The sudden emergence of a <i>Neisseria gonorrhoeae</i> strain with reduced susceptibility to extended-spectrum cephalosporins, Norway

Osnes, Magnus N; Didelot, Xavier; Korne-Elenbaas, Jolinda de; Alfsnes, Kristian; Brynildsrud, Ola Brønstad; Syversen, Gaute; Nilsen, O; Caugant, Dominique A.; Blasio, Birgitte Freiesleben de; Eldholm, Vegard

doi:10.1101/2020.02.07.935825

Cited by 6 publications

(9 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The estimated evolutionary rate was 6.46 mutations per genome per year (CI: 5.81–7.29), translating to 2.91 × 10 −6 (CI: 2.61 × 10 −6 to 3.28 × 10 −6 ) mutations/site/year, which falls in line with previously estimated rates for N. gonorrhoeae ( Didelot et al. 2016 ; Osnes et al. 2020 ).…”

Section: Resultssupporting

confidence: 85%

Antibiotic Treatment Regimes as a Driver of the Global Population Dynamics of a Major Gonorrhea Lineage

Osnes

Dorp

Brynildsrud

et al. 2020

Molecular Biology and Evolution

Self Cite

View full text Add to dashboard Cite

The Neisseria gonorrhoeae multilocus sequence type (ST) 1901 is among the lineages most commonly associated with treatment failure. Here we analyze a global collection of ST-1901 genomes to shed light on the emergence and spread of alleles associated with reduced susceptibility to extended-spectrum cephalosporins (ESCs). The genetic diversity of ST-1901 falls into a minor and a major clade, both of which were inferred to have originated in East Asia. The dispersal of the major clade from Asia happened in two separate waves expanding from around 1987 and 1996, respectively. Both waves first reached North America, and from there spread to Europe and Oceania, with multiple secondary reintroductions to Asia. The ancestor of the second wave acquired the penA 34.001 allele, which significantly reduces susceptibility to extended-spectrum cephalosporins (ESCs). Our results suggest that the acquisition of this allele granted the second wave a fitness advantage at a time when ESCs became the key drug class used to treat gonorrhea. Following its establishment globally, the lineage has served as a reservoir for the repeated emergence of clones fully resistant to the ESC ceftriaxone, an essential drug for effective treatment of gonorrhea. We infer that the effective population sizes of both clades went into decline as treatment schemes shifted from fluoroquinolones via ESC monotherapy to dual therapy with ceftriaxone and azithromycin in Europe and the USA. Despite the inferred recent population size decline, the short evolutionary path from the penA 34.001 allele to alleles providing full ceftriaxone resistance is a cause of concern.

show abstract

Section: Resultssupporting

confidence: 85%

Antibiotic Treatment Regimes as a Driver of the Global Population Dynamics of a Major Gonorrhea Lineage

Osnes

Dorp

Brynildsrud

et al. 2020

Molecular Biology and Evolution

Self Cite

View full text Add to dashboard Cite

show abstract

“…S3 and S4). The resulting evolutionary rate was 5.67 (95% CI: 3.81-8.28) mutations/genome/year which is similar to earlier studies of N. gonorrhoeae (7,12) .…”

Section: Methodssupporting

confidence: 85%

“…Illumina-only and Illumina+nanopore hybrid assemblies were generated as described previously (7) . For analyses of base modifications, nanopore reads were demultiplexed using Deepbinner (8) .…”

Section: Methodsmentioning

confidence: 99%

High-frequency phase-switching of modB methylase is associated with phenotypic ceftriaxone susceptibility in Neisseria gonorrhoeae

Brynildsrud

Osnes

Kévin³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The gonococcal adenine methylase modB , belonging to a Type III restriction modification system, is phase variable, but both the frequency of phase variation and phenotypic impact of phase variation is largely unknown.Here we show that modB switches between the ON and OFF states at a high frequency, with multiple transition events identified over the time scale of a single outbreak. Expanding our analyses, we find a clear association between modB status and azithromycin susceptibility.Among isolates lacking canonical 23S and mtrR promoter mutations, carrying modB in the ON configuration is strongly associated with increased azithromycin minimum inhibitory concentrations. Our findings suggest that modB adenine methylation controls the expression of genes modulating azithromycin susceptibility.1 Importance Despite significant progress, our current understanding of the genetic basis of antibiotic susceptibility remains incomplete. The gonococcal methylase modB is phase variable, meaning that it can be switched ON or OFF via contraction or expansion of a repeat tract in the gene. We find that transitions between the ON and OFF state occur at high frequency. Among strains lacking well-known resistance mutations, a functional modB was found to be associated with decreased susceptibility to azithromycin, a key drug used to treat gonorrhea. This finding brings us a step closer to a full understanding of the genetic underpinnings of antibiotic resistance.

show abstract

“…Peng et al reported MLST7827 as the most prevalent MLST in China already in 2012-2013, although then this MLST was not particularly associated with cephalosporin reduced susceptibility (31). When this strain emerged in Norway in 2016-2018 it was associated with cephalosporin reduced susceptibility (13) and we now confirm that the same emergence has occurred in the Netherlands during the last 3 years. Since isolates from other European countries from the last few years are scarce, these results can only suggest the circulation of this ST in other parts of Europe.…”

Section: Discussionsupporting

confidence: 75%

“…Isolates belonging to MLST1901 and NG-MAST1407, and containing the mosaic penA were most prevalent among ceftriaxone reduced susceptible isolates as well, which suggests that tracking this strain is most important for monitoring emerging resistance. However, Osnes et al recently reported the emergence of a reduced susceptible strain between 2016-2018 in Norway, belonging to MLST7827 and carrying a non-mosaic penA allele with A501V mutation (13). They showed that this strain with an alarming antimicrobial resistance profile likely originated from Asia and potentially circulates in Europe.…”

Section: Introductionmentioning

confidence: 99%

Emergence of a cephalosporin reduced susceptible Neisseria gonorrhoeae clone between 2014-2019 in Amsterdam, the Netherlands, revealed by a genomic population analysis

Korne-Elenbaas¹,

Bruisten²,

Vries

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background Emerging resistance to cephalosporins in Neisseria gonorrhoeae (Ng) is a major public health threat, since these are considered antibiotics of last resort. Continuous surveillance is needed to monitor the circulation of reduced susceptible and resistant strains. Aim For the purpose of epidemiological surveillance, a genomic population analysis was performed on Ng isolates from Amsterdam with a focus on ceftriaxone reduced susceptible isolates. Methods Whole genome sequences were obtained from 318 isolates from 2014-2019 from Amsterdam, the Netherlands. Isolates were typed according to the Multi-Locus Sequence Typing (MLST) scheme and resistance markers were identified. Phylogenetic trees were created to identify genetic clusters and to compare Dutch- and global MLST7827 isolates. Results The majority of ceftriaxone reduced susceptible isolates belonged to MLST7363, MLST1901 and MLST7827. MLST7363 and MLST1901 were dominant reduced susceptible strains from 2014-2016 although MLST7827 emerged and became dominant during 2017-2019. MLST7827 reduced susceptible isolates carried a non-mosaic penA gene with A501V mutation and porB G121K/A121D mutations, which were lacking in susceptible MLST7827 isolates. Phylogenetic analysis of all publicly available MLST7827 isolates showed strong genetic clustering of Dutch- and other European MLST7827 isolates. Conclusion Ceftriaxone reduced susceptible MLST7827 isolates emerged during recent years in Amsterdam. Co-occurrence of penA A501V and porB G121K/A121D mutations was strongly associated with ceftriaxone reduced susceptibility. Genetic clustering of Dutch- and other European MLST7827 isolates indicates extensive circulation of this strain in Europe. Therefore, close monitoring of the spread of this strain with an alarming susceptibility profile is needed.

show abstract

The sudden emergence of a Neisseria gonorrhoeae strain with reduced susceptibility to extended-spectrum cephalosporins, Norway

Cited by 6 publications

References 34 publications

Antibiotic Treatment Regimes as a Driver of the Global Population Dynamics of a Major Gonorrhea Lineage

Antibiotic Treatment Regimes as a Driver of the Global Population Dynamics of a Major Gonorrhea Lineage

High-frequency phase-switching of modB methylase is associated with phenotypic ceftriaxone susceptibility in Neisseria gonorrhoeae

Emergence of a cephalosporin reduced susceptible Neisseria gonorrhoeae clone between 2014-2019 in Amsterdam, the Netherlands, revealed by a genomic population analysis

Contact Info

Product

Resources

About