Tip:
Highlight text to annotate it
X
AREAS OF YOUR EXPERTISE
PARTICULARLY THE POST DOCS,
WHICH HAS BEEN THE LARGEST GROUP
OF THE AUDIENCE, WHAT YOU KNOW
MAY INTERACT WITH SOME OF THE
BIG PROBLEMS THAT ARE BEING
PRESENTED.
AND WE'RE VERY FORTUNATE BECAUSE
HERE AT NIH, THERE ARE
EXTRAORDINARY PEOPLE WORKING ON
DIFFERENT ASPECTS OF THIS
SO-CALLED CLINICAL AND BASIC
BUSINESS, AND SO FOR THAT, I'VE
ALWAYS USED THE LOGO OF THE MOST
FAMOUS BRIDGE IN THE WORLD,
WHICH IS THE BROOKLYN BRIDGE,
AND THOSE GUYS ACTUALLY COULD
WALK ACROSS MUCH OF THAT CATWALK
CATWALK, AND THE POINT OF IT WAS
VERY SIMPLY THAT LIFE ON BOTH
SIDES OF THE BRIDGE ARE NEVER
THE SAME AFTER YOU BUILT IT.
SO THE PARADIGM OR THE
RELATIONSHIP PERTAINS TO THE BIG
PROBLEM THAT WE HAVE OF TRYING
TO RELATE THE EXCITING
DEVELOPMENTS IN BIOLOGICAL AND
ENGINEERING SCIENCES TO HUMAN
HEALTH.
AND THAT'S THE PURPOSE HERE.
SO IF YOU'RE AN UNDERGRADUATE, A
MEDICAL STUDENT, POST DOC, P.I.,
ADMINISTRATOR, EVERYONE IS
WELCOME, AND YOU DON'T HAVE
TO -- THE WAY YOU REGISTER IS TO
SIGN UP ON THE LISTERV, AND THAT
HEN IT GETS YOU ACCESS TO
VARIOUS INFORMATION I'LL SEND
AROUND, BIOGRAPHICAL SKETCH OF
THE SPEAKER OF THE WEEK, VERY
OFTEN THE POWERPOINTS AND SOME
SELECTED REFERENCES AND SO
FORTH, WHICH HOPEFULLY YOU WILL
PERUSE BEFORE YOU COME, AND HAVE
A BETTER IDEA AND APPRECIATE
MORE MATERIAL THAT'S BEING
PRESENTED.
THE PROGRAM HERE IS ON SITE,
IT'S ONLINE, THERE ARE HUNDREDS
OF PEOPLE, LAST YEAR THE AVERAGE
WAS 260 WHO WATCH ON SITE AROUND
THE CAMPUS, IT'S ON YOUTUBE, AND
AFTER THREE OR FOUR DAYS, IT'S
IN THE NIH VIDEO ARCHIVE, WHERE
IT SORT OF GOES AROUND THE WORLD
AND YOU CAN WATCH PROGRAMS OVER
THE COURSE OF THE LAST 11 YEARS.
IF YOU WANT TO AT YOUR OWN TIME.
IT'S KIND OF INTERESTING, I FIND
IT VERY EXCITING THAT THIS
APPROACH, WHICH IS SORT OF LIKE
WHAT OLD-FASHIONED MEDICAL GRAND
ROUNDS USED TO BE, HAS BEEN
REPLICATED NOW IN 17 COUNTRIES
AND OVER TWO DOZEN NORTH
AMERICAN INSTITUTIONS, AND
THAT'S VERY EXCITING.
THERE'S NO ACADEMIC CREDIT FOR
THOSE STUDENTS WHO'VE CONTACTED
ME WHO WANT TO REGISTER AND PAY
TUITION AND GET CREDIT, NO
PROBLEM.
THERE'S NO CREDIT, THERE'S NO
TUITION, AND FOR THOSE WHO ARE
LOOKING FOR CLINICAL
CERTIFICATION CREDIT, THERE'S NO
CLINICAL CERTIFICATION CREDIT.
SO DON'T WORRY ABOUT IT.
IF YOU REALLY WANT SOME
ACKNOWLEDGMENT THAT YOU'VE TAKEN
PART IN THIS, IF YOU ATTEND
ABOUT TWO-THIRDS OF THE
SESSIONS, REGISTER IN THE BOOK
THAT GOES AROUND, AND AT THE
END, ELECTRONIC FINAL EXAM,
YOU'LL GET A CERTIFICATE
INDICATING THAT YOU TOOK PART IN
IT.
SO WE ENCOURAGE YOU TO ASK
QUESTIONS, HOPEFULLY ASK
QUESTIONS, NOT MAKE SPEECHES,
AND ENJOY AND BE EXCITED BY
WHAT'S GOING ON.
ANY SUGGESTIONS, COMMENTS,
CRITICISMS, THE BETTER
SUGGESTIONS FOR FUTURE SPEAKERS,
ET CETERA, WE REALLY WELCOME IT.
OKAY.
SO SO THIS IS SORT OF A SUBTITLE
IN A WAY OF TODAY'S TOPIC, AND
IT'S SOMETHING THAT RECURS WITH
MANY OF THE TOPICS THAT WE HAVE,
BUT PROBABLY THERE'S NO BETTER
EXAMPLE OF THIS THAN THE SORT OF
ETERNAL BATTLE IT BETWEEN MAN,
OTHER MAMMALS AND
MICROORGANISMS.
YOU SORT OF WONDER, WE THINK IN
TERMS OF AN ANTIBIOTIC THAT
KNOCKS OFF A CERTAIN BACTERIUM,
BUT I'VE ALWAYS WONDERED WHEN
YOU CONSIDER THE DIVERSITY AND
THE CAPABILITY OF MICROORGANISMS
TO ADAPT TO THE ENORMOUS CHANGES
IN THEIR ENVIRONMENT AND ALL THE
CHEMICALS AND STUFF THAT WE POUR
INTO IT, AS WELL AS ANTIBIOTICS,
YOU MIGHT LIKE AT IT THE OTHER
WAY AROUND, ISN'T IT AMAZING
THAT AN ANTIBIOTIC ACTUALLY
KILLS CERTAIN ORGANISMS AND
PREVENTS DISEASES.
THANK GOD IT DOES.
BUT IT'S NOT AN OPEN AND SHUT
CASE.
THIS IS ONE OF THE GREAT GLOBAL
PROBLEMS OF DRUG RESISTANCE.
SO TODAY WE'RE REALLY MOST
FORTUNATE TO BEGIN THIS SERIES
BY HAVING TWO SPEAKERS WHO ARE
VERY MUCH AT THE FOREFRONT OF OF
WORK AND THINKING ABOUT THIS.
OUR FIRST SPEAKER IS GOING TO BE
TOE NIGTONY PFAU CHEE, FAUCI, DIRECTOR OF NIAID.
HE TRAINED IN MEDICINE,
GRADUATED FROM CORNELL, TRAINED
IN NEW YORK, CAME TO THE NIH AS
A CLINICAL INVESTIGATOR, AND
BECAME VERY ACTIVE IN THE
IMMUNOLOGY, THEN THE EXPLODING
ARENA OF *** DISEASE, AND TONY
HAS GONE ON TO BECOME REALLY ONE
OF THE INTERNATIONAL MOST HIGHLY
ACCOMPLISHED PEOPLE IN ACADEMIC
MEDICINE.
HE HAS RECEIVED RECOGNITIONS
WHICH WOULD KEEP US HERE FOR THE
REST OF THE HOUR IF I WERE TO
ITEMIZE HIS PRESIDENTIAL AWARDS,
THE NATIONAL SCIENCE AWARD,
SOMETHING LIKE 30
HONORARY DEGREES, ET CETERA, AND
SO WE'RE REALLY MOST GRATEFUL
THAT GIVEN ALL OF THE ENORMOUS
RESPONSIBILITIES HERE, AROUND
THE WORLD, THE WHITE HOUSE, ET
CETERA, THAT HE'S ALWAYS BEEN
VERY SUPPORTIVE OF THE CONCEPT
OF THIS DEMYSTIFYING MEDICINE,
AND TONY IS GOING TO SPEAK
FIRST.
WE'LL HAVE TIME FOR QUESTIONS,
PLEASE KEEP THEM KIND OF BRIEF
BECAUSE HE MAY HAVE TO LEAVE AND
WE CERTAINLY WANT TO LEAVE
ADEQUATE TIME FOR OUR SECOND
SPEAKER, JEFF TAUBENBERGER, WHO
IS A -- RECEIVED HIS MD
PH.D. DEGREE AT THE UNIVERSITY
OF VIRGINIA AND IS A MOLECULAR
PATHOLOGIST.
ONE OF THOSE BEGINNING WHEN
PATHOLOGY BEGAN TO SHIFT FROM
STRICTLY MORPHOLOGY INTO THE
LINKAGE TO MORE BASIC SCIENCE.
HE STUDIED -- HE WAS TRAINED IN
PATHOLOGY AT THE NIH, AND THEN
FOR QUITE A FEW YEARS, WAS
ACROSS THE STREET, THE ARMED
FORCES INSTITUTE OF PATHOLOGY,
WHERE HE REALLY IN INTRODUCED
MOLECULAR PA WILLIN PATHOLOGY, AND HE'S
CERTAINLY BEST KNOWN FOR HIS
INCREDIBLY DRAMATIC SEQUENCING
OF THE PANDEMIC INFLUENZA VIRUS
FROM THE GREAT PAN IT DEMI PANDEMIC OF 191 8.
THAT'S A STORY THAT I WOULD URGE
TO YOU GO TO THE WEBSITE AND
READ ABOUT BECAUSE IT'S
INCREDIBLY DRAMATIC AS TO HOW IT
ALL HAPPENED AND I WILL NOT TAKE
THE TIME TO RELATE THAT TO YOU.
JEFF RETURNED ACROSS THE STREET
HERE TO THE NIH, WHERE HE'S
CONTINUED WORK IN HIS MAJOR
INTEREST, WHICH IS IN INFLUENZA
VIRUS, FROM THE CLINICAL
STANDPOINT, CONFRONTING THE
QUESTION OF, YOU KNOW, ARE WE
GOING TO HAVE ANOTHER PANDEMIC,
WHAT IS IT IS A PANDEMIC, WHAT
ACCOUNTS FOR THE GREAT VARIATION
IN THE VIRUS.
TODAY HE'S GOING TO EMPHASIZE
THE COMMON THEME, WHICH IS
RESISTANCE.
SO I WILL STOP, AND TONY, THANK
YOU VERY MUCH.
>> THANK YOU VERY MUCH.
IT'S A REAL PLEASURE TO BE HERE
AGAIN THIS YEAR TO TALK ABOUT
SOME TOPICS OF CONSIDERABLE
INTEREST IN MEDICINE.
THIS YEAR, THEY ASKED ME TO TALK
ABOUT ANTIBUY ROBE YAL
RESISTANCE AND I'M VERY HAPPY TO
DO THAT BECAUSE RIGHT NOW WE'RE
REALLY FACING AN EXTRAORDINARY
CHALLENGE AS YOU SEE ON THE
FIRST SLIDE HERE, I CALL IT
PERPETUAL CHALLENGE, AND I'M
GOING TO TRY TO DEVELOP DURING
MY TALK WITH YOU THE THEME OF
THOUSAND THIS IS SOMETHING THAT
IS REALLY ENDURING THAT JUST IS
NOT GOING TO GO AWAY, BUT WE'RE
REALLY FACING SOMEWHAT OF A
CRISIS NOW IN THIS COUNTRY AND
GLOBALLY IN THE ARENA OF
ANTIMICROBIAL RESISTANCE,
PARTICULARLY WITHIN THE ARENA OF
BACTERIA.
THAT'S THE REASON WHY WE CHOSE
THE TITLE, WILL WE LOSE THE RACE
OR CHANGE THE GAME, BECAUSE
THERE REALLY IS A RACE AGAINST
MICROBES THAT HAS BEEN GOING ON
FOR A CONSIDERABLE PERIOD OF
TIME.
SO I'M GOING TO BREAK THE TALK
DOWN INTO MULTIPLE SMALL
COMPONENTS, THEY'RE IDENTIFIED
ON THIS SLIDE, SO WHY DON'T WE
START OFF WITH THE FIRST WHICH I
ALWAYS LIKE TO DO IS DEFINE WHAT
YOU'RE TALKING ABOUT, AND THE
DEFINITION OF ANTIMICROBIAL
RESISTANCE THAT WE GET FROM A
NUMBER OF VENUES BUT
PARTICULARLY THE CDC IS THAT THE
RESISTANCE TO A MICROBE IS THE
RESULT OF THEIR CHANGING THEIR
WAYS THAT REDUCE OR ELIMINATE
THE EFFECTIVENESS OF DRUGS,
CHEMICALS OR OTHER AGENTS TO
CURE OR PREVENT THEM.
NOW YOU CAN GET ANTIMICROBIAL
RESISTANCE TO ANY OF A NUMBER OF
MICROBES, VIRUSES, FUNGI,
PARASITES, BACTERIA.
YOU KNOW THAT JEFF IS GOING TO
TALK IN A BIT ABOUT INFLUENZA.
I'M GOING TO CONFINE MY REMARKS
BECAUSE OF THE URGENCY OF THE
PARTICULAR PROBLEM, WE COULD
TALK A LOT ABOUT MALARIA
RESISTANCE, WE COULD TALK ABOUT
RESISTANCE OF FUNGI, BUT WE'RE
GOING TO CONCENTRATE ON THE
BACTERIA EXCLUSIVE OF MICRO
BACTERIUM TUBERCULOSIS, BECAUSE
THERE ARE ENOUGH INFORMATION
THAT REALLY TO OCCUPY EVEN MORE
THAN THE TIME THAT I HAVE.
SO LET'S START OFF WHAT IS THE
SCOPE OF THE PROBLEM?
WE KNOW WHAT THE PROBLEM IS, WE
KNOW THE DEFINITION.
WHAT IS THE SCOPE?
IT'S VERY INTERESTING THAT IN
1928, FLEMING DISCOVERED
PENICILLIN, AND AS WE ALL KNOW,
THAT WAS A VERY HISTORIC TIME
BECAUSE THE ERA OF ANTIBIOTICS
BEGAN, BUT IN FACT, AT THE VERY
MOMENT, IN FACT, I'M GOING TO
SHOW YOU IN A MINUTE EVEN BEFORE
THE ANTIBIOTIC ERA BEGAN, THERE
WAS ANTIBIOTIC RESISTANCE, BUT
THERE REALLY WASN'T ANY
ANTIBIOTICS AT THE TIME, AND
I'LL EXPLAIN TO YOU WHAT I MEAN
BY THAT SOMEWHAT PARADOX.
IN FACT, FLEMING HIMSELF WHEN
THE -- WHEN HE RECEIVED THE
NOBEL PRIZE IN 1945, AND AS I'M
SURE THE HISTORY BUFFS AMONG YOU
KNOW THE IMPORTANT ROLE THAT
PENICILLIN PLAYED IN WORLD WAR
II, WHEN IT WAS FIRST USED IN
OUR TROOPS, BUT WITH
CONSIDERABLE INSIGHT, FLEMING
MADE THE STATEMENT IN HIS NOBEL
LECTURE THAT THE TIME MAY COME
WHEN PENICILLIN CAN BE BOUGHT BY
ANYONE IN THE SHOP.
THEN THERE'S THE DANGER THAT THE
IGNORANT MAN MAY EASILY
UNDERDOSE HIMSELF AND BY
EXPOSING HIS MICROBES TO
NON-LETHAL QUANTITIES OF THE
DRUG MIGHT MAKE THEM RESISTANT.
SPECTACULAR INSIGHT FOR SOMEBODY
TO TALK ABOUT THAT LONG BEFORE
ANY PROBLEM OF ANTIMICROBIAL
RESISTANCE CAME ABOUT.
AND IN FACT HE WAS QUITE
CORRECT, BECAUSE IF YOU LOOK,
THESE ARE ACTUAL SIGNS FROM
STORES HERE IN THE UNITED
STATES.
FREE ANTIBIOTICS, WITH SOMETHING
ELSE THAT YOU BUY, IT'S REALLY
QUITE EXTRAORDINARY.
AND IN FACT, THEY'RE NOT FREE,
BUT THEY'RE CERTAINLY ON SALE IN
OTHER COUNTRIES, PARTICULARLY IN
EUROPEAN COUNTRIES AND IN SOUTH
AMERICA.
SO IN THE UNITED STATES,
ANTIBIOTIC RESISTANCE IS A
SIGNIFICANT PROBLEM THAT IS
GETTING WORSE.
IT IT RESULTS IN LOST LIVES,
2 MILLION DRUG RESISTANT
INFECTIONS, EACH YEAR, IN THE
UNITED STATES, WITH 23,000
DEATHS PER YEAR.
THE ANNUAL COSTS ARE REALLY
SPECTACULAR.
ABOUT $20 BILLION IN EXCESS
HEALTHCARE EXPENDITURES THAT WE
USUALLY SEE IN HOSPITALIZATIONS
THAT ARE PROLONGED.
I'VE HAD THE UNFORTUNATE
EXPERIENCE AS A PHYSICIAN WHO
TAKES CARE OF PATIENTS TO BE
MAKING ROUNDS DAY AFTER DAY ON
INDIVIDUALS THAT HAVE RESISTANT
MICROBES.
AND IF YOU LOOK AT LOST
PRODUCTIVITY, IT'S EVEN MORE
THAN THAT, 35 BILLION.
NOW IF YOU LOOK AT IT, IT IS
ALSO AN INCREASING GLOBAL HEALTH
PROBLEM.
AND THE NUMBERS OF THESE ARE
REALLY ASTOUNDING.
IN SOUTH AFRICA, 72% THAT CARRY
THE KLEBSIELLA PNEUMONIAE
CARRIED AN EXTENDED SPECTRUM
BETA-LACTAMASE.
IN INDIA, E. COLI IN URINE
CULTURES FROM PREGNANT WOMEN
SHOWED AN ASTOUNDING 59% BACTRIM
RESISTANCE.
BACTRIM IS A VERY CHEAP DRUG, A
VERY GOOD DRUG FOR URINARY TRACT
INFECTIONS AND HAD BECOMES A
REAL PROBLEM WHEN YOU HAVE MORE
THAN A 50% RESISTANCE, AND IN
LOWER INCOME COUNTRIES, MORE
THAN 50% OF THE STAPH CULTURES
IN INTENSIVE CARE UNITS ARE ***
SI LIN RESISTANT OF.
SO THIS IS NOT JUST A PROBLEM
THAT WE'RE FACING, IT'S AROUND
THE WORLD.
NOT ONLY AROUND THE WORLD, RIGHT
HERE ON CAMPUS, AND THIS IS A
SLIDE THAT SAYS ANTIMICROBIAL
RESI TANS HITS CLOSE TO HOME.
I'M SURE MANY IN THIS ROOM HAVE
READ ABOUT OVER THE PAST COUPLE
OF YEARS THE PROBLEM THAT WE
HAVE IN THE CLINICAL CENTER WITH
A CARBAPENEM RESISTANT CLEB
KLEBSIELLA PNEUMONIA, PATIENTS
WHO HAD TRANSFERRED UNWITTINGLY
KNOWING THEY HAD A RESISTANT
MICROBE INTO OUR WARDS, AND
DESPITE EXTRAORDINARY ATTEMPTS
TO PREVENT THE SPREAD BY GOOD
HOSPITAL PRACTICE, THERE WERE
STILL OVER 17 CASES, SIX OF WHOM
DIED.
THIS WAS SOMETHING THAT WAS
REALLY VERY SERIOUS AND IT IS
NOT PARTICULAR TO THE NIH
HOSPITAL.
IT'S GOING ON ALL OVER EXCEPT
PEOPLE ARE NOT RECOGNIZING.
WE JUST HAPPEN TO HAVE THE TOOLS
TO DO THE DEEP SEQUENCING TO DO
THE KIND OF TRACING.
THIS SEEMS PROBABLY GOING ON, I
WOULDN'T SAY IN EVERY HOSPITAL
BUT IN MOST HOSPITALS.
SO IF YOU LOOK AT THE TIMETABLE
AND JUST TAKE AS AN EXAMPLE,
SPASTAPH AUREUS, PEOPLE TALK ABOUT
IT ON THE HEELS OF THE
INTRODUCTION OF AN ANTIBIOTIC,
BUT IN FACT, BECAUSE OF THE
MECHANISMS OF RESISTANCE, NAMELY
MUTATIONS, THAT MIGHT LEAD TO
RESISTANCE, IT DOESN'T HAPPEN
VERY OFTEN BECAUSE THERE'S NOT A
LOT OF PRESSURE, THAT IF YOU
LOOK AT PENICILLIN AND STAPH
AUREUS AND BEFORE PENICILLIN WAS
ACTUALLY USED, ISOLATING
BACTERIA FROM SPECIMENS, THERE
WAS SOME PENICILLIN RESISTANCE
EVEN BEFORE PENICILLIN WAS USED.
IT'S ONLY THE USE OF PENICILLIN
THAT AMPLIFIES THE PE PENICILLIN
RESISTANCE.
THIS IS A STORY AGAIN FOR THOSE
OF YOU IN MEDICINE, WHEN I WAS
IN MEDICAL SCHOOL IN A HOUSE
OFFICE, WE WERE JUST STARTING TO
SEE THE BEGINNING OF *** SI LIN
RESISTANT STAPH AUREUS, THEN
WHEN I GOT TO THE NIH, WE WERE
USING VANCOMYCIN, THEN WE NOW
HAVE OTHER DRUGS LIKELY NAIZ
LIED AND OTHERS.
WE'LL GET BACK TO THIS IN A
MOMENT.
NOW, A LOT OF SCHOLARS HAVE BEEN
IMPRESSED BY THE WHOLE ISSUE OF
ANTIBIOTIC RESISTANCE, AND PAUL
EHRLICH, THE NOBEL PRIZE WINNING
PHYSICIAN SCIENTIST IN GERM GERMANY,
WHO AS YOU KNOW DEVELOPED THE
FIRST SIEVE POLICE TREATMENT,
DIP TIER YA ANTITOXIN, MADE THE
STATEMENT THAT IT FOLLOWS THE
DRUG LIKE A FAITHFUL SHADOW.
THAT'S A BIT MELODRAMATIC, BUT
IN FACT THAT IS WHAT IS GOING
ON.
SO LET ME GO THROUGH SOME OF THE
ISSUES THAT ARE ASSOCIATED WITH
THIS.
THIS SLIDE MAKES THE STATEMENT
THAT'S QUITE TRUE.
WE TALK ABOUT THE PIPELINE RACE,
AS ANTIBIOTICS BECOME -- AS
MICROBES BECOME RESISTANT TO
ANTIBIOTICS, YOU HAVE OTHER
ANTIBIOTICS TO COME IN AND
REPLACE THEM.
IT'S KIND OF A PIPELINE RACE,
MORE RESISTANCE, MORE DRUGS.
THE ONLY TROUBLE IS THAT WE'RE
LOSING THAT PIPELINE RACE
BECAUSE OF THE DISCOVERY AND THE
DEVELOPMENT OF NEW ANTIBIOTICS
HAS ACTUALLY DECREASED.
AND IF YOU LOOK AT BRACKETS OF
YEARS GOING FROM 1983-87 TO THE
PRESENT TIME, THE APPROVAL BY
THE FDA IN THIS COUNTRY OF NEW
ANTIBIOTICS HAS DRAMATICALLY
DIMINISHED AS EXACTLY THE SAME
TIME AS THE NUMBER OF ANTIBIOTIC
RESISTANT MICROBES HAS ACTUALLY
INCREASED.
SO YOU HAVE A DOUBLE JEOPARDY OF
TWO LINES CROSSING AND THAT'S
WHAT I MEAN WHEN WE SAY WE'RE
LOSING THE RACE.
SO YOU SAY HOW DOES THIS HAPPEN,
HOW DOES IT EMERGE?
ANTIBIOTIC RESISTANCE IS
ANCIENT.
IF YOU LOOK AT -- AND YOU'RE
GOING TO HEAR A LITTLE BIT
PROBABLY ABOUT -- IF YOU LOOK AT
SAMPLES THAT ARE TENS OF
THOUSANDS OF YEARS AGO, AND YOU
ISOLATE BACTERIA AND TAKE A LOOK
AT THE SEQUENCING, THEY HAVE
RESISTANCE GENES RELATED TO
PENICILLIN, TETRACYCLINE, AND
VANCOMYCIN.
AND THE REASON IS THAT MICROBES
MUTATE, I KNOW I'M TELLING THIS
TO A LOT OF PEOPLE IN THIS ROOM
WHO UNDERSTAND THAT, BUT LET ME
JUST PUT IT IT INT INTO PERSPECTIVE OF
WHAT I'M SAYING.
MICROBES THAT REPLICATE --
PARTICULARLY THOSE THAT
REPLICATE ANNOT, TEND TO MUTATE.
MANY OF THE MUTATIONS DON'T MEAN
ANYTHING.
BUT JUST BY CHANCE ALONE, YOU'RE
GOING TO GET MUTATIONS OF A
MICROBE THAT'S RESISTANT TO AN
ANTIBIOTIC.
IF YOU THEN TREAT, YOU SELECT
AND THERE ARE SOME SITUATIONS
WHERE FITNESS VERSUS A
PARTICULAR ANTIBIOTIC IS
CONFERRED BY A MUTATION, AND IF
YOU TREAT WITH AN ANTIBIOTIC AND
PARTICULARLY IF YOU DON'T TREAT
ADEQUATELY FOR THE RIGHT
DURATION OR THE RIGHT DOSE, YOU
WIND UP SELECTING FOR
ANTIMICROBIAL RESISTANCE.
SO IT HAPPENS ANYWAY, YOU JUST
MAKE IT MUCH, MUCH MORE AM MI
AMPLIFIED WHEN YOU
INAPPROPRIATELY TREAT.
WE'LL GET BACK TO THAT IN A
MOMENT.
THE MECHANISMS INVOLVED, AGAIN,
ARE WELL DESCRIBED.
ONE OF THE MOST IMPORTANT OF
WHICH IS THE PLASMID BASE, WHERE
IF YOU LOOK AT A RESISTANT
BACTERIUM AND THE PLASMID THAT
CONTAINS THE RESISTANT GENE AND
YOU HAVE A BACTERIA NEXT TO IT
THAT'S ACTUALLY SENSITIVE, YOU
HAVE TRANSFER BY CO CONJUGATION --
THIS HAS PLAYED A SIGNIFICANT
ROLE IN THE OUTBREAK WHEN YOU
HAVE THE TRANSFER IT OF THE
RESISTANT GENE.
NOW THE TARGETS FOR ANTIBIOTICS,
YOU ALL WELL KNOW THESE ARE
TEXTBOOKS, CELL WALL, LIKE
VANCOMYCIN AND THE BETA LACK
TINS, DNA, RNA WITH THE
FLUOROQUINOLONES, PROTEIN
SYNTHESIS, AND FOLATE SYNTHESIS,
BY EXAMPLE, THOSE ARE THE
TARGETS.
IF YOU LOOK AT THE MECHANISMS OF
RESISTANCE, AS SOME OF THEM ARE
NOW VERY WELL DESCRIBED, YOU CAN
BLOCK THE ENTRY OF THE
ANTIBIOTIC SUCH AS WITH
PENICILLIN, YOU HAVE BETA
LACTAMASE, YOU HAVE ENZYMES THAT
INACTIVATE THE DRUG, YOU HAVE
EFFLUX OF THE ANTIBIOTIC, IT
GETS IN AND THEN IT IT EFFLUXES
RIGHT OUT OF THE CELL, BUT YOU
CAN HAVE AN ALTERATION OF THE
TARGET AS WE HAVE WHEN WE HAVE
COMPETITION FOR VANCOMYCIN
RESISTANCE.
SO WHY DOES IT EMERGE?
WE KNOW WHAT THE MECHANISMS OF
EMERGENCE, SO HOW IS IT THAT WE
HAVE A BIG PROBLEM RIGHT NOW?
WHAT ARE WE DOING TO MAKE THIS
PROBLEM WORSE?
WELL, WHEN YOU LOOK AT IT, FIRST
OF ALL, THE OVERWHELMING ISSUE
FROM A POSITIVE CONTRIBUTION TO
THE EMERGENCE OF RESISTANCE IS
THE INAPPROPRIATE USE OF
ANTIBIOTICS.
THAT'S ALMOST A SOCIOLOGICAL
MEDICAL LITIGATION ISSUE.
AND THAT IS PHYSICIANS OFTEN ARE
SUBLIMINALLY COERCED, AS IT
WERE, BY FAMILIES TO GET SOMEONE
ON AN ANTIBIOTIC.
LET ME GIVE YOU AN EXAMPLE.
73% OF ADULTS PRESENTING WITH
ACUTE BRONCHITIS RECEIVE AN
ANTIBIOTIC.
IF YOU LOOK AT BRONCHITIS AS
USUALLY POST NASAL DRIP AND
PEOPLE START COUGHING, YOU GO
AND YOU THINK YOU HAVE A
SINUSITIS, SIX IT TI IT% OF -- 60 IT%
OF ADULTS PRESENTING WITH A SORE
THROAT RECEIVE AN ANTIBIOTIC AND
ONLY 10% NEED THEM.
NOW, ONE OF THE THINGS THAT
WE'RE GOING TO GET TO IN A
MINUTE IS THE IMPORTANCE OF
DIAGNOSTICS, BECAUSE THE ONE
THING IT YOU DON'T WANT TO MISS,
AND WE HAVE VERY EASY TESTS FOR
IT, IS A STREP THROAT IN
SOMEONE.
BECAUSE THAT COULD HAVE SOME
SIGNIFICANT CONSEQUENCES, AND
WHEN SOMEONE COMES IN FOR A SORE
THROAT, SOMETIMES PARTICULARLY
SINUSITIS, YOU INAPPROPRIATELY
GET TREATED.
AND THESE ARE JUST SOME OF THE
NUMBERS THAT WE KNOW FROM A
RECENT ARTICLE.
NOW THE OTHER ONE THAT'S REALLY
ATTRACTED THE ATTENTION, YOU MAY
HAVE HEARD OF THE RECENT FDA
TRYING TO WORK WITH THE
PHARMACEUTICAL COMPANIES IN THE
DEPARTMENT OF AGRICULTURE ABOUT
THE USE OF ANTIBIOTICS IN
ANIMALS, VETERINARY USE, THIS IS
AMAZING.
MOST PEOPLE DON'T APPRECIATE
THIS.
ABOUT 75% OF ALL THE ANTIBIOTICS
SOLD IN THE UNITED STATES ARE
USED IN THE VETERINARY FIELD IN
ANIMALS.
NOT NECESSARILY TO TREAT
INFECTION, BUT MAINLY FOR GROWTH
PROMOTION, ABOUT HALF OF THEM
ARE USED FOR GROWTH PROMOTION.
WE COULD GET INTO A DISCUSSION
ABOUT GROWTH PROMOTION, DOES IT
REALLY PROMOTE GROWTH OR WHEN
YOU CROWD ALL THESE ANIMALS
TOGETHER AND YOU'RE ESSENTIALLY
PROVE LACING THEM, THAT MAY BE
THE REASON THAT THEY'RE GROWING,
NOT THAT YOU'RE METABOLICALLY
PROMOTING GROWTH.
WE DON'T KNOW THAT.
AND RESISTANCE AMONG ANIMALS IS
WIDESPREAD AND THERE'S A LOT OF
WORK GOING ON TALKING ABOUT AND
TRYING TO FIND OUT DATA AS TO
WHETHER OR NOT THAT'S
TRANSFERRED TO HUMANS.
THERE ARE OTHER REASONS WHY
RESISTANCE SPREADS, AND THOSE
ARE THINGS THAT SOMETIMES YOU
DON'T HAVE GOOD CONTROL OVER,
PARTICULARLY IN DEVELOPING
NATIONS.
WHERE LABORATORY CAPACITY IS
POOR, MAINLY TO SEE IF YOU'RE
DEALING WITH A RESISTANT STRAIN,
HEALTH WORKERS ARE OFTEN SCARCE,
DETECTION IS LIMITED BECAUSE OF
POOR SURVEILLANCE BECAUSE OF
RESOURCE LIMITATION, INFORMAL
ANTIBIOTIC SALES ARE PERVASIVE,
PEOPLE COME AROUND SELLING ANY
ANTIBIOTICS, AND THERE'S
COUNTERFEIT AND EXPIRED DRUGS.
AND I WOULDN'T UNDERESTIMATE THE
IMPORTANCE OF THAT BECAUSE THAT
GETS TO FLEMING'S ISSUE OF
UNDERUSING OR NOT USING ADEQUATE
AMOUNTS.
THERE ARE OTHER FACTORS
INVOLVED.
THE OVERUSE OF BROAD SPECTRUM
ANTIBIOTICS, SOMEBODY COMES IN,
WE DON'T KNOW WHAT YOU HAVE,
LET'S JUST BLANKET EVERYTHING,
WHICH IS A BAD IDEA UNLESS YOU
ABSOLUTELY HAVE TO DO THAT.
URBANIZATION AND GLOBALIZATION
FACILITATES POPULATION SPREAD OF
RESISTANT BACTERIA.
INSTITUTION-BASED CARE, YOU GO
FROM DAYCARE TO NURSING HOMES,
THEN YOU HAVE THE INDIVIDUAL
SPREAD.
WE'VE SEEN EXAMPLES OF ALL OF
THESE WITH INDIVIDUAL MICROBES.
SO WHERE DOES IT EMERGE?
WELL, HOSPITALS ARE THE BIG
PLAYERS IN THE EMERGENCE OF
ANTIMICROBIAL RESISTANCE.
SO FOR EXAMPLE, IF YOU LOOK AT
THE CASES OF CLOSTRIDIUM
DIFFICILE IN ACUTE CARE
HOSPITALS, IT HAS REALLY GONE UP
OVER THE LAST 10 YEARS FROM
ABOUT 130-PLUS THOUSAND TO OVER
THROO 46,000.
THAT'S IN THE ACUTE CARE
HOSPITALS.
WE'RE ALSO SEEING IT A LOT NOW
IN NURSING FACILITIES AND
LONG-TERM CARE HOSPITALS.
NOW THE DIFFERENCE THAT GETS A
LITTLE BIT SCARY IS THAT IT'S
BAD ENOUGH WHEN YOU HAVE SOMEONE
IN THE HOSPITAL AT RISK OF
GETTING A RESISTANT MICROBE, BUT
WHAT HAPPENED SOME YEARS AGO, A
CAN COUPLE DECADES AGO, WAS A
TRANSFER FROM THINGS BEING
PURELY HOSPITAL-ACQUIRED
INFECTIONS THAT ARE RESISTANT,
TO COMMUNITY-ACQUIRED
INFECTIONS.
AND THAT'S EXACTLY WHAT HAPPENED
IN STAPHYLOCOCCUS AUREUS.
IT WAS ALMOST EXCLUSIVELY
SOMETHING THAT YOU COULD GET IN
A HOSPITAL, AND THEN WHEN THERE
WAS CLOSE SKIN CONTACT SUCH AS
IN LOCKER ROOMS, WRESTLERS, IT
BECAME CLEAR THAT THERE WERE
OUTBREAKS IN SPORTS.
THE FIRST REPORTS WERE WITH
WRESTLERS, THEN FOOTBALL IT
TEAMS.
THE FAMOUS EPISODE OF THE DALLAS
COWBOYS YEARS AGO WHO BEFORE A
SUPER BOWL HAD A BUNCH OF STAPH
AND THEY WERE TREATING THEM ALL
WITH ANTISTAFSTAPHYLOCOCCAL.
ALSO IN INDIA, RESISTANT
BACTERIA RECOVERED IN PUDDLES
AND EVEN DRINKING WATER.
BUT WHO KNOWS IF THE DRINKING
WATER WAS CONTAMINATED ANYWAY,
BUT IT WAS THERE, SO THAT'S THE
ISSUE OF A SPREAD.
ONCE SOMETHING BECOMES
COMMUNITY-ACQUIRED, THEN YOU
REALLY HAVE A SERIOUS PROBLEM,
BECAUSE THEN YOU HAVE SOMEONE
WHO WALKS INTO AN OFFICE WITH AN
INFECTIOUS AND MOST OF THE
PRIMARY CARE PHYSICIANS ARE NOT
THINKING ABOUT A DRUG-RESISTANT
MICROBE.
WHEREAS IN THE HOSPITAL, THE
FIRST THING THE HOUSE STAFF OR
THE ATTENDING THINKS ABOUT IS
ARE WE DEALING WITH A RESISTANT
MICROBE, AND THAT'S WHAT
HAPPENED.
SO WHAT ABOUT THE SPREAD OF IT?
LET'S TAKE A LOOK AT THE KPC
RESISTANCE.
IN 2001, THIS IS THE ONLY STATE
THAT HAD IT.
IN 2011, IT'S REALLY SPREAD
ESSENTIALLY THROUGHOUT THE
UNITED STATES.
AND THIS IS A COMBINATION OF
REAL SPREAD, REALIZATION OF THE
SPREAD.
BECAUSE REMEMBER THE PERSON WHO
CAME FROM ANOTHER HOSPITAL TO
OUR CLINICAL CENTER, WE DIDN'T
KNOW THAT THAT PERSON HAD A
RESISTANT MICROBE, SO THAT NEVER
REALLY WENT REPORTED FROM THAT
PLACE SO YOU WOULD HAVE NEVER
KNOWN IT WAS IN THAT HOSPITAL.
THEN ALSO THE SPREAD ABROAD, AND
THIS IS IN THE NEW DEHLI STRAIN
THAT AS YOU KNOW CAME TO THE
UNITED STATES, BACK THEN TO
EUROPE AND THEN CAME FROM IT THE
FAR EAST BACK TO THE
SOUTHWESTERN PART OF THE UNITED
STATES.
THE CDC HAS INDICATED
APPROPRIATELY THAT THERE ARE A
NUMBER OF HIGH PRIORITY
PATHOGENS, SO WHAT I'D LIKE TO
DO IS TO JUST SPEND A COUPLE OF
MINUTES, JUST GIVING YOU SOME
EXAMPLES OF WHAT I'VE BEEN
TALKING ABOUT.
SO THERE ARE TWO MAJOR GROUPS,
ONE THAT ARE CALLED URGENT
THREATS, AND I MENTIONED SOME OF
THESE, NOT ALL OF THEM, THE
CARBAPENEM RESISTANT
ENTEROBACTERACIAE.
CLOSTRIDIUM DIFFICILE IN IT
ACUTE CARE HOSPITALS AND NURSING
HOMES, THEN THE GOOD OLD
NEISSERIA GONORRHOEAE.
SERIOUS AND CONCERNING THREATS
ARE STAPH AUREUS.
IN FACT, BECAUSE OF THE
ATTENTION THAT HAS BEEN PAID TO
METMETHICILLIN RESISTANT STRAINS
HAS ACTUALLY LED TO A DECREASE
IN STAPH AUREUS THAT ARE
RESISTANT.
AND THAT ACTUALLY IS AN
INTERESTING ISSUE BECAUSE IT
SHOWS THAT WHEN YOU PAY
ATTENTION TO SOMETHING AND
IDENTIFY IT, IT ACTUALLY CAN
DECREASE.
BUT LET'S GO THROUGH A FEW OF
THESE AND I'LL JUST GIVE YOU A
QUICK FEEL FOR THEM.
SO TAKE THE CARBAPENEM RESISTANT
ENTEROBACTERACIAE, IN THE GUL
FLORA, IT'S A BROAD SPECTRUM BUT
VERY POTENT ANTIBIOTIC,
CARBAPENEM.
THE CLINICAL MANIFESTATIONS ARE
SEVERE G.I., G.U., PULMONARY, AS
WELL AS GRAN NEGATIVE SEPSIS.
NOW, THE EPIDEMIOLOGY WAS FIRST
REPORTED AS I MENTIONED IN 2001,
IT'S NOW SEEN IN 44 STATES.
THERE WERE 9,000 INFECTIONS PER
YEAR NOW, AND THE NIH OUTBREAK
AS I MENTIONED RIGHT HERE ON
CAMPUS IN OUR CLINICAL CENTER
WAS CAUSED BY ONE OF THESE
ORGANISMS.
THE RESISTANCE MECHANISM, AS I
MENTIONED VERY EARLY, IS PLASMID
MEDIATED FOR KPC AND THE NEW
DEHLI METALLO BETA-LACTAMASE
THAT PEOPLE REFER TO IN THE
ARTICLES AS NDM-1.
THEY BOTH BREAK UP THE
CARBAPENEMS.
NOW THE TOOL TO COMBAT THIS ARE
SOME REALLY SIMPLE LOW TECH
THINGS.
WE DID A LOT OF HIGH-TECH
SEQUENCING TO DO THE TRACING
HERE IN OUR HOSPITAL, BUT THINGS
LIKE SURVEILLANCE, HOSPITAL
CONTROL, TYPICAL SIMPLE THINGS
LIKE HYGIENE PRACTICES, PATIENT
COHORTING, ACTIVE CONTACT
TRACING, AND THEN TREATMENT.
AND UNFORTUNATELY, WHEN YOU'RE
DEALING WITH SUCH A RESISTANT
MICROBE, YOU HAVE TO RESORT TO
OLDER ANTIBIOTICS THAT HAVE
CONSIDERABLE TOXICITY, SO THIS
CRE -- IF THOSE OF YOU WHO HAVE
EVER TREATED, YOU HAVE TO BE
CAREFUL.
WHEN I WAS -- THAT WAS THE
PRIMARY DRUG WE USED TO USE FOR
PSEUDOMONAS SEPSIS, AND WE WOUND
UP SAVING THEM FROM THAT AND
PUTTING THEM INTO RENAL FAILURE
HALF THE TIME, A DEADLY DISEASE.
NOW, CLOSTRIDIUM DIFFICILE,
AGAIN, A COME COMMENSAL ORGANISM IN
THE GUT, SEVERE ANTIBIOTIC
ASSOCIATED DIARRHEA,
PSEUDOMEMBRANOUS COLITIS AND
SEPSIS.
FOREMOST ON THE MIND OF
HOSPITALISTS WHO ARE TREATING
INDIVIDUALS WITH ANTIBIOTICS,
THAT'S WHAT YOU GET WHEN YOU ARE
AN ANTIBIOTICS FOR A LONGER
PERIOD OF TIME.
IT'S NOT AN UNCOMMON FINDING.
IT THEN HAS TO BE TREATED, WE'LL
GET INTO IT IN A MOMENT, WITH
ORAL ANTIBIOTICS LIKE
VANCOMYCIN.
THE EPIDEMIOLOGY IS SIGNIFICANT
AND SEVERE.
THERE ARE ABOUT 250,000
INFECTIONS IN THE UNITED STATES
PER YEAR AND ABOUT 14,000
DEATHS.
THE DEATHS HAVE INCREASED
DRAMATICALLY OVER THE SEVEN
YEARS FROM 2000 TO 2007, 400%.
ELDERLY ARE PARTICULARLY
VULNERABLE.
THEY SUFFER HALF THE INFECTIONS
BUT 90% OF THE MORTALITIES.
THERE'VE BEEN SOME REALLY
SERIOUS TRAGIC SITUATIONS IN
NURSING AND EXTENDED CARE HOMES
WITH ELDERLY INDIVIDUALS WHO
WEREN'T REALLY UNDERLYING SICK
EXCEPT THAT THEY WERE SOMEWHAT
INFIRM ELDERLY INDIVIDUALS WHERE
THEY ACTUALLY GOT INFECTED WITH
AN ANTIBIOTIC RESISTANT MICROBE
AND DIED.
THE RESISTANCE MECHANISMS ARE
NUMEROUS, INCLUDING PLASMID AND
CHROMOSOMAL, AND THERE'S THE
MORE VIRULENT
QUINOLONE-RESISTANT STRAIN THAT
IS ON THE RISE.
AND THAT'S THE DISCUSSION THERE
ON THAT PAPER.
SO THE CURRENT TREATMENTS AS I
MENTIONED, THERE'S BEEN A NEW
APPROVAL OF A DRUG WHICH IS
BACTERIACIDAL, PEOPLE HAVE USED
ANTIBODIES WHEN THINGS REALLY
GET SERIOUS ON THE REALLY
EXTREME SITUATIONS THAT SOME
PHYSICIANS AND SURGEONS HAD A TO
RESORT TO COLECTOMY, AND THERE'S
AN INTERESTING APPROACH CALLED
FECAL TRANSPLANTS, WHICH WE'LL
GET BACK TO IN A MOMENT.
AGAIN, DISEASE CONTROL IS A
MINIMIZATION, WHERE APPROPRIATE,
OF ANTIBIOTICS.
BECAUSE THE MORE ANTIBIOTICS YOU
GIVE, THE MORE YOU SELECT FOR
CLOSTRIDIUM DIFFICILE.
AND AGAIN, SURVEILLANCE AND
PROPER VIGILANCE AND HAND
WASHING, WIPES AND GELS DON'T
KILL THE SPORES.
THE AMOUNT OF EFFORT THAT'S PUT
INTO HOSPITAL CONTROL NOW,
PARTICULARLY BECAUSE OF THE
SENSITIVITY ACROSS THE STREET IN
THE CLINICAL CENTER, IS REALLY
SOMEWHAT STUNNING.
I MAKE ROUNDS OVER THERE WITH MY
COLLEAGUE, HILLARY, AND WE HAVE
SOMEBODY STANDING THERE WATCHING
TO MAKE SURE WE DO TWO SQUIRTS.
ONE SQUIRT IS NOT ENOUGH, TWO
SQUIRTS, WASH YOUR HANDS, PUT ON
THE GOWN, ET CETERA, AND YOU
LOSE ACCREDITATION IF YOU DON'T
DO THAT.
SO THEY'RE TAKING THIS REALLY
QUITE SERIOUSLY.
OKAY.
FECAL TRANSPLANTS USUALLY
PERFORMED VIA AN NASOGASTRIC
TUBE.
THE IDEA OF A FECAL TRANSPLANT
TURNS PEOPLE OFF, BUT WHEN YOU
HAVE A PILL FORM, IT ACTUALLY
WORKS.
AND THAT REALLY IS AN
INTERESTING BACK DOORWAY OF
LOOKING AT THE HUMAN MICROBIOME
HOW THE ENVIRONMENT OF THE GUT
IS REALLY AN INCREDIBLY DYNAMIC
EQUILIBRIUM OF DIFFERENT TYPES
OF ORGANISMS, AND WHEN YOU PUT
IN ORGANISMS THAT ARE SOMEWHAT
LUDICROUS BUT IT'S NOT A FECAL
TRANSPLANT, YOU ACTUALLY WIND UP
HAVING A VERY HIGH CURE RATE FOR
SOME OF THESE DISEASES.
SO GONORRHEA.
SEXUALLY TRANSMITTED GRAM
NEGATIVE DI DIPLOCOCCI.
BACK WHEN EVERYTHING WAS
SENSITIVE TO PENICILLIN, THERE
WAS NOTHING BETTER, I WOULDN'T
SAY BETTER, THAN HAVING SOMEBODY
COME IN WITH ACUTE GONORRHEA.
IT WAS LIKE, ONE SHOT, THEY COME
BACK TWO DAYS LATER, THEY'RE ALL
BETTER.
WITH PENICILLIN.
WELL, IT ISN'T THE CASE RIGHT
NOW BECAUSE WE HAVE A LOT OF
SERIOUS RESISTANCE WITH
GONORRHEA.
THE SYMPTOMS OF GONORRHEA, QUITE
SYMPTOMATIC, VERY SERIOUS,
PURULENT URETHRITIS, FOR WOMEN
IT'S A SERIOUS DISEASE, YOU CAN
GET SERIOUS PELVIC INFLAMMATORY
DISEASE THAT CAN LEAD IN SOME
CASES TO STERILITY, DISSEMINATED
INFECTION CAN BE VERY SERIOUS,
YOU CAN HAVE GY CONJUNCTIVITIS IN
BABIES BORN TO MOTHERS WHO HAVE
UNDETECTED GONORRHEA IN THE
VAGINAL TRACT WHEN THE BABY
COMES THROUGH THE VAGINAL VAULT,
YOU CAN WIND UP, IF IT'S
UNRECOGNIZED, GETTING NEONATAL
BLINDNESS.
SO IT'S NOT A TRIVIAL DISEASE.
PEOPLE JOKE ABOUT IT, I GOT THE
CLAP AS THEY USED TO SAY BACK IN
THE MILITARY TIME.
WELL, IT CAN BE A SERIOUS
DISEASE.
IT BECOMES EVEN MORE SERIOUS
WHEN YOU HAVE TROUBLE WITH
RESISTANCE.
THE EPIDEMIOLOGY, IF YOU LOOK AT
IT, GLOBALLY THERE ARE
60 MILLION CASES PER YEAR.
IN THE UNITED STATES, THERE WERE
820,000 CASES PER YEAR, 30% NOW
ARE ANTIBIOTIC RESISTANT.
SO HERE'S AN INTERESTING CHART.
IF YOU LOOK AT THE PERCENT
RESISTANCE, PENICILLIN FROM 1987
IS JUST A LOT OF RESISTANCE TO
PENICILLIN, LIKE TETRACYCLINE,
YOU WOULD NEVER USE
TETRACYCLINE.
FLOOR A QUINOLONE WAS GOOD FOR A
WHILE, THEN THE E EMERGENCE OF
OTHER DRUGS, NOW IF YOU LOOK,
YOU HAVE REDUCED CEFIXIME.
CHROMOSOMAL CHAIX I CHANGES IN THE
BINDING PROTEINS, PLASMID
MEDIATED LACTAMASES.
THE TREATMENT NOW IS REALLY
TOTALLY DIFFERENT THAN IT WAS
DECADES AGO.
THE ADVANTAGE OF AN IN-OFFICE
TREATMENT, I'M GOING TO GET TO
IN A SECOND THE NEW TREATMENTS
THAT ARE BEING INVESTIGATED, BUT
AGAIN, THE CONTROL MECHANISMS
ARE DISEASE SURVEILLANCE AND
CONTACT TRACING, AND TREATMENT
OF PERHAPS AN UNSUSPECTING A
ASYMPTOMATIC PARTNER.
THE NIAID AND THE CDC HAD A
JOINT CLINICAL TRIAL THAT WAS
JUST ANNOUNCED LAST SUMMER WHERE
THE LICENSED DRUG COMBINATIONS
OF INJECTABLE GENTAMICIN AND
ORAL AZITHROMYCIN OR ORAL
GEMIFLOXACIN AND ORAL
AZITHROMYCIN TURNED OUT TO BE
ALMOST 100% EFFECTIVE.
THIS IS NOT RECOMMENDED FOREGONE
REA RIGHT NOW.
RIGHT -- FOR GONORRHEA RIGHT
NOW.
THIS IS SORT OF IN YOUR BACK
POCKET BECAUSE WE'RE STARTING TO
SEE THE EMERGENCE OF SOME
RESISTANCE THAT ISN'T YESTERDAY
TO THE POINT WHERE YOU WOULD SAY
YOU WANT TO GO TO THIS REGIMENT,
BUT WE'RE TRYING TO STAY AHEAD
OF THE GAME TO HAVE A REGIMEN
THAT'S HIGHLY EFFECTIVE JUST IN
CASE WE HAVE THAT BURST OF
RESISTANCE TO THE ANTIBIOTICS
THAT WE'RE CURRENTLY USING.
NOW STAPH AUREUS, THE ONE THAT
REALLY PUT THE SPOTLIGHT ON
ANTIBIOTIC RESISTANCE.
IT RAPIDLY ACQUIRES RESISTANCE
TO ANTIBIOTICS, AND IT COULD BE
ANYTHING FROM AS, YOU KNOW,
LOCALIZED AS A SKIN INFECTION TO
TOTAL SEPSIS, AND THE KEY
RESISTANT ORGANISMS INCLUDE
MRSA, EVERYBODY KNOWS WHICH MRSA
IS, WHICH STANDS FOR METHICILLIN
RESISTANT STAFF AUREUS,
INTERMEDIATE RESISTANCE TO
VANCOMYCIN INTERMEDIA STAFF
AUREUS, THN THERE'S THE
VANCOMYCIN RESISTANT STAPH
AUREUS WHICH IS RARE BUT SCARY,
BECAUSE VANCOMYCIN IS A GREAT
DRUG FOR METHICILLIN RESISTANCE.
THEN YOU GO TO THE NEXT ONE, NOT
USED VERY OFTEN, BUT THAT'S AT
LEAST ONE THAT WE TEND TO USE.
THE EPIDEMIOLOGY AS I SHOWED
YOU, IT'S COMMON, THERE ARE
80,000 SEVERE INFECTIONS IN THE
UNITED STATES WITH 11,000
DEATHS, BUT AS YOU CAN SEE, THE
RATES ARE STARTING TO DECLINE.
VISA IS RARE AS I MENTIONED,
LESS THAN A PRIF LENS AMONG THE
ICE LATS AS WELL AS VANCOMYCIN
RESISTANCE BEING RARE.
THE MECHANISMS ARE GIVEN HERE,
THE ONES THAT I MENTIONED FROM
CHROMOSOMAL TO PLASM PLASMID MEDIATED.
SO THE TREATMENT, I'VE ALREADY
ALLUDED TO THEM FOR METHICILLIN
RESISTANT.
IT'S VANCOMYCIN FOR THE
INTERMEDIATE AND RESISTANT
VANCOMYCIN IS LINEZOI.
LINEZOIID, THESE
ARE THE THINGS THAT HAVE MADE
THE CURVE GO DOWN.
THE CAMPAIGN TO END
HOSPITAL-ASSOCIATED INFECTIONS,
WHICH IS REALLY VERY MUCH NOW ON
EVERYBODY'S FRONT BURNER.
I MET THIS MORNING WITH FRANCIS
COLLINS AND LARRY TABAK ABOUT
THE WHITE HOUSE BECOMING
EXTREMELY INTERESTED IN
ADDRESSING THE PROBLEM OF
ANTIMICROBIAL RESISTANCE BECAUSE
IT'S LIKE PART OF A GLOBAL
DISEASE SURVEILLANCE ISSUE.
YOU'RE GOING TO BE READING ABOUT
THAT PROBABLY IN THE NEWSPAPERS
OVER THE NEXT MONTH OR SO.
BECAUSE ONCE IT GETS TO THE AIT
TENSION OF THE PRESIDENT,
SOMETHING USUALLY HAPPENS,
PROBABLY WITH NO NEW MONEY, BUT
IT WILL HAPPEN.
WE'LL DO IT.
OKAY.
WHAT ARE SOME OF THEIR POTENTIAL
SOLUTIONS?
IT BOTH THE SURVEILLANCE -- IF
YOU LOOK IT AT THE TOOLS WE
ALREADY HAVE, EVEN WITHOUT NEW
ANTIBIOTICS, THERE'S A LOT THAT
YOU CAN DO TO GET YOUR ARMS
AROUND ANTIMICROBIAL RESISTANCE.
WE NEED PIPELINE OF NEW DRUGS
BUT BOLSTER SURVEILLANCE KNOW
THAT YOU'RE DEALING WITH A
RESISTANT MICROBE, AVOID WHAT
HAPPENED WHEN THE PERSON WITH
THE CARBAPENEM RESISTANCE CAME
INTO OUR HOSPITAL AND WE WERE
COMPLETELY UNSUSPECTING THAT WE
WERE GETTING SOMEBODY WITH THAT
INFECTION.
THE OTHER IS INFECTION CONTROL.
NOW INFECTION CONTROL IN THE
HOSPITAL IS A SERIOUS DISCIPLINE
WITH HOSPITAL EPIDEMIOLOGISTS
DEVOTED JUST TO THAT PROBLEM.
THAT WAS UNHEARD OF WHEN I WAS
IN TRAINING AND WHEN I WAS DOING
HOSPITAL WORK.
AND THEN CONTROL THE
INAPPROPRIATE USE, WHICH IS
REALLY DIFFICULT BECAUSE THIS IS
A BEHAVIORAL SOCIETAL LITIGATION
ISSUE THAT IS NOT EASY TO
ATTACK, NAMELY, THE
INAPPROPRIATE USE.
SO ALSO EDUCATING THE PUBLIC,
EDUCATION AS THOSE OF US WHO
HAVE BEEN INVOLVED IN HEALTHCARE
FOR A LONG TIME, EDUCATION
DOESN'T NECESSARILY EQUATE WITH
BEHAVIORAL CHANGE.
YOU CAN EDUCATE SOMEBODY TO DO
SOMETHING AND THEY WON'T CHANGE
THEIR BEHAVIOR, SO EVEN THOUGH
THERE'S A LOT GOING ON,
CAMPAIGNS AT THE CDC IS PUTTING
A LOT OF RESOURCES IN, ABOUT
GETTING PEOPLE NOT TO
INAPPROPRIATELY PRESCRIBE
ANTIBIOTICS FOR THINGS LIKE
SNIFFLES AND SNEEZES AND UPPER
RESPIRATORY INFECTIONS, THE
OVERWHELMING MAJORITY OF WHICH
IS A VIRUS THAT DOESN'T HAVE A
SECONDARY BACTERIAL COMPONENT.
YOU KNOW THE FDA HAS RECENTLY
JUST THIS PAST MONTH IN DECEMBER
ACTED IN A VERY CIRCUMSPECT WAY
OF NOT TRYING TO DOING THINGS
THAT ARE NOT GOING TO BE WELL
RECEIVED BY THE INDUSTRY TO
REALLY HAVE VERY STRONG
ENCOURAGEMENT ON THE PART OF
BOTH THE LIVESTOCK INDUSTRY AND
THE ANTIBIOTIC PHARMACEUTICAL
INDUSTRY TO CURTAIL THE USE OF
ANTIBIOTICS IN THE VETERINARY
INDUSTRY, TO PUT VETERINARY
OVERSIGHT OVER IT SO THAT
ANTIBIOTICS ARE NO LONGER GOING
TO BE SOLD OVER THE COUNTER,
ANIMAL ANTIBIOTICS, TO USE IT IN
AN ANTIINFECTIVE USE ONLY AS
OPPOSED TO TRYING TO USE IT IN A
WAY TO PROMOTE GROWTH.
THAT'S SOMETHING THAT I THINK WE
HAVE A VERY LIGHTWEIGHT SCIENCE
THERE ABOUT THE RELATIONSHIP
BETWEEN CROWDING AND PREVENTION
OF INFECTION VERSUS THE REAL
GROWTH PROMOTING.
THE U.S. DEPARTMENT OF
AGRICULTURE REALLY HAS A LOT OF
WORK TO DO AND THE CDC AND THE
FDA, TO SOME EXTENT WE AT NIH
ARE GOING TO BE COLLABORATING
WITH THEM.
SO VERY QUICKLY, WHAT ABOUT THE
ROLE OF BIOMEDICAL RESEARCH IN
ADDRESSING ANTIBIOTIC
RESISTANCE?
IN 2008, WE PUT OUT OUR RESEARCH
AGENDA WHICH LOOKED AT THE THREE
MAJOR COMPONENTS, WHAT WE CAN DO
IN BASIC RESEARCH SUCH AS GENE
SEQUENCING, TRANSLATIONAL
RESEARCH, AND CLINICAL RESEARCH.
THE IMPORTANCE OF APPROVED
DIAGNOSTICS, THAT'S THE ROLE WE
PLAY, GETTING STATE OF THE ART
POINT OF CARE, IT IT WILL SAVE
LIVES.
TESTS USUALLY TAKE ONE TO FIVE
DAYS TO YIELD SUSCEPTIBILITY.
WE NEED SUSCEPTIBILITY IT
TESTING THAT'S MEASURED IN
HOURS.
BECAUSE YOU COULD EVEN MAKE
THINGS WORSE BECAUSE IF YOU
DON'T HAVE THE SUSCEPTIBILITY,
THEN YOUR REFLEXES PUT THEM ON A
BROAD SPECTRUM ANTIBIOTIC OR PUT
THEM ON MULTIPLE ANTIBIOTICS
THAT ACTUALLY MAKES THE PROBLEM
WORSE IF YOU KNEW THAT YOU WERE
DEALING WITH RIGHT FROM THE
BEGINNING.
REDUCED SIDE EFFECTS SUCH AS
DRUG ALLERGIES, CUT COSTS, RAPID
TESTING IF YOU CAN GET THE RIGHT
DIAGNOSTICS, CERTAIN STUDIES
SHOW YOU CAN SAVE OVER $20,000
PER PATIENT FOR MRSA.
WE HAVE BEEN PUTTING SOME MONEY
INTO THIS AND WE'RE SUPPORTING
RESEARCHERS.
THERE IS A NEW TEST THAT CAME
OUT JUST THIS PAST YEAR IN
SEPTEMBER WHICH IS
DISTINGUISHING VIRAL FROM
BACTERIAL INFECTION.
SO IT'S NOT GOING TO TELL YOU
WHAT BACTERIA OR WHAT VIRUS, BUT
IT'S GOING TO TELL YOU THAT
YOU'RE DEALING WITH A VIRUS AND
YOU'RE NOT DEALING WITH A
BACTERIA.
SO THAT, I THINK, IS GOING TO BE
REALLY IMPORTANT, AND I THINK
THAT'S GOING TO REALLY LIMIT THE
INAPPROPRIATE USE.
GENOME SEQUENCING CENTERS RIGHT
NOW BY DEEP SEQUENCING, WE HAVE
THE CAPABILITY WHEN YOU SEQUENCE
MULTIPLE STRAINS TO REALLY
PINPOINT WHAT THE MECHANISM IS
AND TRACE WHETHER OR NOT YOU'RE
DEALING WITH A POINT SOURCE THAT
IS TRANSMITTING IT TO SOMEONE
ELSE, AND THAT'S WHAT WE DID
WITH THE CLINICAL CENTER.
SO WE HAVE THE SEQUENCES FOR
MORE THAN 800 BACTERIAL STRAINS.
IT'S IN GENBANK, OPEN ACCESS TO
ANYBODY WHO WANTS TO LOOK AT THE
SEQUENCE.
AND WE HAVE ABOUT 170 STAPH
AUREUS STRAINS THAT WE'RE GOING
TO SEQUENCE.
THE KNOWN ANTIBIOTIC PRODUCING
BACTERIA SEQUENCES MINED FOR NEW
ANTIMICROBIAL GENES, AND THIS IS
JUST A SCHEMATIC SHOWING ALL OF
THE ISSUES THAT YOU CAN ADDRESS
WHEN YOU GET WHOLE GENOMIC
SEQUENCE, NOT ONLY THROUGH THE
BIOSIN THEY IT TICK PATHWAYS,
BUT THE DRUG RESISTANT
MECHANISM, THE IMMUNE EVASION
VAC TORES AND THE PROTEINS GOOD
FOR THE DEVELOPMENT OF VACCINES.
AND SPEAKING OF VACCINES, PEOPLE
TEND TO DISASSOCIATE THE ISSUE
OF ANTIBIOTIC TREATMENT WITH
VACCINES, BUT REALLY ONE OF THE
BEST WAYS TO AVOID ANTIBIOTIC
RESISTANCE IS TO PREVENT THE
INFECTION IN THE FIRST PLACE.
AND THERE ARE PEOPLE WHO HAVE
HIGHER DEGREE OF SUSCEPTIBILITY
TO STAPH AUREUS AND YOU WANT TO
DEVELOP A STAPH AUREUS-TYPE
VACCINE.
IF YOU LOOK AT HEE MOV -- PRIOR TO THE
VACCINE, IT WAS THE LEADING
CAUSE OF BACTERIAL MENINGITIS,
MENTAL RETARDATION AND DEAFNESS
IN CHILDREN.
AND NOW IT'S A DISEASE THAT IS
ESSENTIALLY DISAPPEARED FROM THE
UNITED STATES.
SO WITH THIS AS THE MODEL, WE'RE
GOING TO TRY AND WILL,
HOPEFULLY, GET A VACCINE AGAINST
STAPHYLOCOCCUS AS WELL AS
AGAINST CERTAIN OF THE GRAM
NEGATIVES AND BE VACCINATING
PEOPLE AT HIGH RISK FOR THAT.
SO IN THE LAST SLIDE, I JUST
WANT TO GO RIGHT BACK TO WHERE I
STARTED WITH WHERE WE WERE
TALKING ABOUT LOSING THE RACE OR
CHANGING THE GAME.
THIS REALLY IS A PERPETUAL
CHALLENGE, AND WE THOUGHT THAT A
GOOD ANALOGY TO THAT OR A
METAPHOR WOULD BE IT'S REALLY
KIND OF LIKE A CHESS GAME.
THE BACTERIA MAKES A MOVE, YOU
MAKE A MOVE.
THE BACTERIA MAKES A MOVE, YOU
MAKE A MOVE.
YOU CAN'T GET UP AND GO TO SLEEP
OR GO AWAY, BECAUSE IT TRULY IS,
IN MEDICINE, ONE OF THE FEW
THINGS THAT IS AND WILL ALWAYS
BE A PERPETUAL CHALLENGE JUST
THE WAY ALEXANDER FLEMING SAID
IN 1945 IN HIS SPEECH FOR THE
NOBEL PRIZE.
SO I'LL STOP THERE AND I THINK I
STOPPED ON TIME.
[APPLAUSE]
>> IF YOU HAVE A QUESTION,
PLEASE SPEAK VERY LOUDLY, THERE
ARE A LOT OF PEOPLE LISTENING TO
THIS.
>> SO THAT WAS TERRIFIC.
I JUST HAD A QUESTION THAT SEEMS
TO ME TO BE OBVIOUS.
WITH RESPECT TO THE EMERGENCE OF
DRUG RESISTANT INFECTIONS
SECONDARY TO INAPPROPRIATE USE,
THE WAY THAT MEDICINE IS
PRACTICED IN THE UNITED STATES
FOSTERS THIS SORT OF SITUATION,
DOESN'T IT, BECAUSE PATIENTS
COME IN, THEY'RE SICK, THEY WANT
TO BE TREATED IMMEDIATELY, THEY
WANT WHATEVER IT IS THAT THEY
HAVE TO GO AWAY WITHIN THE NEXT
30 SECONDS, AND THEY OFTEN COME
IN AND THEY SAY, I'M SICK, I'D
LIKE AN ANTIBIOTIC.
THAT KIND OF SITUATION SEEMS TO
BE GETTING WORSE IN THE UNITED
STATES AS THESE URGENT CARE
CENTERS KEEP CROPPING UP, I'VE
NOTICED A LOT OF THEM OVER THE
LAST SEVERAL YEARS CROPPING UP
JUST WITHIN THIS REGION.
AND IT SEEMS THAT IT'S REALLY
THE CLIENT, THE PATIENT, THAT IS
FOS IFOSTERING THIS, AND IN ORDER FOR
COMPANIES TO SUSTAIN THEIR LOAD
OF OF PATIENTS SO THAT THEY CAN
MAKE A PROFIT, THEY ENCOURAGE
THIS BY GIVING THE PATIENT
WHATEVER HE OR SHE WANTS TO
TREAT THEIR ILLNESS.
SO HOW DO WE DEAL WITH THAT KIND
OF SITUATION IN THE UNITED
STATES WHERE HEALTHCARE REALLY
IS A BUSINESS AND THE CUSTOMER
SEEMS TO ALWAYS BE RIGHT PLUS
THE FACT THAT WE SEEM TO BE
FOCUSING INCREASINGLY ON BE
PATIENT-ORIENTED MEDICINE AND
GIVE THE CUSTOMER WHAT HE OR SHE
WANTS?
>> AS YOU SAID, THE QUESTION IS
OBVIOUS BUT THE ANSWER IS NOT
EASY, AND IT HAS TO DO A LOT
WITH THE EDUCATION BEHAVIOR
ISSUE THAT I MENTIONED, WE COULD
EDUCATE AS TO THE REASON WHY
THAT'S A BAD IDEA.
YOU CAN GO FM EDUCATION AND
THE HOPE FOR BEHAVIORAL
MODIFICATION TO SOMETHING THAT
MIGHT RELATE TO REGULATION.
FOR EXAMPLE, REIMBURSEMENTS
ABOUT GIVING ANTIBIOTICS, WHAT
WAS THE REASON FOR THE
ANTIBIOTICS.
THE ONLY TROUBLE WITH THAT IS
THAT THAT REALLY STARTS TO
ENCROACH UPON MEDICAL JUDGMENT,
AND THAT'S A VERY FUZZY LINE.
LIKE SOMEONE COMES IN AND WHAT
WAS THE REASON WHY YOU GAVE THIS
ANTIBIOTIC?
DID YOU DO A CULTURE, DID YOU DO
THIS, DID YOU DO THAT?
I PERSONALLY THINK THE ONLY WAY
TO REALLY MAKE THAT HAVE SOME
TEETH IS IF YOU DO HAVE A POINT
OF CARE DIAGNOSTIC.
AND SOMEONE COMES IN AND SAYS
THEY WANT AN ANTIBIOTIC AND YOU
DO IT AND YOU SAY THE PERSON
DOESN'T HAVE A BACTERIAL INIT
FEKTION BUT TO GIVE THEM AN
ANTIBIOTIC FOR ANY OTHER REASON
OTHER THAN IMPERIC -- I DON'T
THINK IT'S GOING TO WORK WITH BUT
THAT'S THE BEST I CAN DO.
>> WITH REGARD TO THE DRUG
PIPELINE, DO YOU THINK THE
SOLUTION IS PUTTING MORE FUNDS
INTO RESEARCH FOR
ANTIBACTERIALS, WHY IS IT THAT
WE HAVE SOME MORE ANTIVIRALS,
NEWER ANTIVIRALS IN THE PAST --
>> GOOD POINT.
IT'S INNOCENT VIIZATION OF
INDUSTRY THAT I JUST SPENT AN
HOUR AND A HALF THIS MORNING
WITH FRANCIS COLLINS AND LARRY
TALKING ABOUT, BECAUSE WE'RE
GOING TO HAVE TO GO DOWN TO THE
THE WHITE HOUSE AND TALK ABOUT
THAT IN THE NEXT WEEK OR SO.
AND THAT IS REALLY INDUSTRY,
WITH SOME EXCEPTIONS, HAS VERY
LITTLE INCENTIVE TO -- IT COSTS
ANYWHERE BETWEEN 700 MILLION AND
A BILLION DOLLARS TO BRING A NEW
DRUG FROM A CONCEPT TO
LICENSURE.
THAT'S THE COST RIGHT NOW.
WHATEVER IT IS.
SO WHEN YOU'RE LOOKING AT AN
ANTIBIOTIC, YOU'RE LOOKING AT
SOMETHING THAT IS GOING TO BE
SPARINGLY USED, USUALLY IN
COURSES OF 7 TO 10 DAYS AND
SOMETIMES TWO WEEKS, BY A
MINORITY OF PEOPLE, AND YOU KNOW
FOR ABSOLUTELY CERTAIN THAT
SOONER OR LATER, THERE'S GOING
TO BE RESISTANCE TO THAT
ANTIBIOTIC LONG BEFORE THE
PATENT EXPIRES, SO THE INCENTIVE
DO THAT IS VERY LITTLE.
SWITCH OVER TO ***.
YOU HAVE 35 MILLION PEOPLE
INFECTED.
THEY GET ON THERAPY.
AND THEY'RE ON THERAPY FOR THE
REST OF THEIR LIFE.
SO THE INCENTIVE, EVEN NOW,
WHERE WE HAVE GREAT
ANTIRETROVIRAL DRUGS, THE
COMPANIES ARE STILL FALLING ALL
OVER THEMSELVES TO MAKE THE NEXT
GENERATION.
LESS TOXICITY, LONGER ACTING OR
WHAT HAVE YOU.
IT'S REALLY AN INCENTIVE
SITUATION, AND WHAT WE'RE
DISCUSSING IS WHAT DOES THE DRUG
COMPANY WANT T TO INCENTIVIZE
THEM?
WE, NIH, CAN DO SOMETHING.
WE CAN DERISK WHAT THEY DO, WE
CAN DO SOME OF THE THINGS IN
RESEARCH THAT BRINGS THEM TO THE
POINT WHERE THEY SEE THE CONCEPT
LOOKS GOOD.
YOU CAN DO SCREENING,
PHARMACOCAN KINETICS,
PHARMACODYNAMICS, WE'RE DOING
THAT ESSENTIALLY FOR FREE, BUT
THAT STILL DOESN'T OVERCOME THE
DISINCENTIVE THAT THEY HAVE.
WHAT THEY REALLY WANT ARE THINGS
LIKE EXTENSION OF A PATENT.
SO IF YOU COULD TELL PFIZER,
WE'RE GOING TO EXTEND YOUR
*** PATENT, A $7 BILLION A
YEAR INDUSTRY FOR ONE YEAR,
WOULD YOU PUT IN A BILLION
DOLLARS TO MAKE A NEW
ANTIBIOTIC?
THEY'D DO IT IN A HEARTBEAT.
BUT THERE'S A LOT OF RELUCTANCE
TO GIVE THEM PATENT EXTENSION.
>> HI.
I HAVE A QUESTION ABOUT ONE OF
THE GRAPHS THAT WAS IN IT YOUR
PRESENTATION WHICH SHOWED THAT
CERTAIN BACTERIA CAN LOSE
RESISTANCE.
THEY CAN LOSE RESISTANCE TO A
CERTAIN ANTIBIOTIC.
HOW DOES THAT HAPPEN AND IS IT
EVER VIABLE TO BRING BACK AN OLD
ANTIBIOTIC THAT --
>> WELL, I DON'T KNOW IF -- WE
GO BACK AND USE ANTIBIOTICS LIKE
COLISTIN TO WHICH RESISTANCE HAD
NEVER BEEN DEVELOPED, BUT YOU
HAVE A MICROBE THAT'S RESISTANT
TO EVERYTHING WE HAVE AND YOU
HAVE WHAT'S CALLED REPURPOSING
OF GOING BACK AND USING AN OLD
ANTIBIOTIC FOR SOMETHING NOW
BECAUSE YOU HAVEN'T USED IT IN
SO LONG THAT IT REVERTS BACK TO
WILD TYPE.
SO THAT'S WHAT YOU MEAN BY
LOSING RESISTANCE.
SO IT'S WILD TYPE FOR COLISTIN
BECAUSE THE GENERATIONS OF
MICROBES THAT HAVE BEEN PASSED
ON FROM ONE PERSON TO ANOTHER,
ET CETERA, WIND UP BEING
RESISTANT TO THE DRUGS IN 2010,
BUT NO LONGER RESISTANT TO THE
DRUGS FROM 1965 AND 1970.
THAT'S WHAT WE MEAN BY THAT.
>> GREAT TALK.
WITH THE RESURGENCE OF SOME OF
THE OLDER DRUGS, DO YOU THINK IT
WILL BE LIKE A RETURN FROM THE
OLDER TREATMENT OPTIONS LIKE
FAIJ THERAPY OR --
>> YOU KNOW, FAIJ THERAPY IS
ALWAYS ON THE BURNER OF THE
KINDS OF EXPERIMENTAL THINGS YOU
MIGHT WANT TO DO.
I THINK THAT EVEN WITHOUT GOING
BACK IT TO OLD DRUGS, THAT'S
SOMETHING THAT'S BEING PURSUED
RIGHT NOW.
SO THAT'S A VERY HOT AREA OF
RESEARCH.
>> [INAUDIBLE]
>> PEPTIDES, AGAIN, ARE
DIFFICULT FROM THE STANDPOINT OF
ADMINISTRATION AND GETTING
CONCENTRATIONS ENOUGH, BUT
ANTIMICROBIAL PEPTIDES ARE AN
AREA OF RESEARCH THAT ARE BEING
SCREENED.
COMPANIES DO IT, WE HAVE SOME
WITH NCATS NOW A LITTLE BIT OF
IT, NOT A LOT.
>> MY QUESTION WAS ABOUT
ALTERNATIVES TO -- BASED ON THE
CHEMISTRY.
MY OTHER QUESTION IS -- HOW DO
YOU THINK IT WILL BE WELCOMING
IN THE CONGRESS, BECAUSE I JUST
READ ISSUES LIKE --
>> YOU SHOULD HAVE SEEN THE
HEARING WHEN THEY BEAT ME UP
WHEN I SUGGESTED THAT, IN FACT,
IT WAS A BAD THING, THAT IT WAS
LOBBY-DRIVEN.
SO YEAH, THERE ARE ALTERNATIVE
APPROACHES, AND SOME OF IT THEM
ARE, FOR EXAMPLE, TO BLOCK THE
TOXINS OF ANTIBIOTICS -- EXCUSE
ME -- OF MICROBE WHOSE MAJOR --
THE OTHER IS TO NOT NECESSARILY
HAVE TO KILL EVERY SINGLE
MICROBE, BUT TO ACTUALLY BRING
DOWN THE TITER OF SOME OF THEM,
WE COULD GET SOME BAKE TIER YOE
STATIC THAT ESSENTIALLY GETS
WIPED OUT EVEN IF YOU DON'T KILL
EVERY ONE OF THEM.
VACCINES IS ANOTHER ALTERNATIVE,
MONOCLONAL ANTIBODIES,
PARTICULARLY SOME AGAINST THE
TOXINS.
WE'RE WORKING WITH THAT.
THAT RESEARCH STARTED WITH THE
BUBIODEFENSE WHEN WE WERE MAKING
ANTIBODIES AGAINST, FOR EXAMPLE,
ANTHRAX TOXINS.
SO THERE ARE NON-ANTIBIOTIC
APPROACHES.
THE MOST -- I THINK THE MOST
IMPORTANT OF WHICH IS PROBABLY
VACCINATIONS AGAINST THE
SUSCEPTIBLE POPULATION.
>> WHAT ABOUT THE ENTEROBACK
TIER YEA -- OTHER THAN C. DIFF C
DIFFICILE -- THERE ARE REPORTS
IN THE LITERATURE OF PEOPLE WITH
DRUG-RESISTANT E. COLI AND SO
FORTH --
>> OH, NO, NO, THE TROUBLE IS
SINCE IT'S PLASMID, YOU CAN GET
KLEBSIELLA RESISTANCE PLASMID
TRANSFER TO A PLAIN OLD BENIGN
E. COLI, SO THAT'S REALLY AN
ISSUE YOU'VE GOT TO BE CAREFUL
ABOUT.
>> I WAS REFERRING TO THE FECAL
TRANSPLANT --
>> OH, I SEE.
RIGHT.
EXACTLY.
WE'RE WORRIED ABOUT FECAL
TRANSPLANT, ORGAN TRANSPLANTS
CONTAMINATED WITH --
>> IT REALLY IS A REPLACEMENT OF
FLORA.
IF YOU TAKE NORMAL FLOOR YA -- WHAT YOU'RE
REALLY DOING IS TRANSPLANTING OF
NORMAL INTESTINAL FLORA TO
REPOPULATE A FLORA IN A SICK
PERSON THAT'S DOMINATED BY C
DIFFICILE OR DOMINATED BY
ANOTHER MICROBE THAT'S CAUSING
THE PROBLEM.
SO IT REALLY IS A BALANCE OF THE
MICROBIOMES.
SO IF YOU TAKE SOMEBODY WITH A
TOTALLY NORMAL FLORA AND YOU PUT
THAT EITHER WITH A PILL OR BY AN
N G-TUBE, YOU'RE ESSENTIALLY
GOING TO OVERPOPULATE IT WITH
NORMAL NON-PATHOGENIC,
NON-RESISTANT MICROBES.
THAT'S THE REASON FOR IT.
>> [INAUDIBLE]
>> YOU MEAN INFECTIONS THAT ARE
OUTSIDE OF THE -- NO, BUT THAT
WOULDN'T DO ANY GOOD THERE
BECAUSE IT'S ALREADY IN THE
TISSUE OUT OF THE GUT.
YOU WOULDN'T WANT TO DO A FECAL
TRANSPLANT ON SOMEONE -- OH,
YEAH, SURE.
THERE'S A LOT OF
EXPERIMENTATION.
THE WHOLE MICROBIOME PROJECT IS
TRYING TO LOOK AT THAT DYNAMIC
BETWEEN MICROBES.
THAT'S THE REALLY HOT FIELD
RIGHT NOW.
THAT'S A GOOD QUESTION.
WHAT GLOBAL APPROACH IS -- SO
THERE'S -- WHO AND INTERNATIONAL
TRANS-ATLANTIC CONSORTIUM NOW OF
WHICH WE ARE A PART OF THAT IS
LOOKING AT HOW WE CAN GET SOME
HARHARMONIZATION -- VERY MUCH
INVOLVED.
THE U.K. IS PLAYING A PRETTY
GOOD LEADERSHIP ROLE IN THAT.
>> [INAUDIBLE]
>> ABSOLUTELY.
ABSOLUTELY.
THE QUESTION IS, IF YOU'RE GOING
TO DO A PCR AND YOU HAVE A
SOPHISTICATED ENOUGH PROCESS
THAT YOU COULD TELL IF IT'S A
VIRUS OR BACTERIA, YOU COULD
ALSO TAKE A LOOK AT THE VIRUS OR
THE BACTERIA AND SINCE YOU KNOW
WHAT THE RESISTANT GENES ARE,
YOU CAN IDENTIFY BY PCR IF YOU
HAVE THE RESISTANT GENE.
THE ANSWER IS YES, AND IN FACT,
THAT IS DONE WITH THE POINT OF
CARE GENE EXPERT MACHINE THAT
YOU USE TO DIAGNOSE TUBERCULOSIS
AND WHETHER OR NOT IT'S --
RESISTANT.
SO THAT'S ALREADY BEING DONE FOR
TUBERCULOSIS.
THERE'S NO REASON AT ALL NOT TO
DO IT IN THE SITUATION I JUST
MENTIONED TO YOU.
>> OKAY.
I THINK WE'D BETTER MOVE ALONG
AND THANK YOU YOU HAVE, VERY VERY, VERY MU CH.
>> YOU'RE WELCOME.
[APPLAUSE]
>> NOW WE'RE GOING TO SHIFT TO
INFLUENZA, WHICH IS A VIRUS,
WHICH HAS A WHOLE DIFFERENT SET
OF PROBLEMS ASSOCIATED WITH IT.
JEFF TAUBENBERGER IS GOING TO
DISCUSS THIS.
>> THANKS VERY MUCH.
MY VERY FIRST PIECE OF ADVICE,
NEVER FOLLOW DR. FAUCI ON THE
PODIUM.
THAT'S THE MOST IMPORTANT THING
YOU'LL HEAR FROM ME TODAY.
SO WE'RE GOING TO FOCUS IN ON A
SMALLER PROBLEM, LITERALLY, AND
METAPHORICALLY, FROM THE BIGGER
PROBLEM OF ANTIBIOTIC RESISTANCE
GENERALLY TO SPECIFICALLY ONE
PARTICULAR PATHOGEN, WHICH IS
INFLUENZA VIRUSES, WHICH ARE A
MAJOR PUBLIC HEALTH PROBLEM IN
BOTH THEIR SEASONAL INFLUENZA
AND PANDEMIC INFLUENZA
MANIFESTATIONS.
SO FIRST JUST TO INTRODUCE YOU
TO THE BUG IN QUESTION, THESE
ARE SINGLE STRANDED RNA VIRUS,
MID SIZED RNA VIRUSES, AND THEY
HAVE A COUPLE FEATURES WHICH ARE
IMPORTANT FOR UNDERSTANDING HOW
THEY RIPPLY KATE AN REPLICATE.
ONE OF THEM IS THE FACT THAT THE
GENE SEGMENTS OF THE VIRUS, THE
RNA SEGMENTS ARE NOT ONE PIECE
OF RNA BUT EIGHT SEPARATE LITTLE
PIECES OF RNA CALLED SEGMENTS
THAT EACH ENCODE ONE OR MORE
OPEN READING FRAMES.
THEY EXPRESS 13 DIFFERENT
PROTEINS THROUGH THESE EIGHT
GENES, AND SO IF TWO DIFFERENT
INFLUENZA VIRUSES CO-INFECT ONE
HOST AT THE SAME TIME, YOU CAN
CREATE VIRUSES THAT MIX AND
MATCH GENE SEGMENTS FROM THE TWO
DIFFERENT VIRUSES AND CREATE
PROGENY VIRUSES THAT HAVE
DIFFERENT PROPERTIES, BOTH
GENETIC AND ANTIGENIC AND
PHYSIOLOGIC PROPERTIES.
SO THAT QUESTION IS AN IMPORTANT
QUESTION.
THE SECOND ISSUE IS THAT THE
POLYMERIZED JEANS OF THPOLYMERIZED GENES O F THE VIRUSES
LACK PROOFREADING AND IS
INCREDIBLY ERROR-PRONE SO UNLIKE
THE RARE MUTATIONS THAT YOU'VE
SEEN IN DNA, INFLUENZA VIRUSES
LIVE TO MUTATE AND LIVE IN A
QUASI SPECIES POOL WITH VERY
FREQUENT MUTATIONS.
THERE ARE TWO MAJOR SURFACE
PROTEINS ON THE SURFACE OF
INFLUENZA VIRUS, HA OR H, WHICH
HAS 16 DIFFERENT VARIANTS
CIRCULATING IN BIRDS, SEVERAL OF
WHICH HAVE ADAPTED TO HUMANS,
AND NINE DIFFERENT SUBTYPES IN
BIRDS AND ADDITIONAL SUBTIGHTS
HAVE BEEN IDENTIFIED RECENTLY IN
BATS.
AND THESE ARE ON DIFFERENT
SEGMENTS SO DIFFERENT INFLUENZA
VIRUSES WITH DIFFERENT
COMBINATIONS OF -- N1 THROUGH
9 HAVE BEEN SEEN.
THE HA AND NA HAVE BASICALLY
OPPOSITE PROPERTIES.
THE HA HAS ONE OF ITS MAJOR
ROLES TO BIND ACIDS ON THE
SURFACE OF GLYCOPROTEINS
DECORATING THE IT TIP OF
RESPIRATORY EPITHELIAL CELLS IN
MAMMALS AND IT BASICALLY HAS THE
OPPOSITE EFFECT TO CLEAVE OFF
THE ACID OFF THE TIP OF THESE
GLYCOPROTEINS DURING VIRAL
BUDDINGS, THE PROJECT KNEE
VIRUSES CAN BE RELEASED FROM THE
CELLS.
THERE IS A SMALL M2 -- BY THE
MATRIX GENE WHICH IS IMPORTANT
IN THE EARLY STA I STATUS AND THE
SECOND CLASS OF ANTIVIRAL DRUGS
AVAILABLE TO TREAT INFLUENZA
VIRUSES ARE INHIBITORS OF THE NA
ENZYME.
SO INFLUENZA VIRUSES ARE
FANTASTIC AT RESPONDING TO DAR
YIN WIN PRESSURES OF DIFFERENT
SORES, WHETHER THAT PRESSURE IS
THE PRESSURE TO ADAPT TO A NEW
HOST OR TO ESCAPE FROM
PRE-EXISTING IMMUNITY OR IN THE
TOPIC OF TODAY, TO ESCAPE FROM
IT ANTIVIRAL DRUG TREATMENT.
BECAUSE THEY LIVE IN THIS SORT
OF QUASI SPECIES POOL SO THAT IT
HAS SOME ERRORS IN IT COMPARED
TO ITS NEIGHBOR, YOU CAN FIND
MUTATIONS AT BASICALLY EVERY
NUCLEOTIDE IN THE POOL OF
INFLUENZA VIRUSES.
IT'S AS EASY TO ACQUIRE
MUTATIONS.
WITH SUCH A HIGH ERROR RATE.
SO ONE OF THE FIRST PROBLEMS
FACING INFLUENZA AS A PUBLIC
HEALTH PROBLEM IS THE FACT THAT
INFLUENZA VIRUSES ARE PATHOGENS
OF A VERY LARGE NUMBER OF WARM
BLOODED ANIMAL SPECIES, IT'S
THOUGHT THAT WHILE BIRDS LIKE
THESE DUCKS AND OTHER AQUATIC
WATER FOWL ARE THE NATURAL
RESERVOIR OF INFLUENZA VIRUSES
WHERE THEY TEND TO BE G.I.
RATHER THAN RESPIRATORY VIRUSES,
THEY'RE SHED ANATOMICALLY THERE,
AND THESE VIRUSES CAN CIRCULATE
IN HUNDREDS OF SPECIES OF WILD
BIRDS, BUT ALSO HAVE THE ABILITY
TO CAUSE INFECTIONS NOT JUST --
BUT STABLY ADAPTING TO DIFFERENT
HOST SPECIES, EITHER DOMESTIC --
BUT ALSO VARIOUS MAMMALIAN
SPECIES INCLUDING MAMMALS VERY
IMPORTANT TO US AGRICULTURALLY
AND ECONOMICALLY LIKE HORSES,
PIGS, DOGS, ET CETERA.
AND IMPORTANTLY, THESE VIRUSES
HAVE THE ABILITY TO ADAPT TO
HUMANS.
SO NEW INFLUENZA VIRUSES HAVE
NEW STRAINS FOR WHICH THERE IS
LITTLE POPULATION IMMUNITY, POP
UP OCCASIONALLY IN HUMANS
AVERAGING ABOUT EVERY 40 YEARS
OR SO, ALTHOUGH -- AND IF A
STRAIN THAT IS IMMUNE LOGICALLY
LOGICALLY -- ABILITY TO SPREAD
PERSON TO PERSON, YOU CAN CREATE
A SITUATION THAT WOULD CAUSE A
PANDEMIC.
THESE PANDEMICS HAVE BEEN
OCCURRING FOR HUNDREDS IF NOT
THOUSANDS OF YEARS, THERE HAVE
BEEN FOUR IN THE LAST HUNDRED
YEARS FOR WHICH WE HAVE SOME
GENETIC INFORMATION.
THE WORST ONE ON RECORD, THE
1918 SPANISH FLU, WHICH RESULTED
IN OVER 600,000 DEATHS IN THE
UNITED STATES AND UP TO PERHAPS
50 MILLION DEATHS GLOBALLY WITH
AN H1N1 VIRUS.
SUBSEQUENT TO THAT, THERE HAVE
BEEN PANDEMICS IN IT 1957 AND
'68 WITH THE REPLACEMENT -- TO
H2N2 AND H3N2 AND THEN
H1N1 VIRUSES OF THE 1918 LINEAGE
RECIRCULATED AGAIN STARTING IN
1977, THEN IN 2009, A NEW FLAVOR
OF H1N1 APPEARED, WHICH WAS
SWINE ORIGIN VIRUS, PANDEMIC
H1N1 VIRUS A COUPLE YEARS AGO.
WHILE THERE'S A LOT OF OF
CONCERN ABOUT PANDEMIC VIRUSES,
SEASONAL INFLUENZA VIRUSES
CONTINUE TO BE A MAJOR PROBLEM.
AND IN FACT, ANNUAL DEATH RATES
TO SEASONAL INFLUENZA VIRUSES
CAN BE HIGHER THAN THE MORTALITY
IMPACT OF PANDEMIC VIRUSES.
THE 1918 VIRUS IS CERTAINLY A
VERY SEVERE OUTBREAK, BUT
SEASONAL FLU IS A HUGE PROBLEM,
AND IN THE UNITED STATES, AS
MANY AS 49,000 PEOPLE DIE IN ONE
YEAR OF THE FLU, IT'S QUITE
VARIABLE, BUT THERE HAVE BEEN
YEARS WHERE THE MORTALITY RATE
OF SEASONAL FLU AS I SAID IS
HIGHER THAN THE IMPACT OF
PANDEMIC WITH THE EXCEPTION OF
1918, WHICH STANDS OUT BY
ITSELF.
SO I INFLUENZA IS A PROBLEM, A
MULTIFACETED PROBLEM AND TRYING
TO PREVENT AND DEAL WITH THE
CONSEQUENCES OF THESE INFECTIONS
ARE IMPORTANT PUBLIC HEALTH
CONSEQUENCES AND IMPORTANT
AGRICULTURAL PROBLEMS AS WELL.
SO JUST TO LOOK BRIEFLY AT THE
AMAZING ABILITY OF INFLUENZA
VIRUSES TO EVOLVE, I JUST SHOWED
YOU A BIT OF A TREE OF SOME
HUMAN ISOLATES OVER ABOUT A
10-YEAR PERIOD.
CAN YOU -- YOU CAN PRETTY
RELIABLY DATE VERY ACCURATELY BY
YEAR.
SO YOU CAN SAY THIS IS A 2002
VIRUS AND THIS IS A 2001 VIRUS,
AND A 2000 VIRUS.
THIS AMOUNT OF INCREDIBLE
PLASTICITY IN THE GENOME AND THE
ABILITY OF THE VIRUS TO NOT JUST
RANDOMLY MEU TAKE BUT IN THIS
CASE TO ACQUIRE MUTATIONS THAT
CHANGE CODING SEQUENCES ON THE
SURFACE OF THE GLOB LAR HEAD OF
THE -- SO THAT PRE-EXISTING
ANTIBODIES ARE NO LONGER
NEUTRALIZING ALLOW THE VIRUS TO
ESCAPE, WHICH IS WHY THE
INFLUENZA VIRUS VACCINE HAS TO
BE REFORMULATED EVERY YEAR TO
KEEP UP WITH THIS DRIFT.
THIS CHART SHOWS THE NUMBER OF
SIGNIFICANT CHANGES THAT OCCUR
TO THE H3 -- OVER ITS 30 YEARS,
EACH ONE REFLECTED A STRAIN
CHANGE IN THE VACCINE.
SO JUST KEEPING UP WITH
INFLUENZA EVOLUTION AND
PRODUCING VACCINES FOR SEASONAL
FLU IS A HUGE PROBLEM.
MUCH -- NOT EVEN TAKING INTO
ACCOUNT THE UNEXPECTED EMERGENCE
OF A PANDEMIC VIRUS FOR WHICH WE
DO NOT HAVE A VACCINE, IN WHICH
THERE WOULD BE A LAG OF SEVERAL
MONTHS TO PRODUCE A VACCINE.
SO THE BEST WAY TO PREVENT -- TO
TREAT INFLUENZA IS TO PREVENT IT
BY VACCINATION, NOT ANTIVIRAL
TREATMENT, BUT THERE ARE
PROBLEMS WITH THE VACCINES SO
NOT EVERY YEAR'S VACCINE IS A
PERFECT MATCH TO THE VIRUSES
CIRCULATING.
PANDEMICS OCCUR IN WHICH THERE
WOULD BE A DELAY OF AT LEAST SIX
OR EIGHT MONTHS PF VACCINES ARE
AVAILABLE, BUT EVEN IF
EVERYTHING IS WELL MATCHED, THE
VACCINE IS NOT COMPLETELY
EFFICACIOUS AND ESPECIALLY
PEOPLE WHO ARE IMMUNOCOMPROMISED
AND THE ELDERLY MAY NOT HAVE
SUCH A GOOD RESPONSE TO THE
VACCINE THAT THEY ARE NOT
PROTECTED, AND SO THE FUTURE
GOAL IS TO MAKE BETTER VACCINES,
MORE BROADLY REACTIVE ARE
UNIVERSAL VEAK SEEN VACCINES THAT WOULDN'T
REQUIRE REFORMULATION EVERY
YEAR, BUT PEOPLE IN WHOM VACCINE
IS EITHER UNAVAILABLE OR HAS NOT
BEEN EFFECTIVE, THE BEST
STRATEGY IS THE USE OF ANTIVIRAL
DRUGS.
TYPICAL CASES OF INFLUENZA ARE
SELF LIMITED AND FOR MOST PEOPLE
WHO GET INFECTED WITH INFLUENZA,
YOU MAY BE SICK AS A DOG FOR A
WEEK AND FEEL REALLY, REALLY
TERRIBLE, BUT YOU'RE GOING TO
GET BETTER AND YOU DON'T NEED
ANTIVIRAL TREATMENT OR
ANTIBIOTIC TREATMENT, BUT PEOPLE
WHO HAVE UNDERLYING
CO-MORBIDITIES, HEART DISEASE,
PULL KNOW MARPULMONARY DISEASE, CANCER,
DIABETES, OTHER CO-MORBIDITIES,
CAN GET MORE SEVERE INFECTIONS
THAT RESULT IN SEVERE AND
LIFE-THREATENING INFLUENZA
INFECTIONS, OFTEN FOLLOWED BY
SEVERE AND LIFE-THREATENING
SECONDARY BACTERIAL PNEUMONIA.
SO IN THE FUTURE, WE NEED BETTER
ANTIINFLUENZA DRUGS, AND I WILL
SHOW YOU WHERE WE ARE AND WHERE
I THINK WE NEED TO GO.
SO I THINK THAT THERE ARE REALLY
SORT AFTER TRIPARTATE VIEW OF
THE FACTORS IN SEVERE AND FATAL
INFLUENZA INFECTION.
THE FIRST ONE IS THAT VIRAL
FACTORS, CERTAIN VIRUSES ARE
JUST INHERENTLY MORE PATHOGENIC
THAN OTHERS.
THE 1918 VIRUS WAS JUST A VERY
PATHOGENIC VIRUS.
IT WAS PATHOGENIC IN HUMANS,
IT'S PATHOGENIC WITHOUT
ADAPTATION IN A NUMBER OF
ANIMAL -- EXPERIMENTAL ANIMAL
MODEL SYSTEM.
THERE ARE HOST FACTORS INCLUDING
PARTICULARLY THE INFLAMMATORY
RESPONSE TO SEVERE INFLUENZA
INFECTIONS IN WHICH THE
INFLAMMATORY RESPONSE ITSELF
BECOMES PART OF THE PROBLEM AND
YOU GET AN IMMUNOPATHOGENESIS IN
WHICH YOU ARE ACTUALLY DAMAGING
RESPIRATORY EASY PAY THEEL YAL
CELLS IN THE LUNG BECAUSE OF THE
INFLAMMATORY RESPONSE, AND THEN
SECONDARY BACTERIAL PNEUMONIA
HAS COME IN AS THE SORT OF FINAL
STRAW THAT OFTEN LEADS TO A
FATAL INFECTION.
SO INTERVENING IN ALL THREE OF
THESE SPOTS IS PROBABLY
IMPORTANT IN TREATING INFLUENZA
UNDER DIFFERENT CONDITIONS.
SO MOST OF THE EFFORT OVER THE
PAST DECADES HAS BEEN TO DEVELOP DEVELOP
DRUGS TO PREVENT REPLICATION, SO
WE'LL START THERE.
THERE ARE TWO CLASSES OF
ANTIVIRAL ANTIINFLUENZA DRUGS
THAT ARE APPROVED AND EACH OF
THEM HAVE TWO APPROVED DRUGS
EACH IN THE UNITED STATE.
THEY'RE THE OLDER ADAMANTANE
FROM THE 1960s AND 70s WHICH
ARE CHANNEL BLOCKER, THEN THERE
ARE THE NEWER DRUGS, THE
NEURAMINIDASE INHIBITORS FROM
THE 90s.
JUST TO CUT TO THE CHASE,
MANY -- OR THE VAST MAJORITY OF
RECENT H3N2 VIRUSES CIRCULATING
ARE RESISTANT TO THE ADD MAN
TAIN, AND SEASONAL H1N1 VIRUSES
FROM ABOUT 2007, BEFORE THE
PANDEMIC, BECAME NEARLY 100%
RESISTANT TO OSELTAMIVIR.
THOSE SWINE VIRUSES WERE ALREADY
RESISTANT BUT THEY WERE
SENSITIVE ALSO.
BRIEFLY, THE TH VIRUS IS TAKEN UP
INTO THE CELL, INTO THE ENDOSOME
WHERE HA HAS ITS SECOND FUNCTION
TO FUSE WITH THE MEMBRANE, THE
GUTS OF THE VIRUS, THE GENES OF
THE VIRUS, THE RNP WHICH HAS TO
DISASSOCIATE WITH THE NECESSITY
OF LOWERING THE PH INSIDE AND
THAT'S WHERE THE CHANNEL COMES
INTO PLAY.
THE RNP GOES INTO THE NUCLEUS,
REPLICATION OCCURS IN THE
NUCLEUS, PACKAGED, CLEAVES THE
BUDDING BARS ON THE WAY OUT.
SO THE TWO DRUGS THAT ARE
APPROVED OR RELATIVELY EARLY
STAGE, THE M2 AT EARLY STAGE,
BEFORE THE VIRAL GENES ARE
COPIED AND THE N O -- IN A SENSE
AFTER MOST OF THE DAMAGE HAS
BEEN DONE, WHICH IS THE RELEASE
OF VIRAL PROJECT DEFRO VIRAL PROGENY FROM THE
SURFACE OF THE SELL.
SO THE M2 PROTON PUMPS PROTONS
FROM THE ENDOSOME -- ALLOWING
THE RNP TO TRANSLOCATE TO THE
NUCLEUS, WHERE THEY UNDERGO
REPLICATION, SO THE ADAMANTANE
DRUGS, CHANNEL BLOCKERS,
LITERALLY KIND OF PLUG UP THIS
PORE AND BLOCK THIS PROTON PUMP
WHICH, IF IT WORKED, STOPPED THE
REPLICATION AT THIS EARLY STAGE.
THE DRUGS, THE CLASS OF
ADAMANTANES, HAVE THE VERY
INTERESTING SORT OF CAGE-LIKE
CUBICAL STRUCTURE, AND THEY SIT
IN HERE IN THIS CORE.
UNFORTUNATELY SOMETHING THAT'S
BEEN KNOWN FOR DECADES IS THAT
RESISTANCE TO THESE DRUGS
DEVELOP VERY QUICKLY.
IF YOU LOOK AT PATIENTS WHO ARE
TREATED WITH ADAMANTANE VERY
QUICKLY, THEY DEVELOP
RESISTANCE, SO IT LIMITS THE
UTILITY OF THESE DRUGS.
THERE ARE A NUMBER OF PARTICULAR
MUTATIONS WHICH DEVELOP, BUT ONE
OF THE MORE COMMON ONES IS A
MUTATION AMINO ACID -- WHICH
REQUIRES A CHANGE THAT ALLOWS IT
TO REMAIN FUNCTIONAL BUT THE
RESISTANCE TO BOTH AMANT DEAN
AND -- SO IN WORK DONE BY MY
COLLEAGUES AT THE FOGARTY --
THEIR COLLEAGUES, THEY WERE ABLE
TO DO ANALYSES OF H3N2 VIRUSES
IN THE EARLY PART OF THIS PAST
DECADE TO SHOW THAT IN THIS
STUDY, THAT ADAMANTANE RESISTANT
MUTATIONS IN THE M2 GENE
OCCURRED AT LEAST 11 TIMES
INDEPENDENTLY.
MOST OF THEM WERE JUST SHORT
LIVED, THEY DIDN'T SPREAD, BUT
THAT IN ABOUT 2003, A LINEAGE
OCCURRED THAT DEVELOPED AD DEVELOP -- IT H AD
BEEN REASSORTED WITH AN HA THAT
HAD ANTIGENICALLY VARIANT
HEMOGLUTE NIN, SELECTED FOR
BECAUSE THERE WAS IMMUNOLOGIC
PRESSURE TO ESCAPE.
IT CARRIED THAT MATRIX ALONG
WITH IT THAT HAD ADAMANTANE
RESISTANCE.
SO IT WAS KIND OF A SELECTIVE
SWEEP IN WHICH MOST WERE
RESISTANT TO ADAMANTANE BUT
ALMOST NONE OF THOSE PATIENTS
WERE TREATED WITH THE DRUG.
SO I WOULD CALL THIS KIND OF A
HITCHHIKER MUTATION.
SO THE DRUG PRESSURE CAUSED THE
MUTATION TO OCCUR IN A
PARTICULAR VIRUS.
THAT VIRUS ITSELF, THE DRUG
PRESSURE WAS NOT THE PRESSURE
THAT SELECTED FOR THAT VIRUS
BEING AMPLIFIED IN THE
POPULATION.
BUT ITS RELATIONSHIP WITH
ASSORTMENT OF -- ALLOWED THAT
ADAMANTANE RESISTANCE TO SPREAD
GLOBALLY SO THAT THE MAJORITY OF
THE VIRUSES IN 2007 AND
THEREAFTER WERE
ADAMANTANE-RESISTANT.
SO THE NEWER CLASS OF INFLUENZA
ANTIVIRALS TARGET THE
NEURAMINIDASE, H.A. IS TRIMERIN
PLAYS A ROLE IN BINDING, AS I
SAID, AND FUSION, AND THE N.A.
PLAYS BASICALLY THE OPPOSITE
ROLE, WHICH IS RELEASE OF THE
VIRUS FROM -- BUDDING BARS FROM
THE INFEK TANT.
AND EXPRESSED AS A TETRAMER,
KIND OF LIKE A MUSHROOM-SHAPED
STRUCTURE, THIS IS LOOKING DOWN
ON THE CRYSTAL STRUCTURE, EACH
ONE CONTAINS -- AND THE
INHIBITORS WERE DESIGNED TO
BLOCK THIS N.A. FUNCTION.
SO RATHER THAN BEING ABLE TO
RELEASE PROGENY VIRUS, THE
INHIBITOR, WHEN PRESENT, CAN ACT
AS A COMPETITIVE INHIBITOR,
PREVENTING RELEASE AND LIMITING
THE SPREAD OF VIRUS.
THIS IS A COMPETITIVE INHIBITOR,
THE SUGAR ON THE TIP OF THE
GLYCOPROTEINS, WHICH IS CLEAVED
OFF BY THE -- AND YOU CAN SEE
THAT THE ORALLY AVAILABLE TAM
VEER AND -- ARE STRUCTURAL -- OF
SIALIC ACID AND BIND INTO THIS
POCKET.
AND BECAUSE THEY WERE BINDING
INTO THE ENZYME ACTIVE SIDE AS
COMPETITIVE INHIBITORS AND
DESIGNED AS -- FROM THE KNOWN
STRUCTURE AND FUNCTION OF THE
ENZYME, THE RATIONALE WAS THAT
MUTATIONS WOULD OCCUR BUT THEY
WOULD BE ATTENUATING, SINCE
YOU'D BE ATTENUATING ENZYMATIC
ACTIVITY NECESSARY FOR VIRAL
FUNCTION.
THAT WAS CERTAINLY THE CASE, AND
WHEN THESE DRUGS WERE TESTED
BOTH IN THE LABORATORY AND THEN
IN CLINICAL TESTING, THAT WAS
THE RESULT THAT WAS OBSERVED.
BUT AN INTERESTING THING THAT
HAPPENED IS THAT SEASONAL
H1N1 VIRUSES ULTIMATELY DERIVED
FROM THE 1918 FLU, IN ABOUT 2005
AND 2006, STARTED TO CIRCULATE
THAT IT HAD ACQUIRED OSELTAMIVIR
RESISTANCE, AND THEY HAD
ACQUIRED A PARTICULAR MUTATION
IN THE ENZYME ACTIVE SITE, AND
THAT BECAME FIXED, AND THESE
VIRUSES WERE NOT' 10 WAITED.
AND WHAT HAPPENED WAS SOMETHING
VERY SIMILAR TO THE ADAMANTANE
STUDY, WORKED ON BY JESSE BLOOM
AND DAVID BALTIMORE AND THEIR
COLLEAGUES SHOWED A SIMILAR
FEATURE, WHICH WAS THAT
MUTATIONS OCCURRED IN THE N1NE
N1NE -- PRIOR TO THE EMERGENCE
OF OSELTAMIVIR -- THE H275Y
OCCURRED BECAUSE OF DRUG
PRESSURE, IT WAS NO LONGER' 10
WAITING IN THE VIRUS.
SO ONCE THAT HAPPENED, AND THOSE
CHANGES PROBABLY OCCURRED AGAIN
BY ANTIGENIC DRIFT OF THE NEUR
NEURA -- SO WHILE THIS MUTATION
LIKELY OCCURRED IN THE PRESENCE
OF OSELTAMIVIR USE, ITS
SELECTION AND THEN PURIFYING
SELECTION IN THE POPULATION SO
THAT NEARLY 100% OF VIRUSES
THEREAFTER WERE NOT DUE TO
CONTINUED USE OF IT IN THE
POPULATION, BUT TO OTHER
FEATURES THAT WERE SELECTED FOR.
SO AGAIN, THE ANTIVIRAL
MUTATIONS SORT OF BY HITCHHIKER.
SO UNFORTUNATELY, THE SITUATION
BEFORE 2009 WHICH IS THAT THE
TWO CIRCULATING STRAINS, H1N1s
WERE RESISTANT AND -- CERTAINLY
LIMITS OUR -- FOR INFLUENZA
VIRUS ANTIVIRALS.
SO I'M JUST GOING TO SHOW YOU
SOME PATIENT-RELATED DATA FROM
OUR STUDIES HERE AT THE NIH
CLINICAL CENTER.
TO SHOW YOU THE IMPACT OF
ANTIVIRALS ON DIRECT PATIENT
CARE.
SO MY GROUP BE HAS BEEN RUNNING
CLINICAL INFLUENZA RESEARCH
STUDIES IN THE LAB THE LAST
SEVEN OR EIGHT YEARS AND ONE OF
THOSE STUDIES IS A NATURAL
HISTORY STUDY IN WHICH WE
RECRUIT PATIENTS INFECTED WITH
INFLUENZA, ONCE WE RECRUIT THEM
INTO OUR STUDY, THEY'RE TREATED
BY STANDARD OF CARE, BUT THEN WE
DO DAILY NATAL WASH ON THEM,
SEQUENCE ANALYSIS, DEEP
SEQUENCING, FOLLOW UP WHAT'S
HAPPENING TO THE VIRUS AS
THEY'RE INFECTED, RATHER THAN
JUST GETTING ONE INITIAL
DIAGNOSTIC SPECIMEN.
AND MANY OF THE PATIENTS TREATED
HERE AT THE NIH ARE IMMUNOCROW
MIEZED WITH CANCER OR OTHER
IMMUNODEFICIENCIES, AND MANY OF
THE PATIENTS WE'VE SEEN WITH
IMMUNODEFICIENCIES HAVE VERY
EXTENSIVE INFLUENZA INFECTIONS
THAT LAST MUCH LONGER THAN THE
FIVE TO SEVEN DAYS THAN A NORMAL
PERSON WOULD HAVE, SOMETIMES FOR
WEEKS, EVEN MONTHS, THEY CAN
SHED INFLUENZA VIRUS.
MANY OF THESE PATIENTS ARE
TREATED WITH ANTIVIRALS FOR A
VERY LONG TIE LONG TIME.
THIS IS A SITUATION WHERE THE
PATIENT CAN'T CLEAR THE
INFECTION BECAUSE THEIR IMMUNE
RESPONSE IS INADEQUATE, THE
PRESSURE BEING APPLIED TO THIS
VIRUS IS ANTIVIRAL RESISTANCE.
WE'VE SEEN THE RAPID DEVELOPMENT
OF ANTIVIRAL RESISTANCE IN BOTH
H1 AND H3 STRAINS IN
IMMUNOCOMPROMISED PATIENTS.
SO FIRST EXAMPLE, A PATIENT WHO
WAS BEING TREATED HERE AT THE
CLINICAL CENTER A FEW YEARS AGO
WITH LYMPHOMA WHO HAD A STEM
CELL TRANSPLANT, SEVERELY
IMMUNOCOMPROMISED, DEVELOPED
INFLUENZA, WAS IN THE HOSPITAL,
WAS BEING TREATED FOR OTHER
MEDICAL PROBLEMS BUT THEN WAS
BEING TREATED FOR HIS INFLUENZA,
AND RECEIVED TAMIFLU BY STANDARD
DOSE BUT LONGER THAN FIVE DAYS.
HE WAS EVENTUALLY ABLE TO CLEAR
HIS INFLUENZA INFECTION, BUT
BECAUSE WE WERE DOING DAILY
NASAL WASH, WHEN WE SEQUENCED
EVERY DAY, THIS PATIENT ON DAY
FIVE OR SIX DEVELOPED AN IN
FRAME MUTATION OF FOUR AMINO
ACIDS, 12 KNE NUCLEOTIDE DELETION,
VERY NEAR THE ACTIVE SITE.
THIS MUTATION HAD NOT BEEN
DESCRIBED BEFORE AND INTO
SUBTYPE VIRUSES.
AND WE THOUGHT THIS WAS QUITE
INTERESTING.
WHEN WE EVALUATED THIS IN THE
LAB, WE FOUND THAT THE VIRUS
WITH THE MUTATION ACQUIRED A
HUGE A RESISTANCE TO -- THAT IT
TOOK MORE THAN 2,000 TIMES TO
INHIBIT THE VIRUS IN VITRO THAN
THE -- VIRUS.
IT ALSO HAD A SIGNIFICANT
REDUCTION OF EFFICACY -- EVEN
THOUGH THE PATIENT -- SINCE IT
WAS AN H3 VIRUS, IT ALSO WAS
ALREADY RESISTANT TO ADAMANTANE,
SO WE HAD A VIRUS THAT WAS
RESISTANT TO ALL FOUR AVAILABLE
DRUGS AND WHAT WE HOPED WAS THAT
THIS VIRUS WAS ATTENUATED.
UNFORTUNATELY WHEN YOU PUT IT
INTO THE BEST MODEL, WE HAVE
SPIR MENTAL MODELS OF INFLUENZA
INFECTION, WHICH ARE FERRETS, WE
FIND IT REPLICATED I'DICALLY TO
THE WILD TYPE VIRUS, INCLUDING
ITS ABILITY TO TRANSMIT FROM ONE
TO THE OTHER, SO THERE WAS NO
DIFFERENCE IN TERMS OF THE
ABILITY TO REPLICATE, CAUSE
DISEASE OR TRANSMIT, SO WHAT WE
HAVE IS A PAN RESISTANT
INFLUENZA VIRUS THAT PRESUMABLY
IS COMPLETELY FIT.
NOW, LUCKILY FOR US, WE HAVE NO
EVIDENCE THIS VIRUS SPREAD AND
THAT THERE WAS NO SELECTIVE
ADVANTAGE FOR THIS VIRUS TO
SPREAD, THAT IS, IF ANOTHER
PERSON WAS INFECTED WITH THIS
VIRUS AND HAD A SELF LIMITED
INFECTION AND DIDN'T REQUIRE
ANTIVIRALS, THERE WOULD BE NO
REASON FOR THIS PARTICULAR VIRUS
TO SURVIVE BECAUSE IT DIDN'T
HAVE DRIFT PRESSURE OR OTHER
THINGS, BUT THIS SHOWS YOU THE
ABILITY IN JUST A FEW DAYS FOR A
VIRUS TO BECOME RESISTANT TO
EVERYTHING WE COULD THROW AT IT.
WHEN THE 2009 PANDEMIC APPEARED,
WE SAW A VERY SIMILAR THING.
SO I SHOW YOU TWO PATIENTS, BOTH
FROM OCTOBER 2009, SORT OF AT
THE HEIGHT OF THE PANDEMIC HERE
AT THE CLINICAL CENTER, BOTH OF
THEM ALSO WITH CANCERS AND
IMMUNODEFICIENT, AND THEY BOTH
SHED VIRUS FOR A VERY LONG TIME,
AND THEY WERE BOTH TREATED WITH
ANTIVIRAL DRUGS FOR A VERY LONG
TIME.
PATIENT B BECAME VERY CRITICALLY
ILL AND WAS IN THE CRITICAL CARE
UNIT FOR A LONG TIME, AFTER IT
BECAME CLEAR THEY WERE CLINICAL
RESISTANT, EXEMPTION WAS GRANTED
TO TREAT THEM WAN EXPERIMENTAL
ANTIVIRAL WHICH IS NOT LICENSED,
PATIENT WAS TREATED 10 DAYS FOR
THAT THEN TREATED WITH
INHALED -- ONCE THEY WERE
EXTUBATED.
IN THESE TWO CASES, THEY BOTH
DEVELOPED THIS MUTATION 275, THE
MUTATION WITHIN ONE TO TWO
WEEKS, NINE OR 14 DAYS AFTER
TREATMENT, AND THEY BOTH
DEVELOPED, AGAIN, SEVERE
EVIDENCE OF IN VITRO RESISTANCE
TO THESE DRUGS BY VARIOUS
ASSAYS, HUNDREDS OF FOLD CHANGE
IN THEIR SENSITIVITY TO THESE
DRUGS.
THIS WAS THE FIRST EVIDENCE OF
CLINICAL RESISTANCE TO PARAMAVIR
RECORDED IN INFLUENZA, USING A
MOLECULAR ASSAY TO LOOK AT WILD
TYPE OR RESISTANT VIRUSES, WE
WERE ABLE TO SEE ADDITIONAL
ISOLATES, THERE WAS NO
EVIDENCE -- OF THE MUTATION THAT
IN PATIENT B BY DAY NINE, IT WAS
IN ABOUT EQUAL MEASURE 50-50
BETWEEN WILD TYPE AND MUTANT
VIRUS, THROUGH DAY 17, ONLY THE
RESISTANT VIRUS AND NO EVIDENCE
OF WILD TYPE SEQUENCE PRESENT.
UNFORTUNATELY LIKE THE CASE WITH
H3N2, THESE 2009 PANDEMIC
VIRUSES LIKE THEIR SEASONAL
H1N1 VIRUSES ACQUIRING THIS NA
MUTATION WERE NOT ATTENUATED IN
THEIR ABILITY TO CAUSE DISEASE,
REPLICATE OR TRANSMIT BETWEEN
FERRETS.
THE PATHOLOGY THAT THEY INDUCED
WAS IDENTICAL, THEY BOTH INDUCED
VIRAL PNEUMONIA AS EVIDENCED BY
THE ACUTE WRON BRONCHIOLEITIS.
FRED HAYDEN HAS RECENTLY WRITTEN
A VERY NICE REVIEW ON NEW DRUGS
THAT ARE IN VARIOUS STAGES OF
RESEARCH AND INVESTIGATION IN
THE PIPELINE, THIS ARTICLE WAS
AVAILABLE ONLINE.
THIS VERY LONG LIST OF
INVESTIGATIONAL ANTIVIRALS,
LOOKING AT ALL STAGES OF VIRAL
REPLICATION FROM A BLOCKING HA
BINDING TO TARGET CELLS TO
INHIBITING ALL DIFFERENT STAGES
OF REPLICATION, ARE BEING
INVESTIGATED IN THE LABORATORY.
THE QUESTION IS, WHICH, IF ANY,
OF THESE DRUGS COULD ACTUALLY
MAKE IT TO MARKET IS UNCLEAR.
THERE ARE SOME DRUGS THAT ARE
FURTHER ALONG IN PHASE 2 AND
PHASE 3 TRIALS.
THERE ARE DIFFERENT INBE HIB
TORES FOR WHICH RESISTANCE
MUTATIONS MIGHT BE SUDDENLY
DIFFERENT BUT ONE OF THEM,
PERAMIVIR IS THE ONE THAT
WHEN -- TREATMENT OCCURRED IN
SOME OF OUR PATIENTS AND THEN --
THEY DEVELOPED CLINICAL
RESISTANCE TO PERAMIVIR, SO --
UNCLEAR, AT LEAST FOR
H1N1 VIRUSES.
THERE ARE LONG ACTING AND OTHER
DRUGS THAT ARE BEING EVALUATED.
IF YOU WANT MORE INFORMATION ON
THESE NEW DRUGS, THIS IS A NICE
REVIEW FOR YOU TO LOOK AT.
LET ME -- THE LAST PART OF THE
TALK, TURN TO THE OTHER TWO
FACTORS THAT CAN RESULT IN
SEVERE DISEASE WITH INFLUENZA.
LET ME TALK ABOUT INFLAMMATORY
RESPONSE FACTORS OF THE HOST AND
THE POSSIBILITY OF TARGETING
SEVERE INFECTION NOT BY
TARGETING THE VIRUS, BUT BY
TARGETING THE INFLAMMATORY
RESPONSE.
THE 1918 VIRUS HAS AS ONE OF ITS
FEATURES THE ABILITY TO INDUCE
DISEASE IN VARIOUS ANIMALS
WITHOUT PRIOR ADAPTATION, A VERY
SEVERE PANDEMIC IN HUMANS, BUT
ONE OF THE FEATURES IS THAT YOU
SEE IN ALL OF THESE ANIMAL
SPECIES IS PROFOUND UPREGULATION
OF A PRO INFLAMMATORY RESPONSE,
INCLUDING PRO I INFLAMMATORY GENES
COMPARED TO LESS PATHOGENIC
VIRUSES LIKE SEASONAL
H1N1 VIRUSES.
SO ONE OF THE FACTORS THAT WE
SEE IS A LOT OF NUTRAPHILS, WE
FORMED A COLLABORATION IN WHICH
WE WANTED TO LOOK AT THE
POSSIBILITY OF TREATING SEVERE
INFLUENZA INFECTION NOT BY
TARGETING THE VIRUS BY BY
TARGETING A PART OF THE
INFLAMMATORY RESPONSE, IN THIS
CASE, THE ROS RESPONSE, AND SO
THE CHOICE WAS GIVEN TO -- MAN -- SO
INTERESTINGLY, IF MICE GIVEN A
LETHAL INJECTION -- TREATED WITH
THE DRUG HAD A MARKED DIFFERENCE
IN SURVIVAL ANTHOLOGY IN THE
TREATED ANIMALS, MUCH LESS
EVIDENCE OF R OSM S DAMAGE AND
MUCH LESS EVIDENCE OF APOP
PTOSIS.
IT DIDN'T AFFECT -- AT ALL AND
BY DEEP SEQUENCING, THERE WERE
NO VIRAL -- SEE MUTATIONS SEEN AFTER
EIGHT DAYS.
YOU'RE TREATING PART OF THE
INFLAMMATORY RESPONSE THAT YOU
CAN SAVE MICE WITH LETHAL
INFECTION SO THEY CAN GET PAST
THE INITIAL DAMAGE TO CLEAR
THEIR VIRAL INFECTION.
FINALLY LET ME TALK ABOUT
BACTERIAL FACTORS.
OF COURSE ANTIBIOTICS ARE USED
TO TREAT BACTERIA, AND ONE OF
THE THINGS THAT DR. FAUCI
MENTIONED WAS THE FACT THAT WHEN
PEOPLE GET A VIRAL INFECTION
LIKE INFLUENZA, THEY WANT
ANTIBIOTICS, WHICH OF COURSE
THEY DON'T NEED.
BUT THERE ARE PATIENTS WHO DO
NEED ANTIBIOTICS, THOSE PATIENTS
WHO DEVELOP SECONDARY BACTERIAL
PNEUMONIA REALLY DO NEED
ANTIBIOTICS, THE KEY FOR
CLINICIANS IS TO DETERMINE WHO
OF THE SUBSET OF PATIENTS NEEDS
ANTIBIOTIC THERAPY AND MAKING AN
EARLY DIAGNOSIS AND APPROPRIATE
INTERVENTION BEFORE A SERIOUS
AND LETHAL INFECTION CAN OCCUR.
IN 1918, A METADATA ANALYSIS OF
OVER 8,000 AUTOPSIES THAT WERE
PUBLISHED AT THE TIME OF THE
PANDEMIC SUGGESTS THAT OVER 95%
OF THEM HAD SECONDARY BACTERIAL
PNEUMONIAS AT THE TIME OF THEIR
DEATHS.
AND YOU THINK THIS WAS IT BEFORE
ANTIBIOTICS WERE USED SO THAT
SORT OF MAKES SENSE.
WELL, SECONDARY BACTERIAL
PNEUMONIAS CONTINUE TO BE THE
MAJOR REASON FORCIER JUST
ILLNESS AND DEATH IN INFLUENZA
INFECTION EVEN TODAY.
WHILE IN 1918, IN THE AUTOPSIES,
YOU CAN SETONS O SEE TONS -- GROUP A --
AND STAPH.
YOU CAN SEE THE SAME INFECTIONS
TODAY IN HOSPITALS ACROSS THE
COUNTRY OF PEOPLE WHO GET AN
INFLUENZA INFECTION WHO HAVE
UNDERLYING CO-MORBIDITIES, THEN
DEVELOP SECONDARY BACK TIER YOUR
PNEUMONIAS.
IN STUDIES OF THE 2009 PANDEMIC
AUTOPSY STUDY DONE IN THE FIRST
COUPLE MONTHS AFT EMERGENCE OF
THE PANDEMIC IN 2009, THE
MAJORITY OF PATIENTS DIED WITH
SECONDARY BACTERIAL PNEUMONIAS,
EVEN THOUGH ALMOST ALL OF THEM
WERE TREATED WITH BROAD SPECTRUM
ANTIBIOTICS, INCLUDING MRSA
INFECTIONS, AND WE HAD SEVERAL
COMMUNITY ACQUIRED MRSA
INFECTIONS.
THIS PARTICULARLY TRAGIC CASE IN
A 2-YEAR-OLD CHILD WHO GOT THE
FLU AND THEN DEVELOPED A MRSA
PNEUMONIA WITH ABSCESS
FORMATION, ANECK ADVERTISING
PNEUMONIA IN THE LUNG.
COMMUNITY ACQUIRED, NOT IN THE
HOSPITAL.
SO THERE'S BEEN MUCH WORK DONE
IN MY GROUP, AND THEIR
COLLEAGUES, DOING A NUMBER OF
EXPERIMENTS PLUS A NUMBER OF
LABS ACROSS THE WORLD LOOKING AT
THE ROLE OF SECONDARY BACTERIAL
PNEUMONIAS IN FOLLOWING VIRAL
INFECTIONS, AND WHILE THIS
INTERACTION IS QUITE COMPLICATED
COMPLICATED, BASICALLY ONE OF
THE TAKE-HOME MESSAGES SEEMENTS
TO BE THAT INFLUENZA VIRUSES IN
A SENSE KIND OF CLEAR A PATH FOR
SECONDARY BACTERIAL INFECTIONS
WHICH ARE EITHER GOING TO BE
ACQUIRED LOCALLY WITHIN A
HOSPITAL SETTING OR MIGHT EVEN
BE COMMENSALS BEING CARRIED IN
YOUR UPPER PHARYNX, YOU MIGHT BE
CARRYING STAPH OR MRSA, BUT ONCE
INFLUENZA VIRUSES GO THROUGH AND
CAUSE ENOUGH DAMAGE TO
RESPIRATORY EPITHELIAL CELLS IN
THE LUNGS, THEY CAN FEED THESE
BACTERIAL INFECTIONS AND YOU CAN
BE SET UP FORCIER JUST AND EVEN
FATAL BACTERIAL PNEUMONIAS.
SO IN THE LAST COUPLE MINUTES,
LET ME JUST BRING THIS TOGETHER
SO THAT INFLUENZA VIRUSES KIND
OF LIVE TO MUTATE THEIR REASON
FOR BEING IN A SENSE IS TO
MUTATE TO RESPOND TO VARIOUS
KINDS OF PRESSURES, AS I SAID
THE PRESSURES TO CHANGE HOSTS,
TO ADAPT TO NEW HOSTS, TO ESCAPE
PRE-EXISTING IMMUNITY, MORE
RECENTLY THE ABILITY TO ESCAPE
ANTIVIRAL DRUG PRESSURE.
CLEARLY, THE FOUR DRUGS THAT WE
HAVE, THE TWO CLASSES OF DRUGS
WE HAVE ARE PROVING INADEQUATE,
A AND WE NEED NEW DRUGS.
BUT I'M NOT SURE HOW CLOSE ANY
OF THESE NEW DRUGS ARE FOR
APPROVAL AND THIS IS CLEARLY AN
IMPORTANT ISSUE.
THE ROLE OF DRUGS THAT WOULD
TARGET THE INFLAMMATORY RESPONSE
IN SE INFLUENZA INFECTIONS LIKE
IN 1918 ARE NOT YET KNOWN AND
THEY'RE CERTAINLY NOTHING CLOSE
TO CLINICAL TRIALS FOR DRUGS
LIKE THIS.
AND OF COURSE THE ROLE OF
ANTIBIOTICS IS REALLY IMPORTANT.
AS I SAID, YOU DON'T WANT TO
OVERUSE ANTIBIOTICS AS DR. FAUCI
MENTIONED, BUT FOR PATIENTS WHO
ARE AT HIGH RISK FOR SECONDARY
BACTERIAL PNEUMONIA, PEOPLE WITH
UNDERLYING CO-MORBIDITIES, LUNG
DISEASE, HEART DISEASE,
IMMUNODEFICIENCY, FOR THOSE
PATIENTS, KNOWING EXACTLY WHEN
TO INTERVENE WITH ANTIBIOTICS
AND BEING AWARE CLINICALLY OF
THE IMPORTANCE OF APPLYING
SECONDARY ANTIBIOTIC PRESSURE
FOR PATIENTS WHO ARE AT RISK OF
A SECONDARY BACTERIAL PNEUMONIA
IS EXTREMELY IMPORTANT.
SO I THINK IN THE FUTURE, WE'RE
GOING TO BE -- WE NEED NEW
CLASSES OF ANTIVIRAL DRUGS,
HOPEFULLY WE'LL HAVE NEWER
CLASSES OF OTHER DRUGS THAT CAN
TARGET INFLAMMATORY RESPONSE AND
SEVERE DISEASE.
WE NEED MORE ANTIBIOTICS AND
BACTERIAL VACCINES TO REDUCE
BACTERIAL SECONDARY PNEUMONIAS
LIKE THE PNEUMONIA COULD CAL
VACCINE FOR EXAMPLE, BUT I THINK
WA WE REALLY NEED ARE BETTER
VACCINES TO STOP INFLUENZA
INFECTION IN THE FIRST PLACE.
WHAT WE NEED ARE MORE BROADLY
REACTIVE OR SO CALLED UNIVERSAL
VACCINES THAT COULD ALLOW US TO
BE BETTER PREPARED FOR BOTH THE
UNEXPECTED DRIFT CHANGES
OCCURRING IN SEASONAL FLU AS
WELL AS UNEXPECTED PANDEMICS.
SO I WILL STOP THERE.
THE PER ACTUAL CHALLENGE WITH
FLU IS SOMETHING I IT THINK WE
WILL ALWAYS FACE AND I THANK ALL
THE PEOPLE IN MY GROUP AS WELL
AS COLLEAGUES HERE AT NIH AND
ELSEWHERE WHO CONTRIBUTED TO
STUDIES I DESCRIBED HERE.
THANK YOU.
>> THANK YOU VERY MUCH, JEFF.
DO WE HAVE SOME QUESTIONS OR
COMMENTS?
YEAH.
BY THE WAY, ARE THOSE -- THE
PATIENTS WHO WERE IN THE
CLINICAL CENTER WHO WERE
SHEDDING VIRUS FOR 40, 45 DAYS,
WERE THEY CLINICALLY ILL DURING
THAT PERIOD OF TIME SO THIS
PARALLELS THEIR --
>> THAT'S AN EXCELLENT QUESTION
AND I SHOULD HAVE MADE THAT
CLEAR.
ONE OF THE INTEREST ITING THINGS
WITH THE IMMUNOCOMPROMISED
PATIENTS IS THAT THEY OFTEN STOP
HAVING ANY CLINICAL ILLNESS.
WE'VE HAD PATIENTS SHED
INFLUENZA VIRUS FOR OVER SIX
MONTHS AND NOT BE SYMPTOMATIC.
SO I THINK AGAIN, THE SYMPTOMS
RELATE TO THE INFLAMMATORY
RESPONSE, INTERFERONS AND
OTHERS, SO IF YOU'RE NOT
MOUNTING AN IMMUNE RESPONSE, IT
PROBABLY CONTRIBUTES TO A LACK
OF SYMPTOMATOLOGY.
THAT'S ACTUALLY ANOTHER ISSUE,
IS THE AWARENESS OF THE FACT
THAT AN IMMUNOEXROA NIEZED
PATIENT MAY NOT BE MANIFESTING
AN INFLUENZA-LIKE ILLNESS BUT
ACTUALLY MIGHT BE SHEDDING
VIRUS, WHICH COULD SPREAD TO
SOMEONE ELSE.
>> RIGHT.
SO WHAT I WAS GETTING TO, IS
THERE A RECOMMENDATION THEN OF
WHAT PEOPLE IN A FAMILY,
CHILDREN, OTHER -- COULD DO IF
SOMEBODY WHO HAS CANCER, FOR
EXAMPLE, GETS INFLUENZA, THEN
RECOVERS?
>> WHAT WE TRY TO DO IS TYPICAL
KIND OF RESPIRATORY PRECAUTIONS
THAT YOU WOULD DO, BUT FOR
PATIENTS WHO ARE HOSPITALIZED,
THAT HE EASIETHAT'S EASIER TO DO, BUT WHEN
THEY'RE HOME, IT'S MORE
DIFFICULT TO HAVE -- YOU CAN
ENCOURAGE PEOPLE TO WEAR MASKS,
FOR EXAMPLE, WASH THEIR HANDS,
BUT IT IS A COMPLICATED PROBLEM.
AND FOR THESE MULTIDRUG
RESISTANT VIRUSES THAT WE SEE
EMERGE IT IN THESE PATIENTS,
THIS IS OUR BIG CONCERN, IS THAT
THESE COULD THEN SPREAD IN THE
COMMUNITY.
>> WHO WEARS THE MASK?
>> WELL, AT HOME IT'S THE
PATIENT.
IN THE HOSPITAL, IT'S SORT OF
THE OPPOSITE.
>> WHY DOES THE SEASONAL FLU
VIRUS TEND TO DIE AWAY WHEN
SPRING AND SUMMER COME AND
SIMILARLY, WHY DOES THE PANDEMIC
VIRUS GO AWAY AT ALL?
>> OKAY.
SO PANDEMIC VIRUSES DON'T GO
AWAY IN THE SENSE THAT THE PAFN
DEMIC VIRUSES BECOME SEASONAL
VIRUSES WITHIN A COUPLE OF
YEARS.
SO THEY'RE PAN DENIC PANDEMIC YEAR OR TWO,
THEN BEGIN TO CIRCULATE ANNUALLY
THROUGH HUMANS, SO SEASONAL
VIRUSES ARE JUST PANDEMIC
VIRUSES THAT HAVE BEEN
CIRCULATING IN HUMANS FOR
SEVERAL YEARS.
SO IN 1918, A PANDEMIC OCCURRED,
MAYBE THE PANDEMIC THEORETICALLY
STOPPED IN 1919, AND IN 1920,
H1N1 VIRUSES DIRECTLY DERIVED
FROM THE 1918 VIRUS WERE STILL
CIRCULATING BUT WERE NOW
QUOTE-UNQUOTE SEASONAL VI VIRUSES.
THEY TEND TO CAUSE DISEASE
PREDOMINANTLY IN THE WINTER
MONTHS.
IT'S NOT EXACTLY CLEAR WHY THAT
IS.
IT'S PROBABLY
TEMPERATURE-HUMIDITY ISSUES,
PEOPLE CROWDING DRY MEMBRANES,
HEATING, ALL SORTS OF FACTORS
THAT PROBABLY CONTRIBUTE TO
THAT.
OF COURSE WE HAVE TWO WINTERS,
RIGHT, TWO MONTHS APART -- I
MEAN SIX MONTHS APART, SO THE
NORTHERN HEMISPHERE AND THE
SOUTHERN HEMISPHERE SEASONS,
SOUTH AFRICA AND AUSTRALIA GET
THERAFLU SEASON IN OUR SUMMER,
THE VIRUSES ARE CIRCULATING, AND
IF YOU LOOK VERY CAREFULLY,
YOU'LL FIND INFLUENZA VIRUSES
CIRCULATING HERE, YOU'LL SEE IT
IN OUR HOSPITALS IN JULY.
IT'S JUST NOT A BIG EPIDEMIC BUT
IT'S NOT THAT THE VIRUSES GO
AWAY, BUT ENVIRONMENTALLY, I
THINK THEY SPREAD BETTER IN
WINTER SO THEY TEND TO KIND OF
FOLLOW THE COLD MONTHS.
>> IS IT KNOWN WHETHER THE VIRUS
THAT YOU SEQUENCE FROM THE 1918
PANDEMIC, DID THAT HAVE ANY
ADAMANTANE KNE MUTATIONS OR TAMIFLU
MUTATIONS?
>> IT DID NOT HAVE THOSE
MUTATIONS.
>> SO WHAT'S YOUR EXPLANATION AS
TO WHAT THE CAUSE OF THE
PANDEMIC, THE 50 MILLION PEOPLE,
5 MILLION, WHO DIED, WHAT DO WE
THICTHINK WAS GOING ON?
>> WELL, I THINK IT'S A
DIFFICULT QUESTION.
I THINK THAT, ONE, IT WAS A VERY
VIRULENT VIRUS.
I THINK IT WAS INHERENTLY
VIRULENT VIRUS, AND ONE OF THE
WAYS IT MANIFESTED ITS VIRULENCE
WAS TO HAVE THE HOST MOUNT A
VERY STRONG PRO INFLAMMATORY
RESPONSE, AND I THINK THAT THAT
INFLAMMATORY RESPONSE WAS A BIG
PART OF OF THE DAMAGE IN 1918.
IT COULD BE THAT THAT'S UNIQUE
TO A VIRUS OF 1918.
THE BIRD FLU INDUCING A SIMILAR
INFLAMMATORY RESPONSE, BUT I
THINK IT'S THAT CHICKEN AND EGG
ISSUE.
THE VIRUS IN INDUCING THAT, AND
WE'RE TRYING TO WORK OUT WHAT
THOSE ME CAN NICHES ARE.
>> WAS IT A CAUSE OF PARKINSON'S
DISEASE?
>> I DO NOT THINK SO, NO.
>> [INAUDIBLE] THE 1918 -- THE
POPULATION, WERE YOUNG PEOPLE
GETTING IT?
>> SO AN INTERESTING FEATURE OF
THE DEMOGRAPHICS OF PANDEMIC
VERSUS SEASONAL FLEW, THE IMPACT
TENDS TO BE IN THE ELDERLY,
WHERE IN PANDEMICS, THE AGE
SHIFTS.
NOVEL SURFACE PROTEINS FOR WHICH
THERE'S NO POPULATION IMMUNITY,
YOUNGER PEOPLE ARE AT RISK TOO,
SO YOU SEE A LOWER SHIFT.
THIS IS TRUE IN ALL PANDEMICS.
BUT IN 1918, THERE WAS A
PARTICULAR PROPENSITY OF PEOPLE
BETWEEN ABOUT AGE 15 TO ABOUT
35, TO HAVE VERY HIGH -- RATES
TO INFECTION, FAR DIFFERENT THAN
OTHER PANDEMICS.
IT'S UNCLEAR EXACTLY WHY THAT
IS.
AN OLDER IDEA THAT STILL COULD
BE RELEVANT IS THAT PATIENTS AT
THIS SORT OF PRIME OF LIFE WERE
ABLE TO MOUNT THE MOST ROBUST
INFLAMMATORY RESPONSE, AND IF
THE INFLAMMATORY RESPONSE WAS
PART OF THE PROBLEM, THAT COULD
BE ONE EXPLANATION.
BUT IT'S STILL NOT REALLY
CERTAIN WHAT ALL THE
EXPLANATIONS WERE FOR THE
UNUSUAL AGE-SPECIFIC MORTALITY.
>> A FEW YEARS AGO, WHEN THERE
WAS GREAT CONCERN ABOUT THE
POSSIBILITY OF ANOTHER PANDEMIC
AND THE NEWSPAPERS, MAGAZINES
WERE FULL OF IT, THERE WAS A
CRASH PROGRAM TO STORE TAMIFLU
AND VACCINES.
WHAT'S THE STATUS OF THAT NOW?
IS IT HAS IT SORT OF SIMMERED
DOWN OR CRANKED UP?
>> THERE'S A BIG IMPORTANCE TO
THAT, THE NATIONAL STOCKPILES,
NATIONAL VACCINE STOCKPILES FOR
WHICH THEY ARE STOCKPILING
TOMORROW'S ANTIBIOTICS,
VACCINES, THEY'RE GOING TO MAKE
A NEW ONE AGAINST H7 AND 9.
SO THAT'S CERTAINLY IMPORTANT TO
TRY TO BE PREPARED.
BUT I THINK IN TERMS OF
VACCINES, AS I SAID IN THE
FUTURE, RATHER THAN TRYING TO
MAKE SPECIFIC VACCINES AGAINST
INDIVIDUAL STRAINS, SORT OF
OLD-FASHIONED WAY, IS TO TRY TO
TAKE ADVANTAGE OF MORE CONSERVED
EPITOPES THAT COULD BE PRESENT
ON THE VIRUS THAT WOULD ALLOW
FOR VACCINES TO BE MORE BROADLY
REACTIVE.
>> OKAY.
I WANT TO THANK YOU VERY, VERY
MUCH.
[APPLAUSE]