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1.	Brueggemann, AB, et al. (författare) Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data 2021 Ingår i: The Lancet. Digital health. - : Elsevier. - 2589-7500. ; 3:6, s. E360-E370 Tidskriftsartikel (refereegranskat)
2.	Cole, Michelle J., et al. (författare) Ten years of external quality assessment (EQA) of Neisseria gonorrhoeae antimicrobial susceptibility testing in Europe elucidate high reliability of data 2019 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 19:1 Tidskriftsartikel (refereegranskat)abstract 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.
3.	Ingberg, Edvin, 1988-, et al. (författare) 16S metagenomics for bacterial identification versus cultures in acute pharyngotonsillitis patients and controls 2018 Konferensbidrag (refereegranskat)abstract 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.
4.	Jacobsson, Susanne, 1974-, et al. (författare) In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae 2017 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 61:11 Tidskriftsartikel (refereegranskat)abstract 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.
5.	Saarentausta, Katariina, et al. (författare) Potential impact of the COVID-19 pandemic on the national and regional incidence, epidemiology and diagnostic testing of chlamydia and gonorrhoea in Sweden, 2020 2022 Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Munksgaard Forlag. - 0903-4641 .- 1600-0463. ; 130:1, s. 34-42 Tidskriftsartikel (refereegranskat)abstract The COVID-19 pandemic has challenged the societies and health care systems globally, and resulted in many social and physical distancing restrictions to limit the spread of SARS-CoV-2. These restrictions have also likely affected the frequency of intimate contacts and the spread of sexually transmitted infections (STIs). Compared to most other countries, Sweden especially in Spring-Autumn 2020 pursued mainly milder voluntary, i.e. not mandatory enforced by laws, recommended restrictions and the impacts of these on society and spread of STIs remain largely unknown. We describe the potential impact of the COVID-19 pandemic on the national and regional incidence, epidemiology and diagnostic testing of chlamydia and gonorrhoea in Sweden in 2020. Compared to 2019, we found a significant decrease in incidence of chlamydia (-4.5%) and gonorrhoea (-17.5%), and in diagnostic testing (-10.5% for chlamydia, -9.4% for gonorrhoea) in 2020. However, the decrease in chlamydia incidence, which has mainly been decreasing last 10 years, was not significant when compared with the average incidence in 2017-2019. The largest decrease in national incidence of both infections was observed among young and heterosexual patients, however some Swedish regions showed an increased incidence, particularly of chlamydia. Increased "internet-based self-sampling" testing approach partly compensated for a decreased attendance at STI clinics. Studies, including sexual behavior, prevention, reasons for attending STI health care, STIs in different anatomical sites, and management of STIs, are required to elucidate the impact of COVID-19-associated social and physical distancing restrictions on sexual activity and the incidence and epidemiology of chlamydia and gonorrhoea in Sweden.
6.	Säll, Olof, 1980-, et al. (författare) Atypical presentation of Neisseria meningitidis serogroup W disease is associated with the introduction of the 2013 strain 2021 Ingår i: Epidemiology and Infection. - : Cambridge University Press. - 0950-2688 .- 1469-4409. ; 149 Tidskriftsartikel (refereegranskat)abstract Since 2015, the incidence of invasive meningococcal disease (IMD) caused by serogroup W (MenW) has increased in Sweden, due to the introduction of the 2013 strain belonging to clonal complex 11. The aim of this study was to describe the clinical presentation of MenW infections, in particular the 2013 strain, including genetic associations. Medical records of confirmed MenW IMD cases in Sweden during the years 1995-2019 (n = 113) were retrospectively reviewed and the clinical data analysed according to strain. Of all MenW patients, bacteraemia without the focus of infection was seen in 44%, bacteraemic pneumonia in 26%, meningitis in 13% and epiglottitis in 8%, gastrointestinal symptoms in 48% and 4% presented with petechiae. Phylogenetic analysis was used for possible links between genetic relationship and clinical picture. The 2013 strain infections, particularly in one cluster, were associated with more severe disease compared with other MenW infections. The patients with 2013 strain infections (n = 68) were older (52 years vs. 25 years for other strains), presented more often with diarrhoea as an atypical presentation (P = 0.045) and were more frequently admitted for intensive care (P = 0.032). There is a risk that the atypical clinical presentation of MenW infections, with predominantly gastrointestinal or respiratory symptoms rather than neck stiffness or petechiae, may lead to delay in life-saving treatment.
7.	Säll, Olof, 1980-, et al. (författare) Prevalence and persistence of Neisseria meningitidis carriage in Swedish university students Annan publikation (övrigt vetenskapligt/konstnärligt)
8.	Säll, Olof, 1980-, et al. (författare) Prevalence and persistence of Neisseria meningitidis carriage in Swedish university students 2023 Ingår i: Epidemiology and Infection. - : Cambridge University Press. - 0950-2688 .- 1469-4409. ; 151 Tidskriftsartikel (refereegranskat)abstract The bacterium Neisseria meningitidis causes life-threatening disease worldwide, typically with a clinical presentation of sepsis or meningitis, but can be carried asymptomatically as part of the normal human oropharyngeal microbiota. The aim of this study was to examine N. meningitidis carriage with regard to prevalence, risk factors for carriage, distribution of meningococcal lineages and persistence of meningococcal carriage. Throat samples and data from a self-reported questionnaire were obtained from 2744 university students (median age: 23 years) at a university in Sweden on four occasions during a 12-month period. Meningococcal isolates were characterised using whole-genome sequencing. The carriage rate among the students was 9.1% (319/3488; 95% CI 8.2-10.1). Factors associated with higher carriage rate were age ≤22 years, previous tonsillectomy, cigarette smoking, drinking alcohol and attending parties, pubs and clubs. Female gender and sharing a household with children aged 0-9 years were associated with lower carriage. The most frequent genogroups were capsule null locus (cnl), group B and group Y and the most commonly identified clonal complexes (cc) were cc198 and cc23. Persistent carriage with the same meningococcal strain for 12 months was observed in two students. Follow-up times exceeding 12 months are recommended for future studies investigating long-term carriage of N. meningitidis.
9.	Thulin Hedberg, Sara, et al. (författare) Invasive meningococcal disease in Sweden 2016 2017 Ingår i: 14th Congress of the EMGM, European Meningococcal and Haemophilus Disease Society. - Prague : The European Meningococcal and Haemophilus Disease Society EMGM. - 9788090666238 ; , s. 69-69 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract 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.
10.	Aniskevich, Aliaksandra, et al. (författare) Antimicrobial resistance in Neisseria gonorrhoeae isolates and gonorrhoea treatment in the Republic of Belarus, Eastern Europe, 2009-2019 2021 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 21:1 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Limited antimicrobial resistance (AMR) data for Neisseria gonorrhoeae are available in Eastern Europe. We investigated AMR in N. gonorrhoeae isolates in the Republic of Belarus from 2009 to 2019, antimicrobial treatment recommended nationally, and treatment given to patients with gonorrhoea.METHODS: N. gonorrhoeae isolates (n = 522) cultured in three regions of Belarus in 2009-2019 were examined. Determination of minimum inhibitory concentrations (MICs) of eight antimicrobials was performed using Etest. Resistance breakpoints from the European Committee on Antimicrobial Susceptibility Testing were applied where available. A Nitrocefin test identified β-lactamase production. Gonorrhoea treatment for 1652 patients was also analysed. Statistical significance was determined by the Z-test, Fisher's exact test, or Mann-Whitney U test with p-values of < 0.05 indicating significance.RESULTS: In total, 27.8% of the N. gonorrhoeae isolates were resistant to tetracycline, 24.7% to ciprofloxacin, 7.0% to benzylpenicillin, 2.7% to cefixime, and 0.8% to azithromycin. No isolates were resistant to ceftriaxone, spectinomycin, or gentamicin. However, 14 (2.7%) isolates had a ceftriaxone MIC of 0.125 mg/L, exactly at the resistance breakpoint (MIC > 0.125 mg/L). Only one (0.2%) isolate, from 2013, produced β-lactamase. From 2009 to 2019, the levels of resistance to ciprofloxacin and tetracycline were relatively high and stable. Resistance to cefixime was not identified before 2013 but peaked at 22.2% in 2017. Only sporadic isolates with resistance to azithromycin were found in 2009 (n = 1), 2012 (n = 1), and 2018-2019 (n = 2). Overall, 862 (52.2%) patients received first-line treatment according to national guidelines (ceftriaxone 1 g). However, 154 (9.3%) patients received a nationally recommended alternative treatment (cefixime 400 mg or ofloxacin 400 mg), and 636 (38.5%) were given non-recommended treatment.CONCLUSIONS: The gonococcal resistance to ciprofloxacin and tetracycline was high, however, the resistance to azithromycin was low and no resistance to ceftriaxone was identified. Ceftriaxone 1 g can continuously be recommended as empiric first-line gonorrhoea therapy in Belarus. Fluoroquinolones should not be prescribed for treatment if susceptibility has not been confirmed by testing. Timely updating and high compliance with national evidence-based gonorrhoea treatment guidelines based on quality-assured AMR data are imperative. The need for continued, improved and enhanced surveillance of gonococcal AMR in Belarus is evident.
11.	Asfaw Idosa, Berhane, 1977-, et al. (författare) Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18 Annan publikation (övrigt vetenskapligt/konstnärligt)
12.	Asfaw Idosa, Berhane, 1977-, et al. (författare) LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils Annan publikation (övrigt vetenskapligt/konstnärligt)
13.	Asfaw Idosa, Berhane, PhD, 1977-, et al. (författare) Neisseria meningitidis-Induced Caspase-1 Activation in Human Innate Immune Cells Is LOS-Dependent 2019 Ingår i: Journal of Immunology Research. - : Hindawi Publishing Corporation. - 2314-8861 .- 2314-7156. Tidskriftsartikel (refereegranskat)abstract 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.
14.	Berçot, Béatrice, et al. (författare) Ceftriaxone-resistant, multidrug-resistant Neisseria gonorrhoeae with a novel mosaic penA-237.001 gene, France, June 2022 2022 Ingår i: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 27:50, s. 17-22 Tidskriftsartikel (refereegranskat)abstract We report a ceftriaxone-resistant, multidrug-resistant urogenital gonorrhoea case in a heterosexual woman in France, June 2022. The woman was successfully treated with azithromycin 2 g. She had unprotected sex with her regular partner, who developed urethritis following travel to Vietnam and Switzerland. Whole genome sequencing of the gonococcal isolate (F92) identified MLST ST1901, NG-STAR CC- 199, and the novel mosaic penA-237.001, which caused ceftriaxone resistance. penA-237.001 is 98.7% identical to penA-60.001, reported in various ceftriaxone-resistant strains, including the internationally spreading FC428 clone.
15.	Bettoni, Serena, et al. (författare) C4BP-IGM FUSION PROTEIN AS A NOVEL THERAPEUTIC APPROACH TO TREAT NEISSERIA GONORRHOEAE INFECTIONS 2019 Ingår i: Molecular Immunology. - : Elsevier. - 0161-5890 .- 1872-9142. ; 114, s. 470-470 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
16.	Birhanu, Muluken, et al. (författare) Antimicrobial susceptibility in Neisseria gonorrhoeae and epidemiological data of gonorrhoea patients in five cities across Ethiopia, 2021-22 2024 Ingår i: JAC - Antimicrobial Resistance. - : Oxford University Press. - 2632-1823. ; 6:1 Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global public health concern and enhanced global gonococcal AMR surveillance is imperative. As in many African countries, regular, representative and quality-assured gonococcal AMR is lacking in Ethiopia. We describe the AMR in gonococcal isolates from five cities across Ethiopia, 2021-22, and patient epidemiological data.METHODS: Urethral discharge from males and cervical discharge from females were collected from October 2021 to September 2022. Epidemiological data were collected using a questionnaire. MIC determination (ETEST; eight antimicrobials) was performed on gonococcal isolates and EUCAST breakpoints (v13.1) were used.RESULTS: From 1142 urogenital swab samples, 299 species-identified gonococcal isolates were identified; 78.3% were from males and 21.7% from females. The median age for males and females was 25 and 23 years, respectively. Most isolates (61.2%) were identified in Addis Ababa, followed by Gondar (11.4%), Adama (10.4%), Bahir Dar (10.0%) and Jimma (7.0%). The resistance level to ciprofloxacin, tetracycline and benzylpenicillin was 97.0%, 97.0% and 87.6%, respectively, and 87.6% of isolates were producing β-lactamase. All isolates were susceptible to ceftriaxone, cefixime, azithromycin and spectinomycin. Recommended therapy [ceftriaxone (250 mg) plus azithromycin (1 g)] was used for 84.2% of patients.CONCLUSIONS: We present the first national quality-assured gonococcal AMR data from Ethiopia. Resistance levels to ciprofloxacin, tetracycline and benzylpenicillin were exceedingly high. However, all isolates were susceptible to ceftriaxone, cefixime, azithromycin and spectinomycin. In Ethiopia, it is essential to strengthen the gonococcal AMR surveillance by including further epidemiological data, more isolates from different cities, and WGS.
17.	Boiko, Iryna, et al. (författare) Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and treatment of gonorrhoea patients in Ternopil and Dnipropetrovsk regions of Ukraine, 2013-2018 2019 Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : John Wiley & Sons. - 0903-4641 .- 1600-0463. ; 127:7, s. 503-509 Tidskriftsartikel (refereegranskat)abstract 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.
18.	Boiko, Iryna, et al. (författare) Genomic epidemiology and antimicrobial resistance determinants of Neisseria gonorrhoeae isolates from Ukraine, 2013-2018 2020 Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 128:7, s. 465-475 Tidskriftsartikel (refereegranskat)abstract Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major health threat compromising the gonorrhoea treatment globally. AMR surveillance including whole genome sequencing (WGS)-based epidemiology provides ideal resolution to identify and describe AMR gonococcal clones, AMR determinants and populations, which can inform management guidelines and antimicrobial stewardship policies. Our aims were to, for the first time, elucidate the WGS-based epidemiology and characterise AMR determinants of gonococcal strains spreading in Ukraine, 2013-2018. Gonococcal isolates (n=150) from Ternopil and Dnipro, Ukraine (2013-2018) were subjected to AMR testing (Etest) for eight antimicrobials and WGS. Overall, 11.3% of isolates were resistant to ciprofloxacin, 6.0% to tetracycline and 0.7% to benzylpenicillin. No isolates were resistant to azithromycin, spectinomycin, ceftriaxone, or cefixime, but one isolate was bordering resistance to both cephalosporins. Twenty-five MLST STs, 50 NG-MAST STs, and 34 NG-STAR types were identified. The phylogenomic analysis revealed six main clusters, mostly associated with the internationally described multidrug-susceptible gonococcal lineage. Resistance to ciprofloxacin was associated with GyrA S91F and ParC S87R mutations; tetracyclines with rpsJ V57M and tetM; penicillins with mosaic penA-34.001 and β-lactamase; mtrR; PorB1b G101D, and PBP1 L421P mutations. One isolate of the multidrug-resistant NG-MAST ST1407, MLST ST1901 was found, which was bordering resistance to ceftriaxone and cefixime. The susceptibility of gonococcal strains spreading in Ternopil and Dnipro, Ukraine, 2013-2018 was surprisingly high. Continued and expanded gonococcal AMR surveillance, ideally including WGS, in Ukraine is essential. This could inform action plans and public health policies to control the spread of AMR gonococcal strains in Ukraine.
19.	Brehony, Carina, et al. (författare) Implications of Differential Age Distribution of Disease-Associated Meningococcal Lineages for Vaccine Development 2014 Ingår i: Clinical and Vaccine Immunology. - : American Society for Microbiology. - 1556-6811 .- 1556-679X. ; 21:6, s. 847-853 Tidskriftsartikel (refereegranskat)abstract New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and >= 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.
20.	Broeker, Michael, et al. (författare) Meningococcal serogroup Y emergence in Europe High importance in some European regions in 2012 2014 Ingår i: Human Vaccines & Immunotherapeutics. - : Landes Bioscience. - 2164-5515 .- 2164-554X. ; 10:6, s. 1725-1728 Tidskriftsartikel (refereegranskat)abstract Neisseria meningitidis is differentiated into 12 distinct serogroups, of which A, B, C, W, X, and Y are medically most important and represent an important health problem in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Recent epidemiological surveillance has indicated an increase of serogroup Y invasive meningococcal disease in some parts of Europe as shown in the epidemiological data for 2010 and 2011 from various European countries previously published in this journal. 1,2 Here, data from 33 European countries is reported indicating that the emergence of serogroup Y continued in 2012 in various regions of Europe, especially in Scandinavia, while in Eastern and South-Eastern Europe the importance of serogroup Y remained low.
21.	Cole, Michelle J., et al. (författare) Is the tide turning again for cephalosporin resistance in Neisseria gonorrhoeae in Europe? : Results from the 2013 European surveillance 2015 Ingår i: BMC Infectious Diseases. - London, United Kingdom : BioMed Central. - 1471-2334. ; 15 Tidskriftsartikel (refereegranskat)abstract 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.
22.	Cole, Michelle J., et al. (författare) Overall Low Extended-Spectrum Cephalosporin Resistance but high Azithromycin Resistance in Neisseria gonorrhoeae in 24 European Countries, 2015 2017 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 17 Tidskriftsartikel (refereegranskat)abstract 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.
23.	Cole, Michelle J., et al. (författare) The European response to control and manage multi- and extensively drug-resistant Neisseria gonorrhoeae 2022 Ingår i: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 27:18, s. 37-43 Tidskriftsartikel (refereegranskat)abstract Because cefixime and ceftriaxone resistance in Neisseria gonorrhoeae and gonorrhoea treatment failures were increasing, a response plan to control and manage multidrug-resistant N. gonorrhoeae (MDR-NG) in Europe was published in 2012. The three main areas of the plan were to: (i) strengthen surveillance of antimicrobial resistance (AMR), (ii) implement monitoring of treatment failures and (iii) establish a communication strategy to increase awareness and disseminate AMR results. Since 2012, several additional extensively drug-resistant N. gonorrhoeae (XDR-NG) strains have emerged, and strains with high-level ceftriaxone resistance spread internationally. This prompted an evaluation and review of the 2012 European Centre for Disease Prevention and Control (ECDC) response plan, revealing an overall improvement in many aspects of monitoring AMR in N. gonorrhoeae; however, treatment failure monitoring was a weakness. Accordingly, the plan was updated in 2019 to further support European Union/European Economic Area (EU/EEA) countries in controlling and managing the threat of MDR/XDR-NG in Europe through further strengthening of AMR surveillance and clinical management including treatment failure monitoring. The plan will be assessed biennially to ensure its effectiveness and its value. Along with prevention, diagnostic, treatment and epidemiological surveillance strategies, AMR surveillance is essential for effective control of gonorrhoea.
24.	Day, Michaela J., et al. (författare) Significant increase in azithromycin "resistance" and susceptibility to ceftriaxone and cefixime in Neisseria gonorrhoeae isolates in 26 European countries, 2019 2022 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 22:1 Tidskriftsartikel (refereegranskat)abstract 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 2019 (26 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 clinical breakpoints, where available) of 3239 N. gonorrhoeae isolates from 26 countries across the EU/EEA. Significance of differences compared with Euro-GASP results in previous years was analysed using Z-test and the Pearson's χ2 test was used to assess significance of odds ratios for associations between patient epidemiological data and antimicrobial resistance.RESULTS: European N. gonorrhoeae isolates collected between 2016 and 2019 displayed shifting MIC distributions for; ceftriaxone, with highly susceptible isolates increasing over time and occasional resistant isolates each year; cefixime, with highly-susceptible isolates becoming increasingly common; azithromycin, with a shift away from lower MICs towards higher MICs above the EUCAST epidemiological cut-off (ECOFF); and ciprofloxacin which is displaying a similar shift in MICs as observed for azithromycin. In 2019, two isolates displayed ceftriaxone resistance, but both isolates had MICs below the azithromycin ECOFF. Cefixime resistance (0.8%) was associated with patient sex, with resistance higher in females compared with male heterosexuals and men-who-have-sex-with-men (MSM). The number of countries reporting isolates with azithromycin MICs above the ECOFF increased from 76.9% (20/26) in 2016 to 92.3% (24/26) in 2019. Isolates with azithromycin MICs above the ECOFF (9.0%) were associated with pharyngeal infection sites. Following multivariable analysis, ciprofloxacin resistance remained associated with isolates from MSM and heterosexual males compared with females, the absence of a concurrent chlamydial infection, pharyngeal infection sites and patients ≥ 25 years of age.CONCLUSIONS: Resistance to ceftriaxone and cefixime remained uncommon in EU/EEA countries in 2019 with a significant decrease in cefixime resistance observed between 2016 and 2019. The significant increase in azithromycin "resistance" (azithromycin MICs above the ECOFF) threatens the effectiveness of the dual therapy (ceftriaxone + azithromycin), i.e., for ceftriaxone-resistant cases, currently recommended in many countries internationally and requires close monitoring.
25.	Day, Michaela J., et al. (författare) Stably high azithromycin resistance and decreasing ceftriaxone susceptibility in Neisseria gonorrhoeae in 25 European countries, 2016 2018 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 18:1 Tidskriftsartikel (refereegranskat)abstract 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.
26.	Day, Michaela, et al. (författare) THE EUROPEAN GONOCOCCAL ANTIMICROBIAL SURVEILLANCE PROGRAMME FINDINGS 2017 2019 Ingår i: Sexually Transmitted Infections. - : BMJ Publishing Group Ltd. - 1368-4973 .- 1472-3263. ; 95:Suppl. 1, s. A43-A43 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract 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.
27.	Eriksson, Lorraine, 1990-, et al. (författare) Genetic variants linked to the phenotypic outcome of invasive disease and carriage of Neisseria meningitidis 2023 Ingår i: Microbial Genomics. - : Microbiology Society. - 2057-5858. ; 9:10 Tidskriftsartikel (refereegranskat)abstract Neisseria meningitidis can be a human commensal in the upper respiratory tract but is also capable of causing invasive diseases such as meningococcal meningitis and septicaemia. No specific genetic markers have been detected to distinguish carriage from disease isolates. The aim here was to find genetic traits that could be linked to phenotypic outcomes associated with carriage versus invasive N. meningitidis disease through a bacterial genome-wide association study (GWAS). In this study, invasive N. meningitidis isolates collected in Sweden (n=103) and carriage isolates collected at Örebro University, Sweden (n=213) 2018-2019 were analysed. The GWAS analysis, treeWAS, was applied to single-nucleotide polymorphisms (SNPs), genes and k-mers. One gene and one non-synonymous SNP were associated with invasive disease and seven genes and one non-synonymous SNP were associated with carriage isolates. The gene associated with invasive disease encodes a phage transposase (NEIS1048), and the associated invasive SNP glmU S373C encodes the enzyme N-acetylglucosamine 1-phosphate (GlcNAC 1-P) uridyltransferase. Of the genes associated with carriage isolates, a gene variant of porB encoding PorB class 3, the genes pilE/pilS and tspB have known functions. The SNP associated with carriage was fkbp D33N, encoding a FK506-binding protein (FKBP). K-mers from PilS, tbpB and tspB were found to be associated with carriage, while k-mers from mtrD and tbpA were associated with invasiveness. In the genes fkbp, glmU, PilC and pilE, k-mers were found that were associated with both carriage and invasive isolates, indicating that specific variations within these genes could play a role in invasiveness. The data presented here highlight genetic traits that are significantly associated with invasive or carriage N. meningitidis across the species population. These traits could prove essential to our understanding of the pathogenicity of N. meningitidis and could help to identify future vaccine targets.
28.	Eriksson, Lorraine, 1990-, et al. (författare) Whole-Genome Sequencing of Emerging Invasive Neisseria meningitidis Serogroup W in Sweden 2018 Ingår i: Journal of Clinical Microbiology. - : American Society for Microbiology. - 0095-1137 .- 1098-660X. ; 56:4 Tidskriftsartikel (refereegranskat)abstract 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.
29.	Foerster, Sunniva, et al. (författare) Genetic Resistance Determinants, In Vitro Time-Kill Curve Analysis and Pharmacodynamic Functions for the Novel Topoisomerase II Inhibitor ETX0914 (AZD0914) in Neisseria gonorrhoeae 2015 Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 6 Tidskriftsartikel (refereegranskat)abstract 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.
30.	Golparian, degn, 1984-, et al. (författare) Antimicrobial-resistant Neisseria gonorrhoeae in Europe in 2020 compared with in 2013 and 2018 : a retrospective genomic surveillance study 2024 Ingår i: The Lancet. Microbe. - : Elsevier. - 2666-5247. ; 5:5, s. e478-e488 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Regular quality-assured whole-genome sequencing linked to antimicrobial resistance (AMR) and patient metadata is imperative to elucidate the shifting gonorrhoea epidemiology, both nationally and internationally. We aimed to examine the gonococcal population in the European Economic Area (EEA) in 2020, elucidate emerging and disappearing gonococcal lineages associated with AMR and patient metadata, compare with 2013 and 2018 whole-genome sequencing data, and explain changes in gonococcal AMR and gonorrhoea epidemiology.METHODS: In this retrospective genomic surveillance study, we analysed consecutive gonococcal isolates that were collected in EEA countries through the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) in 2020, and made comparisons with Euro-GASP data from 2013 and 2018. All isolates had linked AMR data (based on minimum inhibitory concentration determination) and patient metadata. We performed whole-genome sequencing and molecular typing and AMR determinants were derived from quality-checked whole-genome sequencing data. Links between genomic lineages, AMR, and patient metadata were examined.FINDINGS: 1932 gonococcal isolates collected in 2020 in 21 EEA countries were included. The majority (81·2%, 147 of 181 isolates) of azithromycin resistance (present in 9·4%, 181 of 1932) was explained by the continued expansion of the Neisseria gonorrhoeae sequence typing for antimicrobial resistance (NG-STAR) clonal complexes (CCs) 63, 168, and 213 (with mtrD/mtrR promoter mosaic 2) and the novel NG-STAR CC1031 (semi-mosaic mtrD variant 13), associated with men who have sex with men and anorectal or oropharyngeal infections. The declining cefixime resistance (0·5%, nine of 1932) and negligible ceftriaxone resistance (0·1%, one of 1932) was largely because of the progressive disappearance of NG-STAR CC90 (with mosaic penA allele), which was predominant in 2013. No known resistance determinants for novel antimicrobials (zoliflodacin, gepotidacin, and lefamulin) were found.INTERPRETATION: Azithromycin-resistant clones, mainly with mtrD mosaic or semi-mosaic variants, appear to be stabilising at a relatively high level in the EEA. This mostly low-level azithromycin resistance might threaten the recommended ceftriaxone-azithromycin therapy, but the negligible ceftriaxone resistance is encouraging. The decreased genomic population diversity and increased clonality could be explained in part by the COVID-19 pandemic resulting in lower importation of novel strains into Europe.
31.	Golparian, Daniel, 1984-, et al. (författare) Complete Reference Genome Sequence of the Clinical Neisseria gonorrhoeae Strain H035, with Resistance to the Novel Antimicrobial Zoliflodacin, Identified in Japan in 2000 2023 Ingår i: Microbiology Resource Announcements. - : American Society for Microbiology. - 2576-098X. ; 12:3 Tidskriftsartikel (refereegranskat)abstract Zoliflodacin is a promising novel antimicrobial in clinical development for treatment of gonorrhea; currently, it is in a global phase 3 randomized controlled clinical trial. High activity against global Neisseria gonorrhoeae strains has been shown. We present the complete reference genome of the zoliflodacin-resistant strain H035, which was identified in Japan in 2000.
32.	Golparian, Daniel, 1984-, et al. (författare) Complete Reference Genome Sequence of the Extensively Drug-Resistant Strain Neisseria gonorrhoeae AT159, with Ceftriaxone Resistance and High-Level Azithromycin Resistance, Using Nanopore Q20+ Chemistry and Illumina Sequencing 2022 Ingår i: Microbiology Resource Announcements. - : American Society for Microbiology. - 2576-098X. ; 15:11 Tidskriftsartikel (refereegranskat)abstract Extensively drug-resistant Neisseria gonorrhoeae (XDR-NG) strains with resistance to the last remaining first-line treatments (ceftriaxone monotherapy or combined with azithromycin) represent the emerging threat of untreatable gonorrhea. We present the complete reference genome sequence of the XDR-NG strain AT159, with ceftriaxone and high-level azithromycin resistance, from Austria.
33.	Golparian, Daniel, 1984-, et al. (författare) Genomic surveillance and antimicrobial resistance in Neisseria gonorrhoeae isolates in Bangkok, Thailand in 2018 2022 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 77:8, s. 2171-2182 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a substantial global public health problem. Gonococcal infections acquired in or from Asia represent most verified ceftriaxone treatment failures, and several ceftriaxone-resistant strains have emerged in Asia and subsequently spread globally. Additionally, in Thailand the gonorrhoea incidence remains high. Herein, we investigate the genomic diversity, AMR and AMR determinants in gonococcal isolates cultured in 2018 in Bangkok, Thailand.METHODS: Gonococcal isolates from males (n = 37) and females (n = 62) were examined by Etest and WGS. AMR determinants and molecular epidemiological STs were characterized. For phylogenomic comparison, raw sequence data were included from China (432 isolates), Japan (n = 270), Vietnam (n = 229), Thailand (n = 3), a global dataset (n = 12 440) and the 2016 WHO reference strains plus WHO Q (n = 15).RESULTS: In total, 88, 66 and 41 different NG-MAST, NG-STAR and MLST STs, respectively, and 31 different NG-STAR clonal complexes were found. A remarkably high frequency (88%) of β-lactamase TEM genes was detected and two novel TEM alleles were found. The phylogenomic analysis divided the isolates into the previously described lineages A and B, with a large proportion of Thai isolates belonging to the novel sublineage A3.CONCLUSIONS: We describe the first molecular epidemiological study using WGS on gonococcal isolates from Thailand. The high prevalence of AMR and AMR determinants for ciprofloxacin, tetracycline and benzylpenicillin, and some strains belonging to clones/clades especially in sublineage A2 that are prone to develop resistance to extended-spectrum cephalosporins (ESCs) and azithromycin, should prompt continued and strengthened AMR surveillance, including WGS, of N. gonorrhoeae in Thailand.
34.	Golparian, Daniel, 1984-, et al. (författare) GyrB in silico mining in 27 151 global gonococcal genomes from 1928-2021 combined with zoliflodacin in vitro testing of 71 international gonococcal isolates with different GyrB, ParC and ParE substitutions confirms high susceptibility 2022 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 78:1, s. 150-154 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global threat and novel treatment alternatives are imperative. Herein, susceptibility to the novel antimicrobial zoliflodacin, currently in a global Phase 3 randomized controlled clinical trial for gonorrhoea treatment, was investigated by screening for zoliflodacin GyrB target mutations in publicly available gonococcal genomes and, where feasible, determination of the associated zoliflodacin MIC.METHODS: The European Nucleotide Archive was queried using the search term 'Taxon: 485'. DNA sequences from 27 151 gonococcal isolates were analysed and gyrB, gyrA, parC and parE alleles characterized.RESULTS: GyrB amino acid alterations were rare (97.0% of isolates had a wild-type GyrB sequence). GyrB V470L (2.7% of isolates) was the most prevalent alteration, followed by S467N (0.12%), N. meningitidis GyrB (0.092%), V470I (0.059%), Q468R/P (0.015%), A466T (0.0074%), L425I + L465I (0.0037%), L465I (0.0037%), G482S (0.0037%) and D429V (0.0037%). Only one isolate (0.0037%) carried a substitution in a resistance-associated GyrB codon (D429V), resulting in a zoliflodacin MIC of 8 mg/L. None of the other detected gyrB, gyrA, parC or parE mutations caused a zoliflodacin MIC outside the wild-type MIC distribution.CONCLUSIONS: The zoliflodacin target GyrB was highly conserved among 27 151 global gonococcal isolates cultured in 1928-2021. The single zoliflodacin-resistant clinical isolate (0.0037%) was cultured from a male patient in Japan in 2000. Evidently, this strain has not clonally expanded nor has the gyrB zoliflodacin-resistance mutation disseminated through horizontal gene transfer to other strains. Phenotypic and genomic surveillance, including gyrB mutations, of zoliflodacin susceptibility are imperative.
35.	Golparian, Daniel, 1984-, et al. (författare) High-level in vitro resistance to gentamicin acquired in a stepwise manner in Neisseria gonorrhoeae 2023 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 78:7, s. 1769-1778 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: Gentamicin is used in several alternative treatments for gonorrhoea. Verified clinical Neisseria gonorrhoeae isolates with gentamicin resistance are mainly lacking and understanding the mechanisms for gonococcal gentamicin resistance is imperative. We selected gentamicin resistance in gonococci in vitro, identified the novel gentamicin-resistance mutations, and examined the biofitness of a high-level gentamicin-resistant mutant.METHODS: Low- and high-level gentamicin resistance was selected in WHO X (gentamicin MIC = 4 mg/L) on gentamicin-gradient agar plates. Selected mutants were whole-genome sequenced. Potential gentamicin-resistance fusA mutations were transformed into WT strains to verify their impact on gentamicin MICs. The biofitness of high-level gentamicin-resistant mutants was examined using a competitive assay in a hollow-fibre infection model.RESULTS: WHO X mutants with gentamicin MICs of up to 128 mg/L were selected. Primarily selected fusA mutations were further investigated, and fusAR635L and fusAM520I + R635L were particularly interesting. Different mutations in fusA and ubiM were found in low-level gentamicin-resistant mutants, while fusAM520I was associated with high-level gentamicin resistance. Protein structure predictions showed that fusAM520I is located in domain IV of the elongation factor-G (EF-G). The high-level gentamicin-resistant WHO X mutant was outcompeted by the gentamicin-susceptible WHO X parental strain, suggesting lower biofitness.CONCLUSIONS: We describe the first high-level gentamicin-resistant gonococcal isolate (MIC = 128 mg/L), which was selected in vitro through experimental evolution. The most substantial increases of the gentamicin MICs were caused by mutations in fusA (G1560A and G1904T encoding EF-G M520I and R635L, respectively) and ubiM (D186N). The high-level gentamicin-resistant N. gonorrhoeae mutant showed impaired biofitness.
36.	Golparian, Daniel, 1984-, et al. (författare) Multidrug-resistant Neisseria gonorrhoeae isolate SE690 : mosaic penA-60.001 gene causing ceftriaxone resistance internationally has spread to the more antimicrobial- susceptible genomic lineage, Sweden, September 2022 2023 Ingår i: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 28:10 Tidskriftsartikel (refereegranskat)abstract We report a ceftriaxone-resistant, multidrug-resist-ant urogenital Neisseria gonorrhoeae in a female sex worker in Sweden, September 2022, who was treated with ceftriaxone i g, but did not return for test-of-cure. Whole genome sequencing of isolate SE690 identified MLST ST8i30, NG-STAR CCi885 (new NG-STAR ST4859) and mosaic penA-6o.oo1. The latter, causing ceftriax-one resistance in the internationally spreading FC428 clone, has now also spread to the more antimicrobial -susceptible genomic lineage B, showing that strains across the gonococcal phylogeny can develop ceftri-axone resistance.
37.	Hadad, Ronza, 1984-, et al. (författare) Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeae 2021 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 76:1, s. 84-90 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance.OBJECTIVES: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively.METHODS: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays.RESULTS: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions.CONCLUSIONS: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).
38.	Hadad, Ronza, 1984- (författare) Implementation of strategies for management and prevention of sexually transmitted infections with focus on Neisseria gonorrhoeae and Chlamydia trachomatis 2022 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Sexually transmitted infections (STIs) are a public health issue of great importance worldwide, with effects on fertility and reproduction. Chlamydia trachomatis and Neisseria gonorrhoeae, causative agents of chlamydia and gonorrhoea, respectively, are the most common bacterial STIs with an estimated 127 million new global cases of chlamydia and 87 million new gonorrhoea cases. The continued emergence of antimicrobial resistance (AMR) in N. gonorrhoeae may in the future lead to an untreatable infection. Prevention of these infections and controlling the development of AMR rely on several strategies developed by the World Health Organization (WHO). This thesis aimed to implement several of these strategies, including supporting vaccine development for C. trachomatis and N. gonorrhoeae, evaluating molecular methods for detecting N. gonorrhoeae, predicting AMR and supporting surveillance of the spread and prevalence of AMR in N. gonorrhoeae. The present studies on a C. trachomatis recombinant vaccine antigen and the investigation of similarities of N. gonorrhoeae antigen amino acid sequences to the antigens included in the meningococcal vaccine 4CMenB contributed to the field of vaccine development for STIs. The assay SpeeDx ResistancePlus® GC performed well in detecting N. gonorrhoeae and predicting ciprofloxacin resistance and could be used in AMR surveillance and individualised treatment. In 2016, the first national genomic surveillance of all N. gonorrhoeae isolates in Sweden was performed. This national surveillance study included whole-genome sequencing combined with phenotypic AMR and epidemiological data, which provides valuable information on circulating strains, epidemiology and phylogeny. Greater knowledge of gonorrhoea and gonococcal AMR epidemiology could inform decisions on guidelines and prevention. It is essential to continue to implement WHO strategies at the national and global levels to prevent and control chlamydia and gonorrhoea infections.
39.	Hadad, Ronza, 1984-, et al. (författare) Novel meningococcal 4CMenB vaccine antigens : prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae 2012 Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 120:9, s. 750-760 Tidskriftsartikel (refereegranskat)abstract 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.
40.	Harris, Simon R., et al. (författare) Public health surveillance of multidrug-resistant clones of Neisseria gonorrhoeae in Europe : a genomic survey 2018 Ingår i: The Lancet - Infectious diseases. - : Elsevier. - 1473-3099 .- 1474-4457. ; 18:7, s. 758-768 Tidskriftsartikel (refereegranskat)abstract 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.
41.	Hellsmark, Hans, 1974, et al. (författare) Teknologiska innovationssystem inom energiområdet: En praktisk vägledning till identifiering av systemsvagheter som motiverar särskilda politiska åtaganden 2014 Rapport (övrigt vetenskapligt/konstnärligt)abstract Syftet med denna rapport är att illustrera hur ett praktiskt inriktat ramverk, tekno- logiska innovationssystem (TIS), kan användas av analytiker och beslutsfattare vid departement och myndigheter för att analysera strategiskt viktiga teknikområden ?????????????????????????????????????????????????????????????????????????????I rapporten analyseras fem TIS centrerade kring havsbaserad vindkraft, marin energi, ????????????????????????????????????????????????????????????????????????????????????? systemsvagheter som bromsar områdets vidare utveckling, vilka som kan åtgärdas av systemets aktörer och vilka som motiverar särskilda politiska åtaganden. Rapporten utgör därmed ett underlag för att formulera åtgärder för att åstadkomma ökad innova- tion, teknikspridning och industrialisering inom ovan nämnda teknikområden.Studien har även möjliggjort en jämförande analys av likheter och skillnader ???????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????????? mellan områdena – de är starka respektive svaga av olika orsaker. Detta visar att ???????????????????????????????????????????????????????????????????????Samtidigt har områdena gemensamma drag. Systemets aktörer, där även politiska ???????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????- skapsnätverk. Men de har varit sämre på att skapa tidiga nischmarknader som ger utrymme för fortsatt lärande och kostnadsreduktion. Sådana nischer kan ibland skapas av marknadens aktörer, men ofta krävs politiska styrmedel. De behövs för att investeringar i kunskapsutveckling ska kunna nyttiggöras och för att en bred industriell utveckling inom nya områden skall göras möjlig i Sverige.Vidare presenteras lärdomar kring vad en aktiv teknikpolitik innebär. Två huvud- ??????????????????????????????????????????????????????????????????????????????- hällsbygget och därför bör vara ett politikområde bland många samt att den skarpa ??????????????????????????????????????????????????????????????????????????????- ?????????????????????????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????????????????????? olika faser av innovationssystemets utveckling.För att lyckas med en aktiv teknikpolitik behövs en hög grad av koordinering ??????????????????????????????????????????????????????????????????????? teknikområden så att ”rätt” typ av åtgärder kan sättas in vid ”rätt” tidpunkt av ”rätt” aktör. TIS-ramverket lyfts här fram som en metod för att skapa ett sådant underlag. Slutligen presenteras en metod för projektbedömningar som syftar till att stötta handläggare i utvärderingar av projekt inom nya teknikområden.Rapporten i sin helhet riktar sig särskilt till beslutsfattare och handläggare vid myndigheter, departement och politiker, men även andra organisationer och indi- vider med intresse av att högt ställda klimatmål ska kunna nås samtidigt som en positiv näringslivsutveckling möjliggörs.
42.	Jabeen, Kauser, et al. (författare) Antimicrobial resistance and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST) genotypes in N. gonorrhoeae during 2012-2014 in Karachi, Pakistan 2016 Ingår i: BMC Infectious Diseases. - London, United Kingdom : BioMed Central. - 1471-2334. ; 16:1 Tidskriftsartikel (refereegranskat)abstract 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.
43.	Jacobsson, Susanne, 1974-, et al. (författare) Associations between antimicrobial susceptibility/resistance of Neisseria gonorrhoeae isolates in European Union/European Economic Area and patients' gender, sexual orientation and anatomical site of infection, 2009-2016 2021 Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 21:1 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The emergence and spread of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, nationally and internationally, is a serious threat to the management and control of gonorrhoea. Limited and conflicting data regarding the epidemiological drivers of gonococcal AMR internationally have been published. We examined the antimicrobial susceptibility/resistance of gonococcal isolates (n = 15,803) collected across 27 European Union/European Economic Area (EU/EEA) countries in 2009-2016, in conjunction to epidemiological and clinical data of the corresponding patients, to elucidate associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection.METHODS: In total, 15,803N. gonorrhoeae isolates from the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP), 2009-2016, were examined. Associations between gonococcal susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection were investigated using univariate and multivariate logistic regression analysis. Statistical significance was determined by Pearson chi (2)-test or Fisher's exact test with two-tailed p-values of <0.05 indicating significance.RESULTS: The overall gonococcal resistance from 2009 to 2016 was 51.7% (range during the years: 46.5-63.5%), 7.1% (4.5-13.2%), 4.3% (1.8-8.7%), and 0.2% (0.0-0.5%) to ciprofloxacin, azithromycin, cefixime, and ceftriaxone, respectively. The level of resistance combined with decreased susceptibility to ceftriaxone was 10.2% (5.7-15.5%). Resistance to cefixime and ciprofloxacin, and resistance combined with decreased susceptibility to ceftriaxone were positively associated with urogenital infections and heterosexual males, males with sexual orientation not reported and females (except for ciprofloxacin), i.e. when compared to men-who-have-sex-with-men (MSM). Azithromycin resistance was positively associated with heterosexual males, but no association was significant regarding anatomical site of infection.CONCLUSIONS: Overall, sexual orientation was the main variable associated with gonococcal AMR. Strongest positive associations were identified with heterosexual patients, particularly males, and not MSM. To provide evidence-based understanding and mitigate gonococcal AMR emergence and spread, associations between antimicrobial susceptibility/resistance and patients' gender, sexual orientation and anatomical site of infection need to be further investigated in different geographic settings. In general, these insights will support identification of groups at increased risk and targeted public health actions such as intensified screening, 3-site testing using molecular diagnostics, sexual contact tracing, and surveillance of treatment failures.
44.	Jacobsson, Susanne, 1974- (författare) Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens 2009 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract 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).
45.	Jacobsson, Susanne, 1974- (författare) Despite successful vaccines Neisseria meningitidis strikes again 2016 Ingår i: The Lancet - Infectious diseases. - : Elsevier. - 1473-3099 .- 1474-4457. ; 16:11, s. 1212-1213 Tidskriftsartikel (refereegranskat)
46.	Jacobsson, Susanne, 1974-, et al. (författare) High in vitro activity of DIS-73285, a novel antimicrobial with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae 2020 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 75:11, s. 3244-3247 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The rising incidence of antimicrobial resistance in Neisseria gonorrhoeae may result in untreatable gonorrhoea in certain circumstances and development of novel antimicrobials is urgently needed.OBJECTIVES: To evaluate the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, DIS-73285, against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates (n = 262).METHODS: MICs (mg/L) of DIS-73285 were determined by agar dilution and by Etest for ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline.RESULTS: DIS-73285 was substantially more potent than any of the currently or previously used therapeutic antimicrobials, with MICs ranging from ≤0.001 to 0.004 mg/L, and the MIC50, MIC90 and modal MIC all ≤0.001 mg/L (lowest MIC tested). No correlation with the MICs of DIS-73285 and the MICs of any of the currently or previously used antimicrobials was observed.CONCLUSIONS: The novel chemotype, small-molecule antimicrobial DIS-73285, demonstrated high in vitro potency against all tested N. gonorrhoeae isolates. Further in vitro and in vivo studies, evaluating efficacy, resistance emergence, pharmacokinetic/pharmacodynamic parameters, toxicity and safety, should be conducted to evaluate DIS-73285 as a therapy specifically for urogenital and extra-genital gonorrhoea.
47.	Jacobsson, Susanne, 1974-, et al. (författare) High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea 2014 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 58:9, s. 5585-5588 Tidskriftsartikel (refereegranskat)abstract We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n = 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials.
48.	Jacobsson, Susanne, 1974-, et al. (författare) High In Vitro Susceptibility to the First-in-Class Spiropyrimidinetrione Zoliflodacin among Consecutive Clinical Neisseria gonorrhoeae Isolates from Thailand and South Africa 2019 Ingår i: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 63:12 Tidskriftsartikel (refereegranskat)abstract 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.
49.	Jacobsson, Susanne, 1974-, et al. (författare) In vitro activity of the ketolide cethromycin in multidrug-resistant clinical Neisseria gonorrhoeae isolates and international reference strains 2019 Ingår i: Journal of chemotherapy. - : Taylor & Francis. - 1120-009X .- 1973-9478. ; 252:Part B, s. 1399-1405 Tidskriftsartikel (refereegranskat)abstract 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.
50.	Jacobsson, Susanne, 1974-, et al. (författare) 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? 2019 Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press. - 0305-7453 .- 1460-2091. ; 74:6, s. 1591-1594 Tidskriftsartikel (refereegranskat)abstract 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.

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