Abstract
SummaryBackgroundWhole-genome sequencing (WGS) can be used in genomic epidemiology investigations to confirm or refute outbreaks of bacterial pathogens, and to support targeted and efficient infection control interventions. We aimed to define a genetic relatedness cutoff, quantified as a number of single-nucleotide polymorphisms (SNP), for meticillin-resistant Staphylococcus aureus (MRSA), above which recent (ie, within 6 months) patient-to-patient transmission could be ruled out.MethodsWe did a retrospective genomic and epidemiological analysis of MRSA data from two prospective observational cohort studies in the UK to establish SNP cutoffs for genetic relatedness, above which recent transmission was unlikely. We used three separate approaches to calculate these thresholds. First, we applied a linear mixed model to estimate the S aureus substitution rate and 95th percentile within-host diversity in a cohort in which multiple isolates were sequenced per individual. Second, we applied a simulated transmission model to this same genomic dataset. Finally, in a second cohort, we determined the genetic distance (ie, the number of SNPs) that would capture 95% of epidemiologically linked cases. We applied the three approaches to both whole-genome and core-genome sequences.FindingsIn the linear mixed model, the estimated substitution rate was roughly 5 whole-genome SNPs (wgSNPs) or 3 core-genome SNPs (cgSNPs) per genome per year, and the 95th percentile within-host diversity was 19 wgSNPs or 10 cgSNPs. The combined SNP cutoffs for detection of MRSA transmission within 6 months per this model were thus 24 wgSNPs or 13 cgSNPs. The simulated transmission model suggested that cutoffs of 17 wgSNPs or 12 cgSNPs would detect 95% of MRSA transmission events within the same timeframe. Finally, in the second cohort, cutoffs of 22 wgSNPs or 11 cgSNPs captured 95% of epidemiologically linked cases within 6 months.InterpretationOn the basis of our results, we propose conservative cutoffs of 25 wgSNPs or 15 cgSNPS above which transmission of MRSA within the previous 6 months can be ruled out. These cutoffs could potentially be used as part of a genomic sequencing approach to the management of outbreaks of MRSA in conjunction with traditional epidemiological techniques.FundingUK Department of Health, Wellcome Trust, UK National Institute for Health Research.
Highlights
The potential benefits of using bacterial-sequencing techniques in routine clinical practice has been well documented in the past 10 years
Interpretation On the basis of our results, we propose conservative cutoffs of 25 whole-genome single-nucleotide polymorphisms (SNPs) (wgSNPs) or 15 cgSNPS above which transmission of meticillin-resistant Staphylococcus aureus (MRSA) within the previous 6 months can be ruled out
We focused on a subset of 429 (55%) individuals who were positive for an MRSA strain that was within 50 wgSNPs of the MRSA carried by at least one other patient, because recent transmission beyond this gen etic distance is very unlikely.[4]
Summary
The potential benefits of using bacterial-sequencing techniques in routine clinical practice has been well documented in the past 10 years. Sequencing can be used to rule out the possibility of an outbreak when MRSA-positive patients are clustered by chance,[3] thereby reducing unnecessary investigation and interventions. Prospective sequencing can detect far more outbreaks than standard infection control surveillance: a genomic surveillance study[4] of MRSA isolated in a clinical micro biology laboratory in the east of England over 12 months identified 173 separate transmission clusters (cluster sizes ranged from two to 44 cases) involving 598 people, none of which were detected by conventional infection control approaches
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