March 18, 2018
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High-level, drug-resistant gonorrhea transmission persists in England

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Whole-genome sequencing analyses revealed that a high-level, azithromycin-resistant gonorrhea strain that was first detected during an outbreak that began in England in 2014 has been circulating throughout the country for years.

Helen Fifer, FRCPath , of the Antimicrobial Resistance and Healthcare-Associated Infections Reference Unit at Public Health England, and colleagues said their study, recently published in The Lancet Infectious Diseases, is the first to demonstrate sustained transmission of a clonal outbreak of high-level, azithromycin-resistant Neisseria gonorrhoeae over an extended period.

According to the researchers, many countries recommend using azithromycin in combination with extended-spectrum cephalosporins (ESCs), such as ceftriaxone, to delay the emergence of resistance to ESCs — the last-line treatment options for N. gonorrhoeae. Data published last year in PLoS Medicine showed that resistance to gonorrhea treatment has been on the rise. Of 77 countries surveyed by WHO, 66% detected gonococcal isolates with decreased susceptibility or resistance to ESCs between 2009 to 2014, and 81% reported isolates resistant to azithromycin.

Although cases of high-level, azithromycin-resistant gonorrhea (defined as having a minimum inhibitory concentration (MIC) of 256 mg/L or higher) were rarely reported in England, prevalence has increased following an outbreak that affected 16 people in Leeds between November 2014 and October 2015, according to the researchers. Since then, 98 cases were reported as of October 2017.

A three-dimensional computer-generated image of drug-resistant Neisseria gonorrhoeae diplococcal bacteria.
Researchers identified sustained transmission of high-level, drug-resistant gonorrhea in England.
Source: CDC

Fifer and colleagues performed whole-genome sequencing analyses on 60 isolates that were collected between November 2014 and February 2017 to determine whether the increase in cases represented clonal spread of the outbreak strain. They found that 37 of the 60 isolates were genetically similar to the ST9768 outbreak strain, which had a mutation in three of all four alleles of the 23S rRNA gene.

The researchers compared high-level, azithromycin-resistant isolates with 110 additional gonorrhea isolates from the United Kingdom and Ireland. They identified six isolates with lower azithromycin MICs that had the same mutation as ST9768, suggesting that high-level, azithromycin-resistant isolates likely derived from low-level, azithromycin-resistant isolates within a “short amount of time.” Fifer and colleagues hypothesized that exposure to azithromycin may have provided the selection pressure for the emergence of the high-level resistant phenotype.

In a related editorial, Magnus Unemo, PhD, director of WHO’s Collaborating Center for Gonorrhea and Other Sexually Transmitted Infections, and Kimberly A. Workowski MD, FACP, FIDSA, chief of the guidelines unit in the epidemiology and surveillance branch at CDC’s Division of Sexually Transmitted Diseases Prevention and professor of medicine at Emory University, noted that the use of azithromycin as part of dual therapy for gonorrhea has been questioned for years because of resistance concerns. However, they said the clinical relevance of decreased susceptibility or resistance to azithromycin remains unknown because of a lack of treatment failures, and there is “no clinical evidence to suggest that current dual therapy effectiveness is waning.”

Kimberly A. Workowski, MD
Kimberly A. Workowski

“The induction or selection of azithromycin resistance in gonococci by the use of dual gonorrhea therapy is probably limited because ceftriaxone resistance remains exceedingly uncommon, particularly in azithromycin-resistant gonococcal isolates,” they wrote. “Accordingly, even if azithromycin resistance was induced or selected for in some gonococci when using dual therapy, ceftriaxone would quickly eradicate the azithromycin-resistant organisms with its rapid bactericidal activity.”

Nevertheless, Unemo and Workowski stressed the need to continue monitoring trends in resistance and possible clinical treatment failures.

“New antimicrobials are currently being assessed and further research should investigate alternative antimicrobial combinations, which will be essential to provide optimum therapy against this formidable pathogen, and probably other sexually transmitted infections also, such as Mycoplasma genitalium,” they wrote. – by Stephanie Viguers

References:

Alirol E, et al. PLoS Med. 2017;doi:10.1371/journal.pmed.1002344.

Fifer H, et al. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30122-1.

Unemo M, Workwoski K. Lancet Infect Dis. 2018;doi:10.1016/S1473-3099(18)30162-2.

Disclosures: Fifer reports being a member of the scientific advisory board for Discuva. Unemo and Workowski report no relevant financial disclosures.