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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.

SUBMITTER: Deng X

PROVIDER: S-EPMC7386398 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Deng Xiaomeng X Allan-Blitz Lao-Tzu LT Klausner Jeffrey D JD

Sexual health 20190901 5

<h4>Background</h4>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 prop ...[more]

PMID: 31230613

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Project description:Treatment regimens for gonorrhea have limited efficacy worldwide due to the rapid spread of antimicrobial resistance. Cefixime (CFM) is currently not recommended as a first-line treatment for gonorrhea due to the increasing number of resistant strains worldwide. Nonetheless, Neisseria gonorrhoeae strains can be eradicated by CFM at a 400 mg/day dose, provided that the strains are CFM responsive (MIC ≤ 0.064 mg/L). To develop a nonculture test for predicting the CFM responsiveness of N. gonorrhoeae strains, we developed an assay to detect N. gonorrhoeae nonmosaic penA using loop-mediated isothermal amplification (LAMP). To avoid false-positive reactions with commensal Neisseria spp. penA, we amplified specific regions of the N. gonorrhoeae penA (NG-penA-LAMP1) and also the nonmosaic N. gonorrhoeae penA (NG-penA-LAMP3). This assay was validated using isolated N. gonorrhoeae (n = 204) and Neisseria spp. (n = 95) strains. Clinical specimens (n = 95) with confirmed positivity in both culture and real-time PCR were evaluated to validate the system. The combination of the previously described NG-penA-LAMP1 and our new NG-penA-LAMP3 assays had high sensitivity (100%) and specificity (100%) for identifying N. gonorrhoeae carrying the nonmosaic type. To determine whether CFM could be applicable for gonorrhea treatment without culture testing, we developed a LAMP assay that targets penA allele-specific nonmosaic types for use as one of the tools for point-of-care testing of antimicrobial resistance. IMPORTANCE Neisseria gonorrhoeae is among the hot topics of "resistance guided therapy," one of the top 5 urgent antimicrobial threats according to the Centers for Disease Control and Prevention (CDC). There is a need either to develop new agents or to make effective use of existing agents, with the current limited number of therapeutic agents available. Knowing the drug susceptibility information of the target microorganism prior to treating patients is very useful in selecting an effective antibiotic, especially in gonococcal infections where drug resistance is prominent, and is also important in preventing treatment failure. In this study, we developed a new method for obtaining drug susceptibility profiles of Neisseria gonorrhoeae using the loop-mediated isothermal amplification (LAMP) method. The LAMP assay does not require expensive devices. Therefore, this method is expected to be a tool for point-of-care testing of antimicrobial resistance for individualized treatment in the future.

Project description:BackgroundNeisseria gonorrhoeae (NG) infection is a serious public health problem. The third-generation extended-spectrum cephalosporins (ESCs) have been used as the first-line treatment for NG infection for almost three decades. However, in recent years, treatment failures with the oral third-generation ESCs have been reported worldwide. This study aimed to estimate worldwide susceptibility rates of NG to cefixime and cefpodoxime by analyzing data from all relevant published studies.Methodology/principal findingsTwo researchers independently searched five databases to identify studies on susceptibilities of NG to cefixime and cefpodoxime published between January 1, 1984 and October 15, 2012. A fixed-effect model was used to perform group analysis, and a χ2 test was employed to make subgroup comparison. Publication bias was assessed with the Begg rank correlation test. The pooled susceptibility rate of NG isolates to cefixime was 99.8% (95% CI: 99.7%-99.8%). The cefixime susceptibility rate of NG isolates from men was significantly lower than that from patients without information of gender or from men and women; the susceptibility rate of NG isolates from Asia was significantly lower than that from other continents; and the susceptibility rate of NG isolates collected before or during 2003 was significantly higher than that after 2003. The pooled susceptibility rate of NG isolates to cefpodoxime was 92.8% (95% CI: 89.0%-95.3%), which was lower than that to cefixime (92.8% vs. 99.8%, χ2 = 951.809, P<0.01).ConclusionsThe susceptibility rate of NG isolates to cefixime varied with the gender of patients and geographical location from which NG isolates were collected, and declined with time. The reported lower susceptibility rate of NG isolates to cefixime and associated treatment failures, as well as the emergence of NG strains with cephalosporin resistance call for the more effective control of NG infection and the development of new antibiotics.

Project description:BackgroundThe emergence of Neisseria gonorrhoeae with decreased susceptibility to extended spectrum cephalosporins raises the prospect of untreatable gonorrhoea. In the absence of new treatments, efforts to slow the increasing incidence of resistant gonococcus require insight into the factors that contribute to its emergence and spread. We assessed the relatedness between isolates in the USA and reconstructed likely spread of lineages through different sexual networks.MethodsWe sequenced the genomes of 236 isolates of N gonorrhoeae collected by the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project (GISP) from sentinel public sexually transmitted disease clinics in the USA, including 118 (97%) of the isolates from 2009-10 in GISP with reduced susceptibility to cefixime (cef(RS)) and 118 cefixime-susceptible isolates from GISP matched as closely as possible by location, collection date, and sexual orientation. We assessed the association between antimicrobial resistance genotype and phenotype and correlated phylogenetic clustering with location and sexual orientation.FindingsMosaic penA XXXIV had a high positive predictive value for cef(RS). We found that two of the 118 cef(RS) isolates lacked a mosaic penA allele, and rechecking showed that these two were susceptible to cefixime. Of the 116 remaining cef(RS) isolates, 114 (98%) fell into two distinct lineages that have independently acquired mosaic penA allele XXXIV. A major lineage of cef(RS) strains spread eastward, predominantly through a sexual network of men who have sex with men. Eight of nine inferred transitions between sexual networks were introductions from men who have sex with men into the heterosexual population.InterpretationGenomic methods might aid efforts to slow the spread of antibiotic-resistant N gonorrhoeae through augmentation of gonococcal outbreak surveillance and identification of populations that could benefit from increased screening for asymptomatic infections.

Dataset Information

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

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

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