Using the genetic characteristics of Neisseria gonorrhoeae strains with decreased susceptibility to cefixime to develop a molecular assay to predict cefixime susceptibility

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.

Epidemiology, Treatments, and Vaccine Development for Antimicrobial-Resistant Neisseria gonorrhoeae: Current Strategies and Future Directions

“…There has also been progress in predicting antimicrobial susceptibility to cefixime. Deng et al previously detailed six codons that could be used to detect cefixime decreased susceptibility with 99.5% sensitivity [ 62 ]. Although an assay is currently in development, these alleles have correctly predicted 115/121 (95.9%) N. gonorrhoeae strains with decreased susceptibility to cefixime [ 63 ].…”

The antimicrobial resistance landscape of Neisseria gonorrhoeae in New Zealand from November 2018 to March 2019 and the role of sexual orientation in transmission

“…MIC breakpoints were interpreted following European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [ 25 ] (Table S1). Decreased susceptibility to ceftriaxone (CTRX) and cefixime (CFIX) was defined as MIC ≥0.06 and ≥0.12 mg l −1 , respectively, with the definition of the ceftriaxone MIC in line with the Australian Gonococcal Surveillance Programme (AGSP) [ 26 ] and the cefixime MIC based on definitions by Deng et al [ 27 ].…”

Reducing bacterial antibiotic resistance by targeting bacterial metabolic pathways and disrupting RND efflux pump activity

“…The mosaic pbp genes originated from the continued mixture and rearrangements of DNA by the bacteria named Streptococcus mitis [18]. The influx of a class of antibiotics known as cefiximes, which are thirdgeneration cephalosporins, has also been blocked after mosaicism and point mutations in penA genes that code for Pbp expression in N. gonorrhoeae [19]. Additionally, A. baumanii becomes antibiotic resistant by obtaining resistant genes from conjugation, which is mostly a horizontal transfer of genes, and via mutations in its DNA.…”