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Azithromycin-Resistant Gonorrhea

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    Posted: March 08 2018 at 5:50am

UK seeing outbreak of highly azithromycin-resistant gonorrhea

Mar 07, 2018

Researchers with Public Health England (PHE) are reporting sustained transmission of high-level azithromycin-resistant (HL-AziR) Neisseria gonorrhoeae infections across England, and a separate paper notes ceftriaxone-resistant gonorrhea in Australia.

In a study yesterday in The Lancet Infectious Diseases, the PHE researchers report that 37 of 60 HL-AziR N gonorrhoeae isolates collected in England from November 2014 through February 2017 belonged to a single multi-antigen sequence type (ST9768). This is the same sequence type that was initially identified in seven N gonorrhoeae isolates tested when the outbreak was first identified in Leeds in 2015.

When compared with 110 N gonorrhoeae isolates from the United Kingdom and Ireland with ranges of azithromycin resistance, the isolates from ST9768 clustered into three phylogenetic clades and were all found to be genetically similar, with a mean distance of 4.3 single nucleotide polymorphisms (SNPs). All of the ST9768 isolates shared a recent common ancestor indicative of recent transmission.

Further analysis detected mutation 2059A→G in the 3-4 allelles of the 23S rRNA gene in almost all the HL-AziR isolates, a mutation known to be responsible for high-level azithromycin resistance. But it also detected this mutation in six of the comparator isolates from Scotland, one with low-level resistance to azithromycin and five that were susceptible. The phylogeny provides evidence that the HL-AziR isolates were descendants of the low-level azithromycin-resistant isolates, which were in turn descendants of the susceptible isolates.

The authors of the study report that there was no confirmed gonorrhea treatment failure in any of these cases, most likely because the isolates were still susceptible to ceftriaxone. But the findings are a concern because azithromycin, in combination with ceftriaxone, forms the last-line of therapy for treating gonorrhea, which has become resistant to all other drugs that have been used against it. Dual therapy is recommended in England and other countries to prevent further development of resistance.

Currently, the prevalence of low-level azithromycin resistant in England is 5%. But the finding that high-level azithromycin resistance can emerge from low-level resistance, the authors argue, raises the possibility that azithromycin exposure may be providing selection pressure for the emergence of high-level resistance.

"Dual therapy for gonorrhea using azithromycin with ceftriaxone is clearly under threat, and we might not be able to rely on azithromycin to protect ceftriaxone," the authors write.

An additional concern is that HL-AziR N gonorrhoeae has previously been observed only sporadically in England and other parts of the world, possibly because high-level azithromycin resistance might lead to fitness costs, the authors suggest. Why sustained transmission of ST9768 exists in England remains unclear.

Ceftriaxone-resistant gonorrhea in Australia

Meanwhile, in a paper yesterday in Emerging Infectious Diseases, an international team of investigators report two more instances of a clone of a ceftriaxone-resistant N gonorrhoeae strain that appears to be spreading internationally.

The strain, FC428, was first identified in Japan in 2015 in a heterosexual man in his 20s. Two years later, gonococcal isolates with FC428-like susceptibility profiles (including ceftriaxone resistance) were reported in a Canadian woman and a heterosexual man from Denmark. The two newly reported cases, identified in Australia in two heterosexual men from the Philippines and China, also had a similar susceptibility profile to FC428.

Phylogenetic analysis of isolates from the Japanese, Canadian, and Australian cases showed close genetic relatedness, and molecular typing demonstrated that all the strains, as well as the strain from Denmark, belonged to the same sequence type (ST1903).

All cases were successfully treated, but the investigators say the findings provide new evidence that there is sustained international transmission of a ceftriaxone-resistant N gonorrhoeae strain that appears to have been circulating for more than 2 years, and that it's highly likely the strain is prevalent elsewhere but has yet to be detected.

"These findings warrant the intensification of surveillance strategies and establishment of collaborations with other countries to monitor spread and inform national and global policies and actions," the authors write.

See also:

Mar 6 Lancet Infect Dis abstract

Mar 6 Emerg Infect Dis paper


Absence of proof is not proof of absence.
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ECDC report on the above disease:

Molecular typing of Neisseria gonorrhoeae – a study of 2013 isolates

technical report

This report describes the second molecular typing survey of N. gonorrhoeae across the European Union/European Economic Area (EU/EEA) and provides recent information on NG-MAST STs/Gs and genotypes based on whole genome sequencing (WGS) circulating in 21 EU/EEA Member States. This is the first time WGS has been used in any international surveillance programme for sexually transmitted infections.

Executive summary

In 2011, a pilot study was conducted to assess the public health value of molecular surveillance for gonorrhoea in 21 European Union/European Economic Area (EU/EEA) countries. A total of 1066 isolates collected as part of the 2010 European gonococcal antimicrobial surveillance programme (Euro-GASP) were typed using Neisseria gonorrhoeae Multi-Antigen Sequence typing (NG-MAST). The study highlighted many issues of importance for public health on national as well as EU/EEA level, including the identification of a highly heterogeneous gonococcal population with some predominant genogroups (Gs) and the establishment of a baseline for sequence types (STs) and Gs. The study showed that NG-MAST appeared to have a high discriminatory ability, provided enhanced surveillance data and improved the understanding of emergence and dissemination of gonococcal strains, including those with therapeutically relevant resistance profiles. Therefore NG-MAST (linked to antimicrobial resistance (AMR) profiles and epidemiological metadata) was considered useful for public health purposes at the EU/EEA level.  

The present study represents a new molecular epidemiological survey using Euro-GASP isolates from 2013 to further assess the spread of AMR gonococcal strains in the EU/EEA, to investigate the stability of the relationships between AMR and STs/Gs and to address additional issues of importance for public health. In addition, whole genome sequencing (WGS) was performed on all available isolates to establish if multidrug resistant STs/Gs are clonal and to detail their distribution, to assess the public health relevance of WGS in the surveillance and control of N. gonorrhoeae at EU/EEA level and to form an evidence base for a molecular surveillance strategy for N. gonorrhoeae in the EU/EEA.

The 2013 study aimed to type 50 isolates from each country and 100 isolates from countries with higher rates of gonorrhoea by both NG-MAST and WGS. A total of 1189 isolates were typed by NG-MAST; 430 (STs) were identified, 146 of which were represented by two or more gonococcal isolates. Twenty-three types were represented by ten or more isolates. While considerable diversity was observed in different countries, four STs (ST1407, ST2992, ST2400 and ST4995) were predominant, albeit at different levels in individual countries. ST1407 and ST2992 also predominated in 2010. However, in 2013, ST1407 represented only 7.6% of all isolates, while in 2009-2010 it represented 15.6% of isolates. The continuing predominance of a single NG-MAST ST is interesting given that the gonococcus is highly heterogeneous and that NG-MAST measures variation within two highly variable genes. 
Further analysis of the 23 most common STs showed that other STs within the study were strongly genetically related to these, enabling 18 major genogroups (49% of all typed isolates) of closely related STs to be defined. G1407 remained the predominant genogroup, but the overall prevalence of G1407 has decreased significantly (from 23.3% in 2009–2010 to 14.8% in 2013). Genogroup G1407 was observed in 19 out of 21 countries, although it was predominant in only six countries compared to 13 countries in 2010.  
Statistical analyses demonstrated associations between patient characteristics and genogroups. For some genogroups (e.g. G51 and G2), patients were younger and a lower proportion of males were infected, which may indicate that some genotypes are more associated with heterosexual patients. In contrast, other genogroups were isolated more frequently in men who have sex with men (MSM), given the apparent associations with older patients and male gender (G2992, G4995 and G5624). However, given the limitations of the study population and the lower reporting rates of epidemiological variables such as sexual orientation, all associations should be interpreted with caution. This is a major limitation of the current study in terms of evaluating the public health benefits of linking genogroups or STs to epidemiological characteristics.  

Significant associations were identified between ciprofloxacin resistance and the predominant genogroups G1407, G2400, G225, G4995, G5624, G5333, and G7232. A strong association was identified between G1407 and resistance to cefixime and ciprofloxacin, with also a relatively large proportion (34%) of the G1407 isolates showing intermediate susceptibility or resistance to azithromycin. Similar associations were also found in the previous Euro-GASP molecular typing study. Consequently, G1407 genogroup continues to predominate even though cefixime is no longer recommended as the first-line therapeutic agent to treat gonorrhoea. Six G1407 isolates were also resistant to the first-line treatment ceftriaxone. Accordingly, the continued predominance of G1407 isolates in many EU/EEA Member States is worrying, given their potential to be therapeutically challenging. While G1407 was more associated with MSM in the Euro-GASP molecular typing study in 2009–2010 (despite being present in the heterosexual population), G1407 was associated with heterosexual patients as well as older patients (>45 years of age) in 2013 at a higher level. Thus, this multidrug-resistant genogroup appears to have crossed over to the heterosexual population in 2013. Obviously, the G1407 genogroup is circulating both in the heterosexual population as well as among MSM and, consequently, the potential risks of future treatment failure are not restricted to any one patient group.

Quality assured WGS data linked to AMR profiles and epidemiological data was obtained for 1054 (89%) isolates and the phylogenomics based on the whole genome sequences revealed a significantly higher and more accurate resolution of the isolates. WGS further discriminated isolates with identical NG-MAST STs and Gs mostly reflecting specific evolutionary traits in the same country. The WGS data revealed that NG-MAST Gs (based on diversity in only two genes) do not always reflect the genomic similarities or differences of isolates. Additionally, 114 different multilocus sequence typing (MLST) STs (40 new STs), including 68 clusters (≥2 isolates with identical ST) and 46 STs represented by single isolates, were identified in silico from the WGS data. AMR determinants, mainly all known resistance determinants for sulphonamides, penicillins, tetracyclines, spectinomycin, rifampicin, fluoroquinolones, macrolides (e.g. azithromycin), cefixime and ceftriaxone were also identified in silico. 
This report describes the second molecular typing survey of N. gonorrhoeae across the EU/EEA and provides recent information on NG-MAST STs/Gs and genotypes based on WGS circulating in 21 EU/EEA Member States. This is the first time WGS has been used in any international surveillance programme for sexually transmitted infections. This study provided an up-to-date baseline in regard to genetic heterogeneity of gonococcal isolates in the EU/EEA, including identification of many novel genotypes, which can inform outbreak investigations and identification of AMR gonococcal strains. The use of molecular typing to predict AMR profiles has clear public health benefits as it could aid understanding of the dissemination of resistance within a population and facilitate development of targeted mitigation strategies. If the prediction of AMR is sufficiently reliable this approach could have a direct impact on appropriate management of patients for whom culture and associated susceptibility testing has not been performed. WGS provided a significantly higher and more accurate resolution, and additional information can easily be evaluated such as additional markers (diagnostic, molecular epidemiologic (e.g. MLST), antimicrobial resistance and evolutionary traits). Using WGS it has been possible to appropriately assess whether G1407 and other multidrug resistant STs/Gs are clonal, stable and persist over time. In general, the use of WGS will provide enhanced and detailed understanding of the emergence and transmission of different gonococcal strains, AMR phenotypes, and gonorrhoea in general, both nationally and internationally.

There is a clear public health benefit to be gained from performing molecular surveillance of gonorrhoea in Europe, particularly by WGS. However there are a number of areas that require further development before the maximum benefit can be gained from such a scheme, such as improving representativeness, improving the reporting of epidemiological variables and the public availability of user-friendly external databases and analysis tools.

The full PDF is available at: 
Absence of proof is not proof of absence.
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