Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden

Golparian, Daniel; Hellmark, Bengt; Fredlund, Hans; Unemo, Magnus

doi:10.1136/sti.2010.045377

Cited by 82 publications

(93 citation statements)

References 30 publications

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“…The molecular markers previously described as contributing to cephalosporin resistance, such as penA, mtrR, porB, ponA, and pilQ mutations, do not adequately account for the observed phenotypes (4,9,10,15,20,(24)(25)(26)51). Of these markers identified in silico using the WGS data, the presence of a penA mosaic allele, mtrR Ϫ35A deletion and/or a porB G120K mutation were the best indicators of decreased susceptibility to cephalosporins (Table 2).…”

Section: Discussionmentioning

confidence: 99%

“…Other genes associated with penicillin resistance include pilQ and ponA; however, the role in ESC-DS remains unclear (3,9,10,20,(23)(24)(25)(26)(27). The currently identified resistance determinants do not fully account for the observed ESC MICs, and it is hypothesized that other factors may be involved (4,9,10,15,20,24,25). AZM resistance has been associated with mutations in 23S rRNA alleles (4,28) as well as mtrR (29)(30)(31).…”

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confidence: 99%

“…Mutations in the promoter and/or the coding region of the repressor gene mtrR cause overexpression of the MtrCDE efflux pump (3,4,15,19,20) and porB1b gene mutations (penB G120 and/or A121 mutation) have been shown to cause decreased membrane permeability and contribute to decreased susceptibility toward cephalosporins (3,4,15,(19)(20)(21)(22). Other genes associated with penicillin resistance include pilQ and ponA; however, the role in ESC-DS remains unclear (3,9,10,20,(23)(24)(25)(26)(27). The currently identified resistance determinants do not fully account for the observed ESC MICs, and it is hypothesized that other factors may be involved (4,9,10,15,20,24,25).…”

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confidence: 99%

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Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013

et al. 2015

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A large-scale, whole-genome comparison of Canadian Neisseria gonorrhoeae isolates with high-level cephalosporin MICs was used to demonstrate a genomic epidemiology approach to investigate strain relatedness and dynamics. Although current typing methods have been very successful in tracing short-chain transmission of gonorrheal disease, investigating the temporal evolutionary relationships and geographical dissemination of highly clonal lineages requires enhanced resolution only available through whole-genome sequencing (WGS). Phylogenomic cluster analysis grouped 169 Canadian strains into 12 distinct clades. While some N. gonorrhoeae multiantigen sequence types (NG-MAST) agreed with specific phylogenomic clades or subclades, other sequence types (ST) and closely related groups of ST were widely distributed among clades. Decreased susceptibility to extended-spectrum cephalosporins (ESC-DS) emerged among a group of diverse strains in Canada during the 1990s with a variety of nonmosaic penA alleles, followed in 2000/2001 with the penA mosaic X allele and then in 2007 with ST1407 strains with the penA mosaic XXXIV allele. Five genetically distinct ESC-DS lineages were associated with penA mosaic X, XXXV, and XXXIV alleles and nonmosaic XII and XIII alleles. ESC-DS with coresistance to azithromycin was observed in 5 strains with 23S rRNA C2599T or A2143G mutations. As the costs associated with WGS decline and analysis tools are streamlined, WGS can provide a more thorough understanding of strain dynamics, facilitate epidemiological studies to better resolve social networks, and improve surveillance to optimize treatment for gonorrheal infections. N eisseria gonorrhoeae is a Gram-negative diplococcus bacterium that causes gonorrhea infections. Gonorrhea is the second most reported bacterial sexually transmitted infection (STI) in Canada, with reported cases increasing from 15.5 per 100,000 in 1997 to 36.2 per 100,000 in 2012 (1), and approximately 106 million cases are estimated annually worldwide (2). N. gonorrhoeae bacteria have developed resistance against sulfonamides, penicillins, tetracyclines, and fluoroquinolones (3, 4), and current treatment options now include third-generation extended-spectrum cephalosporins (ESC), namely, cefixime (CFM) and ceftriaxone (CRO) (5). MIC creep has seen the modal MIC values rise between 2001 and 2010 in Canada from 0.016 g/ml to 0.125 g/ml and 0.063 g/ml for CFM and CRO, respectively (6). These results coincide with recent clinical reports of treatment failures to primarily CFM monotherapy in Canada (7,8) and additional global reports of high-level CRO MICs in isolates from Japan and Europe (9-13). Furthermore, isolates with decreased susceptibility to cephalosporins and coresistance to azithromycin (AZM), a recommended cotherapy (5), have recently been identified in Canada (14).Decreased susceptibility to extended-spectrum cephalosporins (ESC-DS) and resistance to AZM have been attributed to several molecular mechanisms. The primary mechanism for ESC-DS is modification of the ...

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Section: Discussionmentioning

confidence: 99%

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Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013

et al. 2015

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“…All isolates with elevated cefixime resistance showed the presence of por allele 908 or another highly related allele (less than 0.5% variation at the nucleotide level). An association of ST 1407 with decreased cefixime susceptibility and the wide circulation of this clone has been extensively reported (3,8,14,14,(21)(22)(23). A study comparing antimicrobial resistance surveillance with molecular typing of gonococcal isolates from Europe showed that the genogroup (G1407) accounted for 23% of the overall isolates and predominated in several countries.…”

Section: Discussionmentioning

confidence: 99%

Utility of Specimens Positive for Neisseria gonorrhoeae by the Aptima Combo 2 Assay for Assessment of Strain Diversity and Antibiotic Resistance

et al. 2013

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In our jurisdiction, the Aptima Combo 2 assay (Gen-Probe, Inc.) is used to detect Neisseria gonorrhoeae from specimens collected at clinics for sexually transmitted infections (STI) and from select community patients. In addition, swabs are also collected for N. gonorrhoeae culture, susceptibility testing, and sequence typing (ST). Since only a small proportion of samples from provincial cases undergo culture, the available trends in antimicrobial susceptibility and predominant strain types may not be representative of all N. gonorrhoeae infections. Due to the limitations facing the use of N. gonorrhoeae culture to understand these trends in the general community, we performed a molecular analysis for markers of cephalosporin resistance and ST determination by using nucleic acid extracts of specimens sent for Aptima testing. Thirty-four samples submitted for both Aptima testing and N. gonorrhoeae culture from the same anatomic location (within 24 h) were included in the study. Sequence type was determined based on the sequence of the por and tbpB genes, and amino acid changes in the PBP 2 protein, encoded by the penA gene, were considered representative for the assessment of antimicrobial susceptibility. Sequence identity of 100% was observed between the sequences obtained from Aptima-analyzed samples and culture samples. Sequencing results showed an association between decreased susceptibility to extended-spectrum cephalosporins (ESC ds ), tbp allele 110, ST 1407, and amino acid changes (G545S, I312M, and V316T) in the PBP 2 protein. Our data, generated based on a few representative genes, suggest that gonococcal samples positive by Aptima testing can be used to determine single nucleotide polymorphisms associated with ESC ds and the sequence type based on molecular strain typing. Confirmation of these findings may obviate the need for gonorrhea culture in the future. N eisseria gonorrhoeae is a common sexually transmitted infection that affects mucosal surfaces and causes a spectrum of conditions, including urethritis, endocervicitis, pelvic inflammatory disease, and infertility (1). Over the years, gonococci have developed resistance to multiple classes of antibiotics, including penicillins, tetracyclines, macrolides, and quinolones (2). Of recent concern is a steady increase in the MICs to extended-spectrum cephalosporins, including cefixime and ceftriaxone, in several countries including Canada, with reported levels at 0.12 g/ml, one doubling dilution away from the Clinical and Laboratory Standards Institute (CLSI) limit of 0.25 g/ml for susceptibility (3-7; CLSI standard M100-S23, January 2013). According to a recent U.S. Centers for Disease Control and Prevention (CDC) update, untreatable gonorrhea could soon be a reality in the United States (http://www.cdc.gov/mmwr/preview /mmwrhtml/mm6131a3.htm). The agency noted that N. gonorrhoeae seems to be developing resistance to the oral antibiotic cefixime, and it no longer recommends cefixime at any dose as a firstline regimen for treatment of gonococcal infec...

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“…Furthermore, specific porB1b mutations that alter amino acid G101 and A102 in the PorB1b porin (the penB resistance determinant) result in additional decreases in ESC susceptibility (3, 11, 16-18, 25, 26, 30, 36, 38, 50). Nevertheless, based on the relatively few studies of gonococcal isolates with decreased ESC susceptibility, polymorphisms in ponA (encoding PBP1) and pilQ (encoding the pore-forming secretin PilQ protein in the type IV pili), which both can be involved in high-level penicillin resistance, do not seem to substantially enhance the MICs of ESCs (11,29,45,49,50). At least one unknown resistance determinant exists (11,18,38,50).…”

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Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone

Ohnishi

Golparian

Shimuta

et al. 2011

Antimicrob Agents Chemother

604

624

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Recently, the first Neisseria gonorrhoeae strain (H041) that is highly resistant to the extended-spectrum cephalosporin (ESC) ceftriaxone, the last remaining option for empirical first-line treatment, was isolated. We performed a detailed characterization of H041, phenotypically and genetically, to confirm the finding, examine its antimicrobial resistance (AMR), and elucidate the resistance mechanisms. H041 was examined using seven species-confirmatory tests, antibiograms (30 antimicrobials), porB sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST), multilocus sequence typing (MLST), and sequencing of ESC resistance determinants (penA, mtrR, penB, ponA, and pilQ). Transformation, using appropriate recipient strains, was performed to confirm the ESC resistance determinants. H041 was assigned to serovar Bpyust, MLST sequence type (ST) ST7363, and the new NG-MAST ST4220. H041 proved highly resistant to ceftriaxone (2 to 4 g/ml, which is 4-to 8-fold higher than any previously described isolate) and all other cephalosporins, as well as most other antimicrobials tested. A new penA mosaic allele caused the ceftriaxone resistance. In conclusion, N. gonorrhoeae has now shown its ability to also develop ceftriaxone resistance. Although the biological fitness of ceftriaxone resistance in N. gonorrhoeae remains unknown, N. gonorrhoeae may soon become a true superbug, causing untreatable gonorrhea. A reduction in the global gonorrhea burden by enhanced disease control activities, combined with wider strategies for general AMR control and enhanced understanding of the mechanisms of emergence and spread of AMR, which need to be monitored globally, and public health response plans for global (and national) perspectives are important. Ultimately, the development of new drugs for efficacious gonorrhea treatment is necessary.

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Emergence, spread and characteristics of Neisseria gonorrhoeae isolates with in vitro decreased susceptibility and resistance to extended-spectrum cephalosporins in Sweden

Cited by 82 publications

References 30 publications

Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013

Whole-Genome Phylogenomic Heterogeneity of Neisseria gonorrhoeae Isolates with Decreased Cephalosporin Susceptibility Collected in Canada between 1989 and 2013

Utility of Specimens Positive for Neisseria gonorrhoeae by the Aptima Combo 2 Assay for Assessment of Strain Diversity and Antibiotic Resistance

Is Neisseria gonorrhoeae Initiating a Future Era of Untreatable Gonorrhea?: Detailed Characterization of the First Strain with High-Level Resistance to Ceftriaxone

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