history caused by bacillus anthracis human zoonotic disease spores found in soil worldwide ...
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History
Caused by Bacillus anthracis Human zoonotic disease
Spores found in soil worldwide Primarily disease of herbivorous animals
Sheep, goats, cattle Many large documented epizootics
Occasional human disease Epidemics have occurred but uncommon Rare in developed world
Epidemiology
Three forms of natural disease Inhalational
Rare (<5%) Most likely encountered in bioterrorism
event Cutaneous
Most common (95%) Direct contact of spores on skin
Gastrointestinal Rare (<5%), never reported in U.S. Ingestion
All ages and genders affected Occurs worldwide Endemic areas - Africa, Asia True incidence not known
World 20,000-100,000 in 1958 U.S. 235 total reported cases 1955-1994
18 cases inhalational since 1900, last one 1976
Until 2001, last previous case cutaneous 1992
Mortality Inhalational 86-100% (despite
treatment) Era of crude intensive supportive care
Cutaneous <5% (treated) – 20% (untreated)
GI approaches 100%
Incubation Period Time from exposure to symptoms Very variable for inhalational
2-43 days reported Theoretically may be up to 100 days Delayed germination of spores
Human cases – historical risk factors Agricultural
Exposure to livestock Occupational
Exposure to wool and hides Woolsorter’s disease = inhalational
anthrax Rarely laboratory-acquired
Transmission No human-to-human Naturally occurring cases
Skin exposure Ingestion Airborne
Bioterrorism Aerosol (likely) Small volume powder (possible) Foodborne (unlikely)
Transmission Cutaneous
Handling hides/skins of infected animals Bites from arthropods (very rare) Handling powdered form in letters, etc. Intentional aerosol release
May see some cutaneous if large-scale
Microbiology
Bacillus anthracis Aerobic, Gram positive rod Long (1-10μm), thin (0.5-2.5μm) Forms inert spores when exposed to O2
Infectious form, hardy Approx 1μm in size
Vegetative bacillus state in vivo Result of spore germination Non-infectious, fragile
Classification Same family: B. cereus, B. thuringiensis Differentiation from other Bacillus
species Non-motile Non β-hemolytic on blood agar Does not ferment salicin
Note: Gram positive rods are usually labeled as “contaminants” by micro labs
Environmental Survival Spores are hardy
Resistant to drying, boiling <10 minutes Survive for years in soil Still viable for decades in perma-frost
Favorable soil factors for spore viability High moisture Organic content Alkaline pH High calcium concentration
Transmission Inhalational
Handling hides/skins of infected animals Microbiology laboratory Intentional aerosol release Small volume powdered form
In letters, packages, etc Questionable risk, probably small
Transmission Gastrointestinal
Ingestion of meat from infected animal Ingestion of intentionally contaminated food
Not likely in large scale Spores not as viable in large volumes of water
Ingestion from powder-contaminated hands Inhalational of spores on particles >5 m
Land in oropharynx
Virulence Factors All necessary for full virulence Two plasmids
Capsule (plasmid pXO2) Antiphagocytic
3 Exotoxin components (plasmid pXO1) Protective Antigen Edema Factor Lethal Factor
Protective Antigen Binds Edema Factor to form Edema Toxin Facilitates entry of Edema Toxin into cells
Edema Factor Massive edema by increasing intracellular
cAMP Also inhibits neutrophil function
Lethal Factor Stimulates macrophage release of TNF-α,
IL-1β Initiates cascade of events leading to sepsis
Pathogenesis
Disease requires entry of spores into body
Exposure does not always cause disease Inoculation dose Route of entry Host immune status May depend on pathogen strain
characteristics
Forms of natural disease Inhalational Cutaneous Gastrointestinal
Determined by route of entry Disease occurs wherever spores
germinate
Pathogenesis.
Inhalational Spores on particles 1-5 m Inhaled and deposited into alveoli Estimated LD50 = 2500 – 55,000 spores
Dose required for lethal infection in 50% exposed
Contained in imperceptibly small volume
Inhalational Phagocytosed by alveolar macrophages Migration to mediastinal/hilar lymph nodes Germination into vegetative bacilli
Triggered by nutrient-rich environment May be delayed up to 60 days
Factors not completely understood Dose, host factors likely play a role Antibiotic exposure may contribute
Delayed germination after antibiotic suppression
Vegetative bacillus is the virulent phase Active toxin production Hemorrhagic necrotizing mediastinitis
Hallmark of inhalational anthrax Manifests as widened mediastinum on CXR
Does NOT cause pneumonia Followed by high-grade bacteremia
Seeding of multiple organs, including meninges
Toxin production Has usually begun by time of early symptoms Stimulates cascade of inflammatory
mediators Sepsis Multiorgan failure DIC
Eventual cause of death Symptoms mark critical mass of bacterial
burden Usually irreversible by this time
Clearance of bacteria unhelpful as toxin-mediated
Pathogenesis of cutaneous form. Cutaneous
Spores in contact with skin Entry through visible cuts or microtrauma
Germination in skin Disease begins following germination
Toxin production Local edema, erythema, necrosis,
lymphocytic infiltrate No abscess or suppurative lesions
Eventual eschar formation
. In cutaneous anthrax, a malignant pustule develops at the infection site. This pustule is a central area of coagulation necrosis (ulcer) surrounded by a rim of vesicles filled with bloody or clear fluid. A black eschar forms at the ulcer site. Extensive edema surrounds the lesion.
The organisms multiply locally and may spread to the bloodstream or other organs (eg, spleen) via the efferent lymphatics. B anthracis remains in the capillaries of invaded organs, and the local and fatal effects of the infection are due, in large part, to the toxins elaborated by B anthracis.
Dissemination from the liver, spleen, and kidneys back into the bloodstream may result in bacteremia. Secondary hemorrhagic intestinal foci of anthrax result from B anthracis bacteremia.
Cutaneous Systemic disease
Can occur, especially if untreated Spores/bacteria carried to regional lymph
nodes Lymphangitis/lymphadenitis Same syndrome as inhalational Sepsis, multiorgan failure
Pathogenisis GI form
Gastrointestinal Spores contact mucosa
Oropharynx Ingestion Aerosolized particles >5 m
Intestinal mucosa – terminal ileum, cecum Ingestion
Larger number of spores required for disease
Incubation period 2-5 days
Gastrointestinal Spores migrate to lymphatics
Submucosal, mucosal lymphatic tissue Mesenteric nodes
Germination to vegetative bacilli Toxin production
Massive mucosal edema Mucosal ulcers, necrosis
Death from perforation or systemic disease
Oropharyngeal anthrax
Oropharyngeal anthrax is a variant of intestinal anthrax and occurs in the oropharynx after ingestion of meat products contaminated by anthrax. Oropharyngeal anthrax is characterized by throat pain and difficulty in swallowing. The lesion at the site of entry into the oropharynx resembles the cutaneous ulcer.
Inhalational
Asymptomatic incubation period Duration 2-43 days, ~10 days in Sverdlovsk
Prodromal phase Correlates with germination, toxin production Nonspecific flu-like symptoms
Fever, malaise, myalgias Dyspnea, nonproductive cough, mild chest
discomfort Duration several hours to ~3 days Can have transient resolution before next
phase
Fulminant Phase Correlates with high-grade
bacteremia/toxemia Critically Ill Fever, diaphoresis Respiratory distress/failure, cyanosis Septic shock, multiorgan failure, DIC
50% develop hemorrhagic meningitis Headache, meningismus, delirium,
coma May be most prominent finding
Usually progresses to death in <36 hrs Mean time from symptom onset to
death ~3 days
Laboratory Findings
Gram positive bacilli in direct blood smear
Electrolyte imbalances common Radiographic Findings
Widened mediastinumMinimal or no infiltrates
Can appear during prodrome phase
Cutaneous
Most common areas of exposureHands/armsNeck/head
Incubation period3-5 days typical12 days maximum
Cutaneous – progression of painless lesions
Papule – pruritic
Vesicle/bulla
Ulcer – contains organisms, sig. edema
Eschar – black, rarely scars
Systemic disease may developLymphangitis and lymphadenopathy
If untreated, can progress to sepsis, death
Gastrointestinal
OropharyngealOral or esophageal ulcer Regional lymphadenopathy Edema, ascites Sepsis
AbdominalEarly symptoms - nausea, vomiting, malaise
Late - hematochezia, acute abdomen, ascites
Diagnosis.
Early diagnosis is difficult Non specific symptoms Initially mild No readily available rapid specific tests
Presumptive diagnosis History of possible exposure Typical signs & symptoms Rapidly progressing nonspecific
illness Widened mediastinum on CXR Large Gram+ bacilli from specimens
Can be seen on Gram stain if hi-grade bacteremia
Appropriate colonial morphology Necrotizing mediastinitis, meningitis
at autopsy
Definitive diagnosis Direct culture on standard blood agar
Gold standard, widely available Alert lab to work up Gram + bacilli if found 6-24 hours to grow Sensitivity depends on severity, prior antibiotic
Blood, fluid from skin lesions, pleural fluid, CSF, ascites
Sputum unlikely to be helpful (not a pneumonia)
Very high specificity if non-motile, non-hemolytic
Requires biochemical tests for >99% confirmation Available at Reference laboratories
Other diagnostic tests Anthraxin skin test
Chemical extract of nonpathogenic B. anthracis
Subdermal injection 82% sensitivity for cases within 3
days symptoms 99% sensitivity 4 weeks after
symptom onset
Testing for exposure Nasal swabs
Can detect spores prior to illness Currently used only as epidemiologic tool
Decision based on exposure risk May be useful for antibiotic sensitivity
in exposed Culture on standard media Swabs of nares and facial skin
Serologies May be useful from epidemiologic
standpoint Investigational – only available at CDC
Differential diagnostics
Inhalational Expect if anthrax
Influenza
Pneumonia Community-acquired Atypical Pneumonic tularemia Pneumonic plague
Mediastinitis Bacterial meningitis Thoracic aortic
aneurysm
Flu rapid diagnostic –More severe in young ptsNo infiltrate
No prior surgeryBloody CSF with GPBsFever
Cutaneous Spider bite Ecthyma gangrenosum Pyoderma gangrenosum Ulceroglandular
tularemia Mycobacterial ulcer Cellulitis
Expect if anthraxfever
no response to 3º cephs
painless, black eschar
+/- lymphadenopathy
usually sig. local edema
Gastrointestinal Gastroenteritis Typhoid Peritonitis Perforated ulcer Bowel
obstruction
Expect if anthraxCritically illAcute abdomenBloody diarrheaFever
Treatment.
Hospitalization IV antibiotics
Empiric until sensitivities are known Intensive supportive care
Electrolyte and acid-base imbalances Mechanical ventilation Hemodynamic support
Antibiotic selection Naturally occurring strains
Rare penicillin resistance, but inducible β-lactamase
Penicillins, aminoglycosides, tetracyclines, erythromycin, chloramphenicol have been effective
Ciprofloxacin very effective in vitro, animal studies
Other fluoroquinolones probably effective Engineered strains
Known penicillin, tetracycline resistance Highly resistant strains = mortality of
untreated
Empiric Therapy Until susceptibility patterns known Adults
Ciprofloxacin 400 mg IV q12° OR
Doxycycline 100mg IV q12°AND (for inhalational)
One or two other antibiotics
Pregnant womenSame as other adultsWeigh small risks (fetal arthropathy) vs benefit
Immunosuppressedsame as other adults
Susceptibility testing should be done Narrow antibiotic if possible Must be cautious
Multiple strains with engineered resistance to different antibiotics may be coinfecting
Watch for clinical response after switching antibiotic
Antibiotic therapy Duration
60 days Risk of delayed spore germination Vaccine availability
Could reduce to 30-45 days therapy Stop antibiotics after 3rd vaccine dose
Switch to oral Clinical improvement Patient able to tolerate oral medications
Other therapies Passive immunization
Anthrax immunoglobulin from horse serum Risk of serum sickness
Antitoxin Mutated Protective Antigen
Blocks cell entry of toxin Still immunogenic, could be an alternative
vaccine Animal models promising
Postexposure Prophylaxis
Who should receive PEP? Anyone exposed to anthrax Not for contacts of cases, unless also
exposed Empiric antibiotic therapy Vaccination
Avoid unnecessary antibiotic usage Potential shortages of those who
need them Potential adverse effects
HypersensitivityNeurological side effects, especially elderly
Bone/cartilage disease in childrenOral contraceptive failure
Future antibiotic resistance Individual’s own floraCommunity resistance patterns
Post exposure prophylaxis. Antibiotic therapy
Treat ASAP Prompt therapy can improve survival Continue for 60 days
30-45 days if vaccine administered
Antibiotic therapy Same regimen as active treatment
Substituting oral equivalent for IV Ciprofloxacin 500 mg po bid empirically Alternatives
Doxycycline 100 mg po bid Amoxicillin 500 mg po tid
Prevention.
Vaccine Anthrax Vaccine Adsorpbed (AVA) Supply
Limited, controlled by CDC Production problems
Single producer – Bioport, Michigan Failed FDA standards None produced since 1998
Vaccine Inactivated, cell-free filtrate Adsorbed onto Al(OH)3
Protective Antigen Immunogenic componentNecessary but not sufficient
Vaccine Administration
Dose schedule 0, 2 & 4 wks; 6, 12 & 18 months initial series
Annual booster0.5 ml SQ
Vaccine Adverse Effects
>1.6 million doses given to military by 4/2000
No deaths <10% moderate/severe local reactions
Erythema, edema <1% systemic reactions
Fever, malaise
Infection control.
No person to person transmission
Standard Precautions Laboratory safety
Biosafety Level (BSL) 2 Precautions
Decontamination.
Skin, clothing Thorough washing with soap and water Avoid bleach on skin
Instruments for invasive procedures Sterilize, e.g. 5% hypochlorite solution
Sporicidal agents Sodium or calcium hypochlorite (bleach)