>> GOOD AFTERNOON. WELCOME TO THE NEW ACADEMIC YEAR OF CLINICAL CENTER GRAND ROUNDS. THIS YEAR WE BELIEVE WE HAVE A VERY EXCITING SCHEDULE AND WE HOPE THAT YOU'LL ALL BE ABLE TO PARTICIPATE IN THIS MEDICAL EDUCATION PROGRAM WHICH ALLOWS YOU TO BECOME AWARE OF SOME OF THE EXCITING BIOMEDICAL RESEARCH BEING DONE HERE IN THE PROGRAM AT THE NIH. TODAY'S A SPECIAL DAY, ONE STARTED AT ABOUT 8:00 THIS MORNING AS I WAS PULLING INTO MY OFFICE AND LEARNED THE JOINT COMMISSION IS HERE DURING THE TRIANNUAL REVIEW OF THE CLINICAL CENTER. DAVID HENDERSON LOOKS A LITTLE PALE, YOU'LL UNDERSTAND THERE IS A LITTLE BIT OF PRESSURE AS THE TEAM IS GOING AROUND MEETING WITH MANY OF YOU TO DISCUSS HOW WE OPERATE IN THIS CLINICAL CENTER. TODAY WE HAVE A SPECIAL GRAND ROUNDS THAT'S TITLED THE KLEBSIELLA PNEUMONIA, EPIDEMIOLOGY AND GENOMICS. WE HAVE THREE SPEAKERS WHO ARE GOING TO COVER DIFFERENT ASPECTS OF A CLUSTER OF INFECTIONS THAT WE'VE HAD IN THE CLINICAL CENTER OVER THE PAST YEAR. AND TRY TO PUT IT ALL IN CONTEXT FOR YOU TO BRING YOU UP-TO-DATE ON THE INFECTION EPIDEMIOLOGY, VERY EXCITING NEW SCIENTIFIC APPROACHES FOR TACKLING THAT INFECTION, AND THEN FOR PUTTING IT IN PERSPECTIVE. SO YOU'LL SEE HOW THIS INFECTION WE'VE HAD FITS IN TO THE CONTEXT OF A LOCAL, STATEWIDE, NATIONAL AND INTERNATIONAL PROBLEM THAT WE'RE ALL FACING. SO LET ME NOW INTRODUCE OUR SPEAKERS. OUR FIRST SPEAKER, IS DR. TARA PALMORE WHO GRADUATED FROM HARVARD FROM HONORS IN HISTORY AND LITTURE, RECEIVED HER M.D. AT THE UNIVERSITY OF VIRGINIA SCHOOL OF MEDICINE. SHE COMPLETED AN INTERNSHIP AND RESIDENCY AT THE NEW YORK PRESS BEERTARIAN -- PRESBYTERIAN MEDICAL CENTER AND CAME TO THE NIH IN 2001 AS THE CLINICAL INEFFICIENCY DISEASES FELLOW. BEEN IN THE CLINICAL CENTERS DEPUTY HOSPITAL EPIDEMIOLOGY POSITION SINCE 2007 MUCH AND DIRECTOR OF THE INFECTIOUS DISEASE TRAINING PROGRAM SINCE 2011. A MEMBERSHIPS INCLUDE THE INFECTIOUS DISEASES SOCIETY OF AMERICA, THE AMERICAN COLLEGE OF PHYSICIANS, AND THE SOCIETY OF HEALTHCARE EPIDEMIOLOGY OF AMERICA. SHE IS THE 2009 RECIPIENT OF THE NIH DISTINGUISHED CLINICAL TEACHER'S AWARD. OUR SECOND SPEAKER IS GOING TO BE DR. JULIE SEGRE, EARNED AND B.A. DEGREE IN MATHEMATICS WHICH SHE SERVED ON THE BOARD OF TRUSTEES. SHE RECEIVED HER P.H.D. IN PENTAGON AND GENETICS FROM M.I.T. AND DID POSTDOC TROPICAL TRAINING IN CELL BIOLOGY AT THE UNIVERSITY OF CHICAGO. SH HE JOINED THE NHGRI INTERMURAL PROGRAM IN 2000, A LEADERSHIP ROLE IN THE HUMAN MICROBIOME PROJECT SEQUENCING REFERENCE DATA FOR MICROBES LIVING IN HEALTHY ADULTS. RESEARCH INVOLVES PATIENCE WITH ATOPIC DERMATITIS AND IMMUNO DEFICIENCIES. HER ROLE ALSO INCLUDES COLLABORATIC WITH THE EPIDEMIOLOGISTS AND CLINICAL MICROBIOLOGISTS HERE AT THE CLINICAL CENTER TO MONITOR AND ASSIST DIAGNOSTIC OUTBREAKS BACTERIAL INFECTION. OUR LAST SPEAKER TODAY TO PUT ALL OF THIS IN PERSPECTIVE, IN TERMS OF THE NATIONAL AND GLOBAL CONTEXT, DR. HENRY MASUR. HE EARNED HIS MEDICAL DEGREE FROM CORNELL, COMPLETED HIS INTERNSHIP AND RESIDENCY IN INTERNAL MEDICINE AT THE NEW YORK HOSPITAL AND JOHNS HOPKINS HOSPITAL. HE WAS RECRUITED TO THE NIH TO JOINTLY FOUND THE NEW DEPARTMENT THEN OF CRITICAL CARE MEDICINE, AND HIV PROGRAMS AT NAIAD AND BECAME CHIEF OF CRITICAL CARE MEDICINE IN 1989. TODAY HE COLEADS THE DISTRICT OF COLUMBIA PARTNERSHIP FOR AIDS PROGRESS, A UNIQUE COLLABORATION BETWEEN NIH AND THE DC GOVERNMENT THAT AIMS TO CREATE URBAN MODEL FOR DECREASING THE IMPACT OF HIV-AIDS IN UNDERSERVED POPULATIONS. HE'S CURRENTLY ALSO A PROFESSOR OF MEDICINE AT GEORGE WASHINGTON UNIVERSITY AND HOLDS APPOINTMENTS AT THE UNIVERSITY OF MEDICINE, MARYLAND AND THE WASHINGTON HOSPITAL CENTER. HE WAS PRESIDENT OF THE INFECTIOUS DISEASE SOCIETY OF AMERICA FROM 2006 TO 2007. SO I THINK WE HAVE A STELLAR CAST TO BRING YOU THIS STORY. AND I NOW WOULD LIKE TO WELCOME DR. PALMORE TO THE PODIUM. >> THANK YOU. THE TOPIC OF TODAY'S SESSION IS THE EPIDEMIOLOGY AND JOKES OF HOSPITAL A-- GENOMICS OF HOSPITAL ACQUIRED KLEBSIELLA PNEUMONIAE. THERE ARE NO DISCLOSURES FROM THE SPEAKERS OR PLANNING STAFF OF THE GROUND ROUNDS SESSION. THE OBJECTIVES OF OUR TALK ARE TO DIFFERENTIATE BETWEEN TRADITIONAL CULTURE BASED AND GENOMIC DNA SEQUENCING APPROACHES FOR STUDYING BACTERIA, TO EXAMINE FINDINGS OF DNA SEQUENCE BASED TRACKING, AND TO RECOGNIZE POTENTIAL [APPLAUSE] PLICATIONS OF CLINICAL DIAGNOSTICS BASED ON DNA SEQUENCE IN HOSPITAL AND FOOD BOURNE OUTBREAKS. HOSPITAL ACQUIRED INFECTIONS HAVE BEEN A RECOGNIZED COMPLICATION OF HEALTHCARE SINCE THE BEGINNING OF ORGANIZED MEDICINE. THE EXACT AND ENORMOUS HUMAN TOLL. COMPLICATING 5% OF ALL HOSPITAL ADMISSIONS IN THE UNITED STATES, 2 MILLION PEOPLE ABLY IN THIS COUNTRY -- ANNUALLY, CAUSING 99,000 DEATHS PER YEAR. BRINGS THEM INTO THE TOP TEN LEADING CAUSES OF DEATH IN THE UNITED STATES. 2/3 OF THOSE DEATHS ARE FROM GRAM NEGATIVE BACTERIA, WHICH EFFECTS PATIENTS WITH COMPROMISED IMMUNE SYSTEMS. THERE IS A LARGE ECONOMIC TOLL AND A PROFOUND SOCIETAL TOLL. THE HUMAN TOLL OF HEALTHCARE ASSOCIATED INFECTIONS CONTRIBUTES TO PUBLIC CONCERNS ABOUT SEEKING HOSPITAL CARE AND ERODES PUBLIC CONFIDENCE IN HEALTHCARE ESTABLISHMENTS. THIS IS A GRAPH SHOWING THE INCREASE IN MULTIDRUG RESISTANCE IN A NUMBER OF GRAM NEGATIVE BACTERIAL SPECIES FROM 1993 TO 2004. THESE ORGANISMS HAVE ALWAYS BEEN IMPORTANT CAUSES OF HOSPITAL ACQUIRED INFECTIONS. WHAT HAS CHANGED OVER THE LAST TWO DECADES IS THAT AN INCREASING PROPORTION OF THEM ARE MULTIDRUG RESISTANT WHICH COMPLICATES THEIR TREATMENT. WHAT ARE KPC, LET ME REVIEW THIS PATHOGEN. KLEBSIELLA SPECIES ARE NORMAL IN ALL OF US, AND HAVE BEEN IMPORTANT IN HOSPITAL ACQUIRED INFECTIONS. THE KPC ENZYME IS CARRIED ON A PLASMID THAT HAVE ACQUIRED IT, ALONG WITH OTHER RESISTANCE ENZYMES. TOGETHER THEY CONFER RESISTANCE TO MOST ANTIBIOTICS. THE GENE ENCODES THIS, THAT HYDROLIESES. MOST IMPORTANT DRUGS AGAINST GRAM NEGATIVE BACTERIA WHEN THEY ENTER THE BACTERIAL CELL. THE KPC PLASMID IS TRANSFERABLE TO OTHER MEMBERS OF THE FAMILY. SUCH AS E-COLI AND INTRO BACKER. KPC KLEBSIELLA WERE IF I UNDERSTOOD REPORTED IN A NORTH CAROLINA -- FIRST REPORTED IN 2001, AND SOON BECAME ENDEMIC IN HEALTHCARE FACILITIES IN NEW YORK AND NEW JERSEY. GLOBAL SPREAD SOON FOLLOWED. THE FIRST CASE REPORTED OUTSIDE THE UNITED STATES WAS IN FRANCE. AND SOON THERE AFTER, THERE WERE OUTBREAKS, MULTIOUTBREAKS IN HEALTHCARE FACILITIES IN ISRAEL. THE CBC ISSUED GUIDANCE FOR STRINGENT INFECTION CONTROL MEASURES IN 2009. IN THE PUBLISHED MEDICAL LITERATURE, THERE ARE MANY OUTBREAK REPORTS AND THE MORTALITY RATE IN THESE REPORTS IN SERIOUSLY ILL HOSPITAL ICED PATIENTS RANGES FROM 40 TO 60%. HOSPITALIZED PATIENTS WITH UNDETECTED COLONIZATION CAN SERVE AS RESERVOIRS FOR TRANSMISSION TO OTHER HOSPITALIZED PATIENTS. THIS IS A MAP FROM THE CENTERS FOR DISEASE CONTROL FROM 2011, SHOWING THE PREVALENCE OF KPC, KLEBSIELLA IN THE UNITED STATES. AND WHAT YOU CAN EASILY SEE IS THAT MOST OF THE CONTENTAL UNITED STATES IS BLUE IN THIS MAP MEANING THAT IT HAS BEEN REPORTED FROM ALL OF THESE STATES. THIS IS GRAPHIC REPRESENTATION OF THE WORLDWIDE DISTRIBUTION OF KPC KLEBSIELLA PNEUMONIAE. SO -- SORRY. IN THE AMERICAS, THERE ARE SUBSTANTIAL PARTS OF SOUTH AMERICA IN WHICH KPC HAS CAUSED HOSPITAL ACQUIRED OUTBREAKS. THE ORGANISMS IS ENDEMIC IN PUERTO RICO AND COLOMBIA. IN ISRAEL AND SOUTHERN EUROPE, HEAVILY EFFECTED AND THE ORGANISMS HAVE ALSO CAUSED OUTBREAKS AND HAVE BEEN FOUND IN MOST COUNTRIES IN WESTERN EUROPE AND SOME COUNTRIES IN ASIA. IN THE UNITED STATES, PURPLE ON THIS MAP IS -- THE ORGANISM IS ENDEMIC IN HEALTHCARE FACILITIES IN NEW JERSEY, NEW YORK, AND PENNSYLVANIA. WE IDENTIFY KPC KLEBSIELLA IN THIS HOSPITAL USING A SPECIAL SELECTED MEDIA. GROIN, THROAT AND RECTAL SWABS FROM PATIENTS ARE INOCULATED ON TO PLATES THAT CONTAIN THE CARBAPENEM ANTIBIOTIC, ANYTHING THAT GROWS IS RESIS WANT TO THOSE ANTIBIOTICS, SO THAT'S OUR SCREENING TOOL FOR KPC KLEBSIELLA. KLEBSIELLA ON THE SPECIAL MEDIA TURN BLUE WHICH IS VERY HELPFUL WITHIN 24 HOURS OF INOCULATION GIVING US AN EARLY IDEA OF POSITIVITY. ISOLATES THAT ARE BLUE ARE SUBJECTED TO MODIFIED HODGE TESTS. WHICH TESTS FOR CARBAPENEM PRODUCTION. WE IDENTIFY THE ENZYME USING A PCR. IN JUNE OF 2011, A 43-YEAR OLD PATIENT FOLLOW AT THE NIH FOR PULMONARY WAS TRANSFERRED. THE PATIENT WAS COLONIZED WITH KPC KLEBSIELLA. OUR HOSPITAL HAD NEVER HAD A PATIENT WITH IT BEFORE. PATIENT WAS PLACED IN CONTACT ISOLATION IN THE ICU. AFTER 24 HOURS SHE WAS TRANSFERRED TO A MEDICAL WARD AND TWO WEEKS LATER IN LATE JUNE SPENT 24 HOURS IN THE ICU. WAS DISCHARGED FROM THE CURRICULUM CENTER IN MID JULY. MEDICAL CENTER IN MID JULY. THE PATIENT WAS ON INSTANCED CONTACT ISOLATION THROUGHOUT THE HOSPITAL STAY. GROIN AND THROAT SURVEILLANCE CULTURES WERE SELECTED ON OTHER ICU PATIENTS AFTER HER SECOND I THIS. U STAY. WERE NEGATIVE. FIVE WEEKS AFTER HER SECOND ICU STAY OR THREE WEEKS AFTER DISCHARGE FROM THE HOSPITAL, KPC KLEBSIELLA GREW FROM THE SPUTUM OF A CRITICALLY ILL MAN. BEEN IN INTENSE CARE FOR 18 DAYS. THIS IS A TIMELINE SHOWING THE INDEX CASE IN OUR CLUSTER. THE DOTTED LINE REPRESENTS THE INDEX CASES SECOND ICU STAY. THIS IS PATIENT NO. 2. ORANGE BALLS ON THESE GRAPHS REPRESENT CASES IDENTIFIED THROUGH CLINICAL CULTURES AND THE BLUE CIRCLES ARE THOSE IDENTIFIED THROUGH SURVEILLANCE CULTURES. SO AFTER THE IDENTIFICATION OF PATIENT NUMBER TWO, WE DID AGGRESSIVE SURVEILLANCE IN THE INTENSIVE CARE UNIT AND THE SURVEILLANCE CULTURES TURNED UP OUR THIRD CASE. SOON AFTER A FOURTH CASE CAME TO OUR ATTENTION WHEN KPC KLEBSIELLA GREW FROM PERTO KNEEL FLUID. THE FIFTH CASE IN THE MONTH OF AUGUST WAS IDENTIFIED THROUGH SURVEILLANCE CULTURE. SO DURING THE MONTH OF AUGUST, WHEN WE RECOGNIZED THAT THERE WAS ONGOING TRANSMISSION, WE THROUGH THE KITCHEN SINK AT THESE OAT THESE HOSPITAL ACQUIRED ORGANISMS. HAND HYGIENE PRACTICES WERE STEPPED UP AND ENHANCED SUCH THAT WE BEGAN USING TWO PUMPS OF HAND GEL INSTEAD OF ONE TO ACHIEVE BETTER BACTERIAL KILLING. WE HAD ADHERENCE MONITORS STATIONED OUTSIDE THE COLONIZED PATIENT'S ROOMS, ENSURING AND EDUCATING THAT HEALTHCARE WORKERS FOLLOW ALL INFECTION CONTROL PRECAUTIONS AND FAMILY MEMBERS AS WELL. AND WE COHORTED THE PATIENT WHICH MEANS WE PUT THEM IN A GEOGRAPHICALLY SEPARATE LOCATION SO THAT THEY WOULD NOT BE IN THE SAME WARD AS THE UNCOILNIZED PATIENTS. THAT WARD HAD ITS OWN COHORTED NURSING STAFF AND MANY OTHER ALLIED FIELDS WERE COHORTED AS WELL SO THAT HEALTHCARE WORK, WE WOULD MINIMIZE THE NUMBER OF HEALTHCARE WORKERS TAKING CARE OF KPC COOLNIZED AND UNCOILNIZED PATIENTS. IN AUGUST OF 2011, WE TEAMED UP THE GENOMIC STAFF WITH THE HOSPITAL INFECTIOUS CONTROL TO TRY TO SEE IF WE COULD, TOGETHER, ANSWER THIS QUESTION OF WHETHER WE HAD TWO OR MORE SEPARATE INTRODUCTIONS OF THE CARBAPENEM RESISTANCE OR WHETHER WE HAD HOSPITAL TRANSMISSION. THIS QUESTION WAS REALLY IMPORTANT IN TERMS OF UNDERSTANDING WHAT WAS HAPPENING AT THE VERY EARLIEST STAGES OF THIS CLUSTER OF PATIENTS. SO OUR STANDARD CLINICAL MICROBIOLOGICAL TESTS, THE MOST DISCRIMTRY ASSAY IS SHOWN HERE, LOOKSITATE DNA FRAGMENTS. WE COULD TELL THAT PATIENT ISOLATES 1, 2, 3 AND 4 WERE ALL OF THIS SEQUENCED TYPE 258, VERY SIMILAR. BUT THE QUESTION HERE REMAINS OF WHETHER OR NOT THIS IS A MATCH. BECAUSE THIS PATTERN THAT YOU SEE OF THESE DNA FINGERPRINTS IS THE -- IS FOUND IN 70% OF THE HEALTHCARE ACQUIRED KLEBSIELLA PNEUMONIAES. THE FACT THAT THEY WERE BOTH SEQUENCE TYPE 258 MEANT THAT THEY WERE VERY SIMILAR TO EACH OTHER, BUT DIDN'T ANSWER THE QUESTION FOR US OF WHAT WHETHER THEY COULD HAVE POSSIBLY COME IN INDEPENDENTLY INTO THE HOSPITAL OR WHETHER THEY HAD -- WHETHER THERE HAD BEEN A TRANSMISSION IN THE HOSPITAL. SO OUR QUESTION IS WHETHER DNA SEQUENCING CAN BE A MORE POWERFUL MICROSCOPE FOR IDENTIFICATION. PHYSICALLY, THE PULSE FIELD GEL GIVES YOU A FINGERPRINT OF THE DNA. BUT IF WE LOOKED AT THE DNA AND READ OUT EVERY SINGLE BASE PAIR, WOULD THIS GIVE US THE RESOLUTION THAT WE NEEDED IN ORDER TO ASARETAIN WHETHER THERE WAS -- ASCERTAIN WHETHER THERE WAS A MATCH BETWEEN THESE ORGANISMS? HOW WE ACTUALLY DO THIS HAS BEEN REALLY REVOLUTIONIZED BY THE TECHNOLOGY OF DNA SEQUENCING THAT WAS INSTRUMENTAL IN MOVING FROM SEQUENCING THE HUMAN GENOME TO THE TECHNOLOGY THAT WAS DEVELOPED TO MORE RAPIDLY SEQUENCE DNA AND AT A MUCH LOWER PRICE. SO BASICALLY, WHAT WE DO IS WE TAKE THE GENOMIC DNA FROM THIS BACTERIA. THE KLEBSIELLA PNEUMONIAE IS A 6 MILLION BASED PAIR DNA. THIS IS ACTUALLY REALLY WHAT THE PIRACY SEQUENCERS ARE EXTREMELY GOOD AT. YOU RANDOMLY CHOP UP THE DNA INTO THESE LITTLE FRAGMENTS. AND THEN THE NEW TECHNOLOGY CAN SEQUENCE A MILLION OF THESE 400 BASE PACE SEQUENCES IN JUST AN OVERNIGHT RUN. SO YOU'RE GETTING EACH BASE PAIR OF DNA READ OUT ABOUT 25 TIMES. AND SINCE THEY EACH HAVE DIFFERENT BEGINNINGS AND ENDS OF THE SEQUENCE, THEY ACTUALLY OVERLAP SUFFICIENTLY THAT YOU CAN CREATE THESE PIECES OF DNA WHERE YOU MOVE FROM READING THE BASE PAIRS AND ASMUCHTAIN ACCURACY HERE, ALL THE WAY ACROSS THE DNA. FROM THE 6 MILLION BASE PAIRS OF DNA, WE COULD STITCH THIS TOGETHER AND GET ABOUT 100 PIECES OF JUST CONTINUOUSLY READ OUT ACCGT. AND THEN WE STITCH THOSE TOGETHER, BASED ON OTHER REFERENCE GENOMES SO WE HAVE A COMPLETE DNA SEQUENCE OF ALL 6 MILLION BASE PAIRS. NOW, FOR THIS, THOSE 6 MILLION BASE PAIRS ARE REALLY GREAT FOR TELLING YOU WHETHER OR NOT YOU HAVE WHAT PROTEINS ARE ENCODED AND SO ON. OUR QUESTION WAS REALLY TO COMPARE THE SEQUENCE OF GENOME 1 AND GENOME 2. NOW, WHAT WAS VERY USEFUL TO US WAS THAT WE WOULD COMPARE SEQUENCES FROM GENOME 1 AND 2, AND WE WOULD LOOK FOR ANY TIMES THAT THERE WAS EVEN A SINGLE BASE PAIR CHANGE, WHERE ONE OF THE GENOMES MIGHT HAVE AN A, THIS WOULD HAVE A T. THESE SINGLE VARIANTS WOULD ARISE JUST THROUGH THE REGULAR PROCESS OF DNA REPLICATION. THAT WE ESTIMATED THAT ABOUT 1 BASE PAIR PER WEEK WOULD CHARACTER IN THE BACTERIAL DNA, JUST BECAUSE OF THE NORMAL PROCESS OF GOING THROUGH DNA REPLICATION. IT DIDN'T EVEN MEAN THAT THIS SINGLE NUCLEOTIGHT VARIANT ACTUALLY CAUSED A MUTATION. THIS WOULD BE IN THE THIRST BASE PAIR -- THIRD BASE PAIR OF THE IMMUNE OACID SEQUENCE. SOMETIMES WE WOULD FIND MUTATIONS AND THAT WOULD BE VERY USEFUL. THESE METHODS COULD BE USED FOR FINDING DELETIONS AND INSERTIONS, BUT THESE GENOMICS WERE VERY STABLE. OUR ANALYSIS WAS BASED AT LOOKING AT THE SINGLE NUCLEOTIDE VARIATIONS. SO WE START WITH OUR INDEXED PATIENT CASE ONE. SHE HAD BEEN COLONIZED FOR A VERY LONG TIME WITH THIS KLEBSIELLA PNEUMONIA. AND HAD ISOLATED THAT WERE IDENTIFIED IN THE URINE, THE THROAT, THE BRONCHIAL AND THE GROIN. SO WE SEQUENCED ALL THREE -- ALL FOUR OF THESE SITES. WHAT WE FOUND WAS THAT COMPARED TO THE URINE ISOLATE, THERE WERE THREE NUCLEOTIDES THAT HAD CHANGED IN THE ATHLETE AND THREE DIFFERENT ONES THAT WE COULD FIND THAT CHANGED IN THE B.A.L. AND IN THE GROIN. THESE TWO WERE THE SAME DNA SEQUENCE BUT THESE THREE SNIPS, EVEN THOUGH THIS IS THREE BASE PAIRS THAT ACTUALLY IS ENOUGH FOR US TO LOOK AT THE EVOLUTION OF TRANSMISSION. SO LET ME SHOW YOU THAT. SO WE SEQUENCED PATIENTS TWO AND THREE. AND WHAT WE FOUND WAS THAT ACTUALLY PATIENTS TWO AND THREE WERE A PERFECT MATCH TO PATIENT ONE. SPECIFICALLY, THEY MATCHED THE THROAT ISOLATE. THEY HAD THOSE -- EVERY NUCLEOTIED WAS EXACTLY THE SAME, INCLUDING THE THREE CHANGES WE HAD SEEN AS THE ISOLATE WAS NOW IN THE THROAT, LOCALIZED AWAY FROM THE URINARY TRACT ISOLATE. AND IF THESE -- EVEN IF THESE WERE OF THOSE SAME PATTERNS THAT YOU WOULD SEE ON THE PULSED FIELD GEL FROM CLINICAL MICROBIOLOGY DIAGNOSTICS, EVEN IF THEY WERE BOTH THAT SAME PATTERN TYPE, THEY WERE NOT A TRANSMISSION -- THEY WOULD BE HUNDREDS OF BASE PAIRS DIFFERENT. THAT'S THE LEVEL OF RESOLUTION THAT WE'RE NOW ACHIEVING WITH DNA SEQUENCING. WE DID SEE THAT THERE WAS ONE SINGLE BASE PAIR CHANGE BETWEEN THE ISOLATE AND THE THROAT -- IN THE THROAT OF PATIENTS ONE AND THEE. PATIENT TWO HAD ACQUIRED ONE ADDITIONAL NUCLEOTIDE CHANGE. LOOKING AT THESE RESULTS, WE ACTUALLY HAD TWO -- WELL, THE CENTRAL FINDING, OF COURSE, WAS THAT THIS SUGGESTED THERE HAD BEEN A TRANSMISSION IN THE HOSPITAL. ADDITIONALLY, THOUGH, IT SUGGESTS TO US FROM A GENETIC PERSPECTIVE, THAT PERHAPS THE TRANSMISSION HAD GONE FROM PATIENT ONE TO PATIENT THREE, AND THEN TO PATIENT TWO. BECAUSE IF PATIENT TWO HAD BEEN THE INTERMEDIATE, I WOULD HAVE EXPECTED THAT THIS ONE BASE PAIR CHANGE WOULD HAVE BEEN FOUND HERE. NOW, I WOULDN'T HAVE HUNG MY HAT ON THIS. BUT WHEN WE WENT TO TARA WITH THIS INFORMATION, SHE SAID YES, THAT'S WHAT WE ALSO WOULD MAKE SENSE TO US FROM OUR EPIDEMIOLOGICAL DATA, WHICH IS HERE I SHOW YOU WHERE THESE PATIENTS WERE IN THE HOSPITAL EVERY DAY OF THEIR STAY. AND PATIENT ONE AND PATIENT THREE OVERLAPPED IN THE. CU. THEN PATIENT 3 OVERLAPPED WITH PATIENT TWO IN THE ICU. THERE WAS NO TIME THAT PATIENT ONE AND TWO OVERLAPPED IN THE HOSPITAL. BUT WHAT WE SEE FROM HERE IS THAT THERE IS THIS STRONG SUGGESTION THAT THERE WAS A TRANSMISSION, BUT IN FACT, IN THIS SCENARIO, OF COURSE, DOES SUGGEST THAT THERE WAS LONG TERM COLONIZATION, THAT THESE PATIENTS WERE COLONIZED FOR THREE WEEKS BEFORE PATIENT 2 BECAME ILL. THAT WAS SURPRISING TO US BECAUSE THESE WERE COMPROMISED, SEVERELY ILL PATIENTS. AND THE FACT THAT THESE PATIENTS COULD ACTUALLY HARBOR THIS BACTERIA WITHOUT BECOMING -- SHOWING SIGNS OF BEING ILL WAS -- HAD NOT PREVIOUSLY BEEN DESCRIBED. SO NOW WE HAVE PATIENT FOUR. WE SEE -- NEXT, WE SEQUENCED PATIENT 4. THIS PEELED BACK MORE OF THE LAYERS OF THIS MEDICAL MYSTERY FOR US. IN THAT PATIENT 4 HAS THE SEQUENCED NUCLEOTIGHT CHANGES THAT WOULD MATCH THE INDEX PATIENT'S BAL AND GROIN ISOLATES. THOSE THREE CHANGES THAT WERE ONLY FIND IN THESE AND NOT THE THROAT WERE FOUND IN PATIENT 4 AS WELL AS 6 ADDITIONAL SINGLE NUCLEOTIDE CHANGES. WHICH IS CONSISTENT WITH THIS HAVING, AGAIN, SPENT 6 WEEKS TRAVELING FROM PATIENT -- BETWEEN WHEN WE DETECTED IT IN PATIENT 1 AND 4. SO THE MYSTERY FOR US HERE WAS THAT PATIENT 1 AND 4 HAD NEVER OVERLAPPED IN THE HOSPITAL. WE HAD THOUGHT FROM THIS, PREVIOUSLY, THAT PATIENT 2 HAD BEEN THE SOURCE OF INFECTION FROM PATIENT 4. BUT NOW SEEING THIS, WE REALIZED THAT PATIENT 4 WAS AN INDEPENDENT TRANSMISSION. AND SO WORKING TOGETHER WITH THE HOSPITAL EPIDEMIOLOGY STAFF, WE PULLED TOGETHER THE THOUSANDS OF PATIENTS THAT HAD BEEN SEEN IN THE NIH CLINICAL CENTER DURING THIS TIME. AND ASKED THE QUESTION OF, YOU KNOW, WHO POSSIBLY COULD HAVE OVERLAPPED WITH PATIENT 1 AND THEN OVERLAPPED WITH PATIENT 4? SO WE ONLY IDENTIFIED FIVE PATIENTS THAT HAVE THIS. SO FOR EXAMPLE, PATIENT B HERE OVERLAPPED IN THE ICU WITH PATIENT ONE, AND THEN WENT ON TO THE WARD WHERE PATIENT 4 WAS BEING CARED FOR. SO THIS WOULD RAISE THE POSSIBILITY THAT THERE MAY BE SILENTLY COLONIZED INTERMEDIATES. THIS IS A CONSTANT PROBLEM WITH HOSPITAL SURVEILLANCE. NO THAT IT'S A PROBLEM WITH THE SURVEILLANCE BUT THAT THERE IS A LIMIT OF DETECTION THAT THESE PATIENTS WOULD HAVE CULTURED NEGATIVE, BUT MAY BE HARBORING THEOLOGYISM IN A VERY LOW LEVEL -- THE ORGANISM IN A VERY LOW LEVEL. FOR EACH TEST WE ALWAYS HAVE THE PROBLEM THAT THERE COULD BE UNDETECTED SILENTLY COLONIZED INTERMEDIATES. TO RECAP WHAT WE HAD WAS TWO INDEPENDENT TRANSMISSIONS FROM THE INDEXED PATIENT, ONE LEADING TO PATIENT 3 BEING INFECTED AND ONE TO PATIENT NO. 4 BEING INFECTED. SO NOW I TURN YOU BACK OVER TO TARA WHO IS GOING TO TALK ABOUT [INAUDIBLE] THIS IS OUR TIMELINE AGAIN. AND WHAT YOU CAN SEE HERE IS THE CASES THAT OCCURRED IN JUNE AND AUGUST. AND IN EACH MONTH THERE AFTER, BETWEEN AUGUST AND MID DECEMBER, SEVERAL CASES WERE IDENTIFIED THROUGH SURVEILLANCE CULTURES. DURING THIS PERIOD OF TIME, IN ADDITION TO MANY OTHER INFECTIOUS CONTROL INTERVENTIONS WE WERE MAKING, WE DID SURVEILLANCE CULTURES ON ADMISSION TO THE ICU AND TWICE WEEKLY, ALSO IN HIGH RISK UNITS. AND OUR CULTURES IDENTIFIED THE REMAINING PATIENTS IN THIS CLUSTER. IN NOVEMBER, WHEN WE -- BASED ON THE GENOMIC DATA, WE REALIZED THAT TRANSMISSION WAS FAR MORE COMPLEX THAN WE REALIZED. AND WE MADE A DECISION TO CULTURE THE ENTIRE HOSPITAL. THAT'S WHAT WE DID SELF TIMES OVER. SEVERAL TIMES OVER. THAT STRATEGY YIELDED THE LAST FOUR PATIENTS IN THIS 2011 CLUSTER. AFTER THAT, WE CONTINUED SURVEILLANCE CULTURES BOTH IN THE HIGH RISK AREAS, AND THROUGHOUT THE ENTIRE HOSPITAL. IN EARLY JANUARY, WE IDENTIFIED THROUGH SURVEILLANCE CULTURE A KPC KLEBSIELLA THAT WAS A TOTALLY DISTINCT TRAIN. IT HAD AN KPC ENZYME, ON A DIFFERENT PLASMID. THAT WAS NOT OUR HOSPITAL ACQUIRED STRAIN. THAT WAS PROBABLY IMPORTED FROM ANOTHER HOSPITAL. IN EARLY JULY, SO SURVEILLANCE CULTURES CONTINUED ALL THIS TIME. WE IDENTIFIED NO PATIENTS, NEW PATIENTS WITH KPC COLONIZATION. IN EARLY JULY WE IDENTIFIED ANOTHER DISTINCT STRAIN OF KPC KLEBSIELLA IN A PATIENT WHO HAD BEEN HOSPITALIZED FOR THE PREVIOUS 6 WEEKS IN TWO OTHER MARYLAND HEALTHCARE FACILITIES. AND WAS TRANSFERRED HERE FROM ONE OF THOSE FACILITIES. AND WAS FOUND ON SURVEILLANCE CULTURE TO HARBOR THIS ORGANISM. AGAIN, NOT THE STRAIN THAT HAD EFFECTED THE CLINICAL CENTER IN 2011. AND THEN IN LATE JULY, SURVEILLANCE CULTURE IDENTIFIED ANOTHER PATIENT WHO HARBORED KPC KLEBSIELLA AND WE LATER LEARNED FROM THE GENOMIC SEQUENCING THAT THE PATIENT HAD THIS STRAIN FROM OUR 2011 CLUSTER. SO THIS IS A GRAPHIC REPRESENTATION OF THE TIME HONORED SHOE LEATHER EPIDEMIOLOGY INVESTIGATION TECHNIQUE OF LOOKING AT WHERE PATIENTS WERE AND WHEN. SO ON THE Y AXIS IS A NUMBER REPRESENTING EACH PATIENT. IN THE 2011 CLUSTER. AND THIS IS OBVIOUSLY TIME. AND IN THE DIFFERENT COLORS REPRESENT THE DIFFERENT WARDS. AND SO THIS IS SHOWING WHERE -- IN WHAT WARD THESE PATIENTS WERE INPATIENTS, AT WHAT TIME. YOU CAN SEE WHERE THEY OVERLAPPED, AND THE BLACK LINES REPRESENT THE IDENTIFICATION OF KPC COOL INTOIZATION. IF YOU USED JUST THIS INFORMATION, THESE DATA, TO RECONSTRUCT A CHAIN OF TRANSMISSION, THIS IS WHAT YOU GET. WHICH IS A REAL MESS AND IT'S HARD TO EXTRAPOLATE ANY INFORMATION FROM THIS. >> THIS IS THE DNA SEQUENCING THAT WE PERFORMED OF EACH OF THE ORGANISMS. AND HERE, INSTEAD OF USING THOSE LITTLE BALLS WHEN I'M SHOWING YOU, ANY TIME THAT THE SEQUENCE AT ANY BASE PAIR WAS DIFFERENT THAN WHAT WAS OBSERVED IN THE URINE ISOLATE, THEN THAT CHANGES FROM GRAY TO BLACK. THESE CHANGES, THESE S AND Vs ARE CLUSTERED TO SHOW THE RELATIONSHIP OF THE ORGANISMS, THEY ARE ACTUALLY NOT SHOWED ACROSS THE LINEAR CHROMOSOME. THESE THREE SNVs THAT ARE -- THAT IDENTIFY THIS PATIENT CLUSTER TWO ARE ACTUALLY, AS I SHOWED YOU BEFORE, IN THREE VERY DIFFERENT PLACES OF THE CHROMOSOME. AND SHOW INDEPENDENTLY THAT THERE IS A RELATIONSHIP BETWEEN PATIENTS ONE, TWO, THREE AND FIVE. FROM THE THROAT ISOLATE OF PATIENT ONE. SO WITH THIS INFORMATION, WE WERE ABLE TO TRACK THE EVOLUTION OF THIS ORGANISM. AS I DESCRIBED IN DETAIL ABOUT PATIENTS 1, 2, 3, BUT YOU CAN SEE THAT ALSO HERE, THAT PATIENT 4 HAD THOSE 6 ADDITIONAL SNVs. AND YOU CAN SEE, THEN, THAT AS WE GO TO SOME OF THE LATER PATIENTS HERE, THAT THERE ARE AN ADDITIONAL 3SNVs THAT ARE BEING ASQUIRED. AND THEN -- ACQUIRED. WHEN YOU SEE PATIENT 7 UP HERE, YOU KNOW THAT PATIENT 7 HAD TO, FIRST OF ALL -- WAS COLONIZED WITH THE ISOLATE THAT ORIGINATED DOWN HERE FROM THE GROIN OR THE THROAT -- GROIN OR THE LUNG, NOT FROM THE THROAT ISOLATE. BUT THAT AS WELL, TEMPERATURERLY THE TRANSMISSION TO 7 OCCURRED AFTER THESE THREE BASE PAIR CHANGES WERE ACQUIRED. SO IS THIS GENOMIC SEQUENCING TELLS YOU ABOUT WHAT AREA OF THE BODY COULD HAVE POSSIBLY BEEN THE SOURCE FOR THE INFECTION. IT ALSO PUTS A TIME STAMP ON THESE BACTERIA IN TERMS OF WHICH PATIENTS WERE COLONIZED AT WHICH TIME, AND WHO NEEDS TO BE FOLLOWED. SO TOGETHER, USING THE GENETIC AND EPIDEMIOLOGIC DATA, WE TAKE THAT SPAGHETTI SPRING AND WE CAN NOW RECONSTRUCT WHAT IS THE MOST LIKELY TRANSMISSION ROUTE WHERE YOU CAN SEE, AGAIN, THOSE INITIAL TRANSMISSIONS. AND NOW THAT THERE WAS ACTUALLY AN OVERLAP BETWEEN PATIENT FOUR AND 10, ON THE WARD, THAT THAT IS CONSISTENT WITH THE GENETIC INFORMATION, THEN GOING FROM PATIENT TEN TO PATIENT 6. WHAT WE SAW HERE WAS THAT EACH OF THESE PATIENTS IS NUMBERED BASED ON WHEN WE WERE -- THEY WERE DETECTED IN THE HOSPITAL. BUT IN FACT THE DETECTION IS NOT -- THAT OFTEN, THE COLONIZATION MUST HAVE OCCURRED IN A DIFFERENT ORDER THAN THE PATIENT PRESENTED AS BEING SICK. IMPORTANTLY, THOUGH, THIS TELLS US WHAT WE NEED TO TRACK DOWN IN TERMS OF WHAT WAS THE POTENTIAL EVENTS THAT COULD HAVE LED FROM A TRANSMISSION OF PATIENT 6 TO PATIENT 7, AND IMPORTANTLY, IT ALSO TELLS US THAT IF YOU SAY WELL, PATIENT 5 AND 6 HAD THESE THREE THINGS IN COMMON, THEY WERE IN THE SAME ROOM, OR THEY WERE -- WE DON'T NEED TO LOOK AT THOSE BECAUSE PATIENT 5 DID NOT TRANSMIT TO PATIENT 6. EVEN THOUGH ANY OTHER MEASURE WOULD SAY THAT THEY'RE IDENTICAL. BASED ON THE GENETIC EVIDENCE FROM THE WHOLE DNA SEQUENCING, PATIENT 5 DID NOT TRANSMIT TO PATIENT 6. AND IT'S THAT LEVEL OF ADDITIONAL RESOLUTION THAT WE ACHIEVED WITH THE WHOLE GENOME SEQUENCING THAT IS PART OF THE SCIENTIFIC BREAK THROUGH OF THIS WORK. SO WHAT WE SHOWED IN THIS STUDY WAS THAT HOSPITALS LIKE OURS, THE NIH CLINICAL CENTER, CAN APPLY THESE INVOLVE TECHNOLOGIES TO TRACK HOSPITAL TRANSMISSION ROUTES AND FIND SPECIFIC OPPORTUNITIES FOR INTERVENTION. THIS IS PARTICULARLY IMPORTANT AS WE HAVE VERY FEW IF ANY ANTIBIOTICS LEFT FOR THE TREATMENT OF INFECTIONS DUE TO THESE MULTIPLE DRUG RESISTANT GRAM NEGATIVE BACTERIA. DURING THESE CLUSTER OF -- THIS CLUSTER, THERE WERE SOME PATIENTS WHO STRAINS HAD RESISTANCE TO ALL KNOWN ANTIBIOTICS. THAT BRINGS US BACK TO THE POINT THAT INFECTION PREVENTION IS KEY, INCLUDING ENVIRONMENTAL SOURCES AND PATIENT TO PATIENT TRANSMISSION IN THE HOSPITAL ENVIRONMENT. SO WE WOULD LIKE TO REALLY THANK THE BRIDGE BETWEEN THE JOKES AND THE CLINICAL -- GENOMICS AND THE CLINICAL MIKE BIOLOGICAL AND HOSPITAL INFECTION CONTROL. IT WAS LEADERSHIP THAT INSPIRED THE PROJECT, RECOGNIZING THAT JOKES COULD BRING -- GENOMICS COULD BRING A NEW DIAGNOSTIC TOOL TO THE CENTER. DAVID HENDERSON, THE HEAD OF HOSPITAL INFECTION CONTROL HERE AND THE DEPUTY DIRECTOR OF THE CLINICAL CENTER, WHO'S VISION AND LEADERSHIP FOSTERED THIS COLLABORATION. BUT THE STORY IS -- OUR GREATEST KNOWLEDGEMENT AND APPRECIATION GOES TO THE PHYSICIANS AND HEALTHCARE PROVIDERS IN THIS HOSPITAL WHO PROVIDED THE CARE FOR THESE PATIENTS AND IN PARTICULAR, REALLY, WE DEDICATE THIS TALK TO THE PATIENTS AND THEIR FAMILIES WHO WERE EFFECTED BY THIS TERRIBLE BACTERIAL OUTBREAK. AND RECOGNIZE THEIR TREMENDOUS CONTRIBUTION TO RESEARCH AT THE NIH CLINICAL CENTER. I THINK I'M GOING TO NOW TURN IT OVER TO HENRY. DR. HENRY MASUR. >> THANK YOU VERY MUCH. I THINK THIS STORY IS A CLEAR DEMONSTRATION OF HOW THE INTERMURAL HERE CAN COMBINE OUTSTANDING BASIC RESEARCH AND TRANSLATIONAL RESEARCH TO LEARN A LOT THAT CAN BENEFIT OUR PATIENTS. AND AS HEALTHCARE PROVIDERS, I THINK IT'S CLEAR THAT IN DEALING WITH THE PATIENTS THAT JULIE DESCRIBED, OR IN PUTTING A FACE ON OTHER PATIENTS WHO HAVE BEEN EFFECTED BY HOSPITAL ACQUIRED INFECTIONS, WHAT WE CLEARLY WANT IS THE BEST OUTCOME POSSIBLE FOR OUR PATIENTS. WE WANT TO MAKE HOSPITALS AS SAFE AS POSSIBLE. THIS SLIDE HERE SHOWS SOME INDIVIDUALS WHO ARE WILLING -- WHO HAVE BEEN WILLING TO SHARE THEIR PERSONAL STORIES WITH THE PUBLIC ON THE INFECTIOUS DISEASE SOCIETY WEBSITE, HOW THEIR LOVED ONES HAVE BEEN DEVASTATED BY THESE INFECTIONS, THIS IS CLEARLY A MAJOR PROBLEM. WE REALIZE AS CLINICIANS THAT WE NEED TO DO SOMETHING ABOUT HOSPITAL ACQUIRED INFECTIONS, YET AS SCIENTISTS WE REALIZE THAT MICROBES CAN ADAPT WITH AMAZING REPEDTY. WE KNOW FROM THE LITERATURE THAT MICROORGANISMS CAN LIVE IN ALL SORTS OF EXTREME ENVIRONMENTS. THEY CAN LIVE WITHOUT OXYGEN. THEY CAN LIVE IN BOILING WATER. THEY CAN LIVE ON ICE. AND THEY CAN LIVE WITH ALL SORTS OF ANTIBIOTIC PRESSURE. AS FAST AS WE MAKE ANTIBIOTICS, MICROORGANISMS CAN ADOPT. THE PROBLEMS THAT WE'RE DISCUSSING IS NOT JUST INFECTIONS SPREAD WITHIN HOSPITALS, ALTHOUGH THAT ALONE IS A MAJOR PROBLEM. THE PROBLEM WE'RE DEALING IS WE DON'T HAVE ENOUGHACHES, WE ARE -- ANTIBIOTICS, WE'RE NOT MAKING THEM RAPIDLY ENOUGH TO KEEP AHEAD OF THE MICROORGANISMS. THE ORGANISM IS ONE OF A NUMBER OF HOSPITAL ACQUIRED INFECTIONS THAT BECOME RESISTANT THAT TARA EMPHASIZED. FOR MANY YEARS WE HAVE BEEN DEALING WITH SUED MOMUS, WE KNOW THE HOSPITALS HAVE M. RESISTANT ORGANISMS WE NEED TO DEAL W OVER THE LAST DECADE, THERE HAS BEEN FOCUS INCREASINGLY ON CARBAPENEM RESISTANCE, ORGANISMS NOT CAUSING DISEASE IN THE COMMUNITY. THESE ORGANISMS ONLY EFFECT PATIENTS IN THE HOSPITAL, MOST LIKELY TO EFFECT THOSE WHO ARE SEVERELY IMMUNE COMPROMISED OR IN INTENSIVE CARE UNITS WITH MANY LINES IN THEM AND ON VENTILATORS. THESE DO NOT EFFECT PEOPLE IN THE COMMUNITY. IT'S INTERESTING THAT OF ALL THE RELATIVES THAT COME TO VISIT THEIR PATIENTS, OF HEALTHCARE PROVIDERS, NO ONE WHO IS HEALTHY HAS GOTTEN CITIES FROM THIS PARTICULAR -- DISEASE FROM THIS PARTICULAR ORGANISM. THE CDC HAS RECOGNIZED THIS IS A GROWING PROBLEM. AND 2009, AGAIN, 2012, THEY'VE ISSUED GUIDANCE ON HOW WE THINK WE CAN REDUCE THE IMPACT OF THESE ORGANISMS ON OUR PATIENTS. THE PUBLIC FOR THE LAST SEVERAL YEARS HAS ALWAYS PICKED UP ON THIS. AND I THINK THIS HAS LED TO A USEFUL DIALOGUE ON HOW, IN OUR HEALTHCAREFULLIES WE CAN REDUCE THE IMPACT OF ALL THESE INFECTIONS, NOT JUST KPCs, BUT ALL HOSPITAL ACQUIRED INFECTIONS, AND PARTICULARLY THOSE THAT ARE RESISTANT. BUT THE REASON WE'RE HAVING SO MUCH DIFFICULTY WITH THESE CPCs, AGAIN, IS YES -- KPCs, YES, THEY'RE COMMON. BUT THE PROBLEM FOR THE LAST DECADE HAS BEEN THE DEVELOPMENT OF ANTIBIOTICS HAS BEEN DIMINISHING. OVER THE LAST DECADE, THE INFECTIOUS DISEASE SOCIETY AND OTHER PROFESSIONAL GROUPS HAVE GOTTEN TOGETHER TO FOCUS ON WHAT THEY CALL A PROGRAM OF BAD BUGS, NO DRUGS. THIS RECOGNIZES WE HAVE MANY VIRULENT PATHOGENS IN OUR HOSPITALS AND IN THE COMMUNITY, ALTHOUGH ONE IS NOT IN THE COMMUNITY, AND THAT WE DON'T HAVE ENOUGH DRUGS. IF WE LOOK AT THE NUMBER OF NEW ANTIBACTERIAL DRUGS APPROVED IN THE UNITED STATES, YOU CAN SEE THAT THE 1980s AND 1990 SAID, WE HAD A ROBUST PHARMACEUTICAL INDUSTRY THAT WAS PRODUCING ENOUGH DRUGS THAT WE WERE ALWAYS AHEAD OF THE CURVE. WHEN AN ORGANISM DEVELOPED RESISTANCE, WE HAD NEW DRUGS ON THE SHELF WHICH COULD TREAT THAT ORGANISM EFFECTIVELY. OVER THE LAST DECADE, SEVERAL THINGS HAVE HAPPENED. PHARMACEUTICAL INDUSTRY HAS SEEN THE INCREASING COST NEEDED TO GET ANTES BACTERIALED APPROVED, AND THERE IS A MUCH BETTER PROFIT MARGIN IN DRUGS THAT YOU TAKE FOR YEARS AND YEARS AND YEARS, AND HAVE A LONG SHELF LIFE, RATHER THAN DRUGS TO WHICH ORGANISMS DEVELOP RESISTANCE AND VARIOUS PEOPLE LIKE ME SAY DON'T TAKE THESE NEW DRUGS, DON'T SELL THESE NEW DRUGS, LET'S WAIT UNTIL WE REALLY NEED THEM. SO THERE HAS NOT BEEN ENOUGH INCENTIVE FOR THE PHARMACEUTICAL INDUSTRY TO DEVELOP NEW DRUGS. THAT IS A HUGE PROBLEM IN THE UNITED STATES AND GLOBALLY. SO AS YOU LOOK AT THE NUMBERS THAT TARA EMPHASIZED, 15% OF PATIENTS COMING INTO PATIENTS -- I'M SORRY, 15% OF PATIENTS COMING INTO INTENSIVE CARE UNITS, DEVELOP HOSPITAL ACQUIRED INFECTIONS, 5% OF ALL PATIENTS DEVELOP A HOSPITAL ACQUIRED INFECTION. WE HAVE 100,000 DEATHS IN THE UNITED STATES ALONE. CLEARLY, WE MUST DO BETTER. WE NEED TO HAVE MORE BASIC RESEARCH SO WE UNDERSTAND HOW THESE ORGANISMS ARE TRANSMITTED. THE KIND THAT JULIE AND TARA HAVE DONE. AND WE THEY'D TO DEVELOP NEW DRUGS -- NEED TO DEVELOP NEW DRUGS. NAIAD HAS BEEN SPENDING MILLIONS OF DOLLARS PER YEAR ON THIS RESEARCH AND TRANSLATIONAL RESEARCH WE NEED TO UNDERSTAND HOW THESE ORGANISMS SPREAD AND HOW WE CAN LIMIT THEIR SPREAD. WE ALSO NEED TO PUT MORE MONEY INTO OPERATIONAL RESEARCH SO THAT WE CAN SEE WHEN WE APPLY BETTER HAND WASHING TECHNIQUES, WHEN WE APPLY BETTER ENVIRONMENTAL CONTROLS, WE SEE WHETHER OR NOT THESE REALLY WORK. BECAUSE WE'VE SEEN OVER AND OVER AGAIN THE PLAUSIBLE INTERVENTIONS DON'T ALWAYS WORK. WE NEED EVIDENCE TO SHOW THERE ARE INVESTMENT IN THESE NEW TECHNOLOGIES, REALLY MERITS BY BETTER OUTCOMES. AND WE CLEARLY NEED SOME PUBLIC POLICY INTERVENTIONS. WE NEED TO GIVE INCENTIVES TO HEALTHCARE PROVIDERS AND HOSPITALS TO IMPLEMENT THE STRATEGIES THAT WE DEVELOP, WE ALSO NEED INCENTIVES FOR THE PHARMACEUTICAL INDUSTRY SO WE DEVELOP MORE DRUGS. AND THERE ARE A NUMBER OF RECOMMENDATIONS THAT HAVE BEEN PUT FORWARD BY PROFESSIONAL ORGANIZATIONS TO CONGRESS. I THINK IF YOU LOOK AT THE BIG PICTURE, I THINK ONE OF THE THINGS YOU HAVE TO RECOGNIZE IF YOU'RE LOOKING TO THE FUTURE, IS THAT THE CLINICAL CENTER AS THE NATION'S PREMIER RESEARCH HOSPITAL S REALLY PART OF A LARGER GLOBAL NETWORK OF HEALTHCARE. WE SHARE OUR PATIENTS WITH HOSPITALS AND NURSING HOMES ALL OVER THE WORLD. BUT IN SHARING THOSE PATIENTS WE ALSO SHARE THEIR MICROORGANISMS. SO THAT THIS IS A GLOBAL PROBLEM THAT EVERY ONE MUST ADDRESS. IS THERE REASON TO BE OPTIMISTIC? I THINK THERE IS REAL REASON TO BE OPTIMISTIC. IF YOU LOOK AT WHAT INITIATIVES THE INSTITUTE FOR HEALTHCARE IMPROVEMENT, MEDICAID, MEDICARE HAVE IMPLEMENTED, YOU CAN SEE IN AREAS LIKE CATHETER RELATED INFECTIONS, ISSUES THAT USED TO BE MAJOR PROBLEMS IN HOSPITALS ARE NOW DIMINISHED IN FREQUENCY IN OUR HEALTHCARE FACILITIES WHICH I THINK IS A TESTIMONY TO THE FACT THAT RESEARCH AND IMPLEMENTATION CAN BE EFFECTIVE. MY HOPE IS THAT A YEAR FROM NOW WE CAN COME BACK AND REPORT TO YOU THAT YI KNOW A LOT MORE ABOUT THESE KPCs, THAT WE'VE REDUCED THEIR IMPACT. ARE WE EVER GOING TO REDUCE THIS COMPLETELY? I THINK WE'RE ALWAYS GOING TO HAVE THIS PROBLEM, BUT I THINK THAT WE'RE REALLY ON THE VERGE OF USING BASIC SCIENCE AND THE KIND OF TRANSLATIONAL RESEARCH THAT YOU'VE HEARD ABOUT SO WE CAN REALLY REDUCE THIS DRAMATICALLY IN THE YEARS TO COME. THANK YOU VERY MUCH. [APPLAUSE]