Global Transmission of the penA Allele 60.001–Containing High-Level Ceftriaxone-Resistant Gonococcal FC428 Clone and Antimicrobial Therapy of Associated Cases: A Review

Abstract

Neisseria gonorrhoeae is a multidrug-resistant bacterial pathogen for which ceftriaxone is the only remaining recommended first-line therapy. However, ceftriaxone susceptibility has been waning in a number of countries over the last decade and ceftriaxone treatment failures have been reported, commonly as a result of sporadic high-level ceftriaxone-resistant strains. In recent years, N. gonorrhoeae strains associated with the high-level ceftriaxone-resistant FC428 clone or strains that acquired its main ceftriaxone resistance determinant, penA allele 60.001, have shown global transmission, resulting in ceftriaxone treatment failure in a number of cases. The FC428 clone was first encountered in Japan in 2015 and subsequently in China, Europe, Australia, North America and Southeast Asia afterward. Strains associated with the FC428 clone commonly display a ceftriaxone minimum inhibitory concentration of 0.5–1 mg/L. However, where penA alleles encountered in sporadic high-level ceftriaxone-resistant isolates induce an in vitro growth defect, penA allele 60.001 does not seem to affect in vitro growth. The limited impact of penA allele 60.001 on biological fitness might be associated with its successful global transmission. Although the FC428 clone displays high-level ceftriaxone resistance, most gonorrhea cases associated with this clone were still successfully cured with ceftriaxone when intramuscular or intravenous doses of 500 mg to 2 g were used. A successful alternative therapy seems to be ertapenem given at 1-g doses, although further clinical studies are required to validate ertapenem efficacy. This review summarizes the global transmission of strains associated with the FC428 clone and antimicrobial treatment of associated cases.

Complete reference genomes of two ceftriaxone-resistant Neisseria gonorrhoeae strains identified in routine surveillance in Bangkok, Thailand, using Nanopore Q20+ chemistry, VolTRAX V2b, and Illumina sequencing

“…Many Neisseria gonorrhoeae strains resistant to ceftriaxone, last-remaining gonorrhea treatment option, were identified in Europe, but nearly all were linked to Asia and several to Thailand ( 1 – 3 ). We report the complete reference genomes of two ceftriaxone-resistant gonococcal isolates (TH1713,TH2288) identified in the routine surveillance in Bangkok, Thailand.…”

“…Both isolates had identical genotypes ( Table 1 ), and pairwise distance calculation shows that the isolates were highly related with only 27 single nucleotide polymorphism (SNP) differences ( https://pathogen.watch/collection/bx7vedyhw7v7-th1713-th2288 ). However, they were very distant from the internationally spreading ceftriaxone-resistant FC428 ( 3 ) clade (>5,000 SNPs), and the first described high-level ceftriaxone-resistant gonococcal strains [WHO X and Y ( 10 )], all belonging to gonococcal genomic lineage A. Only one ceftriaxone-resistant isolate with mosaic penA -60.001 has been previously described in lineage B ( 8 ).…”

High prevalence of ceftriaxone-resistant and XDR Neisseria gonorrhoeae in several cities of Cambodia, 2022–23: WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP)

“…acting as a reservoir, in several Asian countries such as Japan and China. 6 Furthermore, the first two strains with resistance to ceftriaxone combined with high-level azithromycin resistance (MIC ≥ 256 mg/L) were identified in 2018 (the same strain in the UK and Australia) 8 and 2022 (in Austria). 9 The vast majority of ceftriaxone-resistant isolates have been linked to Asia, either by being cultured in Asia or cultured in patients with infection likely acquired in Asia.…”

Bacitracin enhances ceftriaxone susceptibility of the high-level ceftriaxone-resistant gonococcal FC428 clone

“…This is exemplified by sporadic reports of ceftriaxone treatment failure due to ceftriaxone-resistant isolates ( 9 – 11 ). Specifically, recent years have demonstrated global transmission of strains associated with the high-level ceftriaxone-resistant FC428 clone (minimum inhibitory concentration, MIC = 0.5–1 mg/L) ( 12 – 15 ), which carries semi-mosaic penA allele 60.001 that confers high-level ceftriaxone resistance due to its A311V and T483S polymorphisms ( 14 , 16 ). Additionally, penA allele 60.001 also contains the polymorphisms I312M, F504L, N512Y, and G545S, which are related to reduced cephalosporin susceptibility ( 17 , 18 ).…”

“…Additionally, penA allele 60.001 also contains the polymorphisms I312M, F504L, N512Y, and G545S, which are related to reduced cephalosporin susceptibility ( 17 , 18 ). High prevalence of strains associated with the FC428 clone, particularly in China and the Asia Pacific region ( 13 , 15 , 19 – 22 ), jeopardizes the effectiveness of ceftriaxone-based therapies for the treatment of gonorrhea.…”