Analysis of Neisseria gonorrhoea samples from diagnostic laboratories throughout Germany shows a significant decrease in susceptibility to azithromycin, one of the two remaining antibiotics recommended for gonorrhoea infections, researchers have reported in Eurosurveillance.
The analysis of 3,253 N gonorrhoea isolates collected from January 2014 until May 2021 noted a substantial increase in the proportion of isolates with an azithromycin minimum inhibitory concentration (MIC) value higher than 1 mg/L (above the epidemiologic cut-off), rising from 1.3% of isolates in 2014 to 12.2% in 2020.
Preliminary data for 2021 showed the proportion with an azithromycin MIC >1 climbing to 20.7%, but those data have yet to be confirmed.
"According to our current observations and data described by others, we may not be fully able to rely on azithromycin as a therapeutic agent for the treatment of gonorrhoea," the researchers from Germany's Robert Koch Institute wrote. Only two isolates—one from 2015, the other from 2018—were found to be resistant to ceftriaxone, the other antibiotic recommended for gonorrhoea.
Dual therapy consisting of azithromycin and ceftriaxone has been the standard treatment for gonorrhoea infections in Germany since 2013, but the authors note that ceftriaxone monotherapy has become the preferred treatment in well-controlled settings where adherence can be guaranteed.
Study details
Markedly decreasing azithromycin susceptibility of Neisseria gonorrhoeae, Germany, 2014 to 20
Regina Selb, Susanne Buder , Sandra Dudareva , Thalea Tamminga, Viviane Bremer, Sebastian Banhart, Dagmar Heuer , Klaus Jansen
Published in Eurosurveillance 5 August 2021
Abstract
We monitored antimicrobial susceptibility developments of Neisseria gonorrhoeae in Germany from January 2014 to May 2021. The proportion of isolates with azithromycin minimum inhibitory concentrations above the epidemiological cut-off increased substantially, from 1.3% in 2014 to 12.2% in 2020. Preliminary data from 2021 showed a further rise (January to May: 20.7%). Therefore, azithromycin as part of the recommended dual therapy in Germany for non-adherent patients is challenged. Antimicrobial susceptibility testing in clinical practice is crucial and continuous susceptibility surveillance indispensable.
Discussion
The emergence and spread of NG-AMR in Europe and worldwide poses a serious threat to the treatment and control of gonorrhoea. In Germany, NG isolates with azithromycin MIC values above the ECOFF increased considerably from 2014 to 2020, with a pronounced rise in 2020. First data for the year 2021 underline the trend of decreasing azithromycin susceptibility; however, data are preliminary and have yet to be confirmed. At the same time, ceftriaxone remains effective for the treatment of gonorrhoea in Germany.
Dual therapy consisting of azithromycin and ceftriaxone is the standard treatment recommended for gonorrhoea in Germany. Because of the recent development of reduced azithromycin susceptibility, ceftriaxone monotherapy is preferred in the new German treatment guideline from December 2018 in well-controlled settings if adherence (adherence to therapy and control of cure) can be guaranteed. The same approach is recommended in the current European guidelines. Dual therapy was introduced to mitigate a possible development of resistances, especially against ceftriaxone, and to target possible co-infections with Chlamydia trachomatis and Mycoplasma genitalium.
According to our current observations and data described by others, we may not be fully able to rely on azithromycin as a therapeutic agent for the treatment of gonorrhoea. Antimicrobial susceptibility testing of all isolates in clinical practice and follow-up of the patients including test of cure are highly recommended and indispensable in particular for cases where monotherapeutic treatment with ceftriaxone is applied in accordance with the currently valid German guideline. Also, coinfections with C. trachomatis and M. genitalium should be checked and treated appropriately to avoid further AMR development. NG with high-level azithromycin resistance (> 256 mg/L) have been reported from several European countries and worldwide, and sustained transmission of these isolates has been described.
Interestingly, these isolates remain rare in Germany. In contrast, our data show that the increase in isolates with MIC values above the ECOFF for azithromycin concerns in particular isolates with MIC values in the range of 1–4 mg/L. Furthermore, starting from 2016, we observed a shift within the population of sensitive isolates to higher MIC values just below ECOFF (> 0.25–1 mg/L), isolates that were considered as intermediate or resistant until 2019.
One possible explanation for the high proportions of isolates with MIC values in this range in the early project period (2014–2015) might be commonly applied monotherapeutic azithromycin treatment at the time. The first German guideline recommending dual therapy for the treatment of gonorrhoea was published in 2013; however, dual therapy was most probably fully implemented in clinical practice only after a transition phase of several years. In addition, a sampling effect in the establishing phase of the surveillance project might have played a role.
Our data show that the population of isolates with increased azithromycin MIC values can be distinguished from the Gaussian MIC distribution of sensitive isolates, but these populations overlap partly. We could recently show that in 2018 in Germany, the increase in these isolates with MIC values around 1 mg/L can be attributed to the expansion of a clonal line harbouring a mosaic mtr locus acquired from commensal Neisseria species. Since these isolates with acquired resistance also display MIC values 1 mg/L between January 2014 and May 2021, this could challenge the currently recommended dual therapy consisting of ceftriaxone and azithromycin in the near future.
To this end, consistent antimicrobial susceptibility testing and control of cure are inevitable.
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