Microbial genomics of hospital-associated pathogens

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

With a dearth of new classes of antimicrobials in development, hospital infection control is crucial to prevent the rise of intractable multi-drug resistant bacterial and fungal infections. Whole genome sequencing provides a level of resolution that far exceeds traditional typing methods. This high level resolution enables tracking the spread of pathogens within and between hospitals, thus identifying possible weaknesses in existing practices and points of intervention. We aim to use genomic information to model outbreaks, monitor evolution of antibiotic resistance and develop risk assessment strategies. Hospital-acquired infections result in 100,000 deaths per year, and represent a tremendous social cost to patients and their families. My laboratory's mission is to use genomic information to model clusters of bacterial infections and transmissions, monitor evolution of antibiotic resistance and develop risk assessment strategies. Klebsiella pneumoniae is a Gram-negative bacteria, which represents a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of strains resistant to carbapenems has left few treatment options, making infection containment critical. In 2011 the National Institutes of Health Clinical Center had a cluster of infections of carbapenem-resistant K. pneumoniae that affected 19 patients, 12 of who died. Whole-genome sequencing was performed on K. pneumoniae isolates to gain insight into why the outbreak progressed in spite of early implementation of infection control procedures. Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient, who was discharged three weeks before the next case became clinically apparent. Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data providing possible explanations for these transmissions. Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission. Our long-term goal is both to promote hospital infection control and to tailor drug strategies to minimize the acquisition of antibiotic resistance. Collaboration among physicians who have expertise in healthcare epidemiology, microbiologists who have expertise in diagnostics, and scientists who have expertise in genomics is critical to take advantage of emerging technologies and translate them into improved patient care. For immunosuppressed patients, healthcare-associated infections are a significant cause of morbidity and mortality. Hospital plumbing is an infrequent, but known reservoir for opportunistic microbial pathogens that can infect hospitalized patients. We study clusters of patients with infections of organisms that could be associated with the hospital environment. We perform full genome DNA sequencing on multidrug-resistant organisms, such as Sphingomonas koreensis with clinical isolates identified between 2006 and 2016 at the NIH Clinical Center (NIHCC). NIH isolates were compared with clinical and environmental S. koreensis isolates obtained from other institutions. Unique single nucleotide variants identified in S. koreensis strains elucidated the existence of multiple point sources in the hospital. Clinical S. koreensis isolates from other facilities were genetically distinct, but still highly antibiotic resistant. We study multiple aspects of the emerging human pathogen Candida auris to inform clinical care, including identifying sites of colonization and genetic diversification on patients. We study transmissions in ongoing hospital outbreaks within the United States in collaboration with colleagues at CDC and others. Together with collaborators we aim to test possible strategies to protect or to decolonize patients.We explore the genetic diversity of Candida auris colonizing patients combining shotgun metagenomic, isolate, and plate metagenomic sequencing. Shotgun metagenomic sequencing reveals both bacterial and fungal pathogens that colonize the skin of residents of nursing homes. Combining genomic data with epidemiological clinical metadata we explore strain sharing within facilities. We are developing mouse models to understand the skin colonization of an emerging human pathogen, Candida auris. This new project explores both commensalism and colonization resistance, exploring Candida auris ability to colonize skin given different perturbations to host physiology, modulated through either targeted deletions in important immunologic pathways or perturbations to the native bacterial/fungal populations. These studies have identified sites of Candida auris colonization and tested strategies used to control colonization in vulnerable patient populations.