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  • 1.
    Al Janabi, Jasmina
    et al.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Tevell, Staffan
    Örebro University, School of Medical Sciences. Department of Infectious Diseases, Karlstad Hospital and Centre for Clinical Research and Education, Region Värmland, Karlstad, Sweden.
    Sieber, Raphael Niklaus
    Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Stegger, Marc
    Örebro University, School of Medical Sciences. Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Emerging resistance in Staphylococcus epidermidis during dalbavancin exposure: a case report and in vitro analysis of isolates from prosthetic joint infections2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 3, p. 669-677Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dalbavancin, a semisynthetic lipoglycopeptide with exceptionally long half-life and Gram-positive spectrum, is an attractive option for infections requiring prolonged therapy, including prosthetic joint infections (PJIs).

    OBJECTIVES: To investigate the prevalence of reduced susceptibility to dalbavancin in a strain collection of Staphylococcus epidermidis from PJIs, and to investigate genomic variation in isolates with reduced susceptibility selected during growth under dalbavancin exposure.

    METHODS: MIC determination was performed on S. epidermidis isolates from a strain collection (n = 64) and from one patient with emerging resistance during treatment (n = 4). These isolates were subsequently cultured on dalbavancin-containing agar and evaluated at 48 h; MIC determination was repeated if phenotypical heterogeneity was detected during growth. Population analysis profile (PAP-AUC) was performed in isolates where a  ≥ 2-fold increase in MIC was detected, together with corresponding parental isolates (n = 21). Finally, WGS was performed.

    RESULTS: All strains grew at 48 h on agar containing 0.125 mg/L dalbavancin. PAP-AUC demonstrated significant differences between parental and derived strains in four of the eight analysed groups. An amino acid change in the walK gene coinciding with emergence of phenotypic resistance was detected in the patient isolates, whereas no alterations were found in this region in the in vitro derived strains.

    CONCLUSIONS: Exposure to dalbavancin may lead to reduced susceptibility to dalbavancin through either selection of pre-existing subpopulations, epigenetic changes or spontaneous mutations during antibiotic exposure. Source control combined with adequate antibiotic concentrations may be important to prevent emerging reduced susceptibility during dalbavancin treatment.

  • 2.
    Bala, Manju
    et al.
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Singh, Vikram
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Philipova, Ivva
    WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden; National Reference Laboratory for Mycology and Sexually Transmitted Infections (STIs), National Center of Infections and Parasitic Diseases, Sofia, Bulgaria.
    Bhargava, Aradhana
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Chandra Joshi, Naveen
    Apex Regional STD Teaching, Training & Research Centre, VMMC and Safdarjung Hospital, New Delhi, India.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Gentamicin in vitro activity and tentative gentamicin interpretation criteria for the CLSI and calibrated dichotomous sensitivity disc diffusion methods for Neisseria gonorrhoeae2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 7, p. 1856-1859Article in journal (Refereed)
    Abstract [en]

    Objectives: XDR Neisseria gonorrhoeae imposes the threat of untreatable gonorrhoea. Gentamicin is considered for future treatment; however, no interpretation criteria for the CLSI and calibrated dichotomous sensitivity (CDS) disc diffusion (DD) techniques are available for N. gonorrhoeae. We investigated the in vitro gentamicin activity by MIC and DD methods, proposed DD breakpoints and determined DD ranges for 10 international quality control (QC) strains.

    Methods: Gentamicin susceptibility of 333 N. gonorrhoeae isolates, including 323 clinical isolates and 10 QC strains, was determined. MIC determination (Etest) and DD methods (CLSI and CDS) were performed. The relationship between MIC, inhibition zone diameter and annular radius was determined by linear regression analysis and the correlation coefficient (r) was calculated.

    Results: Gentamicin MICs for the QC strains were within published ranges. Of the 323 clinical isolates, according to published breakpoints 75.9%, 23.5% and 0.6% were susceptible, intermediately susceptible and resistant, respectively. Based on error minimization with MICs of ≤4, 8-16 and ≥32 mg/L, breakpoints proposed are susceptible ≥16 mm, intermediately susceptible 13-15 mm and resistant ≤12 mm for the CLSI method and susceptible ≥6 mm, less susceptible 3-5 mm and resistant ≤2 mm for the CDS technique.

    Conclusions: Low resistance to gentamicin was identified and gentamicin might be a future treatment option for gonorrhoea. Tentative gentamicin zone breakpoints were defined for two DD methods and QC ranges for 10 international reference strains were established. Our findings suggest that in resource-poor settings where MIC testing is not a feasible option, the DD methods can be used to indicate gentamicin resistance.

  • 3.
    Bazzo, M. L.
    et al.
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Golfetto, L.
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Gaspar, P. C.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil.
    Pires, A. F.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil; University of Brasilia Postgraduate Program in Collective Health, Brasilia, Brazil.
    Ramos, M. C.
    Brazilian STD Society, Porto Alegre, Brazil.
    Franchini, M.
    Laboratory Consultant, Brasília, Brazil.
    Ferreira, W. A.
    Alfredo da Mata Foundation, Manaus, Brazil.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Benzaken, A. S.
    Department of Surveillance, Prevention and Control of Sexually Transmitted Infections, HIV/AIDS and Viral Hepatitis, Ministry of Health, Brasilia, Brazil.
    First nationwide antimicrobial susceptibility surveillance for Neisseria gonorrhoeae in Brazil, 2015-162018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 7, p. 1854-1861Article in journal (Refereed)
    Abstract [en]

    Objectives: Gonorrhoea and antimicrobial resistance (AMR) in Neisseria gonorrhoeae are major public health concerns globally. Enhanced AMR surveillance for gonococci is essential worldwide; however, recent quality-assured gonococcal AMR surveillance in Latin America, including Brazil, has been limited. Our aims were to (i) establish the first nationwide gonococcal AMR surveillance, quality assured according to WHO standards, in Brazil, and (ii) describe the antimicrobial susceptibility of clinical gonococcal isolates collected from 2015 to 2016 in all five main regions (seven sentinel sites) of Brazil.

    Methods: Gonococcal isolates from 550 men with urethral discharge were examined for susceptibility to ceftriaxone, cefixime, azithromycin, ciprofloxacin, benzylpenicillin and tetracycline using the agar dilution method, according to CLSI recommendations and quality assured according to WHO standards.

    Results: The levels of resistance (intermediate susceptibility) to tetracycline, ciprofloxacin, benzylpenicillin and azithromycin were 61.6%(34.2%), 55.6%(0.5%), 37.1% (60.4%) and 6.9% (8.9%), respectively. All isolates were susceptible to ceftriaxone and cefixime using the US CLSI breakpoints. However, according to the European EUCAST cefixime breakpoints, 0.2% (n= 1) of isolates were cefixime resistant and 6.9% (n = 38) of isolates had a cefixime MIC bordering on resistance.

    Conclusions: This study describes the first national surveillance of gonococcal AMR in Brazil, which was quality assured according to WHO standards. The high resistance to ciprofloxacin (which promptly informed a revision of the Brazilian sexually transmitted infection treatment guideline), emerging resistance to azithromycin and decreasing susceptibility to extended-spectrum cephalosporins necessitate continuous surveillance of gonococcal AMR and ideally treatment failures, and increased awareness when prescribing treatment in Brazil.

  • 4.
    Berglund, Carolina
    et al.
    Örebro University, School of Health and Medical Sciences.
    Ito, Teruyo
    Ma, Xiao Xue
    Ikeda, Megumi
    Watanabe, Shinya
    Söderquist, Bo
    Örebro University, School of Health and Medical Sciences.
    Hiramatsu, Keiichi
    Genetic diversity of methicillin-resistant Staphylococcus aureus carrying type IV SCCmec in Orebro County and the western region of Sweden2009In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 63, no 1, p. 32-41Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Recent studies have shown a predominance of type IV SCCmec among the methicillin-resistant Staphylococcus aureus (MRSA) isolated in the low endemic areas of Orebro County and the western region of Sweden. However, many of these isolates were not possible to classify as existing subtypes IVa, IVb, IVc or IVd. METHODS: We analysed 16 such MRSA isolates by multilocus sequence typing, spa typing, staphylocoagulase (SC) typing and detection of type IVg and IVh SCCmec. MRSA that remained as unknown type IV SCCmec were investigated by long-range PCR covering the J1 region; however, only two isolates were possible to amplify by PCR. The nucleotide sequences of the entire SCCmec of these two MRSA were determined. In addition, isolates that had unknown SC types were investigated by nucleotide sequencing of the coa genes. RESULTS: Five of 16 isolates were classified as type IVg SCCmec, and four isolates had type IVh SCCmec. Two subtypes of type IV SCCmec shared J1 regions previously identified in other types of SCCmec, types I.2 and II.2. The novel elements were designated as type IVi and IVj SCCmec. In addition, the genetic backgrounds of these Swedish MRSA were diverse and constituted at least nine sequence types and eight SC types, including four new types of SC. CONCLUSIONS: Type IV SCCmec is occurring in heterogeneous clones of MRSA in Sweden, and the majority of the type IV SCCmec were identified in community-acquired MRSA. We describe two novel subtypes of type IV SCCmec with common J1 regions shared by other types of SCCmec, which indicate that J1 regions occurred as primordial SCC.

  • 5.
    Cameron-McDermott, Suzette M.
    et al.
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Barrow, Geoffrey J.
    Department of Medicine, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Webster, Alicia M.
    Comprehensive Health Centre STI Clinic, Kingston, Jamaica.
    De La Haye, Carrington O.
    Comprehensive Health Centre STI Clinic, Kingston, Jamaica.
    Wood, Denise H. E.
    Comprehensive Health Centre STI Clinic, Kingston, Jamaica.
    Lewis, Violet M.
    Comprehensive Health Centre STI Clinic, Kingston, Jamaica.
    Nicholson, Alison
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Reynolds-Campbell, Glendee Y.
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Thoms-Rodriguez, Camille-Ann A.
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Roye-Green, Karen J.
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Otto-Stewart, Nakeisha
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Miller, Zahra N.
    Epidemiology Unit, Ministry of Health and Wellness, Kingston, Jamaica.
    Tomlinson, Jennifer A.
    HIV/STI/TB Unit, Ministry of Health and Wellness, Kingston, Jamaica; Jamaica AIDS Support for Life, Kingston, Jamaica.
    Skyers, Nicola
    HIV/STI/TB Unit, Ministry of Health and Wellness, Kingston, Jamaica.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine.
    Anzinger, Joshua J.
    Department of Microbiology, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica.
    Antimicrobial susceptibility of Neisseria gonorrhoeae isolates and syndromic treatment of men with urethral discharge in Kingston, Jamaica, 2018-192022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 1, p. 218-222Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To quantitatively determine the antimicrobial susceptibility of clinical Neisseria gonorrhoeae isolates from men with urethral discharge in Jamaica and to describe the syndromic treatment therapies administered.

    METHODS: Urethral eSwabs (Copan) were collected from 175 men presenting with urethral discharge to the Comprehensive Health Centre STI Clinic, Kingston, Jamaica. Clinical information was collected and MICs of eight antimicrobials were determined for N. gonorrhoeae isolates (n = 96) using Etest and interpreted using CLSI criteria.

    RESULTS: The median age of the subjects was 28 years (range: 18-73 years) with a median of 2 sexual partners (range: 1-25) per male in the previous 3 months. All examined N. gonorrhoeae isolates were susceptible to ceftriaxone (96/96), azithromycin (91/91), cefixime (91/91) and spectinomycin (91/91). For ciprofloxacin and gentamicin, respectively, 98.9% (91/92) and 91.3% (84/92) of the isolates were susceptible and 1.1% (1/92) and 8.7% (8/92) showed intermediate susceptibility/resistance. For tetracycline and benzylpenicillin, respectively, 38.0% (35/92) and 22.0% (20/91) of the isolates were susceptible, 52.2% (48/92) and 74.7% (68/91) showed intermediate susceptibility/resistance and 9.8% (9/92) and 3.3% (3/91) were resistant. Syndromic treatment was administered as follows: 93.1% received 250 mg of ceftriaxone intramuscularly plus 100 mg of doxycycline orally q12h for 1-2 weeks and 6.9% received 500 mg of ciprofloxacin orally plus 100 mg of doxycycline orally q12h for 1 week.

    CONCLUSIONS: Ceftriaxone (250 mg) remains appropriate for gonorrhoea treatment in the examined population of men in Kingston, Jamaica. Surveillance of N. gonorrhoeae AMR should be expanded in Jamaica and other Caribbean countries to guide evidence-based treatment guidelines.

  • 6.
    Chen, Shao-Chun
    et al.
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Yin, Yue-Ping
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Dai, Xiu-Qin
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    Unemo, Magnus
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Chen, Xiang-Sheng
    National Center for STD Control, Chinese Center for Disease Control and Prevention, and Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, and Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
    First nationwide study regarding ceftriaxone resistance and molecular epidemiology of Neisseria gonorrhoeae in China2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 1, p. 92-99Article in journal (Refereed)
    Abstract [en]

    Objectives: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major public health concern worldwide. This is the first nationwide study, performed within the China Gonococcal Antimicrobial Susceptibility Programme (China-GASP), regarding AMR, including ceftriaxone genetic resistance determinants, and molecular epidemiology of gonococci in China.

    Methods: Gonococcal isolates (naEuroS=aEuroS1257) from consecutive patients were collected at 11 sentinel sites distributed across China during 2012-13. Susceptibility to ceftriaxone, spectinomycin, ciprofloxacin and tetracycline was determined using the agar dilution method. Ceftriaxone resistance determinants penA and penB were examined using sequencing. N. gonorrhoeae multiantigen sequence typing (NG-MAST) was performed for molecular epidemiology.

    Results: Among isolates, 0.2% were resistant to spectinomycin, 4.4% to ceftriaxone, 42.9% to tetracyclines (high-level resistance) and 99.8% to ciprofloxacin. Among 890 sequenced isolates, 16 (1.8%) possessed a penA mosaic allele; 4 of these isolates belonged to the MDR internationally spread NG-MAST genogroup G1407 (first description in China). Non-mosaic penA alleles with an A501T mutation and an A102D alteration in porB1b were statistically associated with decreased susceptibility/resistance to ceftriaxone. NG-MAST G10339, G1424 and G1053 were associated with decreased susceptibility/resistance to ceftriaxone.

    Conclusions: In China, ceftriaxone and spectinomycin can continue to be recommended for gonorrhoea treatment, with the possible exception of Hainan and Sichuan provinces where ceftriaxone resistance exceeded 5% and AMR surveillance needs to be strengthened. Molecular approaches including genotyping and AMR determinant analysis can be valuable to supplement and enhance conventional surveillance of gonococcal AMR in China.

  • 7.
    Cole, Michelle J.
    et al.
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, UK.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Grigorjev, Vlad
    Sexually Transmitted Bacteria Reference Unit, Public Health England, London, UK.
    Quaye, Nerteley
    National Mycobacterium Reference Laboratory, Public Health England, London, UK.
    Woodford, Neil
    Antimicrobial Resistance and Healthcare Associated Infections Reference Unit, Public Health England, London, UK.
    Genetic diversity of bla(TEM) alleles, antimicrobial susceptibility and molecular epidemiological characteristics of penicillinase-producing Neisseria gonorrhoeae from England and Wales2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 12, p. 3238-3243Article in journal (Refereed)
    Abstract [en]

    Objectives: The objective of this study was to investigate the genetic diversity of bla(TEM) alleles, antimicrobial susceptibility and molecular epidemiological characteristics of penicillinase-producing Neisseria gonorrhoeae (PPNG) isolates collected in 2012 from England and Wales.

    Methods: PPNG isolates were from the 2012 Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP). Their susceptibility to seven antimicrobials was determined using agar dilution methodology. beta-Lactamase production was detected using a nitrocefin test. beta-Lactamase plasmid types were determined and bla(TEM) genes were sequenced. Isolates were also typed by N. gonorrhoeae multi-antigen sequence typing (NG-MAST).

    Results: Seventy-three PPNG isolates were identified in the 2012 GRASP collection (4.6%, 73/1603). Three different bla(TEM) alleles were identified, encoding three TEM amino acid sequences: TEM-1 (53%), TEM-1 with a P14S substitution (19%) and TEM-135 (27%). The bla(TEM-135) allele was present in nine different NG-MAST types and was found mostly on Asian (60%) and Toronto/Rio (35%) plasmids. By contrast, most TEM-1-encoding plasmids were African (98%). All the TEM-135 isolates displayed high-level ciprofloxacin and tetracycline resistance.

    Conclusions: The high proportion of bla(TEM-135) alleles (27%) demonstrates that this variant is circulating within several gonococcal lineages. Only a single specific mutation near the beta-lactamase active site could result in TEM-135 evolving into an ESBL. This is concerning particularly because the TEM-135 isolates were associated with high-level ciprofloxacin and tetracycline resistance. It is encouraging that no further TEM alleles were detected in this gonococcal population; however, vigilance is vital as an ESBL in N. gonorrhoeae would render the last remaining option for monotherapy, ceftriaxone, useless.

  • 8.
    Foerster, Sunniva
    et al.
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland; WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University, Örebro, Sweden; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
    Desilvestro, Valentino
    World Trade Institute (WTI), University of Bern, Bern, Switzerland.
    Hathaway, Lucy J
    Institute for Infectious Diseases, University of Bern, Bern, Switzerland.
    Althaus, Christian L
    Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Örebro University Hospital, Örebro, Sweden.
    A new rapid resazurin-based microdilution assay for antimicrobial susceptibility testing of Neisseria gonorrhoeae2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 7, p. 1961-1968Article in journal (Refereed)
    Abstract [en]

    Objectives: Rapid, cost-effective and objective methods for antimicrobial susceptibility testing of Neisseria gonorrhoeae would greatly enhance surveillance of antimicrobial resistance. Etest, disc diffusion and agar dilution methods are subjective, mostly laborious for large-scale testing and take ∼24 h. We aimed to develop a rapid broth microdilution assay using resazurin (blue), which is converted into resorufin (pink fluorescence) in the presence of viable bacteria.

    Methods: The resazurin-based broth microdilution assay was established using 132 N. gonorrhoeae strains and the antimicrobials ceftriaxone, cefixime, azithromycin, spectinomycin, ciprofloxacin, tetracycline and penicillin. A regression model was used to estimate the MICs. Assay results were obtained in ∼7.5 h.

    Results: The EC 50 of the dose-response curves correlated well with Etest MIC values (Pearson's r  = 0.93). Minor errors resulting from misclassifications of intermediate strains were found for 9% of the samples. Major errors (susceptible strains misclassified as resistant) occurred for ceftriaxone (4.6%), cefixime (3.3%), azithromycin (0.6%) and tetracycline (0.2%). Only one very major error was found (a ceftriaxone-resistant strain misclassified as susceptible). Overall the sensitivity of the assay was 97.1% (95% CI 95.2-98.4) and the specificity 78.5% (95% CI 74.5-82.9).

    Conclusions: A rapid, objective, high-throughput, quantitative and cost-effective broth microdilution assay was established for gonococci. For use in routine diagnostics without confirmatory testing, the specificity might remain suboptimal for ceftriaxone and cefixime. However, the assay is an effective low-cost method to evaluate novel antimicrobials and for high-throughput screening, and expands the currently available methodologies for surveillance of antimicrobial resistance in gonococci.

  • 9.
    Foerster, Sunniva
    et al.
    WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Drusano, George
    Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, FL, USA.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other STIs, Swedish Reference Laboratory for STIs.
    Neely, Michael
    Children's Hospital of Los Angeles, Department of Pediatrics, Division of Infectious Diseases, University of Southern California, CA, USA.
    Piddock, Laura J. V.
    Global Antibiotic Research & Development Partnership (GARDP), 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, Swedish Reference Laboratory for STIs.
    In vitro antimicrobial combination testing of and evolution of resistance to the first-in-class spiropyrimidinetrione zoliflodacin combined with six therapeutically relevant antimicrobials for Neisseria gonorrhoeae2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 12, p. 3521-3529Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Resistance in Neisseria gonorrhoeae to all gonorrhoea therapeutic antimicrobials has emerged. Novel therapeutic antimicrobials are imperative and the first-in-class spiropyrimidinetrione zoliflodacin appears promising. Zoliflodacin could be introduced in dual antimicrobial therapies to prevent the emergence and/or spread of resistance. We investigated the in vitro activity of and selection of resistance to zoliflodacin alone and in combination with six gonorrhoea therapeutic antimicrobials against N. gonorrhoeae.

    METHODS: The international gonococcal reference strains WHO F (WT) and WHO O, WHO V and WHO X (strains with different AMR profiles) were examined. Zoliflodacin was evaluated alone or combined with ceftriaxone, cefixime, spectinomycin, gentamicin, tetracycline, cethromycin or sitafloxacin in chequerboard assays, time-kill curve analysis and selection-of-resistance studies.

    RESULTS: Zoliflodacin alone or in combination with all six antimicrobials showed rapid growth inhibition against all examined strains. The time-kill curve analysis indicated that tetracycline or cethromycin combined with zoliflodacin can significantly decrease the zoliflodacin kill rate in vitro. The frequency of selected zoliflodacin-resistance mutations was low when evaluated as a single agent and further reduced for all antimicrobial combinations. All resistant mutants contained the GyrB mutations D429N, K450T or K450N, resulting in zoliflodacin MICs of 0.5-4 mg/L.

    CONCLUSIONS: Zoliflodacin, alone or in combination with sexually transmitted infection therapeutic antimicrobials, rapidly kills gonococci with infrequent resistance emergence. Zoliflodacin remains promising for gonorrhoea oral monotherapy and as part of dual antimicrobial therapy with low resistance emergence potential. A Phase III trial evaluating efficacy and safety of zoliflodacin for uncomplicated gonorrhoea treatment is planned in 2019.

  • 10.
    Gianecini, Ricardo A.
    et al.
    National Reference Laboratory of Sexually Transmitted Diseases, National Institute of Infectious Diseases - ANLIS 'Dr Carlos G. Malbrán', Ciudad Autónoma de Buenos Aires, Argentina.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology.
    Zittermann, Sandra
    Public Health Ontario Laboratories, Toronto, Canada.
    Litvik, Ana
    Rawson Infectious Diseases Hospital, Córdoba, Argentina.
    Gonzalez, Silvia
    Rawson Infectious Diseases Hospital, Córdoba, Argentina.
    Oviedo, Claudia
    National Reference Laboratory of Sexually Transmitted Diseases, National Institute of Infectious Diseases - ANLIS 'Dr Carlos G. Malbrán', Ciudad Autónoma de Buenos Aires, Argentina.
    Melano, Roberto G.
    Public Health Ontario Laboratories, Toronto, Canada.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology.
    Galarza, Patricia
    National Reference Laboratory of Sexually Transmitted Diseases, National Institute of Infectious Diseases - ANLIS 'Dr Carlos G. Malbrán', Ciudad Autónoma de Buenos Aires, Argentina.
    Genome-based epidemiology and antimicrobial resistance determinants of Neisseria gonorrhoeae isolates with decreased susceptibility and resistance to extended-spectrum cephalosporins in Argentina in 2011-162019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 6, p. 1551-1559Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Our aim was to describe the molecular epidemiology and antimicrobial resistance determinants of isolates of Neisseria gonorrhoeae with decreased susceptibility and resistance to extended-spectrum cephalosporins (ESCs) in Argentina in 2011-16.

    METHODS: Gonococcal isolates (n = 158) with decreased susceptibility and resistance to ESCs collected in 2011-16 across Argentina were subjected to WGS and antimicrobial susceptibility testing for six antimicrobials.

    RESULTS: In total, 50% of the isolates were resistant to cefixime, 1.9% were resistant to ceftriaxone, 37.3% were resistant to azithromycin and 63.9% of the isolates showed an MDR phenotype. Resistance and decreased susceptibility to ESCs was mainly associated with isolates possessing the mosaic penA-34.001, in combination with an mtrR promoter A deletion, and PorB1b amino acid substitutions G120K/A121N. Phylogenetic analysis revealed two main clades of circulating strains, which were associated with the N. gonorrhoeae multiantigen sequence typing (NG-MAST) ST1407 and closely related STs, and characterized by a high prevalence rate, wide geographical distribution and temporal persistence.

    CONCLUSIONS: N. gonorrhoeae isolates with decreased susceptibility and resistance to ESCs in Argentina have emerged and rapidly spread mainly due to two clonal expansions after importation of one or two strains, which are associated with the international MDR NG-MAST ST1407 clone. The identification of the geographical dissemination and characteristics of these predominant clones may help to focus action plans and public health policies to control the spread of ESC resistance in Argentina. Dual antimicrobial therapy (ceftriaxone plus azithromycin) for gonorrhoea needs to be considered in Argentina.

  • 11.
    Golparian, Daniel
    et al.
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology.
    Bazzo, Maria Luiza
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Golfetto, Lisléia
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Gaspar, Pamela Cristina
    Department of Diseases of Chronic Condition and Sexually Transmitted Infection, Secretariat of Health Surveillance, Ministry of Health of Brazil, Brasília, Brazil.
    Schörner, Marcos André
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Schwartz Benzaken, Adele
    Foundation of Tropical Medicine of Amazonas, Manaus, Brazil.
    Ramos, Mauro Cunha
    Brazilian STD Society, Porto Alegre, Brazil.
    Ferreira, William Antunes
    Alfredo da Mata Foundation, Manaus, Brazil.
    Alonso Neto, José Boullosa
    Department of Diseases of Chronic Condition and Sexually Transmitted Infection, Secretariat of Health Surveillance, Ministry of Health of Brazil, Brasília, Brazil.
    Mendes Pereira, Gerson Fernando
    Department of Diseases of Chronic Condition and Sexually Transmitted Infection, Secretariat of Health Surveillance, Ministry of Health of Brazil, Brasília, Brazil.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine.
    Genomic epidemiology of Neisseria gonorrhoeae elucidating the gonococcal antimicrobial resistance and lineages/sublineages across Brazil, 2015-162020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3163-3172Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Neisseria gonorrhoeae antimicrobial resistance (AMR) surveillance is imperative internationally, but only eight (22.9%) countries in the WHO Region of the Americas reported complete AMR data to the WHO Global Gonococcal Antimicrobial Surveillance Program (WHO GASP) in 2016. Genomic studies are ideal for enhanced understanding of gonococcal populations, including the spread of AMR strains. To elucidate the circulating gonococcal lineages/sublineages, including their AMR determinants, and the baseline genomic diversity among gonococcal strains in Brazil, we conducted WGS on 548 isolates obtained in 2015-16 across all five macroregions in Brazil.

    METHODS: A total of 548 gonococcal isolates cultured across Brazil in 2015-16 were genome sequenced. AMR was determined using agar dilution and/or Etest. Genome sequences of isolates from Argentina (n = 158) and the 2016 WHO reference strains (n = 14) were included in the analysis.

    RESULTS: We found 302, 68 and 214 different NG-MAST, MLST and NG-STAR STs, respectively. The phylogenomic analysis identified one main antimicrobial-susceptible lineage and one AMR lineage, which was divided into two sublineages with different AMR profiles. Determination of NG-STAR networks of clonal complexes was shown as a new and valuable molecular epidemiological analysis. Several novel mosaic mtrD (and mtrR and mtrE) variants associated with azithromycin resistance were identified.

    CONCLUSIONS: We describe the first genomic baseline data to support the Brazilian GASP. The high prevalence of resistance to ciprofloxacin, tetracycline and benzylpenicillin, and the high number of isolates with mosaic penA and azithromycin resistance mutations, should prompt continued and strengthened AMR surveillance, including WGS, of N. gonorrhoeae in Brazil.

  • 12.
    Golparian, Daniel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections.
    Holley, Concerta L.
    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
    Shafer, William M.
    Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA; The Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, GA, USA; Laboratories of Bacterial Pathogenesis, Veterans Affairs Medical Center, Decatur, GA, USA.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden; Institute for Global Health, University College London (UCL), London, UK.
    High-level in vitro resistance to gentamicin acquired in a stepwise manner in Neisseria gonorrhoeae2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 7, p. 1769-1778Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Gentamicin is used in several alternative treatments for gonorrhoea. Verified clinical Neisseria gonorrhoeae isolates with gentamicin resistance are mainly lacking and understanding the mechanisms for gonococcal gentamicin resistance is imperative. We selected gentamicin resistance in gonococci in vitro, identified the novel gentamicin-resistance mutations, and examined the biofitness of a high-level gentamicin-resistant mutant.

    METHODS: Low- and high-level gentamicin resistance was selected in WHO X (gentamicin MIC = 4 mg/L) on gentamicin-gradient agar plates. Selected mutants were whole-genome sequenced. Potential gentamicin-resistance fusA mutations were transformed into WT strains to verify their impact on gentamicin MICs. The biofitness of high-level gentamicin-resistant mutants was examined using a competitive assay in a hollow-fibre infection model.

    RESULTS: WHO X mutants with gentamicin MICs of up to 128 mg/L were selected. Primarily selected fusA mutations were further investigated, and fusAR635L and fusAM520I + R635L were particularly interesting. Different mutations in fusA and ubiM were found in low-level gentamicin-resistant mutants, while fusAM520I was associated with high-level gentamicin resistance. Protein structure predictions showed that fusAM520I is located in domain IV of the elongation factor-G (EF-G). The high-level gentamicin-resistant WHO X mutant was outcompeted by the gentamicin-susceptible WHO X parental strain, suggesting lower biofitness.

    CONCLUSIONS: We describe the first high-level gentamicin-resistant gonococcal isolate (MIC = 128 mg/L), which was selected in vitro through experimental evolution. The most substantial increases of the gentamicin MICs were caused by mutations in fusA (G1560A and G1904T encoding EF-G M520I and R635L, respectively) and ubiM (D186N). The high-level gentamicin-resistant N. gonorrhoeae mutant showed impaired biofitness.

  • 13.
    Golparian, Daniel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Örebro University, Örebro, Sweden.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections.
    Sánchez-Busó, Leonor
    Genomics and Health Area, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO-Public Health), Valencia, Spain and Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
    Bazzo, Maria Luiza
    Molecular Biology, Microbiology and Serology Laboratory, Federal University of Santa Catarina, Florianópolis, Brazil.
    Lan, Pham Thi
    Hanoi Medical University, National Hospital of Dermatology and Venereology, Hanoi, Vietnam.
    Galarza, Patricia
    National Reference Laboratory for STDs, National Institute of Infectious Diseases-ANLIS 'Dr Carlos G. Malbrán', Buenos Aires, Argentina.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections; Institute for Global Health, University College London, London, UK.
    GyrB in silico mining in 27 151 global gonococcal genomes from 1928-2021 combined with zoliflodacin in vitro testing of 71 international gonococcal isolates with different GyrB, ParC and ParE substitutions confirms high susceptibility2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 1, p. 150-154Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global threat and novel treatment alternatives are imperative. Herein, susceptibility to the novel antimicrobial zoliflodacin, currently in a global Phase 3 randomized controlled clinical trial for gonorrhoea treatment, was investigated by screening for zoliflodacin GyrB target mutations in publicly available gonococcal genomes and, where feasible, determination of the associated zoliflodacin MIC.

    METHODS: The European Nucleotide Archive was queried using the search term 'Taxon: 485'. DNA sequences from 27 151 gonococcal isolates were analysed and gyrB, gyrA, parC and parE alleles characterized.

    RESULTS: GyrB amino acid alterations were rare (97.0% of isolates had a wild-type GyrB sequence). GyrB V470L (2.7% of isolates) was the most prevalent alteration, followed by S467N (0.12%), N. meningitidis GyrB (0.092%), V470I (0.059%), Q468R/P (0.015%), A466T (0.0074%), L425I + L465I (0.0037%), L465I (0.0037%), G482S (0.0037%) and D429V (0.0037%). Only one isolate (0.0037%) carried a substitution in a resistance-associated GyrB codon (D429V), resulting in a zoliflodacin MIC of 8 mg/L. None of the other detected gyrB, gyrA, parC or parE mutations caused a zoliflodacin MIC outside the wild-type MIC distribution.

    CONCLUSIONS: The zoliflodacin target GyrB was highly conserved among 27 151 global gonococcal isolates cultured in 1928-2021. The single zoliflodacin-resistant clinical isolate (0.0037%) was cultured from a male patient in Japan in 2000. Evidently, this strain has not clonally expanded nor has the gyrB zoliflodacin-resistance mutation disseminated through horizontal gene transfer to other strains. Phenotypic and genomic surveillance, including gyrB mutations, of zoliflodacin susceptibility are imperative.

  • 14.
    Golparian, Daniel
    et al.
    Örebro University, School of Medical Sciences. World Health Organization Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology.
    Kittiyaowamarn, Rossaphorn
    Bangrak STIs Center, Division of AIDS and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Paopang, Porntip
    Bangrak STIs Center, Division of AIDS and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sangprasert, Pongsathorn
    Bangrak STIs Center, Division of AIDS and STIs, Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
    Sirivongrangson, Pachara
    Department of Disease Control, Ministry of Public Health, Bangkok, Thailan.
    Franceschi, Francois
    Global Antibiotic Research & Development Partnership (GARDP), Geneva, Switzerland.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. World Health Organization Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology.
    Wi, Teodora
    Department of the Global HIV, Hepatitis and STI programmes, World Health Organization, Geneva, Switzerland.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. World Health Organization Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Institute for Global Health, University College London, London, UK .
    Genomic surveillance and antimicrobial resistance in Neisseria gonorrhoeae isolates in Bangkok, Thailand in 20182022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 8, p. 2171-2182Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a substantial global public health problem. Gonococcal infections acquired in or from Asia represent most verified ceftriaxone treatment failures, and several ceftriaxone-resistant strains have emerged in Asia and subsequently spread globally. Additionally, in Thailand the gonorrhoea incidence remains high. Herein, we investigate the genomic diversity, AMR and AMR determinants in gonococcal isolates cultured in 2018 in Bangkok, Thailand.

    METHODS: Gonococcal isolates from males (n = 37) and females (n = 62) were examined by Etest and WGS. AMR determinants and molecular epidemiological STs were characterized. For phylogenomic comparison, raw sequence data were included from China (432 isolates), Japan (n = 270), Vietnam (n = 229), Thailand (n = 3), a global dataset (n = 12 440) and the 2016 WHO reference strains plus WHO Q (n = 15).

    RESULTS: In total, 88, 66 and 41 different NG-MAST, NG-STAR and MLST STs, respectively, and 31 different NG-STAR clonal complexes were found. A remarkably high frequency (88%) of β-lactamase TEM genes was detected and two novel TEM alleles were found. The phylogenomic analysis divided the isolates into the previously described lineages A and B, with a large proportion of Thai isolates belonging to the novel sublineage A3.

    CONCLUSIONS: We describe the first molecular epidemiological study using WGS on gonococcal isolates from Thailand. The high prevalence of AMR and AMR determinants for ciprofloxacin, tetracycline and benzylpenicillin, and some strains belonging to clones/clades especially in sublineage A2 that are prone to develop resistance to extended-spectrum cephalosporins (ESCs) and azithromycin, should prompt continued and strengthened AMR surveillance, including WGS, of N. gonorrhoeae in Thailand.

  • 15.
    Golparian, Daniel
    et al.
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology.
    Sánchez-Busó, Leonor
    Genomics and Health Area, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO-Public Health), Valencia, Spain.
    Cole, Michelle
    National Infection Service, Public Health England, London, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology.
    Neisseria gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR) clonal complexes are consistent with genomic phylogeny and provide simple nomenclature, rapid visualization and antimicrobial resistance (AMR) lineage predictions2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 4, p. 940-944Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Surveillance of antimicrobial resistance (AMR) in Neisseria gonorrhoeae, supported by molecular typing, ideally through genome sequencing, is imperative. We defined N. gonorrhoeae Sequence Typing for Antimicrobial Resistance (NG-STAR) clonal complexes (CCs) and validated their usefulness in gonococcal AMR surveillance.

    METHODS: All NG-STAR alleles and STs available in the public database (https://ngstar.canada.ca/) were analysed using PHYLOViZ 2.0 to define CCs according to the closest founder ST with ≥5 identical alleles and founding ST with the highest number of links. The published 2013 European gonococcal dataset (n = 1054), the 2016 WHO reference strain panel (n = 14) and N. gonorrhoeae isolates with ceftriaxone resistance determinant penA-60.001 (n = 7) from several countries were used for validation.

    RESULTS: The majority of the isolates (n = 1063) were designated to 71 CCs. The most common CC was CC90 (n = 194), followed by CC63 (n = 166), CC139 (n = 73), CC158 (n = 73) and CC127 (n = 62). CC90 included isolates belonging to the internationally spread MDR clone N. gonorrhoeae Multi-Antigen Sequence Typing (NG-MAST) G1407 (predominantly MLST ST1901). The ceftriaxone-resistant isolates with penA-60.001 (n = 7) belonged to CC73 or STs linking between CC90 and CC73 (ST233 and ST1133). Phylogenomic analysis revealed that NG-STAR CCs more appropriately correlated to phylogenomic AMR clusters compared with MLST STs, NG-MAST STs, NG-MAST genogroups and NG-STAR STs.

    CONCLUSIONS: NG-STAR CCs: are consistent with the gonococcal genome phylogeny; allow rapid visualizations with limited computational requirements; provide a simple, reproducible and portable nomenclature (for WGS and conventional Sanger sequencing data); and predict AMR lineages. Phenotypic AMR surveillance, supplemented with WGS, is imperative and NG-STAR CCs can effectively support this.

  • 16.
    Gouveia, A. C. Damiao
    et al.
    Research Unit for Reproductive Tract Microbiology, Statens Serum Institut, Copenhagen, Denmark.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Department of Laboratory Medicine, Microbiology, Öebro University Hospital, Örebro, Sweden.
    Jensen, J. S.
    Research Unit for Reproductive Tract Microbiology, Statens Serum Institut, Copenhagen, Denmark.
    In vitro activity of zoliflodacin (ETX0914) against macrolide-resistan fluoroquinolone-resistant and antimicrobial-susceptible Mycoplasma genitalium strains2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 5, p. 1291-1294Article in journal (Refereed)
    Abstract [en]

    Background: Mycoplasma genitalium is estimated to be the second most common cause of bacterial sexually transmitted infection in Europe. It is of increasing public health concern due to the rapid development of resistance to different antimicrobial classes, including the preferred first- and second-line treatments azithromycin and moxifloxacin. Thus, new antimicrobial agents are urgently needed, especially for the treatment of MDR strains.

    Methods: The in vitro activity of the new spiropyrimidinetrione zoliflodacin against 47 M. genitalium strains was assessed by growing M. genitalium in Vero cell culture and measuring growth by quantitative PCR. The collection included 34 moxifloxacin-susceptible (MIC <1 mg/L) and 13 moxifloxacin-resistant (MIC >= 1 mg/L) strains. Twenty-three of the strains were azithromycin resistant (MIC >= 16 mg/L) and 12 of these strains were MDR.

    Results: Only one (2.1%) strain with substantially increased MIC (4 mg/L) and potential resistance to zoliflodacin was found. Zoliflodacin was overall more potent than moxifloxacin (P = 0.009) and no cross-resistance was observed between the two drug classes of topoisomerase II inhibitors. Differences in the MICs of zoliflodacin and azithromycin were not statistically significant; however, 23 (48.9%) compared with potentially 1 (2.1%) of the strains were resistant to azithromycin and zoliflodacin, respectively.

    Conclusions: Zoliflodacin is a promising candidate for the treatment of M. genitalium and it is important to further develop and evaluate this drug.

  • 17.
    Hadad, Ronza
    et al.
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Cole, Michelle Jayne
    National Infection Service, Public Health England, London, UK.
    Ebeyan, Samantha
    SpeeDx Pty Ltd, Sydney, New South Wales, Australia.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Tan, Lit Yeen
    SpeeDx Pty Ltd, Sydney, New South Wales, Australia.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Erskine, Simon
    SpeeDx Pty Ltd, Sydney, New South Wales, Australia.
    Day, Michaela
    National Infection Service, Public Health England, London, UK.
    Whiley, David
    Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Herston, Queensland, Australia.
    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.
    Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeae2021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 1, p. 84-90Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance.

    OBJECTIVES: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively.

    METHODS: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays.

    RESULTS: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions.

    CONCLUSIONS: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).

  • 18.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences.
    Golparian, Daniel
    Örebro University, School of Medical Sciences.
    Cole, Michelle
    Public Health England, London, UK.
    Spiteri, Gianfranco
    European Centre for Disease Prevention and Control, Stockholm, Sweden.
    Martin, Irene
    Public Health Agency of Canada, Winnipeg, Canada.
    Bergheim, Thea
    Oslo University Hospital Ullevål, Oslo, Norway.
    Borrego, Maria José
    National Institute of Health, Lisbon, Portugal.
    Crowley, Brendan
    St James’s Hospital, Dublin, Ireland.
    Crucitti, Tania
    Institute of Tropical Medicine, Antwerp, Belgium.
    Van Dam, Alje P.
    Public Health Service Amsterdam, Amsterdam, The Netherlands.
    Hoffmann, Steen
    Statens Serum Institut, Copenhagen, Denmark.
    Jeverica, Samo
    Institute of Microbiology and Immunology, University of Ljubljana, Ljubljana, Slovenia.
    Kohl, Peter
    Vivantes Klinikum Neukölln, Berlin, Germany.
    Mlynarczyk-Bonikowska, Beata
    Medical University of Warsaw, Warsaw, Poland.
    Pakarna, Gatis
    Infectology Centre of Latvia, Riga, Latvia.
    Stary, Angelika
    Outpatients’ Centre for Infectious Venereodermatological Diseases, Vienna, Austria.
    Stefanelli, Paola
    Istituto Superiore di Sanitá, Rome, Italy.
    Pavlik, Peter
    HPL Laboratory Ltd, Bratislava, Slovakia.
    Tzelepi, Eva
    Hellenic Pasteur Institute, Athens, Greece.
    Abad, Raquel
    Institute of Health Carlos III, Madrid, Spain.
    Harris, Simon R.
    Pathogen Genomics, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, UK.
    Unemo, Magnus
    Örebro University, School of Health Sciences.
    WGS analysis and molecular resistance mechanisms of azithromycin-resistant (MIC >2 mg/L) Neisseria gonorrhoeae isolates in Europe from 2009 to 20142016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 11, p. 3109-3116Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 19.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Scangarella-Oman, Nicole
    GlaxoSmithKline, Collegeville PA, USA.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the novel triazaacenaphthylene gepotidacin (GSK2140944) against MDR Neisseria gonorrhoeae2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 8, p. 2072-2077Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 20.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Mason, Clive
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Khan, Nawaz
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Meo, Paul
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    High in vitro activity of DIS-73285, a novel antimicrobial with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3244-3247Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The rising incidence of antimicrobial resistance in Neisseria gonorrhoeae may result in untreatable gonorrhoea in certain circumstances and development of novel antimicrobials is urgently needed.

    OBJECTIVES: To evaluate the in vitro activity of a novel small-molecule antimicrobial with a new mechanism of action, DIS-73285, against a large geographically, temporally and genetically diverse collection of clinical N. gonorrhoeae isolates and reference strains, including various types of high-level resistant, MDR and XDR gonococcal isolates (n = 262).

    METHODS: MICs (mg/L) of DIS-73285 were determined by agar dilution and by Etest for ceftriaxone, cefixime, azithromycin, ciprofloxacin, ampicillin, spectinomycin and tetracycline.

    RESULTS: DIS-73285 was substantially more potent than any of the currently or previously used therapeutic antimicrobials, with MICs ranging from ≤0.001 to 0.004 mg/L, and the MIC50, MIC90 and modal MIC all ≤0.001 mg/L (lowest MIC tested). No correlation with the MICs of DIS-73285 and the MICs of any of the currently or previously used antimicrobials was observed.

    CONCLUSIONS: The novel chemotype, small-molecule antimicrobial DIS-73285, demonstrated high in vitro potency against all tested N. gonorrhoeae isolates. Further in vitro and in vivo studies, evaluating efficacy, resistance emergence, pharmacokinetic/pharmacodynamic parameters, toxicity and safety, should be conducted to evaluate DIS-73285 as a therapy specifically for urogenital and extra-genital gonorrhoea.

  • 21.
    Jacobsson, Susanne
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    Mason, Clive
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Khan, Nawaz
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Meo, Paul
    Summit Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, UK.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, National Reference Laboratory for Sexually Transmitted Infections, Department of Laboratory Medicine.
    In vitro activity of the novel oral antimicrobial SMT-571, with a new mechanism of action, against MDR and XDR Neisseria gonorrhoeae: future treatment option for gonorrhoea?2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 6, p. 1591-1594Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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

  • 22.
    Jeverica, Samo
    et al.
    Fac Med, Inst Microbiol & Immunol, Univ Ljubljana, Ljubljana, Slovenia.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Lab. Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Hanzelka, Brian
    Vertex Pharmaceut Inc, Boston MA, USA.
    Fowlie, Andrew J.
    Vertex Pharmaceut Inc, Boston MA, USA.
    Maticic, Mojca
    Clin Infect Dis & Febrile Illnesses, Univ Med Ctr Ljubljana, Ljubljana, Slovenia..
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Lab. Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    High in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (VT12-008911) against Neisseria gonorrhoeae isolates with various high-level antimicrobial resistance and multidrug resistance2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 7, p. 1866-1872Article in journal (Refereed)
    Abstract [en]

    Clinical resistance to the currently recommended extended-spectrum cephalosporins (ESCs), the last remaining options for empirical antimicrobial monotherapy of gonorrhoea globally, has been reported. New antimicrobials are essential to avoid the emergence of untreatable gonorrhoea. We have investigated the in vitro activity of a novel dual bacterial topoisomerase inhibitor of the ATPase activities of GyrB and ParE (Vertex aminobenzimidazole VT12-008911), compared with antimicrobials currently or previously recommended for gonorrhoea treatment.

    MICs were determined using agar dilution (VT12-008911) or Etest (seven antimicrobials) for international reference strains (naEuroS=aEuroS28) and clinical Neisseria gonorrhoeae isolates (naEuroS=aEuroS220). The latter included three extensively drug-resistant isolates with high-level ceftriaxone resistance, additional isolates with clinical ESC resistance and a high number of isolates with ciprofloxacin resistance and multidrug resistance.

    The MIC50, MIC90 and MIC range of VT12-008911 were 0.064, 0.125 and a parts per thousand currency sign0.002-0.25 mg/L, respectively. One-hundred and seventy (69%) isolates were ciprofloxacin resistant; however, only 54 of those isolates had a VT12-008911 MIC > 0.064 mg/L (47 and 7 with MICaEuroS=aEuroS0.125 mg/L and MICaEuroS=aEuroS0.25 mg/L, respectively). The in vitro activity of VT12-008911 was superior to that of ciprofloxacin and all additional antimicrobials investigated. Time-kill curve analysis showed that VT12-008911 exhibited potent time-dependent bactericidal activity, at or very close to the MIC, against N. gonorrhoeae.

    In vitro results suggest that VT12-008911 might be an effective treatment option for gonorrhoea. However, it will be important to detail the pharmacokinetics/pharmacodynamics, toxicity, selection and mechanisms of VT12-008911 resistance in N. gonorrhoeae and, finally, to perform well-designed in vivo randomized clinical trials.

  • 23.
    Jeverica, Samo
    et al.
    Fac Med, Inst Microbiol & Immunol, Univ Ljubljana, Ljubljana, Slovenia.
    Golparian, Daniel
    WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Maticic, Mojca
    Clin Infect Dis & Febrile Illnesses, Univ Med Ctr Ljubljana, Ljubljana, Slovenia.
    Potocnik, Marko
    Dept Dermatovenereol, Univ Med Ctr Ljubljana, Ljubljana, Slovenia.
    Mlakar, Bostjan
    Surg Ctr Zdrav Splet, Ljubljana, Slovenia.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Phenotypic and molecular characterization of Neisseria gonorrhoeae isolates from Slovenia, 2006-12: rise and fall of the multidrug-resistant NG-MAST genogroup 1407 clone?2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 6, p. 1517-1525Article in journal (Refereed)
    Abstract [en]

    To determine the phenotypic and molecular characteristics of Neisseria gonorrhoeae isolates obtained between 2006 and 2012 in Slovenia.

    Gonococcal isolates obtained between 2006 and 2012 in Slovenia (naEuroS=aEuroS194) were investigated with Etest for susceptibility to cefixime, ceftriaxone, penicillin, ciprofloxacin, azithromycin, tetracycline, gentamicin and spectinomycin. All isolates were examined with N. gonorrhoeae multiantigen sequence typing for molecular epidemiology and sequencing of the major extended-spectrum cephalosporin (ESC) resistance determinants (penA, mtrR and penB) was performed.

    The overall prevalence of decreased susceptibility or resistance to cefixime and ceftriaxone (MIC a parts per thousand yen0.125 mg/L) was 11% and 5%, respectively. The decreased susceptibility or resistance showed an epidemic peak in 2011 (33% for cefixime and 11% for ceftriaxone), decreasing to 6% and 4%, respectively, in 2012. ST1407 (9% of isolates), ST21 (6%) and ST225 (6%) were the most common sequence types (STs) during 2006-12. Genogroup G1407 (ST1407 most prevalent ST), an internationally spread clone with decreased susceptibility or resistance to ESCs, was most prevalent (48%) in 2009. However, the G1407 prevalence then declined: in 2010, 30%; in 2011, 28%; and in 2012, 8%. Instead, in 2012 the ESC- and ciprofloxacin-susceptible G21 was the predominant genogroup (26%).

    The prevalence of gonococcal resistance to ESCs in Slovenia has been high, but fluctuating. Fortunately, in 2012 some ESC- and ciprofloxacin-susceptible clones, such as genogroups G21, G1195 and G2992, appeared to have mainly replaced the multidrug-resistant G1407 clone, a replacement also seen in several European countries.

  • 24.
    Kakooza, Francis
    et al.
    Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Örebro University, Örebro, Sweden.
    Matoga, Mitch
    UNC Project Malawi, Lilongwe, Malawi.
    Maseko, Venessa
    Centre for HIV and STIs, National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa.
    Lamorde, Mohammed
    Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda.
    Krysiak, Robert
    UNC Project Malawi, Lilongwe, Malawi.
    Manabe, Yuka C.
    Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala, Uganda; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
    Chen, Jane S.
    Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Kularatne, Ranmini
    Labtests Laboratory and Head Office, Mt Wellington, Auckland, New Zealand; Department of Clinical Microbiology and Infectious Diseases, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs.
    Godreuil, Sylvain
    Laboratoire de Bactériologie, Centre Hospitalier Universitaire de Montpellier, and MIVEGEC, Université de Montpellier, CNRS, IRD, Montpellier, France.
    Hoffman, Irving
    UNC Project Malawi, Lilongwe, Malawi; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Bercot, Beatrice
    Infectious Agents Department, French National Reference Centre for Bacterial STIs, Associated Laboratory for Gonococci, and APHP, Saint Louis Hospital, Paris, France.
    Wi, Teodora
    Department of the Global HIV, Hepatitis and STI Programmes, WHO, Geneva, Switzerland.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and other STIs, National Reference Laboratory for STIs, Örebro University, Örebro, Sweden; Institute for Global Health, University College London, London, UK.
    Genomic surveillance and antimicrobial resistance determinants in Neisseria gonorrhoeae isolates from Uganda, Malawi and South Africa, 2015-202023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 8, p. 1982-1991Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Global antimicrobial resistance (AMR) surveillance in Neisseria gonorrhoeae is essential. In 2017-18, only five (10.6%) countries in the WHO African Region reported to the WHO Global Gonococcal Antimicrobial Surveillance Programme (WHO GASP). Genomics enhances our understanding of gonococcal populations nationally and internationally, including AMR strain transmission; however, genomic studies from Africa are extremely scarce. We describe the gonococcal genomic lineages/sublineages, including AMR determinants, and baseline genomic diversity among strains in Uganda, Malawi and South Africa, 2015-20, and compare with sequences from Kenya and Burkina Faso.

    METHODS: Gonococcal isolates cultured in Uganda (n = 433), Malawi (n = 154) and South Africa (n = 99) in 2015-20 were genome-sequenced. MICs were determined using ETEST. Sequences of isolates from Kenya (n = 159), Burkina Faso (n = 52) and the 2016 WHO reference strains (n = 14) were included in the analysis.

    RESULTS: Resistance to ciprofloxacin was high in all countries (57.1%-100%). All isolates were susceptible to ceftriaxone, cefixime and spectinomycin, and 99.9% were susceptible to azithromycin. AMR determinants for ciprofloxacin, benzylpenicillin and tetracycline were common, but rare for cephalosporins and azithromycin. Most isolates belonged to the more antimicrobial-susceptible lineage B (n = 780) compared with the AMR lineage A (n = 141), and limited geographical phylogenomic signal was observed.

    CONCLUSIONS: We report the first multi-country gonococcal genomic comparison from Africa, which will support the WHO GASP and WHO enhanced GASP (EGASP). The high prevalence of resistance to ciprofloxacin (and empirical use continues), tetracycline and benzylpenicillin, and the emerging resistance determinants for azithromycin show it is imperative to strengthen the gonococcal AMR surveillance, ideally including genomics, in African countries.

  • 25.
    Kong, Fabian Yuh Shiong
    et al.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
    Horner, Patrick
    Population Health Sciences, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK; National Institute for Health Research Health Protection Research Unit in Evaluation of Interventions, University of Bristol, Bristol, UK.
    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, Microbiology.
    Hocking, Jane S.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
    Pharmacokinetic considerations regarding the treatment of bacterial sexually transmitted infections with azithromycin: a review2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 5, p. 1157-1166Article, review/survey (Refereed)
    Abstract [en]

    Rates of bacterial sexually transmitted infections (STIs) continue to rise, demanding treatments to be highly effective. However, curing infections faces significant challenges due to antimicrobial resistance in Neisseria gonorrhoeae and Mycoplasma genitalium and especially treating STIs at extragenital sites, particularly rectal chlamydia and oropharyngeal gonorrhoea. As no new antimicrobials are entering the market, clinicians must optimize the currently available treatments, but robust data are lacking on how the properties or pharmacokinetics of antimicrobials can be used to inform STI treatment regimens to improve treatment outcomes. This paper provides a detailed overview of the published pharmacokinetics of antimicrobials used to treat STIs and how factors related to the drug (tissue distribution, protein binding and t(1/2)), human (pH, inflammation, site of infection, drug side effects and sexual practices) and organism (organism load and antimicrobial resistance) can affect treatment outcomes. As azithromycin is commonly used to treat chlamydia, gonorrhoea and M. genitalium infections, and its pharmacokinetics are well studied, it is the main focus of this review. Suggestions are also provided on possible dosing regimens when using extended and/or higher doses of azithromycin, which appropriately balance efficacy and side effects. The paper also emphasizes the limitations of currently published pharmacokinetic studies including oropharyngeal gonococcal infections, where very limited data exist around ceftriaxone pharmacokinetics and its use in combination with azithromycin. In future, the different anatomical sites of infections may require alternative therapeutic approaches.

  • 26.
    Kong, Fabian Yuh Shiong
    et al.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
    Kenyon, Chris
    HIV/STI Unit, Institute of Tropical Medicine, Antwerp, Belgium; Division of Infectious Diseases and HIV Medicine, University of Cape Town, Cape Town, South Africa.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Örebro University, Örebro, Sweden; Faculty of Population Health Sciences, Institute for Global Health, University College London, London, UK.
    Important considerations regarding the widespread use of doxycycline chemoprophylaxis against sexually transmitted infections2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 7, p. 1561-1568Article, review/survey (Refereed)
    Abstract [en]

    Rates of sexually transmitted infections (STIs) continue to rise across the world and interventions are essential to reduce their incidence. Past and recent studies have indicated this may be achieved using doxycycline post-exposure prophylaxis (PEP) and this has sparked considerable interest in its use. However, many unanswered questions remain as to its long-term effects and particularly potentially negative impact on human microbiomes and antimicrobial resistance among STIs, other pathogens, and commensals. In this review, we discuss seven areas of concern pertaining to the widespread use of doxycycline PEP.

  • 27.
    Lan, Pham Thi
    et al.
    Hanoi Medical University, National Hospital of Dermatology and Venereology, Hanoi, Vietnam.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Swedish Reference Laboratory for STIs.
    Ringlander, Johan
    WHO Collaborating Centre for Gonorrhoea and Other Sexually Transmitted Infections, Swedish Reference Laboratory for STIs, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Infectious Diseases at Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
    Van Hung, Le
    Hanoi Medical University, National Hospital of Dermatology and Venereology, Hanoi, Vietnam.
    Van Thuong, Nguyen
    Hanoi Medical University, National Hospital of Dermatology and Venereology, Hanoi, Vietnam.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Genomic analysis and antimicrobial resistance of Neisseria gonorrhoeae isolates from Vietnam in 2011 and 2015-162020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 6, p. 1432-1438Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae, compromising gonorrhoea treatment, is a threat to reproductive health globally. South-East and East Asia have been major sources of emergence and subsequent international spread of AMR gonococcal strains during recent decades. We investigated gonococcal isolates from 2011 and 2015-16 in Vietnam using AMR testing, WGS and detection of AMR determinants.

    METHODS: Two hundred and twenty-nine gonococcal isolates cultured in 2015-16 (n = 121) and 2011 (n = 108) in Vietnam were examined. AMR testing was performed using Etest and WGS with Illumina MiSeq.

    RESULTS: Resistance among the 2015-16 isolates was as follows: ciprofloxacin, 100%; tetracycline, 79%; benzylpenicillin, 50%; cefixime, 15%; ceftriaxone, 1%; spectinomycin, 0%; and 5% were non-WT to azithromycin. Eighteen (15%) isolates were MDR. The MIC range for gentamicin was 2-8 mg/L. Among the 2015-16 isolates, 27% (n = 33) contained a mosaic penA allele, while no isolates had a mosaic penA allele in 2011. Phylogenomic analysis revealed introduction after 2011 of two mosaic penA-containing clones (penA-10.001 and penA-34.001), which were related to cefixime-resistant strains spreading in Japan and Europe, and a minor clade (eight isolates) relatively similar to the XDR strain WHO Q.

    CONCLUSIONS: From 2011 to 2015-16, resistance in gonococci from Vietnam increased to all currently and previously used antimicrobials except ceftriaxone, spectinomycin and tetracycline. Two mosaic penA-containing clones were introduced after 2011, explaining the increased cefixime resistance. Significantly increased AMR surveillance, antimicrobial stewardship and use of WGS for molecular epidemiology and AMR prediction for gonococcal isolates in Vietnam and other Asian countries are crucial.

  • 28.
    Lee, Hyukmin
    et al.
    Department of Laboratory Medicine, International St Mary’s Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea.
    Unemo, Magnus
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Kim, Hyo Jin
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Seo, Younghee
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Lee, Kyungwon
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Chong, Yunsop
    Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, Seoul, Korea.
    Emergence of decreased susceptibility and resistance to extended-spectrum cephalosporins in Neisseria gonorrhoeae in Korea2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 9, p. 2536-2542Article in journal (Refereed)
    Abstract [en]

    Objectives: Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a major concern globally; however, no comprehensive AMR data for gonococcal isolates cultured after 2006 in Korea have been published internationally. We determined the susceptibility of N. gonorrhoeae isolates cultured in 2011-13, the mechanism of extended-spectrum cephalosporin (ESC) resistance and the molecular epidemiology of gonococcal strains in Korea.

    Methods: In 2011-13, 210 gonococcal isolates were collected in Korea and their AMR profiles were examined by the agar dilution method. The penA, mtrR, penB, ponA and pilQ genes were sequenced in 25 isolates that were resistant to ESCs and 70 randomly selected isolates stratified by year. For molecular epidemiology, N. gonorrhoeae multiantigen sequence typing and MLST were performed.

    Results: None of the N. gonorrhoeae isolates was susceptible to penicillin G and most were resistant to tetracycline (50%) and ciprofloxacin (97%). The rates of resistance to ceftriaxone, azithromycin, cefpodoxime and cefixime were 3%, 5%, 8% and 9%, respectively. However, all isolates were susceptible to spectinomycin. Twenty-one (84%) of the 25 ESC-resistant isolates contained the non-mosaic PBP2 XIII allele; however, the remaining 4 (16%) possessed the mosaic PBP2 X allele, which has been previously associated with ESC resistance including treatment failures.

    Conclusions: In Korea, susceptibility to spectinomycin remains high. However, the recent emergence of ESC-resistant N. gonorrhoeae strains, including strains possessing the PBP2 mosaic X and non-mosaic XIII alleles, is a major concern and enhanced AMR surveillance is necessary to prevent transmission of these strains.

  • 29.
    Lee, Kenichi
    et al.
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Nakayama, Shu-Ichi
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Osawa, Kayo
    Division of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
    Yoshida, Hiroyuki
    Division of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
    Arakawa, Soichi
    Sanda City Hospital, Sanda, Japan.
    Furubayashi, Kei-Ichi
    Sonezaki Furubayashi Clinic, Osaka, Japan.
    Kameoka, Hiroshi
    Kameoka Clinic, Osaka, Japan.
    Shimuta, Ken
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Kawahata, Takuya
    Osaka Institute of Public Health, Osaka, Japan.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicin.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Clonal expansion and spread of the ceftriaxone-resistant Neisseria gonorrhoeae strain FC428, identified in Japan in 2015, and closely related isolates2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 7, p. 1812-1819Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Ceftriaxone resistance in Neisseria gonorrhoeae is a major public health concern globally because a high-dose (1 g) injection of ceftriaxone is the only remaining option for empirical monotherapy of gonorrhoea. The ceftriaxone-resistant gonococcal strain FC428, cultured in Osaka in 2015, is suspected to have spread nationally and internationally. We describe the complete finished genomes of FC428 and two closely related isolates from Osaka in 2015, and examine the genomic epidemiology of these isolates plus three ceftriaxone-resistant gonococcal isolates from Osaka and Hyogo in 2016-17 and four ceftriaxone-resistant gonococcal isolates cultured in 2017 in Australia, Canada and Denmark.

    METHODS: During 2015-17, we identified six ceftriaxone-resistant gonococcal isolates through our surveillance systems in Kyoto, Osaka and Hyogo. Antimicrobial susceptibility testing (six antimicrobials) was performed using Etest. Complete whole-genome sequences of the first three isolates (FC428, FC460 and FC498) from 2015 were obtained using PacBio RS II and Illumina MiSeq sequencing. The three complete genome sequences and draft genome sequences of the three additional Japanese (sequenced with Illumina MiSeq) and four international ceftriaxone-resistant isolates were compared.

    RESULTS: Detailed genomic analysis suggested that the Japanese isolates (FC428, FC460, FC498, KU16054, KM383 and KU17039) and the four international MLST ST1903 isolates from Australia, Canada and Denmark formed four linked subclades.

    CONCLUSIONS: Using detailed genomic analysis, we describe the clonal expansion of the ceftriaxone-resistant N. gonorrhoeae strain FC428, initially identified in 2015 in Japan, and closely related isolates. FC428 and its close relatives show some genomic diversity, suggesting multiple genetic subclades are already spreading internationally.

  • 30.
    Lewis, David A.
    et al.
    Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa; Dept Internal Med, Fac Hlth Sci, University of Witwatersrand, Johannesburg, South Africa; Sch Med, Div Med Microbiol, Univ Cape Town, Cape Town, South Africa.
    Sriruttan, Charlotte
    Dept Clin Microbiol, Ampath Natl Lab Serv, Centurion, South Africa.
    Mueller, Etienne E.
    Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa.
    Golparian, Daniel
    Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, WHO Collaborating Ctr Gonorrhoea & Other STIs, Örebro University Hospital, Örebro, Sweden.
    Gumede, Lindy
    Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa.
    Fick, Donald
    Meldene Medicross Clin, Melville, South Africa.
    de Wet, Johan
    Springs Medicross Clin, Springs, South Africa.
    Maseko, Venessa
    Ctr HIV & Sexually Transmitted Infect, Natl Hlth Lab Serv, Natl Inst Communicable Dis, Johannesburg, South Africa.
    Coetzee, Jennifer
    Dept Clin Microbiol, Ampath Natl Lab Serv, Centurion, South Africa.
    Unemo, Magnus
    Örebro University Hospital. Dept Lab Med, Swedish Reference Lab Pathogen Neisseria, WHO Collaborating Ctr Gonorrhoea & Other STIs, Örebro University Hospital, Örebro, Sweden.
    Phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure2013In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 6, p. 1267-1270Article in journal (Refereed)
    Abstract [en]

    To describe the phenotypic and genetic characteristics of the first two cases of extended-spectrum cephalosporin (ESC)-resistant Neisseria gonorrhoeae in South Africa, one of which was associated with verified cefixime treatment failure. Two ESC-resistant N. gonorrhoeae isolates were cultured from the urethral discharge of two men who have sex with men (MSM). One man reported a persistent urethral discharge that had failed to respond to previous therapy with oral cefixime. Agar dilution MICs were determined for eight antibiotics. -Lactam-associated resistance mutations were identified through PCR-based amplification and sequencing for several key genes: penA, mtrR and its promoter, porB1b (penB), ponA and pilQ. For molecular epidemiological characterization, full-length porB gene sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST) and multilocus sequence typing (MLST) were performed. Both isolates were resistant to cefixime, ciprofloxacin, penicillin and tetracycline and intermediate/resistant to azithromycin, but susceptible to ceftriaxone, gentamicin and spectinomycin. Both isolates had the type XXXIV penA mosaic allele in addition to previously described resistance mutations in the mtrR promoter (A deletion), porB1b (penB) (G101K and A102N) and ponA1 (L421P). Both isolates had an identical NG-MAST sequence type (ST4822) and MLST sequence type (ST1901). Both isolates were resistant to cefixime and possessed a number of identical mutations in key genes contributing to ESC resistance in N. gonorrhoeae. The two isolates contained the type XXXIV penA mosaic allele and belonged to a successful international MSM-linked multidrug-resistant gonococcal clone (MLST ST1901) associated with several cefixime treatment failures in Europe and North America.

  • 31.
    Li, Jiyun
    et al.
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
    Hulth, Anette
    Public Health Agency of Sweden, Stockholm, Sweden.
    Nilsson, Lennart E
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Börjesson, Stefan
    Department of Animal Health and Antimicrobial Strategies, National Veterinary Institute (SVA), Uppsala, Sweden.
    Chen, Baoli
    Shandong Center for Disease Control and Prevention, Jinan, China.
    Bi, Zhenwang
    Shandong Center for Disease Control and Prevention, Jinan, China.
    Wang, Yang
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
    Schwarz, Stefan
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Institute of Microbiology and Epizootics, Centre for Infection Medicine, Department of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
    Wu, Congming
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
    Occurrence of the mobile colistin resistance gene mcr-3 in Escherichia coli from household pigs in rural areas2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 6, p. 1721-1723Article in journal (Other academic)
  • 32.
    Lynagh, Yvonne
    et al.
    Virol Lab, St James Hosp, Dublin, Ireland.
    Mac Aogain, Micheal
    Dept Clin Microbiol, Trinity Coll Dublin, Dublin, Ireland.
    Walsh, Anne
    Virol Lab, St James Hosp, Dublin, Ireland.
    Rogers, Thomas R.
    Dept Clin Microbiol, Trinity Coll Dublin, Dublin, Ireland.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Ctr Gonorrhoeae & Other STIs, Örebro University Hospital, Örebro, Sweden.
    Crowley, Brendan
    Virol Lab, St James Hosp, Dublin, Ireland.
    Detailed characterization of the first high-level azithromycin-resistant Neisseria gonorrhoeae cases in Ireland2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 8, p. 2411-2413Article in journal (Refereed)
  • 33.
    Ma, Shizhen
    et al.
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
    Sun, Chengtao
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
    Hulth, Anette
    Public Health Agency of Sweden, Stockholm, Sweden; Global Health - Health Systems and Policy, Department of Public Health Sciences, Karolinska Institutet, Solna, Sweden.
    Li, Jiyun
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
    Nilsson, Lennart E
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Zhou, Yuqing
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
    Börjesson, Stefan
    Department of Animal Health and Antimicrobial Strategies, National Veterinary Institute (SVA), Uppsala, Sweden.
    Bi, Zhenwang
    Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, Shandong, China.
    Bi, Zhenqiang
    Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention, Jinan, Shandong, China.
    Sun, Qiang
    Center for Health Management and Policy, Shandong University, Jinan, Shandong, China; Key Lab of Health Economics and Policy Research of Ministry of Health, Shandong University, Jinan, Shandong, China.
    Wang, Yang
    Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, China.
    Mobile colistin resistance gene mcr-5 in porcine Aeromonas hydrophila2018In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 7, p. 1777-1780Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To characterize the mobile colistin resistance gene mcr-5 in Aeromonas hydrophila from backyard pigs in rural areas of China.

    METHODS: Pig faecal samples from 194 households were directly tested for the presence of mcr-5 by PCR assay and the phenotypic antimicrobial susceptibility profiles of the mcr-5-positive isolates were determined using the broth dilution method. The genomic location and transferability of mcr-5 were analysed by S1-PFGE with Southern blotting and DNA hybridization, and natural transformation, respectively. One strain isolated from an mcr-5-positive sample was subjected to WGS and the stability of the mcr-5-harbouring plasmid over successive generations was examined by subculturing.

    RESULTS: One mcr-5-positive A. hydrophila isolate showing resistance, with a colistin MIC of 4 mg/L, was isolated from a backyard pig faecal sample. mcr-5 was located on a 7915 bp plasmid designated pI064-2, which could naturally transform into a colistin-susceptible A. hydrophila strain of porcine origin and mediated colistin resistance in both the original isolate and its transformants. The plasmid backbone (3790 bp) of pI064-2 showed 81% nucleotide sequence identity to the corresponding region of the ColE2-type plasmid pAsa1 from Aeromonas salmonicida, while similar replication primases are widely distributed among aeromonads, Enterobacteriaceae and Pseudomonas species.

    CONCLUSIONS: To the best of our knowledge, this is the first identification of the novel colistin resistance gene mcr-5 in an A. hydrophila isolate from the faeces of a backyard pig. mcr-5 is expected to be able to disseminate among different bacterial species and genera.

  • 34.
    Morita-Ishihara, Tomoko
    et al.
    Natl Inst Infect Dis, Tokyo, Japan.
    Unemo, Magnus
    Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden.
    Furubayashi, Kei-ichi
    Sonezaki Furubayashi Clin, Osaka, Japan.
    Kawahata, Takuya
    Osaka Prefectural Inst Publ Hlth, Osaka, Japan.
    Shimuta, Ken
    Natl Inst Infect Dis, Tokyo, Japan.
    Nakayama, Shu-ichi
    Natl Inst Infect Dis, Tokyo, Japan.
    Ohnishi, Makoto
    Natl Inst Infect Dis, Tokyo, Japan.
    Treatment failure with 2 g of azithromycin (extended-release formulation) in gonorrhoea in Japan caused by the international multidrug-resistant ST1407 strain of Neisseria gonorrhoeae2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 8, p. 2086-2090Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern globally. We report the first verified treatment failure of gonorrhoea with 2 g of azithromycin (extended-release formulation) in Japan and characteristics of the corresponding N. gonorrhoeae isolates.

    Pre- and post-treatment isolates (naEuroS=aEuroS4) were investigated by Etest for antimicrobial susceptibility. The isolates were examined for molecular epidemiology by multilocus sequence typing (MLST), N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and multiple-locus variable-number tandem repeat analysis (MLVA), and for the presence of azithromycin resistance determinants (23S rRNA gene mutations, erm genes and mtrR mutations).

    All isolates were resistant to azithromycin (MIC 4 mg/L) and ciprofloxacin, but remained susceptible to cefixime, ceftriaxone and spectinomycin. All isolates were assigned to MLST ST1901 and NG-MAST ST1407 and three of four isolates possessed MLVA profile 8-3-21-16-1. All isolates contained the previously described C2599T mutation (N. gonorrhoeae numbering) in all four 23S rRNA alleles and the previously described single-nucleotide (A) deletion in the mtrR promoter region.

    This verified treatment failure occurred in a patient infected with an MLST ST1901/NG-MAST ST1407 strain of N. gonorrhoeae. While this international strain commonly shows resistance or decreased susceptibility to multiple antimicrobials, including extended-spectrum cephalosporins, the strain reported here remained fully susceptible to the latter antimicrobials. Hence, two subtypes of azithromycin-resistant gonococcal MLST ST1901/NG-MAST ST1407 appear to have evolved and to be circulating in Japan. Azithromycin should not be recommended as a single antimicrobial for first-line empirical treatment of gonorrhoea.

  • 35.
    Nilsson, Lennart
    et al.
    Department of Clinical Bacteriology, University Hospital, Linköping, Sweden.
    Nilsson, Maud
    Department of Clinical Bacteriology, University Hospital, Linköping, Sweden.
    Jendle, Johan
    Department of Clinical Bacteriology, University Hospital, Linköping, Sweden.
    Subpopulations of variants resistant to imipenem in Pseudomonas aeruginosa1988In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 22, no 5, p. 643-649Article in journal (Refereed)
    Abstract [en]

    Selection and regrowth of resistant variants, which were present in low frequencies in the initial inoculum, was seen when large inocula of Pseudomonas aeruginosa were incubated with imipenem. The selective growth of resistant variants resulted in an inoculum effect, and an increase in MIC with longer incubation. When large inocula taken from strains that had been classified as sensitive in conventional MIC determinations were incubated with 4, 8 and 16 mg/l imipenem, 62%, 24% and 10%, respectively, of the strains regrew. None of the resistant variants thereby selected showed cross resistance to other beta-lactam antibiotics or aminoglycosides. In vitro evaluation of regrowth of resistant variants may be justified when choosing imipenem for therapy in the treatment of serious P. aeruginosa infections.

  • 36.
    Nilsson, Oskar
    et al.
    Department of Animal Health and Antimicrobial Strategies , National Veterinary Institute , SE-751 89 Uppsala , Sweden.
    Börjesson, Stefan
    Department of Animal Health and Antimicrobial Strategies , National Veterinary Institute, Uppsala , Sweden.
    Landén, Annica
    Department of Animal Health and Antimicrobial Strategies , National Veterinary Institute , SE-751 89 Uppsala , Sweden.
    Bengtsson, Björn
    Department of Animal Health and Antimicrobial Strategies , National Veterinary Institute , SE-751 89 Uppsala , Sweden.
    Vertical transmission of Escherichia coli carrying plasmid-mediated AmpC (pAmpC) through the broiler production pyramid2014In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 69, no 6, p. 1497-1500Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: In Sweden the prevalence of Enterobacteriaceae with transferable resistance to extended-spectrum cephalosporins (ESCs) is low. However, in broilers ESC-resistant Escherichia coli is common, with a clear dominance of blaCMY-2. Antimicrobials are rarely used in broiler production in Sweden and cephalosporins are never used. Introduction through imported breeding stock and subsequent vertical transmission of the bacteria through the production pyramid could be one explanation for this high prevalence.

    METHODS: To test this hypothesis, paper linings from imported flocks of grandparent animals were screened for the presence of ESC-resistant E. coli and a positive flock, together with its progeny, was followed longitudinally through the production pyramid using boot swabs. The relationship of isolated ESC-resistant E. coli was investigated using multiple-locus variable number tandem repeat analysis (MLVA).

    RESULTS: ESC-resistant E. coli carrying blaCMY-2 was isolated from six out of eight imported flocks of grandparent animals. One clone of E. coli carrying blaCMY-2 occurred in all levels of the production pyramid and in flocks of imported grandparent animals.

    CONCLUSIONS: E. coli carrying blaCMY-2 is frequently present among grandparent animals imported to Sweden for breeding purposes. The occurrence of one clone in all levels of the production pyramid indicates that its introduction through imported breeding stock and vertical transmission through the production pyramid could be one explanation for the high proportion of Swedish broilers colonized with ESC-resistant E. coli.

  • 37.
    Ny, Sofia
    et al.
    Public Health Agency of Sweden, Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Löfmark, Sonja
    Public Health Agency of Sweden, Stockholm, Sweden.
    Börjesson, Stefan
    National Veterinary Institute, Uppsala, Sweden.
    Englund, Stina
    National Veterinary Institute, Uppsala, Sweden.
    Ringman, Maj
    Public Health Agency of Sweden, Stockholm, Sweden.
    Bergström, Jakob
    Public Health Agency of Sweden, Stockholm, Sweden.
    Nauclér, Pontus
    Infectious Disease Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
    Giske, Christian G
    Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Stockholm, Sweden; Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden.
    Byfors, Sara
    Public Health Agency of Sweden, Stockholm, Sweden.
    Community carriage of ESBL-producing Escherichia coli is associated with strains of low pathogenicity: a Swedish nationwide study2017In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 72, no 2, p. 582-588Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Community carriage of ESBL-producing Escherichia coli (EPE) is common worldwide and there is a need to understand the connection between carriage and infection. We compared the molecular characteristics of EPE among Swedish community carriers with those of EPE causing invasive infections.

    METHODS: We collected 2134 faecal samples from randomly selected Swedish inhabitants and examined them for the presence of EPE. All participating volunteers answered a questionnaire about putative risk factors for EPE carriage. Suspected EPE isolates (n = 418) from patients with bloodstream infection (BSI) were collected from Swedish laboratories. Isolates were genotypically and phenotypically characterized.

    RESULTS: Our results show that the EPE population found in carriers generally had lower pathogenicity compared with the isolates from BSIs, since carriers had a lower proportion of E. coli belonging to phylogroup B2, ST131 and ST131 subclone H30-Rx. Isolates from carriers also had lower levels of multiresistance. The Swedish carriage rate of EPE was 4.7% (101/2134) among healthy volunteers. Risk factors associated with carriage were travel to countries in Asia (OR = 3.6, 95% CI = 1.4-9.2) and Africa (OR = 3.6, 95% CI = 1.7-7.7) and a diet without pork (OR = 0.5, 95% CI = 0.3-0.8 for pork eaters).

    CONCLUSIONS: E. coli host factors previously associated with higher pathogenicity were all more common in BSIs compared with carriers. This indicates that the risk of invasive infection with EPE may be relatively modest in many community carriers and that EPE carriage of high-risk strains should be the focus of attention for prevention.

  • 38.
    Ong, Jason J.
    et al.
    Central Clinical School, Monash University, Melbourne, Australia; Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.
    Aguirre, Ivette
    Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. Institute for Global Health, University College London (UCL), London, UK.
    Kong, Fabian Y. S.
    Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
    Fairley, Christopher K.
    Central Clinical School, Monash University, Melbourne, Australia; Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia.
    Hocking, Jane S.
    Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
    Chow, Eric P. F.
    Central Clinical School, Monash University, Melbourne, Australia; Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia; Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia.
    Tieosapjaroen, Warittha
    Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia.
    Ly, Jenny
    Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia.
    Chen, Marcus Y.
    Central Clinical School, Monash University, Melbourne, Australia; Melbourne Sexual Health Centre, Alfred Hospital, Melbourne, Australia.
    Comparison of gastrointestinal side effects from different doses of azithromycin for the treatment of gonorrhoea2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 7, p. 2011-2016Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Azithromycin is commonly used to treat Neisseria gonorrhoeae. We compared its gastrointestinal side effects using 1 g single, 2 g single or 2 g split (i.e. 1 g plus 1 g 6-12 h later) dosing, representing our clinic's changing guidelines over the study period.

    METHODS: We recruited consecutive sexual health clinic patients who received azithromycin (and 500 mg ceftriaxone) for uncomplicated gonorrhoea. Each patient received a text message 48 h after their attendance to complete a questionnaire.

    RESULTS: Patients received 1 g single (n = 271), 2 g single (218) or 2 g split (105) doses. Vomiting was less common for 1 g versus 2 g single dose [1.1% versus 3.7%; risk difference (RD): -2.6%; 95% CI: -0.2 to -5.4] and 2 g split versus 2 g single dose (0.9% versus 3.7%; RD: -2.8%; 95% CI: -0.3 to -5.8). Nausea was less common for 1 g versus 2 g single dose (13.7% versus 43.1%; RD: -29.5%; 95% CI: -21.7 to -37.2) and 2 g split versus 2 g single dose (16.4% versus 43.1%; RD: -26.8; 95% CI: -17.2 to -36.3). Diarrhoea was less common for 1 g versus 2 g single dose (25.5% versus 50.9%; RD: -25.5%; 95% CI: -17.0 to -33.9) and 2 g split versus 2 g single dose (30.9% versus 50.9%; RD: -20.0; 95% CI: -9.1 to -30.9). Almost all were willing to retake the same dosing for gonorrhoea in the future: 97% for 1 g single; 94% for 2 g single; and 97% for 2 g split dose.

    CONCLUSIONS: Azithromycin 2 g split dose for gonorrhoea resulted in significantly less vomiting, nausea and diarrhoea than a 2 g single dose.

  • 39. Scandinavian study group,
    Loracarbef versus doxycycline in the treatment of acute bacterial maxillary sinusitis1993In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 31, no 6, p. 949-961Article in journal (Refereed)
    Abstract [en]

    In a double-blind, multicentre study, 662 patients with acute maxillary sinusitis were randomly assigned to receive either loracarbef 400 mg bd (332 patients) or doxycycine, 200 mg for the first dose followed by 100 mg od, (330 patients) for ten days. One hundred and sixty-eight patients in the loracarbef group and 164 in the doxycycline group were evaluable for efficacy. Streptococcus pneumoniae and/or Haemophilus influenzae were isolated from approximately 75% of patients. The clinical response rate (cure or improvement) was significantly higher for patients receiving loracarbef (98·2%) than for those who received doxycycline (92·2%). There was no significant difference between the two groups with respect to bacteriological outcome, although more of the pre-treatment isolates were resistant to doxycycline (35 strains) than to loracarbef (five strains). Adverse events related to the gastrointestinal tract occurred in 11·7% and 10·6% of loracarbef- and doxycycline-treated patients respectively; therapy was terminated prematurely in ten patients in the loracarbef group and in nine in the doxycycline group. The results indicate that loracarbef is effective and safe treatment for acute maxillary sinusitis.

  • 40.
    Sid Ahmed, Mazen
    et al.
    Örebro University, School of Science and Technology. Microbiology Division, Hamad Medical Corporation, Doha, Qatar.
    Abdel Hadi, Hamad
    Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar.
    Hassan, Abubaker A. I.
    Division of General Medicine, Wayne State University, Detroit, MI, USA.
    Abu Jarir, Sulieman
    Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar.
    Al-Maslamani, Muna A.
    Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar.
    Eltai, Nahla Omer
    Biomedical Research Center, Qatar University, Doha, Qatar.
    Dousa, Khalid M.
    University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
    Hujer, Andrea M.
    Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Louis Stokes Cleveland, Department of Veterans Affairs Medical Center, Cleveland, OH, USA.
    Sultan, Ali A.
    Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar.
    Söderquist, Bo
    Örebro University, School of Medical Sciences.
    Bonomo, Robert A.
    Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Louis Stokes Cleveland, Department of Veterans Affairs Medical Center, Cleveland, OH, USA; Departments of Pharmacology, Molecular Biology and Microbiology, Biochemistry, and Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; The CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH, USA.
    Ibrahim, Emad Bashir
    Microbiology Division, Hamad Medical Corporation, Doha, Qatar.
    Jass, Jana
    Örebro University, School of Science and Technology.
    Omrani, Ali S.
    Communicable Diseases Center, Hamad Medical Corporation, Doha, Qatar.
    Evaluation of in vitro activity of ceftazidime/avibactam and ceftolozane/tazobactam against MDR Pseudomonas aeruginosa isolates from Qatar2019In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 12, p. 3497-3504Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the in vitro activity of ceftazidime/avibactam and ceftolozane/tazobactam against clinical isolates of MDR Pseudomonas aeruginosa from Qatar, as well as the mechanisms of resistance.

    METHODS: MDR P. aeruginosa isolated between October 2014 and September 2015 from all public hospitals in Qatar were included. The BD PhoenixTM system was used for identification and initial antimicrobial susceptibility testing, while Liofilchem MIC Test Strips (Liofilchem, Roseto degli Abruzzi, Italy) were used for confirmation of ceftazidime/avibactam and ceftolozane/tazobactam susceptibility. Ten ceftazidime/avibactam- and/or ceftolozane/tazobactam-resistant isolates were randomly selected for WGS.

    RESULTS: A total of 205 MDR P. aeruginosa isolates were included. Of these, 141 (68.8%) were susceptible to ceftazidime/avibactam, 129 (62.9%) were susceptible to ceftolozane/tazobactam, 121 (59.0%) were susceptible to both and 56 (27.3%) were susceptible to neither. Twenty (9.8%) isolates were susceptible to ceftazidime/avibactam but not to ceftolozane/tazobactam and only 8 (3.9%) were susceptible to ceftolozane/tazobactam but not to ceftazidime/avibactam. Less than 50% of XDR isolates were susceptible to ceftazidime/avibactam or ceftolozane/tazobactam. The 10 sequenced isolates belonged to six different STs and all produced AmpC and OXA enzymes; 5 (50%) produced ESBL and 4 (40%) produced VIM enzymes.

    CONCLUSIONS: MDR P. aeruginosa susceptibility rates to ceftazidime/avibactam and ceftolozane/tazobactam were higher than those to all existing antipseudomonal agents, except colistin, but were less than 50% in extremely resistant isolates. Non-susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam was largely due to the production of ESBL and VIM enzymes. Ceftazidime/avibactam and ceftolozane/tazobactam are possible options for some patients with MDR P. aeruginosa in Qatar.

  • 41.
    Simon, Sebastian
    et al.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria; Second Department, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria.
    Frank, Bernhard J. H.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria.
    Hartmann, Susana
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria.
    Aichmair, Alexander
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria; Second Department, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Hofstaetter, Jochen G.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria; Second Department, Orthopaedic Hospital Vienna-Speising, Speisinger Straße 109, 1130 Vienna, Austria.
    Dalbavancin in Gram-positive periprosthetic joint infections-authors' response2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 5, p. 1316-1316Article in journal (Other academic)
  • 42.
    Simon, Sebastian
    et al.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria; 2nd Department, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Frank, Bernhard J. H.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Hartmann, Susana
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Hinterhuber, Laetitia
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Reitsamer, Michael
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Aichmair, Alexander
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria; 2nd Department, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Dominkus, Martin
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria; School of Medicine, Sigmund Freud University Vienna, Vienna, Austria.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Hofstaetter, Jochen G.
    Michael Ogon Laboratory for Orthopaedic Research, Orthopaedic Hospital Vienna-Speising, Vienna, Austria; 2nd Department, Orthopaedic Hospital Vienna-Speising, Vienna, Austria.
    Dalbavancin in Gram-positive periprosthetic joint infections2022In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 77, no 8, p. 2274-2277Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The unique properties of dalbavancin (DAL) emphasize the need to explore its clinical benefits to treat periprosthetic joint infections (PJIs). The present study aimed to compare the treatment outcome of dalbavancin with Standard of Care (SoC) in hip and knee PJIs.

    METHODS: Eighty-nine patients were selected for each group of this study based on our prospectively maintained PJI database. A 1:1 propensity score-matching was performed between patients who received at least two doses of dalbavancin and those who received SoC. Patients were matched based on demographics, joint, patient risk factors, Musculoskeletal Infection Society (MSIS) criteria, surgical management and type of infection. Treatment outcome was evaluated considering re-infection and re-revision rates, safety and tolerability of dalbavancin after a minimum of 1 year follow-up.

    RESULTS: Infection eradication was achieved in 69 (77.5%) and 66 (74.2%) patients of the DAL and SoC groups, respectively. Thirteen (14.6%) patients in the DAL group and 12 (13.5%) patients in the SoC group had an infection-related re-revision. The most prevalent microorganisms among the two groups were Staphylococcus epidermidis (32.3%), Staphylococcus aureus (13.8%) and Cutibacterium spp. (11.3%). There were significantly less Gram-positive bacteria (P = 0.03) detected in patients who received dalbavancin (17.4%) treatment compared with those treated with SoC (48.0%) in culture-positive re-revisions.

    CONCLUSIONS: Dalbavancin treatment for Gram-positive PJIs resulted in a similar outcome to SoC, with excellent safety and low rate of adverse effects. Dalbavancin seems to be a promising antimicrobial against PJIs by reducing the risk of Gram-positive re-infections and allowing a less frequent dosage with potential outpatient IV treatment.

  • 43.
    Skow, Marius
    et al.
    The Antibiotic Centre for Primary Care, Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Fossum, Guro H.
    The Antibiotic Centre for Primary Care, Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; General Practice Research Unit (AFE), Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Høye, Sigurd
    The Antibiotic Centre for Primary Care, Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Straand, Jørund
    General Practice Research Unit (AFE), Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Brænd, Anja Maria
    The Antibiotic Centre for Primary Care, Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; General Practice Research Unit (AFE), Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway.
    Emilsson, Louise
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway; Vårdcentralen Värmlands Nysäter and Centre for Clinical Research, County Council of Värmland, Värmlands Nysäter, Karlstad, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Hospitalizations and severe complications following acute sinusitis in general practice: a registry-based cohort study2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 9, p. 2217-2227Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate complication rates of acute sinusitis in general practice, and whether antibiotic prescribing had an impact on complication rate.

    Methods: All adult patients diagnosed with sinusitis in Norwegian general practice between 1 July 2012 and 30 June 2019 were included. GP consultation data from the Norwegian Control and Payment for Health Reimbursements Database were linked with antibiotic prescriptions (Norwegian Prescription Database) and hospital admissions (Norwegian Patient Registry). Main outcomes were sinusitis-related hospitalizations and severe complications within 30 days. Logistic regression was used to estimate associations between antibiotic prescriptions, prespecified risk factors, individual GP prescribing quintile, and outcomes.

    Results: A total of 711 069 episodes of acute sinusitis in 415 781 patients were identified. During the study period, both annual episode rate (from 30.2 to 21.2 per 1000 inhabitants) and antibiotic prescription rate (63.3% to 46.5%; P < 0.001) decreased. Yearly hospitalization rate was stable at 10.0 cases per 10 000 sinusitis episodes and the corresponding rate of severe complications was 3.2, with no yearly change (P = 0.765). Antibiotic prescribing was associated with increased risk of hospitalization [adjusted OR 1.8 (95% CI 1.5-2.1)] but not with severe complications. Individual GP prescribing quintile was not associated with any of the outcomes, whereas risk factors such as previous drug abuse, or head injury, skull surgery or malformations, and being immunocompromised were significantly associated with increased risk of both outcomes.

    Conclusions: Severe complications of acute sinusitis were rare and no protective effect of high prescribing practice among GPs was found. Recommendations to further reduce antibiotic prescribing are generally encouraged, except for high-risk groups.

  • 44.
    Somajo, Sofia
    et al.
    Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
    Nilsson, Frida
    Department of Clinical Microbiology, Region Kronoberg, Växjö/Karlskrona, Sweden.
    Ekelund, Oskar
    Department of Clinical Microbiology, Region Kronoberg, Växjö/Karlskrona, Sweden.
    Unemo, Magnus
    Örebro University, School of Medical Sciences. Örebro University Hospital. Faculty of Medicine and Health, WHO Collaborating Centre for Gonorrhoea and Other STIs, Örebro University, Örebro, Sweden; Institute for Global Health, University College London, London, UK.
    Detection of antimicrobial resistance in <5 h in Neisseria gonorrhoeae isolates using flow cytometry-proof of concept for seven clinically relevant antimicrobials2024In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, article id dkae034Article in journal (Refereed)
    Abstract [en]

    Introduction: Antimicrobial resistance in Neisseria gonorrhoeae compromises gonorrhoea treatment and rapid antimicrobial susceptibility testing (AST) would be valuable. We have developed a rapid and accurate flow cytometry method (FCM) for AST of gonococci.

    Methods: The 2016 WHO gonococcal reference strains, and WHO Q, R and S (n = 17) were tested against seven clinically relevant antibiotics (ceftriaxone, cefixime, azithromycin, spectinomycin, ciprofloxacin, tetracycline and gentamicin). After 4.5 h incubation of inoculated broth, the fluorescent dye Syto (TM) 9 was added, followed by FCM analysis. After gating, the relative remaining population of gonococci, compared with unexposed growth control samples, was plotted against antimicrobial concentration, followed by non-linear curve regression analysis. Furthermore, the response at one single concentration/tested antibiotic was evaluated with the intention to use as a screening test for detection of resistant gonococci.

    Results: A dose-dependent response was seen in susceptible isolates for all tested antimicrobials. There was a clear separation between susceptible/WT and resistant/non-WT isolates for ceftriaxone, cefixime, spectinomycin, ciprofloxacin and tetracycline. In contrast, for azithromycin, only high-level-resistant isolates were distinguished, while resistant isolates with MICs of 4 mg/L were indistinguishable from WT (MIC <= 1 mg/L) isolates. For gentamicin, all tested 17 isolates were WT and FCM analysis resulted in uniform dose-response curves. Using a single antibiotic concentration and a 50% remaining cell population cut-off, the overall sensitivity and specificity for resistance detection were 93% and 99%, respectively.

    Conclusions: By providing results in <5 h for gonococcal isolates, FCM-based AST can become a rapid screening method for antimicrobial resistance or antimicrobial susceptibility in gonococci.

  • 45.
    Unemo, Magnus
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology.
    Ahlstrand, Josefine
    WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Sánchez-Busó, Leonor
    Centre for Genomic Pathogen Surveillance, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK; Genomics and Health Area, Foundation for the Promotion of Health and Biomedical Research in the Valencian Community (FISABIO-Public Health), Valencia, Spain.
    Day, Michaela
    National Infection Service, Public Health England, London, UK.
    Aanensen, David
    Centre for Genomic Pathogen Surveillance, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK; Centre for Genomic Pathogen Surveillance, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. Örebro University Hospital. WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology.
    Cole, Michelle J.
    National Infection Service, Public Health England, London, UK.
    High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 20182021In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 5, p. 1221-1228Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Novel antimicrobials for treatment of gonorrhoea are imperative. The first-in-class spiropyrimidinetrione zoliflodacin is promising and currently in an international Phase 3 randomized controlled clinical trial (RCT) for treatment of uncomplicated gonorrhoea. We evaluated the in vitro activity of and the genetic conservation of the target (GyrB) and other potential zoliflodacin resistance determinants among 1209 consecutive clinical Neisseria gonorrhoeae isolates obtained from 25 EU/European Economic Area (EEA) countries in 2018 and compared the activity of zoliflodacin with that of therapeutic antimicrobials currently used.

    METHODS: MICs of zoliflodacin, ceftriaxone, cefixime, azithromycin and ciprofloxacin were determined using an agar dilution technique for zoliflodacin or using MIC gradient strip tests or an agar dilution technique for the other antimicrobials. Genome sequences were available for 96.1% of isolates.

    RESULTS: Zoliflodacin modal MIC, MIC50, MIC90 and MIC range were 0.125, 0.125, 0.125 and ≤0.004-0.5 mg/L, respectively. The resistance was 49.9%, 6.7%, 1.6% and 0.2% to ciprofloxacin, azithromycin, cefixime and ceftriaxone, respectively. Zoliflodacin did not show any cross-resistance to other tested antimicrobials. GyrB was highly conserved and no zoliflodacin gyrB resistance mutations were found. No fluoroquinolone target GyrA or ParC resistance mutations or mutations causing overexpression of the MtrCDE efflux pump substantially affected the MICs of zoliflodacin.

    CONCLUSIONS: The in vitro susceptibility to zoliflodacin was high and the zoliflodacin target GyrB was conserved among EU/EEA gonococcal isolates in 2018. This study supports further clinical development of zoliflodacin. However, additional zoliflodacin data regarding particularly the treatment of pharyngeal gonorrhoea, pharmacokinetics/pharmacodynamics and resistance selection, including suppression, would be valuable.

  • 46.
    Unemo, Magnus
    et al.
    Örebro University, School of Health Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Golparian, Daniel
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Sánchez-Busó, Leonor
    Pathogen Genomics, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute, Hinxton, UK.
    Grad, Yonatan
    Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, USA; Division of Infectious Diseases Brigham andWomen’s Hospital, Harvard Medical School, Boston, USA.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences. WHO Collaborating Centre for Gonorrhoea and other Sexually Transmitted Infections, National Reference Laboratory for Pathogenic Neisseria, Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Ohnishi, Makoto
    Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
    Lahra, Monica M.
    WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Randwick, Sydney, Australia.
    Limnios, Athena
    WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, The Prince of Wales Hospital, Randwick, Sydney, Australia.
    Sikora, Aleksandra E.
    Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, USA.
    Wi, Teodora
    Department of Reproductive Health and Research, World Health Organization, Geneva, Switzerland.
    Harris, Simon R.
    Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
    The novel 2016 WHO Neisseria gonorrhoeae reference strains for global quality assurance of laboratory investigations: phenotypic, genetic and reference genome characterization2016In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 11, p. 3096-3108Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 47.
    Åkerlund, Anna
    et al.
    Division of Clinical Microbiology, County Hospital Ryhov, Jönköping, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Division of Clinical Microbiology, Linköping University Hospital, Linköping, Sweden.
    Jonasson, Emma
    Department of Clinical Microbiology, Central Hospital, Växjö, Sweden; EUCAST Development Laboratory, Växjö, Sweden.
    Matuschek, Erika
    EUCAST Development Laboratory, Växjö, Sweden.
    Serrander, Lena
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Division of Clinical Microbiology, Linköping University Hospital, Linköping, Sweden.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology.
    Kahlmeter, Gunnar
    Department of Clinical Microbiology, Central Hospital, Växjö, Sweden; EUCAST Development Laboratory, Växjö, Sweden.
    EUCAST rapid antimicrobial susceptibility testing (RAST) in blood cultures: validation in 55 European laboratories2020In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 75, no 11, p. 3230-3238Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: When bloodstream infections are caused by resistant bacteria, rapid antimicrobial susceptibility testing (RAST) is important for adjustment of therapy. The EUCAST RAST method, directly from positive blood cultures, was validated in a multi-laboratory study in Europe.

    METHODS: RAST was performed in 40 laboratories in northern Europe (NE) and 15 in southern Europe (SE) from clinical blood cultures positive for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus or Streptococcus pneumoniae. Categorical results at 4, 6 and 8 h of incubation were compared with results for EUCAST standard 16-20 h disc diffusion. The method, preliminary breakpoints and the performance of the laboratories were evaluated.

    RESULTS: The total number of isolates was 833/318 in NE/SE. The number of zone diameters that could be read (88%, 96% and 99%) and interpreted (70%, 81% and 85%) increased with incubation time (4, 6 and 8 h). The categorical agreement was acceptable, with total error rates in NE/SE of 2.4%/4.9% at 4 h, 1.1%/3.5% at 6 h and 1.1%/3.3% at 8 h. False susceptibility at 4, 6 and 8 h of incubation was below 0.3% and 1.1% in NE and SE, respectively, and the corresponding percentages for false resistance were below 1.9% and 2.8%. After fine-tuning breakpoints, more zones could be interpreted (73%, 89% and 93%), with only marginally affected error rates.

    CONCLUSIONS: The EUCAST RAST method can be implemented in routine laboratories without major investments. It provides reliable antimicrobial susceptibility testing results for relevant bloodstream infection pathogens after 4-6 h of incubation.

  • 48.
    Åkerlund, Anna
    et al.
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Division of Clinical Microbiology, Linköping University Hospital, Linköping, Sweden.
    Serrander, Lena
    Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden; Division of Clinical Microbiology, Linköping University Hospital, Linköping, Sweden.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine, Clinical Microbiology.
    Short incubation of disc diffusion for Streptococcus pneumoniae and Haemophilus influenzae to reduce time to susceptibility report2023In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 78, no 10, p. 2563-2571Article in journal (Refereed)
    Abstract [en]

    Background: Rapidly instituted antimicrobial therapy is important in severe infections, and reduced time to the antimicrobial susceptibility testing (AST) report is thus of importance. Disc diffusion (DD) is a cheap, rapidly adaptable, flexible and comprehensive method for phenotypic AST. Previous studies have shown that early reading of inhibition zones for non-fastidious species is possible.

    Objectives: To evaluate zone reading after short incubation of DD in Haemophilus influenzae (n = 73) and Streptococcus pneumoniae (n = 112).

    Methods: The readability was evaluated and susceptibility interpretation (SIR) was performed, using the EUCAST 18 & PLUSMN; 2 h incubation breakpoint table (version 12.0), after 6 and 8 h of incubation. Categorical agreement (CA) and error rates were calculated using standard DD and broth microdilution as reference.

    Results: The proportion of readable zones in H. influenzae was 19% (6 h) and 89% (8 h). The CA was 98% after 8 h. The corresponding readability in S. pneumoniae was 63%/98% and CA was 95%/97% after 6 and 8 h, respectively. Early reading of the screening discs (benzylpenicillin 1 unit in H. influenzae and oxacillin 1 & mu;g in S. pneumoniae) correctly identified 18/22 of the H. influenzae isolates and all the readable S. pneumoniae isolates with reduced & beta;-lactam susceptibility. For non-& beta;-lactam agents, very major errors were most common for quinolones in S. pneumoniae. Introduction of areas of technical uncertainty (ATUs) reduced the error rate to & LE;1.1%.

    Conclusions: We conclude that shortened incubation is feasible for H. influenzae and S. pneumoniae. To reduce the risk of false categorization a buffer zone (i.e. ATU) near the breakpoints must be used.

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