Ceftriaxone Reduced Susceptible Neisseria gonorrhoeae in the Netherlands, 2009 to 2017: From PenA Mosaicism to A501T/V Nonmosaicism

Abstract

Objectives To compare molecular and epidemiological differences between ceftriaxone-reduced susceptible (CRO-RS) and ceftriaxone-susceptible (CRO-S) N. gonorrhoeae (Ng) and to study the genetic relatedness of CRO-RS isolates. Methods Demographic and clinical data and samples for cultures were routinely collected from gonorrhoea patients visiting the Amsterdam STI clinic in 2009 to 2017. Ng multiantigen sequence typing (NG-MAST) and penA types were compared between CRO-RS and CRO-S Ng (frequency matched on year of isolation and sexual risk group). Minimum spanning trees were produced based on multilocus variable number of tandem repeats analysis for Ng (NG-MLVA) genotypes. Results We selected 174 CRO-RS isolates (minimum inhibitory concentration, ≥0.064 mg/L) and 174 CRO-S isolates (minimum inhibitory concentration, ≤0.016 mg/L). Demographic and clinical characteristics of patients were overall comparable between those infected with CRO-RS Ng and CRO-S Ng. However, CRO-RS isolates were more often collected from the pharyngeal site (odds ratios [OR], 3.64; P < 0.001), and patients with CRO-RS Ng were less often human immunodeficiency virus (HIV) and syphilis positive (OR, 0.63; P = 0.041 and OR, 0.58; P = 0.028, respectively). We identified 12 clusters based on NG-MLVA genotypes, including 3 large (>25 isolates) clusters predominantly containing CRO-RS isolates. Those from cluster 1 (n = 32) were mostly from 2009 to 2012 (n = 24; 75.0%), with a mosaic penA XXXIV pattern (n = 27; 84.4%) and belonging to NG-MAST genogroup G1407 (n = 24; 75.0%). Isolates from cluster 2 (n = 29) were mostly from 2013 to 2015 (n = 24; 82.7%), had a nonmosaic penA IX + A501T mutation (n = 22; 75.9%) and NG-MAST G2400 (n = 14; 48.3%). Most isolates from cluster 3 (n = 37) were from 2015 to 2017 (n = 26; 70.2%), had a nonmosaic penA IV + A501V mutation (n = 24; 64.9%) and NG-MAST G2318 (n = 22; 59.5%). Conclusions We observed a shift in the predominant penA (from mosaic toward nonmosaic plus A501T/V mutation), NG-MAST and NG-MLVA types among CRO-RS Ng over time. This indicates a successive spread of different CRO-RS Ng clones.

Emergence of a Neisseria gonorrhoeae clone with reduced cephalosporin susceptibility between 2014 and 2019 in Amsterdam, The Netherlands, revealed by genomic population analysis

“…This genomic population study extended the previous NG-MAST and penA typing study, which identified NG-MAST and penA shifts among Ng isolates with reduced ceftriaxone susceptibility from Amsterdam, obtained up until 2017. 13 Here we studied this phenomenon in more detail using WGS and including more recent isolates. The results showed that previous observations represented a shift from MLST1901 to MLST7363 and more recently to MLST7827.…”

“…They showed that this strain, with an alarming antimicrobial resistance profile, likely originated from Asia and potentially circulates in Europe. Analysing Dutch isolates with reduced susceptibility from 2009–17, De Laat et al 13 found a shift from a mosaic penA allele towards a non-mosaic penA allele with A501 mutation. We have now further examined the genetic change among isolates with reduced susceptibility in Amsterdam.…”

Reliability of Genetic Alterations in Predicting Ceftriaxone Resistance in Neisseria gonorrhoeae Globally

“…Strains without reported MIC and susceptibility data were excluded from the study ( n = 2,995), leaving 9,948 N. gonorrhoeae isolates. Due to the ambiguity of decreased ceftriaxone susceptibility status, which we defined as >0.064 mg/liter ( n = 46) as commonly classified by other investigators ( 36 – 39 ), isolates were excluded if they (i) were categorized without exact MIC values according to a MIC cutoff of 0.125 mg/liter ( n = 362) or (ii) had MIC value ranges that overlapped with the decreased susceptibility cutoff. For example, isolates ERR3623188 and ERR3623235 used a MIC cutoff of ≥0.125 mg/liter, and isolates SRR8566948 and SRR8566968 had a MIC range of 0.06 to 0.125 mg/liter.…”

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

“…This genomic population study extends the NG-MAST and penA typing study on Ng isolates from Amsterdam, isolated up until 2017 (14). Back then, a shift in penA (from mosaic to non-mosaic with an A501T or A501V mutation) and NG-MAST was found among ceftriaxone reduced susceptible isolates.…”

“…They showed that this strain with an alarming antimicrobial resistance profile likely originated from Asia and potentially circulates in Europe. Analysing Dutch reduced susceptible isolates from 2009-2017, De Laat et al found a shift from a mosaic penA allele towards a non-mosaic penA allele with A501 mutation (14). In this study, the genetic change among reduced susceptible isolates in Amsterdam is further examined.…”