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PREVENTION AND TREATMENT OF ILLNESSES FROM BIOTERRORRIST AGENTS COA 2003 PHARMACY CATEGORY DAY MICHAEL KATZ, PHARM.D,

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BIOLOGICAL AGENTS CDC has 3 categories based on risk priority Category A Easily disseminated or transmitted High mortality, major public health impact May cause public panic, social disruption Required special action for preparedness Anthrax Botulism Plague Smallpox Tularemia Viral hemorrhagic fevers

BIOLOGICAL AGENTS Category B Moderately easy to disseminate Moderate morbidity, low mortality Requires enhancement of CDC diagnostic, surveillance activities Brucellosis Epsilon toxin of Clostridium perfringens Food safety threats (salmonella, E. coli O157:H7, shigella) Glanders Mellioidosis Psittacosis Q fever Ricin toxin from Ricinus communis (castor bean) Staphylococcal enterotoxin B Typhus Viral encephalitis Water safety threats (cholera, Cryptosporidium)

BIOLOGICAL AGENTS Category C Emerging pathogens that could be engineered for mass dissemination in future because of Availability Ease of production, dissemination Potential for high morbidity, mortality, major health impact Nipah virus Hantavirus ?

WHERE TO FIND INFORMATION Rapidly changing knowledge base, recommendations Internet CDC Bioterrorism site best place to start http://www.bt.cdc.gov/healthprofessionals/index.asp

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ANTHRAX Bacillus anthracis, aerobic, gram positive rod; spore-forming Pathogen of animals—cows, sheep, goats Historically, human disease from infected animals or animal products; wool-sorters disease Last reported case in U.S. of inhalation anthrax 1978 prior to October 2001 Spores survive for decades in environment

WHY ARE WE WORRIED? Anthrax may be stockpiled as offensive weapon by at least 13 countries Weaponized anthrax spores can be produced in 1 month for $1 million 50kg released over large city—250,000 sick, 100,000 dead (1970 WHO) 100kg—130,000-3 million dead (1993 USCOT)

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ANTHRAX PATHOPHYSIOLOGY Spores introduced by inhalation, abrasion, ingestion Pulmonary, skin, GI disease LD50 2500-55,000 spores Letter to Sen. Daschle—2gm, 0.1-1 trillion spores With inhalation, spores germinate, multiply in lymphatics, disseminate hematogenously Not known what triggers germination of spores Virulence factors Capsule inhibits phagocytosis Protective antigen binds to anthrax toxin receptor Edema toxin disrupts cellular water metabolism Lethal toxin (zinc metalloprotease)—cytokine (TNF, IL-1, IL-6) release

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CLINICAL ANTHRAX Cutaneous—head, neck, extremity; painless pruritic papule 3-5d after exposure; vesicle with central necrosis 24-36hr; black eschar, surrounding edema, purple vesicles Inhalation—mean incubation period 10d (2- 43d, Sverdlovsk); animal studies up to 98d Initial fever, nonproductive cough, malaise (“flu-like syndrome”_ 1-3 days, rapid progression of dyspnea, cough, respiratory failure (wide mediastinum, hilar adenopathy on CXR, shock, death (3 days mean at Sverdlovsk); meningitis in ~50% 2001 cases Antibiotics poorly effective after toxin accumulates

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POST-EXPOSURE PROPHYLAXIS Risk of disease post-exposure not clear Accidental aerosolization from bioweapon plant Sverdlovsk 1979 Unknown number exposed At least 358 cases, 100 dead Spores can persist in lymphatics at least 60 days Who should receive prophylaxis? Risk of exposure to spores Choice of antibiotic Not based on randomized, controlled trials

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ANTHRAX POST-EXPOSURE PROPHYLAXIS Adults, children >8yr Doxycycline 100mg bid 1st line; alternative ciprofloxacin 500mg bid Amoxicillin if proven susceptibility Children <8yr Ciprofloxacin 15mg/kg (~6mg/lb) bid, up to 500mg bid 1st line; can use doxycycline if necessary; amoxicillin Pregnant, breastfeeding woman Ciprofloxacin 500mg bid; can use doxycycline if necessary; amoxicillin

DURATION OF PROPHYLAXIS Current CDC recommendation 60 days of antibiotic Based on Sverdlovsk experience December 2001 DHHS gave 2 additional options to those already undergoing prophylaxis Additional 40 days antibiotic (total 100d) Based on trials with monkeys Additional 40 days antibiotic PLUS anthrax vaccine under IND Best approach not known

MASS PROPHYLAXIS 2001 Approximately 10,000 people in NY, NJ, CT, DC, FL; cipro as initial agent, many switched to doxy CDC collected data on 6178 Most were 40-64yr old; 60% men 2% of women were pregnant 150 were <18 years old 42% Black, 41% White 97% obtained initial supply of meds 10% did not start 3% reported difficulty in obtaining meds

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TREATMENT AND PROPHYLAXIS OF OTHER BACTERIAL AGENTS

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"Variola major," Variola major, spread by droplet nuclei or aerosols from oropharynx or direct contact with infected person, clothing, etc. Incubation period 7-17d; asymptomatic, not contagious Prodrome (?contagious, 2-4d): fever (101-104F), malaise, head/body ache

SMALLPOX Early rash: (contagious, 4 d) small red spots on mouth, tongue; mouth sores highly contagious; skin rash face, to arms/legs, then  hands/feet; progression over 24 hr, symptomatic improvement; vesicular Pustular rash (contagious, 5 d) Crusting/scabbing (contagious, 5 d) Resolving scabs (contagious, 6 d) Scabs resolved (not contagious)

Smallpox Acute communicable infection caused by variola virus No proven treatment Case fatality of 20-30% in un-immunized Last case in 1977.  Eradication declared in 1980.  Last US case in 1949 Identified as potential bioterrorism threat.

Smallpox Control Measures Ring vaccination Method that eradicated smallpox Vaccinate contacts and their close contacts Non-contact high risk personnel Surveillance of contacts Isolation of cases, febrile contacts and possibly unimmunized contacts Mass vaccination never used during world-wide eradication effort

PHARMACIST ADMINISTRATION OF SMALLPOX VACCINE: LEGAL/REGULATORY No Arizona statue or regulation prohibits pharmacist administration of any drug Board of Pharmacy opinion: outside scope of practice AZ Attorney General opinion: no law against it, no law needed Proposed regulations being written Arizona State of Emergency statute Federal Homeland Security Act

Smallpox Vaccine: Dryvax Live virus (vaccinia not variola) Genetic variant of Edward Jenner’s cowpox vaccine? 1-2 yrs of age.  Boosters every 3-5 yrs Calf lymph Last routinely used in US in 1972 Later use in military and for international travel

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Smallpox Vaccine 90 million doses in US Can be diluted 1/5-1/10 Use of diluted vaccine provides adequate supply for entire U.S. Diluted vaccine would require IND Vaccinia Immune Globulin--limited, but growing supplies Major national effort to develop and distribute educational materials, and train public and community health care workers in preparation for phases I and II of the Federal Pre-Event Vaccination Plans

Smallpox Vaccine Contraindications Skin disorders Eczema/atopic dermatitis Any history, even if not currently active Acute chronic or exfoliative skin conditions Burns, impetigo, chickenpox, contact dermatitis, herpes zoster, severe acne, severe diaper rash Darier’s disease

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VACCINE CONTRAINDICATIONS Immunodeficiency/immunosuppression Diseases: HIV/AIDS, transplant, malignancy, leukemia, lymphoma, agammaglobulinemia; autoimmune diseases (SLE, etc.) HIV testing should be readily available prior to vaccination Immunosuppressive therapy Radiation, chemotherapy, high-dose steroids (>2mg/kg/day or >2wks 20mg/day prednisone or equiv.), transplant meds Wait at least 1 month after steroids, 3 months after other immunosuppressives stopped before vaccinating

PREGNANCY/BREASTFEEDING Contraindicated in pregnancy or close contacts of pregnant women (risk of rare fetal vaccinia) Do not become pregnant within 4 wks post-vaccination Recent report from CDC that 103 pregnant women (85 military) received vaccine despite adequate screening Contraindicated in breastfeeding mother (even if pumping and using bottle) OK for close contacts to receive vaccine if proper infection control

CARDIAC CONTRAINDICATIONS Due to recent cases of myocarditis and pericarditis post-vaccination Angina, MI; link to vaccine not known Current cardiac contraindications Known coronary artery disease Previous MI; angina CHF; cardiomyopathy Stroke or TIA Exertional chest pain or SOB Any other heart disease under medical care 3 or cardiovascular risk factors Hypertension, hypercholesterolemia, diabetes, early heart disease in 1st degree relative, smoker

OTHER CONTRAINDICATIONS Prior allergic reaction to vaccine or its components (polymyxin B, streptomycin, chlortetracycline, neomycin, phenol) New vaccine will not contain antibiotics Moderate or severe acute illness Wait until illness subsides Other live vaccine in past 4 weeks Children <12 months of age ACIP recommends against non-emergent use <18 Inflammatory eye condition requiring steroids Likely non-adherence with site care

Smallpox Vaccine Contraindications With actual smallpox disease exposure, there are no contraindications! Post-event strategy likely would be ring vaccination Disease is always worse than vaccine  in high risk individuals Standing orders for contacts will be different than those without exposure

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VACCINE SCREENING Designed to identify those who should not receive it in pre-event setting The most important and complicated part of the process Patient completes Section A (demographics) and Section B (vaccine, medical history) Patient information screened If no contraindications, refer for further screening CDC Pre-Event Worksheet for Smallpox Vaccine Streamlined version will be produced for mass vaccination clinic If still no contraindications, refer for vaccination

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PATIENT SCREENING

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Smallpox Vaccine Administration Scarification with bifurcated needle Localized infection develops “Take” should be verified by evaluating site at 7 days Site is potentially infectious until scab separates Covering site probably reduces risk of transmission.

Smallpox Vaccine Administration Diluent and syringe in current package 100 doses undiluted per vial 100 needles per vial Secure vial in vaccine holder Easy to tip over Dilute per protocol Availability of extra needles? Remove, but keep, plastic top

Smallpox Vaccine Administration Do not use alcohol or acetone in preparing skin Soap and water for visible dirt only Skin should be completely dry

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Smallpox Vaccine Administration Dip needle into vial once Pull skin taut on deltoid area of non-dominant arm Rest wrist on arm of vaccinee Make rapid perpendicular insertions to area <5mm in diameter 3 insertions for 1st vaccination Trace of blood should appear in 15-20 sec. If not, apply 3 additional insertions 15 insertions for revaccination

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Smallpox Vaccine Administration Dispose of needle in sharps container Dispose of empty vial in sharps Loosely cover vaccine site with bandage Remove gloves and wash hands All materials considered infectious!

SITE CARE EDUCATION

NORMAL VACCINE RESPONSE

Smallpox Vaccine Side Effects Local reactions ~ 30% Mild systemic: (myalgia, headache, fatigue, fever)  16-37% Serious adverse events ~ 1/1000 vaccinated

Smallpox Vaccine Side Effects Fever, axillary adenopathy   15-20% Auto-inoculation         1:2000 Generalized vaccinia     1:5000 Eczema vaccinatum       1:26,000 Progressive vaccinia        1:1,000,000 Post- vaccination encephalitis  1:300,000 Death  1-2:1,000,000 Different age groups being vaccinated now. More data will become available.

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Smallpox Vaccine Civilian Experience: Jan-May 2003 36,217  vaccinated 1  generalized vaccinia (1:36000) 13 (3) autoinoculation (ocular) 1:2000 24 myocarditis/pericarditis (1:1500) 1 encephalomyelitis (1:36000) 59 other serious 488 other nonserious Fever, HA, pain, fatigue 1 VIG release

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Smallpox Vaccine Military Experience (3/31/03) >350,000 doses 3% sick leave (1.5 days average) 29 (14) accidental inoculations (nonmilitary contacts) 25 generalized vaccinia 3 encephalitis 14 myocarditis/pericarditis (5/1/03)   1:20,000 3 VIG treatment

Vaccine Side Effect Management Mild reactions handled with acetaminophen, NSAID, and antihistamines. Avoid ointments, steroids Vaccinia immune globulin (VIG) Use only for selected, severe reactions Contraindicated with corneal lesions Ineffective with encephalitis Limited supply Cidofovir

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GENERALIZED VACCINIA

ECZEMA VACCINATUM

PROGRESSIVE VACCINIA

PROGRESSIVE VACCINIA

VACCINIA KERATITIS

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