Molecular epidemiology of healthcareassociated infections

Practices of Molecular Epidemiology Lecture 12: Molecular epidemiology of healthcare-associated infections National Institute of Infectious Disease January 18, 2017 Learning objectives  Name the surveillance systems for healthcare infections in your country  Describe epidemiologic problems in hospitals that can be addressed by the application of molecular biology methods  Describe examples of how a hospital infection problem addressed by a molecular epidemiologic investigation led to correction of the problem Infectious disease epidemiological problems addressed by molecular biology techniques (2016)               Tracking strains across time and geography Distinguishing endemic from epidemic disease occurrence Stratification of data to refine study designs Distinguishing pathovars vs commensal flora or saprophytes Identifying new modes of transmission Studying microorganisms associated with healthcare or institutional infections Surveillance and monitoring response to intervention Characterizing population distribution and determinants of distribution of parasitic organisms Identifying genetic basis for disease transmission Validating microdiversity genotyping methods applied to epidemiology Virus quasispecies population structure analysis Identifying direction and chain of transmission Identifying hidden social networks and transmission links Analyzing microbiomes to study non-infectious disease epidemiology Epidemiologic problems associated with healthcare-associated infections  Endemic vs epidemic occurrence of infections in healthcare settings  Identifying mode and chain of transmission within a hospital  Risk factors for drug-resistant infections in hospitals  Distinguishing commensals/saprophytes from pathogens (e.g., coagulase-negative Staphylococcus)  Surveillance (drug-resistance and resistance genes) Hospital surveillance systems  US:  National Nosocomial Infection Surveillance System (NNIS)  Replaced in 2005 by National Health Safety Network (NHSN)  Europe:  Hospitals in Europe Links for Infection Control Surveillance (HELICS)  European Centre for Disease Prevention and Control (ECDC)  Japan:  Japan Nosocomial Infection Surveillance (JANIS)  International Nosocomial Infection Control Consortium Surveillance (INICC) Websites for drug-resistance surveillance systems  Europe: European Antibiotic Resistance Surveillance System (http://www.rivm.nl./earss/)  United States: National Health Safety Network: http://www.cdc.gov/nhsn/ Antimicrobial Resistance Reports CDC NIH WHO Major bacterial agents associated with hospitals  Gram-positive bacterial pathogens (3 genera)  Staphylococcus spp: MRSA, CA-MRSA, Coagulase-negative SA  Enterococcus spp: VRE  Clostridium difficile  Gram-negative bacterial pathogens (>10 genera)  Enterobacteriaceae  Glucose non-fermenters Gram-negative bacterial (GNB) infections in hospitals  Enterobacteriaceae  E coli  Klebsiella pneumoniae  Proteus spp  Enterobacter spp  Serratia spp  Citrobacter spp  Morganella spp  Providentia spp  Salmonella spp  Glucose non-fermentors  Pseudomonas aeruginosa  Acinetobacter baumanii  Stenotrophomonas maltophilia Other agents associated with hospitals  Fungal agents  Candida spp  Aspergillus spp  Diarrheagenic E coli, especially enteropathogenic E coli (EPEC)  Hepatitis B, C  HIV Blood-borne  Mycobacterium tuberculosis  SARS virus (coronavirus) Air-borne  Clostridium difficile Associated with use of broad-spectrum antibiotics Patient Results PFGE  Infection ESBLKp isolates  17 of 20 genotyped  genotype A:14 isolates  isolates from patients admitted before the study period  isolates during study period  genotype B:  genotype H:  Colonization ESBLKp isolates  39 genotyped  genotype A; 25  genotype B – 12 neonates  genotype C, D (one each)  non-ESBLKp isolates – all different genotypes Strain typing results  One genotype (A) comprised  75% (9/12) of isolates typed from infection and  64% (25/39) of isolates typed from colonization  A second genotype (B) comprised  17% (2/12) of isolates typed from infection and  31% (12/39) of isolates typed from colonization Genotype A Genotype B Other genotypes 13 patients with ESBLKp infection:  neonates with colonization detected before infection (3 to 23 days)  pairs of isolates (GI colonization and infection) available for typing  all genotype A Identifying modes of transmission in a hospital—Summary:  Both colonization and infection isolates of ESBLKp in the NICU were comprised of a limited number of clonal groups  Predominant colonization strains served as a reservoir for infection  Invasive procedure (CVC) in colonized neonates increased the risk of infection Identifying chain of transmission: Example 2: Hospital transmission of carbapenem-resistant Klebsiella pneumoniae at Clinical Center, NIH— Question: How does one demonstrate chain of transmission of a recognized outbreak strain in a hospital, and can something be done to interrupt this chain? Problem  Outbreak of carbapenem-resistant (KPC) Kp in Clinical Center of NIH, US, June-Dec 2011  18 cases, 11 deaths  Outbreak continued for months despite infection control measures Outbreak  June 13, 2011: Pt admitted to ICU; spent two 24-hr stays; discharged July 15 Pt  Aug 5: Kp isolated from tracheal aspirate of Pt (Snitkin et al, Science Transl Med, 2012) Outbreak—cont  Both strains of Kp belonged to ST258  Nearly one isolate per week through Dec 2011  11 deaths—6 attributed to Kp; others to underlying disease  Rigorous infection control measure implemented and outbreak stopped:  Cohorting colonized patients  Minimizing sharing of equipment and healthcare staff Analysis  Whole genome sequence analysis—index patient  isolates from index patient from body sites  Comprised of single nucleotide variants (SNV)  urine isolates identical SNV  others (throat, groin, BAL): SNVs  Whole genome sequence analysis—18 patients  41 distinct SNVs Single nucleotide variants (SNV) of whole genome sequences Constructed transmission link • Three independent transmission events from the index patient, based on SNV analysis (Snitkin et al, Science Transl Med, 2012) Identifying chain of transmission of a clone in a hospital: Summary  Three independent transmission events based on SNV analysis  Whole genome sequence SNVs provided greater resolution of genotype data and therefore transmission link  SNV comparison, together with time and place information can be used to construct a possible transmission chain  The identification of transmission chain may identify sites/conditions that most likely facilitate transmission  Interestingly, ventilator contamination was documented, but no subsequent transmission from the ventilator occurred References  Martins IS et al Endemic extended-spectrum beta- lactamase-producing Klebsiella pneumoniae at an intensive care unit: risk factors for colonization and infection Microb Drug Res 2006;12(1):50-8  Snitkin, ES et al Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with wholegenome sequencing Sci Transl Med 2012;4:148ra116 ... disease epidemiology Epidemiologic problems associated with healthcare-associated infections  Endemic vs epidemic occurrence of infections in healthcare settings  Identifying mode and chain of transmission... for healthcare infections in your country  Describe epidemiologic problems in hospitals that can be addressed by the application of molecular biology methods  Describe examples of how a hospital... Associated with use of broad-spectrum antibiotics Gram positive vs Gram negative bacteria differences  GPB  More common in hospital infections  Limited number of species  Limited number of drug-resistance