Local emergence and global evolution of Neisseria gonorrhoeae with high-level resistance to azithromycin

Abstract

Antimicrobial resistance in Neisseria gonorrhoeae (Ng) has severely reduced treatment options, including azithromycin (AZM), which had previously been recommended as dual therapy with ceftriaxone. This study characterizes the emergence of high-level resistance to AZM (HLR-AZM) Ng in Baltimore, Maryland, USA, and describes the global evolution of HLR-AZM Ng. Whole genome sequencing (WGS) of 30 Ng isolates with and without HLR-AZM from Baltimore was used to identify clonality and resistance determinants. Publicly available WGS data from global HLR-AZM Ng (n = 286) and the Baltimore HLR-AZM Ng (n = 3) were used to assess the distribution, clonality, and diversity of HLR-AZM Ng. The HLR-AZM Ng isolates from Baltimore identified as multi-locus sequencing typing sequence type (ST) 9363 and likely emerged from circulating strains. ST9363 was the most widely disseminated ST globally represented in eight countries and was associated with sustained transmission events. The number of global HLR-AZM Ng, countries reporting these isolates, and strain diversity increased in the last decade. The majority (89.9%) of global HLR-AZM Ng harbored the A2059G mutation in all four alleles of the 23S rRNA gene, but isolates with two or three A2059G alleles, and alternative HLR-AZM mechanisms were also identified. In conclusion, HLR-AZM in Ng has increased in the last few years, with ST9363 emerging as an important gonococcal lineage globally. The 23S rRNA A2059G mutation is the most common resistance mechanism, but alternative mechanisms are emerging. Continued surveillance of HLR-AZM Ng, especially ST9363, and extensively drug-resistant Ng is warranted.

Keywords: Neisseria gonorrhoeae; antimicrobial resistance; azithromycin; gonorrhea; high-level azithromycin resistance.

Fig 1

Maximum-likelihood phylogeny of the 54 global HLR-AZM Ng MLST ST9363 included in the study (13, 15–18, 20–28). AZM-susceptible and non-MLST ST9363 Ng Isolates were included in the tree as they were the nearest neighbors. Isolates from Indianapolis, Indiana, USA, are in boxes. *This study. AZM, azithromycin; SRA, sequence read archive; mtrR, multiple transferable resistance repressor; mtrRP, mtrR promoter; NR, not reported; NP, not performed.

Fig 2

Maximum-likelihood phylogeny of publicly available Ng genomes, including HLR-AZM Ng. @, HLR-AZM Ng (# of @ represents the number of isolates); AZM-susceptible Ng isolates from Baltimore (the number of isolates is shown). *Pharyngeal and penile isolate from the same patient. ^#All eight HLR-AZM Ng isolates also displayed decreased susceptibility to ceftriaxone. ^%Seven HLR-AZM Ng isolates also displayed decreased susceptibility/resistance to ceftriaxone: ERR2865779, ERR2865780, ERR2560140, ERR2560139 (WHO-Q), SRR21311934, SRR19905848, and SRR1661207. Two HLR-AZM Ng isolates from China with decreased susceptibility to ceftriaxone were excluded because sequencing data were not available.

Fig 3

Molecular typing of global Ng isolates with HLR-AZM. (A) MLST distribution of 226 isolates. (B) NG-MAST distribution of 275 isolates. ■, MLST/NG-MAST ST first reported from Ng isolates prior to and including 2012. ●, MLST/NG-MAST ST first reported during and after 2013. ▲, some of the 3, 5, 11, and 9 NG-MAST STs from Argentina, Australia, China, and the United Kingdom, respectively, were first reported prior to and including 2012, and some were reported during and after 2013. See Table S2 for additional details regarding MLST ST and NG-MAST ST profiles.