Occurrence of high-level azithromycin-resistant<i>Neisseria gonorrhoeae</i>isolates in China
Bibliographic record
Abstract
Contributed equally to this work. Contributed equally to this work. Sir, The most important threat to the future management and treatment of Neisseria gonorrhoeae infections is multidrug resistance. Resistance to ceftriaxone, the latest available first-line empirical monotherapy, is rising globally and confirmed treatment failures have been reported in several countries.1 Therefore, dual antimicrobial therapies containing ceftriaxone and azithromycin are now the standard recommendation in Europe2 and the USA.3 This dual antimicrobial therapy is also currently being considered as the standard first-line therapy in China.4 However, several countries have reported the occurrence of isolates with high-level azithromycin resistance,5–7 which is defined by an MIC ≥256 mg/L. The emergence of these high-level azithromycin-resistant isolates poses a serious threat to the future efficacy of ceftriaxone and azithromycin dual antimicrobial therapy. As far as we are aware, this is the first report on the incidence and characterization of two high-level azithromycin-resistant isolates in China. Both N. gonorrhoeae isolates were collected from patients at the Zhejiang Xiaoshan Hospital in Hangzhou, Zhejiang Province. Antimicrobial susceptibility testing of the N. gonorrhoeae isolates was performed using the agar dilution method. Both isolates showed high-level resistance to azithromycin, with MICs of 2048 mg/L. In addition, they were resistant to penicillin (MIC = 256 mg/L), ciprofloxacin (MIC = 16 mg/L) and tetracycline (MIC = 32 mg/L), but susceptible to ceftriaxone (MIC = 0.016–0.03 mg/L), cefixime (MIC = 0.03 mg/L) and spectinomycin (MIC = 16 mg/L). The genomes of the isolates were subsequently analysed by PCR amplification and sequencing to determine which azithromycin resistance determinants were present. Both isolates contained an A2059G mutation in loop V of all four 23S rRNA alleles encoded in the N. gonorrhoeae genome. This mutation has previously been associated with high-level azithromycin resistance of N. gonorrhoeae when present in minimally three of the four 23S rRNA alleles.5 In addition, sequence analysis of the mtrR gene showed that both isolates contained a single base-pair deletion (A) in the 13 bp inverted repeat in the mtrR promoter and a G45D substitution in the coding sequence. These mutations have previously been shown to result in increased azithromycin resistance due to induced expression of the MtrCDE efflux pump.8 The genes erm(A), erm(B), erm(C) and erm(F), encoding rRNA methylases, and mef(A), encoding an efflux pump, were not present in these isolates. Molecular epidemiology analysis of the isolates was performed using the N. gonorrhoeae multiantigen sequence typing (NG-MAST) method,9 which assigns an ST based on a combination of the highly variable por and tbpB alleles. The isolates were assigned ST3102 and ST1866, which are almost identical and differ only by one SNP in por. Thus far, the high-level azithromycin-resistant N. gonorrhoeae strains that have been isolated in various countries belong to 16 different STs, of which ST649 isolates appear to be most widespread.5–7 The por and tbpB alleles of these STs differ by a total of 33–92 SNPs from the por and tbpB alleles of the strains described in this study, except for the Australian ST10133 isolate,7 which contains an identical tbpB allele (33) and a por allele (2573) that only differs by 16 and 17 SNPs from the por alleles of ST3102 and ST1866, respectively. Interestingly, it was reported that this isolate was most likely contracted in China or Hong Kong, which might explain its closer genetic relationship. How widespread high-level azithromycin-resistant strains are in China remains to be determined. Several years earlier, in 2009, two ST1866 strains were isolated from patients in the city of Nanjing,10 which is located in a neighbouring province. These strains were reported to have an azithromycin MIC of >64 mg/L. It is not known whether these strains actually are directly related to the ST1866 isolate described in this study, but if they are related it would indicate that this high-level azithromycin-resistant ST might be spreading in China. Azithromycin susceptibility testing is currently not the standard in China. However, the identification of high-level azithromycin-resistant N. gonorrhoeae isolates stresses the need for a more thorough overview of azithromycin susceptibility in China, particularly when ceftriaxone and azithromycin dual antimicrobial therapy is considered as a future first-line therapy. These high-level azithromycin-resistant isolates might have a major impact on the efficacy of this dual antimicrobial therapy. This study was supported by start-up funding from Zhejiang University to S. v. d. V. None to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.003 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".