.0/igo/. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

                History
                Page count
                Figures: 3, Tables: 1, Pages: 16
                Funding
                The authors received no specific funding for this work.
                Categories
                Policy Forum
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobial Resistance
                Medicine and Health Sciences
                Pharmacology
                Antimicrobial Resistance
                Medicine and Health Sciences
                Urology
                Genitourinary Infections
                Gonorrhea
                Medicine and Health Sciences
                Infectious Diseases
                Sexually Transmitted Diseases
                Gonorrhea
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Neisseria Gonorrhoeae
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                Pathology and Laboratory Medicine
                Pathogens
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                Bacterial Pathogens
                Neisseria Gonorrhoeae
                Biology and Life Sciences
                Organisms
                Bacteria
                Neisseria
                Neisseria Gonorrhoeae
                Medicine and Health Sciences
                Epidemiology
                Disease Surveillance
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                Medicine and Health Sciences
                Public and Occupational Health
                Global Health
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                Public and Occupational Health
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                Medicine
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