WGS to predict antibiotic MICs for Neisseria gonorrhoeae.
Tracking the spread of antimicrobial-resistant Neisseria gonorrhoeae is a major priority for national surveillance programmes.



We investigate whether WGS and simultaneous analysis of multiple resistance determinants can be used to predict antimicrobial susceptibilities to the level of MICs in N. gonorrhoeae.



WGS was used to identify previously reported potential resistance determinants in 681 N. gonorrhoeae isolates, from England, the USA and Canada, with phenotypes for cefixime, penicillin, azithromycin, ciprofloxacin and tetracycline determined as part of national surveillance programmes. Multivariate linear regression models were used to identify genetic predictors of MIC. Model performance was assessed using leave-one-out cross-validation.



Overall 1785/3380 (53%) MIC values were predicted to the nearest doubling dilution and 3147 (93%) within ±1 doubling dilution and 3314 (98%) within ±2 doubling dilutions. MIC prediction performance was similar across the five antimicrobials tested. Prediction models included the majority of previously reported resistance determinants. Applying EUCAST breakpoints to MIC predictions, the overall very major error (VME; phenotypically resistant, WGS-prediction susceptible) rate was 21/1577 (1.3%, 95% CI 0.8%-2.0%) and the major error (ME; phenotypically susceptible, WGS-prediction resistant) rate was 20/1186 (1.7%, 1.0%-2.6%). VME rates met regulatory thresholds for all antimicrobials except cefixime and ME rates for all antimicrobials except tetracycline. Country of testing was a strongly significant predictor of MIC for all five antimicrobials.



We demonstrate a WGS-based MIC prediction approach that allows reliable MIC prediction for five gonorrhoea antimicrobials. Our approach should allow reasonably precise prediction of MICs for a range of bacterial species.
Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research Health Protection Research Unit, Oxford, UK.
David W
DW
Eyre
Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research Health Protection Research Unit, Oxford, UK.
Dilrini
D
De Silva
Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.|National Infection Service, Public Health England, UK.
Kevin
K
Cole
Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.|National Infection Service, Public Health England, UK.
Joanna
J
Peters
Antimicrobial Resistance and Healthcare Associated Infections (AMRHAI) Reference Unit, National Infection Service, London, UK.
Michelle J
MJ
Cole
Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA.|Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA.
Yonatan H
YH
Grad
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Walter
W
Demczuk
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Irene
I
Martin
National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Michael R
MR
Mulvey
Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research Health Protection Research Unit, Oxford, UK.|National Infection Service, Public Health England, UK.
Derrick W
DW
Crook
Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research Health Protection Research Unit, Oxford, UK.
A Sarah
AS
Walker
Nuffield Department of Medicine, University of Oxford, Oxford, UK.|Oxford National Institute for Health Research Health Protection Research Unit, Oxford, UK.
Tim E A
TEA
Peto
National Institute for Health Research Biomedical Research Centre, Oxford, UK.|Brighton and Sussex University Hospitals NHS Trust, Brighton, UK.|National Infection Service, Public Health England, UK.
John
J
Paul
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D002170:Canada / Q000453:epidemiology; D020682:Cefixime / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004739:England / Q000453:epidemiology; D016680:Genome, Bacterial; D006069:Gonorrhea / Q000453:epidemiology / Q000382:microbiology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000235:genetics*; D010400:Penicillin G / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology; D014481:United States / Q000453:epidemiology; D000073336:Whole Genome Sequencing
D000900:Anti-Bacterial Agents; D002939:Ciprofloxacin; D017963:Azithromycin; D020682:Cefixime; D013752:Tetracycline; D010400:Penicillin G