A Year of Infection in the Intensive Care Unit: Prospective Whole Genome Sequencing of Bacterial Clinical Isolates Reveals Cryptic Transmissions and Novel Microbiota

Abstract

Bacterial whole genome sequencing holds promise as a disruptive technology in clinical microbiology, but it has not yet been applied systematically or comprehensively within a clinical context. Here, over the course of one year, we performed prospective collection and whole genome sequencing of nearly all bacterial isolates obtained from a tertiary care hospital’s intensive care units (ICUs). This unbiased collection of 1,229 bacterial genomes from 391 patients enables detailed exploration of several features of clinical pathogens. A sizable fraction of isolates identified as clinically relevant corresponded to previously undescribed species: 12% of isolates assigned a species-level classification by conventional methods actually qualified as distinct, novel genomospecies on the basis of genomic similarity. Pan-genome analysis of the most frequently encountered pathogens in the collection revealed substantial variation in pan-genome size (1,420 to 20,432 genes) and the rate of gene discovery (1 to 152 genes per isolate sequenced). Surprisingly, although potential nosocomial transmission of actively surveilled pathogens was rare, 8.7% of isolates belonged to genomically related clonal lineages that were present among multiple patients, usually with overlapping hospital admissions, and were associated with clinically significant infection in 62% of patients from which they were recovered. Multi-patient clonal lineages were particularly evident in the neonatal care unit, where seven separate Staphylococcus epidermidis clonal lineages were identified, including one lineage associated with bacteremia in 5/9 neonates. Our study highlights key differences in the information made available by conventional microbiological practices versus whole genome sequencing, and motivates the further integration of microbial genome sequencing into routine clinical care.

Author Summary

Bacterial whole genome sequencing is becoming increasingly common to microbiological research, but despite its great potential, has not yet been meaningfully integrated into clinical care. Here, we generated whole genome sequencing data from nearly all of the bacterial isolates prospectively collected from a hospital’s intensive care units over an entire year. Our analysis identifies novel microbiota in hospitalized patients, a high incidence of patient infection with multiple unrelated lineages of a bacterial species, and the possibility of cryptic transmission of bacteria among patients. Our study is unprecedented in providing a broad and unbiased view of bacterial infections that affect the hospital’s sickest patients, and demonstrates the extent of information that can be learned from comprehensive genomic surveillance of clinical bacterial isolates over an extended period of time.