1. Bioterrorism Agents: Smallpox, Botulism, and Tularemia
Jeff Kuper, Pharm.D., BCPS
Clinical Associate Professor
Ernest Mario School of Pharmacy
Rutgers, The State University of New Jersey

2. Outline Diseases Smallpox Botulism Tularemia Topics History
Jeff Kuper, Pharm.D., BCPS
9/24/02
Outline
Diseases
Smallpox
Botulism
Tularemia
Topics
History
Epidemiology
Manifestations
Diagnosis
Prevention and treatment
Rutgers School of Pharmacy

3. Smallpox Variola Virus
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Variola Virus
DNA orthopoxvirus
among the largest & most complex viruses
brick-shaped
Rutgers School of Pharmacy

4. Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox History
: British distribute blankets used by smallpox patients to Native Americans during the French and Indian Wars
1796: Edward Jenner demonstrates that deliberate infection with cowpox protects people from smallpox, introducing the practice of “vaccination”
: WHO campaign to eradicate smallpox
1980: WHO recommends transfer of all remaining variola virus to two reference labs
During F&I Wars, >50% of some tribes died from smallpox
Rutgers School of Pharmacy

5. Smallpox Epidemiology
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Epidemiology
Person-to-person transmission
Aerosol droplets
Direct contact with lesions or contaminated clothing, bedding, etc.
Transmission usually slower than chickenpox
Not contagious until rash appears
Incubation period is typically days
Fever precedes rash, so pts. are often already bedridden by the time viral shedding occurs
infectious for 7-10 days, until lesions scab
ea. primary case may lead to secondary cases
Natural incidence highest in winter & early spring
infectious dose is unknown but believed to be only a few virions
incubation period range = 7-17 days
Rutgers School of Pharmacy

6. Smallpox Variola Major
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Variola Major
Initial presentation: high fever, prostration, headache, backache, ± abdominal pain
Maculopapular rash begins on the face and arms, spreading to the trunk and legs
 vesicles  pustules  scabs over 7-10 days
Lesions in one area appear at same stage
May leave residual scarring
Complications: toxemia, encephalitis
Mortality rate > 30% in the unvaccinated
rash begins 1-2 days after fever onset
lesions also appear in the mouth & throat & on the palms (unlike chickenpox)
in chickenpox, lesions may appear at different stages w/in a single area
involvement of other organs is rare, as are secondary bacterial infxns.
Rutgers School of Pharmacy

7. Henderson DA. JAMA 1999; 281:2127 Jeff Kuper, Pharm.D., BCPS 9/24/02
more lesions on face & arms than trunk & legs
Henderson DA. JAMA 1999; 281:2127
Rutgers School of Pharmacy

8. Smallpox Other Clinical Manifestations
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Other Clinical Manifestations
Hemorrhagic smallpox
Malignant smallpox
Variola minor
In partially immune patients, the rash may be milder and more atypical and evolve more quickly
“classic” smallpox (variola major) accounts for 90% of cases
hem. smallpox more common in Pg women, w/ bleeding into the skin & mucous mems. & death occurring w/in 5 days of rash
malignant smallpox: rather than becoming pustules, lesions remain flat & become confluent
gen. disappear w/out scabbing, but sig. skin peeling may occur
often fatal
variola minor has mortality rate < 1%, milder constitutional Sx, milder rash
Rutgers School of Pharmacy

9. Smallpox Diagnosis
Clinical diagnosis in the setting of a known outbreak
Lab diagnosis requires biolevel 4 facility
Sample vesicular fluid or scab
Characteristic appearance under an electron microscope
Culture and/or PCR for confirmation

10. Smallpox Chickenpox vs. Smallpox
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Chickenpox vs. Smallpox
Chickenpox
Smallpox
Prodrome
none or mild
pronounced
Lesion types
superficial, different stages
deep-seated, same stage
Lesion distribution
mostly on trunk, face; palms/soles uncommon
mostly on face, extremities; palms/soles common
Lesion evolution
rapid
slow
Systemic symptoms
minimal
toxic, moribund
entire evolution over 24 hrs. for chickenpox vs. 1-2 days per stage for smallpox
From
Rutgers School of Pharmacy

11. Smallpox Management Post-exposure vaccination: ring vaccination
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Management
Post-exposure vaccination: ring vaccination
For all contacts and emergency/essential workers
Vaccination within 4 days of exposure may prevent or reduce the severity of illness
Isolation of persons with fever
? Cidofovir
accelerated vaccine response in persons who have been previously vaccinated
Rutgers School of Pharmacy

12. Smallpox Vaccine Consists of live vaccinia virus (cowpox)
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine
Consists of live vaccinia virus (cowpox)
Dryvax® is the only FDA-licensed vaccine
Other vaccines held in reserve by CDC
duration of protection is unknown, but the entire US pop. is now assumed to be unprotected
Ab titers (which have an unclear correlation w/ protection anyway) decr. 3-5 yrs. after vacc., but then stabilize for next 30 yrs.
Taiwanese study (CID 2004: 38:86) shows T cell reactivity remaining in those vaccinated in past 3 decades IF THEY HAD A SCAR
those w/out scars or vaccinated > 4 decades ago had no sig. response
Rutgers School of Pharmacy

13. Smallpox Vaccination Method
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccination Method
Multiple-puncture technique using bifurcated needle
Needle prongs are calibrated to hold the correct dose when dipped into vaccine vial
Hold needle perpendicular to skin and make rapid, vigorous punctures
Should see trace blood
2-3 punctures for primary vaccination
The skin over the insertion of the deltoid muscle or the posterior aspect of the arm over the triceps muscle is the preferred site for smallpox vaccination. Skin preparation for vaccination is not required unless the area is grossly contaminated, in which case soap and water should be used to clean the site. If alcohol or another chemical antiseptic is used, the skin must be allowed to dry thoroughly to prevent inactivation of the vaccine virus by the antiseptic. The multiple-puncture technique uses a presterilized bifurcated needle that is inserted vertically into the vaccine vial, causing a small droplet of vaccine (approximately mL) to adhere between the prongs of the needle. The droplet contains the recommended dosage of vaccine, and its presence within the prongs of the bifurcated needle should be confirmed visually. Holding the bifurcated needle perpendicular to the skin, punctures are made rapidly, with strokes vigorous enough to allow a trace of blood to appear after seconds. According to the product labeling, 2--3 punctures are recommended for primary vaccination and 15 punctures for revaccination. If no trace of blood is visible after vaccination, an additional three insertions should be made by using the same bifurcated needle without reinserting the needle into the vaccine vial. If no evidence of vaccine take is apparent after 7 days, the person can be vaccinated again. Any remaining vaccine should be wiped off the skin with dry sterile gauze and the gauze disposed of in a biohazard waste container.
Rutgers School of Pharmacy

14. Smallpox Vaccine “Take”
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine “Take”
“take” used as surrogate marker of immunity
progression from papule (d3-5) to vesicle (d5-8) to pustule to scab
max. size at day 8-10
pustule dries from center outward to form scab
scab separates at day 14-21, leaving pitted scar
From
Rutgers School of Pharmacy

15. Smallpox Vaccine “Take”
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine “Take”
Take
Non-Take
evaluate for take at days 6-8
earlier eval. may result in false pos. d/t dermal hypersensitivity
later eval. may result in false neg. among revaccinees, who may have more rapid progression
revaccinees may have “accelerated rxns.” that resolve in < 6 days—NOT counted as take
take defined as a pustular lesion or an area of definite induration or erythema surrounding a central lesion, which can be a scab or ulcer
all other responses are equivocal, or “nontakes”, & revaccination is rec.
“nontake” d/t suboptimal vaccination technique, subpotent vaccine, or residual immunity among previously vaccinated persons
lrg., painful rxns. (> 10 cm) occur in 10% of 1st-time vaccinees—known as “robust takes” (RTs)
may be mistaken for cellulitis, but bact. superinfxn. is rare
RTs occur on days 8-10 & improve w/in 3 days vs. cellulitis, which occurs in < 5d or > 30d & progresses w/out ABX
manage w/ limb rest, non-ASA PO analgesic, antipruritics; AVOID top. Tx
From
Rutgers School of Pharmacy

16. Smallpox Vaccine Site Care
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine Site Care
Cover with gauze and semipermeable dressing to decrease risk of transmission of vaccinia virus
Vaccinia is shed from time lesion appears until scab falls off
Rate of transmission during the ’60s was 2-6 cases per 100,000 first-time vaccinees
No evidence of respiratory transmission
Routine infection control procedures
Avoid direct contact with the vaccination site
Healthcare workers do NOT need to be furloughed from work
vaccinia is shed from appearance of lesion (day 2-5 post-vaccination) until scab falls off (day 14-21)
close contact appears to be required
HCWs do NOT need to be furloughed
for persons in non-pt. care settings, gauze & clothing is sufficient
self-adhesive bandage may be just as good (CID 2004; 39:1004)
defer donating blood for 21 days
rate of transmission during the ’60s was 2-6/100K 1st-time vaccinees
approx. enough VIG available to treat 4,000 ADRs (equiv. to amt. expected from vaccinating 40 mil. people)
Rutgers School of Pharmacy

17. Smallpox Relative Vaccine Contraindications
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Relative Vaccine Contraindications
Atopic dermatitis or eczema (active or history)*
Other active exfoliative skin conditions*
Immunosuppressive conditions*
Steroid doses ≥ 2 mg/kg or 20 mg/day of prednisone for > 2 weeks within past week
Other immunosuppressive meds within past 3 weeks
other skin conditions incl. burns, HSV, VZV, impetigo, acne, psoriasis, Darier’s DZ
HSCT w/in past 2 yrs. or > 2 yrs. w/ GVHD or DZ relapse
well tolerated in 10 military vaccinees w/ HIV (although CD4 = )
* Also contraindicated for household contacts
Rutgers School of Pharmacy

18. Smallpox Relative Vaccine Contraindications
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Relative Vaccine Contraindications
Pregnancy*
Breastfeeding
Infants < 1 year old
Allergy to vaccine component
Including neomycin, tetracycline, polymyxin B, streptomycin, glycerin, and phenol
?? Cardiac disease
women should avoid becoming Pg for > 4 wks. after vaccination
fetal vaccinia: typical skin lesions, organ involvement, high rate of fetal or early neonatal death
ACIP does not rec. pre-event vaccination for any children < 18yo
cardiac events noted in 2003 vacc.: MI, angina, myopericarditis
age range = 43-60yo
additional precaution: infl. eye DZ (i.e. requiring steroid)
incr. risk of autoinoc. b/c of rubbing the eye
can be given at the same time as other vaccines
if not given simultaneously, avoid other live vaccines w/in 4 wks. (inactive vaccines OK)
avoid VZV vaccine w/in 4 wks. to avoid confusion of the resulting skin lesions
vaccine may result in false neg. results w/ PPD testing, so avoid w/in 4 wks.
* Also contraindicated for household contacts
Rutgers School of Pharmacy

19. Smallpox Expected Vaccine Reactions
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Expected Vaccine Reactions
665 1st-time, adult vaccinees
some got 1:5 or 1:10 dilutions of vaccine
rxns. reported for days 7-9
100% reported at least 1 of the above rxns.
1/3 were sufficiently ill to miss some sleep, work, school, etc.
most rxns. occur days 3-7
fever is probably more common among children & lower among revaccinees
may also see satellite lesions at the perimeter of the vacc. site
SE Frey et al. NEJM 2002; 346:
Rutgers School of Pharmacy

20. Smallpox Vaccine Complications
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine Complications
Satellite lesions
Nonspecific rashes
rashes occur 10 days (range, 4-17) after 1st-time vacc. & resolve in 2-4 days
Rx w/ antihist. (if anything)
incl. maculopapular rash, lymphangitic streaking, generalized urticaria, roseola-like erythematous macules/patches
Rutgers School of Pharmacy

21. Smallpox Vaccine Complications
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccine Complications
Cases per million vaccinees
Non-life threatening
Inadvertent inoculation
25-529
Generalized vaccinia
23-242
Erythema multiforme
165
Life-threatening
Encephalitis
3-12
Progressive vaccinia
1-2
Eczema vaccinatum
10-39
Death
overall complication rate = 1 in ,000 1st-time vaccinees
may be higher today b/c of incr. # of persons in whom vaccine is contra.
other assoc. AEs: myocarditis, pericarditis, osteo., skin tumors at vacc. site, transverse myelitis, SZ, paralysis, polyneuritis, brachial neuritis, ppt. of erythema nodosum leprosum or neuritis among leprosy pts.
avoid revacc. of persons w/ h/o enceph. or PV
revacc. after EV is OK, but give proph. VIG
MMWR 2003; 52(RR-4):9
Rutgers School of Pharmacy

22. Smallpox Erythema Multiforme
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Erythema Multiforme
can appear as macules, papules, or target (bull’s eye) lesions
gen. occurs w/in 10 days of vacc. & lasts up to 4 wks.
may be v. pruritic (Rx w/ PO antipruritic)
may also see S-J synd. (+/- EM)
Rx w/ steroids is controversial
Rutgers School of Pharmacy

23. Smallpox Inadvertent Inoculation
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Inadvertent Inoculation
most common complication
risk factors: age < 4yo, burns, acne, psoriasis, etc.
lesions are self-limiting (w/in 3 wks.)
may Rx w/ VIG if extensive lesions or severe ocular infxn. (?or cidof.)
speeds recovery & prevents further spread
however, may worsen vaccinial keratitis (scarring, edema)
may Rx w/ top. trifluridine (Viroptic) for ocular infxn.
vidarabine also active but no longer on market
can also use as proph. if facial lesions near the eye
Rx until scabs have fallen off, but no more than 14 days w/ triflur. (d/t incr. in keratopathy)
top. antibacterial for proph. w/ keratitis
consider top. steroid w/ corneal ulceration or iritis
Rutgers School of Pharmacy

24. Smallpox Generalized Vaccinia
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Generalized Vaccinia
maculopapular or vesicular rash (often on erythematous base)
vesicles can be mistaken for smallpox, but distribution is diff.
may be dissem. or localized
may have febrile prodrome
onset 6-9 days after 1st-time vacc.
self-limited in immunocompetent pts.
supportive mgmt. (PO antipruritic, NSAID)
VIG for immunocompromised pts. or rare pt. who appears systemically ill
unlike EM, lesions are thought to contain vaccinia virus (from hematog. spread)
Rutgers School of Pharmacy

25. Smallpox Eczema Vaccinatum
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Eczema Vaccinatum
localized or generalized papular, vesicular, or pustular rash w/ predilection for areas of previous atopic dermatitis lesions
lesions often confluent
follow same evolution as vacc. site
often w/ fever, LAD, systemic illness
most MDs do not distinguish b/t atopic dermatitis & eczema (both chronic exfoliative skin conditions), so both are contra.
occas. seen w/ other skin DZs
onset concurrent w/ or shortly after vacc. site lesion
secondary cases appear 5-19 days after exposure to vaccinee
lesions contain vaccinia virus
mortality 30-40% w/out VIG, 7% w/ VIG
other mgmt. is supportive (hemodynamic, fluid/’lytes, skin care, Rx of secondary bact./fungal infxns.)
Rutgers School of Pharmacy

26. Smallpox Progressive Vaccinia
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Progressive Vaccinia
a.k.a. vaccinia necrosum, dissem. vaccinia, prolonged vaccinia, vaccinia gangrenosa
painless, progressive necrosis at vacc. site +/- met. lesions (incl. to bones or viscera)
suspect in persons whose vacc. lesion does not show signs of healing 2 wks. after vacc.
unlike a robust take, no infl. (at least initially)
d/t immune deficiency (esp. cell-mediated defect)
high mortality (100% w/out VIG)
other mgmt.: supportive care, Rx for secondary bact. infxn.
surg. debridement NOT shown to be useful
Rutgers School of Pharmacy

27. Smallpox Encephalitis/Encephalomyelitis
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Encephalitis/Encephalomyelitis
Diagnosis of exclusion
Encephalitis in infants < 2yo
Onset 6-10 days post-vaccination
Encephalomyelitis in older persons
Onset days post-vaccination
Mortality 25%, neurological sequelae 25%
Management: supportive, symptomatic
manifestations incl. fever, HA, malaise, lethargy, NV, SZ, paralysis, decr. MS, coma, transient amnesia, aphasia, hemiplegia, anorexia
more common w/ European vaccinia strain
proph. VIG may decr. incidence, but incidence is too low w/ US strain to warrant
not shown to be effective as Tx
LP may be WNL or w/ incr. opening pressure, monocytosis, lymphocytosis, incr. prot.
enceph. d/t vasc. changes
encephalomyelitis d/t demyelinating changes
Rutgers School of Pharmacy

28. Smallpox Fetal Vaccinia
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Fetal Vaccinia
complication of vacc. during Pg or shortly before (w/in 4 wks.) conception (also seen in contacts of vaccinees)
< 50 cases reported, so still v. uncommon (therefore proph. VIG or abortion is NOT indicated)
cases have occurred after vacc. in all 3 trimesters
skin lesions similar to PV or GV + organ involvement
high rate of fetal or neonatal mortality
other than FV, no evidence that vacc. during Pg is assoc. w/ adverse fetal or maternal outcomes
consider VIG for viable infant born w/ lesions, but no data
Rutgers School of Pharmacy

29. Smallpox Vaccinia Management
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccinia Management
Vaccinia immune globulin (VIG)
Indications
Eczema vaccinatum
Progressive vaccinia
Generalized vaccinia (severe or immunocompromised)
Inadvertent inoculation (severe or ocular other than keratitis)
Dose: mg/kg x 1
Has also been used as proph. in high-risk persons, but supplies not sufficient for this today
AEs: local rxns. after IM; joint pain; HA; NVD; rash; dizziness; drowsiness
severe: anaphylactoid rxns.; ARF; aseptic meningitis; infxns.
3 preps.: 1 IM (original) & 2 IV
IM prep. contains thimerosal
contra.: selective IgA deficiency
ltd. data in Pg or breastfeeding
dose depends on prep. used
IM to inject in buttock or anterolateral thigh
Rutgers School of Pharmacy

30. Smallpox Vaccinia Management
Jeff Kuper, Pharm.D., BCPS
9/24/02
Smallpox Vaccinia Management
Topical trifluridine for ocular infection
Cidofovir (Vistide®)
In vitro activity against orthopoxviruses
Nephrotoxic—administer with probenecid and hydration
Will be released by CDC as IND if:
Patient fails VIG treatment OR
Patient is near death OR
VIG supplies have been exhausted
other cidof. AEs: neutropenia, decr. IOP, uveitis/iritis, metabolic acidosis
proposed dosing: 5 mg/kg IV x 1, w/ 2nd dose 1 wk. later if necessary
Rutgers School of Pharmacy

31. Botulism Clostridium botulinum toxin
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Clostridium botulinum toxin
Spore-forming, obligate anaerobe found naturally in soil & marine sediment
7 distinct antigenic types, A-G, which are useful for epidemiologic tracing
see subterminal spore
From “Todar’s Online Textbook of Bacteriology”
Rutgers School of Pharmacy

32. Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism History
1812: link recognized between sausage (botulus in Latin) and paralytic illness in Germany
1897: C. botulinum and associated toxin first identified
1930s: Japanese army feeds botulinum toxin to Chinese POWs
: Aum Shinrikyo cult disperses aerosolized botulinum toxin at multiple sites in Japan, but no illnesses result
1990s: Iraq produces 19,000 L of toxin, half of which is loaded into weapons
Sverdlovsk: 68 deaths out of 79 cases
cases reported > 50km from site of release
’40s: Japanese army used anthrax in Manchuria
’90s: Aum Shinrikyo cult disperse aerosols of anthrax & botulinum toxin on at least 8 occasions, but no illnesses resulted
used an anthrax strain used for animal vaccination, which may be why no DZ resulted
Rutgers School of Pharmacy

33. Botulism Epidemiology
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Epidemiology
Transmission from exposure of mucous membranes to spores or toxin
Outbreaks most often associated with home-canned vegetables, fruits, and fish
12-72 hr. incubation period
Clues to intentional release
Large number of cases
Unusual toxin type
Simultaneous outbreaks with no common source
not contagious
wound botulism increasingly assoc. w/ injection of black tar heroin
achlorhydria & ABX use predispose to intestinal botulism
no cases of waterborne illness
not likely to contaminate water supply b/c: a) toxin inactivated by chlorine, other Tx; & b) lrg. inoculum would be needed
toxin may be stable for several days in untreated water or beverages, however
any food may be implicated, esp. high pH veggies (beans, carrots, corn, peppers); infant botulism assoc. w/ honey
toxin inactivated by temps of 85C x 5 mins., but spores are heat-resistant (cook in pressure cooker to kill)
w/ foodborne outbreaks, incubation ranges from 2 hr. to 8 days
mean outbreak size = 2.5 cases
most common toxin types are A (54%), B (15%), & E (27%, mostly assoc. w/ native Eskimo/Inuit foods)
Rutgers School of Pharmacy

34. Botulism Clinical Manifestations
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Clinical Manifestations
Most poisonous substance known
Toxin blocks acetylcholine release, resulting in flaccid muscle paralysis
Disease forms
Wound botulism
Infant botulism
Foodborne botulism
Inhalational botulism
natural
A single gram of crystalline toxin, evenly dispersed & inhaled, could kill 1 mil. people
Based on primate studies, the lethal dose is ng IV, ng by inhalation, or 70 mcg PO
Commercially available, therapeutic toxin A is an impractical weapon b/c ea. vial only contains 0.3% of the lethal inhalation dose (0.005% of the lethal PO dose)
used to treat conditions marked by excessive muscle activity (e.g. torticollis)
200 cases/yr. in US
intestinal botulism (a.k.a. infant botulism) is from ingestion of environmental spores (vs. ingestion of preformed toxin w/ foodborne)
man-made
Rutgers School of Pharmacy

35. Botulism Clinical Manifestations
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Clinical Manifestations
Symmetric, descending muscle weakness with prominent cranial nerve palsies
Acute onset
4 D’s: diplopia, dysarthria, dysphonia, dysphagia
May later involve autonomic system (e.g., bradycardia, hypotension, hypothermia, urinary retention)
Afebrile
No cognitive or sensory defects (other than blurred vision)
prodromal signs of foodborne illness affect the GI tract (NVD, cramps, dry mouth)
GI Sx may be d/t other bacterial toxins & therefore may not occur with pure toxin ingestion
rapidity of onset and severity relate to amt. of toxin
Sx may last for wks. to months & full recovery may take 1 yr.
Rutgers School of Pharmacy

36. Botulism Diagnosis Testing only available in specialty labs
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Diagnosis
Testing only available in specialty labs
Mouse bioassay of blood, stool, vomit, food for toxin (results in 1-2 days)
Culture of stool (results in 7-10 days)
Electromyogram
Common misdiagnoses: Guillain-Barré syndrome, myasthenia gravis, stroke, intoxication, tick paralysis
in many states, reporting is required even if only based on clinical suspicion
Rutgers School of Pharmacy

37. Botulism Equine Antitoxin Treatment
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Equine Antitoxin Treatment
Give as soon as diagnosis made to decrease severity and further damage
Does NOT reverse existing paralysis
Available from CDC via state health depts.
Antibodies against toxins A, B, and E
Dose: 1 10-mL vial given by IV infusion + 2nd vial given IM
First skin test and desensitize if necessary
mortality has decr. from >60% prior to critical care to 25% to 6% with modern Tx
investigational pentavalent (A-E) & heptavalent (A-G) antitoxins
additional doses may be needed for BT exposure after confirming adequacy of toxin neutralization by retesting pt. serum
PI recommends repeating the dose in 4 hrs. for severe or progressive DZ, but this is not necessary
can desensitize over 3-4 hrs.; regardless, diphen. & epi. should be readily available during Tx
Rutgers School of Pharmacy

38. Botulism Supportive Treatment
Jeff Kuper, Pharm.D., BCPS
9/24/02
Botulism Supportive Treatment
Fluid and nutrition support
Mechanical ventilation
Antibiotics for secondary infections
Avoid aminoglycosides, tetracyclines, and clindamycin
? Role for activated charcoal
? Botulism immune globulin (BIG)
Reverse Trendelenburg positioning for non-ventilated patients
Monitor non-ventilated patients for deteriorating respiratory function
BIG available from Cal. Dept. of Health for Tx of infant botulism
human origin, for IV admin.
ADRs: nephrotox., rash, GI, aseptic meningitis
dose: 50 mg/kg IV x 1 (for infants < 1yo)
high cost ($45K/dose for infant) but shown to sig. decr. hosp. LOS (5.5 wks. to 2.5 wks.) w/ infant botulism (assoc. w/ decr. cost of $70K)
wound botulism: also debride +/- Rx w/ pen. G or metro.
PEP
antitoxin given to primates after inhal. exposure led to 7/7 survival vs. 2/4 in primates treated after Sx appeared
not feasible given supply limitations & potential for anaphylaxis
investigational pentavalent (A-E) toxoid & recombinant vaccine
toxoid has been in use by the CDC & military for > 30 yrs.
induces immunity over several months, so not useful as PEP
decontamination
decay rate of 1-4% per min., so toxin is substantially inactivated by 2 days after aerosolization
wash clothing & skin w/ soap & water
clean surfaces w/ bleach (or wait for natural decay)
Rutgers School of Pharmacy

39. Tularemia Francisella tularensis
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Francisella tularensis
1 of the most infectious organisms known—only requires inoculation of 10 organisms for DZ
Est. that aerosol dispersal of 50 kg over a metropolitan city of 5 mil. would result in 250K incapacitating casualties, incl. 19K deaths
aerobic gram(-) coccobacillus
survives for wks. at low temps. in the environment
2 maj. subspecies (biovars)
biovar tularensis (type A) is most common in N. Am. & may be highly virulent
biovar holarctica (type B) is most common in Eurasia & is relatively avirulent
intracellular—multiplies in macrophages
1912: identified as cause of illness in squirrels in Tulare County, CA (1st human case identified in 1914)
called Bacterium tularense initially; later renamed for Dr. Edward Francis, a PHS researcher
From
Rutgers School of Pharmacy

40. Tularemia Epidemiology
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Epidemiology
Found naturally throughout N. Am. & Eurasia in water, soil, veg.
approx. 200 cases/yr. reported in US, w/ case-fatality rate of 1-2%
more common in men, age extremes (<10, >50), summer months
usually sporadic, but outbreaks are more common in Eurasia
MMWR 2002; 51:183
Rutgers School of Pharmacy

41. Tularemia Epidemiology
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Epidemiology
Routes of human transmission
Bites by infected insects
Handling infectious animals
Contact with infected food, water, soil
Aerosol inhalation
NOT contagious from person to person
Clues to intentional release
Abrupt onset of large numbers of people with febrile, mild respiratory illness, many of whom progress to life-threatening pneumonitis ± sepsis
Young, healthy people affected
Multiple cases in urban setting
insect vectors incl. ticks, flies, mosquitoes
animal reservoirs incl. rabbits, hares, squirrels, mice, rats, voles
exposure risks incl. hunting, trapping, butchering, farming, lab work
Rutgers School of Pharmacy

42. Tularemia Clinical Manifestations
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Clinical Manifestations
Ulceroglandular, glandular, oculoglandular disease
Oropharyngeal tularemia
Pneumonic tularemia
Typhoidal tularemia
Septic tularemia
infxn. can occur through skin, mucous mems., GIT, lungs
maj. targets are lymph nodes, lungs/pleura, spleen, liver, kidneys, causing granulomatous lesions
Begins as a nonspecific, often incapacitating febrile illness: abrupt onset, fever, HA, chills, myalgias, coryza, sore throat, pulse-temp. dissoc., dry cough, NVD, malaise, anorexia, wt. loss
oropharyngeal: pharyngitis, tonsillitis more common than stomatitis; +/- ulceration, cervical/retropharyngeal LAD
typhoidal tularemia: systemic illness in the absence of signs indicating either a site of inoculation or anatomic localization
progression gen. slower than anthrax or plague (also lower mortality)
onset 3-5d after inhalational exposure, w/ PNA developing days to wks. later
plague distinguished by rapid progression, copious sputum, hemoptysis, septic shock
anthrax distinguished by CXR findings (symmetric mediastinal widening, lack of bronchopneumonia)
plague/anthrax easier to Dx microbiologically
milder forms may be confused w/ Q fever
Rutgers School of Pharmacy

43. Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Diagnosis
Routine Gram staining and culturing will miss tularemia
Direct microscopic examination of infected fluids or tissues
Confirmed by special culture media
Results may take 10 days
Special safety precautions necessary
Other tests available at reference labs
DFA testing provides results w/in hrs., but only available at ref. labs.
sputum Cx gen. pos. w/ inhal. tularemia, but BCx gen. neg.
other tests: Ag detection assays, PCR, ELISA, PFGE, serologic titers
PCR has 50-75% sensitivity & may remain pos. after ABX are started
Rutgers School of Pharmacy

44. Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Treatment
Preferred: streptomycin 1 Gm IM q12h OR gentamicin 5 mg/kg IV/IM q24h
Alternatives:
Doxycycline 100 mg IV/PO q12h
Ciprofloxacin 400 mg IV q12h OR mg PO q12h
Chloramphenicol 15 mg/kg IV q6h
can complete Rx w/ PO
same Tx for Pg women, but higher rate of fetal toxicity w/ strepto. than gent.
cidal agents (AG, FQ) preferred for immunocompromised pts.
in mass casualty setting, use PO doxy. or cipro.
Rutgers School of Pharmacy

45. Tularemia Treatment Duration of therapy: Pediatrics:
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Treatment
Duration of therapy:
Aminoglycoside or quinolone: 10 days
Doxycycline or chloramphenicol: days
Mass casualty setting (Rx entirely PO): 14 days
Pediatrics:
Same agents as for adults
Strepto., gent., doxy., cipro. dosing as for plague
Chloramphenicol 15 mg/kg q6h
doxy. & chlor. require longer Tx duration b/c static, higher rate of Tx failure & relapse
potential Tx: monoclonal Ab to LPS, serum from vaccinated people
decontamination
clean surfaces w/ 10% bleach followed by 70% EtOH
wash body & clothing w/ soap water
chlorine should protect municipal water sources
Rutgers School of Pharmacy

46. Tularemia Prophylaxis
Jeff Kuper, Pharm.D., BCPS
9/24/02
Tularemia Prophylaxis
Live, attenuated vaccine is not currently available
Previously available to lab workers, others at high risk
Would NOT be useful as post-exposure prophylaxis
Post-exposure antibiotics
Recommended for persons known to have had high-risk exposures and who are identified during incubation period
Oral doxycycline or ciprofloxacin x 14 days
If exposure is unclear, start treatment for persons who develop fever or flu-like illness within 14 days
FDA suspended investigational use of vaccine pending more data
vaccine had been based on live vaccine strain (LVS) that was imported from Moscow
unclear how this strain had been attenuated
derived from type B subspecies
vaccine not helpful for PEP d/t short incubation period & incomplete protection
takes 2 wks. for Ab’s to appear
previous infxn. usually provides lifelong immunity
Rutgers School of Pharmacy