Tracking Antibiotic-resistant Gonorrhea Using Whole Genome Sequencing

Researchers from the United Kingdom have demonstrated how whole genome sequencing technology can be used to track the spread of infection in Neisseria gonorrhea—an important finding given that the number of drug-resistant strains of the sexually transmitted infection (STI) has reportedly been increasing.

In a study published in The Lancet Infectious Diseases on July 12, scientists and clinicians from Brighton and Sussex University Hospitals, Oxford University, and Public Health England used blood samples collected in Britain and the United States to identify genetic evidence that individual cases of gonorrhea were linked to each other, which could provide researchers with a roadmap for new treatment approaches for the troubling STI. In a report issued by World Health Organization (WHO) in 2014, it was reported that “decreased susceptibility to third-generation cephalosporins, the treatment of last resort for gonorrhea, has been verified in 36 countries and is a growing problem.” According to the WHO, gonorrhea accounts for 88 million of the 448 million STIs diagnosed globally each year.

For their study, the UK researchers collected nearly 1,500 blood samples over a 5-year period from patients who sought sexual health services in Brighton, UK and compared these samples to each other and to samples from London, Wales, northern England and the United States. According to the authors, the collected samples underwent nucleic acid amplification testing (NAAT), with positive samples and samples from symptomatic patients cultured for Neisseria gonorrhea. Resulting isolates were whole-genome sequenced.

The researchers also performed cefixime susceptibility testing in select isolates by agar incorporation, and determined multi-antigen sequence types and penA genotypes using sequencing data. Cefixime is a third-generation cephalosporin used in the treatment of gonorrhea. Finally, and perhaps most interestingly, they derived a transmission nomogram to determine the plausibility of direct or indirect transmission between any 2 cases.

In all, they identified 1,061 infections in 907 patients, and 281 of these infections were indistinguishable—meaning, they differed by zero single nucleotide polymorphisms—from one or more previous cases. The remaining 786 had “evidence of a sampled direct or indirect Brighton source,” indicating they were linked to earlier cases in the city. In addition, of 1,273 infections found in samples collected in Brighton, 225 were linked to cases from elsewhere in the United Kingdom, and 115 were linked to a single case in the United States. The authors noted that 4 lineages initially identified in Brighton could be linked to 70 of the US sequences in the study, including 61 “from a lineage carrying the mosaic penA XXXIV allele.” This allele has been associated with reduced cefixime susceptibility.

“[T]his study… clearly shows that action to tackle antibiotic-resistant gonorrhea needs to be coordinated across national boundaries,” study co-author David Eyre, DPhil, specialist registrar in infectious diseases at Oxford said in a statement released by the school. “However, using whole genome sequencing to track transmission of these infections is feasible. Sequencing can overcome some of the weaknesses in traditional partner notification tracing, while at the same time enabling us to spot risk factors and better target health interventions. It could even be used to notify contacts by using the same apps used to set up sexual encounters.”

In a related commentary published in The Lancet Infectious Diseases, researchers Vanessa G. Allen, MDCM, and Roberto G. Melano, PhD, from the Department of Laboratory Medicine and Pathobiology at the University of Toronto note that while “whole-genome sequencing has been widely used in bacteriology… several innovative approaches in [the author’s] methods define the strength of their work,” including that “they included isolates without selection based on antimicrobial susceptibility, which allowed them to do an extensive genetic and epidemiological analysis of the whole gonococcal population” in Brighton, UK over a 5-year period.” The study was “further strengthened by the authors' analysis of reproducibility… and, crucial to interpretation of genomic epidemiological analyses, their examination of the potential for multiple clones to infect the same patient,” which enabled them to analyze a “large, local sample.”

They write, “Although direct or person-to-person transmission cannot be proved with the tool alone, the nomogram can be used in combination with contact and clinical data to help control the further spread of gonorrhea in a manner that was not possible with traditional microbiological methods.”

Added Dr. Allen in explaining the significance of The Lancet study during a separate interview with Contagion: “Gonorrhea is the second most common reportable disease and, while resistance has always been an issue, the difference now is that there is resistance to the last-available antibiotics [to treat it]. [As a result] it is expected that we will have untreatable gonorrhea in the next 5 to 10 years.”

Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous healthcare-related publications. He is the former editor of Infectious Disease Special Edition.