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  • 1.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3737-3744Article in journal (Refereed)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 2.
    Berglund, Carolina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Ito, Teruyo
    Ikeda, Megumi
    Ma, Xiao Xue
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences.
    Hiramatsu, Keiichi
    Novel type of staphylococcal cassette chromosome mec in a methicillin-resistant Staphylococcus aureus strain isolated in Sweden2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 10, p. 3512-3516Article in journal (Refereed)
    Abstract [en]

    We identified a novel type of staphylococcal cassette chromosome mec (SCCmec) element carried by methicillin-resistant Staphylococcus aureus (MRSA) strain JCSC6082 isolated in Sweden. The SCCmec element was demarcated by characteristic nucleotide sequences at both ends and was integrated at the 3' end of orfX. The element carried a novel combination of a type 5 ccr gene complex and class C1 mec gene complex. The J regions of the element were homologous to those of the SCCmercury element of S. aureus strain 85/2082, with nucleotide identity greater than 99%. However, the novel SCCmec element from JCSC6082 did not carry the mer operon nor Tn554, suggesting that evolution to SCCmec could have been from a common ancestor by acquisition of the class C1 mec gene complex. The novel SCCmec element from JCSC6082 was flanked by a novel SCC-like chromosome cassette (CC6082), which was demarcated by two direct repeats and could be excised from the chromosome independently of the SCCmec element. Our data suggest that novel SCCmec elements can be generated on the staphylococcal chromosome through the recombination between extant SCC elements and mec gene complexes.

  • 3.
    Connolly, Kristie L.
    et al.
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
    Eakin, Ann E.
    Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
    Gomez, Carolina
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States.
    Osborn, Blaire L.
    Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, United States.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine, Clinical Microbiology.
    Jerse, Ann E.
    Department of Microbiology and Immunology, Uniformed Services University of Health Sciences, Bethesda, MD, United States .
    Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 63, no 3, article id e01644-18Article in journal (Refereed)
    Abstract [en]

    There is a pressing need for drug development for gonorrhea. Here we describe pharmacokinetics/pharmacodynamics (PK/PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. PK determined in uninfected mice displayed a clear dose response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESCS strain FA1090 were 5 mg/kg (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (time of free drug above the MIC, fTMIC) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against the ESCR strain H041. However, fractionation (TIDq8h) of a 120 mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤ 50% of mice with therapeutic times estimated from single-dose PK data, of 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships in mice reflected that observed in humans with in vivo efficacy against an ESCS strain requiring doses that yielded an fTMIC in excess of 20-24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCR strain and were useful in designing effective dosing regimens.

  • 4.
    Fouhy, Fiona
    et al.
    Teagasc Food Research Centre, Fermoy, Ireland; Microbiology Department, University College Cork, Cork, Ireland .
    Guinane, Caitriona M.
    Teagasc Food Research Centre, Fermoy, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    Hussey, Seamus
    Department of Paediatrics and Child Health, University College Cork, Cork, Ireland; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, Toronto ON, Canada.
    Wall, Rebecca
    Teagasc Food Research Centre, Fermoy, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    Ryan, C. Anthony
    Department of Paediatrics and Child Health, University College Cork, Cork, Ireland .
    Dempsey, Eugene M.
    Department of Paediatrics and Child Health, University College Cork, Cork, Ireland; Department of Neonatology, Cork University Maternity Hospital, Cork, Ireland.
    Murphy, Brendan
    Department of Paediatrics and Child Health, University College Cork, Cork, Ireland .
    Ross, R. Paul
    Teagasc Food Research Centre, Fermoy, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    Fitzgerald, Gerald F
    Microbiology Department, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    Stanton, Catherine
    Teagasc Food Research Centre, Fermoy, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    Cotter, Paul D.
    Teagasc Food Research Centre, Fermoy, Ireland; Alimentary Pharmabiotic Centre, Cork, Ireland.
    High-throughput sequencing reveals the incomplete, short-term recovery of infant gut microbiota following parenteral antibiotic treatment with ampicillin and gentamicin2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5811-5820Article in journal (Refereed)
    Abstract [en]

    The infant gut microbiota undergoes dramatic changes during the first 2 years of life. The acquisition and development of this population can be influenced by numerous factors, and antibiotic treatment has been suggested as one of the most significant. Despite this, however, there have been relatively few studies which have investigated the short-term recovery of the infant gut microbiota following antibiotic treatment. The aim of this study was to use high-throughput sequencing (employing both 16S rRNA and rpoB-specific primers) and quantitative PCR to compare the gut microbiota of nine infants who underwent parenteral antibiotic treatment with ampicillin and gentamicin (within 48 h of birth), 4 and 8 weeks after the conclusion of treatment, relative to that of nine matched healthy controls. The investigation revealed that the gut microbiota of the antibiotic-treated infants had significantly higher proportions of Proteobacteria (P = 0.0049) and significantly lower proportions of Actinobacteria (P = 0.00001) (and the associated genus Bifidobacterium [P = 0.0132]) as well as the genus Lactobacillus (P = 0.0182) than the untreated controls 4 weeks after the cessation of treatment. By week 8, the Proteobacteria levels remained significantly higher in the treated infants (P = 0.0049), but the Actinobacteria, Bifidobacterium, and Lactobacillus levels had recovered and were similar to those in the control samples. Despite this recovery of total Bifidobacterium numbers, rpoB-targeted pyrosequencing revealed that the number of different Bifidobacterium species present in the antibiotic-treated infants was reduced. It is thus apparent that the combined use of ampicillin and gentamicin in early life can have significant effects on the evolution of the infant gut microbiota, the long-term health implications of which remain unknown.

  • 5.
    Golparian, Daniel
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige; Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Fernandes, Prabhavathi
    Cempra Pharmaceuticals, Inc., Chapel Hill NC, United States.
    Ohnishi, Makoto
    National Institute of Infectious Diseases, Tokyo, Japan.
    Jensen, Jörgen S
    Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sverige.
    In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical Neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea?2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 5, p. 2739-2742Article in journal (Refereed)
    Abstract [en]

    Gonorrhea may become untreatable, and new treatment options are essential. We investigated the in vitro activity of the first fluoroketolide, solithromycin. Clinical Neisseria gonorrhoeae isolates and reference strains (n = 246), including the two extensively drug-resistant strains H041 and F89 and additional isolates with clinical cephalosporin resistance and multidrug resistance, were examined. The activity of solithromycin was mainly superior to that of other antimicrobials (n = 10) currently or previously recommended for gonorrhea treatment. Solithromycin might be an effective treatment option for gonorrhea.

  • 6.
    Golparian, Daniel
    et al.
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Shafer, William M.
    Department of Microbiology and Immunology, School of Medicine, Emory University, Atlanta GA, United States; Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur GA, United States.
    Ohnishi, Makoto
    National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Importance of Multidrug Efflux Pumps in the Antimicrobial Resistance Property of Clinical Multidrug-Resistant Isolates of Neisseria gonorrhoeae2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 6, p. 3556-3559Article in journal (Refereed)
    Abstract [en]

    The contribution of drug efflux pumps in clinical isolates of Neisseria gonorrhoeae that express extensively drug-resistant or multidrug-resistant phenotypes has heretofore not been examined. Accordingly, we assessed the effect on antimicrobial resistance of loss of the three gonococcal efflux pumps associated with a known capacity to export antimicrobials (MtrC-MtrD-MtrE, MacA-MacB, and NorM) in such clinical isolates. We report that the MIC of several antimicrobials, including seven previously and currently recommended for treatment was significantly impacted.

  • 7.
    Goswami, Manish
    et al.
    Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India; The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden .
    Subramanian, Mahesh
    Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India.
    Kumar, Ranjeet
    The Life Science Center, School of Science and Technology, Örebro University, Örebro, Sweden.
    Jass, Jana
    Örebro University, School of Science and Technology. The Life Science Center.
    Jawali, Narendra
    Molecular Biology Division, Bhabha Atomic Research Centre, Mumbai, India.
    Involvement of Antibiotic Efflux Machinery in Glutathione-Mediated Decreased Ciprofloxacin Activity in Escherichia coli2016In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 60, no 7, p. 4369-4374Article in journal (Refereed)
    Abstract [en]

    We have analyzed the contribution of different efflux components to glutathione-mediated abrogation of ciprofloxacin's activity in Escherichia coli and the underlying potential mechanism(s) behind this phenomenon. The results indicated that glutathione increased the total active efflux, thereby partially contributing to glutathione-mediated neutralization of ciprofloxacin's antibacterial action in E. coli However, the role of glutathione-mediated increased efflux becomes evident in the absence of a functional TolC-AcrAB efflux pump.

  • 8.
    Hauser, Christoph
    et al.
    Dept Infect Dis, Univ Hosp Bern, Bern, Switzerland; Univ Bern, Bern, Switzerland; Inst Infect Dis, Univ Bern, Bern, Switzerland.
    Hirzberger, Lea
    Dept Infect Dis, Univ Hosp Bern, Bern, Switzerland; Univ Bern, Bern, Switzerland.
    Unemo, Magnus
    Örebro University Hospital.
    Furrer, Hansjakob
    Dept Infect Dis, Univ Hosp Bern, Bern, Switzerland; Univ Bern, Bern, Switzerland.
    Endimiani, Andrea
    Inst Infect Dis, Univ Bern, Bern, Switzerland.
    In Vitro Activity of Fosfomycin Alone and in Combination with Ceftriaxone or Azithromycin against Clinical Neisseria gonorrhoeae Isolates2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 3, p. 1610-1616Article in journal (Refereed)
    Abstract [en]

    New therapeutic strategies are needed to combat the emergence of infections due to multidrug-resistant Neisseria gonorrhoeae. In this study, fosfomycin (FOS) was tested against 89 Neisseria gonorrhoeae isolates using the Etest method, showing MIC50/MIC(90)s of only 8/16 mu g/ml (range, <= 1 to 32 mu g/ml). FOS in combination with ceftriaxone (CRO) or azithromycin (AZT) was then evaluated using the checkerboard method for eight strains, including Neisseria gonorrhoeae F89 (CRO-resistant) and AZT-HLR (high-level AZT-resistant). All combinations that included FOS gave indifferent effects (fractional inhibitory concentration [FIC] index values, 1.2 to 2.3 for FOS plus CRO, 1.8 to 3.2 for FOS plus AZT). Time-kill experiments for FOS, CRO, AZT, and their combinations (at 0.5x, 1x, 2x, and 4x the MIC) were performed against Neisseria gonorrhoeae strain ATCC 49226, one Neisseria gonorrhoeae multi-antigen sequence typing (NG-MAST) sequence type 1407 (ST1407) strain, F89, and AZT-HLR. For all strains, at 24 h, the results indicated that (i) FOS was bactericidal at 2X the MIC, but after >24 h, there was regrowth of bacteria; (ii) CRO was bactericidal at 0.5x the MIC; (iii) AZT was bactericidal at 4x the MIC; (iv) CRO plus AZT was less bactericidal than was CRO alone; (v) FOS plus AZT was bactericidal at 2x the MIC; and (vi) CRO plus AZT and FOS plus CRO were both bactericidal at 0.5x the MIC, but FOS plus CRO had more rapid effects. FOS is appealing for use in the management of Neisseria gonorrhoeae infections because of its single and oral formulation. However, our results suggest it be used in combination with CRO. After the appropriate clinical trials are conducted, this strategy could be implemented for the treatment of infections due to isolates possessing resistance to CRO and/or AZT.

  • 9.
    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.

  • 10.
    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.

  • 11.
    Hess, David
    et al.
    Department of Biology, Santa Clara University, Santa Clara CA, United States.
    Wu, Abel
    San Francisco Public Health Laboratory, San Francisco CA, United States.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.
    Esmaili, Sarah
    Department of Biology, Santa Clara University, Santa Clara CA, United States.
    Pandori, Will
    Department of Biology, Santa Clara University, Santa Clara CA, United States.
    Sena, Emilee
    Department of Biology, Santa Clara University, Santa Clara CA, United States.
    Klausner, Jeffrey D.
    Division of Infectious Diseases, David Geffen School of Medicine, University of California, Los Angeles CA, United States.
    Barry, Pennan
    San Francisco Department of Public Health, San Francisco CA, United States.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University Hospital, Örebro, Sweden.
    Pandori, Mark
    San Francisco Public Health Laboratory, San Francisco CA, United States.
    Genome Sequencing of a Neisseria gonorrhoeae Isolate of a Successful International Clone with Decreased Susceptibility and Resistance to Extended-Spectrum Cephalosporins2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 11, p. 5633-5641Article in journal (Refereed)
  • 12.
    Heymans, Raymond
    et al.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, The Netherlands.
    Bruisten, Sylvia M.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, Netherlands; Department of Experimental Virology, University of Amsterdam, Amsterdam, The Netherlands.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Unemo, Magnus
    Örebro University Hospital. Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    de Vries, Henry J. C.
    STI Outpatient Clinic, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, Netherlands; Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands; Department of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
    van Dam, Alje P.
    Public Health Laboratory, Cluster of Infectious Diseases, Health Service of Amsterdam, Amsterdam, Netherlands; Department of Medical Microbiology, Onze Lieve Vrouwe Gasthuis General Hospital, Amsterdam, The Netherlands.
    Clonally Related Neisseria gonorrhoeae Isolates with Decreased Susceptibility to the Extended-Spectrum Cephalosporin Cefotaxime in Amsterdam, the Netherlands2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 3, p. 1516-1522Article in journal (Refereed)
    Abstract [en]

    From 2006 to 2008, Neisseria gonorrhoeae isolates were identified with decreased susceptibility to the extended-spectrum cephalosporin (ESC) cefotaxime among visitors of the Amsterdam sexually transmitted infections (STI) clinic, the Netherlands. Spread, clonality, and characteristics of 202 isolates were examined using antibiograms, conventional penA mosaic gene PCR, and N. gonorrhoeae multiple-locus variable-number tandem repeat analysis (NG-MLVA). A strictly defined subset was further characterized by N. gonorrhoeae multiantigen sequence typing (NG-MAST) and sequencing of ESC resistance determinants (penA, mtrR, and porB1b). Seventy-four N. gonorrhoeae isolates with a cefotaxime MIC of >0.125 mu g/ml (group A), 54 with a cefotaxime MIC of 0.125 mu g/ml (group B), and a control group of 74 with a cefotaxime MIC of <0.125 mu g/ml (group C) were included. Fifty-three clonally related penA mosaic-positive isolates (penicillin-binding protein 2 type XXXIV) were identified in group A (n = 47 isolates; 64%) and B (n = 6 isolates; 11%). The 53 penA mosaic-positive isolates were predominantly NG-MAST ST1407 (87%) and contained an mtrR promoter A deletion (98%) and porB1b alterations G101K/A102N. All were assigned to the same NG-MLVA cluster that comprised in total 56 isolates. A correlation was found between decreased cefotaxime susceptibility and ST1407 that was highly prevalent among visitors of the Amsterdam STI clinic. The rapid spread of this strain, which also has been identified in many other countries, might be facilitated by high-risk sexual behavior and should be monitored closely to identify potential treatment failure. Quality-assured surveillance of ESC susceptibility on the national and international levels and exploration of new drugs and/or strategies for treatment of gonorrhea are crucial.

  • 13.
    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.

  • 14. International Working Group on the Classification of Staphylococcal Cassette Chromosome Elements, (IWG-SCC)
    et al.
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences.
    Classification of staphylococcal cassette chromosome mec (SCCmec): guidelines for reporting novel SCCmec elements.2009In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 53, no 12, p. 4961-4967Article in journal (Refereed)
  • 15.
    Ito, Teruyo
    et al.
    Dept Bacteriol, Juntendo Univ, Tokyo, Japan .
    Hiramatsu, Keiichi
    Rockefeller University, New York NY, USA .
    Tomasz, Alexander
    Rockefeller University, New York NY, USA .
    de Lencastre, Herminia
    Rockefeller University, New York NY, USA; Inst Tecnol Quim & Biol, University Nova Lisboa, Oeiras, Portugal.
    Perreten, Vincent
    Inst Vet Bacteriol, University Bern, Bern, Switzerland.
    Holden, Matthew T. G.
    Wellcome Trust Sanger Inst, Hinxton, England.
    Coleman, David C.
    Dublin Dent University Hospital, Univ Dublin, Dublin, Ireland; Trinity College, Dublin, Ireland.
    Goering, Richard
    Medical Center, University of Nebraska, Omaha NE, USA.
    Giffard, Philip M.
    Menzies School of Heallth Research, Darwin NT, Australia.
    Skov, Robert L.
    Statens Serum Institut, Copenhagen, Denmark .
    Zhang, Kunyan
    Univ Calgary, Calgary AB, Canada.
    Westh, Henrik
    Faculty of Health, Copenhagen University, Copenhagen, Denmark; Hvidovre Hospital, Copenhagen University, Copenhagen, Denmark.
    O'Brien, Frances
    Curtin Univ Technol, Perth WA, Australia.
    Tenover, Fred C.
    Cepheid, Sunnyvale CA, USA.
    Oliveira, Duarte C.
    Inst Tecnol Quim & Biol, University Nova Lisboa, Oeiras, Portugal; Faculty of Ciencias & Tecnol, Dept Life Sciences, CREM, University Nova Lisboa, Caparica, Portugal .
    Boyle-Vavra, Susan
    Faculty of Ciencias & Tecnol, Dept Life Sciences, CREM, University Nova Lisboa, Caparica, Portugal .
    Laurent, Frederic
    French Natl Reference Ctr Staphylococci, Hosp Civils Lyon, Lyon, France.
    Kearns, Angela M.
    Staphylococcus Reference Unit, Heallth Protecttion Agency, London, England.
    Kreiswirth, Barry
    Pubicl Health Research Institute, New York NY, USA .
    Ko, Kwan Soo
    School of Medicine, Sungkyunkwan University, Seoul, South Korea .
    Grundmann, Hajo
    Nationall Insitute of Public Health & Environment, Utrecht, Netherlands .
    Sollid, Johanna E.
    Tromsø University, Tromsø, Norway .
    John, Joseph F. Jr.
    Ralph H Johnson VA Med Ctr, Charleston SC, USA.
    Daum, Robert
    University of Chicago, Chicago IL, USA.
    Söderquist, Bo
    Örebro University, School of Medicine, Örebro University, Sweden.
    Buist, Girbe
    Guidelines for Reporting Novel mecA Gene Homologues2012In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 56, no 10, p. 4997-4999Article in journal (Other academic)
  • 16.
    Jacobsson, Susanne
    et al.
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Alm, Richard A.
    Infection IMed, AstraZeneca RandD Boston, Waltham MA, United States.
    Huband, Michael
    Infection IMed, AstraZeneca RandD Boston, Waltham MA, United States.
    Mueller, John
    Infection IMed, AstraZeneca RandD Boston, Waltham MA, United States.
    Jensen, Jorgen Skov
    Statens Serum Institut, Copenhagen, Denmark.
    Ohnishi, Makoto
    National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    Örebro University Hospital. National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    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 Gonorrhea2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 9, p. 5585-5588Article in journal (Refereed)
    Abstract [en]

    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.

  • 17.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Kularatne, Ranmini
    Centre for HIV & STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
    Kittiyaowamarn, Rossaphorn
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Maseko, Venessa
    Centre for HIV & STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
    Paopang, Porntip
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sangprasert, Pongsathorn
    Bangrak STI Center, Bureau of AIDs TB and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sirivongrangson, Pachara
    Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Piddock, Laura
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Wi, Teodora
    Department of Reproductive Health, World Health Organization, Geneva, Switzerland.
    Alirol, Emilie
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    isolates from Thailand (2018) and South Africa (2015-2017)2019In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, article id AAC.01479-19Article in journal (Refereed)
    Abstract [en]

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

  • 18.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Faculty of Medicine and Health, , Örebro University Hospital, Örebro, Sweden.
    Paukner, Susanne
    Nabriva Therapeutics AG, Vienna, Austria.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Jensen, Jörgen S.
    Department of Microbiology and Infection Control, Sexually Transmitted Infections, Research and Development, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    In Vitro Activity of the Novel Pleuromutilin Lefamulin (BC-3781) and Effect of Efflux Pump Inactivation on Multidrug-Resistant and Extensively Drug-Resistant Neisseria gonorrhoeae2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 11, article id e01497-17Article in journal (Refereed)
    Abstract [en]

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

  • 19.
    Norén, Torbjörn
    et al.
    Örebro University, Department of Clinical Medicine.
    Wullt, M.
    Åkerlund, Thomas
    Bäck, Erik
    Örebro University, Department of Clinical Medicine.
    Odenholt, I.
    Burman, L. G.
    Frequent emergence of resistance in Clostridium difficile during treatment of C-difficile-associated diarrhea with Fusidic acid2006In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 9, p. 3028-3032Article in journal (Refereed)
    Abstract [en]

    Samples from patients with Clostridium difficile-associated diarrhea (CDAD) that were randomized to fusidic acid (n = 59) or metronidazole (n = 55) therapy for 7 days were cultured for Clostridium difficile in feces on days 1, 8 to 13, and 35 to 40. Of the patients who were culture positive only before treatment, 77% (36/47) were permanently cured (no treatment failure and no clinical recurrence), compared to 54% (22/41) of those with persistence of C. difficile at one or both follow-ups (P = 0.03). A similar association between bacterial persistence and a worse outcome of therapy was seen in both treatment groups. Resistance to fusidic acid was found in 1 of 88 pretherapy isolates available, plus in at least 1 subsequent isolate from 55% (11/20) of patients who remained culture-positive after fusidic acid therapy. In 10 of these 11 patients, the resistant follow-up isolate(s) belonged to the same PCR ribotype as the susceptible day 1 isolate, confirming frequent emergence of resistance to fusidic acid during treatment. Despite this, 5 of these 11 patients were permanently cured with fusidic acid, relative to 5 of 9 patients with susceptible C. difficile at follow-up (P = 1.0). None of the 36 PCR ribotypes of C. difficile identified was associated with any particular clinical outcome or emergence of fusidic acid resistance. In conclusion, culture positivity for C. difficile was common after both fusidic acid and metronidazole therapy and was associated with treatment failure or recurrence of CDAD. Development of resistance in C. difficile was frequent in patients given fusidic acid, but it was without apparent negative impact on therapeutic efficacy in the actual CDAD episode.

  • 20.
    Norén, Torbjörn
    et al.
    Örebro University, School of Health and Medical Sciences.
    Åkerlund, T.
    Wullt, M.
    Burman, L. G.
    Unemo, M.
    Mutations in fusA associated with posttherapy fusidic acid resistance in Clostridium difficile2007In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 51, no 5, p. 1840-1843Article in journal (Refereed)
    Abstract [en]

    In silico, we identified fusA (2,067 bp) in Clostridium difficile 630. Sequencing of fusA in posttherapy fusidic acid-resistant C. difficile isolates from 12 patients with C. difficile-associated diarrhea (CDAD) identified fusA mutations, one or two nonsynonymous substitutions, or in one case a deletion of one codon associated with resistance. Five of these mutations have previously been described in fusA of fusidic acid-resistant Staphylococcus aureus, but seven were novel fusA mutations. Fusidic acid monotherapy for CDAD seemed to rapidly select conserved resistant mutants.

  • 21.
    Shimuta, Ken
    et al.
    Natl Inst Infect Dis, Tokyo, Japan.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, WHO Collaborating Ctr Gonorrhoea & Other STIs, Örebro University Hospital, Örebro, Sweden.
    Nakayama, Shu-ichi
    Natl Inst Infect Dis, Tokyo, Japan.
    Morita-Ishihara, Tomoko
    Natl Inst Infect Dis, Tokyo, Japan.
    Dorin, Misato
    Natl Inst Infect Dis, Tokyo, Japan.
    Kawahata, Takuya
    Osaka Prefectural Inst Publ Hlth, Osaka, Japan.
    Ohnishi, Makoto
    Natl Inst Infect Dis, Tokyo, Japan.
    Antimicrobial Resistance and Molecular Typing of Neisseria gonorrhoeae Isolates in Kyoto and Osaka, Japan, 2010 to 2012: Intensified Surveillance after Identification of the First Strain (H041) with High-Level Ceftriaxone Resistance2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 11, p. 5225-5232Article in journal (Refereed)
    Abstract [en]

    In 2009, the first high-level ceftriaxone-resistant Neisseria gonorrhoeae strain (H041) was isolated in Kyoto, Japan. The present study describes an intensified surveillance (antimicrobial resistance and molecular typing) of Neisseria gonorrhoeae isolates in Kyoto and its neighboring prefecture Osaka, Japan, in 2010 to 2012, which was initiated after the identification of H041. From April 2010 to March 2012, 193 N. gonorrhoeae isolates were collected and the MICs (mu g/ml) to six antimicrobials, including ceftriaxone, were determined. All isolates showed susceptibility to ceftriaxone and cefixime (MIC values,< 0.5 mu g/ml), and spectinomycin. The rates of resistance (intermediate susceptibility) to azithromycin, penicillin G, and ciprofloxacin were 3.6% (19.7%), 24.4% (71.0%), and 78.2% (0.5%), respectively. Multilocus sequence typing (MLST) showed that 40.9%, 19.2%, and 17.1% of isolates belonged to ST1901, ST7359, and ST7363, respectively. Furthermore, N. gonorrhoeae multiantigen sequence typing (NG-MAST) revealed that 12 (63%) of the 19 isolates with decreased susceptibility to ceftriaxone (MIC> 0.064 mu g/ml) were of ST1407. NG-MAST ST1407 was also the most prevalent ST (16.1%; 31 of 193 isolates). In those NG-MAST ST1407 strains, several mosaic type penA alleles were found, including SF-A type (penicillin binding protein 2 allele XXXIV) and its derivatives. These were confirmed using transformation of the penA mosaic alleles as critical determinants for enhanced cefixime and ceftriaxone MICs. The intensified surveillance in Kyoto and Osaka, Japan, did not identify any dissemination of the highlevel ceftriaxone-resistant N. gonorrhoeae strain H041, suggesting that H041 might have caused only a sporadic case and has not spread further.

  • 22.
    Sundqvist, Martin
    et al.
    Örebro University Hospital. Department of Clinical Microbiology, Central Hospital, Växjö, Sweden; Department of Medical Sciences, Division of Infectious Diseases, Uppsala University, Uppsala, Uppsala, Sweden; Department of Laboratory Medicine, Clinical Microbiology, University Hospital, Örebro, Sweden.
    Granholm, Susanne
    Dept Clin Microbiol, Lab Mol Infect Med Sweden, Umeå Univ, Umeå, Sweden.
    Naseer, Umaer
    Dept Microbiol & Infect Control, Reference Ctr Detect Antimicrobial Resistance, Univ Hosp North Norway, Tromsø, Norway; Dept Med Biol, Res Grp Host Microbe Interact, Univ Tromsø, Tromsø, Norway.
    Ryden, Patrik
    Dept Math & Math Stat, Umeå Univ, Umeå, Sweden.
    Brolund, Alma
    Publ Hlth Agcy Sweden, Solna, Sweden; Dept Microbiol Tumor & Cell Biol, Karolinska Inst, Stockholm, Sweden.
    Sundsfjord, Arnfinn
    Dept Microbiol & Infect Control, Reference Ctr Detect Antimicrobial Resistance, Univ Hosp North Norway, Tromsø, Norway; Dept Med Biol, Res Grp Host Microbe Interact, Univ Tromsø, Tromsø, Norway.
    Kahlmeter, Gunnar
    Dept Clin Microbiol, Cent Hosp Växjö, Växjö, Sweden; Div Clin Bacteriol, Dept Med Sci, Uppsala Univ, Uppsala, Sweden.
    Johansson, Anders
    Dept Clin Microbiol, Lab Mol Infect Med Sweden, Umeå Univ, Umeå, Sweden.
    Within-Population Distribution of Trimethoprim Resistance in Escherichia coli before and after a Community-Wide Intervention on Trimethoprim Use2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 12, p. 7492-7500Article in journal (Refereed)
    Abstract [en]

    A 2-year prospective intervention on the prescription of trimethoprim reduced the use by 85% in a health care region with 178,000 inhabitants. Here, we performed before-and-after analyses of the within-population distribution of trimethoprim resistance in Escherichia coli. Phylogenetic and population genetic methods were applied to multilocus sequence typing data of 548 consecutively collected E. coli isolates from clinical urinary specimens. Results were analyzed in relation to antibiotic susceptibility and the presence and genomic location of different trimethoprim resistance gene classes. A total of 163 E. coli sequence types (STs) were identified, of which 68 were previously undescribed. The isolates fell into one of three distinct genetic clusters designated BAPS 1 (E. coli phylogroup B2), BAPS 2 (phylogroup A and B1), and BAPS 3 (phylogroup D), each with a similar frequency before and after the intervention. BAPS 2 and BAPS 3 were positively and BAPS 1 was negatively associated with trimethoprim resistance (odds ratios of 1.97, 3.17, and 0.26, respectively). In before-and-after analyses, trimethoprim resistance frequency increased in BAPS 1 and decreased in BAPS 2. Resistance to antibiotics other than trimethoprim increased in BAPS 2. Analysis of the genomic location of different trimethoprim resistance genes in isolates of ST69, ST58, and ST73 identified multiple independent acquisition events in isolates of the same ST. The results show that despite a stable overall resistance frequency in E. coli before and after the intervention, marked within-population changes occurred. A decrease of resistance in one major genetic cluster was masked by a reciprocal increase in another major cluster.

  • 23.
    Thulin, Elisabeth
    et al.
    Dept Med Biochem & Microbiol, Uppsala Univ, Uppsala, Sweden.
    Sundqvist, Martin
    Örebro University Hospital. Lab Med, Clin Microbiol, Örebro University Hospital, Örebro, Sweden.
    Andersson, Dan I.
    Dept Med Biochem & Microbiol, Uppsala Univ, Uppsala, Sweden.
    Amdinocillin (Mecillinam) Resistance Mutations in Clinical Isolates and Laboratory-Selected Mutants of Escherichia coli2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 3, p. 1723-1732Article in journal (Refereed)
    Abstract [en]

    Amdinocillin (mecillinam) is a beta-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates of Escherichia coli and to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 x 10(-8) to 2 x 10(-5) per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. The cysB gene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of the cysB gene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates of E. coli.

  • 24.
    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.

  • 25.
    Tomberg, Joshua
    et al.
    Dept Pharmacol, University of North Carolina,Chapel Hill NC, USA.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, WHO Collaborating Ctr Gonorrhoea & Other STls, Örebro University Hospital, Örebro, Sweden.
    Ohnishi, Makoto
    Natl Inst Infect Dis, Tokyo, Japan.
    Davies, Christopher
    Dept Biochem & Mol Biol, Medical Univ South Carolina, Charleston SC, USA.
    Nicholas, Robert A.
    Dept Pharmacol, University of North Carolina, Chapel Hill NC, USA; Dept Microbiol & Immunol, University of North Carolina,Chapel Hill NC, USA.
    Identification of Amino Acids Conferring High-Level Resistance to Expanded-Spectrum Cephalosporins in the penA Gene from Neisseria gonorrhoeae Strain H0412013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 7, p. 3029-3036Article in journal (Refereed)
    Abstract [en]

    The recent identification of a high-level-ceftriaxone-resistant (MIC = 2 to 4 mu g/ml) isolate of Neisseria gonorrhoeae from Japan (H041) portends the loss of ceftriaxone as an effective treatment for gonococcal infections. This is of grave concern because ceftriaxone is the last remaining option for first-line empirical antimicrobial monotherapy. The penA gene from H041 (penA41) is a mosaic penA allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance (Ceph(i)) worldwide but has 13 additional mutations compared to the mosaic penA gene from the previously studied Ceph(i) strain 35/02 (penA35). When transformed into the wild-type strain FA19, the penA41 allele confers 300- and 570-fold increases in the MICs for ceftriaxone and cefixime, respectively. In order to understand the mechanisms involved in high-level ceftriaxone resistance and to improve surveillance and epidemiology during the potential emergence of ceftriaxone resistance, we sought to identify the minimum number of amino acid alterations above those in penA35 that confer high-level resistance to ceftriaxone. Using restriction fragment exchange and site-directed mutagenesis, we identified three mutations, A311V, T316P, and T483S, that, when incorporated into the mosaic penA35 allele, confer essentially all of the increased resistance of penA41. A311V and T316P are close to the active-site nucleophile Ser310 that forms the acyl-enzyme complex, while Thr483 is predicted to interact with the carboxylate of the beta-lactam antibiotic. These three mutations have thus far been described only for penA41, but dissemination of these mutations in other mosaic alleles would spell the end of ceftriaxone as an effective treatment for gonococcal infections.

  • 26.
    Unemo, Magnus
    et al.
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Hellmark, Bengt
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    First Three Neisseria gonorrhoeae Isolates with High-Level Resistance to Azithromycin in Sweden: a Threat to Currently Available Dual-Antimicrobial Regimens for Treatment of Gonorrhea?2014In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 58, no 1, p. 624-625Article in journal (Refereed)
  • 27.
    Unemo, Magnus
    et al.
    Örebro University Hospital. WHO Collaborating Ctr Gonorrhoea & Other STIs, Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    WHO Collaborating Ctr Gonorrhoea & Other STIs, Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, Örebro University Hospital, Örebro, Sweden.
    Skogen, Vegard
    Dept Infect Dis, Univ Hosp N Norway, Tromsö, Norway; Inst Clin Med, Univ Tromsö, Tromsö, Norway.
    Olsen, Anne Olaug
    Olafiaklin, Oslo Univ Hosp, Oslo, Norway; Inst Clin Med, Univ Oslo, Oslo, Norway.
    Moi, Harald
    Olafiaklin, Oslo Univ Hosp, Oslo, Norway; Inst Clin Med, Univ Oslo, Oslo, Norway.
    Syversen, Gaute
    Dept Microbiol, Oslo Univ Hosp, Oslo, Norway.
    Hjelmevoll, Stig Ove
    Dept Microbiol & Infect Control, Univ Hosp N Norway, Tromsö, Norway.
    Neisseria gonorrhoeae Strain with High-Level Resistance to Spectinomycin Due to a Novel Resistance Mechanism (Mutated Ribosomal Protein S5) Verified in Norway2013In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 57, no 2, p. 1057-1061Article in journal (Refereed)
    Abstract [en]

    Gonorrhea may become untreatable, and new treatment options are essential. Verified resistance to spectinomycin is exceedingly rare. However, we describe a high-level spectinomycin-resistant (MIC, >1,024 mu g/ml) Neisseria gonorrhoeae strain from Norway with a novel resistance mechanism. The resistance determinant was a deletion of codon 27 (valine) and a K28E alteration in the ribosomal protein 5S. The traditional spectinomycin resistance gene (16S rRNA) was wild type. Despite this exceedingly rare finding, spectinomycin available for treatment of ceftriaxone-resistant urogenital gonorrhea would be very valuable.

  • 28.
    Unemo, Magnus
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University Hospital, Örebro, Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Ringlander, Johan
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Wiggins, Catherine
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, United Kingdom.
    Fredlund, Hans
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Örebro University, Örebro Sweden; Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Cole, Michelle
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, United Kingdom.
    High In Vitro Susceptibility to the Novel Spiropyrimidinetrione ETX0914 (AZD0914) among 873 Contemporary Clinical Neisseria gonorrhoeae Isolates from 21 European Countries from 2012 to 20142015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 9, p. 5220-5225Article in journal (Refereed)
    Abstract [en]

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

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