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.
Mar 6 Lancet Infect Dis abstract
Mar 6 Emerg Infect Dis paper