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  • 1.
    Hedberg, Sara Thulin
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Törös, Bianca
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 20102011In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 16, no 23, article id 19885Article in journal (Refereed)
    Abstract [en]

    Neisseria meningitidis serogroups B and C have beenresponsible for the majority of invasive meningococcaldisease in Europe. Recently, an increase of N. meningitidisdisease due to serogroup Y has been notedin Sweden (in 2010, the proportion was 39%, with anincidence of 0.23 per 100,000 population), as well as inother northern European countries. We aimed to investigatethe clonal pattern of the emerging serogroup Yin Sweden during 2000 to 2010. The serogroup Y isolatesidentified during this time (n=85) were characterisedby multilocus sequence typing and sequencing ofthe fetA, fHbp, penA, porA and porB genes. The mostfrequent clone (comprising 28 isolates) with identicalallele combinations of the investigated genes, waspartly responsible for the observed increased numberof N. meningitidis serogroup Y isolates. It was sulfadiazineresistant, with genosubtype P1.5-2,10-1,36-2,sequence type 23, clonal complex 23, porB allele 3-36,fetA allele F4-1, fHbp allele 25 and penA allele 22. Thefirst case with disease due to this clone was identifiedin 2002: there was a further case in 2004, six during2006 to 2007, eight during 2008 to 2009, with a peakof 12 cases in 2010. An unusual increase of invasivedisease in young adults (aged 20–29 years) caused bythis clone was shown, but no increase in mortality ratewas observed.

  • 2.
    Hedberg, Sara Thulin
    et al.
    Örebro University, School of Health and Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Nicolas, Pierre
    Caugant, Dominique A.
    Olcén, Per
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences.
    Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives2009In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, no 4, p. 1561-1566Article in journal (Refereed)
    Abstract [en]

    Up-to-date information regarding the antibiotic susceptibility of Neisseria meningitidis strains from African countries is highly limited. Our aim was to comprehensively describe the antibiotic susceptibilities of a selection of N. meningitidis isolates recovered between 2000 and 2006 from 18 African countries, mainly those within the meningitis belt. Susceptibilities to 11 antibiotics were determined using Etest for 137 N. meningitidis isolates (stringently selected from 693 available isolates). The isolates were also characterized by serogrouping, multilocus sequence typing, genosubtyping, and penA allele identification. All N. meningitidis isolates were susceptible to ceftriaxone, chloramphenicol, and ciprofloxacin. No isolate produced beta-lactamase. Only three isolates (2%) displayed reduced susceptibility to penicillin G. The two isolates with the highest penicillin G MICs were the only isolates showing reduced susceptibility to ampicillin and cefuroxime. One of these isolates was also resistant to penicillin V. One percent of isolates displayed reduced susceptibility to rifampin, while 52% of the isolates were resistant to tetracycline, 74% were resistant to erythromycin, and 94% were resistant to sulfadiazine. The MICs of rifampin and tetracycline seemed to be associated with the serogroup of the isolates. In total, 18 sequence types (STs), 10 genosubtypes, and 8 different penA alleles were identified; the most common were ST-7, P1.20,9,35-1, and penA4, respectively. A high level of correlation was found between ST, genosubtype, and penA allele. In conclusion, N. meningitidis isolates from the African meningitis belt remain highly susceptible to the antibiotics used. Regarding beta-lactam antibiotics, rare isolates showed a reduced susceptibility to penicillins, but the expanded-spectrum cephalosporins are not affected at present.

  • 3.
    Hedberg, Sara Thulin
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Fredlund, Hans
    Mölling, Paula
    Real-time PCR detection of five prevalent bacteria causing acute meningitis2009In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 117, no 11, p. 856-860Article in journal (Refereed)
  • 4.
    Hedberg, Sara Thulin
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences.
    Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden: the meningococcal population remains susceptible2010In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 1, p. 61-64Article in journal (Refereed)
    Abstract [en]

    The susceptibility to 7 antibiotics was determined for all Swedish invasive Neisseria meningitidis isolates from 1995 to 2008 (N=717). In general, these remain highly susceptible to the antibiotics recommended for use. Accordingly, penicillin G remains effective for the treatment of invasive meningococcal disease and ciprofloxacin appropriate for prophylaxis.

  • 5.
    Hedberg, Sara Thulin
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Unemo, Magnus
    Örebro University, Department of Health Sciences.
    Combined real-time PCR and pyrosequencing strategy for objective, sensitive, specific, and high throughput identification of reduced susceptibility to penicillins in Neisseria meningitidis2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 2, p. 753-756Article in journal (Refereed)
    Abstract [en]

    A segment of penA in Neisseria meningitidis strains (n = 127), including two nucleotide sites closely associated to reduced susceptibility to penicillins, was amplified and pyrosequenced. All results were in concordance with Sanger sequencing, and a high correlation between alterations in the two Pen(i)-specific sites and reduced susceptibility to penicillins was identified.

  • 6.
    Hong, Eva
    et al.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Thulin Hedberg, Sara
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Abad, Raquel
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Fazio, Cecilia
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Enriquez, Rocio
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Deghmane, Ala-Eddine
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Jolley, Keith A.
    Oxford University, Oxford, England.
    Stefanelli, Paola
    Dept Infect Parasites & Immune Mediated Dis, Ist Super Sanita, Rome, Italy.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Vazquez, Julio A.
    Reference Lab Meningococci, Inst Hlth Carlos III, Madrid, Spain.
    Veyrier, Frederic J.
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Taha, Muhamed-Kheir
    Invas Bacterial Infect Unit, Inst Pasteur, Paris, France; Natl Reference Ctr Meningococci, Paris, France.
    Target Gene Sequencing To Define the Susceptibility of Neisseria meningitidis to Ciprofloxacin2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 4, p. 1961-1964Article in journal (Refereed)
    Abstract [en]

    Meningococcal gyrA gene sequence data, MICs, and mouse infection were used to define the ciprofloxacin breakpoint for Neisseria meningitidis. Residue T91 or D95 of GyrA was altered in all meningococcal isolates with MICs of >= 0.064 mu g/ml but not among isolates with MICs of <= 0.032 mu g/ml. Experimental infection of ciprofloxacin-treated mice showed slower bacterial clearance when GyrA was altered. These data suggest a MIC of >= 0.064 mu g/ml as the ciprofloxacin breakpoint for meningococci and argue for the molecular detection of ciprofloxacin resistance.

  • 7. Taha, Muhamed-Kheir
    et al.
    Thulin Hedberg, Sara
    Örebro University, School of Health and Medical Sciences.
    Szatanik, Marek
    Hong, Eva
    Ruckly, Corinne
    Abad, Raquel
    Bertrand, Sophie
    Carion, Francoise
    Claus, Heike
    Enríquez, Rocío
    Heuberger, Sigrid
    Jolley, Keith A.
    Kriz, Paula
    Musilek, Martin
    Neri, Arianna
    Olcén, Per
    Örebro University, School of Health and Medical Sciences.
    Pana, Marina
    Skoczynska, Anna
    Stefanelli, Paola
    Tzanakaki, Georgina
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences.
    Vàzquez, Julio A.
    Vogel, Ulrich
    Wasko, Izabela
    Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing2009Manuscript (preprint) (Other academic)
    Abstract [en]

    Clinical isolates of Neisseria meningitidis resistant to rifampicin are important to identify asthey lead to failure of chemoprophylaxis of meningococcal disease. However, theidentification of these isolates is hindered by the absence of a harmonized breakpoint despiteefforts of standardization. In the present study, a large number (n=352) of clinical N.meningitidis isolates from 12 mainly European countries and spanning over 25 years (1984 to2009) were examined. The collection comprised all clinical isolates with MIC 0.25 mg/lreceived by the national reference laboratories for meningococci in the participating countries(n=161). In addition, representative isolates displaying MIC of rifampicin <0.25 mg/l wereexamined (n=191). Phenotyping and genotyping of isolates were performed and a 660 bpDNA fragment of the rpoB gene was sequenced in all the included isolates. Sequencesdiffering by at least one nucleotide were defined as a unique rpoB allele (n=55). Geometricmeans of MIC were calculated for isolates displaying the same allele. All the clinical isolatesdisplaying MIC >1 mg/l of rifampicin possessed rpoB alleles with critical mutations (in total21 alleles), resulting in substitutions at the codon H552 and less frequently at nearby codons(S548 and S557). These alterations were absent in the alleles (n=34) found in all isolates withMIC 1 mg/l. Based on these findings, rifampicin susceptible isolates could be defined asthose with MIC 1 mg/l. A new web site was created based on the data from this work (http://neisseria.org/nm/typing/rpoB). The rifampicin resistant isolates belonged to diversegenetic lineages and provoked lower bacteremia levels in mice. This biological cost mayexplain the non-expansion of the rifampicin resistant isolates.

  • 8.
    Thulin Hedberg, Sara
    Örebro University, School of Health and Medical Sciences.
    Antibiotic susceptibility and resistance in Neisseria meningitidis: phenotypic and genotypic characteristics2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Neisseria meningitidis, also known as the meningococcus, is a globally spread obligate human bacterium causing meningitis and/or septicaemia. It is responsible for epidemics in both developed and developing countries. Untreated invasive meningococcal disease is often fatal, and despite modern intensive care units, the mortality is still remarkably high (approximately 10%). The continuously increasing antibiotic resistance in many bacterial pathogens is a serious public health threat worldwide and there have been numerous reports of emerging resistance in meningococci during the past decades.

    In paper I, the gene linked to reduced susceptibility to penicillins, the penA gene, was examined. The totally reported variation in all published penA genes was described. The penA gene was highly variable (in total 130 variants were identified). By examination of clinical meningococcal isolates, the association between penA gene sequences and penicillin susceptibility could be determined. Isolates with reduced susceptibility displayed mosaic structures in the penA gene. Two closely positioned nucleotide polymorphisms were identified in all isolates with reduced penicillin susceptibility and mosaic structured penA genes. These alterations were absent in all susceptible isolates and were successfully used to detect reduced penicillin susceptibility by real-time PCR and pyrosequencing in paper II. In papers III and IV, antibiotic susceptibility and characteristics of Swedish and African meningitis belt meningococcal isolates were comprehensively described. Although both populations were mainly susceptible to the antibiotics used for treatment and prophylaxis, the proportion of meningococci with reduced penicillin susceptibility was slightly higher in Sweden. A large proportion of the African isolates was resistant to tetracycline and erythromycin. In paper V, the gene linked to rifampicin resistance, the rpoB gene, was examined in meningococci from 12 mainly European countries. Alterations of three amino acids in the RpoB protein were found to always and directly lead to rifampicin resistance. A new breakpoint for rifampicin resistance in meningococci was suggested. The biological cost of the RpoB alterations was investigated in mice. The pathogenicity/virulence was significantly lower in rifampicin resistant mutants as compared with susceptible wild-type bacteria.

    List of papers
    1. Total variation in the penA gene of Neisseria meningitidis: correlation between susceptibility to beta-lactam antibiotics and penA gene heterogeneity
    Open this publication in new window or tab >>Total variation in the penA gene of Neisseria meningitidis: correlation between susceptibility to beta-lactam antibiotics and penA gene heterogeneity
    2006 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 10, p. 3317-3324Article in journal (Refereed) Published
    Abstract [en]

    In recent decades, the prevalence of Neisseria meningitidis isolates with reduced susceptibility to penicillins has increased. The intermediate resistance to penicillin (Pen(i)) for most strains is due mainly to mosaic structures in the penA gene, encoding penicillin-binding protein 2. In this study, susceptibility to beta-lactam antibiotics was determined for 60 Swedish clinical N. meningitidis isolates and 19 reference strains. The penA gene was sequenced and compared to 237 penA sequences from GenBank in order to explore the total identified variation of penA. The divergent mosaic alleles differed by 3% to 24% compared to those of the designated wild-type penA gene. By studying the final 1,143 to 1,149 bp of penA in a sequence alignment, 130 sequence variants were identified. In a 402-bp alignment of the most variable regions, 84 variants were recognized. Good correlation between elevated MICs and the presence of penA mosaic structures was found especially for penicillin G and ampicillin. The Pen(i) isolates comprised an MIC of >0.094 microg/ml for penicillin G and an MIC of >0.064 microg/ml for ampicillin. Ampicillin was the best antibiotic for precise categorization as Pen(s) or Pen(i). In comparison with the wild-type penA sequence, two specific Pen(i) sites were altered in all except two mosaic penA sequences, which were published in GenBank and no MICs of the corresponding isolates were described. In conclusion, monitoring the relationship between penA sequences and MICs to penicillins is crucial for developing fast and objective methods for susceptibility determination. By studying the penA gene, genotypical determination of susceptibility in culture-negative cases can also be accomplished.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-8529 (URN)10.1128/AAC.00353-06 (DOI)17005811 (PubMedID)
    Available from: 2009-11-25 Created: 2009-11-12 Last updated: 2017-12-12Bibliographically approved
    2. Combined real-time PCR and pyrosequencing strategy for objective, sensitive, specific, and high throughput identification of reduced susceptibility to penicillins in Neisseria meningitidis
    Open this publication in new window or tab >>Combined real-time PCR and pyrosequencing strategy for objective, sensitive, specific, and high throughput identification of reduced susceptibility to penicillins in Neisseria meningitidis
    2008 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 2, p. 753-756Article in journal (Refereed) Published
    Abstract [en]

    A segment of penA in Neisseria meningitidis strains (n = 127), including two nucleotide sites closely associated to reduced susceptibility to penicillins, was amplified and pyrosequenced. All results were in concordance with Sanger sequencing, and a high correlation between alterations in the two Pen(i)-specific sites and reduced susceptibility to penicillins was identified.

    Place, publisher, year, edition, pages
    Washington, DC: American Society for Microbiology, 2008
    Keywords
    Anti-Bacterial Agents/pharmacology, Bacterial Proteins/chemistry/genetics, Base Sequence, Humans, Microbial Sensitivity Tests/methods, Molecular Sequence Data, Neisseria meningitidis/*drug effects, Penicillin Resistance, Penicillin-Binding Proteins/chemistry/genetics, Penicillins/*pharmacology, Polymerase Chain Reaction/methods, Sensitivity and Specificity, Sequence Analysis; DNA
    National Category
    Medical and Health Sciences Infectious Medicine
    Research subject
    Infectious Diseases; Medicine
    Identifiers
    urn:nbn:se:oru:diva-3451 (URN)10.1128/AAC.00914-07 (DOI)18070955 (PubMedID)
    Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2017-12-14Bibliographically approved
    3. Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives
    Open this publication in new window or tab >>Antibiotic susceptibility and characteristics of Neisseria meningitidis isolates from the African meningitis belt, 2000 to 2006: phenotypic and genotypic perspectives
    Show others...
    2009 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, no 4, p. 1561-1566Article in journal (Refereed) Published
    Abstract [en]

    Up-to-date information regarding the antibiotic susceptibility of Neisseria meningitidis strains from African countries is highly limited. Our aim was to comprehensively describe the antibiotic susceptibilities of a selection of N. meningitidis isolates recovered between 2000 and 2006 from 18 African countries, mainly those within the meningitis belt. Susceptibilities to 11 antibiotics were determined using Etest for 137 N. meningitidis isolates (stringently selected from 693 available isolates). The isolates were also characterized by serogrouping, multilocus sequence typing, genosubtyping, and penA allele identification. All N. meningitidis isolates were susceptible to ceftriaxone, chloramphenicol, and ciprofloxacin. No isolate produced beta-lactamase. Only three isolates (2%) displayed reduced susceptibility to penicillin G. The two isolates with the highest penicillin G MICs were the only isolates showing reduced susceptibility to ampicillin and cefuroxime. One of these isolates was also resistant to penicillin V. One percent of isolates displayed reduced susceptibility to rifampin, while 52% of the isolates were resistant to tetracycline, 74% were resistant to erythromycin, and 94% were resistant to sulfadiazine. The MICs of rifampin and tetracycline seemed to be associated with the serogroup of the isolates. In total, 18 sequence types (STs), 10 genosubtypes, and 8 different penA alleles were identified; the most common were ST-7, P1.20,9,35-1, and penA4, respectively. A high level of correlation was found between ST, genosubtype, and penA allele. In conclusion, N. meningitidis isolates from the African meningitis belt remain highly susceptible to the antibiotics used. Regarding beta-lactam antibiotics, rare isolates showed a reduced susceptibility to penicillins, but the expanded-spectrum cephalosporins are not affected at present.

    National Category
    Medical and Health Sciences Microbiology in the medical area
    Research subject
    Microbiology; Physiology; Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-8630 (URN)10.1128/AAC.00994-08 (DOI)19188396 (PubMedID)
    Available from: 2009-11-25 Created: 2009-11-23 Last updated: 2018-01-12Bibliographically approved
    4. Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden: the meningococcal population remains susceptible
    Open this publication in new window or tab >>Antibiotic susceptibility of invasive Neisseria meningitidis isolates from 1995 to 2008 in Sweden: the meningococcal population remains susceptible
    2010 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 1, p. 61-64Article in journal (Refereed) Published
    Abstract [en]

    The susceptibility to 7 antibiotics was determined for all Swedish invasive Neisseria meningitidis isolates from 1995 to 2008 (N=717). In general, these remain highly susceptible to the antibiotics recommended for use. Accordingly, penicillin G remains effective for the treatment of invasive meningococcal disease and ciprofloxacin appropriate for prophylaxis.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-8532 (URN)10.3109/00365540903292682 (DOI)000274210500009 ()19883157 (PubMedID)
    Available from: 2009-11-25 Created: 2009-11-12 Last updated: 2018-02-23Bibliographically approved
    5. Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing
    Open this publication in new window or tab >>Defining the breakpoint for resistance to rifampicin in Neisseria meningitidis by rpoB sequencing
    Show others...
    2009 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Clinical isolates of Neisseria meningitidis resistant to rifampicin are important to identify asthey lead to failure of chemoprophylaxis of meningococcal disease. However, theidentification of these isolates is hindered by the absence of a harmonized breakpoint despiteefforts of standardization. In the present study, a large number (n=352) of clinical N.meningitidis isolates from 12 mainly European countries and spanning over 25 years (1984 to2009) were examined. The collection comprised all clinical isolates with MIC 0.25 mg/lreceived by the national reference laboratories for meningococci in the participating countries(n=161). In addition, representative isolates displaying MIC of rifampicin <0.25 mg/l wereexamined (n=191). Phenotyping and genotyping of isolates were performed and a 660 bpDNA fragment of the rpoB gene was sequenced in all the included isolates. Sequencesdiffering by at least one nucleotide were defined as a unique rpoB allele (n=55). Geometricmeans of MIC were calculated for isolates displaying the same allele. All the clinical isolatesdisplaying MIC >1 mg/l of rifampicin possessed rpoB alleles with critical mutations (in total21 alleles), resulting in substitutions at the codon H552 and less frequently at nearby codons(S548 and S557). These alterations were absent in the alleles (n=34) found in all isolates withMIC 1 mg/l. Based on these findings, rifampicin susceptible isolates could be defined asthose with MIC 1 mg/l. A new web site was created based on the data from this work (http://neisseria.org/nm/typing/rpoB). The rifampicin resistant isolates belonged to diversegenetic lineages and provoked lower bacteremia levels in mice. This biological cost mayexplain the non-expansion of the rifampicin resistant isolates.

    National Category
    Medical and Health Sciences
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-8655 (URN)
    Available from: 2009-11-25 Created: 2009-11-25 Last updated: 2017-10-18Bibliographically approved
  • 9.
    Thulin, Sara
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences.
    Total variation in the penA gene of Neisseria meningitidis: correlation between susceptibility to beta-lactam antibiotics and penA gene heterogeneity2006In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 10, p. 3317-3324Article in journal (Refereed)
    Abstract [en]

    In recent decades, the prevalence of Neisseria meningitidis isolates with reduced susceptibility to penicillins has increased. The intermediate resistance to penicillin (Pen(i)) for most strains is due mainly to mosaic structures in the penA gene, encoding penicillin-binding protein 2. In this study, susceptibility to beta-lactam antibiotics was determined for 60 Swedish clinical N. meningitidis isolates and 19 reference strains. The penA gene was sequenced and compared to 237 penA sequences from GenBank in order to explore the total identified variation of penA. The divergent mosaic alleles differed by 3% to 24% compared to those of the designated wild-type penA gene. By studying the final 1,143 to 1,149 bp of penA in a sequence alignment, 130 sequence variants were identified. In a 402-bp alignment of the most variable regions, 84 variants were recognized. Good correlation between elevated MICs and the presence of penA mosaic structures was found especially for penicillin G and ampicillin. The Pen(i) isolates comprised an MIC of >0.094 microg/ml for penicillin G and an MIC of >0.064 microg/ml for ampicillin. Ampicillin was the best antibiotic for precise categorization as Pen(s) or Pen(i). In comparison with the wild-type penA sequence, two specific Pen(i) sites were altered in all except two mosaic penA sequences, which were published in GenBank and no MICs of the corresponding isolates were described. In conclusion, monitoring the relationship between penA sequences and MICs to penicillins is crucial for developing fast and objective methods for susceptibility determination. By studying the penA gene, genotypical determination of susceptibility in culture-negative cases can also be accomplished.

  • 10.
    Titov, Leonid P.
    et al.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Siniuk, Kanstantsin V.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Wollenberg, Kurt K.
    National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda MD, USA.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Thulin Hedberg, Sara
    Örebro University Hospital. Dept Lab Med, Natl Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Glazkova, Slavyana E.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Lebedzeu, Fiodar A.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Nosava, Alena S.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Yanovich, Volcha O.
    Republ Res & Pract Ctr Epidemiol & Microbiol, Minsk, Byelarus.
    Xirasagar, Sadhia
    National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda MD, USA.
    Hurt, Darrell
    National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda MD, USA.
    Huyen, Yentram
    National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda MD, USA.
    Evolutionary epidemiology of Neisseria meningitidis strains in Belarus compared to other European countries2013In: Acta Microbiologica et Immunologica Hungarica, ISSN 1217-8950, Vol. 60, no 4, p. 397-410Article in journal (Refereed)
    Abstract [en]

    Introduction. Meningococcal infections are major causes of death in children globally. In Belarus, the incidence of cases and fatality rate of meningococcal infections are low and comparable to the levels in other European countries. Aim. In the present study, the molecular and epidemiological traits of Neisseria meningitidis strains circulating in Belarus were characterized and compared to isolates from other European countries. Materials and Methods. Twenty N. meningitidis strains isolated from patients (n = 13) and healthy contacts (n = 7) during 2006-2012 in Belarus were selected for multilocus sequence typing (MLST), genosubtyping and FetA typing. The STs of the Belarusian strains were phylogenetically compared to the STs of 110 selected strains from 22 other European countries. Results. Overall, eleven different genosubtypes were observed, there were seven variants of variable region of the fetA gene detected. The majority of the STs (95%) found in Belarus were novel and all those were submitted to the Neisseria MLST database for assignment. Several newly discovered alleles of fumC (allele 451) and gdh (allele 560 and 621) appeared to be descendants of alleles which are widespread in Europe, and single aroE alleles (602 and 603) occurred as a result of separate evolution. Conclusions. N. meningitidis strains circulating in Belarus are heterogeneous and include sequence types, possibly, locally evolved in Belarus as well as representatives of widespread European hyperinvasive clonal complexes.

  • 11.
    Törös, B.
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Thulin [Hedberg], Sara
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Olcén, P.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology/Molecular diagnostics R&D, Örebro University Hospital, Örebro, Sweden.
    Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 20122014In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 19, no 42, p. 25-33, article id UNSP 20940Article in journal (Refereed)
    Abstract [en]

    An increase of invasive meningococcal disease caused by Neisseria meningitidis serogroup Y has been noted in Sweden since 2005, and to a lower extent throughout Europe. The present study describes the epidemiology of invasive N. meningitidis isolates in Sweden in the period between 2010 and 2012, with a focus on serogroup Y. We also aimed to find an optimal molecular typing scheme for both surveillance and outbreak investigations. All invasive N. meningitidis isolates in Sweden during the study period (n=208) were genetically characterised. Serogroup Y predominated with 22/57, 31/61 and 44/90 of all invasive isolates (incidence 0.23, 0.33 and 0.46 per 100,000 population) in 2010, 2011 and 2012 respectively. In each of these years, 15/22, 22/31 and 19/44 of serogroup Y isolates were genetically clonal (Y: P1.5-2,10-1,36-2: F4-1: ST-23(cc23), 'porB allele 3-36, fHbp allele 25 and penA allele 22). Our findings further support those of others that currently recommended FetA typing could be replaced by FHbp. Moreover, in line with a previous study that we conducted, the current results indicate that highly variable multilocus variable-number tandem repeat analysis (HV-MLVA) can be used as a first-hand rapid method for small outbreak investigations.

  • 12.
    Törös, Bianca
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara Thulin
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Evaluation of molecular typing methods for identification of outbreak-associated Neisseria meningitidis isolates2013In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 6, p. 503-510Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Törös, Bianca
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara [Thulin]
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Olcén, Per
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Surveillance of invasive Neisseria meningitidis with a serogroup Y update, Sweden 2010 to 2012Manuscript (preprint) (Other academic)
    Abstract [en]

    As previously described in this journal, an increase of invasive meningococcal disease caused by Neisseria meningitidis serogroup Y has been noted in Sweden, and to a lower extent throughout Europe. In the present study, we aimed to describe the current epidemiology of invasive N. meningitidis isolates in Sweden, with focus on the still increasing serogroup Y, and to find an optimal molecular typing scheme for both surveillance and outbreak investigations.

    All invasive N. meningitidis isolates in Sweden from 2010 to 2012 (n=208) were genetically characterized.

    The predominant serogroup in Sweden is still serogroup Y, in 2010, 2011 and 2012 corresponding to 22/57, 31/61 and 44/90of all invasive isolates (incidence 0.23, 0.33 and 0.46 per 100,000 population). Of the serogroup Y isolates in 2010, 2011 and 2012: 15/22, 23/32 and 19/44 were genetically clonal (Y: P1.5-2,10-1,36-2: F4-1: ST-23 (cc23), ‘porB allele 3- 36, fHbp allele 25 and penA allele 22), respectively. Our findings further support those of others that currently recommended FetA typing could be replaced by FHbp. Moreover, in line with our previous study, the current results indicate that highly variable multiple-locus variable number tandem repeat analysis (HV-MLVA) can be used as a first-hand rapid method for small outbreak investigations.

  • 14.
    Törös, Bianca
    et al.
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hedberg, Sara Thulin
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hill, Dorothea M. C.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Olcén, Per
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Bratcher, Holly B.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Jolley, Keith A.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Maiden, Martin C. J.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Mölling, Paula
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Genome-based characterization of emergent invasive Neisseria meningitidis serogroup Y isolates in Sweden from 1995 to 20122015In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 53, no 7, p. 2154-2162Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Törös, Bianca
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hedberg, Sara [Thulin]
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hill, Dorothea M.C.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Olcén, Per
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fredlund, Hans
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Bratcher, Holly B.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Jolley, Keith A.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Maiden, Martin C.J.
    Department of Zoology, University of Oxford, Oxford, United Kingdom.
    Mölling, Paula
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Whole-genome characterization of emergent invasive Neisseria meningitidis serogroup Y in Sweden from the two recent decadesManuscript (preprint) (Other academic)
    Abstract [en]

    Background and Objective: Invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup Y has increased in Europe, especially in Scandinavia. In Sweden, serogroup Y is the dominating serogroup and in 2012 the serogroup Y disease incidence was 0.46/100,000 population. We have previously shown that a strain type belonging to ST-23 is responsible for the emergence of this serogroup in Sweden. The objective of this study was to compare the meningococcal population structure and phylogeography of Swedish invasive serogroup Y strains to other countries with different disease incidence.

    Materials and Methods: Whole-genome sequencing was performed on invasive serogroup Y isolates from 1995 to 2012 in Sweden (n=186). A comparison of serogroup Y isolates was performed using a collection of isolates from England, Wales and Northern Ireland (n=143), which has relatively low incidence, and two isolates from the USA, where serogroup Y remains one of the major causes of IMD.

    Results: The meningococcal population structures were similar in the investigated regions; however, different strain types were dominating in each geographic region. A number of genes, known or hypothesized to have an impact on meningococcal virulence, were shown to be associated with different strain types and subtypes.

    Conclusions: The emergence of serogroup Y is most likely not associated with a previously described strain type that has been introduced into the Swedish meningococcal population. The reasons for the disease increase are most probably multifactorial; both increased virulence and host adaptive immunity influence infection and transmission. Future genomewide association studies could reveal additional genes associated with serogroup Y meningococcal disease.

  • 16.
    Unemo, Magnus
    et al.
    Örebro University, School of Health and Medical Sciences.
    Olcén, Per
    Örebro University, School of Health and Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences.
    Hedberg, Sara Thulin
    Örebro University, School of Health and Medical Sciences.
    Real-time PCR and subsequent pyrosequencing for screening of penA mosaic alleles and prediction of reduced susceptibility to expanded-spectrum cephalosporins in Neisseria gonorrhoeae2008In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 116, no 11, p. 1004-1008Article in journal (Refereed)
1 - 16 of 16
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