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  • 1.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18Manuscript (preprint) (Other academic)
  • 2.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Kelly, Anne
    iRiSC-Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Karolinska University Hospital, Solna, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Demirel, Isak
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Fredlund, Hans
    iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Särndahl, Eva
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Persson, Alexander
    Örebro University, School of Medical Sciences. iRiSC-Inflammatory Response and Infection Susceptibility Centre.
    Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent2019In: Journal of Immunology Research, ISSN 2314-8861, E-ISSN 2314-7156, article id 6193186Article in journal (Refereed)
    Abstract [en]

    Meningococcal disease such as sepsis and meningitidis is hallmarked by an excessive inflammatory response. The causative agent, Neisseria meningitidis, expresses the endotoxin lipooligosaccharide (LOS) that is responsible for activation of immune cells and the release of proinflammatory cytokines. One of the most potent proinflammatory cytokines, interleukin-1 (IL-1), is activated following caspase-1 activity in the intracellular multiprotein complex called inflammasome. Inflammasomes are activated by a number of microbial factors as well as danger molecules by a two-step mechanismpriming and licensing of inflammasome activationbut there are no data available regarding a role for inflammasome activation in meningococcal disease. The aim of this study was to investigate if N. meningitidis activates the inflammasome and, if so, the role of bacterial LOS in this activation. Cells were subjected to N. meningitidis, both wild-type (FAM20) and its LOS-deficient mutant (lpxA), and priming as well as licensing of inflammasome activation was investigated. The wild-type LOS-expressing parental FAM20 serogroup C N. meningitidis (FAM20) strain significantly enhanced the caspase-1 activity in human neutrophils and monocytes, whereas lpxA was unable to induce caspase-1 activity as well as to induce IL-1 release. While the lpxA mutant induced a priming response, measured as increased expression of NLRP3 and IL1B, the LOS-expressing FAM20 further increased this priming. We conclude that although non-LOS components of N. meningitidis contribute to the priming of the inflammasome activity, LOS per se is to be considered as the central component of N. meningitidis virulence, responsible for both priming and licensing of inflammasome activation.

  • 3.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophilsManuscript (preprint) (Other academic)
  • 4.
    Bettoni, Serena
    et al.
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Shaughnessy, Jutamas
    Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, USA.
    Maziarz, Karolina
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Ermert, David
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Riesbeck, Kristian
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Blom, Anna
    Lund University - Department of Translational Medicine, Malmö, Sweden.
    Ram, Sanjay
    Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, USA.
    C4BP-IGM FUSION PROTEIN AS A NOVEL THERAPEUTIC APPROACH TO TREAT NEISSERIA GONORRHOEAE INFECTIONS2019In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 114, p. 470-470Article in journal (Other academic)
  • 5.
    Boiko, Iryna
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Clinical Laboratory Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Krynytska, Inna
    Department of Functional and Laboratory Diagnostics, I. Horbachevsky Ternopil State Medical University, Ternopil, Ukraine.
    Bezkorovaina, Halyna
    Outpatient Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Frankenberg, Arkadii
    Dnipropetrovsk Regional Clinical Dermatovenerologic Dispensary, Dnipro, Ukraine.
    Onuchyna, Margarita
    Clinical Laboratory Department, Dnipropetrovsk Regional Clinical Dermatovenerologic Dispensary, Dnipro, Ukraine.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine.
    Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and treatment of gonorrhoea patients in Ternopil and Dnipropetrovsk regions of Ukraine, 2013-20182019In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 127, no 7, p. 503-509Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern globally. However, recent gonococcal AMR data from Eastern Europe are extremely limited and no AMR data for strains spreading in Ukraine have ever been internationally published. We investigated the AMR of N. gonorrhoeae isolates in two regions of Ukraine (Ternopil 2013-2018, Dnipropetrovsk 2013-2014), and, where information was available, the treatment administered to the corresponding gonorrhoea patients. Determination of minimum inhibitory concentration (MIC) of eight antimicrobials was performed using Etest and resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were applied. Overall, 9.3% of the examined 150 isolates were resistant to ciprofloxacin, 6.0% to tetracycline, 2.0% to azithromycin, and 0.7% to benzylpenicillin. No isolates were resistant to ceftriaxone, cefixime, spectinomycin, or gentamicin. However, one (0.7%) isolate showed a MIC value of 0.125 mg/L for both ceftriaxone and cefixime, i.e., bordering resistance. Eighty-eight (67.2%) of 131 patients were administered dual therapy (ceftriaxone 1 g plus doxycycline/clarithromycin/azithromycin/ofloxacin) and 22 (16.8%) ceftriaxone 1 g monotherapy. Worryingly, 21 (16.0%) patients received monotherapy with clarithromycin/doxycycline/azithromycin/ofloxacin/benzylpenicillin. In conclusion, the antimicrobial susceptibility of gonococcal strains spreading in Ternopil and Dnipropetrovsk, Ukraine during 2013-2018 was high. Low levels of resistance to ciprofloxacin, tetracycline, azithromycin, and benzylpenicillin were found, but no resistance to the internationally recommended ceftriaxone, cefixime, or spectinomycin. Ceftriaxone 1 g should remain as empiric first-line treatment, in dual therapy with azithromycin or doxycycline or in monotherapy. Continued and expanded gonococcal AMR surveillance in Ukraine is essential to monitor the susceptibility to particularly extended-spectrum cephalosporins, azithromycin and doxycycline.

  • 6.
    Cole, Michelle J.
    et al.
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK.
    Quaye, Nerteley
    National Mycobacterium Reference Service, National Infection Service, Public Health England, London, UK.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs.
    Day, Michaela
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK.
    Fagan, Elizabeth
    United Kingdom National External Quality Assessment Service (UK NEQAS), National Infection Service, Public Health England, London, UK.
    Ison, Catherine
    Sexually Transmitted Bacteria Reference Unit (retired), Public Health England, London, UK.
    Pitt, Rachel
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK.
    Seaton, Shila
    United Kingdom National External Quality Assessment Service (UK NEQAS), National Infection Service, Public Health England, London, UK.
    Woodford, Neil
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK.
    Stary, Angelika
    Outpatients` Centre for the Diagnosis of Infectious Venero-Dermatological Diseases, Vienna, Austria.
    Pleininger, Sonja
    National Reference Centre for Gonococci, Austrian Agency for Health and Food Safety, Vienna, Austria.
    Crucitti, Tania
    Institute of Tropical Medicine, Antwerp, Belgium.
    Hunjak, Blaženka
    Croatian Institute of Public Health, Zagreb, Croatia.
    Maikanti, Panayiota
    Microbiology Department, Nicosia General Hospital, Nicosia, Cyprus.
    Hoffmann, Steen
    Department for Bacteria, Parasites and Fungi Infectious Diseases Preparedness, Statens Serum Institut, Copenhagen, Denmark.
    Viktorova, Jelena
    Central Laboratory of Communicable Diseases, Tallinn, Estonia.
    Buder, Susanne
    Laboratory for Gonococci, Vivantes Klinikum, South, Berlin, Germany.
    Kohl, Peter
    Laboratory for Gonococci, Vivantes Klinikum, South, Berlin, Germany.
    Tzelepi, Eva
    National Reference Centre for N. gonorrhoeae, Laboratory of Bacteriology of the Hellenic Pasteur Institute, Athens, Greece.
    Siatravani, Eirini
    National Reference Centre for N. gonorrhoeae, Laboratory of Bacteriology of the Hellenic Pasteur Institute, Athens, Greece.
    Balla, Eszter
    Bacterial STI Reference Laboratory, National Public Health Institute, Budapest, Hungary.
    Hauksdóttir, Guðrún Svanborg
    Landspitali University Hospital, Reykjavik, Iceland.
    Rose, Lisa
    National Gonococcal Reference Laboratory, St James's Hospital, Dublin, Ireland.
    Stefanelli, Paola
    Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
    Carannante, Anna
    Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
    Pakarna, Gatis
    National Microbiology Reference Laboratory, Latvian Centre of Infectious Diseases, Riga East University Hospital, Riga, Latvia.
    Mifsud, Francesca
    Bacteriology Laboratory, Mater Dei Hospital, Msida, Malta.
    Cassar, Rosann Zammit
    Bacteriology Laboratory, Mater Dei Hospital, Msida, Malta.
    Linde, Ineke
    Streeklaboratorium/Bacteriologie, GGD Amsterdam, Amsterdam, The Netherlands.
    Bergheim, Thea
    Department of Medical Microbiology, Oslo University Hospital, Oslo, Norway.
    Steinbakk, Martin
    Norwegian Institute of Public Health, Oslo, Norway.
    Mlynarczyk-Bonikowska, Beata
    Department of Diagnostics of Sexually Transmitted Diseases, Medical University of Warsaw, Warsaw, Poland.
    Borrego, Maria-José
    Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisbon, Portugal.
    Shepherd, Jill
    Scottish Bacterial Sexually Transmitted Infections Reference Laboratory, Royal Infirmary of Edinburgh, Edinburgh, UK.
    Pavlik, Peter
    Medirex a.s., Bratislava, Slovakia.
    Jeverica, Samo
    Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
    Vazquez, Julio
    Reference Laboratory for Neisseria National Centre for Microbiology - Instituto de Salud Carlos III, Majadahonda, Spain.
    Abad, Raquel
    Reference Laboratory for Neisseria National Centre for Microbiology - Instituto de Salud Carlos III, Majadahonda, Spain.
    Weiss, Sabrina
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK; Institute of Virology, Charite - Universitätsmedizin Berlin, Berlin, Germany; European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs.
    Ten years of external quality assessment (EQA) of Neisseria gonorrhoeae antimicrobial susceptibility testing in Europe elucidate high reliability of data2019In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 19, no 1, article id 281Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Confidence in any diagnostic and antimicrobial susceptibility testing data is provided by appropriate and regular quality assurance (QA) procedures. In Europe, the European Gonococcal Antimicrobial Susceptibility Programme (Euro-GASP) has been monitoring the antimicrobial susceptibility in Neisseria gonorrhoeae since 2004. Euro-GASP includes an external quality assessment (EQA) scheme as an essential component for a quality-assured laboratory-based surveillance programme. Participation in the EQA scheme enables any problems with the performed antimicrobial susceptibility testing to be identified and addressed, feeds into the curricula of laboratory training organised by the Euro-GASP network, and assesses the capacity of individual laboratories to detect emerging new, rare and increasing antimicrobial resistance phenotypes. Participant performance in the Euro-GASP EQA scheme over a 10 year period (2007 to 2016, no EQA in 2013) was evaluated.

    METHODS: Antimicrobial susceptibility category and MIC results from the first 5 years (2007-2011) of the Euro-GASP EQA were compared with the latter 5 years (2012-2016). These time periods were selected to assess the impact of the 2012 European Union case definitions for the reporting of antimicrobial susceptibility.

    RESULTS: dilutions of the modal MIC, respectively. The most common method used was Etest on GC agar base. There was a shift to using breakpoints published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in the latter 5 years, however overall impact on the validity of results was limited, as the percentage categorical agreement and MIC concordance changed very little between the two five-year periods.

    CONCLUSIONS: The high level of comparability of results in this EQA scheme indicates that high quality data are produced by the Euro-GASP participants and gives confidence in susceptibility and resistance data generated by laboratories performing decentralised testing.

  • 7.
    Cole, Michelle J.
    et al.
    Public Health England, Sexually Transmitted Bacteria Reference Unit, Microbiological Services, London, England, United Kingdom.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Pitt, Rachel
    Public Health England, Sexually Transmitted Bacteria Reference Unit, Microbiological Services, London, England, United Kingdom.
    Grigorjev, Vlad
    Public Health England, Sexually Transmitted Bacteria Reference Unit, Microbiological Services, London, England, United Kingdom.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Is the tide turning again for cephalosporin resistance in Neisseria gonorrhoeae in Europe?: Results from the 2013 European surveillance2015In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 15, article id 321Article in journal (Refereed)
    Abstract [en]

    Background: The emerging resistance to the extended-spectrum cephalosporins (ESCs) in Neisseria gonorrhoeae together with increasing incidence of gonorrhoea cases in many countries have been global public health concerns. However, in recent years the levels of ESC resistance have decreased in several regions worldwide. We describe the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) data from 2013, and compare them to corresponding data from 2009-2012.

    Methods: During 2013, N. gonorrhoeae isolates from 21 participating countries were examined. Antimicrobial susceptibility testing (Etest or agar dilution) was performed for cefixime, ceftriaxone, ciprofloxacin, azithromycin, spectinomycin and gentamicin. Statistical analyses were performed to identify significant changes in resistance between years and to investigate associations between patients with resistant gonococcal isolates and collected epidemiological variables.

    Results: In total, 93 (4.7 %) of 1994 isolates displayed resistance to cefixime, representing an increase compared to the 3.9 % detected in 2012 (p = 0.23). Cefixime resistance was detected in 13 (61.9 %) of the 21 countries. Cefixime resistance among men who have sex with men was only 1.2 %, compared to 5.6 % and 6.1 % in females and male heterosexuals, respectively. The univariate analysis confirmed that isolates resistant to cefixime were more likely to be from females (OR 4.87, p < 0.01) or male heterosexuals (OR 5.32, p < 0.01). Seven (0.4 %) isolates displayed ceftriaxone resistance (in addition to cefixime resistance) compared to three and 10 isolates in 2012 and 2011, respectively. All 93 isolates with cefixime resistance were additionally resistant to ciprofloxacin and 16 (17.2 %) were also resistant to azithromycin. Among all tested isolates (n = 1994), the ciprofloxacin resistance level (52.9 %) was higher than in 2012 (50.1 %; p = 0.08), and azithromycin resistance (5.4 %) increased since 2012 (4.5 %; p = 0.16).

    Conclusions: In 2013, the ESC resistance was again slightly increasing in Europe. This emphasises the importance of implementing the actions outlined in the European and additional response plans, particularly activities strengthening the surveillance of antimicrobial resistance. Ceftriaxone combined with azithromycin remains a satisfactory option for the first-line treatment of gonorrhoea. However novel antimicrobials (new derivatives of previously developed antimicrobials or newly developed antimicrobials) for effective monotherapy or at least inclusion in new dual antimicrobial therapy regimens (combined with previously developed antimicrobials or novel antimicrobials) will likely be required.

  • 8.
    Cole, Michelle J.
    et al.
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, Public Health England, London, United Kingdom.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden.
    Woodford, Neil
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, Public Health England, London, United Kingdom.
    Tripodo, Francesco
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, Public Health England, London, United Kingdom.
    Amato-Gauci, Andrew J.
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden.
    Overall Low Extended-Spectrum Cephalosporin Resistance but high Azithromycin Resistance in Neisseria gonorrhoeae in 24 European Countries, 20152017In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 17, article id 617Article in journal (Refereed)
    Abstract [en]

    Background: Surveillance of Neisseria gonorrhoeae antimicrobial susceptibility in Europe is performed through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), which additionally provides data to inform the European gonorrhoea treatment guideline; currently recommending ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. We present antimicrobial susceptibility data from 24 European countries in 2015, linked to epidemiological data of patients, and compare the results to Euro-GASP data from previous years.

    Methods: Antimicrobial susceptibility testing by MIC gradient strips or agar dilution methodology was performed on 2134 N. gonorrhoeae isolates and interpreted using EUCAST breakpoints. Patient variables associated with resistance were established using logistic regression to estimate odds ratios (ORs).

    Results: In 2015, 1.7% of isolates were cefixime resistant compared to 2.0% in 2014. Ceftriaxone resistance was detected in only one (0.05%) isolate in 2015, compared with five (0.2%) in 2014. Azithromycin resistance was detected in 7.1% of isolates in 2015 (7.9% in 2014), and five (0.2%) isolates displayed high-level azithromycin resistance (MIC = 256 mg/L) compared with one (0.05%) in 2014. Ciprofloxacin resistance remained high (49.4%, vs. 50.7% in 2014). Cefixime resistance significantly increased among heterosexual males (4.1% vs. 1.7% in 2014), which was mainly attributable to data from two countries with high cefixime resistance (similar to 11%), however rates among men-who-have-sex-with-men (MSM) and females continued to decline to 0.5% and 1%, respectively. Azithromycin resistance in MSM and heterosexual males was higher (both 8.1%) than in females (4.9% vs. 2.2% in 2014). The association between azithromycin resistance and previous gonorrhoea infection, observed in 2014, continued in 2015 (OR 2.1, CI 1.2-3.5, p < 0.01).

    Conclusions: The 2015 Euro-GASP sentinel system revealed high, but stable azithromycin resistance and low overall resistance to ceftriaxone and cefixime. The low cephalosporin resistance may be attributable to the effectiveness of the currently recommended first-line dual antimicrobial therapy; however the high azithromycin resistance threatens the effectiveness of this therapeutic regimen. Whether the global use of azithromycin in mono-or dual antimicrobial therapy of gonorrhoea is contributing to the global increases in azithromycin resistance remains to be elucidated. The increasing cefixime resistance in heterosexual males also needs close monitoring.

  • 9.
    Day, Michaela
    et al.
    Public Health England, National Infection Service, London, UK.
    Cole, Michelle
    Public Health England, National Infection Service, London, UK.
    Spiteri, Gianfranco
    ECDC, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Woodford, Neil
    Public Health England, National Infection Service, London, UK.
    Amato-Gauci, Andrew
    ECDC, Stockholm, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    THE EUROPEAN GONOCOCCAL ANTIMICROBIAL SURVEILLANCE PROGRAMME FINDINGS 20172019In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 95, no Suppl. 1, p. A43-A43Article in journal (Other academic)
    Abstract [en]

    Background: The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) annually investigates antimicrobial susceptibility data for Neisseria gonorrhoeae with patient epidemiological data to monitor current and emerging trends in antimicrobial resistance (AMR) across Europe. Susceptibility to ceftriaxone and azithromycin, currently recommended for combination treatment in the European management guideline, has decreased in the past; regular surveillance of AMR is cru-cial. We present the main Euro-GASP findings from 2017.

    Methods: Agar dilution and minimum inhibitory concentration (MIC) gradient strip tests were used to determine the antimicrobial susceptibility to cefixime, ceftriaxone and azithromycin (using EUCAST breakpoints) of 3248 N. gonorrhoeae isolates collected in 2017 from 27 countries across the European Union/European Economic Area (EU/EEA). Significance of changes in resistance compared to 2016 was analysed using Z-tests.

    Results: There were no isolates with ceftriaxone resistance (MIC>0.125 mg/L) (zero in 2016), 7.5% of isolates were azithromycin resistant (MIC>0.5 mg/L) (7.5% in 2016; p=0.93) and cefixime resistance (MIC>0.125 mg/L) was observed in 1.9% of isolates (2.1% in 2016; p=0.53). Seven isolates from four countries displayed high-level azithromycin resistance (MIC256 mg/L), which is the same number as observed in 2016, although in different countries (five countries in 2016). Ceftriaxone MICs for 28 isolates (0.9%) were 0.125 mg/L (on the resistance breakpoint) which is double the number observed in 2016 (14 isolates, 0.5%) although this increase is not statistically significant (p=0.33). Of the 28 isolates on the ceftriaxone resistance breakpoint, four showed intermediate susceptibility to azithromycin.

    Conclusion: Ceftriaxone, azithromycin and cefixime resistance levels remained stable compared with 2016. However, the current azithromycin resistance rate of 7.5% and the number of isolates on the resistance breakpoint for ceftriaxone threaten the effectiveness of the currently recommended European therapeutic regimen of ceftriaxone 500 mg plus azithromycin 2 g. Continued surveillance is essential together with, ultimately, development of new effective antimicrobials.

  • 10.
    Day, Michaela J.
    et al.
    National Infection Service, Public Health England, London, UK.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhea and other STIs.
    Woodford, Neil
    National Infection Service, Public Health England, London, UK.
    Amato-Gauci, Andrew J.
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Cole, Michelle J.
    National Infection Service, Public Health England, London, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhea and other STIs.
    Euro-GASP, network
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Stably high azithromycin resistance and decreasing ceftriaxone susceptibility in Neisseria gonorrhoeae in 25 European countries, 20162018In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 18, no 1, article id 609Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) performs annual sentinel surveillance of Neisseria gonorrhoeae susceptibility to therapeutically relevant antimicrobials across the European Union/European Economic Area (EU/EEA). We present the Euro-GASP results from 2016 (25 countries), linked to patient epidemiological data, and compared with data from previous years.

    METHODS: Agar dilution and minimum inhibitory concentration (MIC) gradient strip methodologies were used to determine the antimicrobial susceptibility (using EUCAST breakpoints) of 2660 N. gonorrhoeae isolates from 25 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-tests.

    RESULTS: No isolates with resistance to ceftriaxone (MIC > 0.125 mg/L) were detected in 2016 (one in 2015). However, the proportion of isolates with decreased susceptibility to ceftriaxone (MICs from 0.03 mg/L to 0.125 mg/L) increased significantly (p = 0.01) from 2015 to 2016. There were 14 (0.5%) isolates with ceftriaxone MICs 0.125 mg/L (on the resistance breakpoint), of which one isolate was resistant to azithromycin and four showed intermediate susceptibility to azithromycin. Cefixime resistance was detected in 2.1% of isolates in 2016 compared with 1.7% in 2015 (p = 0.26) and azithromycin resistance in 7.5% in 2016 compared with 7.1% in 2015 (p = 0.74). Seven (0.3%) isolates from five countries displayed high-level azithromycin resistance (MIC≥256 mg/L) in 2016 compared with five (0.2%) isolates in 2015. Resistance rate to ciprofloxacin was 46.5% compared with 49.4% in 2015 (p = 0.06). No isolates were resistant to spectinomycin and the MICs of gentamicin remained stable compared with previous years.

    CONCLUSIONS: Overall AMR rates in gonococci in EU/EEA remained stable from 2015 to 2016. However, the ceftriaxone MIC distribution shifted away from the most susceptible (≤0.016 mg/L) and the proportion of isolates with decreased susceptibility to ceftriaxone increased significantly. This development is of concern as current European gonorrhoea management guideline recommends ceftriaxone 500 mg plus azithromycin 2 g as first-line therapy. With azithromycin resistance at 7.5%, the increasing ceftriaxone MICs might soon threaten the effectiveness of this therapeutic regimen and requires close monitoring.

  • 11.
    Eriksson, Lorraine
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Hedberg, Sara Thulin
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University, School of Health Sciences. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Whole-Genome Sequencing of Emerging Invasive Neisseria meningitidis Serogroup W in Sweden2018In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 56, no 4, article id e01409-17Article in journal (Refereed)
    Abstract [en]

    Invasive disease caused by Neisseria meningitidis serogroup W (MenW) has historically had a low incidence in Sweden, with an average incidence of 0.03 case/100,000 population from 1995 to 2014. In recent years, a significant increase in the incidence of MenW has been noted in Sweden, to an average incidence of 0.15 case/100,000 population in 2015 to 2016. In 2017 (1 January to 30 June), 33% of invasive meningococcal disease cases (7/21 cases) were caused by MenW. In the present study, all invasive MenW isolates from Sweden collected in 1995 to June 2017 (n = 86) were subjected to whole-genome sequencing to determine the population structure and to compare isolates from Sweden with historical and international cases. The increase of MenW in Sweden was determined to be due to isolates belonging to the South American sublineage of MenW clonal complex 11, namely, the novel U.K. 2013 lineage. This lineage was introduced in Sweden in 2013 and has since been the dominant lineage of MenW.

  • 12.
    Foerster, Sunniva
    et al.
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Hathaway, Lucy J.
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
    Low, Nicola
    Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Shafer, William M.
    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta GA, USA; Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur GA, USA.
    Althaus, Christian L.
    Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden.
    Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae2015In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 6, article id 1377Article in journal (Refereed)
    Abstract [en]

    Resistance in Neisseria gonorrhoeae to all available therapeutic antimicrobials has emerged and new efficacious drugs for treatment of gonorrhea are essential. The topoisomerase II inhibitor ETX0914 (also known as AZD0914) is a new spiropyrimidinetrione antimicrobial that has different mechanisms of action from all previous and current gonorrhea treatment options. In this study, the N. gonorrhoeae resistance determinants for ETX0914 were further described and the effects of ETX0914 on the growth of N. gonorrhoeae (ETX0914 wild type, single step selected resistant mutants, and efflux pump mutants) were examined in a novel in vitro time-kill curve analysis to estimate pharmacodynamic parameters of the new antimicrobial. For comparison, ciprofloxacin, azithromycin, ceftriaxone, and tetracycline were also examined (separately and in combination with ETX0914). ETX0914 was rapidly bactericidal for all wild type strains and had similar pharmacodynamic properties to ciprofloxacin. All selected resistant mutants contained mutations in amino acid codons D429 or K450 of GyrB and inactivation of the MtrCDE efflux pump fully restored the susceptibility to ETX0914. ETX0914 alone and in combination with azithromycin and ceftriaxone was highly effective against N. gonorrhoeae and synergistic interaction with ciprofloxacin, particularly for ETX0914-resistant mutants, was found. ETX0914, monotherapy or in combination with azithromycin (to cover additional sexually transmitted infections), should be considered for phase III clinical trials and future gonorrhea treatment.

  • 13.
    Hadad, Ronza
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Pizza, Mariagrazia
    Novartis V&D, Siena, Italy.
    Rappuoli, Rino
    Novartis V&D, Siena, Italy.
    Fredlund, Hans
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Novel meningococcal 4CMenB vaccine antigens - prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae2012In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 9, p. 750-760Article in journal (Refereed)
    Abstract [en]

    The first cross-protective Neisseria meningitidis vaccine (focus on serogroup B), the protein-based 4 component meningococcus serogroup B (4CMenB), includes the New Zealand outer membrane vesicle and three main genome-derived neisserial antigens (GNAs). These GNAs are fHbp (fused to GNA2091), NHBA (fused to GNA1030) and NadA. In this study, the prevalence and polymorphisms of the nucleotide and amino acid sequences of the 4CMenB antigens in a temporally and geographically diverse collection of N. gonorrhoeae isolates (n similar to=similar to 111) were investigated. All the examined GNA genes, except the nadA gene, were present in all gonococcal isolates. However, 25 isolates contained premature stop codons in the fHbp gene and/or the nhba gene, resulting in truncated proteins. Compared with the 4CMenB antigen sequences in reference strain MC58, the gonococcal strains displayed 67.095.4% and 60.994.9% identity in nucleotide sequence and amino acid sequence, respectively, in the equivalent GNA antigens. The absence of NadA, lack of universal expression of fHbp and NHBA and the uncertainty regarding the surface exposure of fHbp as well as the function of NHBA in N. gonorrhoeae will likely limit the use of the identical 4CMenB antigens in a gonococcal vaccine. However, possible cross-immunity of 4CMenB with gonococci and expression and function of the equivalent gonococcal GNAs, as well as of more appropriate GNAs for a gonococcal vaccine, need to be further examined.

  • 14.
    Harris, Simon R.
    et al.
    Infection Genomics, Wellcome Sanger Institute, Hinxton, United Kingdom.
    Cole, Michelle J.
    Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, National Infection Service, Public Health England, London, United Kingdom.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Sanchez-Buso, Leonor
    Infection Genomics, Wellcome Sanger Institute, Hinxton, United Kingdom.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Goater, Richard
    Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Hinxton, United Kingdom.
    Abudahab, Khalil
    Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Hinxton, United Kingdom.
    Yeats, Corin A.
    Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Hinxton, United Kingdom.
    Bercot, Beatrice
    St Louis Hospital, Assistance Publique Hôpitaux de Paris (APHP), Paris, France.
    Borrego, Maria Jose
    National Institute of Health, Lisbon, Portugal.
    Crowley, Brendan
    St James's Hospital, Dublin, Ireland.
    Stefanelli, Paola
    Istituto Superiore di Sanitá, Rome, Italy.
    Tripodo, Francesco
    Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, National Infection Service, Public Health England, London, United Kingdom.
    Abad, Raquel
    Carlos III Health Institute, Madrid, Spain.
    Aanensen, David M.
    Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Hinxton, United Kingdom; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology, Faculty of Medicine and Health, Örebro University Hospital, Örebro, Sweden.
    Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe: a genomic survey2018In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 18, no 7, p. 758-768Article in journal (Refereed)
    Abstract [en]

    Background: Traditional methods for molecular epidemiology of Neisseria gonorrhoeae are suboptimal. Whole-genome sequencing (WGS) offers ideal resolution to describe population dynamics and to predict and infer transmission of antimicrobial resistance, and can enhance infection control through linkage with epidemiological data. We used WGS, in conjunction with linked epidemiological and phenotypic data, to describe the gonococcal population in 20 European countries. We aimed to detail changes in phenotypic antimicrobial resistance levels (and the reasons for these changes) and strain distribution (with a focus on antimicrobial resistance strains in risk groups), and to predict antimicrobial resistance from WGS data.

    Methods: We carried out an observational study, in which we sequenced isolates taken from patients with gonorrhoea from the European Gonococcal Antimicrobial Surveillance Programme in 20 countries from September to November, 2013. We also developed a web platform that we used for automated antimicrobial resistance prediction, molecular typing (N gonorrhoeae multi-antigen sequence typing [NG-MAST] and multilocus sequence typing), and phylogenetic clustering in conjunction with epidemiological and phenotypic data.

    Findings: The multidrug-resistant NG-MAST genogroup G1407 was predominant and accounted for the most cephalosporin resistance, but the prevalence of this genogroup decreased from 248 (23%) of 1066 isolates in a previous study from 2009-10 to 174 (17%) of 1054 isolates in this survey in 2013. This genogroup previously showed an association with men who have sex with men, but changed to an association with heterosexual people (odds ratio=4.29). WGS provided substantially improved resolution and accuracy over NG-MAST and multilocus sequence typing, predicted antimicrobial resistance relatively well, and identified discrepant isolates, mixed infections or contaminants, and multidrug-resistant clades linked to risk groups.

    Interpretation: To our knowledge, we provide the first use of joint analysis of WGS and epidemiological data in an international programme for regional surveillance of sexually transmitted infections. WGS provided enhanced understanding of the distribution of antimicrobial resistance clones, including replacement with clones that were more susceptible to antimicrobials, in several risk groups nationally and regionally. We provide a framework for genomic surveillance of gonococci through standardised sampling, use of WGS, and a shared information architecture for interpretation and dissemination by use of open access software.

  • 15.
    Ingberg, Edvin
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Mölling, P.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Alm, E.
    Hedin, K.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    16S metagenomics for bacterial identification versus cultures in acute pharyngotonsillitis patients and controls2018Conference paper (Refereed)
    Abstract [en]

    Background: Sore throat/pharyngotonsillitis is a very common condition. While most cases are viral, the primary bacterial pathogen is group A beta-hemolytic streptococcus (Streptococcus pyogenes). Further, Fusobacterium necrophorum has over the last decade attracted attention. rnrnSequence-based techniques continue to gain ground in medical microbiology. To describe the microbiota in a sample, either the whole genomes (metagenomics) or marker genes/genomic regions (metataxonomics), such as the 16S rRNA gene, can be sequenced. Some studies have investigated how findings from these methods correspond to conventional microbiological methods for infectious diseases, such as cultures. However, no previous study has approached the condition acute pharyngotonsillitis this way.

    Methods: Throat samples from patients with acute sore throat (n=129) and controls (n=86), both groups aged 15-45, were collected. DNA was extracted and the V3-V4 regions of the 16S rRNA genes were amplified using PCR. After normalization based on fragment analysis, and size selection with Ampure beads and PCR against adapter sequences coupled to the V3-V4 fragments, clonal amplifiction was performed with isothermal PCR. Finally, sequencing was performed on the Ion Torrent S5 XL. The SILVA database was used for taxonomic classification and the results were compared to culture findings for S. pyogenes and F. necrophorum, using Mann Whitney U tests.

    Results: Among the 215 samples, 46 patients and 1 of the controls were culture-positive for S. pyogenes. For F. necrophorum, 20 patients and 3 controls were culture-positive. Seven of the samples were culture-positive for both S. pyogenes and F. necrophorum. rnrnIn the metataxonomic analysis, S. pyogenes were significantly more abundant among patients than controls (p=0.0046), and in samples culture-positive for S. pyogenes, compared to culture-negative (p<0.0001).

    The percent of reads representing F. necrophorum were significantly higher in patients compared to controls (p<0.001), as well as in culture-positive samples compared to culture-negative (p<0.0001). rnrnAlthough significant differences between culture-positive and culture-negative samples were seen, even among culture-positive samples the abundance of S. pyogenes or F. necrophorum were on average low (2,1% and 10,6%, respectively) and with large variation (0-49,8% and 0-76,1%, respectively).

    Conclusions: Findings from a metataxonomic 16S rRNA gene analysis differed regarding species of interest between groups based on symptoms of a sore throat or culture findings. However, the results were heterogeneous and difficult to interpret for a single sample.

  • 16.
    Jabeen, Kauser
    et al.
    Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
    Bhawan Mal, Pushpa
    Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
    Khan, Erum
    Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
    Chandio, Saeeda
    Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Antimicrobial resistance and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) genotypes in N. gonorrhoeae during 2012-2014 in Karachi, Pakistan2016In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 16, no 1, article id 353Article in journal (Refereed)
    Abstract [en]

    Background: Globally, increasing antimicrobial resistance (AMR) in Neisseria gonorrhoea has led to decreased treatment options for gonorrhoea. Continuous monitoring of resistance is crucial to determine evolving resistance trends in Neisseria gonorrhoea and to suggest treatment recommendations. Quality assured gonococcal AMR data from Pakistan are mainly lacking. This study was performed to determine prevalence and trends of gonococcal AMR and molecular epidemiology of local strains during 2012-2014 in Karachi, Pakistan.

    Methods: Gonococcal isolates (n = 100) were obtained from urogenital specimens submitted to the Aga Khan University Laboratory, Karachi, Pakistan. Antimicrobial susceptibility was determined using Etest and molecular epidemiology was assessed by N. gonorrhoeae multiantigen sequence typing (NG-MAST). Quality control was performed using N. gonorrhoeae WHO reference strains C, F, G, K, L, M, N, O, and P, and ATCC 49226.

    Results: Susceptibility to spectinomycin, ceftriaxone and cefixime was 100 % and to azithromycin was 99 %. All isolates had low ceftriaxone MICs, i.e., ≤0.032 mg/L. Resistance to ciprofloxacin, tetracycline and penicillin G were 86 %, 51 % and 43 %, respectively. NG-MAST analysis identified 74 different sequence types (STs).

    Conclusions: A highly diversified gonococcal population, 74 NG-MAST STs (62 novel STs) with an increased resistance to penicillin G, ciprofloxacin and tetracycline circulated in Karachi, Pakistan. Fortunately, no resistance to ceftriaxone was detected. Accordingly, ceftriaxone can continuously be recommended as the treatment of choice. However it is recommended to increase the dose of ceftriaxone from 125 mg intramuscularly to 250 mg intramuscularly due to ceftriaxone MIC creep and emerging resistance reported in the region. Furthermore, due to the high level of resistance to ciprofloxacin (86 %) it is essential to exclude ciprofloxacin from the recommended first-line therapy. It is imperative to significantly broaden the gonococcal AMR monitoring with participation from other laboratories and cities in Pakistan.

  • 17.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences.
    Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neisseria meningitidis, also referred to as meningococcus, is a Gram-negative diplococcal bacterium best known as an important cause of meningitis and septicaemia worldwide. Meningococcal disease is a rare but life-threatening illness that may progress to death despite optimal medical care including appropriate antibiotic therapy. Case fatality remains high and survivors may suffer from significant sequelae because of impaired circulation and/or damages to the central nervous system. Prevention through vaccination remains a most effective approach to control disease. The main problem, however, is the absence of an effective vaccine against disease caused by a broad spectrum of group B isolates.

    Understanding how the meningococcus can be both a common commensal and a devastating human pathogen is a major task for researchers in the area of meningococcal disease. In paper I, we investigated and described the characteristics of fatal meningococcal isolates and compared these with non-fatal invasive meningococcal isolates. The diversity was high within the isolates from both patient groups. Group Y, serotypes 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2 were more common in fatal cases as were being elderly and female.

    The second major task in the area of meningococcal disease is to develop a group B vaccine. Six genes encoding antigens identified as promising vaccine candidates were examined in papers II & III. Based on our results, the prevalence of these genes and their sequence variation have the potential to constitute a meningococcal vaccine of broad range that also cover group B isolates in Sweden and other countries with a similar distribution of disease causing meningococci.

    In paper IV, we investigated the levels of IgG antibodies in serum directed against fHbp and NadA, two of the antigens included in papers II & III. Overall, the immune response to fHbp seems to be higher than the immune response to NadA, with a clear rise of anti-fHbp in the young adult groups (20-29 years).

    List of papers
    1. Characteristics of Neisseria meningitidis isolates causing fatal disease
    Open this publication in new window or tab >>Characteristics of Neisseria meningitidis isolates causing fatal disease
    Show others...
    2008 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 40, no 9, p. 734-744Article in journal (Refereed) Published
    Abstract [en]

    The objectives of the present study were to describe a selection of characteristics of all available fatal meningococcal isolates (n=62) and to compare these with all the other invasive isolates (non-fatal, n=474) collected in Sweden from 1995 to 2004 (fatality rate of 12%). The coverage of the fatal isolates by presently discussed outer membrane vesicle (OMV) vaccines was also estimated. The isolates were characterized by serogroup, serotype, genosubtype, multilocus sequence type and antibiogram. Basic epidemiological data were gathered. The results of the fatal isolates showed 55% serogroup B, 27% C, 15% Y and 3% W-135, with a fatality rate of 11% for B, 12% for C, 17% for Y and 8% for W-135. Characteristics associated with higher mortality were age, gender, serogroup Y, serotype 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2. In contrast, non-14/non-15 serotypes, the genosubtypes P1.5-1,10-8,36-2; P1.7-2,4,37 and P1.7,16,35, as well as reduced sensitivity for penicillin G were associated with decreased mortality. The presently discussed OMV vaccines could, based solely on the complete genosubtype, theoretically cover up to 44% of the fatal serogroup B cases and up to 100% if every variable region by itself is capable to induce protective immunity.

    Place, publisher, year, edition, pages
    London: Taylor & Francis, 2008
    National Category
    Medical and Health Sciences Infectious Medicine
    Research subject
    Infectious Diseases
    Identifiers
    urn:nbn:se:oru:diva-3456 (URN)10.1080/00365540802029565 (DOI)18609211 (PubMedID)
    Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2017-12-14Bibliographically approved
    2. Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens
    Open this publication in new window or tab >>Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens
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    2006 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 24, no 12, p. 2161-2168Article in journal (Refereed) Published
    Abstract [en]

    By the strategy “reverse vaccinology” a number of new antigens have been identified in Neisseria meningitidis, which are potential candidates for a highly needed broad-spectrum meningococcal vaccine. In the present study we examined the prevalence, sequence constancies and variations of the genes encoding three of these new antigens designated, genome-derived neisserial antigen (GNA) 1870, GNA1946 and GNA2132. All three genes were present in all     N. meningitidis isolates tested. Concerning gna1870, three major variants of the gene sequences and deduced amino acid sequences were identified and 56% of the deduced amino acids were conserved in all isolates. In gna1946, 98% of the deduced amino acids were conserved and in gna2132, 54% of the deduced amino acids were conserved. Based on gene prevalence and conservation, all three antigens are promising candidates for an effective meningococcal vaccine against all N. meningitidis irrespective of serogroup.

    Keywords
    Neisseria meningitidis; Vaccine; Genome-derived neisserial antigen (GNA).
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-6634 (URN)10.1016/j.vaccine.2005.11.006 (DOI)
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13Bibliographically approved
    3. Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease
    Open this publication in new window or tab >>Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease
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    2009 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 10, p. 1579-1584Article in journal (Refereed) Published
    Abstract [en]

    During the recent years, projects are in progress for designing broad-range non-capsular-based meningococcal vaccines, covering also serogroup B isolates. We have examined three genes encoding antigens (NadA, GNA1030 and GNA2091) included in a novel vaccine, i.e. the 5 Component Vaccine against Meningococcus B (5CVMB), in terms of gene prevalence and sequence variations. These data were combined with the results from a similar study, examining the two additional antigens included in the 5CVMB (fHbp and GNA2132).

    nadA and fHbp v. 1 were present in 38% (n=36), respectively 71% (n=67) of the isolates, whereas gna2132, gna1030 and gna2091 were present in all the Neisseria meningitidis isolates tested (n=95). The level of amino acid conservation was relatively high in GNA1030 (93%), GNA2091 (92%), and within the main variants of NadA and fHbp. GNA2132 (54% of the amino acids conserved) appeared to be the most diversified antigen. Consequently, the theoretical coverage of the 5CVMB antigens and the feasibility to use these in a broad-range meningococcal vaccine is appealing.

    Place, publisher, year, edition, pages
    Amsterdam: Elsevier, 2009
    Keywords
    Neisseria meningitidis; 5CVMB vaccine; Genome-derived neisserial antigen (GNA); sequencing; MLST
    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-6635 (URN)10.1016/j.vaccine.2008.12.052 (DOI)
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-12-13Bibliographically approved
    4. Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis
    Open this publication in new window or tab >>Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The IgG antibody levels directed against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis, were examined in order to investigate the extent of natural immunisation against these antigens in different age groups. As a comparison, the IgG antibody levels against Haemophilus influenzae type b were examined.

    In the two youngest age groups, below 10 years of age, relatively low levels of both anti-fHbp and anti-NadA were measured. A 9-fold higher concentration of anti-fHbp was noted in the age groups up to 29 years of age to its peak at 30-39 years, followed by decreased levels with age. Anti-NadA showed a certain increase up to 9 years followed by an even increase up to 49 years.

    Keywords
    Neisseria meningitidis, factor H binding protein (fHbp), Neisseria adhesin A (NadA), seroprevalence, vaccine
    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-6636 (URN)
    Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-10-18Bibliographically approved
  • 18.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Despite successful vaccines Neisseria meningitidis strikes again2016In: Lancet. Infectious diseases (Print), ISSN 1473-3099, E-ISSN 1474-4457, Vol. 16, no 11, p. 1212-1213Article in journal (Refereed)
  • 19.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Alirol, Emilie
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the ketolide cethromycin in multidrug-resistant clinical Neisseria gonorrhoeae isolates and international reference strains2019In: Journal of chemotherapy, ISSN 1120-009X, E-ISSN 1973-9478, Vol. 252, no Part B, p. 1399-1405Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance in Neisseria gonorrhoeae is a major public health problem, which compromises the treatment of gonorrhoea globally. We evaluated the in vitro activity of the ketolide cethromycin against a large panel of clinical gonococcal isolates and international reference strains (n = 254), including numerous multidrug-resistant and extensively drug-resistant isolates. Cethromycin showed potent in vitro activity against most of the gonococcal isolates with the following modal MIC, MIC50 and MIC90: 0.064 mg/L, 0.125 mg/L and 0.5 mg/L, respectively. However, cross-resistance between azithromycin and cethromycin was identified (Spearman's rank correlation coefficient 0.917) and isolates displaying high-level resistance to azithromycin (MIC >256 mg/L; n = 9) also showed high MICs of cethromycin (32-256 mg/L). In conclusion, the cross-resistance with azithromycin indicates that cethromycin may not be considered for empirical first-line monotherapy of gonorrhoea. However, cethromycin might be valuable in combination antimicrobial therapy and for second-line therapy e.g. for cases with ceftriaxone resistance or allergy.

  • 20.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Boiko, Iryna
    Clinical Laboratory Department, Ternopil Regional Clinical Dermatovenerologic Dispensary, Ternopil, Ukraine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Blondeel, Karel
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Kiarie, James
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Toskin, Igor
    Department of Reproductive Health and Research, World Health Organization (WHO), Geneva, Switzerland.
    Peeling, Rosanna W.
    London School of Hygiene and Tropical Medicine (LSHTM), London, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    WHO laboratory validation of Xpert((R)) CT/NG and Xpert((R)) TV on the GeneXpert system verifies high performances2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 12, p. 907-912Article in journal (Refereed)
    Abstract [en]

    Effective tests for diagnosis of sexually transmitted infections (STIs), used point of care to inform treatment and management decisions, are urgently needed. We evaluated the analytical sensitivity and specificity of the Xpert((R)) CT/NG and Xpert((R)) TV tests, examining 339 samples spiked with phenotypically and/or genetically diverse strains of Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis, and other related species that may cross-react. The APTIMA Combo 2 test and APTIMA TV test were used as reference tests. The analytical sensitivity for all three agents in the Xpert((R)) CT/NG and Xpert((R)) TV tests was <= 10(2) genome equivalents/reaction. The analytical specificity of both tests was high. False-positive results were identified in the Xpert((R)) TV test when challenging with high concentrations of Trichomonas tenax, Trichomonas gallinae, Trichomonas stableri, and Trichomonas aotus. However, the clinical relevance of these cross-reactions can likely be neglected, because these species have not been identified in urogenital samples from humans. In conclusion, the analytical sensitivity and specificity of the user-friendly Xpert((R)) CT/NG and Xpert((R)) TV tests on the GeneXpert system were high. The results support the use of specimens from also extra-genital sites, for example, pharynx and rectum. However, appropriate clinical validations are additionally required.

  • 21.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences.
    Golparian, Daniel
    Örebro University, School of Medical Sciences.
    Cole, Michelle
    Public Health England, London, UK.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Martin, Irene
    Public Health Agency of Canada, Winnipeg, Canada.
    Bergheim, Thea
    Oslo University Hospital Ullevål, Oslo, Norway.
    Borrego, Maria José
    National Institute of Health, Lisbon, Portugal.
    Crowley, Brendan
    St James’s Hospital, Dublin, Ireland.
    Crucitti, Tania
    Institute of Tropical Medicine, Antwerp, Belgium.
    Van Dam, Alje P.
    Public Health Service Amsterdam, Amsterdam, The Netherlands.
    Hoffmann, Steen
    Statens Serum Institut, Copenhagen, Denmark.
    Jeverica, Samo
    Institute of Microbiology and Immunology, University of Ljubljana, Ljubljana, Slovenia.
    Kohl, Peter
    Vivantes Klinikum Neukölln, Berlin, Germany.
    Mlynarczyk-Bonikowska, Beata
    Medical University of Warsaw, Warsaw, Poland.
    Pakarna, Gatis
    Infectology Centre of Latvia, Riga, Latvia.
    Stary, Angelika
    Outpatients’ Centre for Infectious Venereodermatological Diseases, Vienna, Austria.
    Stefanelli, Paola
    Istituto Superiore di Sanitá, Rome, Italy.
    Pavlik, Peter
    HPL Laboratory Ltd, Bratislava, Slovakia.
    Tzelepi, Eva
    Hellenic Pasteur Institute, Athens, Greece.
    Abad, Raquel
    Institute of Health Carlos III, Madrid, Spain.
    Harris, Simon R.
    Pathogen Genomics, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, UK.
    Unemo, Magnus
    Örebro University, School of Health Sciences.
    WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 20142016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 11, p. 3109-3116Article in journal (Refereed)
    Abstract [en]

    Objectives: To elucidate the genome-based epidemiology and phylogenomics of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae strains collected in 2009-14 in Europe and clarify the azithromycin resistance mechanisms.

    Methods: Seventy-five azithromycin-resistant (MIC 4 to >256 mg/L) N. gonorrhoeae isolates collected in 17 European countries during 2009-14 were examined using antimicrobial susceptibility testing and WGS.

    Results: Thirty-six N. gonorrhoeae multi-antigen sequence typing STs and five phylogenomic clades, including 4-22 isolates from several countries per clade, were identified. The azithromycin target mutation A2059G (Escherichia coli numbering) was found in all four alleles of the 23S rRNA gene in all isolates with high-level azithromycin resistance (n = 4; MIC ≥256 mg/L). The C2611T mutation was identified in two to four alleles of the 23S rRNA gene in the remaining 71 isolates. Mutations in mtrR and its promoter were identified in 43 isolates, comprising isolates within the whole azithromycin MIC range. No mutations associated with azithromycin resistance were found in the rplD gene or the rplV gene and none of the macrolide resistance-associated genes [mef(A/E), ere(A), ere(B), erm(A), erm(B), erm(C) and erm(F)] were identified in any isolate.

    Conclusions: Clonal spread of relatively few N. gonorrhoeae strains accounts for the majority of the azithromycin resistance (MIC >2 mg/L) in Europe. The four isolates with high-level resistance to azithromycin (MIC ≥256 mg/L) were widely separated in the phylogenomic tree and did not belong to any of the main clades. The main azithromycin resistance mechanisms were the A2059G mutation (high-level resistance) and the C2611T mutation (low- and moderate-level resistance) in the 23S rRNA gene.

  • 22.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Scangarella-Oman, Nicole
    GlaxoSmithKline, Collegeville PA, USA.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 8, p. 2072-2077Article in journal (Refereed)
    Abstract [en]

    Objectives: Increased antimicrobial resistance surveillance and new effective antimicrobials are crucial to maintain treatable gonorrhoea. We examined the in vitro activity of gepotidacin, a novel triazaacenaphthylene, and the effect of efflux pump inactivation on clinical Neisseria gonorrhoeae isolates and international reference strains (n = 252) and compared gepotidacin with antimicrobials currently or previously recommended for gonorrhoea treatment.

    Methods: MICs (mg/L) were determined by agar dilution (gepotidacin) or by Etest (seven other antimicrobials). The gyrA and parC genes were sequenced and the impact of inactivation of the MtrCDE, MacAB and NorM efflux pumps on gepotidacin MICs was examined.

    Results: Gepotidacin showed potent in vitro activity against all gonococcal isolates (n = 252; MIC <= 4 mg/L). The modal MIC, MIC50 , MIC90 and MIC range of gepotidacin were 0.5, 0.5, 1 and 0.032-4 mg/L, respectively. Inactivation of the MtrCDE efflux pump, but not MacAB or NorM, decreased the gepotidacin MICs for most strains. No significant cross-resistance between gepotidacin and any other antimicrobials, including the fluoroquinolone ciprofloxacin, was identified. However, the ParC D86N mutation (possibly together with additional antimicrobial resistance mutation), which is associated with fluoroquinolone resistance, was associated with increased gepotidacin MICs.

    Conclusions: Gepotidacin demonstrated high in vitro activity against gonococcal strains, indicating that gepotidacin could potentially be an effective option for gonorrhoea treatment, particularly in a dual antimicrobialtherapy regimen and for patients with resistance or allergy to extended-spectrum cephalosporins. Nevertheless, elucidating in vitro and in vivo resistance emergence and mechanisms in detail, together with further gonorrhoea clinical studies, ideally also including chlamydia and Mycoplasma genitalium are essential.

  • 23.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Health and Medical Sciences.
    Hedberg, Sara Thulin
    Mölling, Paula
    Unemo, Magnus
    Comanducci, Maurizio
    Rappuoli, Rino
    Olcén, Per
    Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 10, p. 1579-1584Article in journal (Refereed)
    Abstract [en]

    During the recent years, projects are in progress for designing broad-range non-capsular-based meningococcal vaccines, covering also serogroup B isolates. We have examined three genes encoding antigens (NadA, GNA1030 and GNA2091) included in a novel vaccine, i.e. the 5 Component Vaccine against Meningococcus B (5CVMB), in terms of gene prevalence and sequence variations. These data were combined with the results from a similar study, examining the two additional antigens included in the 5CVMB (fHbp and GNA2132).

    nadA and fHbp v. 1 were present in 38% (n=36), respectively 71% (n=67) of the isolates, whereas gna2132, gna1030 and gna2091 were present in all the Neisseria meningitidis isolates tested (n=95). The level of amino acid conservation was relatively high in GNA1030 (93%), GNA2091 (92%), and within the main variants of NadA and fHbp. GNA2132 (54% of the amino acids conserved) appeared to be the most diversified antigen. Consequently, the theoretical coverage of the 5CVMB antigens and the feasibility to use these in a broad-range meningococcal vaccine is appealing.

  • 24.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Kularatne, Ranmini
    Centre for HIV & STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
    Kittiyaowamarn, Rossaphorn
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Maseko, Venessa
    Centre for HIV & STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
    Paopang, Porntip
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sangprasert, Pongsathorn
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sirivongrangson, Pachara
    Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Piddock, Laura
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Wi, Teodora
    Department of Reproductive Health, World Health Organization, Geneva, Switzerland.
    Alirol, Emilie
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    High In Vitro Susceptibility to the First-in-Class Spiropyrimidinetrione Zoliflodacin among Consecutive Clinical Neisseria gonorrhoeae Isolates from Thailand and South Africa2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 12, article id e01479-19Article in journal (Refereed)
    Abstract [en]

    We evaluated the in vitro susceptibility to the first-in-class spiropyrimidinetrione zoliflodacin among recent consecutive clinical Neisseria gonorrhoeae isolates cultured in Thailand (n=99; 2018) and South Africa (n=100; 2015-2017). Zoliflodacin was highly active in vitro against all tested isolates (MIC range: 0.004-0.25; MIC50: 0.064, MIC90: 0.125 μg/ml), with no cross-resistance to any of the seven comparator antimicrobials. Our data support the initiation of the global zoliflodacin phase 3 randomized controlled clinical trial for uncomplicated gonorrhea.

  • 25.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Mason, Clive
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Khan, Nawaz
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Meo, Paul
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the novel oral antimicrobial SMT-571, with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae: future treatment option for gonorrhoea?2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 6, p. 1591-1594Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Lack of effective treatment of gonorrhoea due to increasing antimicrobial resistance in Neisseria gonorrhoeae is a serious threat to the management and control of the infection. Novel antimicrobials are required to prevent the infection becoming untreatable.

    OBJECTIVES: Herein, we investigated the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, SMT-571, against a large collection of clinical N. gonorrhoeae isolates (n = 228) and international gonococcal reference strains (n = 34), including numerous MDR and XDR gonococcal isolates.

    METHODS: MICs of SMT-571 were determined by agar dilution and MICs of ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline were determined by Etest.

    RESULTS: SMT-571 showed potent in vitro activity against all the tested N. gonorrhoeae isolates (n = 262). The MICs ranged from 0.064 to 0.125 mg/L and the MIC50, MIC90 and modal MIC were all 0.125 mg/L. No cross-resistance or correlation between the MICs of SMT-571 and comparator agents was seen.

    CONCLUSIONS: SMT-571 demonstrated potent in vitro activity against all tested gonococcal isolates and no cross-resistance to previously and currently used antimicrobials was seen. With its promising supplementary in vitro and in vivo preclinical data, including high levels of oral bioavailability, SMT-571 could be an effective option for the oral treatment of gonorrhoea. Randomized controlled clinical trials for gonorrhoea that examine the treatment efficacy, pharmacokinetics/pharmacodynamics, toxicity and safety of SMT-571, and include urogenital and extragenital (rectal and pharyngeal) samples, are crucial.

  • 26.
    Jacobsson, Susanne
    et al.
    Örebro University, Department of Clinical Medicine.
    Mölling, Paula
    Olcen, Per
    Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidisManuscript (preprint) (Other academic)
    Abstract [en]

    The IgG antibody levels directed against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis, were examined in order to investigate the extent of natural immunisation against these antigens in different age groups. As a comparison, the IgG antibody levels against Haemophilus influenzae type b were examined.

    In the two youngest age groups, below 10 years of age, relatively low levels of both anti-fHbp and anti-NadA were measured. A 9-fold higher concentration of anti-fHbp was noted in the age groups up to 29 years of age to its peak at 30-39 years, followed by decreased levels with age. Anti-NadA showed a certain increase up to 9 years followed by an even increase up to 49 years.

  • 27.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Health and Medical Sciences.
    Mölling, Paula
    Örebro University, Örebro, Sweden.
    Olcén, Per
    Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis2009In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 42, p. 5755-5759Article in journal (Refereed)
    Abstract [en]

    The IgG antibody levels directed against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis, were examined in order to investigate the extent of natural immunisation against these antigens in different age groups. As a comparison, the IgG antibody levels against Haemophilus influenzae type b were examined. In the two youngest age groups, below 10 years of age, relatively low levels of both anti-fHbp and anti-NadA were measured. A 15-fold higher geometric mean concentration of anti-fHbp was noted in the age group 20-29 years as compared to the age group 15-19 years. The peak concentration was found at 30-39 years, followed by decreased levels with age. Anti-NadA showed a certain increase up to 9 years followed by an even increase up to 40-49 years.

  • 28. Jacobsson, Susanne
    et al.
    Olcén, Per
    Löfdahl, Margareta
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Mölling, Paula
    Characteristics of Neisseria meningitidis isolates causing fatal disease2008In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 40, no 9, p. 734-744Article in journal (Refereed)
    Abstract [en]

    The objectives of the present study were to describe a selection of characteristics of all available fatal meningococcal isolates (n=62) and to compare these with all the other invasive isolates (non-fatal, n=474) collected in Sweden from 1995 to 2004 (fatality rate of 12%). The coverage of the fatal isolates by presently discussed outer membrane vesicle (OMV) vaccines was also estimated. The isolates were characterized by serogroup, serotype, genosubtype, multilocus sequence type and antibiogram. Basic epidemiological data were gathered. The results of the fatal isolates showed 55% serogroup B, 27% C, 15% Y and 3% W-135, with a fatality rate of 11% for B, 12% for C, 17% for Y and 8% for W-135. Characteristics associated with higher mortality were age, gender, serogroup Y, serotype 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2. In contrast, non-14/non-15 serotypes, the genosubtypes P1.5-1,10-8,36-2; P1.7-2,4,37 and P1.7,16,35, as well as reduced sensitivity for penicillin G were associated with decreased mortality. The presently discussed OMV vaccines could, based solely on the complete genosubtype, theoretically cover up to 44% of the fatal serogroup B cases and up to 100% if every variable region by itself is capable to induce protective immunity.

  • 29.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Faculty of Medicine and Health, , Örebro University Hospital, Örebro, Sweden.
    Paukner, Susanne
    Nabriva Therapeutics AG, Vienna, Austria.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Jensen, Jörgen S.
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 11, article id e01497-17Article in journal (Refereed)
    Abstract [en]

    We evaluated the activity of the novel semisynthetic pleuromutilin lefamulin, inhibiting protein synthesis and growth, and the effect of efflux pump inactivation on clinical gonococcal isolates and reference strains (n = 251), including numerous multidrug-resistant and extensively drug-resistant isolates. Lefamulin showed potent activity against all gonococcal isolates, and no significant cross-resistance to other antimicrobials was identified. Further studies of lefamulin are warranted, including in vitro selection and mechanisms of resistance, pharmacokinetics/pharmacodynamics, optimal dosing, and performance in randomized controlled trials.

  • 30.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Neisseria meningitidis, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Neisseria meningitidis, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara Thulin
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Neisseria meningitidis carriage in Swedish teenagers associated with the serogroup W outbreak at the World Scout Jamboree, Japan 20152018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 4, p. 337-341Article in journal (Refereed)
    Abstract [en]

    The aims of the study were to estimate the carrier state of Neisseria meningitidis in Swedish teenagers and its association with an outbreak at the World Scout Jamboree in 2015 as well as to compare sensitivity of throat versus nasopharyngeal swab for optimal detection of carriage. In total, 1 705 samples (cultures n = 32, throat swabs n = 715, nasopharyngeal swabs n = 958) from 1 020 Jamboree participants were collected and sent to the National Reference Laboratory for Neisseria meningitidis for culture and molecular analysis. The overall positivity for N. meningitidis was 8% (83/1 020), whereas 2% (n = 22) belonged to a known sero/genogroup while the majority (n = 61) were non-groupable. Throat sample is clearly the sampling method of choice, in 56 individuals where both throat and nasopharynx samples were taken, N. meningitidis was detected in both throat and nasopharynx in eight individuals, in 46 individuals N. meningitidis was only detected in the throat and in two individuals only in the nasopharynx. Carriage studies are important to provide knowledge of the current epidemiology and association between carrier isolates and disease-causing isolates in a given population. Therefore, planning for a carriage study in Sweden is in progress.

  • 31.
    Jacobsson, Susanne
    et al.
    Örebro University, Department of Clinical Medicine.
    Thulin, Sara
    Mölling, Paula
    Unemo, Magnus
    Comanducci, Maurizio
    Rappuoli, Rino
    Olcén, Per
    Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens2006In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 24, no 12, p. 2161-2168Article in journal (Refereed)
    Abstract [en]

    By the strategy “reverse vaccinology” a number of new antigens have been identified in Neisseria meningitidis, which are potential candidates for a highly needed broad-spectrum meningococcal vaccine. In the present study we examined the prevalence, sequence constancies and variations of the genes encoding three of these new antigens designated, genome-derived neisserial antigen (GNA) 1870, GNA1946 and GNA2132. All three genes were present in all     N. meningitidis isolates tested. Concerning gna1870, three major variants of the gene sequences and deduced amino acid sequences were identified and 56% of the deduced amino acids were conserved in all isolates. In gna1946, 98% of the deduced amino acids were conserved and in gna2132, 54% of the deduced amino acids were conserved. Based on gene prevalence and conservation, all three antigens are promising candidates for an effective meningococcal vaccine against all N. meningitidis irrespective of serogroup.

  • 32.
    Jönsson, Agnez
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Foerster, Sunniva
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden; Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hamasuna, Ryoichi
    Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Dermatovenerology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Jensen, Jörgen Skov
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    In vitro activity and time-kill curve analysis of sitafloxacin against a global panel of antimicrobial-resistant and multidrug-resistant Neisseria gonorrhoeae isolates2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 29-37Article in journal (Refereed)
    Abstract [en]

    Treatment of gonorrhoea is a challenge worldwide because of emergence of resistance in N. gonorrhoeae to all therapeutic antimicrobials available and novel antimicrobials are imperative. The newer-generation fluoroquinolone sitafloxacin, mostly used for respiratory tract infections in Japan, can have a high in vitro activity against gonococci. However, only a limited number of recent antimicrobial-resistant isolates from Japan have been examined. We investigated the sitafloxacin activity against a global gonococcal panel (250 isolates cultured in 1991-2013), including multidrug-resistant geographically, temporally and genetically diverse isolates, and performed time-kill curve analysis for sitafloxacin. The susceptibility to sitafloxacin (agar dilution) and seven additional therapeutic antimicrobials (Etest) was determined. Sitafloxacin was rapidly bactericidal, and the MIC range, MIC50 and MIC90 was ≤0.001-1, 0.125 and 0.25 mg/L, respectively. There was a high correlation between the MICs of sitafloxacin and ciprofloxacin; however, the MIC50 and MIC90 of sitafloxacin were 6-fold and >6-fold lower, respectively. Sitafloxacin might be an option for particularly dual antimicrobial therapy of gonorrhoea and for cases with ceftriaxone resistance or allergy. However, further in vitro and particularly in vivo evaluations of potential resistance, pharmacokinetics/pharmacodynamics and ideal dosing for gonorrhoea, as well as performance of randomized controlled clinical, trials are crucial.

  • 33.
    Jönsson, Agnez
    et al.
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology.
    Foerster, Sunniva
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Cole, Michelle J.
    Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, Public Health England, London, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology.
    Performance characteristics of newer MIC gradient strip tests compared with the Etest for antimicrobial susceptibility testing of Neisseria gonorrhoeae2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 10, p. 822-827Article in journal (Refereed)
    Abstract [en]

    For Neisseria gonorrhoeae susceptibility testing, Etest, comparable to agar dilution, is frequently used. In recent years, newer MIC gradient strip tests have been commercialized. However, these tests have not been appropriately evaluated for gonococci. We evaluated the sensitivity, specificity, accuracy, quality, availability of antimicrobials and cost of the MIC Test Strip (Liofilchem), M.I.C.Evaluator (Oxoid) and Ezy MIC Strip (HiMedia), compared to the reference Etest (bioMérieux), for gonococcal susceptibility testing. The MICs of eight antimicrobials in 103 gonococcal international reference strains (n = 29) and clinical isolates (n = 74) were examined. Coefficient of determination (R2), complete agreement, essential agreement, SIR categorical agreement, sensitivity, specificity and accuracy were calculated. R2 of the MICs for the antimicrobials ranged between 0.674–0.996, 0.617–0.993, and 0.643–0.994 for the MIC Test Strip, M.I.C.Evaluator strips and Ezy MIC Strips respectively. The essential agreement (SIR categorical agreement) was 99.6% (88.6%), 100% (87.1%) and 93.0% (83.1%) respectively. M.I.C.Evaluator strips for gonococcal key antimicrobials were lacking and the Ezy MIC Strips showed an inconsistent accuracy, quality and some strips were contaminated. The Liofilchem MIC Test Strips had limitations, but might be relatively accurate alternatives to Etest for gonococci. Strict quality assurance (at manufacturing and testing laboratory), including quality controls, are required.

  • 34.
    Kelly, Anne
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Hussain, Shahida
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Olcen, Per
    Mölling, Paula
    Örebro University Hospital.
    Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 1, p. 56-63Article in journal (Refereed)
    Abstract [en]

    The factor H binding protein (fHbp) is currently being evaluated in clinical trials as a vaccine candidate for a meningococcal group B vaccine. We have previously described the prevalence and sequence variation of fHbp (Jacobsson et al., 2009) and here we investigate the expression of the antigen. The present study includes isolates from carriers (n = 62) and patients with invasive Neisseria meningitidis infections (n = 146), of which 62 had a fatal outcome. Among the invasive isolates from patients with fatal and non-fatal infections fHbp allele 1 was most common (42% and 29% respectively), but it was only identified in 3% of the carrier isolates, where allele 16 was most frequent (13%). The Fluorescence-activated cell sorting analysis identified fHbp expression in all except seven isolates and further analysis by Western blot showed that five of these seven samples were indeed negative using a polyclonal anti-fHbp serum. The negative isolates belonged to serogroup B fHbp allele 24, Y allele 104, and W-135 allele 16 (all invasive). Two were non-serogroupable carrier isolates (allele 21 and 101). An interesting finding is that isolates from invasive infections with fatal outcome had lower expression of fHbp or lower affinity for the fHbp antibody compared to isolates from non-fatal invasive infections and carriers.

  • 35.
    Lucidarme, J.
    et al.
    Meningococcal Reference Unit, Public Health England, Manchester, United Kingdom.
    Scott, K. J.
    Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory, Glasgow Royal Infirmary, Glasgow, United Kingdom.
    Ure, R.
    Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory, Glasgow Royal Infirmary, Glasgow, United Kingdom.
    Smith, A.
    Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory, Glasgow Royal Infirmary, Glasgow, United Kingdom; College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, University of Glasgow, Glasgow, United Kingdom.
    Lindsay, D.
    Scottish Haemophilus, Legionella, Meningococcus and Pneumococcus Reference Laboratory, Glasgow Royal Infirmary, Glasgow, United Kingdom.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Örebro University, School of Health Sciences. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Cameron, J. C.
    Health Protection Scotland, NHS National Services Scotland, Glasgow, United Kingdom.
    Smith-Palmer, A.
    Health Protection Scotland, NHS National Services Scotland, Glasgow, United Kingdom.
    McMenamin, J.
    Health Protection Scotland, NHS National Services Scotland, Glasgow, United Kingdom.
    Gray, S. J.
    Meningococcal Reference Unit, Public Health England, Manchester, United Kingdom.
    Campbell, H.
    Immunisation Department, Public Health England, London, United Kingdom.
    Ladhani, S.
    Immunisation Department, Public Health England, London, United Kingdom.
    Findlow, J.
    Meningococcal Reference Unit, Public Health England, Manchester, United Kingdom.
    Mölling, Paula
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Borrow, R.
    Meningococcal Reference Unit, Public Health England, Manchester, United Kingdom.
    An international invasive meningococcal disease outbreak due to a novel and rapidly expanding serogroup W strain, Scotland and Sweden, July to August 20152016In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 21, no 45, p. 15-23, article id 30395Article in journal (Refereed)
    Abstract [en]

    The 23rd World Scout Jamboree in 2015 took place in Japan and included over 33,000 scouts from 162 countries. Within nine days of the meeting ending, six cases of laboratory-confirmed invasive serogroup W meningococcal disease occurred among scouts and their close contacts in Scotland and Sweden. The isolates responsible were identical to one-another by routine typing and, where known (4 isolates), belonged to the ST-11 clonal complex (cc11) which is associated with large outbreaks and high case fatality rates. Recent studies have demonstrated the need for high-resolution genomic typing schemes to assign serogroup W cc11 isolates to several distinct strains circulating globally over the past two decades. Here we used such schemes to confirm that the Jamboree-associated cases constituted a genuine outbreak and that this was due to a novel and rapidly expanding strain descended from the strain that has recently expanded in South America and the United Kingdom. We also identify the genetic differences that define the novel strain including four point mutations and three putative recombination events involving the horizontal exchange of 17, six and two genes, respectively. Noteworthy outcomes of these changes were antigenic shifts and the disruption of a transcriptional regulator.

  • 36.
    Meo, Paul
    et al.
    Summit Therapeutics, Cambridge, UK.
    Mason, Clive
    Summit Therapeutics, Cambridge, UK.
    Khan, Nawaz
    Summit Therapeutics, Cambridge, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    IN-VITRO ACTIVITY OF SMT-571 AND COMPARATORS AGAINST CLINICAL ISOLATES AND REFERENCE STRAINS OF NEISSERIA GONORRHOEAE2019In: Sexually Transmitted Infections, ISSN 1368-4973, E-ISSN 1472-3263, Vol. 95, no Suppl. 1, p. A295-A295Article in journal (Other academic)
    Abstract [en]

    Background: The emergence and spread of multidrug resistance to antibiotics used to treat gonorrhoea has resulted in a dramatic loss of effective regimens for the condition. Currently, the extended spectrum cephalosporin, ceftriaxone, is the only viable monotherapy option available, however, resistance to this last line treatment is now emerging globally. Herein, we assessed the in vitro activity of a novel small molecule antimicrobial with a new mechanism of action, SMT-571, against a large collection of N. gonorrhoeae clinical isolates and reference strains including numerous MDR and XDR gonococcal isolates.

    Methods: MICs (mg/L) of SMT-571 were determined by agar dilution according to current CLSI guidelines. The MICs of ceftriaxone, cefixime, azithromycin, ciprofloxacin, spectinomycin, tetracycline, and ampicillin were determined using the Etest method (AB bioMérieux, Marcy l’Etoile, France).

    Results: SMT-571 showed potent in vitro activity against all the tested N. gonorrhoeae isolates (n=262) with MICs ranging from 0.064 to 0.125 mg/L, and the MIC50, MIC90 and modal MIC were all 0.125 mg/L. The compound was not influenced by pre-existing resistance mechanisms with no cross-resistance or correlation between the MICs of SMT-571 and comparator agents being observed.

    Conclusion: This study is the first broad evaluation of the in vitro activities of a new mechanism, novel small molecule anti-microbial for the treatment of gonorrhoea. SMT-571 demonstrated highin vitroactivity against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and international reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates.

  • 37.
    Prag, Gustaf
    et al.
    Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Falk-Brynhildsen, Karin
    Department of Cardiothoracic and Vascular Surgery, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden. Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden; Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.
    Decreased susceptibility to chlorhexidine and prevalence of disinfectant resistance genes among clinical isolates of Staphylococcus epidermidis2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 10, p. 961-967Article in journal (Refereed)
    Abstract [en]

    Staphylococcus epidermidis, despite regarded as a commensal, is recognized as a nosocomial pathogen usually by acting as an opportunist, especially in infections associated with implanted foreign body materials. Pre-operative antiseptic preparation is an important strategy for reducing the risk of complications such as surgical site infection (SSI). The currently most widely used antiseptic compounds are alcohols and quaternary ammonium compounds (QACs), predominantly chlorhexidine.

    The aim of this study was to investigate if decreased susceptibility to chlorhexidine among S. epidermidis was present in our setting. S. epidermidis (n=143) were obtained from prosthetic joint infections (PJI) (n=61), commensals (n=24), post-operative infections after cardiothoracic surgery (n=31), and the skin of the chest after routine disinfection prior cardiothoracic surgery (n=27). Determination of MIC of chlorhexidine was performed on Müeller Hinton agar plates supplemented with serial dilutions of chlorhexidine. Five QAC resistance genes; qacA/B, smr, qacH, qacJ, and qacG, were detected using PCR.

    Decreased susceptibility to chlorhexidine was found in 54% of PJI isolates, 68% of cardiothoracic isolates, 21% of commensals, and 7% of isolates obtained from the skin of cardiothoracic patients, respectively.

    The qacA/B gene was present in 62/143 isolates (43%), smr in 8/143 (6%) and qacH in one isolate (0.7%). The qacA/B gene was found in 52% of PJI isolates, 61% of cardiothoracic isolates, 25% of commensals, and 19% of isolates obtained from the skin of cardiothoracic patients. In conclusion, decreased susceptibility to chlorhexidine as well as QAC resistance genes was highly prevalent among S. epidermidis causing deep SSIs.

  • 38.
    Stenmark, Bianca
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Eriksson, Lorraine
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Thulin Hedberg, Sara
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Whole genome sequencing of the emerging invasive Neisseria meningitidis serogroup W in Sweden2017In: 14th Congress of the EMGM, European Meningococcal and Haemophilus Disease Society: Book of Abstracts, Prague: EMGM , 2017, p. 7-8Conference paper (Other academic)
    Abstract [en]

    Introduction: The incidence of Neisseria meningitidisserogroup W (MenW) causing invasive meningococcal disease has historically been low. In 2015 an increase in MenW was observed in Sweden when an incidence of 0.1/100,000 population (10 cases) was reported, compared to an incidence of 0.02 (2 cases), in 2014. In 2016 the number of cases had almost doubled (18 cases, incidence of 0.2). England and Wales have also reported an increase of MenW from 2009 which was determined to be due to a sublineage in the South American/UK strain, called novel UK-2013 strain1. Both the South American/UK strain cluster and the novel UK-2013 strain belong to clonal complex (cc) 11, which consists of different strains from different serogroups associated with outbreaks that have occurred around the world2.

    Aim: The aim was to determine the population structure of MenW in Sweden compared to historical and international cases.

    Material and methods: All invasive MenW isolates collected in Sweden between 1995 and 2016 (n=71) were whole genome sequenced on the MiSeq (Illumina) using Nextera XT library preparation kit (Illumina) and MiSeq reagent Kit v3, 600 cycles. Reads were de novo assembled using Velvet within SeqSphere (Ridom GmbH). Genomes were uploaded to the Neisseria PubMLST database and genome comparison was performed with the genome comparator tool within pubMLST, comparing 1605 species specific core genes. The generated distance matrices were visualized using SplitsTree4 V4.

    Results: The most common fine type among the Swedish isolates was P1.5-2: F1-1: ST-11 (cc11) (n=31). Theisolates belonged to four different clonal complexes: cc11, cc22, cc60 and cc174, and the majority of isolates (39/71) belonged to cc11. No particular clonal complex dominated during the investigated time period except for cc11 since 2014. Core genome comparison showed that the majority of Swedish MenW isolates clustered with the South American/UK strain (n=26), six isolates clustered with the Hajj-associated strain and seven isolates were not associated to any strain. The majority of Swedish isolates in the South American/UK strain cluster, were from 2015 to 2016 and more specifically belonged to the UK sublineages: 23 isolates in the novel UK-2013 strain and three isolates in the original UK-strain.

    Conclusion: In conclusion, the increase of MenW in Sweden is comprised of isolates belonging to the South American/UK sublineage, more specifically the novel UK-2013 strain currently increasing in England and Wales.

    References:1 Lucidarme J, Scott KJ, Ure R, Smith A, Lindsay D, Stenmark B, et al. An international invasive meningococcal disease outbreak due to a novel and rapidly expanding serogroup W strain, Scotland and Sweden, July to August 2015. Euro Surveill. 2016;21(45):pii=303952 Lucidarme J, Hill DM, Bratcher HB, Gray SJ, du Plessis M, Tsang RS, et al. Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage. The Journal of infection. 2015;71(5):544-52

  • 39.
    Säll, Olof
    et al.
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Glimåker, Martin
    Department of Infectious Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Department of Laboratory Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Olcén, Per Olof
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Department of Laboratory Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Clinical presentation of invasive disease caused by Neisseria meningitidis serogroup Y in Sweden, 1995 to 20122017In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 145, no 10, p. 2137-2143Article in journal (Refereed)
    Abstract [en]

    Over the period 1995-2012, the incidence of invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y (NmY) increased significantly in Sweden. This is mainly due to the emergence of a predominant cluster named strain type YI subtype 1, belonging to the ST-23 clonal complex (cc). The aim of this study was to examine the clinical picture of patients with invasive disease caused by NmY and to analyse whether the predominant cluster exhibits certain clinical characteristics that might explain the increased incidence. In this retrospective observational study, the medical records available from patients with IMD caused by Nm serogroup Y in Sweden between 1995 and 2012 were systematically reviewed. Patient characteristics, in-hospital findings and outcome were studied and differences between the dominating cluster and other isolates were analysed. Medical records from 175 of 191 patients were retrieved. The median age was 62 years. The all-cause mortality within 30 days of admission was 9% (15/175) in the whole material; 4% (2/54) in the cohort with strain type YI subtype 1 and 11% (12/121) among patients with other isolates. Thirty-three per cent of the patients were diagnosed with meningitis, 19% with pneumonia, 10% with arthritis and 35% were found to have bacteraemia but no apparent organ manifestation. This survey included cases with an aggressive clinical course as well as cases with a relatively mild clinical presentation. There was a trend towards lower mortality and less-severe disease in the cohort with strain type YI subtype 1 compared with the group with other isolates.

  • 40.
    Söderquist, Bo
    et al.
    Örebro University, School of Health and Medical Sciences.
    Andersson, Mira
    Nilsson, Martin
    Nilsdotter-Augustinsson, Åsa
    Persson, Lennart
    Friberg, Örjan
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences.
    Staphylococcus epidermidis surface protein I (SesI): a marker of the invasive capacity of S. epidermidis?2009In: Journal of Medical Microbiology, ISSN 0022-2615, E-ISSN 1473-5644, Vol. 58, no Pt 10, p. 1395-1397Article in journal (Refereed)
  • 41.
    Thulin Hedberg, Sara
    et al.
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Stenmark, Bianca
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Lepp, Tiia
    The Public Health Agency of Sweden, Stockholm, Sweden.
    Fredlund, Hans
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Invasive meningococcal disease in Sweden 20162017In: 14th Congress of the EMGM, European Meningococcal and Haemophilus Disease Society: Book of Abstracts, Prague: The European Meningococcal and Haemophilus Disease Society EMGM , 2017, p. 69-69Conference paper (Other academic)
    Abstract [en]

    Invasive meningococcal disease (IMD) is notifiable in Sweden. The reporting system comprises of mandatory notification of cases and mandatory laboratory notification of samples to the Public Health Agency of Sweden, Stockholm. All samples are sent to the National Reference Laboratory for Pathogenic Neisseria, Örebro for further typing and surveillance.

    In 2016, 62 cases of IMD (incidence 0.6/100 000 population) were reported in Sweden. Among the patients 58 % were females and 42 % males, aged from 1 month to95 years with mean age of 42 years. The incidence was highest, as in previous years, in the age group 15-19 years (2.1/100 000 population) followed by elderly ≥80 years (1.8/100 000 population) and infants ≤1 year (1.7/100 000 population). The case fatality rate increased in 2016 to 12.9 % compared with 7.5 % in 2015, eight people died from the disease (MenW, n=3; MenY, n=2; MenB, n=2 and MenC n=1). None of the IMD cases in 2016 had any epidemiological linkage.

    All 62 cases of IMD were laboratory confirmed: 54 were culture-confirmed, three PCR-confirmed and in five cases further typing data are missing because no samples were sent to the National Reference Laboratory for Pathogenic Neisseria. The serogroup distribution was MenW (n=18, 31.5 %), MenY (n=18, 31.5 %), MenB (n=10, 17.5 %), MenC (n=10, 17.5 %) and one non-groupable isolate. The W:P1.5,2:F1-1:ST11 (cc11) (n=15) were predominant among the culture-confirmed meningococci during 2016 followed by Y:P1.5-2,10-1:F4-1:ST23 (cc23) (n=7) och Y:P1.5-1,2-2:F5-8:ST23 (cc23) (n=6). Antibiotic susceptibility testing was performed with Gradient test (Etest, BioMerieux). Decreased susceptibility to penicillin was seen in 30 % of the isolates (MIC >0,064 mg/L) of which one was resistant (MIC=0.5 mg/L). One of the isolates with decreased susceptibility to penicillin was also resistant to ciprofloxacin (MIC=0.125 mg/L). All other isolates were susceptible to cefotaxime, chloramphenicol, ciprofloxacin, rifampicin and meropenem. No β-lactamase producing isolates has so far been found in Sweden.

    To conclude, the incidence of IMD continues to be relatively low in Sweden, however, a shift in the serogroup distribution of N. meningitidisin Sweden is ongoing; the previously dominating disease-causing MenB and MenC have been replaced, first by MenY which emerged in 2009 and since 2015 also by MenW. MenW has gone from only causing invasive disease in a few, 0-6 cases per year from 1990 onwards, to now being the dominating serogroup together with MenY in Sweden 2016.

  • 42.
    Törös, Bianca
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara Thulin
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Evaluation of molecular typing methods for identification of outbreak-associated Neisseria meningitidis isolates2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 6, p. 503-510Article in journal (Refereed)
    Abstract [en]

    It is essential in an outbreak investigation that strain characterization of Neisseria meningitidis is performed in a rapid and accurate manner. This study evaluated two new molecular typing methods, multiple- locus variable number tandem repeat analysis (MLVA) and repetitive sequence-based PCR (rep-PCR) (DiversiLab; bioMe´rieux) and compared them with current recommended methodologies. This retrospective study included 36 invasive N. meningitidis serogroup C isolates collected in Sweden 2001 through 2009 and previously subjected to outbreak investigation. All strains were typed with highly variable- MLVA (HV-MLVA) and rep-PCR. The isolates were further characterized by multilocus sequence typing (MLST) and sequencing of the fetA, fHbp, penA, porA and porB genes. The results showed that HVMLVA had the highest index of diversity (0.99) and rep-PCR had the highest congruence (40%) with the currently recommended typing methods. The HV MLVA correlated best to the spatiotemporal connections and had the overall highest Adjusted Wallace coefficients, suggesting that HV-MLVA can predict the results of the other typing methods in the study. We therefore suggest that after initial confirmation of species, serogroup and genosubtype, HV-MLVA should be used asthe most discriminatorymethod for first hand investigation of N. meningitidis serogroup C isolates.

  • 43.
    Törös, Bianca
    et al.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hedberg, Sara Thulin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hill, Dorothea M. C.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Olcén, Per
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Bratcher, Holly B.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Jolley, Keith A.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Maiden, Martin C. J.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Mölling, Paula
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Genome-based characterization of emergent invasive Neisseria meningitidis serogroup Y isolates in Sweden from 1995 to 20122015In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, no 7, p. 2154-2162Article in journal (Refereed)
    Abstract [en]

    Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is now the dominating serogroup, and in 2012, the serogroup Y disease incidence was 0.46/100,000 population. We previously showed that a strain type belonging to sequence type 23 was responsible for the increased prevalence of this serogroup in Sweden. The objective of this study was to investigate the serogroup Y emergence by whole-genome sequencing and compare the meningococcal population structure of Swedish invasive serogroup Y strains to those of other countries with different IMD incidence. Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n = 186). These isolates were compared to a collection of serogroup Y isolates from England, Wales, and Northern Ireland from 2010 to 2012 (n = 143), which had relatively low serogroup Y incidence, and two isolates obtained in 1999 in the United States, where serogroup Y remains one of the major causes of IMD. The meningococcal population structures were similar in the investigated regions; however, different strain types were prevalent in each geographic region. A number of genes known or hypothesized to have an impact on meningococcal virulence were shown to be associated with different strain types and subtypes. The reasons for the IMD increase are multifactorial and are influenced by increased virulence, host adaptive immunity, and transmission. Future genome-wide association studies are needed to reveal additional genes associated with serogroup Y meningococcal disease, and this work would benefit from a complete serogroup Y meningococcal reference genome.

  • 44.
    Törös, Bianca
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Is the Emergence of the N. meningitidis Serogroup W ST-11 Hajj Outbreak Unraveling in the New Era of WGS?2015In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 2, no 10, p. 1294-1295Article in journal (Other academic)
  • 45.
    Unemo, Magnus
    et al.
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Sánchez-Busó, Leonor
    Pathogen Genomics, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, UK.
    Grad, Yonatan
    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA; Division of Infectious Diseases Brigham andWomen’s Hospital, Harvard Medical School, Boston, USA.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Lahra, Monica M.
    WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Randwick, Sydney, Australia.
    Limnios, Athena
    WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Randwick, Sydney, Australia.
    Sikora, Aleksandra E.
    Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, USA.
    Wi, Teodora
    Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
    Harris, Simon R.
    Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 11, p. 3096-3108Article in journal (Refereed)
    Abstract [en]

    Objectives: Gonorrhoea and MDR Neisseria gonorrhoeae remain public health concerns globally. Enhanced, quality-assured, gonococcal antimicrobial resistance (AMR) surveillance is essential worldwide. The WHO global Gonococcal Antimicrobial Surveillance Programme (GASP) was relaunched in 2009. We describe the phenotypic, genetic and reference genome characteristics of the 2016 WHO gonococcal reference strains intended for quality assurance in the WHO global GASP, other GASPs, diagnostics and research worldwide.

    Methods: The 2016 WHO reference strains (n = 14) constitute the eight 2008 WHO reference strains and six novel strains. The novel strains represent low-level to high-level cephalosporin resistance, high-level azithromycin resistance and a porA mutant. All strains were comprehensively characterized for antibiogram (n = 23), serovar, prolyliminopeptidase, plasmid types, molecular AMR determinants, N. gonorrhoeae multiantigen sequence typing STs and MLST STs. Complete reference genomes were produced using single-molecule PacBio sequencing.

    Results: The reference strains represented all available phenotypes, susceptible and resistant, to antimicrobials previously and currently used or considered for future use in gonorrhoea treatment. All corresponding resistance genotypes and molecular epidemiological types were described. Fully characterized, annotated and finished references genomes (n = 14) were presented.

    Conclusions: The 2016 WHO gonococcal reference strains are intended for internal and external quality assurance and quality control in laboratory investigations, particularly in the WHO global GASP and other GASPs, but also in phenotypic (e.g. culture, species determination) and molecular diagnostics, molecular AMR detection, molecular epidemiology and as fully characterized, annotated and finished reference genomes in WGS analysis, transcriptomics, proteomics and other molecular technologies and data analysis.

  • 46.
    Unemo, Magnus
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Ringlander, Johan
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Wiggins, Catherine
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, United Kingdom.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Cole, Michelle
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, United Kingdom.
    High In Vitro Susceptibility to the Novel Spiropyrimidinetrione ETX0914 (AZD0914) among 873 Contemporary Clinical Neisseria gonorrhoeae Isolates from 21 European Countries from 2012 to 20142015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 9, p. 5220-5225Article in journal (Refereed)
    Abstract [en]

    Resistance in Neisseria gonorrhoeae against all antimicrobials available for the treatment of gonorrhea has emerged. The first gonococcal strains with high-level resistance to ceftriaxone, the last option for first-line empirical antimicrobial monotherapy, were recently described. Consequently, new treatment options are essential. In this study, the in vitro activity of the novel spiropyrimidinetrione ETX0914 (AZD0914), a DNA topoisomerase II inhibitor, was investigated among contemporary consecutive clinical N. gonorrhoeae isolates obtained in 21 European countries and compared to the activities of antimicrobials currently or previously recommended for treatment. Consecutive clinical N. gonorrhoeae isolates (n = 873) cultured in 21 European countries from 2012 to 2014 were examined for their susceptibility to ETX0914. The MICs of ETX0914 were determined using the agar dilution method. For comparison, the MICs of ceftriaxone, cefixime, azithromycin, and ciprofloxacin were determined using Etest or the agar dilution method. For ETX0914, the MIC range, modal MIC, MIC50, and MIC90 were <= 0.002 to 0.25 mg/liter, 0.125 mg/liter, 0.064 mg/liter, and 0.125 mg/liter, respectively. The MIC values were substantially lower than those of the fluoroquinolone ciprofloxacin and most other antimicrobials examined. No cross-resistance with any other examined antimicrobial was observed. In conclusion, the in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical isolates from 21 European countries was high, and no cross-resistance to antimicrobials currently or previously used for gonorrhea treatment was indicated. Additional studies investigating the in vitro and in vivo induction and mechanisms of ETX0914 resistance in gonococci, pharmacokinetics/pharmacodynamics in modeling/simulations and in humans, and performance in randomized controlled gonorrhea treatment trials are essential.

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