Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing
ABSTRACT Timely diagnostic tools are needed to improve antibiotic treatment. Pairing metagenomic sequencing with genomic neighbor typing algorithms may support rapid clinically actionable results. We created resistance-associated sequence elements (RASE) databases for Escherichia coli and Klebsiella...
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American Society for Microbiology
2025-01-01
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| Series: | Microbiology Spectrum |
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| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01366-24 |
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| author | Amanda C. Carroll Leanne Mortimer Hiren Ghosh Sandra Reuter Hajo Grundmann Karel Brinda William P. Hanage Angel Li Aimee Paterson Andrew Purssell Ashley Rooney Noelle R. Yee Bryan Coburn Shola Able-Thomas Martin Antonio Allison McGeer Derek R. MacFadden |
| author_facet | Amanda C. Carroll Leanne Mortimer Hiren Ghosh Sandra Reuter Hajo Grundmann Karel Brinda William P. Hanage Angel Li Aimee Paterson Andrew Purssell Ashley Rooney Noelle R. Yee Bryan Coburn Shola Able-Thomas Martin Antonio Allison McGeer Derek R. MacFadden |
| author_sort | Amanda C. Carroll |
| collection | DOAJ |
| description | ABSTRACT Timely diagnostic tools are needed to improve antibiotic treatment. Pairing metagenomic sequencing with genomic neighbor typing algorithms may support rapid clinically actionable results. We created resistance-associated sequence elements (RASE) databases for Escherichia coli and Klebsiella spp. and used them to predict antibiotic susceptibility in directly sequenced (Oxford Nanopore) urine specimens from critically ill patients. RASE analysis was performed on pathogen-specific reads from metagenomic sequencing. We evaluated the ability to predict (i) multi-locus sequence type (MLST) and (ii) susceptibility profiles. We used neighbor typing to predict MLST and susceptibility phenotype of E. coli (64/80) and Klebsiella spp. (16/80) from urine samples. When optimized by lineage score, MLST predictions were concordant for 73% of samples. Similarly, a RASE-susceptible prediction for a given isolate was associated with a specificity and a positive likelihood ratio (LR+) for susceptibility of 0.65 (95% CI, 0.54–0.76) and 2.26 (95% CI, 1.75–2.92), respectively, with an increase in the probability of susceptibility of 10%. A RASE-non-susceptible prediction was associated with a sensitivity and a negative likelihood ratio (LR-) for susceptibility of 0.79 (95% CI, 0.74–0.84) and 0.32 (95% CI, 0.24–0.43) respectively, with a decrease in the probability of susceptibility of 20%. Numerous antibiotic classes could reasonably be reconsidered empiric therapy by shifting empiric probabilities of susceptibility across relevant treatment thresholds. Moreover, these predictions can be available within 6 h. Metagenomic sequencing of urine specimens with neighbor typing provides rapid and informative predictions of lineage and antibiotic susceptibility with the potential to impact clinical decision-making.IMPORTANCEUrinary tract infections (UTIs) are a common diagnosis in hospitals and are often treated empirically with broad-spectrum antibiotics. These broad-spectrum agents can select for resistance in these bacteria and co-colonizing organisms. The use of narrow-spectrum agents is desirable as an antibiotic stewardship measure; however, it is counterbalanced by the need for adequate therapy. Identification of causative organisms and their antibiotic susceptibility can help direct treatment; however, conventional testing requires days to produce actionable results. Methods to quickly and accurately predict susceptibility phenotypes for pathogens causing UTI could thus improve both patient outcomes and antibiotic stewardship. Here, expanding on previous work showing accurate prediction for certain Gram-positive pathogens, we demonstrate how the use of RASE from metagenomic sequencing can provide informative and rapid phenotype prediction results for common Gram-negative pathogens in UTI, highlighting the future potential of this method to be used in clinical settings to guide empiric antibiotic selection. |
| format | Article |
| id | doaj-art-02cc9ec2a4be406aa33393e2cd2191fa |
| institution | Kabale University |
| issn | 2165-0497 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
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| series | Microbiology Spectrum |
| spelling | doaj-art-02cc9ec2a4be406aa33393e2cd2191fa2025-01-07T14:05:18ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972025-01-0113110.1128/spectrum.01366-24Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typingAmanda C. Carroll0Leanne Mortimer1Hiren Ghosh2Sandra Reuter3Hajo Grundmann4Karel Brinda5William P. Hanage6Angel Li7Aimee Paterson8Andrew Purssell9Ashley Rooney10Noelle R. Yee11Bryan Coburn12Shola Able-Thomas13Martin Antonio14Allison McGeer15Derek R. MacFadden16The Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaThe Eastern Ontario Regional Laboratory, Ottawa, Ontario, CanadaUniversity of Freiburg, Freiburg, GermanyUniversity of Freiburg, Freiburg, GermanyUniversity of Freiburg, Freiburg, GermanyInria, Irisa, Univ. Rennes, Rennes, FranceHarvard T.H Chan School of Public Health, Harvard University, Cambridge, Massachusetts, USASinai Health, Toronto, Ontario, CanadaSinai Health, Toronto, Ontario, CanadaThe Ottawa Hospital, Ottawa, Ontario, CanadaThe University of Toronto, Toronto, Ontario, CanadaThe University of Toronto, Toronto, Ontario, CanadaThe University of Toronto, Toronto, Ontario, CanadaMRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, GambiaMRC Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, GambiaSinai Health, Toronto, Ontario, CanadaThe Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaABSTRACT Timely diagnostic tools are needed to improve antibiotic treatment. Pairing metagenomic sequencing with genomic neighbor typing algorithms may support rapid clinically actionable results. We created resistance-associated sequence elements (RASE) databases for Escherichia coli and Klebsiella spp. and used them to predict antibiotic susceptibility in directly sequenced (Oxford Nanopore) urine specimens from critically ill patients. RASE analysis was performed on pathogen-specific reads from metagenomic sequencing. We evaluated the ability to predict (i) multi-locus sequence type (MLST) and (ii) susceptibility profiles. We used neighbor typing to predict MLST and susceptibility phenotype of E. coli (64/80) and Klebsiella spp. (16/80) from urine samples. When optimized by lineage score, MLST predictions were concordant for 73% of samples. Similarly, a RASE-susceptible prediction for a given isolate was associated with a specificity and a positive likelihood ratio (LR+) for susceptibility of 0.65 (95% CI, 0.54–0.76) and 2.26 (95% CI, 1.75–2.92), respectively, with an increase in the probability of susceptibility of 10%. A RASE-non-susceptible prediction was associated with a sensitivity and a negative likelihood ratio (LR-) for susceptibility of 0.79 (95% CI, 0.74–0.84) and 0.32 (95% CI, 0.24–0.43) respectively, with a decrease in the probability of susceptibility of 20%. Numerous antibiotic classes could reasonably be reconsidered empiric therapy by shifting empiric probabilities of susceptibility across relevant treatment thresholds. Moreover, these predictions can be available within 6 h. Metagenomic sequencing of urine specimens with neighbor typing provides rapid and informative predictions of lineage and antibiotic susceptibility with the potential to impact clinical decision-making.IMPORTANCEUrinary tract infections (UTIs) are a common diagnosis in hospitals and are often treated empirically with broad-spectrum antibiotics. These broad-spectrum agents can select for resistance in these bacteria and co-colonizing organisms. The use of narrow-spectrum agents is desirable as an antibiotic stewardship measure; however, it is counterbalanced by the need for adequate therapy. Identification of causative organisms and their antibiotic susceptibility can help direct treatment; however, conventional testing requires days to produce actionable results. Methods to quickly and accurately predict susceptibility phenotypes for pathogens causing UTI could thus improve both patient outcomes and antibiotic stewardship. Here, expanding on previous work showing accurate prediction for certain Gram-positive pathogens, we demonstrate how the use of RASE from metagenomic sequencing can provide informative and rapid phenotype prediction results for common Gram-negative pathogens in UTI, highlighting the future potential of this method to be used in clinical settings to guide empiric antibiotic selection.https://journals.asm.org/doi/10.1128/spectrum.01366-24antimicrobial resistancemetagenomicsnanoporerapid diagnosticsgenomicsurinary tract infection |
| spellingShingle | Amanda C. Carroll Leanne Mortimer Hiren Ghosh Sandra Reuter Hajo Grundmann Karel Brinda William P. Hanage Angel Li Aimee Paterson Andrew Purssell Ashley Rooney Noelle R. Yee Bryan Coburn Shola Able-Thomas Martin Antonio Allison McGeer Derek R. MacFadden Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing Microbiology Spectrum antimicrobial resistance metagenomics nanopore rapid diagnostics genomics urinary tract infection |
| title | Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| title_full | Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| title_fullStr | Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| title_full_unstemmed | Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| title_short | Rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| title_sort | rapid inference of antibiotic susceptibility phenotype of uropathogens using metagenomic sequencing with neighbor typing |
| topic | antimicrobial resistance metagenomics nanopore rapid diagnostics genomics urinary tract infection |
| url | https://journals.asm.org/doi/10.1128/spectrum.01366-24 |
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