Targeted surveillance strategies for efficient detection of novel antibiotic resistance variants.

Allison L Hicks,Marc Lipsitch,Kevin C Ma,Tatum D Mortimer,Stephen M Kissler,Yonatan H Grad,George Taiaroa,Deborah A Williamson,Melinda Ashcroft

doi:10.7554/elife.56367

Abstract

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in Neisseria gonorrhoeae, a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape.

Highlights

Nucleic acid-based diagnostics that enable rapid pathogen identification and prediction of drug susceptibility profiles can improve clinical decision-making, reduce inappropriate antibiotic use, and help address the challenge of antibiotic resistance (McAdams et al, 2019; Fingerhuth et al, 2017; Tuite et al, 2017)
Use of traditional nucleic acid amplification tests (NAATs) for pathogen identification and genotype-based diagnostics for antibiotic resistance can select for genetic variants that escape detection (Smid et al, 2019)
Mutations and/or deletions at the NAAT target locus that cause an amplification failure have arisen in Neisseria gonorrhoeae, Chlamydia trachomatis, Staphylococcus aureus, and Plasmodium falciparum, resulting in false negative diagnostic errors only detected when using

Summary

Introduction

Nucleic acid-based diagnostics that enable rapid pathogen identification and prediction of drug susceptibility profiles can improve clinical decision-making, reduce inappropriate antibiotic use, and help address the challenge of antibiotic resistance (McAdams et al, 2019; Fingerhuth et al, 2017; Tuite et al, 2017). Pathogen surveillance programs aimed at early detection of novel variants are crucial to ensuring the clinical utility and sustainability of these diagnostics. Use of traditional nucleic acid amplification tests (NAATs) for pathogen identification and genotype-based diagnostics for antibiotic resistance can select for genetic variants that escape detection (Smid et al, 2019). Mutations and/or deletions at the NAAT target locus that cause an amplification failure have arisen in Neisseria gonorrhoeae, Chlamydia trachomatis, Staphylococcus aureus, and Plasmodium falciparum, resulting in false negative diagnostic errors only detected when using

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