Antraks

• Penyakit zoonosis yang disebabkan kuman Bacillus anth

racis
• Yunani --- anthrakis --- “coal”

• Vaksin pertama kali pada hewan dikembangkan oleh Lo

uis Pasteur tahun 1881
• Digunakan untuk bioterorisme pada tahun 2001
 Antraks

• Spora kuman terdapat dalam tanah di seluruh dunia

• Penyakit primer pada hewan herbivora

• Domba, kambing, ternak

• Kadang menyerang manusia

• Epidemi pernah terjadi tetapi jarang
• Jarang pada negara maju
Bacillus anthracis
• bakteri Gram positif; batang
• non motil
• aerob, anaerob fakultatif
• spora dapat bertahan hidup
di dalam tanah selama bertahu
n-tahun
• toksin --- kerusakan jaringan
& edema
B.Anthracis colonies on blood agar

B.cereus B.anthracis

Hemolytic zone (+)

 Antraks
Tiga bentuk gambaran klinis :
 Kutaneus
 Paling sering (95%)
 Kontak langsung spora pada kulit
 mortalitas = 20% tanpa antibiotik
 Inhalasi
 Jarang (<5%)
 Paling sering terjadi pada bioterorisme
 Mortalitas = ~100%
 Gastrointestinal
 Jarang (<5%)
 Ingesti
 Mortalitas = ~100%
 Epidemiologi

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
 Epidemiologi

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
Epidemiologi
Epidemiologi
 Epidemiologi

Transmission
No human-to-human
Naturally occurring cases
•Skin exposure
•Ingestion
•Airborne
Bioterrorism
•Aerosol (likely)
•Small volume powder (possible)
•Foodborne (unlikely)
 Epidemiologi

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
 Epidemiologi

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
 Epidemiologi

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
Patogenesis
 Patogenesis

Virulence Factors
All necessary for full virulence
Two plasmids
• Capsule (plasmid pXO2)
– Antiphagocytic
• 3 Exotoxin components (plasmid pXO1)
– Protective Antigen
– Edema Factor
– Lethal Factor
 Patogenesis

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
 Patogenesis
Protective Antigen
•Gets its name from protective
antibodies elicited against it
•83 = 60 + 23
•4 Domains
1) cleavage site for PA20
2) pore formation
3) self-association of PA63
4) receptor binding
•Forms 7-member ring
•Allows 3 EF/LFs to bind
•Pre-pore  pore after pH change
•Anthrax Toxin Receptor has only
partially been identified (TEM8, no known function)
•Second receptor  CMG2 (very recent)
•Why so elaborate?
Concentrate toxin at cell surface
 Patogenesis

Lethal Factor
•Sequence homology with EF
-Binding to PA
-Requires acidification to activate (delayed)

•Zinc-dependent metalloprotease
-Targets MAPKK 1 & 2 (and more?)
-Targets macrophages
Macrophage suicide
Free oxygen radicals
“Cytokine storm” (or no?)
Mice depleted of macrophages are
resistant to LF’s effects
 Patogenesis
Edema Factor
•Delayed activation
•Calcium-dependent adenylate cyclase
-Produces cAMP  downstream targets
•Causes Edema
•Targets macrophages
-Inhibits phagocytosis, oxidative burst
-Promote bacterial survival and
proliferation in early stages of
infection?
109 bacteria / mL blood
 Patogenesis

Faktor Letal Antigen Protektif Faktor Edema

Toksin Letal Toksin Edema

Kerusakan jaringan Edema

Syok
 Antraks Kutaneus

• Masa inkubasi 3-5 hari, maks 12 hari

• Papul (pruritik) --- vesikel/bullae --- ulkus nekrotik (eskar)

dengan bagian tengah kehitaman
• Tidak nyeri
• Daerah predileksi : - tangan
- leher/kepala
• Penyakit sistemik --> jarang
Antraks Kutaneus
 Antraks Inhalasi

• Masa inkubasi 1-7 hari (bervariasi hingga 43 hari)

• Gejala prodromal : batuk, demam, mialgia, fatigue

• Perburukan cepat : demam, dispnoe, sianosis, syok; sering de
ngan temuan pelebaran mediastinum dengan tidak ada/minima
l infiltrat pada Ro dada
• Dapat terjadi periode resolusi sementara sebelum ke fase beri
kutnya
• Onset --> kematian ~3hari
• Lab : - pulasan darah langsung --> basil Gram positif
- imbalans elektrolit
Antraks Inhalasi
 Antraks Gastrointestinal

• masa inkubasi 1-7 hari

• Faring : ulkus orofaringeal, adenopati servikal, demam

• Abdominal/Intestinal :
- awal : mual, muntah, malaise
- lanjut : nyeri perut, demam, muntah darah, diare, asites
 Diagnosis

• Diagnosis awal sulit :

- gejala awal non-spesifik
- biasanya ringan
- tidak tersedia rapid spesific tests
 Diagnosis

• Presumptive diagnosis
History of possible exposure
Typical signs & symptoms
Rapidly progressing nonspecific illness
Widened mediastinum on CXR
Large Gram+ bacilli from specimens (skin lession, blood, pleural fl
uid, CSF)
• Can be seen on Gram stain if hi-grade bacteremia
Appropriate colonial morphology
Necrotizing mediastinitis, meningitis at autopsy
 Diagnosis

• 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
 Diagnosis

• Definitive diagnosis
Rapid confirmatory tests
• Role is to confirm if cultures are negative
• Currently available only at CDC
– Polymerase Chain Reaction (PCR)
– Hi sensitivity and specificity
– Detects DNA
– Viable bacteria/spores not required
– Immunohistochemical stains
– Most clinical specimens can be used
 Diagnosis

• Testing for exposure

Nasal swabs
•Can detect spores prior to illness
•Currently used only as epidemiologic tool
–Decision for PEP 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
 Pengobatan

• Hospitalization
• IV antibiotics
• Empiric until sensitivities are known
• Intensive supportive care
• Electrolyte and acid-base imbalances
• Mechanical ventilation
• Hemodynamic support
 Pengobatan

• 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
 Pengobatan

• Alternative antibiotics
If susceptible, or cipro/doxy not possible
• Penicillin, amoxicillin
• Gentamicin, streptomycin
• Erythromycin, chloramphenicol

Ineffective antibiotics
Trimethoprim/Sulfamethoxazole
Third generation cephalosporins
 Pengobatan

• 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
 Pengobatan

• 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
 Profilaksis Pasca Paparan

• Who should receive ?

Anyone exposed to anthrax
Not for contacts of cases, unless also exposed

Empiric antibiotic therapy :

Treat ASAP
Prompt therapy can improve survival
Continue for 60 days
• 30-45 days if vaccine administered
Vaccination
 Profilaksis Pasca Paparan

• Antibiotic agents
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 Who should receive PEP?
Anyone exposed to anthrax
Not for contacts of cases, unless also exposed
 Profilaksis Pasca Paparan
• Vaccine
Inactivated, cell-free filtrate
Purified with Al(OH)3
Protective Antigen
• Immunogenic component
• Necessary but not sufficient
Administration
• Dose schedule
– 0, 2 & 4 wks; 6, 12 & 18 months initial series
– Annual booster
• 0.5 ml SQ
Efficacy : >95% protection vs. aerosol in animal models
Profilaksis Pasca Paparan