Dissemination of Neisseria gonorrhoeae with decreased susceptibility to extended-spectrum cephalosporins in Southern China, 2021: a genome-wide surveillance from 20 cities

Susceptibility of ESCs and dual antibiotic resistant

Of 1321 reported cases of gonococci, 347 isolates were monitored for antimicrobiotic susceptibility, with a monitoring rate of 26.27%. Among them, 50 isolates were found to be DSC (decreased susceptibility to cephalosporins), with a DS prevalence of 14.4 (50/347), as shown in Table 1-A. Of which, 16.0% isolates (8/50) were ceftriaxone DS, 38.0% isolates (19/50) were cefixime DS, and 46.0% isolates (23/50) were both ceftriaxone and cefixime DS. Table 1-B shows the proportions that were dual antibiotic resistant in the fifty cephalosporin-DS isolates; 96.0% (48/50) of cephalosporin-DS isolates were simultaneously resistant to penicillin (PEN) and 98.0% (49/50) to tetracycline (TET), ranging from 88.9% to 100.0% in the four regions. All of the cephalosporin-DS isolates were resistant to ciprofloxacin (CIP). Still, all of the strains were sensitive to spectinomycin (SPT), and 10.0% (5/50) of the cephalosporin-DS isolates had azithromycin (AZI) resistance. Among the five isolates with DSC and AZI resistance, two were in the Pearl River Delta region and East Guangdong, respectively, and the rest was in North Guangdong.

Table 1 DS to ceftriaxone/cefixime and dual antibiotic resistance of 50 DS isolatesGenotyping of MLST, NG-STAR, and NG-MAST

For MLST typing, 50 cephalosporin-DS isolates were assigned to 22 unique STs: ST7363 (16%, 8/50), ST1903 (14%, 7/50), ST1901 (12%, 6/50), ST7365 (10%, 5/50), ST7360 (8%, 4/50), ST1579 (4%, 2/50), ST1583 (4%, 2/50), ST7822 (4%, 2/50), and others STs (28%, 14/50). As shown in Fig. 1A, ST7360 (25.0%, 2/8) was the most common MLST among the eight ceftriaxone-DS isolates. ST7363 (31.6%, 6/19) was popular among the 19 Cefixime-DS isolates. For the 23 Ceftriaxone/Cefixime-DS-DS isolates, ST1903 (30.4%, 7/23) played a dominant role, followed by ST1901 (17.4%, 4/23), ST7365 (17.4%, 4/23), ST1579 (8.7%, 2/23), and other STs (26.1%, 6/23). For NG-STAR typing, 32 isolates failed to type (NA); the rest were NG-STAR ST1143 (n = 6), ST1696 (n = 4), and ST497 (n = 2). For NG-MAST, 40 isolates were NA, and four isolates were NG-MAST ST17748, as shown in Figs. 1B, C. Notably, NG-STAR ST1143 clones were detected only among MLST ST1903 strains, and NG-MAST ST17748 was only detected among MLST ST7363 clones, which can be found in Additional file 1: Table S1.

Fig. 1figure 1

MLST, NG-STAR, and NG-MAST of 50 cephalosporin-DS isolates. Among the 50 ceftriaxone-DS, cefixime-DS, or both ceftriaxone/cefixime-DS isolates, the proportions of different STs based on MLST (A), NG-STAR (B), and NG-MAST (C). NA represents strains that failed typing, and “Others” indicates that the number of isolates in ST typing was less than two

Genetic characteristics of resistance

Of the 50 isolates with DS to ceftriaxone or cefixime, 2801 genes were aligned by PubMLST, and mutations of major resistance determinants were found, as shown in Fig. 3 and Additional file 1: Table S1. A total of 64.0% (32/50) of the strains had an adenine deletion (ΔA) in the mtrR promoter. For the ponA gene, 84.0% (42/50) of isolates possessed the L421P mutation, and 16.0% (8/50) were wild-type. For the PorB gene, 88.0% (44/50) possessed the G120D/K mutation, and 76.0% (38/50) had the A121/D/G/N mutation. Other mutants, including gyrA, parC, rpoB_H552N, NEIS2213 (zeta_3 toxin variant), NEIS0013 (308 bp deletion), NEIS0408 (pilQ_S341N/N648S), NEIS1600 (parE), NEIS1609 (folP_R228S), NEIS2357 (TEM-1/TEM-135), and NEIS2958 (54 bp deletion) mutations are shown in Fig. 2.

Fig. 2figure 2

Genetic mutations in the 50 cephalosporin-DS N. gonorrhoeae strains from different regions. The vertical axis represents 50 cephalosporin-DS N. gonorrhoeae strains and their regional distribution, and the horizontal axis represents the characteristics of each strain, including ceftriaxone DS or cefixime DS and the genetic characteristics. Red represents the presence of cephalosporin DS or mutations (Yes), light pink represents no cephalosporin DS or no mutation, namely Wild Type (WT), and colorless represents NA with unknown information. a: A39T/G45D mutation in mtrR; b: D86/S87 mutation in parC; c: NEIS2213 (zeta_3 toxin variant); d: NEIS0013 (308 bp deletion); e: NEIS0408 (pilQ_S341N/N648S), f: NEIS1600 (parE); g: NEIS1609 (folP_R228S); h: NEIS2357 (TEM-1/TEM-135); h: NEIS2958 (54 bp deletion) mutations

There were 16 strains with the zeta_3 toxin variant in the NEIS2213 gene, which may be related to ceftriaxone DS. The prevalence of ceftriaxone DS in NEIS2213 mutant strains was 100.0% (16/16), with a geomean MIC of ceftriaxone = 0.3 mg/L, while in strains without the NEIS2213 mutant, the geomean MIC of ceftriaxone = 0.1 mg/L, and the difference was significant (p value < 0.05).

Phylogenetic analysis of penA-60.001 clones

Twelve mosaic penA-60.001 strains were found, and a phylogenetic tree was used to track the evolutionary spread of the clones, as shown in Fig. 3. The phylogenetic tree is roughly divided into four Clades; most of the penA60.001 clones in this study are clustered in Clade B (10/12), and 75% (9/12) belong to the Pearl River Delta region. GD2021236 and GD2021027 are close to the isolates reported in Australia (A2735, A2543) and the United Kingdom (G7944) in 2018. In addition, the isolate (AT159) reported in Austria in 2022 is also close to them. Clade C contains the first reported clone FC428 and related isolates from Japan. The GD2021266 in our study is very close to this subbranch, and was isolated from Zhuhai in the Pearl River Delta of Guangdong. Clade C also contains the DG19112 previously isolated in Guangdong and three isolates (SC18-26, SC18-25, and SC18-33) from Chengdu, Sichuan, China, in 2018. The isolate GD2021265 is distributed in Clade D and adjacent to GC196, GC185, GC195, and GC249 from Changsha, China. They are closely related to the foreign isolates CA-51742 (Canada), 18DG342 (Singapore), KU17039 (Japan), KM383 (Japan), A7846 (Australia), and 47707 (Canada) in 2017 and 2018, as well as YL201 (Shenzhen, China) isolated in 2020, forming an evolutionary Clade D. Detailed information about the twelve strains of penA60.001 is shown in Additional file 2: Table S2 and Additional file 3: Table S3. The mean age of the 12 patients was 31.6 years old, and ten of twelve were male.

Fig. 3figure 3

Midpoint-rooted phylogenetic tree of mosaic penA-60.001 N. gonorrhoeae clones. Names in blue represent isolates reported in this study; others are isolates previously reported. Year and country show the year and location where isolates were reported. The bootstrap value is labeled with circles of different sizes in green. NA means not available data of gender or NG-STAR or NG-MAST. Reference a: These strains are reported in this study. Male h: the man is reported homosexual

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