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Mechanisms of Resistance

High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure

Magnus Unemo, Daniel Golparian, Robert Nicholas, Makoto Ohnishi, Anne Gallay, Patrice Sednaoui
Magnus Unemo
aWHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden
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Daniel Golparian
aWHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, Örebro University Hospital, Örebro, Sweden
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Robert Nicholas
bDepartment of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA
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Makoto Ohnishi
cNational Institute of Infectious Diseases, Tokyo, Japan
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Anne Gallay
dInstitut de Veille Sanitaire, Saint-Maurice, France
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Patrice Sednaoui
eInstitut Alfred Fournier, Centre National de Référence des Gonocoques, Paris, France
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DOI: 10.1128/AAC.05760-11
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  • Fig 1
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    Fig 1

    Alignment of PBP 2 sequences from strains of Neisseria gonorrhoeae with different penA alleles. M32091, wild-type PBP 2; XXXIV, penA mosaic allele previously described (27, 33); CI, penA mosaic allele of F89; XXVI (27, 36) and XXX (27, 51), the only previously reported true penA mosaic alleles containing an A501 alteration (27); C, penA mosaic allele of H041, which is the first high-level ceftriaxone-resistant strain found in Japan (27); and XIII and XVIII, previously described nonmosaic penA alleles that contain A501V (most prevalent) and A501T alterations (27, 51). Identical amino acids are designated by a dot, and alterations from the wild-type sequence are shown with a single capital letter. The three active-site motifs are marked by dashed boxes, while the location of amino acid Ala501 (position 502 in the alignment due to the D345 insertion) is marked with a solid box.

  • Fig 2
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    Fig 2

    MICs of a set of recipient strains transformed with the full-length penA allele (penA-CI) from the high-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae strain F89 (donor). The MICs of cefixime and ceftriaxone and the number and type of resistance determinants (e.g., mtrR, penB, and ponA) in the recipient strains varied. The MICs of cefixime (A) and ceftriaxone (B) were determined using the Etest method, and the values shown are the means of three transformation experiments (the bars give only whole-MIC steps), with the exact mean MICs in parentheses. The ratios of the MICs of the transformant to the recipient strain (T/R) are indicated.

Tables

  • Figures
  • Table 1

    Susceptibilities of high-level cefixime- and ceftriaxone-resistant N. gonorrhoeae strain F89 to various antimicrobials

    Class, subclass, and antimicrobialMIC Etesta (S, I, or R)b,cCDS (mm)d
    β-Lactams, penicillins
        Penicillin G1 (I)b,c5 (I)
        Ampicillin0.5NDe
        Amdinocillin128ND
        Oxacillin64ND
        Piperacillin0.125ND
        Piperacillin-tazobactam0.016ND
    β-Lactams, monobactams, aztreonam64ND
    β-Lactams, cephalosporins
        Cefuroxime16 (R)bND
        Cefpodoxime16 (R)b6 (R)
        Ceftazidime16 (R)bND
        Cefotaxime4 (R)b,cND
        Cefixime4 (R)b,cND
        Ceftriaxone2 (1)a (R)b,c3 (R)
        Cefepime16 (R)bND
    β-Lactams, carbapenems
        Ertapenem0.016ND
        Meropenem0.016ND
        Imipenem0.5ND
    Fluoroquinolones
        Ciprofloxacin>32 (R)b,c4 (R)
        Levofloxacin8ND
        Moxifloxacin4ND
    Macrolides
        Azithromycin1 (R)cND
        Erythromycin2ND
    Aminoglycosides
        Gentamicin8ND
        Kanamycin16ND
        Tobramycin8ND
    Aminocyclitol, spectinomycin16 (S)b,c13 (S)
    Tetracyclines, tetracycline2 (R)cND
    Glycylcycline, tigecycline0.5ND
    Folic acid antagonists, trimethoprim-sulfamethoxazole1ND
    Rifamycins, rifampin0.5ND
    Chloramphenicol4ND
    Nitrofurantoin1ND
    Fusidic acid2ND
    • ↵a MICs were determined using the Etest method (AB bioMérieux, Solna, Sweden) according to the instructions from the manufacturer. Agar dilution was additionally performed for ceftriaxone (the result is in parentheses) according to the method described by the Clinical Laboratory and Standards Institute (CLSI) (9). The Etest method is capable of providing half-MIC steps; however, in accordance with the interpretation of the agar dilution method described by the CLSI (9), only whole-MIC steps are given.

    • ↵b Where available, interpretative criteria (S, susceptible; I, intermediate susceptible; R, resistant) from the CLSI (9) were used.

    • ↵c Interpretative criteria (susceptible, intermediate susceptible, resistant) from the European Committee on Antimicrobial Susceptibility Testing (EUCAST; available online at www.eucast.org/Clinical breakpoints [accessed 20 November 2011]) are also reported where available.

    • ↵d The calibrated dichotomous sensitivity (CDS) disc diffusion method (40; http://web.med.unsw.edu.au/cdstest) is used for antimicrobial resistance testing in many countries in the World Health Organization (WHO) Western Pacific Region.

    • ↵e ND, not determined.

  • Table 2

    Neisseria gonorrhoeae strains with different cefixime MICs and ceftriaxone MICs and containing different resistance determinants used as recipients in transformation experiments of full-length penA gene from F89

    StrainMLST STaNG-MAST STbMIC (μg/ml)cGenotype
    CefiximeCeftriaxonepenAdmtrRepenBfponAg
    WHO FNewST3303<0.016e<0.002epenA XV (WT)WThWTWT
    WHO MST7367ST3304<0.0160.016epenA II (A345a)A-delYesL421P
    WHO KST7363ST14240.50.064penA X (Mosaic)A-delYesL421P
    35/02ST7363ST3260.50.125penA XXVIII (Mosaic)A-delYesL421P
    WHO LST1590ST14220.250.125penA VII (A501V)A-delYesL421P
    • ↵a MLST, multilocus sequencing typing (29).

    • ↵b NG-MAST, Neisseria gonorrhoeae multiantigen sequence typing (44).

    • ↵c The Etest method reads also half-MIC steps; however, in accordance with the interpretation of the agar dilution method described by the Clinical Laboratory and Standards Institute (CLSI) (9), only whole-MIC steps are given. MICs of <0.002 μg/ml and <0.016 μg/ml were calculated as 0.001 μg/ml and 0.008 μg/ml, respectively, in the MIC ratios in Fig. 2.

    • ↵d penA mosaic allele encodes a mosaic penicillin-binding protein 2 (PBP 2) that causes a decreased susceptibility to extended-spectrum cephalosporins (ESCs) (21, 27, 36, 41, 43, 58).

    • ↵e A-del, a characteristic single-nucleotide (A) deletion in the inverted repeat of the promoter region of mtrR that causes overexpression of the MtrCDE efflux pump, resulting in a further decreased susceptibility to ESCs (21, 27, 41, 58).

    • ↵f Yes, the presence of the alterations of amino acids 101 and 102 in porin PorB (penB determinant) that cause a decreased intake of ESCs and, accordingly, a further decreased susceptibility to ESCs (21, 27, 41, 58).

    • ↵g The alteration of amino acid 421 in PBP 1 (encoded by ponA) causes decreased susceptibility to penicillins (21, 34, 58).

    • ↵h WT, wild type.

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High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure
Magnus Unemo, Daniel Golparian, Robert Nicholas, Makoto Ohnishi, Anne Gallay, Patrice Sednaoui
Antimicrobial Agents and Chemotherapy Feb 2012, 56 (3) 1273-1280; DOI: 10.1128/AAC.05760-11

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High-Level Cefixime- and Ceftriaxone-Resistant Neisseria gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure
Magnus Unemo, Daniel Golparian, Robert Nicholas, Makoto Ohnishi, Anne Gallay, Patrice Sednaoui
Antimicrobial Agents and Chemotherapy Feb 2012, 56 (3) 1273-1280; DOI: 10.1128/AAC.05760-11
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