Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate and ineffective antibiotic use. However, because such assays infer resistance phenotypes based on the presence or absence of known genetic markers, their utility will wane in response to the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance designed to ensure early detection of novel resistance variants, but efficient strategies to do so remain to be defined. Here, we evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting genetic variants associated with antibiotic resistance or diagnostic escape in Neisseria gonorrhoeae, focusing on this pathogen because of its high burden of disease, the imminent threat of treatment resistance, and the use and ongoing development of genotype-based diagnostics. We show that incorporating patient characteristics, such as demographics, geographic regions, or anatomical sites of isolate collection, into sampling approaches is not a reliable strategy for increasing variant detection efficiency. In contrast, sampling approaches informed by pathogen characteristics, such as genomic diversity and genomic background, are significantly more efficient than random sampling in identifying genetic variants associated with antibiotic resistance and diagnostic escape.