Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
>>OUR SPEAKERS
TODAY ARE DR. MARY WRIGHT,
CLINICAL INVESTIGATOR WITH THE
NATIONAL INSTITUTE OF ALLERGY
INFECTIOUS DISEASES, DIVISION OF
CLINICAL RESEARCH AND DR. ARTHUR
FREIDLANDER AND DR. NICHOLAS
JOHN VIETRA, WITH THE BOISE
VETERANS AFFAIRING MEDICAL
CENTER.
DR. WRIGHT EARNED HER MEDICAL
DEGREE AT THE GEORGE WASHINGTON
SCHOOL OF MEDICINE AND A PASTERS
OF PUBLIC HEALTH WITH THE JOHNS
HOPKINS SCHOOL OF PUBLIC HEALTH
AND COMPLETED INTERNSHIP IN
RESIDENCE SKPE BAKUGAN INTERNAL
MEDICINE AT GW.
SHE JOINED THE NIH IN 2000 AS
A--2001, BECAME A MEDICAL
OFFICER AND NIAID DIVISION'S OF
CLINICAL RESEARCH, HELPING TO
PLAN DCR'S HIGH CONTAINMENT
INFECT YOWZ DISEASE LABORATORY
AT FORT DIETRICH, WHILE
COLLABORATING WITH THE UNITED
STATES ARMY AND ALSO SERVINGOT
FDA AND CDC DECISION MAKING
PANELS.
DR. WRIGHT RECEIVED MANY AWARDS
INCLUDING OWS STANDING PERFORM
AS OF THERAPEUTICS TO TREAT
COVID-19 AND NIAID SPECIAL
ACTIVE AWARDS FOR HER SPECIFIC
COVID-19 RESPONSE AND
EXCEPTIONAL EFFORTS IN THE
COORDINATION OF
BIODEFENSISHIAATIVES BETWEEN THE
NIH AND THE DEPARTMENT OF
DEFENSE.
OUR SECOND SPEAKER IS DR. ARTHUR
FRIEDLANDER, AT THE MEDICAL
RESEARCH INSTITUTE OF INFECTIOUS
DISEASES AND ADJUNCT PROFESSOR
OF AT THE UNIVERSITY.
DR. FRIEDLANDER EARNED HIS
DEGREE FOR THE UNIVERSITY OF
PITTSBURGH, AFTER COMPLETING
MEDICAL TRAINING AND A POST
DOCTORAL FELLOWSHIP AT THE NIH,
HE COMPLETED A POST DOCTORAL NIH
FELLOWSHIP AT THE UNIVERSITY OF
CALIFORNIA SAN DIEGO.
DR. FRIEDBERG, THEN WAS CHIEF OF
THE DEPARTMENT OF PATHOBIOLOGY
AND CHIEF OF THE BACTERIAL I
HAVEROLOGY DEVISION, HIS
RESEARCH IS PATHOGEN AFFECTED
DISEASES IN VACCINE DEVELOPMENT.
HE HAD A TARPGETTED ANTHRAX
LETHAL TOXIN AND DEMONSTRATED
THE EXPOSURE AND PROPHYLAXIS
PROVIDING EVIDENCE FOR CURRENT
HUMANS AND DIRECTIVE RESEARCH
THAT RESULT INDEED NEW
GENERATION OF VACCINES FOR
ANTHRAX AND PLAGUED CURRENTLY IN
THE HUMAN TRIALS.
DR. FRIEDLANDER IS A FELLOW WITH
THE INFECT YOWZ DISEASE SOCIETY
OF AMERICA, AND A RESENT YF THE
ARMY RESEARCH AND DEVELOPMENT
AWARD AND THE J. P. SANFORD
AWARD FOR INFECT YOWZ DECEASES.
D
E
C
E
A
SE--INFECTIOUS DISEASES,
SPANS 1999-2008 AND WAS A 2012
FINALIST FOR THE SERVICE TO
AMERICA MEDAL.
OUR FINAL SPEAKER IS
DR. NICHOLAS VIETRI, CHAIRMAN OF
THE BOISE MEDICAL TRUSTEES,
RESEARCH AND INFECT YOWZ
COMMITTEES AND A U.S. ARMY
MEDICAL CORPS OFFICER, RETIRED.
HE SERVED AS A CONSULTANT TO THE
ARMY SURGEON GENERAL FOR
BIOLOGICAL DEFENSE, AMERICAN
CONSULTANT FOR THE COLLEGE OF
PHYSICIANS, EDUCATION ONLINE
MODULE FOR ANTHRAX AND A SUBJECT
MATTER EXPERT FOR U.S. ARMY
MEDICAL DEVELOPMENT MATERIAL
ACTIVITY OF OR HEALTH PROTECTIVE
PROTOCOLS INVOLVING ANTHRAX AND
SMALL POX.
DR. VIERKTS ETRI EARNED HIS
DEGREE FROM THE UNIVERSITY OF
MONTANA.
HE COMPLETED INTERNAL MEDICINE
RESIDENCY IN TEXAS.
DR. VIETRI IS A FELLOW OF THE
INFECTIOUS DISEASE SOCIETY OF
AMERICA.
RECIPIENT OF THE JOHN F. MAYER
M. D. AWARD FOR RESEARCH AND
UNIFORM RESEARCH UNIVERSITY
DEPARTMENT OF MEDICINE AND A
TWICE RECIPIENT OF THE ARMY
PERFORMANCE AWARD AS THE
MICROBIOLOGIST AT THE U.S. ARMY
MEDICAL RESEARCH INSTITUTE OF
INFECTIOUS DISEASES, PLEASE
WELCOME OUR FIRST SPEAKER
DR. WRIGHT, WHO'S TALK IS
ENTITLED 21 YEARS AFTER ANTHRAX,
WHAT CLINICAL QUESTIONS REMAIN.
>>THANK YOU FOR THAT KIND
INTRODUCTION AND THE OPPORTUNITY
TO SHARE RESULTS AND
OBSERVATIONS FROM OUR LONG TIME
COLLABORATION.
WE HAVE NO DISCLOSURES TO
REPORT, ALL OF OUR WORK WAS DONE
THROUGH AN INNER AGENCY
AGREEMENT BETWEEN OUR DIVISION
AND THE DIVISION OF CLINICAL
RESEARCH AT NIAID AND USA MRAD
OF THE ARMY OUR CONCLUSIONS ARE
OUR OWN AND DON'T NECESSARILY
REFLECT THOSE OF OUR INDIVIDUAL
AGENCIES AND ANY DISCUSSION OF
OFFLABEL DRUG USE IS IN THE
CONTEXT OF RESEARCH.
OUR OBJECTIVES ARE TO DESCRIBE
WHAT WAS KNOWN ABOUT HUMAN
INFECTION WITH [INDISCERNIBLE]
AS THE 2001 ANTHRAX LETTER
ATTACKED UNFOLDED, EXAMINE KEY
QUESTIONS THAT AROSE FROM THE
ATTACKS AND RESEARCH TO ADDRESS
THEM AND BECOME AWARE OF
RESEARCH INFRASTRUCTURE AND
CAPACITY THAT GREW OUT OF THE
RESPONSE TO BYEE TERRORISM.
AND LASTLY TO IDENTIFY REMAINING
CLINICAL QUESTIONS, REGARDING
INHALATION OF ANTHRAX.
SO NOW WE WILL GO BACK IN TIME,
MORE THAN 20 YEARS AGO TO
SEPTEMBER 2001 AND AS WE SEE
HERE, WE'RE REMINDED THAT THE
FIRST LETTERS WERE MAILED ON
SEPTEMBER 18th JUST A WEEK
AFTER 9/11 WHEN THE NATION WAS
STILL IN SHOCK AFTER A TERRORIST
ATTACK.
SENATE OFFICES, HOUSE OFFICES
HAD TO CLOSE DOWN BECAUSE THEY
RECEIVED ANTHRAX LETTERS, AND
THERE WAS A BIG OUTCRY
AND--FIGURE OUT HOW TO FACE THIS
UNCERTAINTY, WHAT WAS THE SCOPE
GOING TO BE LIKE, HOW LONG WOULD
THIS LAST?
AND AS TURNS OUT, IT ENDED WITH
22 CASES, 11 CUTANEOUS AND
LISTEN INHALATIONAL WITH 5
DEATHS.
AND IT'S HARD TO BELIEVE THAT
ALL THIS ONLY LASTED A COUPLE OF
MONTHS WITH THE FIRST START DATE
BEING AROUND SEPTEMBER 18th
WITH THAT INITIAL MAILING AND
THEN THE LAST INHALATIONAL DEATH
BEING ON NOVEMBER 21st.
AND LATER ON, IN CONGRESSIONAL
TESTIMONY, IT WOULD BE BROUGHT
OUT THAT IT COST GREATER THAN A
BILLION DOLLARS JUST FOR THE
DECONTAMINATION OF THE POST
OFFICE AND GOVERNMENT BUILDINGS
ALONE.
ANTHRAX IS A BIOLOGICAL WEAPON
TO BE KNOWN FOR THAT FOR YEARS
AND GROUPS ON THE WORKING GROUP
ON CIVILIAN BIODEFENSE HAS COME
TOGETHER AND WRITTEN THIS
CONSENSUS STATEMENT WITH
RECOMMENDATIONS FOR WHAT TO DO
IF THERE WAS A BIOLOGICAL ATTACK
AND THEY WROTE THIS IN JAMA IN
1999.
BEFORE THIS, IN 1975, THE
BIOLOGICAL WEAPONS AND TOXINS
CONVENTION HAD BANNED OFFENSIVE
BIOLOGICAL WEAPONS AND RESEARCH.
NOW THERE'S ACTUALLY 182
SIGNATTORYS ON THIS, AND BACK
THEN THERE WERE MANY COUNTRIES
AS WELL YOU IT WAS STILL KNOWN
THAT SOME COUNTRIES HAD
OFFENSIVE WARFARE PROJECTS THAT
WERE GOING ON AND THE SOVIET
UNION WAS 1 OF THEM.
IN FACT, PROOF OF THIS CAME OUT
IN 1979, THERE WAS A BIG
OUTBREAK IN SVERDLOVSK IN APRIL
OF THAT YEAR AND IT WAS REPORTED
BY THE SCIENTISTS A YEAR LATER
IN 1980 AS HAVING ORIGINATED AS
A NATURAL OCCURRENCE FROM
INFECTED ANIMALS THAT HAD BEEN
INGESTED AND CAUSED
GASTROINTESTINAL ANTHRAX AND THE
FOLKS DIED.
THEY REPORTED MORE THAN 90 DACES
WITH APPROXIMATELY 66 DEATHS AND
THEN THERE WAS A SMALL NUMBER OF
FOLKS THAT HAD CUTANEOUS, THEY
SAID AND DID NOT DIE.
THERE WAS NO THORACIC PATHOLOGY
MENTIONED IN THE PAPER.
SO THEN WHEN THE DISSOLLIEWGZ OF
THE SOVIET UNION UNION OCCURRED
IN 1991, MATTHEW METHYLSON FROM
HARVARD ASKED PER MISSION TO GO
TO SVERDLOVSK, AND INVESTIGATE
THIS AND HE WAS APPROVED.
SO THIS MAP SHOWS THE GEOGRAPHIC
DISTRIBUTION OF THE ANTHRAX
CASES AND YOU CAN SEE THE
STRAIGHT LINES HERE THAT ARE
CONSISTENT BASICALLY WITH WIND
DISTRIBUTION WITH THE ORIGIN
COMING FROM A MILITARY FACILITY.
AND AROUND THAT SAME TIME 2 OF
THE PATHOLOGISTS THAT ACTUALLY
PERFORMED OR WERE INVOLVED WITH
THE AUTOPSIESES IN 1979,
[INDISCERNIBLE] HAD SAVED ALL OF
THEIR DETAILED NOTES AND THEY
KNEW WHERE THIS SECURE LOCATION
WAS TO LOOK AT THE SLIDES AGAIN
AND THEY ACTUALLY PUBLISHED IN
1993, FIND FRTION 1979 INCLUDING
THE THORACIC FINDINGS THAT PROVE
THAT THIS WAS INHALATIONAL
ANTHRAX AND WAS NOT A NATURAL
EVENT.
AND HERE WE CAN SEE THE MOTHER
OF SOMEONE WHO HAD BEEN KILLED
IN WHAT WAS LATER DUBBED A
BIOLOGICAL CHERNOBYL.
SO WHILE WE'RE BACK IN TIME IT'S
WORTH MENTIONING THAT CERTAINLY
NEWS DISSEMINATION SO DIFFERENT
NOW AT HOME AND MOST FOLKS GOT
THEIR NEWS FROM NEWSPAPERS,
RADIO OR THE NIGHTLY NEWS WITH
THESE ANCHORS, THERE WASN'T
FACEBOOK, NO SMART PHONES, THERE
WERE NOT A MULTITUDE OF 24 HOUR
NEWS STATIONS GIVING YOU NEWS
MOMENT BY MOMENT AND SO HERE WE
CAN SEE THE NIGHTLY NEWS
ANCHORS, DAN RATHER, PETER
JENNINGS AND TOM BROKAW, AND ALL
OF THEM WERE TARGETED BY THE
ANTHRAX LETTERS.
LETTERS WENT TO THEIR OFFICES AS
L. SO THEY'RE ALSO AT THE TIME
GOING BACK TO 2001, WE DIDN'T
HAVE THESE OPEN SOURCE PREPRINTS
THAT WE COULD LOOK TO SEE WHAT
OTHER RESEARCHERS HAD FOUND
WHICH IS JUST SOMETHING THAT
HAPPENS SO QUICKLY NOW.
THEY'RE ALSO WASN'T THE
IMMEDIATE POINT OF CARE, WHERE
TO GO TO GET UP TO DATE
INFORMATION ON WHAT TO DO WHEN
SCENARIOS BACK THEN SO WE RELIED
HEAVILYOT CDC'S MPWRs AND THEN
REPORTS LIKE THIS 1 THAT HENRY
MASUR, AND NIH
ALUM[INDISCERNIBLE] WERE
INVOLVED WITH WHICH WAS THE 2
BRENT WOOD POSTAL WORKERS THAT
DIED OF INHALATIONAL ANTHRAX AND
THERE WAS A REAL NEED TO GET
MORE OF AN UNDERSTANDING OF WHAT
TO EXPECT WITH ANTHRAX BECAUSE
MOST CLINICIANS HAD NEVER SEEN
IT, THE LAST CASE HAD BEEN IN
1976 IN THE UNITED STATES AND
THERE HAD ONLY BEEN 18
INHALATIONAL CASES BETWEEN 1900
AND--AND HERE WE HAVE A CASE OF
A 94 YEAR-OLD FEMALE WHO
PRESENTED TO THE EMERGENCY
DEPARTMENT OF FEVER, COUGH
FATIGUE FOR 3 DAYS, SHE HAD
COPD, HYPER TENSION, CHRONIC
RENAL INSUFFICIENCY, SHE WAS ON
THESE MEDICATIONS FOREVER WHAT
WAS DISPRIEBED AS MILD DISEASES
FOR ALL OF THEM AND THEN SHE WAS
AN EX-SMOKER BUT HAD NOT SMOKED
IN 30 YEARS AND AT THE TIME OF
HER PRESENTATION, SHE WAS FEB
RILE, TACKY CARDIC SO SHE MET
THE KRIST TERIAR SERS, SHE DID
NOT HAVE A LEUKOCYTOSIS,
ALTHOUGH HER SEGMENT OF
NUTRIFILLS WERE A BIT ELEVATED.
SHE HAD AN INCREASE IN OUR V. N.
AND KRE TINSA TIEN, SHE HAD A
FEW WHITE CELLS IN URINE, HER
CHEST X-RAY WAS RED AS SHOWING
NO ACUTE PULL MONITORARY DISEASE
AND HER SATURATION WAS 93% ON
ROOM AIR AND SHE WAS GIVEN AN
ADMITTING DIAGNOSIS OF VIRAL
SYNDROME WITH DEHYDRATION AND
THEREFORE WAS NOT STARTED ON
ANTIMICROBIALS AT THAT TIME.
OT NEXT DAY SATURDAY HER URINE
CULTURE WAS GROWING OUT GRAHAM
NEGATIVE RODS WHICH WOULD SHOW
TO BE SIM LACK TO E.COLI AND
OTHER SITUATIONS, IT TURNED OUT
TO BE 4 OUT OF 4 BOTTLES 14
HOURS AFTER THEY WERE DRAWNY,
SHE WAS BEGUN ON CEFTAZIDIME AND
THEN VANCOMYCIN AND THEN AMP
SILLIN AND SULBACTAMAND ORAL
CIPROFLOXACIN, HER CHEST X-RAY
SHOWED LARGE PLURAL EFFUSION AND
OVER THE NEXT COUPLE DAYS SHE
CONTINUED TO DETERIORATE.
ON DAY 3 SHE HAD A THOROUGH SIN
THESIS OF THIS DONE WHICH SHOWED
8 MILs OF HEMORRHAGIC
INFUSION, SHE ALSO HAD TO GET
INTERNATIONAL CLASSIFICATION
BAITED AND PUT ON MECHANICAL
INFLAMMATION, AND ON DAY 4, THE
STATE WAS ABLE TO CONFIRM THAT
THIS WAS THE [INDISCERNIBLE]
INFECTION AND UNFORTUNATELY ON
DAY 5 HER FIO2 REQUIREMENTS WENT
UP TO 80%.
SHE HAD TO HAVE A CHEST TUBE
PLACED ON THE LEFT SIDE AND SHE
DEVELOPED A RIGHT PLEURAL
CERTAINLY--CERTAINLY FUSION AND
PASSED AWAY AND ON AUTOPSY, SHE
HAD NECROSIS AND STONEOSEIS IN
THE LUNGS AND THE CULTURES WOULD
BE NEGATIVE.
SO THIS TURNED OUT TO BE THE
LAST INHALATIONAL CASE IN
NOVEMBER OF 2001 IN THIS 94
YEAR-OLD LADY, EVERYBODY HAD
ANTHRAX ON THEIR MIND, WE WERE
FAMILIAR WITH ANTHRAX FOR MANY
YEARS, BUT YET IT WAS NEW TO US,
THEN, SO JUST AS A QUICK
REFRESHER, WE KNOW THAT ANTHRAX
IS CAUSED BY BACILLUS,
ANTHRACIS, IT IS SPORE FORMING,
NONMOTEILE, LARGE AND BOX CAR
SHAPED IT'S A ZOO NOTTIC
INFECTION THAT INFECTS CATTLE,
SHEEP AND GOATS.
IT HAS 3 MAIN ROOTS OF
INFECTION, GI, CUTANEOUS AND
INHALATIONAL AND THERE WAS AN
INJECTIONAL OUTBREAK IN THE U.
K. CAUSED BY I. V. DRUG USERS
USING HEROIN WHICH THEY DID NOT
KNOW WAS TAINTED WITH ANTHRAX
THAT HAD BEEN CARRIED IN ANIMAL
HIDES SO THIS WAS A CATEGORY
THAT WAS ALSO ADDED LATER ON.
AND IT'S IMPORTANT TO REMEMBER
THAT THERE'S NO PERSON-TO-PERSON
TRANSMISSION FOR ANTHRAX.
ANTHRAX PRODUCES 3 PROTEINS, THE
PROTECTIVE ANTIGEN COMBINES WITH
LETHAL FACTOR OR EDEMA FACTOR TO
FORM THE RESPECTIVE TOXINS AND
THIS MEANS THAT EVEN IF SOMEONE
IS ON THE RIGHT ANTIMICROBIAL
THAT'S EFFECTIVE, THEY CAN STILL
HAVE A POTENTIALLY HIGH
MORTALITY DUE TO TOXINS.
AND 1 OF THE MOST DISCUSSED
FEATURES BACK IN 2001 WAS THIS
PATHOGENESIS AND THE DELAYED
GERM NATION OF SPORES.
DR. FRIEDLANDER WILL TALK ABOUT
THAT IN MORE DETAIL BUT SHOWED
IN THIS CARTOON WE SEE THAT
SOMEONE INHALES THE SPORES, IF
THEY'RE SMALL ENOUGH
1-5-MICRONS, THEY GET INTO THE
ALVERMEN INFECTED O LIAISON.
AND THE IMMUNE SPONSE IS
ACTIVATED AND THE MACROPHAGES
CARRY THE SPORES TO THE MEDIA
STIENAL LYMPHNODES THAT'S WHY WE
SEE THIS ON THE CHEST X-RAYS AND
FROM HERE THERE'S GERMINATION
INTO BACTERIA AND VACTEREMMIA
AND TOXINEMMIA AND THEN
UNFORTUNATELY POTENTIALLY DEATH
IF TREATMENT SUBJECT BEGUN EARLY
ENOUGH.
AND BECAUSE OF THIS DELAY AND
GERMINATION AND THE
UNPREDICTABILITY OF IT, THE
RECOMMENDATION IN 2001 WAS TO
TAKE ANTIBIOTICS FOR MORE THAN
60 DAYS--APPROVAL TO TREAT
ANTHRAX OR TO BE USED AFTER
EXPOSURE, PENICILLIN AND DOCKS
PSYCHE LYNN, PENICILLIN WAS NOT
RECOMMEND BECAUSE OF THE CONCERN
THERE COULD BE RESISTANCE.
CIPROFLOCKSIN HAD BEEN MENTION
INDEED THE CONSENSUS PAPER I
SHOWED YOU EARLIER, SO THAT WAS
STILL AN OFFLABEL USE AND SO,
WHAT ENDED UP HAPPENING WITH THE
PATIENTS RECEIVING, THEY RECEIVE
THE QUINN LONE, SAW IN OUR
YEAR-OLD LADY THAT SHE RECEIVED
MULTIPLE MIKE ROBIALS WHICH IS
ALL ICU AND CRITICAL CARE
SPECIALISTS DO WITH AGGRESSIVE
PATIENTS WITH SUPPORTIVE CARE
BUT THERE ARE A LOT OF QUESTIONS
AND UNKNOWNS ABOUT ANTHRAX IN
THESE MODERN TIMES OF 2001 AND
THEIR JUST WASN'T A ROT OF
INFORMATION.
THE INFRASTRUCTURE TO STUDY
ANTHRAX DIDN'T EXIST OR FOR
OTHER POTENTIAL AGENTS THAT
COULD BE USED AS BIOLOGICAL
THREATS INCLUDING SMALL POX, AND
EBOLA.
SO THERE WAS A LACK OF LABS WITH
BSL 3 CAPACITY WHICH YOU NEEDED
TO HANDLE AEROSOL, ANTHRAX AND
SPORES AND A LACK OF BSL FOR
OTHER TYPE OF PATHOGENS AND
THERE WERE VERY FEW SCIENTISTS
AND CLINICIANS WITH ANTHRAX
EXPERIENCE AND THERE WAS AN
INABILITY TO CONDUCT CLINICAL
TRIALS BECAUSE YOU WEREN'T GOING
TO ETHICALLY GIVE SOMEONE
ANTHRAX AND COMPARE THEM TO A
GROUP THAT DID NOT HAVE ANTHRAX.
SO THERE WERE MANY QUESTIONS.
AND THE QUESTIONS THAT WERE
ESPECIALLY OF INTEREST TO DR. VI
E TRI, FRI DEDLANDER AND I, CAN
HOW MANY DAYS OF ANTIBIOTICS ARE
NEEDED AFTER ANTHRAX EXPOSURE,
CAN EABT BIOTICS DURATION BE
SHORTENED AFTER SYSTEMIC
INFECTION AND DOES THE ADDITION
OF CLINDA MICEIN MAKE A
DIFFERENCE IN SURVIVAL.
SO NOW I WILL TURN IT OVER TO
DR. FREIDLANDER AND SHE WILL
EXPLORE THE ANSWER TO THAT.
>> THANK YOU FOR THE OPPORTUNITY
TO TELL YOU ABOUT THIS LONG
COLLABORATION IN ADDRESSING HOW
TO MEASURE AN AEROSOLEXPOSURE TO
ANTHRAX.
SPECIFICALLY WHAT'S THE BEST
POST EXPOSURE PROPHYLAXIS?
HOW MANY DAYS OF ASPECT BIOTICS
PROPHYLAXIS COMBINED WITH POST
-VACCINATION POST EXPOSURE
ARE NEEDED FOR PROTECTION
AGAINST INHALATIONAL ANTHRAX?
IN THE 19th CENTURY, IT WAS AN
ECONOMICALLY IMPORTANT DISEASE
OF DOMESTICATED ANIMALS, THAT
ENGAGED THE BEST MEDICAL
SCIENTISTS OF THE TIME AND WAS
ASSOCIATED WITH THE ORIGINS OF
MICROBIOLOGY, AND IMMUNOLOGY.
AND NOW IT IS UNFORTUNATELY OF
CONCERN BECAUSE OF ITS POSSIBLE
USE AS AS A BIOWEAPON.
A TRULY DISASTROUS SITUATION.
THE CASES OF INHALATIONAL
INFECTION IN ABOUT 1979, ABOUT
WHICH THE RUSSIANS YET TO THIS
DAY HAVE YET TO SHARE ANY
INFORMATION ABOUT THE CLINICAL
MANAGEMENT OR THE DISEASE THEY
SAW.
AND THEN THE WEAPONIZATION OF
ANTHRAX IN THE FIRST GULF WAR
HEIGHTENED THE AWARENESS OF THE
THREAT OF USING ANTHRAX AS A
BIOLOGICAL WEAPON AND LED TO THE
DECISION FOR THE FIRST TIME IN
HISTORY TO VACCINATE A
POPULATION, THIS IS THE U.S.
ARMED FORCES IN 1998 NOT AGAINST
A NATURALLY OCCURRING DISEASE,
BUT AGAINST THE THREAT OF USING
A MICROORGANISM TO INTENTIONALLY
CAUSE DISEASE.
BUT IT WAS THE USE OF MAIL IN
THE FALL OF 2001 TO SPREAD
ANTHRAX THAT GALVANIZED THE
BIOMEDICAL AND PUBLIC HEALTH
COMMUNITIES AS WAS ALLUDED TO.
THE HORRENDOUS POSSIBILITY OF
USING MICROBES TO INTENTIONAL
CAUSE DISEASE WAS REALIZED,
REVEALING THE DARK SIDE OF
SCIENCE.
IT CHANGED THE FACE OF PUBLIC
HEALTH AND THAT WE WERE NOW
FOCUSED ON PROVIDING MEDICAL
COUNTERMEASURES, AGAINST THE
THREAT OF SOMEONE USING A MY
KROAB TO INTENTIONAL CAUSE
DISEASE.
NEXT SLIDE, PLEASE.
NEXT--OH, YES.
THESE OBSERVATIONS,OT USE OF
ANIMALS TO MODEL HUMAN DISEASE
ARE AT THE HEART OF A DILEMMA
FOR THE LICENSURE OF VACCINES OR
THERAPEUTICS AGAINST
BIOTERRORRISTS, AGENTS THAT
OCCUR SO RARELY THAT CLINICAL
TRIALS CAN'T BE CARRIED OUT, OR
WOULD BE UNETHICAL BECAUSE OF
THE SERIESNESS OF THE INFECTION.
--SERIOUSNESS OF THE INFECTION.
THE EVENTUALLY RESULTED IN THE
ANIMAL RULE BY FDACIN 2002 FOR
SUCH PRODUCTS.
THEREFORE WE MUST TEST PRODUCTS
IN THE BEST ANIMAL MODELS
AVAILABLE AND THE MODELS ARE NOT
NECESSARILY INDICATIVE OF HUMAN
DISEASE.
THAT'S PART OF THE DILEMMA.
AS FELIX D'HERELLE 1 OF THE
FOUNDERS OF INFECTIOUS DISEASE
SAYS, POINTED OUT, THE STUDY OF
IMMUNITY IN ARTIFICIALLY
PRODUCED INFECTIOUS DISEASES
DOES NOT NECESSARILY MEAN THAT
THE SAME CONDIPGZS WILL PREVAIL
UNDER NATURAL INFECTION.
SO THAT EVEN THE BEST ANIMAL
MODELS ARE ONLY THAT AND MAY
WELL BE DIFFERENT FROM THE HUMAN
DISEASE.
NEVERTHELESS, ANIMAL MODELS MAY
BE NECESSARY BECAUSE AS WE
MENTIONED, THE INFREQUENCY OF
SOME DISEASES SUCH AS ANTHRAX
HAS NOTED BY KLEIN AND WHAT HE
SAID WAS THAT BECAUSE OF THE
INFREQUENCY OF OCCURRENCE OF
ANTHRAX, IT IS PROBABLE,
RELATIONSHIP BETWEEN ANTIBODY
TITER AND RESISTANCE TO
INFECTION IN HUMAN POPULATIONS,
WILL NEVER BE CONCLUSIVELY
SHOWN.
WE MUST THEREFORE RELY LARGELY
IF NOT ENTIRELY ON EXTRAPOLATION
OF RESULTS FROM EXPERIMENTAL
HOSTS TO FURNISH INFORMATION ON
MAN.
AND THE SAME HOLDS TRUE FOR
THERAPEUTICS AND VACCINES.
AND FINALLY MAURICE HILLEMAN THE
DISCOVERY OF VACCINES MAKERS
THIS INSIGHTFUL REMARK ABOUT
VACCINES, PROTECTION AND THE
BEST MARKER FOR PROTECTION, NOT
STUDIES IN ANIMALS MORE IN THE
TEST TUBE.
NEXT SLIDE.
THIS IS ANOTHER CONTINUING ISSUE
WE FACE IN INFECTIOUS DISEASES,
NAMELY THE DIFFICULTY IN MAKING
AN EARLY DIAGNOSIS.
ONE APPRECIATED VERY LONG AGO IN
THIS QUOTE ASCRIBED TO
MACHIAVELLY IN THE 16th
CENTURY.
HE SAID THE PHYSICIANS SAY, IT
HAPPENS IN HECTIC FEVER, THAT IN
THE BEGINNING OF THE MALADY IT
IS EASIER TO CURE BUT DIFFICULT
TO DETECT.
BUT IN THE COURSE OF TIME, NOT
HAVING BEEN EITHER DETECTED OR
TREATED IN THE BEGINNING, IT
BECOMES EASY TO DETECT BUT
DIFFICULT TO CURE.
IT IS PARTICULARLY RELEVANT IN
THE SITUATION OF AN AEROSOL
EXPOSURE BEFORE SIGNS OF ILLNESS
HAVE OCCURRED.
HOW DO YOU DIAGNOSE SOMEONE
EARLY?
AND HOW DO YOU TRIAGE THOSE
EXPOSED?
OF COURSE THIS IS VERY MUCH LIKE
THE SITUATION WITH COVID.
ALTHOUGH FOR AN AEROSOL EXPOSURE
IT WOULD BE A MASSIVE EVENT
OCCURRING ALL AT ONCE.
NEXT SLIDE.
AS DISCUSSED EARLIER, ANTHRAX
REPRESENTS A UNIQUE PROBLEM IN
THE MANAGEMENT OF AN AEROSOL
EXPOSURE BECAUSE OF ITS BIOLOGY.
WHERE IN SPORES DO NOT GERMINATE
ALL AT ONCE.
THIS WAS APPRECIATED BY BARNES,
1947.
THAT GERMINATION OF SPORES IS
NOT SYNCHRONOUS.
THAT SPORES MAY REMAIN DORMANT
FOR EXTENDED PERIODS OF TIME IN
THE HOST.
IMPORTANTLY, ANTIBIOTICS ONLY
ACT ON GERMINATED SPORES AND
BACILLI, NOT ON DORMANT SPORES,
THUS SPORES REMAINING FOLLOWING
DISCONTINUANCE OF ANTIBIOTICS
MAY GERMINATE RESULT NOTHING
INFECTION AND DEATH.
NEXT SLIDE.
IN OUR WORK ON ANTHRAX, WE ARE
FOLLOWING ON THE SEMINAL
EXPERIMENTS BY HENNEDDERSON
ET AL, REPORT INDEED 1956.
THEY STUDIED THIS PHENOMENON OF
RETAINED SPORES IN NONHUMAN
PRIMATES OR GIVEN POST EXPOSURE
PROPHYLAXIS, FOR 5 OR 10 DAYS
WITH PENICILLIN, BEGINNING 1 DAY
AFTER AN AEROSOL EXPOSURE.
THEY FOUND THAT 5 OR 10 DAYS OF
POST EXPOSURE PROPHYLAXIS WITH
ANTIBIOTICS PROTECTS NONHUMAN
PRIMATES WHILE THEY ARE ON
ANTIBIOTICS, BUT IS ASSOCIATED
WITH SIGNIFICANT MORTALITY
FOLLOWING DISCONTINUATION OF
ANTIBIOTICS.
THAT IS 8 OF 10 ANIMALS DIED
AFTER DISCONTINUING 5 DAYS OF
PEN SILLEN AND 10 AFTER 10 DIES
AFTER STOPPING OPINION SILLIN.
THEY FIND THAT VACCINATION AFTER
POST EXPOSURE RESULTS IN A
SIGNIFICANT INCREASE IN
SURVIVAL.
SO THESE EXPERIMENTS DID CONFIRM
THE HYPOTHESIS OF BARNES, THAT
AFTER EXPOSURE, RETAINED
UNGERMINATED SPORES MAY
GERMINATE AFTER THE ANTIBIOTICS
ARE DISCONTINUED AND LEAD TO--WE
EXTENDED THE STUDIES OF
HENDERSON TO SEE IF A MORE
PROLONGED PERIOD OF JUST POST
EXOAZURE ANTIBIOTICS ALONE WOULD
INCREASE SURVIVAL.
NEXT SLIDE.
PLEASE.
OUR EXPERIMENTS ON POST EXPOSURE
ANTIBIOTIC PROPHYLAXIS SHOWED
THAT A MORE PROLONGED PERIOD OF
30 DAYS OF ANTIBIOTICS, COULD
PROTECT ANIMALS, WHILE ON
ANTIBIOTICS AGAIN AND
IMPORTANTLY OFFERED SIGNIFICANT
LONG-TERM PROTECTION AFTER
DISCONTINUING ANTIBIOTICS BUT
SOME STILL DIED AFTER THE
ANTIBIOTICS WOULD DISCONTINUE.
WE DID FIND THAT THE ADDITION OF
POST EXPOSURE VACCINATION DID
IMPROVE SURVIVAL BUT IT WAS NOT
STATISTICALLY SIGNIFICANT IN
THIS STUDY.
NEXT SLIDE.
NOW THIS SLIDE SHOWS THE OVERALL
RESULTS.
ANIMALS WERE TREATED 1 DAY AFTER
A LOW DOSE AEROSOL EXPOSURE WITH
PEN SILLEN, CIPRFLOXIN, OR
DOXYCYCLINE FOR 30 DAYS.
ANOTHER GROUP RECEIVED
DOXYCYCLINE PLUS A LICENSED
HUMAN ANTHRAX VACCINE AVA, THE
PERCENT SURVIEWFAL IS SHOWNOT
Y-AXIS AND DAYS AFTER CHAL
EVENLGOT X-AXIS.
OT LEFT, YOU CAN SEE THAT 9 OF
10 CONTROLS IN THE CLOSED
CIRCLES DIED BUT THAT NO ANIMALS
DIED OF ANTIBIOTICS WHILE ON THE
THIRD DAYS OF TREATMENT.
THERE WERE 3 ANIMALS THAT DIED
OF OTHER CAUSES.
NOW UPON STOPPING THE
ANTIBIOTICS AFTER THIRTD DAYS, 3
OF 10 ON PENICILLIN SHOWED IN
THE CLOSED TRIANGLES DIED.
ONE OF 9 IN THE CIPROFLOXIN
GROUP, IN THE OPEN TRIANGLES
DIED AND 1 OF 10 IN THE
DOXYCYCLINE GROUP SHOWED
ENCLOSED SQUARES DIED ON DAY 28
AFTER STOPPING ANTIBIOTICS.
THAT IS TO SAY, 59 DIES AFTER
THE EXPOSURE, THE RESULTS SHOW
THAT PROLONGED EABT BIOTICSS
ALONE COULD RESULT IN
SIGNIFICANT LONG-TERM PROTECTION
AND THIS BECAME THE BASIS FOR
THE 60 DAY RECOMMENDATION FOR
POST EXPOSURE ANTIBIOTICS,
HOWEVER, THIS WAS A LOW
CHALLENGE DOSE, AND MODELING
SUGGESTED THAT YOU MIGHT REQUIRE
MORE THAN 4 MONTHS OF POST
EXPOSURE PROPHYLAXIS WITH
ANTIBIOTICS.
IF A LARGER DOSE OF SPORES WERE
INHALED?
INDEED, HENDERSON IN THEIR
STUDIES FOUND TRACES OF SPORES
100 DAYS AFTER EXPOSURE.
AND WE HAVE FOUND SPORES AS LONG
AS 180 DAYS AFTER EXPOSURE.
IMPORTANTLY IN THIS EXPERIMENT,
NONE OF THE ANIMALS DEVELOPED AN
IMMUNE RESPONSE TO THE EXPOSURE
SO IT APPEARED THAT THE
ANTIBIOTICS SUPPRESSED THE
INFECTION.
INDEED AS SHOWN ON THE RIGHT
CHANNEL, THE RIGHT PANEL IN B,
WHEN ANIMALS WOULD CHALLENGE
ABOUT 4 MONTHS AFTER
DISCONTINUING ANTIBIOTICS THEY
WERE NOT PROTECTED, ONLY 1 OF 23
SURVIVORS SURVIVED THE
RECHALLENGE.
IN CONTRAST THE GROUP GIVEN
DOXYCYCLINE POST EXPOSURE
VACCINATION IN THE SQUARES DID
SURVIVE THE RECHALLENGE AND THIS
IS LIKELY DUE TO THE LOW INITIAL
CHALLENGE DOSE WHERE THE
INFECTION WAS TOTALLY SUPPRESSED
BECAUSE AS WE WILL SLEEP APNEA
AND OBESITYY IN THE SUBSEQUENT
STUDY, IN ANIMALS CHALLENGED
WITH A DOSE, 200 TIMES GREATER,
AND TREATED FOR 14 DAYS, WITH
CIPRO FLOXIN, 4 OF THE 9 ANIMALS
THAT SURVIVED DID DEVELOP
ANTIBODIES AND WERE RESISTANT TO
RECHALLENGE.
NOW IT WAS THE DATA IN THIS
EXPERIMENT DONE, PUBLISHED 1993
THAT FORMED THE BASIS OF THE
ANIMAL RULE ADOPTED BY THE FDA
AND IT LED TO THE LICENSURE OF
CIPRFLOXIN FOR POST EXPOSURE
PROPHYLAXIS OF ANTHRAX.
NEXT SLIDE.
THUS, THESE RESULTS SUGGEST THAT
THERAPY FOR AN UNIMMUNIZED
PERSON EXPOSED TO AN AEROSOL OF
ANTHRAX SPORES SHOULD CONSIST OF
LONG-TERM SUPPRESSIVE
ANTIBIOTICS.
AND VACCINATION MAY PROVIDE AN
ADDITIONAL DEGREE OF PROTECTION
AGAINST RELAPSE AFTER ANTIBIOTIC
TREATMENT AND WOULD PROTECT
AGAINST A SUBSEQUENT EXPOSURE.
NEXT SLIDE.
AS MENTIONED, THIS STUDY WAS THE
GENESIS OF THE ANIMAL RULE BY
THE FDA, AND RESULTED IN THE
APPROVAL OF CIPROFLOXIN, FOR
POST EXPOSURE PROLAXIS, THIS IS
THE ANIMAL RULE.
AS INDICATE INDEED THE SECOND
PARAGRAPH, THIS RULE WILL PERMIT
THE DEMONSTRATION OF EFFICACY,
USING ANIMAL STUDIES IN LIEU OF
HUMAN CLINICAL TRIALS IN THOSE
INSTANCES WHERE HUMAN TRIALS
WOULD BE UNETHICAL BECAUSE OF
THE SERIOUS CLINICAL EFFECTS OF
THE AGENT OR WHERE SUCH TRIALS
WOULD BE UNFEASIBLE BECAUSE OF
THE INFREQUENCY OF HUMAN
EXPOSURE TO THE [INDISCERNIBLE]
AND OF COURSE, BOTH OF THESE ARE
WITH ANTHRAX.
NEXT SLIDE.
THE PREVIOUS EXPERIMENTS
PROMPTED US TO UNDERTAKE THE
FOLLOWING STUDY TO DETERMINE
WHETHER A SHORT COURSE POST
EXPOSURE EABT BIOTICS
PROPHYLAXIS, WHEN COMBINED WITH
VACS NATION POST EXPOSURE COULD
PROTECT AGAINST DISEASE DUE TO
GERMINATION OF RETAINED SPORES
AFTER DISCONTINUATION OF
ANTIBIOTICS.
RECALL THAT AFTER THE 2001
ANTHRAX ATTACK, ABOUT 10,000
PEOPLE WERE PUT ON 60 DAYS POST
EXPOSURE ANTIBIOTIC PROPHYLAXIS
BUT THE ADHERENCE WAS ONLY 44%.
NEXT SLIDE.
THE OBJECTIVE OF THIS EXPERIMENT
WAS TO DETERMINE WHETHER
SURVIVAL CAN BE ENHANCED BY
ADDITION OF VACCINATION TO A
SHORT COURSE OF POST EXPOSURE
ANTIBIOTIC PROPHYLAXIS.
THAT IS CAN VACS NATION SHORTEN
THE DURATION OF PROPHYLAXIS?
NEXT SLIDE.
THIS SLIDE SHOWS EXPERIMENTAL
DESIGN.
TEN ANIMALS RECEIVE
CIPROFLOXACIN AT DAY 0 WITHIN 2
HOURS OF AEROSOL CHALLENGE AND
CONTINUES FOR 14 DAYS.
TEN OTHER ANIMALS RECEIVE
CIPROFLOXACIN ACCORDING TO
SCHEDULE AS FIRST GROUP BUT WERE
ALSO VACCINATED WITH THE HUMAN
ANTHRAX VACCINE ON DAYS 0, 14
AND 28.
THERE WERE 4 ADDITIONAL ANIMALS
USED AS UNTREATED CONTROLS.
AND IN THIS EXPERIMENT AS I
MENTIONED THERE WAS THE DOSE,
THE CHALLENGE DOSE WAS 200 TIMES
GREATER THAN IT WAS IN THE
EXPERIMENT WHERE ANIMALS ARE
TREATED FOR 30 DAYS.
NEXT SLIDE.
ALL 4 TREATED CONTROL ANIMALS
DIE.
NO ANIMALS IN EITHER THE
CIPROFLOXACIN ALONE OR THE
CIPROFLOXACIN PLUS VACCINE
GROUPS DIED WHILE ON ANTIBIOTIC
THERAPY.
AND WHILE ON ANTIBIOTIC THERAPY
4 ANIMALS IN THE CIPROFLOXACIN
ALONE GROUP AND 3 IN THE
CIPROFLOXACIN PLUS VACCINE GROUP
HAD POSITIVE BLOOD CULTURES FOR
ANTHRAX.
NEXT SLIDE.
THIS SLIDE SHOWS THE RESULTS
GRAPHICALLY, SURVIVAL AGAIN IS
SHOWN ON THE Y-AXIS AND DAYS
AFTER CHALLENGE ON THE X-AXIS.
THE UNTREATED CONTROLS SHOWN IN
THE CLOSED SQUARES DIED.
WHILE ON ANTIBIOTICS FOR THE 14
DAYS WERE NO DEATHS IN EITHER
GROUP BUT AFTER THE ASPECT
BIOTICSS WERE DISCONTINUED, ONLY
4 OF 9 ANIMALS, 44% SURVIVED IN
THE CIPROFLOXACIN GROUP SHOWN
INDEED CLOSED CIRCLES.
THIS WAS COMPARED TO 10 OF 10
ANIMALS IN THE GROUP ALSO GIIVE
VACCINATION SHOWN IN THE CLOSED
TRIANGLES.
THAT DIFFERENCE IN SURVIVAL WAS
HIGHLY SIGNIFICANT.
NEXT SLIDE.
AN ADDITIONAL FINDING WAS THAT
THE 4 ANIMALS IN THE
CIPROFLOXACIN GROUP THAT
SURVIVES DEVELOPED ANTIBODY
TITERS TO THE PROTECTIVE ANTIGEN
COMPONENT OF THE TOXIN AND
IMPORTANTLY THESE SURVIVING
ANIMALS WERE RESISTANT TO AN
AEROSOL SPORE RECHALLENGE, 8 TO
11 MONTHS LATER AND AS POINTED
OUT BEFORE THIS, IS A CONTRAST
TO THE 1943 STUDY WHERE THE
ANIMALS RECEIVED A LOW CHALLENGE
DOSE AND DID NOT DEVELOP AN
IMMUNE RESPONSE AND WERE NOT
PROTECTED AGAINST RECHALLENGE.
SO IT'S LIKELY DUE TO THE FACT
THAT WITH A LOW CHALLENGE DOSE,
THE ANTIBIOTICS, POST EXPOSURE
CAN SUPPRESS THE INFECTION IN
THE DEVELOPMENT OF IMMUNITY.
BUT WITH A HIGH CHALLENGE DOSE,
THIS DOES NOT--NEXT SLIDE.
IN CONCLUSION, THE ADDITION OF
VACCINATION TO A SHORT 14 DAY
COURSE OF POST EXPOSURE
ANTIBIOTIC PROPHYLAXIS RECULTED
IN A STATISTICALLY SIGNIFICANT
INCREASE IN SURVIVAL COMPARED TO
THOSE GIVEN ANTIBIOTICS ONLY.
THAT IS A SHORT COURSE OF POST
EXPOSURE ANTIBIOTIC PROPHYLAXIS,
COMBINED WITH VACCINATION,
RESULT INDEED 100% SURVIVAL.
NEXT SLIDE.
SO SHORTENING THE DURATION OF
ANTIIC POST EXPOSURE IN A
BIOTERRORRISM EVENT INVOLVING AX
THRAKS BY ADDING POST EXPOSURE
VACCINATION WOULD BE OF GREAT
BENEFIT BECAUSE OF NONCOMPLIANCE
WITH TAKING THE ANTIBIOTICS AND
THE SIDE EFFECTS ASSOCIATED WITH
PROLONGED THERAPY.
THESE STUDIES PUBLISH THE ADD
VALUE OF POST EXPOSURE
VACCINATION AND ANTIBIOTIC
PROPHYLAXIS AND PROVIDED THE
EVIDENCE FOR THE CDC AND PUBLIC
HEALTH RESPONSE TO BIOTERRORRISM
EVENTS INVOLVING ANTHRAX.
AND FINALLY THE NEXT SLIDE, THE
DEVELOP OF A SUBCLINICAL
INFECTION IN THIS EXPERIMENT
AFTER A HIGH CHALLENGE DOSE, THE
SUBSEQUENT DEVELOPMENT OF AN
IMMUNE RESPONSE AND THE
RESISTANCE TO RECHALLENGE OF THE
SURVIVING ANIMALS STREETED WITH
CIPROFLOCKSIN ALONE SUPPORTS THE
SUGGESTION THAT INDIVIDUALS
TREATED FOR SYMPTOMATIC
ESTABLISHED INHALATIONAL ANTHRAX
AND WHO RECOVER AND SERO-CONVERT
MAY NOT REQUIRE AN ADDITIONAL 60
DAYS OF ANTIBIOTIC THERAPY AS
RECOMMENDED BY THE CURRENT
GUIDELINES AND DR. VIETRI, WILL
ADDRESS THE STUDY ABOUT THIS
ISSUE.
>> THANK YOU DR. FRIEDLANDER.
NEXT SLIDE, PLEASE.
>> THE PRESENCE OF RETAINED
SPORES AFTER AEROSOL EXPOSURE
HAS ALSO GENERATED UNCERTAINTY
REGARDING DURATION OF ANTIBIOTIC
THERAPY REQUIRED TO TREAT AND
ESTABLISHED INHALATIONAL ANTHRAX
INFECTION, NEXT SLIDE.
NOW THE INHALATIONAL ANTHRAX
TREATMENT RECOMMENDATIONS HAVE
EVOLVED BUT IN 2002,LET
GUIDELINES STATED THE
COMBINATION THERAPY SHOULD BE
DELIVERED INTRANSLATIONAL
RESEARCH VENEIOUSLY FOR 2-3
WEEKS FOLLOWED BY TRANSITION TO
A SINGLE ORAL ANTIBIOTIC AFTER
THE PATIENT HAS SHOWN CLINICAL
IMPROVEMENT.
THE RECOMMENDED TOTAL DURATION
OF ANTIBIOTIC TREATMENT WAS 60
DAYS OR LATER A HUNDRED DAYS OR
A HUNDRED DAYS PLUS 3 DOSES OF
THE AVA VACCINE.
NEXT SLIDE, PLEASE.
BUT WE KNOW THAT INDIVIDUALS WHO
RECOVER FROM ESTABLISHED ANTHRAX
AFTER TREATMENT, DEVELOP A
SEROLOGICAL RESPONSE AND IF WE
LOOK IN THE LITERATURE REPEAT
CUTANEOUS ANTHRAX INFECTIONS
HAVE RARELY BEEN REPORTED AND IF
REPORTED TEND TO BE MUCH MILDER
THAN THE ORIGINAL CASE.
NEXT SLIDE, PLEASE.
SO THE HYPOTHESIS WE HAD WAS A
SHORT COURSE OF ANTIBIOTIC
THERAPY 10 DAYS, SUFFICIENT TO
TREAT AND ESTABLISH INHALATIONAL
ANTHRAX AND INFECTION AND THAT
THOSE ANIMALS THAT SURVIVE WOULD
NOT BE AT RISK OF DEVELOPING
DISEASE FOR RETAINED SUPPOSES
DUE TO DEVELOPMENT OF A
PROTECTIVE IMMUNE RESPONSE.
NEXT SLIDE, PLEASE.
SO WE DESIGNED AN EXPERIMENT
THIS HAD 20 ADULT RECESS
Mc CABBINGS THAT WERE IN 2
DIFFERENT GROUPS,A I PROPHYLAXIS
GROUP AND A TREATMENT GROUP.
THE SPORES WERE ADMINISTERED AND
THE AEROSOL DOSE WAS LARGE,
GREATER THAN 400 LV50S, BLOOD
CULTURES WERE OBTAINED EVERY 12
HOURS FOR ALL ANIMALS AT 7 DAYS
AFTER EXPOSURE, TISSUES FOR
HISTOPATHOLOGY WERE
ABNORMALITIES TIANYLED AND SERUM
FOR IGG ANTIBODIES WERE MEASURED
ON STUDY DAYS 14, 21, 28, AND 42
WITHIN EL ISA.
>> NEXT SLIDE, ANIMALS IN THE
GROUP RECEIVED 100 MG EVERY 2
HOURS, 1-2 HOURS AFTER AEROSOL
EXPOSURE, ANIMALS IN THE
TREATMENT GROWM BEGAN ANTIBIOTIC
THERAPY WITH CIPROFLOXACIN AFTER
2 CONSECUTIVE BLOOD CULTURES
WERE POSITIVE PER ANTHRAX, THE
DURATION OF THE PROVE LAX AXIS
GROUP WAS--PROPHYLAXIS GROUP WAS
LINKED TO THE TREATMENT GROUP SO
ONCE THE ANIMAL HAD COMPLETED 10
DAYS ANTIBIOTIC THERAPY,
ANTIBIOTICS WERE DISCONTINUED IN
THAT ANIMAL AND THE MATCHED PAIR
IN THE PROPHYLAXIS GROUP.
NEXT SLIDE, PLEASE.
SO LET'S LOOK ATY THE SURVIVAL
RESULTS WHILE ON ANTIBIOTIC.
AS CAN BE SEEN BY THE GREEN
BARS, ALL 10 ANIMALS IN THE
PROPHYLAXIS GROUP SURVIVE AND
REMAIN--BLUE BARS, 3 OF 10 OR
30% OF THE ANIMALS IN THE
TREATMENT GROUP DIED, WHILE
RECEIVING THEIR 10 DAY COURSE OF
OF
CIPROFLOXACIN TREATMENT.
THESE ANIMALS DIED ON DAYS 5, 8
AND 9 AFTER STARTING TREATMENT,
ALL 3 ANIMALS DEMONSTRATED THE
GROWTH OF THE ANTHRAX.
AND AT NECROPSY, ALL 3 ANIMALS
HAD EVIDENCE OF ANTHRAX AS
MANIFESTED BY THE TRACHIO
BRONCHIAL LYMPHNODE SAYS AND
HEMORRHAGIC MEDIA STINNITEIS.
NEXT SLIDE.
THE NEXT SLIDE SHOWS SURVIVAL
RESULTS AFTER THE COMPLETION OF
ANTIBIOTIC THERAPY.
IN THE PROPHYLAXIS GROUP, 8 OF
THE ANIMALS DIED AFTER SECESSION
OF ANTIBIOTIC THERAPY.
THESE DEATHS OCCURRED BETWEEN 4
AND 9 DAYS AFTER ANTIBIOTICS
WERE STOPPED.
ALL 8 OF THESE ANIMALS HAD
POSITIVE CULTURES FOR ANTHRAX IN
THEIR BLOOD, SPLEEN, BRAIN, LUNG
AND LYMPHNODES AND ALL HAD
NEUROECTODERMAL KRONISH MEDIAL
HEMRITIS ON AUTOPSIES, ON
CONTRAST THE TREATMENT GROUP,
BLUE BARS, NONE OF THE 7 ANIMALS
DIED AFTER COMPLETING A 7 DAY
COURSE OF ANTIBIOTIC THERAPY AND
THIS DIFFERENCE WAS HIGHLY
STATISTICALLY SIGNIFICANT.
THERE WERE NO ILLNESSES IN THESE
ANIMALS FOR AS LONG AS 120 DAYS
AFTER EXPOSE AND YOU ARE ALL 7
ANIMALS DEVELOP DETECTABLE
LEVELS OF ANTIPA AND
IGG ANTIBODIES AFTER DAY 14 OF
EXPOSURE.
NEXT SLIDE, PLEASE.
HERE'S THE DATA PRESENTED AS A
SURVIVAL CURVE.
AS CAN BE SEEN IN THE OPEN
TRIANGLES, WHILE ON ANTIBIOTIC
THERAPY THERE WERE 3 DEATHS IN
THE TREATMENT GROUP.
HOWEVER, AFTER COMPLETING 10
DAYS OF ANTIBIOTIC THERAPY THAT
WAS STARTED AFTER THE BIG
DEVELOPMENT OF BACTERIAEREMMIA,
THERE WERE NO FURTHER DEATHS IN
THE GROUP.
THE HIGHER CIRCLES EXPERIENCED
HIGH MORTALITY RATE DUE TO
SHORTAGE OF PROPHYLAXIS WHICH
AVERAGED ABOUT 13 DAYS.
NEXT SLIDE.
IN SUMMARY AS PREVIOUS WORK SHOZ
SHOWN, RECESS Mc CABBINGS
GIIVE A SHORT COURSE OF
ANTIBIOTICS FOR INHALATIONAL
ANTHRAX EXPERIENCED MORTALITY
ONCE THE ANTIBIOTICS WERE
DISCONTINUED, IN CONTRAST
MACAQUES TREATED WITH A SHORT
COURSE OF ANTIBIOTIC THERAPY FOR
INHALATIONAL ANTHRAX AFTER THE
ONSET OF BACTERIAEREMMIA WERE
NOT AT RISK FOR DEVELOPING
DISEASE AFTER THE CESSATION OF
ANTIBIOTIC THERAPY.
AND THE DEVELOPMENT OF ROUGH
ATOM A PROTECTIVE IMMUNE
RESPONSE.
SO PATIENT WHO IS TREATED FOR
ANTHRAX AND RECOVER, WE
RECOMMENDED OR SUGGEST TODAY
SHOULD BE TESTED FOR A
DEVELOPMENT OF AN IMMUNE
RESPONSE TO THE ANTHRAX, BECAUSE
THE PRESENCE OF AN ANTIP
ANTIBODIES MAY BE USEFUL FOR
DETERMINING WHEN ANTIBIOTIC CANS
SAFELY BE DISCONTINUED IN SUCH
INDIVIDUALS.
NOW I WILL TURN IT BACK OVER TO
DR. WRIGHT.
>> THANKS, NICK.
SO WE IN THE THIRD QUESTION
DECIDED TO TAKE A LOOK AT CLIND
O MICEIN TO SEE IF IT MADE A
DIFFERENCE IN SURVIVAL.
SO WE KNOW THAT CLIND O MICEIN
IS A PROTEIN SIPGHT SIS
INHIBITOR AND IT HAS TOXIN
ACTIVITY AGAINST OTHER
GRAM-POSITIVE ORGANISMS AND IT
HAD BEEN USED DURING THE 2001
ATTACKS BUT SINCE THAT TIME,
ANIMAL DATA HAD BEEN CONFLICTING
IN SOME OF THE RESULTS, SO, WE
DECIDED TO TAKE A LOOK IN
NONHUMAN PRIMATES HAVE A CLINDA
MICEIN ONLY GROUP, A
CIPROFLOXACIN GROUP AND A
COMBINATION ARM TO LOOK AT TOXIN
LEVELS AND SURVIVAL AND AS CAN
YOU SEE ON THIS SURVIVAL CURVE,
IN THE CLOSED CIRCLES, THAT'S
THE CIPRO-ONLY GROUP, THERE WAS
A HUNDRED PERCENT SURVIVAL, OPEN
SQUARES YOU 8 OUT OF 11, 73%
SURVIVEAR FOR CLINDA MICEIN ONLY
AND FOR THE CLOSED TRIANGLES,
THE COMBINATION ARM SIMILAR
SURVIVAL SO THERE WAS NOT A
SIGNIFICANCE SURVIVAL BETWEEN
THE DIFFERENT ARMS BUT THIS WAS
THE FIRST ANIMAL STUDY LOOKING
AT CLINDA MICEIN AND NONHUMAN
PRIMATES TO LOOK AT ANTHRAX, SO
WE DID SHOW THAT CLINDA MICEIN
DID IMPROVE SURVIVAL BY ITSELF
JUST BECAUSE OF THE SMALL
NUMBERS AND THE HUNDRED PERCENT
SURVIVAL IN THE CIPRO GROUP, AND
WE'RE NOT ABLE TO SHOW WHETHER
THE ADDITION OF CLINDA MICEIN
ADDED BENEFIT AND AGAIN FOR
TREATMENT, IT WAS COUNTED AS 2
CONSECUTIVE POSITIVE BLD BLOOD
CULTURES 12 HOURS APART WAS THE
TRIGGER FOR STARTING
ANTIBIOTICS.
SO IN THE LAST FEW MINUTES I
WOULD LIKE TO TOUCH ON THESE
OBJECTIVES, BECOME AWARE OF
RESEARCH INFRASTRUCTURE AND
CAPACITY AS WELL AS IDENTIFY
REMAINING CLINICAL QUESTIONS
REGARDING INHALATIONAL ANTHRAX
AND ANTIBIOTICS THAT WERE FDA
A APPROVED, PENICILLIN AND
DOXYCYCLINE AND THERE WERE SO
MANY QUESTIONS AND THERE WERE
ONT ENOUGH PEOPLE OR PLACES TO
POTENTIALLY LOOK AT THIS, SO
THERE WAS A BLUE RIBBON PANEL IN
2002 WHICH IDENTIFIED A HIGH
PRIORITY TO INCREASE
INFRASTRUCTURE AND TO ADDRESS
THE SERIOUS SHORTAGE OF
FACILITIES TO SAFELY CONDUCT
RESEARCH ON EMERGING INFECTIOUS
DISEASES.
AND 1 THING I WANTED TOADAAD IS
THE FACILITY FORT DIETRICH,
BECAUSE IT WAS THE FIRST LAB TO
INTEGRATE THAT HOSPITAL TYPE
IMAGING EQUIPMENT INTO A
BSL3/BSL4 SPACE FOR RESEARCH.
THE LAB IS PART OF THE NATIONAL
INTERAGENCY BIODEFENSE CAMPUS AT
FORT DETRICK, ALONG WITH THE
ARMY'S USAM RIN, IN ADDITION AT
THE CLINICAL CENTER, A SPECIAL
CLINICAL STUDIES UNIT WAS
CONSTRUCTED THAT WAS ENABLE HIGH
CONTAINMENT INFECTION, ISOLATION
OTHERS PROPER AIR FLOW ROOMS TO
TAKE CARE OF PATIENTS AND
CONDUCT RESEARCH ON PEOPLE THAT
MIGHT HAVE MORE TRANSMISSIBLE
INFECTIONS, AND WHEN THE EBOLA
OUTBREAK IN 2014 HIT, THE SES U
WAS USED TO CARE FOR SOME OF THE
HEALTHCARE WORKERS WHO HAD
GOTTEN EBOLA FROM THE EBOLA
PATES THAT HAD COME TO THE
UNITED STATES.
SO THE MANY CLINICAL RESEARCH
QUESTIONS THAT WE STILL HAVE
THAT I WANTED TO MENTION
SEVERAL, CAN NONINVASIVE IMAGING
FINDINGS BE USED TO CHARACTERIZE
STAGES OF ANTHRAX INFECTION?
WELL THE ACTUAL CATALYST FOR THE
RESEARCH FACILITY WAS QUESTIONS
JUST LIKE THIS AND IMAGING HAS
EVOLVED OVER'RE SIGNIFICANCE 95
CANTILY OVER THE YEARS AND AT
THE THEY PUBLISHED THINGS
LOOKING AT EBOLA AND SARS-COV-2,
AND THE QUESTION ABOUT HOW MANY
ANTIBIOTICS NEEDED DURING ACUTE
INFECTION IS IMPORTANT, WHEN IS
THE BEST TIME TO GIVE ANTITOXIN
TREATMENT AND WHAT IS THE
LONG-TERM SUPPLY OF INHALATIONAL
ANTHRAX?
AND ALL THESE ARE QUESTIONS WE
LOOK AT IN ANY PATHOGEN IS
CERTAINLY COVID HAS BEEN STUDIED
EXTENSIVELY.
FOR THE SECOND QUESTION ABOUT
THE NUMBER OF ANTIBIOTICS TO
USE, THIS GETS COVERED WITH THE
PERIODIC UPDATES BY THE CDC
GUIDELINES AND THE LAST SET
GUIDELINES WAS ISSUED IN 2014,
THE PANEL MET LAST YEAR AND WILL
BE ISSUING ANOTHER 1 SOON.
BUT AT THAT TIME, THE EMPHASIS
WAS PLACED ON LOOKING AT
SYSTEMIC ANTHRAX AND THE CONTEXT
OF WHETHER THERE WAS MENINGITIS
OR NOT MENINGITIS AND THE OLD
LITERATURE SUGGESTS THAT
BASICALLY IF HAVE YOU SYSTEMIC
ANTHRAX, HAVE YOU A HIGH
LIKELIHOOD OF HAVING MENINGITIS
AND IT'S IMPORTANT TO COVER OR
HAVE CNS PENETRATION WITH THE
DRUGS YOU ARE CHIEWZING SO IF
YOU THINK THERE'S MENINGITIS,
THERE'S 3 DRUGS VERSUS 2 IF YOU
RULED IT OUT AND ALSO EMPHASIZED
ABOUT ADDING ANTITOXINS TO
ANTIBIOTICS FOR PEOPLE WHO
REALLY HAVE SYSTEMIC
INVOLVEMENT, AND TO CONTINUE
AGGRESSIVE PLURAL FLUID
MANAGEMENT BECAUSE YOU'RE
BASICALLY GETTING RID OF THE
TOXIN.
THE THIRD QUESTION, TIMING OF
TREATMENTS REMAINS UNKNOWN.
THERE'S BEEN EXTENSIVE
DISCUSSION ON THAT AMONGST
EXPERTS OVER THE YEARS AND THIS
IS ALWAYS A QUESTION FOR ANY
PATHOGEN.
BUT TO UPDATE YOU SINCE 2001, IF
YOU LOOK AT THE GREEN, THESE ARE
THERAPEUTICS OR ANTIMICROBIALS
THAT HAVE BEEN APPROVED BY THE
FDA WITH ANTHRAX, MICROBIALS OFF
LABEL COULD BE NECESSARY FOR
SICK PATIENTS, THERE'S THE
CRITICAL ROLE OF COURSE IN TCs
AND CHEST DIEWBS BUT HERE WE SEE
2 MONOCLONAL ANTIBODIES AND
ANTHRAX IMMUNE GLOBUE LYNN WHICH
WERE ALL APPROVED UNDER THE
ANIMAL RULE.
THERE'S ALL STRATEGIC STOCK PILE
NOW AND IT'S IMPORTANT TO
REMEMBER THAT NONE OF THEM
CROSSLET BLOOD BRAIN BARRIER SO
AGAIN, BEING ABLE TO COVER FOR
POTENTIAL MENINGITIS IS
IMPORTANT.
SO THE QUESTION OF TIMING OF
TREATMENTS IS SEEN WITH SURVIVE
AG SEPSIS CAMPAIGNS AND HOW
EARLY TO GIVE ANTIBIOTICS WILL
CONTINUE TO BE IMPORTANT AS WELL
AS KNOWING ABOUT TARGETS OTHER
THAN JUST INHIBITING THE
PROTECTIVE ANTIGEN LOOKING FOR
OTHER TARGETS.
AND FINALLY WITH THE FOURTH
QUESTION, THE SEQUELAE, WE HAD A
PROTOCOL IN PLACE AT OUR CLINIC
AT NIH FOR MANY YEARS AND
FOLLOWED A SUBSET OF THE 2001
SURVIVORS.
WE SEE WITH 4 ADULT MALES ALL 4
OF OUR ADULT MALES SHOWED
EVIDENCE OF SUSTAINED--LOW
GROWTH HORMONE AND THIS WAS SEEN
AS EARLY AS 4 MONTHS AFTER
INFECTION AND PERSISTED AS LONG
AS 10 YEARS WITHOUT TREATMENT
AND CERTAINLY THIS HAS BEEN
OBSERVED AFTER OTHER INFECT YOWZ
DISEASES AND AFTER TRAUMATIC
BRAIN INJURY BUT IT'S THE FIRST
TIME DESCRIBED IN ANTHRAX.
SO IN SUMMARY, YOU KNOW WE WOULD
LIKE TO SAY, THAT THE ANTHRAX
LETTER ATTACKS OF 2001 REVEALED
THE URGENT NEED TO UNDERSTAND
OLD PATHOGENS USING CURRENT
MEDICAL TOOLS WHICH CHANGE OVER
TIME AND WHEN WE LOOK AT TODAY
COMPARED TO 2001 FOR EXAMPLE.
IN THE ABSENCE OF HUMAN TRIALS,
ANIMAL STUDIES PLAY A PIVOTAL
ROLE IN INFORMING PUBLIC HEALTH
POLICY DECISIONS, THE INVEST
EXPMENT BIODEFENSE AND EMERGING
INFECTIOUSS RESEARCH STRUCTURE
AND IN MECHANISMS SUCH AS THE
ANIMAL ROLE HAVE MADE RAPID
DISCOVERY POSSIBLE YEARS LATER
IN EBOLA AND SARS-COV-2
RESEARCH.
WE WOULD LIKE TO ACKNOWLEDGE ALL
OF OUR COLLABORATORS AT USA
MRID, AND CDC, WE WERE
ESPECIALLY INVOLVED WITH THE
CLINDA MICEIN PAPER.
OUR GROUP AT NIAID AND THE
CLINIC AND THE TEAM WHICH
CLASSIFIES FOLKS FROM
ENDOCRINOLOGY AND OTHER GROUPS,
ANTHRAX STUDY PARFISCHER PANTS
AND THEN I WOULD LIKE TO
PERSONALLY THANK DR. VIETRI AND
DR. FRIEDLANDER, FOR ALL OF YOUR
COLLABORATION, VISION, HOURS
TOGETHER AND OUR FRIENDSHIP.
THANK YOU AND WITH THAT, WE WILL
TURN IT OVER FOR ANY QUESTIONS
IF THERE'S ENOUGH TIME
REMAINING.
>> THERE ACTUALLY IS, DR. WRIGHT
AND THANK YOU DR. WRIGHT,
DR. FRIEDLANDER AND DR. VIETRI,
THIS WAS OBVIOUSLY TO ME A
FASCINATING TOPIC AND I THINK
YOUR PRESENTATION ILLUSTRATED
WELL THE COMPLEXITY OF ANTHRAX,
NOT JUST THE SYMPTOMS BUT THE
REGAFERREDS TO TREATMENT, ISSUES
OF TIMING THROUGHOUT THE
TREATMENTS, PATIENTS AND THE
LENGTH AND COURSE OF THERAPIES.
SO, A COUPLE OF QUESTIONS, 1, SO
AND THIS GETS TO SOMETHING I'M A
LITTLE FAMILIAR WITH, WITH THIS
OCCURRING VACCINE SCHEDULE, IT'S
NOT 1 AND DONE, IF INVOLVES A
SERIES, COULD YOU DESCRIBE LAWN
MOWER A CURRENT LOOKS LIKE AND
FOR THOSE THAT ARE INFECTED,
WHAT WOULD THAT LOOK LIKE?
>> SO MAYBE I CAN ANSWER THAT OR
START.
THE CURRENT RECOMMENDATIONS ARE
FOR PROPHYLACTIC USE OF THE
VACCINATION.
THE SCHEDULE IS NOW 0.
THE FIRST DOSE IS FOLLOWED BY A
DOSE 1 MONTH LATER, THEN 6
MONTHS LATER AND 12 MONTHS LATER
AND THEN 18 MONTHS LATER.
SO IT'S 0, 1, 6 MONTHS.
AND IT'S GIVEN INTRA MUSCULARLY.
NOW, FOR POST EXPOSURE
PROPHYLAXIS, SO THIS RESULTS IN
A--IN AN IMMUNE RESPONSE THAT
DEVELOPS, BUT FOR POST EXPOSURE
PROPHYLAXIS, THE RECOMMENDATION
STILL REMAIN TO GIVE THE VACCINE
MORE FREQUENTLY, THAT IS AT 0
DAYS, AT 2 WEEKS, AND AT 1
MONTH, THEN 6 MONTHS, 12 MONTHS,
18 MONTHS AND THAT ROUTE IS
GIVEN SUBCUTANEOUSLY BECAUSE
BOTH THE EXTRA DOSE AT 2 WEEKS
AND THE ROUTE SUBCUTANEOUS
VERSUS INTRA MUSCULAR RESULTS IN
A MORE RAPID AND HIGHER IMMUNE
RESPONSE.
SO, FOR PROPHYLAXIS AS I SAID 01
FOR MONTH FOR I. M. AND MOST
EXPOSURE VACCINATION AS WE
DESCRIBE IN THESE STUDIES, IT'S
STILL 02 AND THEN 4 WEEKS GET IN
SUBCUTANEOUSLY, NOW THERE IS
EFFORT UNDERWAY USING ADDITIONAL
VACCINE FORMULATIONS WITH OTHER
ADJUVANTS.
TO TRY TO DEVELOP A NEW VACCINE,
THAT'S NOT GIVEN SUBCUTANEOUSLY
AND THAT'S A GIVEN IN A LESS
FREQUENT DOSAGE.
>> THANK YOU VERY MUCH.
ONE OTHER QUESTION HERE, SO
ANTHRAX ENTERED THE PUBLIC
CONSCIOUSNESS WITH THE ANTHRAX
ATTACKS OF 2001, SO WHAT IS THE
SOPHISTICATION OF MANUFACTURING
CAPABILITY THAT'S REQUIRED TO
CREATE SIGNIFICANT QUANTITIES OF
SPORES AND WHAT'S THE CURRENT
RISK OF A ROGUE LABORATORY--
>> DO YOU WANT TO TAKE THAT?
>> YEAH, WELL, THAT'S A BIG
UNKNOWN.
I THINK UNFORTUNATELY THERE'S A
LONG, LONG HISTORY OF THE USE OF
NOT JUST ANTHRAX BUT CERTAINLY
ANTHRAX THAT GOES BACK
UNFORTUNATELY A VERY LONG TIME
FROM MANY COUNTRIES INCLUDING
THE U.S. IN TERMS OF USING
POTENTIALLY USING IT AND THEN OF
COURSE, THE BIOLOGICAL WEAPONS
CONVENTION WAS SIGNED.
SO IN TERMS OF--WE'VE SEEN WHAT
THE LETTER VS DONE IN JUST A
HANDFUL OF LETTERS.
I THINK THE CONSENSUS IS FOR A
LARGE SCALE EXPOSURE THAT
REQUIRES A GREAT DEAL OF
SOPHISTICATION.
>> OKAY, I DON'T BELIEVE WE HAVE
ANY MORE QUESTIONS COMING IN.
AND WE STILL HAVE 2 MINUTES TO
SPARE, SO, YOU HAVE ANSWERED ALL
THE QUESTIONS FOR OUR AUDIENCE,
AND SO WITH THAT I WILL GIVE IT
BACK FOR 2 MINUTES TO SET UP OUR
CLOSING, AGAIN, I WANT THANK ALL
OF YOU ON BEHALF OF THE
COMMUNITY FOR SHARING YOUR
RESEARCH AND MANY YEARS OF
COLLABORATION WHICH CLEARLY ARE
SIGNIFICANT IMPORTANCE NOT ONLY
FOR THE RESEARCH INFECTIOUS
DECEASE DISEASES BUT ALSO FOR
PUBLIC AND BI ONY EEIVETS.
SO THANK YOU VERY MUCH AND I
WISH EVERYBODY A GOOD AFTERNOON.
>> THANK YOU.