Xiaomeng Deng1, Lao-Tzu Allan-Blitz2, Jeffrey D Klausner3. 1. David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; and Corresponding author. Email: dengxiaomeng0416@gmail.com. 2. Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; and Department of Medicine, Children's Hospital of Boston, 300 Longwood Avenue, Boston, MA 02115, USA. 3. David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; and Division of Infectious Disease, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Center for Health Sciences, 37-121, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA; and Department of Epidemiology, Fielding School of Public Health, University of California Los Angeles, 650 Charles E. Young Drive S., Los Angeles, CA 90095, USA.
Abstract
BACKGROUND: In the last two decades, gonococcal strains with decreased cefixime susceptibility and cases of clinical treatment failure have been reported worldwide. Gonococcal strains with a cefixime minimum inhibitory concentration (MIC) ≥0.12 µg mL-1 are significantly more likely to fail cefixime treatment than strains with an MIC <0.12 µg mL-1. Various researchers have described the molecular characteristics of gonococcal strains with reduced cefixime susceptibility, and many have proposed critical molecular alterations that contribute to this decreased susceptibility. METHODS: A systematic review of all published articles in PubMed through 1 November 2018 was conducted that report findings on the molecular characteristics and potential mechanisms of resistance for gonococcal strains with decreased cefixime susceptibility. The findings were summarised and suggestions were made for the development of a molecular-based cefixime susceptibility assay. RESULTS: The penicillin-binding protein 2 (PBP2) encoded by the penA gene is the primary target of cefixime antimicrobial activity. Decreased cefixime susceptibility is conferred by altered penA genes with mosaic substitute sequences from other Neisseria (N.) species (identifiable by alterations at amino acid position 375-377) or by non-mosaic penA genes with at least one of the critical amino acid substitutions at positions 501, 542 and 551. Based on this review of 415 international cefixime decreased susceptible N. gonorrhoeae isolates, the estimated sensitivity for an assay detecting the aforementioned amino acid alterations would be 99.5% (413/415). CONCLUSIONS: Targeting mosaic penA and critical amino acid substitutions in non-mosaic penA are necessary and may be sufficient to produce a robust, universal molecular assay to predict cefixime susceptibility.
BACKGROUND: In the last two decades, gonococcal strains with decreased cefixime susceptibility and cases of clinical treatment failure have been reported worldwide. Gonococcal strains with a cefixime minimum inhibitory concentration (MIC) ≥0.12 µg mL-1 are significantly more likely to fail cefixime treatment than strains with an MIC <0.12 µg mL-1. Various researchers have described the molecular characteristics of gonococcal strains with reduced cefixime susceptibility, and many have proposed critical molecular alterations that contribute to this decreased susceptibility. METHODS: A systematic review of all published articles in PubMed through 1 November 2018 was conducted that report findings on the molecular characteristics and potential mechanisms of resistance for gonococcal strains with decreased cefixime susceptibility. The findings were summarised and suggestions were made for the development of a molecular-based cefixime susceptibility assay. RESULTS: The penicillin-binding protein 2 (PBP2) encoded by the penA gene is the primary target of cefixime antimicrobial activity. Decreased cefixime susceptibility is conferred by altered penA genes with mosaic substitute sequences from other Neisseria (N.) species (identifiable by alterations at amino acid position 375-377) or by non-mosaic penA genes with at least one of the critical amino acid substitutions at positions 501, 542 and 551. Based on this review of 415 international cefixime decreased susceptible N. gonorrhoeae isolates, the estimated sensitivity for an assay detecting the aforementioned amino acid alterations would be 99.5% (413/415). CONCLUSIONS: Targeting mosaic penA and critical amino acid substitutions in non-mosaic penA are necessary and may be sufficient to produce a robust, universal molecular assay to predict cefixime susceptibility.
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