Molecular epidemiology of Neisseria gonorrhoeae isolates in Russia, 2015-2023: current trends and forecasting

Abstract

Introduction: The emergence of multidrug resistance in N. gonorrhoeae is a serious global problem, and gonorrhea may soon become an incurable disease. The aim of the study was to characterize the N. gonorrhoeae population in Russia from 2015 to 2023 and predict the potential spread of the most concerning clones.

Methods: A total of 996 N. gonorrhoeae isolates were examined during the analyzed period. Ceftriaxone and azithromycin susceptibility testing were performed using the agar dilution method. Microarray-based assays and sequencing were employed to identify the genotypes and genetic markers of antimicrobial resistance.

Results: No ceftriaxone-resistant isolates were found in Russia, however, the number of isolates with reduced susceptibility to ceftriaxone has increased to 22.6% in recent years. Since 2020, approximately 12.5% of isolates have exhibited resistance to azithromycin annually. Two clusters of isolates pose a particular threat to Russia: NG-MAST G2212, linked to MLST 1901/1902, carries a mosaic structure in the penA gene; G12302, linked to MLST 9363, contains mosaic alleles in the mtrR and mtrD genes. Additionally, two new high-risk genogroups were characterized: G18898 and G16206. Both are associated with MLST 10314 and harbor mosaic variants of penA or mtrR/mtrD. Analysis of time series data suggests that isolates with mosaic alleles are unlikely to be eradicated from the population in the near future, potentially worsening the epidemiological situation of gonorrhea in Russia.

Conclusions: The native genetic strains of N. gonorrhoeae in Russia, which are susceptible to cephalosporins and macrolides, are being progressively replaced by globally dominant lineages. To further characterize this epidemiologic shift, ongoing surveillance strategies using molecular epidemiology and the identification of genetic markers will be crucial in curbing the growth and spread of N. gonorrhoeae resistance. Such efforts are vital in ensuring the availability of effective treatments for gonococcal infection.

Keywords: Neisseria gonorrhoeae; antibiotic resistance; genetic determinants of drug resistance; genotyping; molecular epidemiology.

Figure 1

Diagram of the distribution of N. gonorrhoeae isolates in the Russian population (2015-2023). (A) Proportion of isolates with reduced susceptibility to ceftriaxone (MIC_cro ≥ 0.06 mg/L). (B) Proportion of isolates resistant to azithromycin (MIC_azi > 1 mg/L). The red dotted line in panel (B) represents the 5% threshold, above which the WHO guidelines no longer recommend azithromycin for the treatment of gonococcal infection.

Figure 2

Maximum likelihood phylogeny of NG-MAST and MLST types for N. gonorrhoeae isolates collected in Russia (2015-2023). The tree consists of 376 terminal nodes, each representing a unique combination of NG-MAST and MLST types (labeled as node names). The years in which a clade is found are marked by ‘plus’ signs and arranged from 2015 to 2023 in increasing radius order. Clades associated with reduced susceptibility to ceftriaxone and/or resistance to azithromycin are marked by ‘hexagon’ and ‘star’ signs, respectively. Colors on the tree correspond to the main NG-MAST genogroups in the Russian population, along with the MLST types linked to each genogroup. The percentage share of each genogroup in the total sample is indicated in bold black font. Sequence types associated with mosaic penA, as well as mtrR promoter + mtrD, are highlighted in red and orange font, respectively. The sequence type with both mosaic penA and mtrR promoter + mtrD is indicated by an arrow.

Figure 3

Distribution of the proportion of N. gonorrhoeae isolates by NG-MAST genogroups and MLST in the Russian population (2015-2023). (A) Isolates with mosaic structure of the penA gene. (B) Isolates with mosaic structure of the mtrR (promoter) and mtrD genes. The black line represents the percentage of isolates with the specified mosaic gene structures. The colored bars indicate the number of isolates belonging to different NG-MAST genogroups and MLST types.

Figure 4

Dynamics of isolates with mosaic penA (A) and mosaic mtrR (promoter) + mtrD (B) in the population, with predictions for the next 5 years (2024-2028). The black line represents the percentage of isolates obtained experimentally between 2015 and 2023. The red line indicates projections for the next 5 years. The light green area represents the 80% confidence interval, while the dark green area represents the 95% confidence interval.