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types C and D and between types E and F has been observed (Smith 1988).

The toxins are produced by vegetat ive cells (ie, germination of spores) and released by cell lysis.

Some toxins are f ully activated by the bacteria that produce them (proteolytic strains o f type A, B, and

F), and some require exogenous proteolytic activation (t ypes E and non-proteolytic types B and F).

Types A, B, E, and F cause natural disease in humans. The vast majorit y of disease is caused by types

A, B, and E; type F rarely occurs (ie, about 1% o f US cases [Gupta 2005]).

In one study, a novel in vivomouse assay was used to correlate toxin type and dosage with the duration

of muscle paralysis f or types A, B, and E (Keller 2006).

Botulinum toxin A produced longer paralysis than botulinum toxin B, consistent with human

observations.

For type A, duration of paralysis was exponentially related to t oxin dose; the paralysis t ime

doubled with every 25% increase of the toxin concentration.

For t ype B, the duration of paralysis was linear relative to the toxin dose.

Type E toxin had the shortest duration o f action, but unlike the other two to xins, the dose o f

toxin did not inf luence recovery time.

Types C and D cause natural disease in birds, horses, and cattle; strains that produce these t ypes

reside in the intestinal tract o f certain animals. Contaminated s ilage has been reported to cause bo tulism

outbreaks among catt le (Myllykoski 2008).

Toxin type G has never clearly been shown to cause human disease.

Toxin types C, D, and G cause botulism in primates when administered through aerosol challenge. As a

result o f these experiments, experts generally believe that humans also are susceptible to these types.

Botulinum toxins are colorless, odorless, and presumably tas teless.

Aeroso lized part icles o f toxin are appro ximately 0.1 to 0.3 mcm in size (Shapiro 1997).

The toxins are inactivated by heating (>85C for 5 minutes) (Siegel 1993).In the event o f an intentional release of botulinum toxin, the causative organisms may or may not be

present.

Clostridium botulinum

The following are key microbiologic characteristics of C botulinum (CDC 1998, Hatheway 1998, Smith 1988,

Sneath 1986).

Gram-positive spore-f orming bacillus (may stain poorly)

Somewhat varying strain sizes but generally in the range of 0.5 to 2.0 mcm in width and 1.6 to 22.0 mcmin length (CDC 1998)

Straight to slightly curved, with a peritrichous f lagellum

Spores are oval, eccentric to subterminal, and usually swell the bacterial cell

Strict anaerobe

"Sluggishly" mot ile

Produce lipase on egg-yo lk agar

Ferment glucose and liquefy gelatin (all st rains)
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Commonly iso lated f rom so il and marine and lake sediments

The classification of C botulinum st rains is based on metabolic activity(groups I to IV) and on toxin types

(types A to G) (Hatheway 1998, Smith 1988, Sneath 1986):

Group I includes type A st rains and proteolytic st rains of types B and F.

Group II includes type E st rains and nonproteolytic strains o f types B and F

Group III includes nonproteolytic strains o f types C and D.

Group IV includes only strains that produce type G.

Strains that produce more t han one to xin type or have genetic sequences encoding more than one toxin

have been identif ied (Barash 2004, Fathalla 2008, Kirma 2004).

Each group has a different optimal growth temperature, but there are no colonial morphology features

that allow distinction between groups o r antigenic types.

Genetic homology has been demonstrated within antigenic groups of C botulinum, and there is minimal

antigenic cross- reactivity between groups.

Antimicrobial susceptibilities of C botulinumst rains vary somewhat by group, but most st rains are

susceptible to penicillin, metronidazole, rif ampin, and erythromycin (Smith 1988).

C botulinumspores have the following features (Smith 1988):

Spores may survive boiling for up to 3 to 4 hours o r temperatures o f 105oC for 100 minutes.

Spores are readily killed by chlorine (either as chlorinated water o r as diluted solutions o f hypochlorite).

Spores undergo maximum germination when activated by heat. For example, type A st rains undergo

maximum germination by heat t reatment (or "heat shocking") at 80C f or 10 to 20 minutes.

Spores are resistant to desiccation and can survive in the dry state for 30 years or more.

Spores are resistant to ultraviolet light, alcohols, and phenolic compounds. They are relatively resistant

to irradiation.

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Pathogenesis

Exposure to botulinum toxin occurs through the following mechanisms (toxin is not absorbed through intact

skin):

Ingest ion of prefo rmed toxin

Inhalation o f prefo rmed toxin

Local production of toxin by C botulinumorganisms in the gastrointestinal tract

Local production of toxin by C botulinumorganisms in devitalized tissue at the site of a wound

Iatrogenic exposure caused by injection of botulinum toxin for cosmetic purposes or to treat certain

musculoskeletal diso rders, such as spast icity or blepharospasm (Coban 2010)

Following exposure, pathogenesis includes the f ollowing steps (Arnon 2001, CDC 1998, Halpern 1995, Schiavo

1995, Simpson 2004):

Botulinum toxin is activated by proteo lytic cleavage; the activated st ructure is a 150-kd polypeptide

comprising two chains (a heavy chain [100 kd] and a light chain [50 kd]) that are connected by a single
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Foodborne Botulism

Wound Botulism

Infant Botulism

Adult Intestinal Toxemia Botulism

Inhalation Botulism

Iatrogenic Botulism

Botulism Caused by Other ClostridiumSpecies

Foodborne Botulism

Foodborne botulism is caused by ingestion of food contaminated with preformed botulinum toxin and

subsequent absorption of toxin through the gastrointestinal tract. The following steps are necessary

f or a f ood item to cause botulism (CDC 1998):

The food item must be contaminated with C botulinumspores, which are normally found in soil

(and may be found in water).

The spores must survive food preservation methods.

Adequate condit ions f or spore germination and neuro toxin product ion must be present.

The food must not be reheated adequately (>85C for 5 minutes) to inactivate the heat-labiletoxin before the food is consumed (Siegel 1993).

Generally, adequate conditions f or germination and neurotoxin production include the f ollowing,

although various caveats exist (CDC 1998, Smith 1988,Solomon 2001):

An anaerobic environment

Nonacidic pH (generally 4.6 to 4.8; pockets o f dif f erent pH may be present within a single fo od

source and allow toxin to be produced in a f oo d that overall has an acidic pH)

Minimum temperature of 10C (the optimum temperature for growth of proteolytic strains is close

to 35C; some nonproteolytic strains of types B, E, and F can produce toxin at refrigerationtemperatures [3C to 4C])

Availability of water with limited solute concent rat ion

Toxin types A, B, and E account f or most cases of f oodborne botulism, and toxin types tend to be

geographically distributed within the United States. The outbreaks reported to the Centers for Disease

Control and Prevention (CDC) between 1950 and 1996 (CDC 1998) were distributed as f ollows:

144 (86%) of 167 type A outbreaks occurred west of the Miss issippi River

37 (61%) of 61 type B outbreaks occurred east of the Mississippi River

56 (84%) of 67 type E outbreaks occurred in Alaska

Type F f oodborne botulism has rarely been reported in humans (CDC 1998, Midura 1972).

Botulism can be recurrent, although only a few such cases have been reported. One case arose f rom

repeated ingest ion of home-prepared hot chili pepper sauce (Bilusic 2008). Another report describes

recurrent wound botulism among injecting drug users in California (Yuan 2011).

The median number of cases of f oo dborne botulism reported to t he CDC annually between 1973 and

1996 was 24 (range, 8 to 86 cases) (Shapiro 1998).

The mean number of f oodborne botulism outbreaks per year between 1950 and 1996 was 9.4, with a

mean number of 2.5 cases per outbreak (CDC 1998).
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Between 1990 and 2000, the median number of botulism events per year was 14 (range, 9 to 24) and the

median number of cases per event was 1 (range, 1-17) (Sobel 2004). During this time period, the highest

incidence rates were in Alaska (19 per million population), Idaho (0.6 per million population), and

Washington (0.3 per million population).

Improperly home-canned or home-prepared f oo ds (particularly vegetables) cont inue to account f or most

of the f ood vehicles associated with f oodborne botulism in the United States (Sobel 2004).

Over the past 20 years, a wide variety o f commercially produced (preserved and nonpreserved) foods

have caused botulism outbreaks. Examples include foil-wrapped baked potatoes, sauteed onions heldunder a layer of butt er, garlic in oil, commercially produced cheese sauce, commercially prepared chili,

hazelnut yogurt, jarred peanuts, matambre (Argentine meat roll) sealed in heat- shrinked plast ic wrap,

commercially prepared carrot juice, green-olive paste, and canned chili sauce (Angulo 1998, CDC 2007,

Chou 1988, Kalluri 2003, MacDonald 1985: Type A botulism f rom sauteed onions, O'Mahony 1990,

Pingeon 2011, St Louis 1988, Sheth 2008, Townes 1996, Villar 1999).

A variety of salted, f ermented, smoked, and canned f ish so urces have been implicated in type E botulism

outbreaks in the United States and elsewhere (King 2009, Lindstrom 2006, Sobel 2007, Telzak 1990).

Foo dborne bo tulism is a s ignif icant public health problem among Alaskan natives and is usually

asso ciated with consumption o f f ermented meat f rom aquatic mammals (eg, whales, seals, walruses,

and beavers) and f ish (Fagan 2011, McLaughlin 2004, Shaff er 1990, Wainwright 1988). The incidence ofdisease among Alaskan natives appears to be decreasing but continues to be more than 800 t imes

higher in this population compared with the general US population (Fagan 2011).

Occasionally, unusual fo od preparation methods (part icularly for home-prepared products) can lead to

botulism. For example, an outbreak in Turkey (eastern Anato lia) in 2005 was asso ciated with eating

suzme (yogurt buried under so il) (Akdeniz 2007). Outbreaks of botulism in prisons have been att ributed

to drinking pruno (an alcoholic beverage concocted by prisoners from food scraps such as potato

peelings and apples that are allowed to f erment unref rigerated) (Vugia 2009).

Sales o f minimally heated, chilled f oods have grown recently in Western countries, such as the United

States and the United Kingdom, and have raised concerns about the potential for foodborne botulism

(Peck 2006).

Waterborne botulism has no t been reported, mos t likely because bo tulinum toxin is rapidly inactivated by

standard treatment of potable water and a very large amount of toxin would be needed to contaminate a

water supply because of the dilution f acto r (Arnon 2001, Siegel 1993). However, water may serve as a

source of contamination f or o ther f oo d items. For example, an investigation by the US Food and Drug

Administ rat ion (FDA) of a canning f acility in Michigan f ound that so me cans o f green beans were

contaminated with viable neurotoxin-producing C botulinum. Further invest igation demonstrated that C

botulinumspores were present in the cooling water system (Sachdeva 2010).

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Wound Botulism

Wound botulism is caused by inf ection of a contaminated wound with C botulinumand subsequent

absorption into the circulation of locally produced toxin.

C botulinumis a natural contaminant o f so il throughout t he United States (Smith 1978).

Wound botulism has been recognized with increasing frequency among injecting drug users, particularly

in Calif ornia, where the disease has been associated with use of black tar heroin (Davis 2008,

MacDonald 1985: Botulism and botulism-like illness in chronic drug users, Passaro 1998, Werner 2000,

Yuan 2011). Similarly, in the United Kingdom, bacterial infections (particularly wound botulism) have
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increased markedly since 2000 among injecting heroin users (Brett 2005: Sof t t issue infections caused

by spore- f orming bacteria in injecting drug users in the United Kingdom). The authors of this study

observed that the major risk f actor was skin- o r muscle-popping. Cases also have been report ed in

Germany (Preuss 2006, Schroeter 2009) and in Sweden, where real-time polymerase chain reaction

(PCR) was used to diagnose a case of type E wound botulism (Art in 2007).

Wound botulism in injecting drug users can be misdiagnosed as drug intoxication (Royl 2007); however,

presenting features can alert physicians to the correct diagnosis (Sam 2010, Wenham 2008). Botulism

should be considered in injecting drug users who present with dysarthria and dysphagia (Preuss 2006).

Wound botulism may occur f ollowing traumatic injury to an extremity, such as a compound f racture,

laceration, puncture wound, gunshot wound, severe abrasion ("road rash"), or crush injury (Merson

1973, Werner 2000).

Sinusitis associated with intranasal cocaine use has been the source of wound botulism in a few cases

(Kudrow 1988, MacDonald 1985: Botulism and botulism-like illness in chronic drug users, Roblot 2011,

Werner 2000).

A f ew cases have occurred postoperat ively (usually f ollowing intra-abdominal procedures) and an

abscessed tooth was the source of C botulinuminfection in one case (Nystrom 2011, Weber 1993).

Between 1943 (when the condition was f irst recognized) and 1985, 33 cases o f wound botulism were

reported to the CDC. Between 1986 and 1996, 78 cases were report ed and mos t were associated withinjecting drug use (CDC 1998).

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Infant Botulism

Most pediatric cases of botulism occur in infants (ie, infant botulism), although foodborne and wound

botulism also can affect the pediatric population.

Infant botulism is caused by ingestion of C botulinumspores. The spores subsequently colonize the

gastrointes tinal tract, germinate, and produce to xin, which is abso rbed into the circulation.

Mos t inf ants are well before illness onset (Wigginton 1993). The disease characteristically begins with

lethargy and poor f eeding (with or without constipation), f ollowed by neuromuscular paralysis,

hypotonia, or weakness (Clemmens 2007). Const ipation may be subtle or overt.

The source of spores f or most cases remains unknown, although the most common so urces of

infection for infants appear to be honey and environmental exposure (Arnon 1979, Brook 2007, Nevas

2005). Infant f ormula was postulated to be the source for one case (Brett 2005: A case of infant

botulism with a possible link to infant f ormula milk powder). Other risk factors identif ied in one study fo r

infants 2 months of age and older included breast- f eeding, less t han one bowel movement per day in

the 2 months befo re illness onset, and ingestion o f corn syrup (Spika 1989). In that s tudy, the only

identif ied risk f actor among infants less than 2 months o ld was living in a rural area or on a farm.Between 1976 (when inf ant botulism was f irst recognized) and 1996, 1,442 cases were reported to the

CDC (CDC 1998).

Cases were reported f rom 46 states, with Delaware, Hawaii, Utah, and California having the

highest incidence rates (9.0, 8.8, 6.3, and 5.7 per 100,000 live births, respectively).

Almost half of all cases were reported f rom California (680 cases; 47.2%).

The mean age at onset was 13 weeks (range, 1 to 63 weeks).

Analysis of inf ant botulism cases occurring globally f rom 1996 through 2008 revealed 524 cases in 26
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countries representing f ive continents. The f act that most countries have not reported cases o f inf ant

botulism suggests that the disorder is underreported, under-recognized, or both, because the organism

is present worldwide and cases of foodborne botulism have been reported in many of these countries

(Koepke 2008).

Five cases of infant botulism caused by C baratiitype F have been identif ied; the youngest patient was

just 38 hours old at presentation (Barash 2005).

A review of charts of inf ant pat ients in Calif ornia who were t reated with the orphan drug Human Botulism

Immune Globulin on the basis o f clinical presentation but did not ultimately have laborato ry-conf irmedbotulism (32 of the 681 who were treated) demonst rated that these patients f ell into f ive categories:

spinal muscular atrophy type I (f ive patients), metabolic diso rders (eight patients), infect ious diseases

(three patients), miscellaneous (seven pat ients; includes Miller Fisher variant of Guillain-Barre syndrome,

neuroblasto ma stage III, and cerebral inf arctions, among others), and probable infant bo tulism lacking

laboratory confirmation (nine patients) (Francisco 2007).

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Adult Intestinal Toxemia Botulism

The pathogenesis of intestinal botulism in adults is similar to that of infant botulism. Disease is causedby ingestion of C botulinumspores, with subsequent colonization of the gastro intest inal tract. Spores

germinate and produce toxin, which is then absorbed into the circulation.

Only a f ew cases have been recognized, and mos t have occurred pos toperatively or in adults with

underlying pathology of the gastrointestinal tract such as Crohn's disease (Bartlett 1986, Chia 1986,

Grif f in 1997, Shapiro 1998, Sheppard 2012). As of early 2012, cases had been reported f rom Canada,

Iceland, Italy, Japan, and the United States (Sheppard 2012).

Several cases caused by type F toxin produced by C baratiihave been reported to the CDC (McCroskey

1991), and cases caused by C butyricumproducing type E toxin also have been recognized (Fenicia

1999).

A review of type F adult botulism in the United States between 1981 and 2002 demons trated the

f ollowing f indings (Gupta 2005):

Thirteen cases o f adult type F botulism were reported to t he CDC during the study period,

representing 1% of US cases.

A toxigenic C baratiiorganism producing type F toxin was isolated in 8 (80%) of 10 positive

stoo l cultures. Type F toxin was identif ied in serum f or nine of the cases.

In 5 (42%) of 12 cases, a history of gastrointestinal disease or an invasive gastrointestinal

procedure was present bef ore illness onset. Also in 5 (42%) of 12 cases, antimicrobials

were report edly taken before illness onset. A possible fo od source was only identif ied in

one instance.

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Inhalat ional Botulism

Disease is caused by inhalation of aerosolized preformed botulinum toxin with subsequent absorption

through the lungs into the circulation.

Three cases o f inhalational botulism were report ed in 1962 in veterinary technicians in Germany who

were working with aerosolized botulinum toxin in animals (Arnon 2001). Symptoms occurred about 72
http://jama.ama-assn.org/cgi/content/full/285/8/1059http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16344510&query_hl=1&itool=pubmed_docsumhttp://www.journals.uchicago.edu/doi/abs/10.1086/313497http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1774272http://wwwnc.cdc.gov/eid/article/18/1/11-0533_article.htmhttp://wwwnc.cdc.gov/eid/article/18/1/11-0533_article.htmhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9696731&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9041335&query_hl=6http://www.nejm.org/doi/full/10.1056/NEJM198607243150407http://www.nejm.org/doi/full/10.1056/NEJM198607243150411http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17403857&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16082001http://pediatrics.aappublications.org/cgi/content/abstract/122/1/e73


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hours af ter exposure.

Inhalational disease also has been produced experimentally in animals. One study, involving primates,

demonstrated that illness occurred 12 to 80 hours af ter exposure (Franz 1993). Another study, involving

mice, demonstrated that f ollowing inhalational challenge, the maximum concentrat ion o f botulinum toxin

in blood occurred at 2 hours postexposure (Park 2003).

A mouse study characterized the pathological consequences of inhalat ional botulinum toxin exposure in

mice given prophylactic pentavalent (ABCDE) toxo id. The authors f ound t hat t he mice sustained severe

histopathological lung damage despite protection f rom the lethal neurotoxic eff ects. Signs included"thickening of the alveolar septa and perivascular areas with a generalized spreading interst itial edema

and a moderate intra-alveola/intrabronchiola hemorrhage" (Taysse 2005). These findings suggest a

direct toxic affect of botulinum toxin on lung tissues; however, more research is needed to better define

this potential effect.

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Iatrogenic Botulism

Iatrogenic botulism is caused inadvertently following injection of botulinum toxin f or therapeutic or

cosmetic reasons (Sobel 2005). See the section: Therapeutic Botulinum Toxin f or more inf ormation.Four cases o f iatrogenic botulism occurred in December 2004 in Florida f ollowing cosmetic injection with

a botulinum toxin that was not approved for use in humans (see Dec 15, 2004, CIDRAP News s to ry). The

injections contained much higher concentrations of botulinum toxin than the FDA-approved product

Boto x. A research f irm in Arizona so ld the raw botulinum toxin to healthcare practitioners as a Botox

substitute.

Another report ident if ied f our patients who developed iat rogenic bo tulism af ter receiving therapeut ic

doses of botulinum toxin for spasticity and blepharospasm; all recovered (Coban 2010).

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Botulism Caused by Ot her ClostridiumSpecies

C butyricumproducing type E toxin has been reported to cause intestinal botulism in inf ants and young

adults in Italy and foodborne botulism in Asia (Aureli 1986, Fenicia 1999, Schechter 1999).

C baratiiproducing type F toxin has caused intestinal botulism in inf ants and adults; in the lat ter it is

usually associated with gastro intest inal patho logy, recent gast rointes tinal surgery, or recent use of

antimicrobial agents (Barash 2005, Gupta 2005, McCroskey 1991, Schechter 1999).

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Agent and Pathogenes is

Epidemiology

Botulinum Toxin as a Biological Weapon

Emergency Response

Therapeutic Botulinum Toxin

Clinical Features and Dif f erential Diagnosis
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.journals.uchicago.edu/doi/full/10.1086/313564http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1774272http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16344510&query_hl=1&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16082001http://www.journals.uchicago.edu/doi/full/10.1086/313564http://www.journals.uchicago.edu/doi/abs/10.1086/313497http://www.ncbi.nlm.nih.gov/pubmed/3722863?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/pubmed/20150804http://www.cidrap.umn.edu/cidrap/content/bt/botulism/news/dec1504botulism.htmlhttp://cid.oxfordjournals.org/content/41/8/1167.fullhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15814363http://iai.asm.org/cgi/content/full/71/3/1147?view=full&pmid=12595426


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Laboratory Diagnosis

Prevention and Treatment Issues

Infection Control (Including Autopsies and Burial)

Case Def initions and Public Health Reporting

Bibliography


Historical Perspective

Mechanisms and Outbreak Features

Pediatric Cons iderations

Historical Perspective

Botulinum toxin poses a significant bioweapon threat "because of its extreme potency and lethality; its ease o

production, transport, and misuse; and the need for prolonged intensive care among affected persons" (Arno

2001). However, some experts believe that the po tent ial of botulinum toxin as a bioweapon is limited becauseof challenges with stabilizing the toxin for aerosol dissemination (Arnon 2001).

Past ef f orts to weaponize botulinum toxin include the f ollowing:

The United States produced botulinum toxin as a potential biological weapon beginning in World War II;

however, the US of f ensive biological weapons program ended aft er the 1972 Biological and Toxin

Weapons Convention (BTWC).

The former Soviet Union conducted research on use of botulinum toxin as a biological weapon as late

as t he early 1990s, despite having signed the BTWC.

At t he t ime of the Gulf War, Iraq had produced 19,000 L of concent rated bo tulinum toxin, some of which

was loaded into military weapons (Zilinskas 1997).

The Japanese cult Aum Shinrikyo at tempted to use aeroso lized bo tulinum toxin in Japanese cities on at

least three occasions between 1990 and 1995. The C bo tulinum used in these attempts was collected

f rom soil in northern Japan. These attacks f ailed because of f aulty microbiological technique, def icient

aerosol-generating equipment, or internal sabotage (Arnon 2001).

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Mechanisms and Outbreak Features

The two most likely mechanisms f or use of botulinum toxin as a terro rist weapon include deliberatecontamination of food or beverages or via an aerosol release (Villar 2006).

Because food products are often widely distributed, contamination of a commercially produced food or

beverage product could result in a high number of casualties and f atalities across t he country. In

addition, such a bioterrorist act would produce severe civic disruption, economic loss, and social anxiety.

According to the CDC, po tent ially cont aminated f ood or beverage items need to be heated at 85C

(185F) f or 5 minutes prior t o consumption to ensure that toxin is destroyed (CDC: Botulism: control

measures overview f or clinicians). Concern has been raised that t ypical temperatures employed f or

pasteurization o f commercially available beverage products (such as milk) may not suf f iciently denature

all botulinum toxin in the product.
http://www.bt.cdc.gov/agent/botulism/clinicians/control.asphttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://jama.ama-assn.org/content/285/8/1059.fullhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9244334&dopt=Abstracthttp://jama.ama-assn.org/content/285/8/1059.fullhttp://jama.ama-assn.org/content/285/8/1059.fullhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#pediatrichttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#mechanismshttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#historical


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Mathematical modeling suggests that 1 g o f botulinum toxin added to commercially distributed milk

consumed by 568,000 people could result in 100,000 cases of botulism (Wein 2005). Ten grams o f

toxin added to the same quantity of milk could result in over 500,000 cases in the exposed

population.

One study reported that conventional milk pasteurization (63C, 30 min) inactivated botulinum

toxin serotype A but did not inactivate bot ulinum toxin sero type B, indicating that serotype B toxin

is potentially heat stable in milk (Rasooly 2010).

However, another s tudy f ound that s tandard high-temperature short- time (HTST) pasteurization(heating milk to 72C and holding it s teady at this temperature for at least 15 seconds) inactivates

at least 99.99% of botulinum toxin types A and B, suggesting that standard pasteurization

conditions would reduce activity of these toxins much more dramatically than o riginally thought

(Weingart 2010).

An aeroso l release could also lead to high numbers o f casualt ies, although the event would be more

localized. Experts have estimated t hat 1 g of aerosolized botulinum toxin could kill up to 1.5 million

people (Shapiro 1997). Aerosolized particles of bot ulinum toxin are approximately 0.1 to 0.3 mcm in size

(Shapiro 1997). Despite these est imates, some experts discount the potential of botulinum toxin as a

bioweapon because the toxin may not be very stable in an aeroso lized f orm (Arnon 2001).

Although contamination of a water supply is f easible, this approach is unlikely since a large amount of toxin

would be needed to initially contaminate water. In general, deliberated contamination o f water with po tent ial

bioterrorism agents may not be very effective for the following reasons: dilution of the agent in a large body

of water; direct inactivation f rom chlorine or o ther disinfectants ; nonspecif ic inactivation by other mechanisms

(such as hydrolysis, sunlight, or microbes); f iltrat ion; and the relatively small amount of water that is actually

ingested f rom the source (Khan 2001).

Botulinum toxin is naturally inactivated in f resh water within 3 to 6 days, and toxin is rapidly (within 20

minutes) inactivated by s tandard po table water t reatment (Siegel 1993).

A 2005 s tudy f ound that two of seven small-scale water purif ication devices tested were able to

ef f ectively eliminate botulinum toxin f rom water. Those based on f iltrat ion (pore s ize 0.2 to 0.4 mcm) or

irradiation f rom a UV-lamp (254 nm) f ailed to remove the toxin f rom inoculated water. Reverse osmosis

and experimental sand f iltrat ion ef f ectively eliminated the toxin (Horman 2005).

It is unlikely that therapeutic botulinum toxin could be used in a terrorist attack, because a vial of the currently

licensed preparation contains only about 0.3% of the estimated human lethal inhalational dose and 0.005% of

the est imated lethal oral dose (Arnon 2001).

The f ollowing f eatures of a botulism outbreak would suggest deliberate toxin release (Arnon 2001).

An outbreak invo lving a larger number of cases than previous outbreaks

An outbreak caused by an unusual toxin type (ie, C, D, F, or G) o r an outbreak invo lving type E toxin

without an apparent aquatic source

Multiple simultaneous o utbreaks with or without an apparent source.

For aerosol release, cases would not have a common f ood exposure but would have been in a common

geographic location during the week befo re symptom onset

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Pediatric Considerations
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://jama.ama-assn.org/cgi/content/full/285/8/1059http://jama.ama-assn.org/cgi/content/full/285/8/1059http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15812023http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1497290/pdf/11571403.pdfhttp://jama.ama-assn.org/content/285/8/1059.fullhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869135/?tool=pubmedhttp://www.ncbi.nlm.nih.gov/pubmed/21053906http://www.pnas.org/cgi/content/abstract/0408526102v1


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In the event o f an aerosol release of botulinum toxin, children may be at an even greater level of risk

than adults , since children have a higher number of respirations per minute and consequently could have

an increased level of exposure to toxin (AAP 2000).

Signs and symptoms of botulism in children following a bioterrorist attack (ie, aerosol or foodborne

exposure) would be similar to those seen in adults.

Ensuring adequate intensive care resources for the pediatric population in the event of a bioterrorism

attack involving an agent such as botulinum toxin should be an important prior ity in bioterrorism

preparedness planning.

However, these analyses pertain to military uses of botulinum toxin to immobilize an opponent (William C.

Patrick, unpublished data, 1998). In contrast , deliberate release of botulinum to xin in a civilian population would

be able to cause substantial disruption and distress . For example, it is est imated that a point- source aerosol

release of botulinum toxin could incapacitate o r kill 10% of perso ns within 0.5 km downwind (William C. Patrick

unpublished data, 1998). In addition, terro rist use o f botulinum toxin might be manif ested as deliberate

contamination of food. Misuse of toxin in this manner could produce either a large botulism outbreak from a

single meal or episodic, widely separated outbreaks (Arnon 2001). In the United States, the CDC maintains a

well-established surveillance system f or human botulism based on clinician report ing that would promptly

detect such events (Arnon 2001).

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Epidemiology


Emergency Response







Bibliography

Emergency Response

Botulism Surveillance

Botulism Outbreak or Intent ional Dissemination

Emergency Response to a Mass Exposure

International Public Health Concerns

Botulism Surveillance

The CDC maintains an intensive surveillance system f or botulism in the United States . Cases are

identified through follow-up of requests f or bo tulinum antitoxin.
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#internationalhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#responsehttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#outbreakhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#surveillancehttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://jama.ama-assn.org/cgi/content/full/285/8/1059http://jama.ama-assn.org/cgi/content/full/285/8/1059http://pediatrics.aappublications.org/content/105/3/662.full


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Cases also may come to detection through requests f or laboratory test ing of f ood or clinical

specimens. Arrangements f or laboratory test ing are made through state public health laboratories.

These laborato ries either have the capability to test specimens directly or they collect and submit

specimens to ano ther laboratory f or t est ing (usually at t he CDC). All posit ive specimens identif ied

through state public health laboratories are report ed to the CDC on at least an annual basis.

All state health departments have 24- hour emergency phone lines f or report ing cases of botulism (CDC:

Emergency response). Requests to the CDC for ant itoxin are usually made through the state

epidemiology of f ices, although some requests are made directly to the CDC by clinicians caring f orsuspect botulism patients.

The authors of a report published in 2012 observed: "The identif ication o f epidemiologic linkages

between foodborne botulism cases is a critical part of diagnostic evaluation and outbreak detection.

Investigation o f an intent ionally contaminated f oo d item with a long shelf lif e and widespread distribution

may be delayed until an astute physician suspects foodborne botulism; suspicion of foodborne botulism

occurs more f requently when more t han one case is hospitalized concurrently. In an ef f ort to augment

national botulism surveillance and antitoxin release systems and to improve f ood defense and public

health preparedness ef f ort s, medical organizations and Homeland Security of f icials should emphasize

the education and training of medical personnel to improve f oo dborne bot ulism diagnostic capabilities to

recognize single foo dborne botulism cases and to look for epidemiologic linkages between suspected

cases" (Newkirk 2012).

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Botulism Outbreak or Intent ional Dissemination

A single case of f oodborne botulism (or bo tulism f rom an unknown source) is considered an outbreak

(MacDonald 1986) and is a public health emergency. Suspected cases should be reported immediately to

state or local public health officials.

Public health of f icials will: (1) assist with appropriate laboratory test ing to conf irm the diagnosis, (2)

authorize use of antitoxin, (3) conduct aggressive surveillance fo r other cases, and (4) immediatelybegin an epidemiologic invest igation to identif y the source or vehicle (such as a contaminated

commercial product) or to determine if there is evidence to suggest a bioterro rism-related event.

Original specimens should be preserved and their custody documented, pursuant to public health and

regulato ry invest igation procedures as well as potent ial criminal invest igation procedures (ASM 2013).

Public health o f f icials will coordinate not if ication o f local FBI agents as appropriate.

If available evidence suggests the po tent ial fo r a cont inued increase in cases while the investigation

proceeds, involved hospitals should establish communication networks between the emergency

department, the intensive care unit, and those services likely to be involved in managing cases (eg,

infectious disease, pulmonary, respirato ry therapy, critical care, neurology). These networks should

f ocus on establishing policies and procedures f or handling large numbers of patients (see below).

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Emergency Response to a Mass Exposure

In the event of a mass exposure, such as a widespread aerosol release of botulinum toxin, the following step

would be necessary.

Rapid administ ration o f antitoxin to ill persons: Although antitoxin does not reverse exist ing paralysis,

once administered it binds t o any toxin remaining in the circulation and, theref ore, can mitigate
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.asm.org/images/PSAB/Botulism_July2013.pdfhttp://www.ncbi.nlm.nih.gov/pubmed/3766512http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/pubmed/22315952http://www.bt.cdc.gov/EmContact/index.asp


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progression o f disease, increase the likelihood of survival, and decrease the duration of mechanical

ventilatory support (if respiratory failure occurs). Release of antitoxin and coordination of

administ ration would be performed by local/state public health o f f icials in conjunction with the CDC.

Rapid mobilization of mechanical ventilato rs: Adequate support ive care resources, including those f or

infants and children, would be critical to successf ul management o f any mass-exposure botulism

outbreak.

Two art icles published in 2009 provide tools f or management o f botulism mass casualty incidents. One

involves an algorithm fo r the evaluation and management o f botulism patients in a triage sett ing (Rega 2009),and the other of f ers a short questionnaire that can assist with screening of potential casualties (Burkholder-

Allen 2009).

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International Public Health Concerns

A large o utbreak in Thailand (209 cases) in 2006 emphasized the need f or addressing global po licy issues

concerning outbreaks in developing countries, including health infrastructure, communication and response

systems, stockpiles of medication and supplies, decision algorithms for notification, and international

response to public health emergencies (Ungchusak 2007).

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Epidemiology


Emergency Response







Bibliography


Therapeutic Uses

Special Considerations

Therapeutic Uses

Patients with a range of spast ic or autonomic neuromuscular disorders may benef it f rom small amounts

of purified botulinum toxin injected into affected muscles (Schantz 1992). There are two types of

therapeutic botulinum to xin: purif ied botulinum to xin type A (Botox, produced by Allergan, Inc) (Allergan,
http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1579114http://www.cidrap.umn.edu/infectious-disease-topics/botulism#specialhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#therapeutichttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.scielosp.org/pdf/bwho/v85n3/v85n3a21.pdfhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://onlinelibrary.wiley.com/doi/10.1111/j.1442-2018.2009.00489.x/fullhttp://www.ncbi.nlm.nih.gov/pubmed/19860161


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Inc) and purif ied botulinum to xin type B (Myobloc, produced by Elan Pharmaceuticals, Inc) (FDA: Myobloc

labeling inf ormation).

Examples of conditions that can be treated with botulinum toxin include:

Spasmodic tort icollis

Strabismus

Blepharospasm

Laryngeal dystonia

Focal dysto nias of the hand

Limb spasticity

Hemifacial spasm

Cerebral palsy

Migraine headache

Hyperhydrosis (severe underarm sweating)

Post-stroke spasticityUrinary incontinence in adults with overactive bladder caused by neurologic disease

In April 2002, the FDA approved use o f botulinum toxin type A f or cosmetic purposes (Allergan, Inc, FDA:

Boto x Cosmetic labeling information).

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Special Considerat ions

Therapeutic botulinum toxin contains about 0.3% of the est imated lethal human inhalational dose and only

0.005% of the estimated lethal human oral dose; therefore, this f orm of toxin is not likely to be used as a

bioterrorist weapon (Arnon 2001). However, iatrogenic cases of botulism have been reported.

A repo rt published in 2010 identif ied f our patients who developed iat rogenic bo tulism f ollowing treatment

with botulinum toxin f or musculoskeletal disorders (Coban 2010). One patient required intensive care,

but all four survived.

An unlicensed, highly concentrated preparation of botulinum toxin caused bo tulism in f our adult pat ients

undergoing cosmetic procedures. Aff ected patients may have received doses 2,857 t imes t he est imated

human lethal dose by injection. Pretreatment serum levels in three of the f our pat ients were f rom 21 to

43 times t he est imated human lethal dose (Chertow 2006). Following protracted hospital courses,

prolonged mechanical ventilation, and physical rehabilitation, all four of these patients survived.

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Epidemiology


Emergency Response

http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17119144&query_hl=63&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/pubmed/20150804http://jama.ama-assn.org/cgi/content/full/285/8/1059http://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.fda.gov/downloads/Drugs/DrugSafety/UCM176360.pdfhttp://www.botox.com/http://www.fda.gov/downloads/Drugs/DrugSafety/UCM176361.pdfhttp://www.botox.com/


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Bibliography


Clinical Features

Differential Diagnosis

Clinical Features

Botulism is characterized by acute af ebrile descending symmetric paralysis. Recovery occurs over weeks

to months and often requires extensive supportive care.Disease generally begins with evidence of cranial nerve dysf unction and then progresses to muscle

weakness (proximal muscle groups are af f ected f irst and may be more severely involved).

Severity of disease ranges f rom mild cranial nerve dysf unction to complete f laccid paralysis. Paralysis o f

pharyngeal or respiratory muscles may result in the need f or prolonged mechanical ventilation.

Severity of disease correlates with the amount of toxin absorbed into the circulation.

Several studies have shown that a shorter incubation period correlates with more severe disease

(MacDonald 1985: Type A botulism f rom sauteed onions, Tacket 1984). Similarly, a study of

botulism cases in Japan revealed that patients who had shorter incubation periods had a

significantly higher risk of death (Nishiura 2007).

Disease caused by toxin type A tends to be more severe than disease caused by toxin type B or E

(Shapiro 1998).

Among more than 200 pat ients in an outbreak in Thailand, respiratory f ailure was less likely to

develop in those who did not manifes t nausea o r vomiting and did not have urinary retention

requiring catheterizat ion. Nausea o r vomiting and any cranial neuropathy with urinary retent ion o r

dif f iculty swallowing were symptoms most predictive of respiratory failure (Wongtanate 2007).

One study of injecting drug users who had wound botulism found that longer time from

presentation in the emergency department to administration of antitoxin and longer time from

presentat ion to wound drainage were independently associated with increased length of stay in

intensive care (Of f erman 2009).

Death can result from airway obstruction or paralysis of respiratory muscles. Death also can result from

complications related to prolonged ventilatory support and intensive care, such as aspiration pneumonia

and other infectious conditions.

Befo re mechanical ventilation was widely available, the case-f atality rate was about 60% (Shapiro

1998).

The case- f atality rate currently is low owing to adequate supportive care; overall the rate is 5% to

10% for f oodborne disease and somewhat higher f or wound botulism (Shapiro 1998, Werner
http://www.journals.uchicago.edu/doi/abs/10.1086/318134http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9696731&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9696731&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791728/?tool=pubmedhttp://www.ajtmh.org/cgi/content/abstract/77/2/386http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9696731&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16684403&query_hl=16&itool=pubmed_docsumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=3968852&ordinalpos=73&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#_Differential_Diagnosishttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#_Clinical_Features


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2000).

In the event o f a mass exposure (such as a bioterro rism attack), clinical resources could be

overwhelmed rapidly and the case- f atality rate could be much higher.

A ret rospective st udy of hospitalized f oodborne botulism cases in the Republic of Georgia, 1980-

2002, found that patients with shortness of breath and impaired gag reflex and without diarrhea

were 23 times more likely to die than were patients without t his syndrome (Varma 2004). In this

case series, the incubation period was similar among those who died and those who survived, as

was the likelihood of receiving antitoxin.

Clinical Feat ures of Foodborne and Wound Botulism

Charact erist ic Feat ures

Incubation perioda Dependent on level of toxin exposureFor foodborne botulism, 2 hr8 daysFor wound botulism, 4-14 daysUnknown for inhalational botulism; estimated to be 24-36 hr;

the only three reported cases in humans had an incubationperiod of 72 hr

Symptoms (compiled f rom reports o ff oodborne botulism outbreaks caused by

to xin types A, B, and E)b

Nausea (88%)c

Dry mouth (82%)Blurred vision (78%)Dysphonia (76%)Dysphagia (75%)Weakness (72%)Fatigue (69%)Dyspnea (65%)Dysarthria (63%)

Double vision (60%)Dizziness (56%)

Vomiting (52%)c

Constipation (related to autonomic dysfunction) (45%)Sore throat (40%)

Abdominal cramps or abdominal pain (40%)d

Diarrhea (35%)c

Paresthesias (29%)
http://www.journals.uchicago.edu/doi/abs/10.1086/422318


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Signs (compiled from cases of types Aand B botulism report ed to CDC in 1973

and 1974)d

Alert mental st atus (90%)Weakness of upper extremities (75%)Ptosis (73%)Weakness of lower extremities (69%)Extraocular muscle weakness (65%)Diminished gag ref lex (65%)Facial nerve dysfunction (63%)Dilated or f ixed pupils (44%)Diminished or absent deep tendon ref lexes in af f ected groups(40%)Nystagmus (22%)Ataxia (17%)Other considerations:~Patients generally afebrile~Mental status generally intact, although pat ients may appearlethargicor have diff iculty communicating because of bulbar dysfunction~Sensory exam generally normal

Laboratory f eatures Normal CSF glucose, protein, cell countNormal CBCNormal imaging of brain and spine (ie, CT scan or MRI)

Characterist ic EMG f indingse:~Incremental response (facilitat ion) to repetitive stimulation (notalways present and often seen only at 50 Hz)~Short duration of motor unit potentials (MUPs); polyphasicMUPs~Decreased amplitude o f compound muscle action potentials(CMAPs) af ter a single nerve stimulus (most prominent inproximalmuscle groups)~Normal sensory nerve function~Normal nerve conduction velocity (moto r and sensory)

Complications Respiratory f ailure (which may require prolonged ventilatorysupport); in some outbreak settings, up to 30%-40% of patientsrequired mechanical ventilationAspiration pneumonia (among pat ients with respirato ry

failure)f

Residual fat igue, dry mouth or eyes, dyspnea on exertion up

to several years after initial presentationg

Case-f atality rateh 5%-10% for f oodborne botulismi

15%-44% f or wound botulismj

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Differential Diagnosis

Differential Diagnosis of Botulism

Condition Features t hat dist inguish each conditio n from bot ulisma
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#top


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Guillain-Barre syndrome(GBS) (particularly MillerFisher variant)

Classic GBS results in ascending paralysisMiller Fisher variant may be descending and may have prono unced cranialnerve involvement; it usually includes a triad of ophthalmoplegia, ataxia, and

aref lexia (5% of GBS cases are of the Miller Fisher variant)b

Abnormal CSF protein 1-6 wk af ter illness onset (although may be normalearly in clinical course)Paresthesias commonly occur (often stocking/glove pattern)EMG shows abnormal nerve conduction velocity; f acilitat ion with repet itivenerve st imulation does no t occur (as with botulism)

Histo ry of antecedent diarrheal illness (suggestive of Campylobacterinf ection, which accounts f or about one third of GBS cases)Outbreaks o f GBS do not occur (unlike botulism)

Myasthenia gravis Dramatic improvement with edrophonium chloride (ie, a posit ive Tensilontest), although some botulism patients may exhibit part ial improvementf ollowing administ ration o f edrophonium chloride (ie, a borderline Tensilontest)EMG shows decrease in muscle action potent ials with repetitive nervestimulation

Tick paralysisc Ascending paralysisParesthesias are common

Careful examination reveals presence of tick attached to skinRecovery occurs within 24 hr af ter tick removalEMG shows abnormal nerve conduction velocity and unresponsiveness torepetitive st imulationUsually does not involve cranial nerves

Lambert-Eaton syndrome Commonly associated with carcinoma (of ten oat cell carcinoma of lung)Although EMG f indings are s imilar to those in botulism, repetitive nervest imulation shows much greater augmentat ion of muscle action potentials,particularly at 20-50 HzIncreased strength with sustained contractionDeep tendon ref lexes of ten absent; ataxia may be presentUsually does not involve cranial nerves

Stroke or CNS mass lesion Paralysis usually asymmetricBrain imaging (CT or MRI) usually abnormalSensory def icits commonAltered mental status may be present

Poliomyelitis Febrile illnessCSF shows pleocytos is and increased proteinAltered mental status may be presentParalysis of ten asymmetric

Paralytic shellf ish poisoning

or ingestion of puff er fish

History of shellfish (ie, clams, mussels) or puffer fish ingestion within

several hours before symptom onsetParesthesias of mouth, f ace, lips, extremities commonly occur

Belladonna toxicity History of recent exposure to belladonna-like alkaloidsFeverTachycardiaAltered mental status

Aminoglycoside toxicity History of recent exposure to aminoglycoside ant ibioticsMore likely to occur in the sett ing of renal insuf f iciencyMost commonly seen with neomycinMost commonly asso ciated with o ther neuromuscular blocking agents suchas succinylcholine and paralytics


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Other toxicities(hypermagnesemia,organophosphates, nervegas, carbon monoxide)

History of exposure to toxic agentsCarbon monoxide toxicity: altered mental st atus may occur, cherry-coloredskinHypermagnesemia: histo ry of use of cathartics or antacids may be present,elevated serum magnesium levelOrganophosphate toxicity: fever, excessive salivation, altered mentalstatus, paresthesias, miosis

Other condit ions CNS infect ions (part icularly brains tem infect ions )

Inf lammatory myopathyHypothyroidismDiabetic neuropathyViral infectionsStreptococcal pharyngitis (pharyngeal erythema and so re throat can occurin botulism owing to dryness caused by parasympathet ic cholinergic blockade)

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Epidemiology


Emergency Response







Bibliography


Specimen Collection and Transport

Laboratory Biosafety

Laboratory Response NetworkDiagnostic Tests for Detection of Botulinum Toxin and C botulinum

Specimen Collection and Transport

Specimen collection and transport procedures f or t est ing related to diagnos ing botulism are outlined in the

following table.

Collect ion and Transport of Laboratory Specimens for the Diagnosis of Botulism
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#diagnostichttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#lrnhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#biosafetyhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#specimenhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#top


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Specimen Clinical Indicat io n Co llect io n and T ranspo rt

Serum Intentional release, f oodbornebotulism, autopsy specimens

Collect >20 mL whole blood before administ ration ofantitoxin using red-top o r separator t ube (noanticoagulant)

Ship >10 mL serum at 4oCDo not ship whole blood, which tends to becomehemolyzed during transitNotif y test ing lab if patient has received "stigminedrugs" or a Tensilon tes tKeep specimen ref rigerated at all times

Wound botulism (criticalspecimen for confirmation)

Collect 30 cc whole blood (before ant itoxinadministration)

Ship at 4oCSera submitted f or toxin detection should not behemolyzedNotif y test ing lab if patient has received "stigminedrugs" or a Tensilon tes tKeep specimen ref rigerated at all times

Wound/t issue Wound botulism Collect exudate, tissue, or swabsShip at room temperature in anaerobic transpo rtsystem

Stoo l, enemafluid, intestinalfluid

Intentional release, foodbornebotulism, infant botulism,

wound botulismb

Obtain 10-50 g of sto ol (as litt le as "pea-size" f or

inf ant botulism); transport at 4oCEnema f luid (20 cc) can be collected as an alternat iveto stool, using minimal amount of sterile

nonbacteriostatic water; ship at 4oCIntestinal f luid collected at autopsy (20 cc); ship at

4oC

Gastric fluid,vomitus

Foodborne botulism,intentional release

Collect within 72 hr of symptom onset

Obtain 20 cc of vomitus; ship at 4oCObtain 20 cc of gastr ic f luid (living cases or at

autopsy); ship at 4oC

Specimens tocollect atautopsy

Intentional release, foodbornebotulism, infant botulism

Serum, according to methods o utlined aboveContents f rom diff erent sections o f small and largeintest ines (10 g per sample in separate containers)Gast ric contents as indicated, according to methodsoutlined aboveTissue samples as indicated, according to methods

outlined above

Food samples(epidemiologicallyimplicated)

Intentional release, foodbornebotulism, infant botulism

Obtain 10-50 g of implicated or suspect food; ship at

4oC in original containerPlace individually in leak-proo f sealed transportdevices

Nasal swab Intent ional releasec Obtain anaerobic swab; ship at roo m temperature


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Environmentalsample

Intent ional release, inf antbotulism

Collect as appropriate:~Environmental swab; ship at roomtemperature~Soil (50-100 g)~Water (>100 mL)

2001bA wound may not be the actual source o f inf ection/intoxication.cToxin may be present on nasal mucosa f or up to 24 hr af ter inhalational exposure (Franz 1997).

Guidelines have been published f or packing and shipping of infectious substances, diagnostic specimens, and

biological agents from suspected bioterrorism (ASM 2012). C botulinum is classif ied under World Health

Organizat ion (WHO) risk group 4. Cultures that are reasonably suspected to contain C botulinummust be

transported as "infectious substances." In addition, the US Department of Transportation (DOT) regulations

and International Air Transport Association (IATA) rules require training of all individuals involved in the

transport of dangerous goods, including inf ectious substances (DOT 2008, IATA 2012). Once botulinum toxin

identif ied, samples may be regulated as select agents and subject t o additional transport requirements (see

below). Chain of custody should be documented f or material that may const itute evidence of criminal activity.

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Laboratory Biosafety

Botulinum toxin and Clostridiumspecies that produce botulinum toxin are classif ied as select agents and

theref ore are regulated under 42 CFR part 73 (Possession, Use, and Transf er of Select Agents and

Toxins), which was published in f inal fo rm in the Federal Registerin March 2005 (HHS 2005). As specif ied

in the Public Health Security and Bioterro rism Preparedness and Response Act of 2002, 42 CFR part 73

provides requirements f or laboratories that handle select agents (including regist ration, security risk

assessments, saf ety plans, security plans, emergency response plans, training, transf ers, record

keeping, inspections, and notifications).

C botulinumtoxin detection should be perfo rmed only by trained individuals at laboratory responsenetwork (LRN) reference or higher laborato ries.

Sodium hypochlorite (0.1%) or sodium hydroxide (0.1 N) inactivate the toxin and are recommended by the

CDC for decontaminating work surfaces and spills of cultures or toxin (CDC 2009).

Biosafety recommendations f rom the FDA f or laboratories that test f or C botulinuminclude the f ollowing

(Solomon 2001):

Place biohazard signs on doors to res trict entrance and keep the number of people in the

laboratory to a minimum.

All workers should wear laboratory coats and saf ety glasses.

Never pipette anything by mouth; use mechanical pipettes.

Use a biohazard hood for t ransfer of toxic material if poss ible.

Centrifuge toxic materials in a hermetically closed centrif uge with safety cups.

Personally take all toxic material to the autoclave and see that it is sterilized immediately.

Do not work alone in the laborato ry or animal rooms af ter hours or on weekends.

Have an eye wash fountain and foo t- pedaled faucet available for hand washing.

Allow no eat ing or drinking in the labo ratory.

In a ver visible location, list hone numbers where thera eutic antitoxin can be obtained.
http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/ucm070879.htmhttp://www.cdc.gov/od/ohs/biosfty/bmbl5/BMBL_5th_Edition.pdfhttp://www.selectagents.gov/resources/42_cfr_73_final_rule.pdfhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttps://www.iataonline.com/Store/default.htm?NRMODE=Published&NRORIGINALURL=%2fStore%2fProducts%2fProduct%2bDetail.htm%3fcs_id%3d9660-30%26cs_catalog%3dPublications&NRNODEGUID=%7b16F5587B-8B15-4B8B-8EB5-498DFA3C1136%7d&NRCACHEHINT=NoModifyGuest&cookie_test=1&cs_id=9065-51&cs_catalog=Publicationshttp://phmsa.dot.gov/portal/site/PHMSA/menuitem.ebdc7a8a7e39f2e55cf2031050248a0c/?vgnextoid=e4439f5cf6f57110VgnVCM1000009ed07898RCRD&vgnextchannel=a45a764e4da7e010VgnVCM1000008055a8c0RCRD&vgnextfmt=print#page3http://www.asm.org/images/PSAB/PackAndShip.pdfhttp://jama.ama-assn.org/cgi/content/short/278/5/399


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Reduce clutter in the laboratory to a minimum and keep all equipment and other materials in their

proper place.

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Laboratory Response Network

The LRN is a network of more than 150 national and international laborato ries. The network includes f ederal,

state and local public health, military, f oo d test ing, environmental, veterinary, and international laboratories(CDC: Facts about the Laboratory Response Network, CDC: The Laboratory Response Network).

The LRN structure for bioterrorism designates laboratories as sentinel, reference, or national. Designation

depends on the types o f tests a laboratory can perform and how it handles infectious agents to protect

workers and the public.

Sentinel laboratories, formally called level A laboratories represent an est imated 25,000 hospital-

based laboratories that have direct contact with patients. In an unannounced or covert terrorist attack,

sentinel laboratories could be the first facilities to encounter suspicious specimens. These laboratories

generally have at least BSL-2 containment capabilities. A sent inel laboratory's responsibility is to rule out

B anthracis or refer a suspicious sample to t he nearest LRN reference laboratory. Sentinel laboratoriesuse t he ASM [American Society f or Microbiology] Sentinel Level Clinical Microbiology Laboratory

Guidelines to rule out microorganisms that might be suspected as agents of bioterrorism (ASM).

Reference laboratories, sometimes ref erred to as "conf irmatory ref erence," can perfo rm tests to detect

and conf irm the presence of a threat agent. These laboratories ensure a t imely local response in the

event of a terrorist incident. Rather than having to rely on confirmation from laboratories at the CDC,

reference laborato ries are capable of producing conclusive results; this allows local authorities to

respond quickly to emergencies. These are mos tly state o r local public health laborato ries but also

include military, international, veterinary, agriculture, and f ood- and water-tes ting laboratories. Reference

laborato ries operate with BSL-3 containment f acilities that have been given access to nonpublic test ing

protocols and reagents. One of the roles of the LRN reference laboratories is to provide guidance,training, outreach, and communications to the sentinel laboratories in their jurisdictions.

National laboratorieshave unique resources to handle highly infect ious agents and the ability to

identify specific agent strains through molecular characterization methods. These laboratories also are

responsible for methods development, bioforensics, and select-agent activity.

Back to top

Diagnostic Tests for Detect ion of Botulinum Toxin and C botulinum

According to the ASM guidelines, LRN sent inel laboratories "should not at tempt t o culture, ident if y the

organism, or att empt to perf orm toxin analysis." Furthermore, LRN sentinel laborato ries should not acceptenvironmental or animal specimens; such specimens should be f orwarded directly to the s tate health

department laboratory (ASM 2012). Only certain LRN reference laboratories have the capability to perform

mouse bioassay tes ting.

The mouse bioassay is currently the primary diagnost ic method used for detection and identif ication o f

botulinum toxin. Other methods (see below) are s till considered investigational.

Mice are injected intraperitoneally with the patient sample, stool or f ood extract, culture f iltrate, or

other sample and observed for up to 4 days.

Control mice are injected with a mixture o f the sample combined with neutralizing antibody to
http://www.asm.org/images/PSAB/Botulism_July2013.pdfhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://www.asm.org/index.php/guidelines/sentinel-guidelineshttp://emergency.cdc.gov/lrn/pdf/lrn-overview-presentation.pdfhttp://www.bt.cdc.gov/lrn/factsheet.asphttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#top


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different toxin types.

Signs of botulism intoxication usually are evident in 6 to 24 hours.

As lit t le as 0.03 ng of toxin can be detected by this method (CDC 1998, Shantz 1992).

One report of a cohort of clinically defined wound botulism cases found that the serum mouse

bioassay was only 68% sensitive in conf irming inf ection (Wheeler 2009). The authors pointed out

that physicians should be aware of the test 's limitations and base their f inal diagnos is on clinical

criteria when the mouse bioassay produces negative results .

Culture for C botulinumf or s tool or gastric specimens has been used for diagnos is, in addition to toxin

test ing (CDC 1998). Iso lates are tested f or neuro toxin by the mouse bioassay. An activation step with

trypsin is required to detect toxin from some group II strains. Isolation of C botulinumf rom stool or a

wound is considered diagnostic in patients with signs and symptoms of botulism.

Nasal swabs could potentially be collected in the event of an aeroso l exposure (CDC: Specimen

selection table, Franz 1997). As with other types of potential bioterrorism exposures, the sensitivity and

diagnostic value of nasal culture is unknown. Nasal swabs should only be used as part of an

epidemiologic investigation o r on the basis o f recommendations made by the CDC in the event o f a

bioterrorist att ack.

Serological assays for botulinum toxin antibody are not useful as a measure of exposure, which doesnot typically induce an antibody response.

Detailed methods for testing food samples have been published by the FDA's Center for Food Safety

and Applied Nutrition (CFSAN) (Solomon 2001). Detection o f botulinum toxin in an epidemiologically

implicated f oo d item conf irms the diagnosis of botulism. SinceC botulinum is widely distributed in nature,

the organism may be present in f oo d without producing toxin or causing disease. Therefore, positive

culture results from food, in the absence of detectable toxin, must be interpreted within the context of

ot her epidemiological f indings.

Pulsed-f ield gel electro phoresis (PFGE), randomly amplif ied polymorphic DNA analysis, and automated

ribotyping methods have been compared f or epidemiological typing of C botulinumtype E using clinical

and food isolates asso ciated with f our botulism outbreaks that occurred in the Canadian Artic. A

modif ied PFGE protocol was judged to be the most usef ul method f or typing epidemiologically related

type E strains, based on its ability to type all strains reproducibly and with an adequate level of

discrimination (Leclair 2006)

Investigators have identif ied high-af f inity monoclonal antibodies (mAbs) that specif ically bind botulism

toxins type A and B. These have been used to develop highly sensitive sandwich immunoassays, which

appear to be promising alternatives to the mouse bioassay (Scot cher 2010, Stanker 2008, USDA 2009).

A "ruggedized" real- time PCR assay called R.A.P.I.D. for use by f irst-responders and in military f ield

hospitals and other rough environments is commercially available but not FDA approved (Idaho

Technology).

Other tests for botulinum toxin (considered investigational):

Other enzyme-linked immunoassays (ELISA) (Dezfulian 1991, Ferreira 2001, Ferreira 2003,

Wictome 1999)

An immuno- PCR assay that measures ant igen-ant ibody react ions using a conjugated reporter

DNA molecule followed by PCR amplif ication (Chao 2004)

Time-resolved f luorescence assays f or C botulinumA/B neuroto xin (Peruski 2002)

Matrix-assisted laser desorption/ionisat ion- time of f light mass spectrometry (MALDI-TOF MS)

(Barr 2005, Cruzan 2006, Darby 2001, Wilkes 2006)
http://www3.interscience.wiley.com/cgi-bin/abstract/112693175/ABSTRACThttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11569541&dopt=Abstracthttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108705.htmhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16318699&query_hl=1&itool=pubmed_DocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12009202&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15037026http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10566787&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12723917&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=11601465&ordinalpos=16&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2013205&dopt=Abstracthttp://www.idahotech.com/RAPID/index.htmlhttp://www.ars.usda.gov/is/AR/archive/may09/botulism0509.pdfhttp://www.sciencedirect.com/science/article/pii/S0022175908000902http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883556/?tool=pubmedhttp://jcm.asm.org/cgi/content/abstract/44/5/1635http://www.fda.gov/Food/ScienceResearch/LaboratoryMethods/BacteriologicalAnalyticalManualBAM/ucm070879.htmhttp://jama.ama-assn.org/cgi/content/short/278/5/399http://www.bt.cdc.gov/Documents/PPTResponse/TABLE2SpecimenSelection.pdfhttp://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/botulism.pdfhttp://cid.oxfordjournals.org/content/48/12/1669.longhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=1579114http://www.cdc.gov/ncidod/dbmd/diseaseinfo/files/botulism.pdf


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An opt ical immunoassay f or rapid detection of neurotoxins A, B, E, and F (Ganapathy 2008)

A micromechanosensor f or detection of botulinum toxin type B (Liu 2003)

Lateral f low devices f or environmental testing (Alexeter Technologies,New Horizon Diagnostics,

Osborn Scientif ic Group)

A botulinum neuro toxin serotype A assay with a large immuno-so rbent surf ace area (BoNT/A

ALISSA) that captures a low number o f toxin molecules and measures their int rins ic

metalloprotease activity with a fluorogenic substrate (Bagramyan 2008)

Other tests f or C botulinum(o rganism)

PCR assays have been used f or the detection of C botulinumto xin genes in animal, food, and

f ecal samples (Craven 2002, Dahlenborg 2001, Fenicia 2007, Franciosa 1994, Lindstrom 2001).

One report published in 2009 described a set o f real-time PCR tests f or detecting botulinum

neurotoxin genes f or A, B, E, and F toxins produced by C botulinum, C baratii,and C butyricum

(Fach 2009). PCR-based assays detect genetic sequences of the organism, not the toxin

molecule itself . This is important to consider, since the o rganism may not be present in clinical

specimens o r may not be involved in an intent ional release of botulinum toxin.

Subtyping methods for C botulinum, such as ribotyping, have been described (Skinner 2000).

An amplif ication method that analyzes variable number tandem repeat regions in C botulinumhas

been shown to be capable of discriminating among type A st rains and may provide laboratories

with a rapid, highly discriminatory diagnost ic too l for use in botulism outbreaks (Macdonald 2008).

Back to top


Epidemiology


Emergency Response







Bibliography


Therapy f or Botulism

Botulinum Toxoid

Research on New Therapies and Vaccines
http://www.cidrap.umn.edu/infectious-disease-topics/botulism#researchhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#botulinumhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#therapyhttp://www.cidrap.umn.edu/infectious-disease-topics/botulism#tophttp://aem.asm.org/cgi/content/abstract/74/3/875http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11041133&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pubmed/19291235http://aem.asm.org/cgi/content/full/67/12/5694?view=full&pmid=11722924http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7989542&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17369349&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSumhttp://aem.asm.org/cgi/content/full/67/10/4781?view=full&pmid=11571185http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12374399&dopt=Abstracthttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2323579/http://www.nhdiag.com/botulism.shtmlhttp://www.alexeter.com/http://www.pnas.org/cgi/content/full/100/23/13621http://www.ncbi.nlm.nih.gov/pubmed/18508597


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Therapy for Botulism

Support ive care is the mainstay f or treatment o f botulism; prolonged intensive care, mechanical

ventilation, and parenteral nutrition may be required.

Botulinum antitoxin can be administered to treat forms of botulism other than infant botulism and is

mos t ef f ective if given early in the clinical course (Sobel 2009: Diagnosis and treatment of botulism).

Although antito xin will not reverse exist ing paralysis, it will prevent addit ional nerve damage if given

before all circulating toxin is bound at the neuromuscular junction.

For botulism cases o ther t han infant bo tulism, the CDC provides heptavalent botulinum antitoxin (HBAT,

Cangene Corpo ration) through a CDC-sponsored FDA Investigational New Drug (IND) protocol. HBAT

replaced bivalent botulinum antitoxin AB in March 2010 (CDC 2010).

The HBAT FDA IND treatment protocol includes specif ic, detailed inst ructions f or intravenous

administration of antitoxin and return of required paperwork to the CDC.

HBAT contains equine-derived antibody to the seven known bot ulinum toxin types (A through G)

with the f ollowing nominal potency values: 7,500 U anti-A; 5,500 U anti-B; 5,000 U anti-C; 1,000 U

anti-D; 8,500 U anti-E; 5,000 U anti-F; and 1,000 U anti-G.

In the sett ing of a bioterro rist at tack, where cases may have been exposed to unusually largeamounts o f toxin, additional doses of antitoxin may be necessary. Alternat ively, the pat ient's

serum could be retested for the ongoing presence of circulating toxin (Arnon 2001); however, this

process would take time. The scarcity o f antitoxin would limit the capacity to provide additional

doses.

In cases o f wound bot ulism, the wound should be surgically debrided and antibiot ics should be

administered (usually penicillin).

Botulism immune globulinintravenous (human) (BIG-IV) f or treatment o f infant bo tulism was licensed by

the FDA in October 2003 as BabyBIG.

A 5-year randomized, do uble-blind, placebo -contro lled trial o f BIG-IV treatment f or inf ant botulismin California demonstrated that it significantly: (1) shortened duration of hospitalization (from a

mean of 5.7 weeks t o 2.6 weeks), (2) shortened time spent in intensive care (f rom 5.0 weeks t o

1.8 weeks), and (3) decreased mean hospital cost s per patient by $88,000 (Arnon 2006).

BIG-IV is available as a public-service orphan drug and may be obtained by contacting the

California Department of Human Services, Infant Bot ulism Treatment and Prevention Program

(Arnon 2006, California Department of Health Services). The circumstances that enabled the

creation of BIG-IV have been presented as a possible paradigm f or development o f other

"orphan" drugs (drugs used to treat relatively fe