Table 1.

Topic area	Questions
Maternal and fetal outcomes associated with botulism	1. Are pregnant and postpartum women more susceptible than nonpregnant women to botulism? 2. Do pregnant women have different signs and symptoms or more severe disease than nonpregnant patients? 3. Is there an increased risk for adverse maternal, fetal, or neonatal outcomes associated with botulism? 4. What are the effects of antitoxin on pregnant women?
Allergic reactions to botulinum antitoxin	1. What is the risk for anaphylaxis from botulinum antitoxin? 2. What is the usefulness of skin testing in determining the risk for allergic reactions to botulinum antitoxin?
Efficacy of antitoxin in foodborne botulism	1. What are the benefits of botulinum antitoxin? 2. Is there a time beyond which antitoxin is no longer beneficial? 3. Do any patient demographic or clinical characteristics predict greater benefit from antitoxin?
Pediatric botulism and use of botulinum antitoxin in children	1. What are the signs and symptoms of diagnostic value in children with botulism? 2. What is the effect of botulinum antitoxin in children?
Epidemiology of foodborne botulism outbreaks	1. What are the demographic characteristics? 2. What are the types of food sources and toxin types? 3. What are the clinical characteristics, including adverse outcomes? 4. What are the times between exposure, symptom onset, and adverse outcomes? 5. What are the outbreak durations?
Clinical features of foodborne and wound botulism	1. What are the signs and symptoms reported at hospital admission? 2. What are the incubation periods and duration of illness before hospital admission? 3. What are the patient factors associated with respiratory failure and death?

Botulism clinical guidelines topic areas and questions for systematic reviews

Table 2.

Definition, setting, and treatment	Standard of care
Definition, setting, and treatment	Conventional	Contingency	Crisis
Definition	• Usual standard of care, and space, staff, supplies, and equipment are available.	• Care is the same as in conventional settings but might involve different methods, medications, or locations; the impact on usual standard of care is minimal.	• Critical space, staff, supplies, or equipment are limited, affecting usual standard of care and requiring medical care prioritization. Care might not be initiated and might be withdrawn from persons to allow resources to be allocated to persons with the highest likelihood of survival or benefit. • Because prognosis in botulism is excellent with appropriate respiratory support, airway control, and ventilation, transfer to an adequately resourced facility should be attempted when at all possible.
Hospitals	• Usual patient care areas are used. • Physicians and advanced practice providers diagnose botulism based on history, examination, and laboratory tests. • Consult public health officials immediately when botulism is suspected, and request antitoxin. • Triage based on severity of illness and respiratory status. • Admit all patients with suspected botulism to the appropriate unit in which close neurologic and respiratory monitoring is available. • If antitoxin is available and a patient needs to be transferred to a higher acuity hospital, consider administering antitoxin before transfer and ensure serial monitoring can be performed while in transit. • Conduct full diagnostic testing, including neurologic examination, brain imaging, lumbar puncture, electromyography, and nerve conduction study as applicable. • Perform serial monitoring with a complete neurologic examination, including cranial nerves, extremity strength, and respiratory status, before and after antitoxin administration. • Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration.	• Critical care surge plans are implemented; use adjunct areas (e.g., procedure rooms). • Physicians and advanced practice providers diagnose botulism based on history, examination, and laboratory tests. • Consult public health officials immediately when botulism is suspected, and request antitoxin. • Triage based on severity of illness and respiratory status. • Admit patients with suspected botulism requiring hospitalization (e.g., patients with respiratory symptoms or difficulty swallowing). • If antitoxin is available and a patient needs to be transferred to a higher acuity hospital, consider administering antitoxin before transfer, and ensure serial monitoring can be performed while in transit. • Conduct more limited testing and evaluation using the clinical criteria tool for early diagnosis of botulism. • Perform serial monitoring using the clinical criteria tool for early diagnosis of botulism to identify illness progression • Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration.	• The maximal critical care surge plan is implemented; use all available areas (e.g., procedure rooms). • All medical staff (e.g., physicians and nurses) diagnose botulism using the clinical criteria tool for early diagnosis of botulism. • Consult public health officials immediately when botulism is suspected, and request antitoxin. • Triage based on severity of illness and respiratory status. • Admit patients with suspected botulism requiring hospitalization based on current capacity (e.g., patients with respiratory symptoms or difficulty swallowing). • If antitoxin is available and a patient needs to be transferred to a higher acuity hospital, consider administering antitoxin before transfer and ensure serial monitoring can be performed while in transit. • For patients not requiring hospitalization, refer stable, moderately ill patients to alternate care sites and send stable, mildly ill patients home (ensure connection with public health resources for telephone check-ins, and provide list of symptoms to self-monitor). • Further limit testing and evaluation subject to resource availability (e.g., limit lumbar punctures, electrodiagnostic testing, and neuroimaging). • Perform serial monitoring focused on illness progression, ability to swallow, and respiratory status for patients who do not require intubation. • Monitor for adverse events (e.g., anaphylaxis) during and after antitoxin administration.
Medical facilities that are not hospitals	• Refer patients with suspected botulism to the hospital.	• Refer patients with suspected botulism to the hospital. • For exposed persons without signs or symptoms of botulism, consider observing on site or asking them to self-monitor at home for signs or symptoms consistent with botulism and go to the hospital if symptomatic. • Discharge asymptomatic persons with unknown exposure home to self-monitor.	• Refer severely ill patients with suspected botulism to the hospital. • Send mildly ill patients who do not require hospitalization home to self-monitor for signs and symptoms with telephone follow-up. • Consider locally established alternate care sites (e.g., federal medical stations) to provide for overflow and convalescent care to augment hospitals. • Discharge concerned, asymptomatic persons with unknown exposure home to self-monitor.
Treatment with antitoxin	• Consider treatment with antitoxin of any patient with suspected botulism. • Patients with mild symptoms, reliably observed to have no progression of paralysis over time, might not require treatment.	• Prioritize treatment of patients with features most suggestive of botulism. • Use antitoxin with the goal of preventing respiratory collapse requiring mechanical ventilation; prioritize patients with progressing paralysis who are not likely to require intubation before antitoxin can be administered.	• Prioritize treatment of patients with features most suggestive of botulism. • Use antitoxin with the goal of preventing respiratory collapse requiring mechanical ventilation; prioritize patients with progressing paralysis who are not likely to require intubation before antitoxin can be administered.

Conventional, contingency, and crisis standards of care for diagnosing, monitoring, and treating botulism*

*Sources: Institute of Medicine. Crisis standards of care: a systems framework for catastrophic disaster response. Washington, DC: The National Academies Press; 2012; and Hick JL, Barbera JA, Kelen GD. Refining surge capacity: conventional, contingency, and crisis capacity. Disaster Med Public Health Prep 2009;3(Suppl 2):S59–67.

Table 3.

Sign or symptom^†	Frequency (%)
Afebrile^§	99
Descending paralysis	93
Dysphagia	85
Weakness or fatigue^¶	85
Ptosis	81
Blurred vision	80
Difficulty speaking**	78
Diplopia	75
Change in voice^††	69
Shortness of breath^§§	65
Dry mouth	63
Thick tongue	62
Extraocular palsy	60
Impaired gag reflex	58
Dizziness	55
Palatal weakness	54
Facial weakness^¶¶	47
Nausea	43
Dilated pupils	37
Vomiting	33
Constipation	30
Abdominal pain	25
Abnormally reactive pupils***	24
Sensory deficits or paresthesias	17
Diarrhea	16
Urinary retention	9
Altered mental status	8
Constricted pupils	3

Signs and symptoms of patients with confirmed botulism reported in medical charts,* by frequency of signs or symptoms

*N = 332. Data were obtained during clinical consultations with physicians treating botulism patients; physicians were asked about the presence or absence of signs and symptoms (Source: Rao AK, Lin NH, Jackson KA, Mody RK, Griffin PM. Clinical characteristics and ancillary test results among patients with botulism—United States, 2002–2015. Clin Infect Dis 2018;66[suppl_1]:S4–10).
^†Some symptoms of botulism are nonspecific and might resemble those of anxiety, including dry mouth, difficulty swallowing, nausea, dizziness; in settings with fewer resources, observation for more specific signs and symptoms may be considered to document progression before treatment. Ocular symptoms are considered most objective.
^§Defined as a temperature <100.4°F [<38°C].
^¶Includes complaints of generalized weakness, fatigue, or malaise.
**Includes slurred speech, trouble speaking clearly, or dysarthria.
^††Includes any changes in the sound of voice, such as hoarseness, nasal speech, or dysphonia.
^§§Includes difficulty breathing, respiratory distress, and dyspnea.
^¶¶Includes droop and paralysis.
***Includes sluggish, poorly reactive, and nonreactive or fixed pupils.

Table 4.

Adults with foodborne or wound botulism* (N = 402)		Pregnant or postpartum women with botulism^† (N = 17)		Children and adolescents with any botulism syndrome^§ (N = 360)
Sign or symptom	%	Sign or symptom	%	Sign or symptom	%
Dysphagia	59	Weakness or fatigue^¶	76	Dysphagia	52
Vomiting	42	Dry mouth	47	Dysarthria or dysphonia**	38
Diplopia	42	Shortness of breath^††	41	Weakness or fatigue^¶	36
Shortness of breath^††	39	Vomiting	41	Ophthalmoplegia^§§	32
Difficulty speaking**	39	Nausea	41	Diplopia	28
Ptosis	35	Diplopia	41	Ptosis	27
Blurry vision	33	Change in voice^¶¶	41	Vomiting	26
Subjective weakness	32	Blurred vision	35	Shortness of breath^††	26
Nausea	28	Dysphagia	29	Dilated pupils	26
Decreased oral secretions	25	Ophthalmoplegia^§§	29	Abnormally reactive pupils***	22
Abnormally reactive pupils***	24	Ptosis	29	Abdominal pain	20
Ophthalmoplegia^§§	24	Difficulty speaking**	29	Dry mouth	19
Abdominal pain	23	Descending paralysis	29	Afebrile	18
Dizziness	20	Abdominal pain	18	Constipation	17
Dilated pupils	20	Dizziness	18	Nausea	15
Change in voice^¶¶	16	Dilated pupils	18	Dizziness	14
Fatigue	11	Facial paralysis^†††	12	Blurred vision	14
Thick tongue	11	Poorly reactive pupils***	12	Apnea	12
Sore throat	10	Pupillary reflexes, decreased	6	Diminished gag reflex	11
Diarrhea	10	Altered mental status	6	Descending paralysis	10
Facial paralysis^†††	8	Cranial nerve palsy unspecified	6	Sore throat	10
Neck weakness	8	Sore throat	6	Facial paralysis^†††	10
Urinary retention	7	Areflexia	6	Urinary retention	7
Impaired gag reflex	7	Nystagmus	6	Hypotonia	6
Epigastric pain	4	Bladder distention	6	Altered mental status	3

Signs and symptoms of botulism in adults with foodborne botulism, pregnant or postpartum women with botulism, and children and adolescents with any botulism syndrome, by frequency of signs or symptoms

*Source: Chatham-Stephens K, Fleck-Derderian S, Johnson SD, Sobel J, Rao AK, Meaney-Delman D. Clinical features of foodborne and wound botulism: a systematic review of the literature, 1932–2015. Clin Infect Dis 2018;66(suppl_1):S11–6.
^† Source: Badell ML, Rimawi BH, Rao AK, Jamieson DJ, Rasmussen S, Meaney-Delman D. Botulism during pregnancy and the postpartum period: a systematic review. Clin Infect Dis 2018;66(suppl_1):S30–7.
^§ Source: Griese SE, Kisselburgh HM, Bartenfeld MT, et al. Pediatric botulism and use of equine botulinum antitoxin in children: a systematic review. Clin Infect Dis 2018;66(suppl_1):S17–29.
^¶Includes complaints of generalized weakness and malaise.
**Includes slurred speech, trouble speaking clearly, and dysarthria in all patients and also change in voice and weak cry in children.
^††Includes difficulty breathing, respiratory distress, and dyspnea.
^§§Includes extraocular palsy and cranial nerve 3, 4, or 6 palsies.
^¶¶Includes change in the sound of voice, such as hoarseness, nasal voice, or dysphonia, except in children, in whom it includes only difficulty speaking.
***Includes sluggish, poorly reactive, nonreactive, and fixed pupils.
^†††Includes droop or weakness.

Table 5.

Specimen type	Optimal amount	Test for botulinum toxin	Test for botulinum toxin–producing Clostridium species	Time from receipt of specimen by laboratory to test result*	Additional information
Serum	5–15 mL (for children: 4 mL)	Yes	No	Preliminary results for toxin in 24–48 hrs, final results in 96 hrs.	• Collect before antitoxin treatment.^† • Blood sample must be collected without anticoagulant.
Stool	10–20 g	Yes	Yes	Preliminary results for toxin in 24–48 hrs, final results in 96 hrs; final results for Clostridium species might take 2–3 wks.	• If an enema is needed, use sterile, nonbacteriostatic water (not tap water) and non–glycerin-containing suppositories. • Ideally, collect before antitoxin treatment; however, can obtain after antitoxin treatment.
Gastric aspirate	5–10 mL	Yes	Yes	Preliminary results for toxin in 24–48 hrs, final results in 96 hrs; final results for Clostridium species might take 2–3 wks.	• Collect before antitoxin treatment.^†
Debrided tissue, wound swab sample, or anaerobic wound culture	No specific requirements	No	Yes	Final results for Clostridium species might take 2–3 wks.	• Broth is preferable to agar slants or plates.
Food suspected as source	10–20 g (or mL)	Yes	Yes	Preliminary results for toxin in 24–48 hrs, final results in 96 hrs; final results for Clostridium species might take 2–3 wks.	• Ideally, the entire food item should be submitted for testing. • Keep foods in original containers; if not available, place in sterile unbreakable containers. • Empty containers with remnants of suspected foods can be tested.

Specimens for botulism laboratory confirmation, by specimen type and testing parameters

*Times are estimates; testing might take longer during an outbreak.
^†Do not delay administration of antitoxin while attempting to obtain a specimen.

Table 6.

Serotype	Antitoxin	Neutralization capacity
Serotype	IU per vial	MIPLD₅₀ per vial
A	4,500	4.5 × 10⁷
B	3,300	3.3 × 10⁷
C	3,000	3.0 × 10⁷
D	600	6 × 10⁶
E	5,100	5.1 × 10⁶
F	3,000	3.0 × 10⁷
G	—^†	6 × 10⁶

International units of antitoxin and neutralization capacity in one vial of botulinum antitoxin, by serotype*

Abbreviations: IU = international units; MIPLD₅₀ = mouse intraperitoneal lethal dose₅₀.
*The standard adult dose is one vial (Source: Botulism antitoxin heptavalent [A, B, C, D, E, F, G—equine] [package insert]. Gaithersburg, MD: Cangene Corporation [Emergent Biosolutions]; 2017. https://www.fda.gov/media/85514/download).
^†Six hundred units that are not recognized internationally.

Box 1.

• Afebrile (<100.4°F [<38°C])^§ • Acute onset of at least one of the following symptoms: • Blurred vision • Double vision • Difficulty speaking, including slurred speech • Any change in sound of voice, including hoarseness • Dysphagia, pooling of secretions, or drooling • Thick tongue • At least one of the following signs: • Ptosis • Extraocular palsy or fatigability (the latter manifested by inability to avert eyes from light shone repeatedly into eye [typically used in infants]) • Facial paresis (manifested, for example, by loss of facial expression or pooling of secretions and in young children by poor feeding, poor suck on breast or pacifier, or fatigue while eating) • Fixed pupils • Descending paralysis, beginning with cranial nerves Source: Rao AK, Lin NH, Griese SE, Chatham-Stephens K, Badell ML, Sobel J. Clinical criteria to trigger suspicion for botulism: an evidence-based tool to facilitate timely recognition of suspected cases during sporadic events and outbreaks. Clin Infect Dis 2017;66(suppl_1):S38–S42.
*Suspect botulism when all three criteria are met. For all patients with botulism, intact mental status is expected. If a patient has altered mental status, this might be from other causes (e.g., respiratory failure, drug or alcohol use, preexisting condition, or concurrent infection). ^†Although this tool can also be used in a conventional standard of care setting, a more detailed evaluation is expected. In a setting of crisis standard of care, meeting these criteria alone might be sufficient to treat for presumed botulism. ^§Fever concurrent with the acute onset of botulism in an adult is exceedingly rare; fever also is rare in infants and young children but might be more common than in adults.

• Afebrile (<100.4°F [<38°C])^§
• Acute onset of at least one of the following symptoms:
   • Blurred vision
   • Double vision
   • Difficulty speaking, including slurred speech
   • Any change in sound of voice, including hoarseness
   • Dysphagia, pooling of secretions, or drooling
   • Thick tongue
• At least one of the following signs:
   • Ptosis
   • Extraocular palsy or fatigability (the latter manifested by inability to avert eyes from light shone repeatedly into eye [typically used in infants])
   • Facial paresis (manifested, for example, by loss of facial expression or pooling of secretions and in young children by poor feeding, poor suck on breast or pacifier, or fatigue while eating)
   • Fixed pupils
   • Descending paralysis, beginning with cranial nerves
Source: Rao AK, Lin NH, Griese SE, Chatham-Stephens K, Badell ML, Sobel J. Clinical criteria to trigger suspicion for botulism: an evidence-based tool to facilitate timely recognition of suspected cases during sporadic events and outbreaks. Clin Infect Dis 2017;66(suppl_1):S38–S42.

*Suspect botulism when all three criteria are met. For all patients with botulism, intact mental status is expected. If a patient has altered mental status, this might be from other causes (e.g., respiratory failure, drug or alcohol use, preexisting condition, or concurrent infection).
^†Although this tool can also be used in a conventional standard of care setting, a more detailed evaluation is expected. In a setting of crisis standard of care, meeting these criteria alone might be sufficient to treat for presumed botulism.
^§Fever concurrent with the acute onset of botulism in an adult is exceedingly rare; fever also is rare in infants and young children but might be more common than in adults.

Clinical criteria tool for early diagnosis of botulism* in crisis and contingency settings^†

Box 2.

• Specimens should be maintained at 36°F–46°F (2°C–8°C) and shipped with cold packs; do not freeze. • Package must have proper labeling for biological hazards: UN 3373 biological substance, Category B. • For specimens submitted to CDC for testing, follow these instructions: • Include a completed CDC form 50.34 in the package (available at https://www.cdc.gov/laboratory/specimen-submission/index.html). • On CDC form 50.34, select test order CDC-10132, Botulism Laboratory Confirmation. Include phone and fax numbers for the state health department and the hospital. • Send package to: STAT (Attn: Botulism Lab, Unit 26) Centers for Disease Control and Prevention 1600 Clifton Rd NE, Atlanta, GA 30329 • Contact CDC National Botulism Laboratory to provide a tracking number to CDC: https://www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10132 • Discuss with CDC consultant whether specimens from hospitals might need to be submitted through the local or state health department or state public health laboratory.

• Specimens should be maintained at 36°F–46°F (2°C–8°C) and shipped with cold packs; do not freeze.
• Package must have proper labeling for biological hazards: UN 3373 biological substance, Category B.
• For specimens submitted to CDC for testing, follow these instructions:
   • Include a completed CDC form 50.34 in the package (available at https://www.cdc.gov/laboratory/specimen-submission/index.html).
   • On CDC form 50.34, select test order CDC-10132, Botulism Laboratory Confirmation. Include phone and fax numbers for the state health department and the hospital.
   • Send package to:
      STAT (Attn: Botulism Lab, Unit 26)
      Centers for Disease Control and Prevention
      1600 Clifton Rd NE, Atlanta, GA 30329
   • Contact CDC National Botulism Laboratory to provide a tracking number to CDC: https://www.cdc.gov/laboratory/specimen-submission/detail.html?CDCTestCode=CDC-10132
   • Discuss with CDC consultant whether specimens from hospitals might need to be submitted through the local or state health department or state public health laboratory.

Specimen storage and shipping

Werner SB, Passaro D, McGee J, Schechter R, Vugia DJ. Wound botulism in California, 1951–1998: recent epidemic in heroin injectors. Clin Infect Dis 2000;31:1018–24. https://doi.org/10.1086/318134
Arnon SS, Schechter R, Inglesby TV, et al.; Working Group on Civilian Biodefense. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001;285:1059–70. PMID:11209178 https://doi.org/10.1001/jama.285.8.1059
Sobel J. Botulism. Clin Infect Dis 2005;41:1167–73. PMID:16163636 https://doi.org/10.1086/444507
Smith LD. Botulism. The organism, its toxins, the disease. Springfield, IL: Charles C. Thomas; 1977.
Dack GM, Wood WL. Serum therapy of botulism in monkeys. J Infect Dis 1928;42:209–12. https://doi.org/10.1093/infdis/42.3.209
Ono T, Karashimada T, Iida H. Studies of the serum therapy of type E botulism. 3. Jpn J Med Sci Biol 1970;23:177–91. PMID:4989998 https://doi.org/10.7883/yoken1952.23.177
Morton HE. The toxicity of Clostridium botulinum type A toxin for various species of animals, including man. Philadelphia, PA: Institute for Cooperative Research, University of Pennsylvania; 1961.
Maslanka SE, Lúquez C, Dykes JK, et al. A novel botulinum neurotoxin, previously reported as serotype H, has a hybrid-like structure with regions of similarity to the structures of serotypes A and F and is neutralized with serotype A antitoxin. J Infect Dis 2016;213:379–85. PMID:26068781 https://doi.org/10.1093/infdis/jiv327
Zhang S, Masuyer G, Zhang J, et al. Identification and characterization of a novel botulinum neurotoxin. Nat Commun 2017;8:14130. PMID:28770820 https://doi.org/10.1038/ncomms14130
Zhang S, Lebreton F, Mansfield MJ, et al. Identification of a botulinum neurotoxin-like toxin in a commensal strain of Enterococcus faecium. Cell Host Microbe 2018;23:169–176.e6. PMID:29396040 https://doi.org/10.1016/j.chom.2017.12.018
Brunt J, Carter AT, Stringer SC, Peck MW. Identification of a novel botulinum neurotoxin gene cluster in Enterococcus. FEBS Lett 2018;592:310–7. PMID:29323697 https://doi.org/10.1002/1873-3468.12969
Humeau Y, Doussau F, Grant NJ, Poulain B. How botulinum and tetanus neurotoxins block neurotransmitter release. Biochimie 2000;82:427–46. PMID:10865130 https://doi.org/10.1016/S0300-9084(00)00216-9
Rao AK, Lin NH, Jackson KA, Mody RK, Griffin PM. Clinical characteristics and ancillary test results among patients with botulism—United States, 2002–2015. Clin Infect Dis 2017;66(suppl_1):S4–10. PMID:29293936 https://doi.org/10.1093/cid/cix935
Chatham-Stephens K, Fleck-Derderian S, Johnson SD, Sobel J, Rao AK, Meaney-Delman D. Clinical features of foodborne and wound botulism: a systematic review of the literature, 1932–2015. Clin Infect Dis 2017;66(suppl_1):S11–6. PMID:29293923 https://doi.org/10.1093/cid/cix811
Caleo M, Restani L. Exploiting botulinum neurotoxins for the study of brain physiology and pathology. Toxins (Basel) 2018;10:175. PMID:29693600 https://doi.org/10.3390/toxins10050175
Hughes JM, Blumenthal JR, Merson MH, Lombard GL, Dowell VR Jr, Gangarosa EJ. Clinical features of types A and B food-borne botulism. Ann Intern Med 1981;95:442–5. PMID:7283294 https://doi.org/10.7326/0003-4819-95-4-442
Woodruff BA, Griffin PM, McCroskey LM, et al. Clinical and laboratory comparison of botulism from toxin types A, B, and E in the United States, 1975–1988. J Infect Dis 1992;166:1281–6. PMID:1431246 https://doi.org/10.1093/infdis/166.6.1281
Demarchi J, Mourgues C, Orio J, Prevot AR. [Existence of type D botulism in man]. Bull Acad Natl Med 1958;142:580–2. PMID:13560962
Prevot AR, Sillioc R. [Biological enigma: cat and botulism]. Ann Inst Pasteur (Paris) 1955;89:354–7. PMID:13403395
Coffield JA, Bakry N, Zhang RD, Carlson J, Gomella LG, Simpson LL. In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches. J Pharmacol Exp Ther 1997;280:1489–98. PMID:9067339
Eleopra R, Tugnoli V, Quatrale R, et al. Botulinum neurotoxin serotypes A and C do not affect motor units survival in humans: an electrophysiological study by motor units counting. Clin Neurophysiol 2002;113:1258–64. PMID:12140005 https://doi.org/10.1016/S1388-2457(02)00103-7
Rogers DE, Koenig MG, Spickard A. Clinical and laboratory manifestations of type E botulism in man. Trans Assoc Am Physicians 1964;77:135–44. PMID:14275409
Dolman CE. Further outbreaks of botulism in Canada. Can Med Assoc J 1961;84:191–200. PMID:13723571
Gupta A, Sumner CJ, Castor M, Maslanka S, Sobel J. Adult botulism type F in the United States, 1981–2002. Neurology 2005;65:1694–700. PMID:16344510 https://doi.org/10.1212/01.wnl.0000187127.92446.4c
Sobel J, Dill T, Kirkpatrick CL, Riek L, Luedtke P, Damrow TA. Clinical recovery and circulating botulinum toxin type F in adult patient. Emerg Infect Dis 2009;15:969–71. PMID:19523306 https://doi.org/10.3201/eid1506.070571
Sobel J, Rao AK. Making the best of the evidence: toward national clinical guidelines for botulism. Clin Infect Dis 2017;66(suppl_1):S1–3. PMID:29293933 https://doi.org/10.1093/cid/cix829
Fleck-Derderian S, Shankar M, Rao AK, et al. The epidemiology of foodborne botulism outbreaks: a systematic review. Clin Infect Dis 2017;66(suppl_1):S73–81. PMID:29293934 https://doi.org/10.1093/cid/cix846
O'Horo JC, Harper EP, El Rafei A, et al. Efficacy of antitoxin therapy in treating patients with foodborne botulism: a systematic review and meta-analysis of cases, 1923–2016. Clin Infect Dis 2017;66(suppl_1):S43–56. PMID:29293927 https://doi.org/10.1093/cid/cix815
Schussler E, Sobel J, Hsu J, et al. Workgroup report by the Joint Task Force Involving American Academy of Allergy, Asthma & Immunology (AAAAI); Food Allergy, Anaphylaxis, Dermatology and Drug Allergy (FADDA) (Adverse Reactions to Foods Committee and Adverse Reactions to Drugs, Biologicals, and Latex Committee); and the Centers for Disease Control and Prevention Botulism Clinical Treatment Guidelines Workgroup—Allergic reactions to botulinum antitoxin: a systematic review. Clin Infect Dis 2017;66(suppl_1):S65–72. PMID:29293931 https://doi.org/10.1093/cid/cix827
Badell ML, Rimawi BH, Rao AK, Jamieson DJ, Rasmussen S, Meaney-Delman D. Botulism during pregnancy and the postpartum period: a systematic review. Clin Infect Dis 2017;66(suppl_1):S30–7. PMID:29293925 https://doi.org/10.1093/cid/cix813
Griese SE, Kisselburgh HM, Bartenfeld MT, et al. Pediatric botulism and use of equine botulinum antitoxin in children: a systematic review. Clin Infect Dis 2017;66(suppl_1):S17–29. PMID:29293924 https://doi.org/10.1093/cid/cix812
Halpin AL, Khouri JM, Payne JR, et al. Type F infant botulism: investigation of recent clusters and overview of this exceedingly rare disease. Clin Infect Dis 2017;66(suppl_1):S92–4. PMID:29293930 https://doi.org/10.1093/cid/cix818
Jacobs Slifka K, Harris JA, Nguyen V, Luquez C, Tiwari T, Rao AK. A case of localized, unilateral (cephalic) wound botulism. Clin Infect Dis 2017;66(suppl_1):S95–8. PMID:29293932 https://doi.org/10.1093/cid/cix828
Parameswaran L, Rao A, Chastain K, et al. A case of adult intestinal toxemia botulism during prolonged hospitalization in an allogeneic hematopoietic cell transplant recipient. Clin Infect Dis 2017;66(suppl_1):S99–102. PMID:29293935 https://doi.org/10.1093/cid/cix847
Harvey RR, Cooper R, Bennett S, et al. Outbreak of foodborne botulism in an immigrant community: Overcoming delayed disease recognition, ambiguous epidemiologic links, and cultural barriers to identify the cause. Clin Infect Dis 2017;66(suppl_1):S82–4. PMID:29293929 https://doi.org/10.1093/cid/cix817
Rao AK, Lin NH, Griese SE, Chatham-Stephens K, Badell ML, Sobel J. Clinical criteria to trigger suspicion for botulism: an evidence-based tool to facilitate timely recognition of suspected cases during sporadic events and outbreaks. Clin Infect Dis 2017;66(suppl_1):S38–42. PMID:29293926 https://doi.org/10.1093/cid/cix814
Yu PA, Lin NH, Mahon BE, et al. Safety and improved clinical outcomes in patients treated with new equine-derived heptavalent botulinum antitoxin. Clin Infect Dis 2017;66(suppl_1):S57–64. PMID:29293928 https://doi.org/10.1093/cid/cix816
Rao AK, Walters M, Hall J, et al. Outbreak of botulism due to illicit prison-brewed alcohol: public health response to a serious and recurrent problem. Clin Infect Dis 2017;66(suppl_1):S85–91. PMID:29293937 https://doi.org/10.1093/cid/cix936
Committee on Guidance for Establishing Crisis Standards of Care for Use in Disaster Situations; Institute of Medicine. Crisis standards of care: a systems framework for catastrophic disaster response. National Academies Press: Washington, DC; 2012. PMID:24830057
Hick JL, Barbera JA, Kelen GD. Refining surge capacity: conventional, contingency, and crisis capacity. Disaster Med Public Health Prep 2009;3(Suppl 2):S59–67. PMID:19349869 https://doi.org/10.1097/DMP.0b013e31819f1ae2
Institute of Medicine. Crisis standards of care: a toolkit for indicators and triggers. Washington, DC: National Academies Press; 2013. https://www.nap.edu/read/18338/chapter/3
Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 1998;129:221–8. PMID:9696731 https://doi.org/10.7326/0003-4819-129-3-199808010-00011
Maslanka S, Agam KR. Botulism. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson JL, Loscalzo J, eds. Harrison's principles of internal medicine, 19th ed. New York, NY: McGraw-Hill Education; 2015.
Sheth AN, Wiersma P, Atrubin D, et al. International outbreak of severe botulism with prolonged toxemia caused by commercial carrot juice. Clin Infect Dis 2008;47:1245–51. PMID:18834318 https://doi.org/10.1086/592574
Sobel J. Diagnosis and treatment of botulism: a century later, clinical suspicion remains the cornerstone. Clin Infect Dis 2009;48:1674–5. PMID:19435432 https://doi.org/10.1086/599030
St Louis ME, Peck SH, Bowering D, et al. Botulism from chopped garlic: delayed recognition of a major outbreak. Ann Intern Med 1988;108:363–8. PMID:3341673 https://doi.org/10.7326/0003-4819-108-3-363
Filozov A, Kattan JA, Jitendranath L, et al. Asymmetric type F botulism with cranial nerve demyelination. Emerg Infect Dis 2012;18:102–4. PMID:22257488 https://doi.org/10.3201/eid1801.110471
Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain 2014;137:33–43. PMID:24163275 https://doi.org/10.1093/brain/awt285
Mallik A, Weir AI. Nerve conduction studies: essentials and pitfalls in practice. J Neurol Neurosurg Psychiatry 2005;76(Suppl 2):ii23–31. PMID:15961865 https://doi.org/10.1136/jnnp.2005.069138
Maselli RA, Bakshi N; American Association of Electrodiagnostic Medicine. AAEM case report 16. Botulism. Muscle Nerve 2000;23:1137–44. PMID:10883013 http://doi.org/10.1002/1097-4598(200007)23:7%3C1137::AID-MUS21%3E3.0.CO;2-7
Maselli RA, Ellis W, Mandler RN, et al. Cluster of wound botulism in California: clinical, electrophysiologic, and pathologic study. Muscle Nerve 1997;20:1284–95. PMID:9324085 http://doi.org/10.1002/(SICI)1097-4598(199710)20:10%3C1284::AID-MUS11%3E3.0.CO;2-3
Padua L, Aprile I, Monaco ML, et al. Neurophysiological assessment in the diagnosis of botulism: usefulness of single-fiber EMG. Muscle Nerve 1999;22:1388–92. PMID:10487905 http://doi.org/10.1002/(SICI)1097-4598(199910)22:10%3C1388::AID-MUS8%3E3.0.CO;2-3
McCarty CL, Angelo K, Beer KD, et al. Large outbreak of botulism associated with a church potluck meal—Ohio, 2015. MMWR Morb Mortal Wkly Rep 2015;64:802–3. PMID:26225479 https://doi.org/10.15585/mmwr.mm6429a6
Maslanka SE, Solomon HM, Sharma S, Johnson EA. Chapter 32. Clostridium botulinum and its toxins. In: Salfinger Y, Tortorello ML, eds. Compendium of methods for the microbiological examination of foods: Washington, DC: American Public Health Association Press; 2013.
Kalb SR, Baudys J, Wang D, Barr JR. Recommended mass spectrometry-based strategies to identify botulinum neurotoxin-containing samples. Toxins (Basel) 2015;7:1765–78. PMID:25996606 https://doi.org/10.3390/toxins7051765
Mighty HE. Acute respiratory failure in pregnancy. Clin Obstet Gynecol 2010;53:360–8. PMID:20436311 https://doi.org/10.1097/GRF.0b013e3181deb3f1
Sandrock CE, Murin S. Clinical predictors of respiratory failure and long-term outcome in black tar heroin-associated wound botulism. Chest 2001;120:562–6. PMID:11502659 https://doi.org/10.1378/chest.120.2.562
Wongtanate M, Sucharitchan N, Tantisiriwit K, et al. Signs and symptoms predictive of respiratory failure in patients with foodborne botulism in Thailand. Am J Trop Med Hyg 2007;77:386–9. PMID:17690419 https://doi.org/10.4269/ajtmh.2007.77.386
Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating mechanical ventilation in Guillain-Barré syndrome. Arch Neurol 2001;58:893–8. PMID:11405803 https://doi.org/10.1001/archneur.58.6.893
Stefanutti D, Fitting J-W. Sniff nasal inspiratory pressure. Reference values in Caucasian children. Am J Respir Crit Care Med 1999;159:107–11. PMID:9872826 https://doi.org/10.1164/ajrccm.159.1.9804052
Uldry C, Fitting JW. Maximal values of sniff nasal inspiratory pressure in healthy subjects. Thorax 1995;50:371–5. PMID:7785009 https://doi.org/10.1136/thx.50.4.371
Laveneziana P, Albuquerque A, Aliverti A, et al. ERS statement on respiratory muscle testing at rest and during exercise. Eur Respir J 2019;53:1801214. PMID:30956204 https://doi.org/10.1183/13993003.01214-2018
Héritier F, Rahm F, Pasche P, Fitting JW. Sniff nasal inspiratory pressure. A noninvasive assessment of inspiratory muscle strength. Am J Respir Crit Care Med 1994;150:1678–83. PMID:7952632 https://doi.org/10.1164/ajrccm.150.6.7952632
Elsheikh B, Arnold WD, Gharibshahi S, Reynolds J, Freimer M, Kissel JT. Correlation of single-breath count test and neck flexor muscle strength with spirometry in myasthenia gravis. Muscle Nerve 2016;53:134–6. PMID:26437790 https://doi.org/10.1002/mus.24929
Harms M. Inpatient management of Guillain-Barré syndrome. Neurohospitalist 2011;1:78–84. PMID:23983841 https://doi.org/10.1177/1941875210396379
Hutchinson D, Whyte K. Neuromuscular disease and respiratory failure. Pract Neurol 2008;8:229–37. PMID:18644909 https://doi.org/10.1136/pn.2008.152611
Hughes RA, Bihari D. Acute neuromuscular respiratory paralysis. J Neurol Neurosurg Psychiatry 1993;56:334–43. PMID:8482951 https://doi.org/10.1136/jnnp.56.4.334
Dressler D, Benecke R. Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol 2003;49:34–8. PMID:12464716 https://doi.org/10.1159/000067023
Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol 2006;13(Suppl 4):1–9. PMID:17112344 https://doi.org/10.1111/j.1468-1331.2006.01648.x
Jenzer G, Mumenthaler M, Ludin HP, Robert F. Autonomic dysfunction in botulism B: a clinical report. Neurology 1975;25:150–3. PMID:1167643 https://doi.org/10.1212/WNL.25.2.150
Koenig MG, Drutz DJ, Mushlin AI, Schaffner W, Rogers DE. Type B botulism in man. Am J Med 1967;42:208–19. PMID:6018532 https://doi.org/10.1016/0002-9343(67)90020-4
Merz B, Bigalke H, Stoll G, Naumann M. Botulism type B presenting as pure autonomic dysfunction. Clin Auton Res 2003;13:337–8. PMID:14564656 https://doi.org/10.1007/s10286-003-0118-2
Potulska-Chromik A, Zakrzewska-Pniewska B, Szmidt-Salkowska E, et al. Long lasting dysautonomia due to botulinum toxin B poisoning: clinical-laboratory follow up and difficulties in initial diagnosis. BMC Res Notes 2013;6:438. PMID:24172031 https://doi.org/10.1186/1756-0500-6-438
Truax BT, ed. Autonomic disturbances in the Guillain-Barré syndrome. Seminars in Neurology; 1984: Thieme Medical Publishers, Inc.
Dalos NP, Borel C, Hanley DF. Cardiovascular autonomic dysfunction in Guillain-Barré syndrome. Therapeutic implications of Swan-Ganz monitoring. Arch Neurol 1988;45:115–7. PMID:3337665 https://doi.org/10.1001/archneur.1988.00520250125034
Hund EF, Borel CO, Cornblath DR, Hanley DF, McKhann GM. Intensive management and treatment of severe Guillain-Barré syndrome. Crit Care Med 1993;21:433–46. PMID:8440115 https://doi.org/10.1097/00003246-199303000-00023
Hughes RA, Wijdicks EF, Benson E, et al.; Multidisciplinary Consensus Group. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol 2005;62:1194–8. PMID:16087757 https://doi.org/10.1001/archneur.62.8.1194
Rabinstein AA. Acute neuromuscular respiratory failure. Continuum (Minneap Minn) 2015;21(5 Neurocritical Care):1324–45. PMID:26426233 https://doi.org/10.1212/CON.0000000000000218
Fiz JA, Haro M, Aguilar J, et al. Spirometry and maximal respiratory pressures in patients with facial paralysis. Chest 1993;103:170–3. PMID:8417873 https://doi.org/10.1378/chest.103.1.170
Cabrera Serrano M, Rabinstein AA. Causes and outcomes of acute neuromuscular respiratory failure. Arch Neurol 2010;67:1089–94. PMID:20837853 https://doi.org/10.1001/archneurol.2010.207
Mangera Z, Panesar G, Makker H. Practical approach to management of respiratory complications in neurological disorders. Int J Gen Med 2012;5:255–63. PMID:22505823
O'Horo JC, Harper EP, El Rafei A, et al. Efficacy of antitoxin therapy in treating patients with foodborne botulism: a systematic review and meta-analysis of cases, 1923–2016. Clin Infect Dis 2017;66(suppl_1):S43–56. PMID:29293927 https://doi.org/10.1093/cid/cix815
Tacket CO, Shandera WX, Mann JM, Hargrett NT, Blake PA. Equine antitoxin use and other factors that predict outcome in type A foodborne botulism. Am J Med 1984;76:794–8. PMID:6720725 https://doi.org/10.1016/0002-9343(84)90988-4
Botulism antitoxin heptavalent. (A, B, C, D, E, F, G)—(Equine) [package insert]. Gaithersburg, MD: Cangene Corporation (as Emergent Biosolutions); 2017. https://www.fda.gov/media/85514/download
Black RE, Gunn RA. Hypersensitivity reactions associated with botulinal antitoxin. Am J Med 1980;69:567–70. PMID:7191633 https://doi.org/10.1016/0002-9343(80)90469-6
Kongsaengdao S, Samintarapanya K, Rusmeechan S, et al.; Thai Botulism Study Group. An outbreak of botulism in Thailand: clinical manifestations and management of severe respiratory failure. Clin Infect Dis 2006;43:1247–56. PMID:17051488 https://doi.org/10.1086/508176
Hatheway CH, Snyder JD, Seals JE, Edell TA, Lewis GE Jr. Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E. J Infect Dis 1984;150:407–12. PMID:6481185 https://doi.org/10.1093/infdis/150.3.407
Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med 2006;354:462–71. PMID:16452558 https://doi.org/10.1056/NEJMoa051926
Lack JA, Stuart-Taylor ME. Calculation of drug dosage and body surface area of children. Br J Anaesth 1997;78:601–5. PMID:9175982 https://doi.org/10.1093/bja/78.5.601
Feng L, Chen X, Liu S, Zhou Z, Yang R. Two-family outbreak of botulism associated with the consumption of smoked ribs in Sichuan Province, China. Int J Infect Dis 2015;30:74–7. PMID:25448333 https://doi.org/10.1016/j.ijid.2014.10.008
Gomez HF, Johnson R, Guven H, et al. Adsorption of botulinum toxin to activated charcoal with a mouse bioassay. Ann Emerg Med 1995;25:818–22. PMID:7755207 https://doi.org/10.1016/S0196-0644(95)70214-8
Osterhoudt KC, Alpern ER, Durbin D, Nadel F, Henretig FM. Activated charcoal administration in a pediatric emergency department. Pediatr Emerg Care 2004;20:493–8. PMID:15295243 https://doi.org/10.1097/01.pec.0000136064.14704.d1
Mazuet C, Dano J, Popoff MR, Créminon C, Volland H. Characterization of botulinum neurotoxin type A neutralizing monoclonal antibodies and influence of their half-lives on therapeutic activity. PLoS One 2010;5:e12416. PMID:20865035 https://doi.org/10.1371/journal.pone.0012416
Cherington M, Ryan DW. Botulism and guanidine. N Engl J Med 1968;278:931–3. PMID:5644559 https://doi.org/10.1056/NEJM196804252781704
Cherington M, Ryan DW. Treatment of botulism with guanidine. Early neurophysiologic studies. N Engl J Med 1970;282:195–7. PMID:5409814 https://doi.org/10.1056/NEJM197001222820405
Puggiari M, Cherington M. Botulism and guanidine. Ten years later. JAMA 1978;240:2276–7. PMID:702753 https://doi.org/10.1001/jama.1978.03290210058027
Kaplan JE, Davis LE, Narayan V, Koster J, Katzenstein D. Botulism, type A, and treatment with guanidine. Ann Neurol 1979;6:69–71. PMID:389150 https://doi.org/10.1002/ana.410060117
Davis LE, Johnson JK, Bicknell JM, Levy H, McEvoy KM. Human type A botulism and treatment with 3,4-diaminopyridine. Electromyogr Clin Neurophysiol 1992;32:379–83. PMID:1526219
Faich GA, Graebner RW, Sato S. Failure of guanidine therapy in botulism A. N Engl J Med 1971;285:773–6. PMID:5567262 https://doi.org/10.1056/NEJM197109302851404
Oh SJ, Halsey JH Jr, Briggs DDJ Jr. Guanidine in type B botulism. Arch Intern Med 1975;135:726–8. PMID:1052669 https://doi.org/10.1001/archinte.135.5.726
Ball AP, Hopkinson RB, Farrell ID, et al. Human botulism caused by Clostridium botulinum type E: the Birmingham outbreak. Q J Med 1979;48:473–91. PMID:575566
Paterson DL, King MA, Boyle RS, et al. Severe botulism after eating home-preserved asparagus. Med J Aust 1992;157:269–70. PMID:1435446 https://doi.org/10.5694/j.1326-5377.1992.tb137135.x
Robinson RF, Nahata MC. Management of botulism. Ann Pharmacother 2003;37:127–31. PMID:12503947 https://doi.org/10.1345/aph.1C034
Wang YC, Burr DH, Korthals GJ, Sugiyama H. Acute toxicity of aminoglycoside antibiotics as an aid in detecting botulism. Appl Environ Microbiol 1984;48:951–5. PMID:6508309 https://doi.org/10.1128/AEM.48.5.951-955.1984
Molgó J, Lemeignan M, Thesleff S. Aminoglycosides and 3,4-diaminopyridine on neuromuscular block caused by botulinum type A toxin. Muscle Nerve 1987;10:464–70. PMID:3497343 https://doi.org/10.1002/mus.880100514
L'Hommedieu C, Stough R, Brown L, Kettrick R, Polin R. Potentiation of neuromuscular weakness in infant botulism by aminoglycosides. J Pediatr 1979;95:1065–70. PMID:501488 https://doi.org/10.1016/S0022-3476(79)80314-5
Paradelis AG, Triantaphyllidis C, Giala MM. Neuromuscular blocking activity of aminoglycoside antibiotics. Methods Find Exp Clin Pharmacol 1980;2:45–51. PMID:6121961
Santos JI, Swensen P, Glasgow LA. Potentiation of Clostridium botulinum toxin aminoglycoside antibiotics: clinical and laboratory observations. Pediatrics 1981;68:50–4. PMID:7243509
Lee JH, Lee SI, Chung CJ, et al. The synergistic effect of gentamicin and clindamycin on rocuronium-induced neuromuscular blockade. Korean J Anesthesiol 2013;64:143–51. PMID:23459675 https://doi.org/10.4097/kjae.2013.64.2.143
Rhee WJ, Lee SY, Lee JH, et al. The effect of high concentration of magnesium with ropivacaine, gentamicin, rocuronium, and their combination on neuromuscular blockade. Korean J Anesthesiol 2015;68:50–61. PMID:25664156 https://doi.org/10.4097/kjae.2015.68.1.50
Pandian SJ, Subramanian M, Vijayakumar G, Balasubramaniam GA, Sukumar K. Therapeutic management of botulism in dairy cattle. Vet World 2015;8:1305–9.
Del Pozo E, Baeyens JM. Effects of calcium channel blockers on neuromuscular blockade induced by aminoglycoside antibiotics. Eur J Pharmacol 1986;128:49–54. PMID:3758187 https://doi.org/10.1016/0014-2999(86)90556-X
Paradelis AG, Triantaphyllidis CJ, Mironidou M, Crassaris LG, Karachalios DN, Giala MM. Interaction of aminoglycoside antibiotics and calcium channel blockers at the neuromuscular junctions. Methods Find Exp Clin Pharmacol 1988;10:687–90. PMID:3221740
Simpson LL. The interaction between 5-hydroxytryptamine and botulinum toxin type A. Toxicol Appl Pharmacol 1968;12:249–59. PMID:4875050 https://doi.org/10.1016/0041-008X(68)90037-9
Hale TW. Maternal medications during breastfeeding. Clin Obstet Gynecol 2004;47:696–711. PMID:15326432 https://doi.org/10.1097/01.grf.0000135653.56778.3f
Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol 2004;44:167–93. PMID:14744243 https://doi.org/10.1146/annurev.pharmtox.44.101802.121554
Middaugh J. Botulism and breast milk. N Engl J Med 1978;298:343. PMID:622098 https://doi.org/10.1056/NEJM197802092980620
Jim J, Johnson B, Millerburg T, Silver T, Funk D, Bixby M. Type A botulism in Alaska. State of Alaska Epidemiology Bulletin. 1976;13.
Douthirt C. An outbreak of botulism in Tucumcari, New Mexico. Southwest Med 1938;(2):51–3.
CDC. Botulism—California. MMWR Morb Mortal Wkly Rep 1972;21:106.
Moodley A, Quinlisk P, Garvey A, Kalas N, Barash JR, Khouri JM. Notes from the field: infant botulism caused by Clostridium baratii type F—Iowa, 2013. MMWR Morb Mortal Wkly Rep 2015;64:400. PMID:25879901
Gould CV, Umscheid CA, Agarwal RK, Kuntz G, Pegues DA; Healthcare Infection Control Practices Advisory Committee. Guideline for prevention of catheter-associated urinary tract infections 2009. Infect Control Hosp Epidemiol 2010;31:319–26. PMID:20156062 https://doi.org/10.1086/651091
Berlowitz D, VanDeusen Lukas C, Parker V, Niederhauser A, Silver J, Logan C, et al. Preventing pressure ulcers in hospitals. Rockville, MD: Agency for Healthcare Research and Quality; 2014. https://www.ahrq.gov/sites/default/files/publications/files/putoolkit.pdf
Klompas M, Branson R, Eichenwald EC, et al.; Society for Healthcare Epidemiology of America (SHEA). Strategies to prevent ventilator-associated pneumonia in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014;35:915–36. PMID:25026607 https://doi.org/10.1086/677144
Marcus SM. Reflections on the care of a patient severely poisoned by 'rogue' botulinum toxin and rendered paralysed for a protracted hospital stay. Botulinum J 2009;1:318–39. https://doi.org/10.1504/TBJ.2009.031683
ten Hoorn S, Elbers PW, Girbes AR, Tuinman PR. Communicating with conscious and mechanically ventilated critically ill patients: a systematic review. Crit Care 2016;20:333. PMID:27756433 https://doi.org/10.1186/s13054-016-1483-2
Cohen RE, Anderson DL. Botulism: emotional impact on patient and family. J Psychosom Res 1986;30:321–6. PMID:3735176 https://doi.org/10.1016/0022-3999(86)90009-7

As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.

Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.

Faculty

Agam K. Rao, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Agam K. Rao, MD, has disclosed no relevant financial relationships.

Jeremy Sobel, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Jeremy Sobel, MD, has disclosed no relevant financial relationships.

Kevin Chatham-Stephens, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Kevin Chatham-Stephens, MD, has disclosed no relevant financial relationships.

Carolina Luquez, PhD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Carolina Luquez, PhD, has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

Associate Director, Accreditation and Compliance
Medscape, LLC

Disclosures

Disclosure: Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

CME / ABIM MOC / CE

Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021

Authors: Agam K. Rao, MD; Jeremy Sobel, MD; Kevin Chatham-Stephens, MD; Carolina Luquez, PhD
CME / ABIM MOC / CE Released: 7/22/2021
THIS ACTIVITY HAS EXPIRED FOR CREDIT
Valid for credit through: 7/22/2022, 11:59 PM EST

Start Activity

Target Audience and Goal Statement

This activity is intended for infectious disease clinicians, internists, neurologists, public health officials, epidemiologists, and other clinicians caring for patients with botulism.

The goal of this activity is to describe recommended best practices for diagnosing, monitoring, and treating single cases or outbreaks of foodborne, wound, and inhalational botulism in the settings of conventional, contingency, and crisis standards of care, according to new comprehensive clinical care guidelines.

Upon completion of this activity, participants will:

Describe recommended best practices for diagnosing foodborne, wound, and inhalational botulism, according to new comprehensive clinical care guidelines
Determine recommended best practices for monitoring illness progression of foodborne, wound, and inhalational botulism, according to new comprehensive clinical care guidelines
Identify recommended best practices for treating foodborne, wound, and inhalational botulism, according to new comprehensive clinical care guidelines

Disclosures

Faculty

Agam K. Rao, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Agam K. Rao, MD, has disclosed no relevant financial relationships.

Jeremy Sobel, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Jeremy Sobel, MD, has disclosed no relevant financial relationships.

Kevin Chatham-Stephens, MD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Kevin Chatham-Stephens, MD, has disclosed no relevant financial relationships.

Carolina Luquez, PhD

Division of Foodborne, Waterborne, and Environmental Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention (CDC)
Atlanta, Georgia

Disclosures

Disclosure: Carolina Luquez, PhD, has disclosed no relevant financial relationships.

CME Author

Laurie Barclay, MD

Freelance writer and reviewer
Medscape, LLC

Disclosures

Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.

CME Reviewer/Nurse Planner

Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

Associate Director, Accreditation and Compliance
Medscape, LLC

Disclosures

Disclosure: Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE, has disclosed no relevant financial relationships.

Medscape, LLC staff have disclosed that they have no relevant financial relationships.

Accreditation Statements

In support of improving patient care, Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

For Physicians

Medscape, LLC designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.25 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

Contact This Provider

For Nurses

Awarded 1.25 contact hour(s) of nursing continuing professional development for RNs and APNs; 0.75 contact hours are in the area of pharmacology.

Contact This Provider

For Pharmacists

Medscape designates this continuing education activity for 1.25 contact hour(s) ( 0.125 CEUs) (Universal Activity Number: JA0007105-0000-21-369-H01-P).

Contact This Provider

For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]

Instructions for Participation and Credit

There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 75% on the post-test.

Follow these steps to earn CME/CE credit*:

Read about the target audience, learning objectives, and author disclosures.
Study the educational content online or print it out.
Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score as designated at the top of the test. We encourage you to complete the Activity Evaluation to provide feedback for future programming.

You may now view or print the certificate from your CME/CE Tracker. You may print the certificate, but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period, you can print out the tally as well as the certificates from the CME/CE Tracker.

*The credit that you receive is based on your user profile.

From Morbidity & Mortality Weekly Report

CME / ABIM MOC / CE

Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021

Authors: Agam K. Rao, MD; Jeremy Sobel, MD; Kevin Chatham-Stephens, MD; Carolina Luquez, PhDFaculty and Disclosures

THIS ACTIVITY HAS EXPIRED FOR CREDIT

CME / ABIM MOC / CE Released: 7/22/2021

Valid for credit through: 7/22/2022, 11:59 PM EST

processing....

Abstract and Introduction

Abstract

Botulism is a rare, neurotoxin-mediated, life-threatening disease characterized by flaccid descending paralysis that begins with cranial nerve palsies and might progress to extremity weakness and respiratory failure. Botulinum neurotoxin, which inhibits acetylcholine release at the neuromuscular junction, is produced by the anaerobic, gram-positive bacterium Clostridium botulinum and, rarely, by related species (C. baratii and C. butyricum). Exposure to the neurotoxin occurs through ingestion of toxin (foodborne botulism), bacterial colonization of a wound (wound botulism) or the intestines (infant botulism and adult intestinal colonization botulism), and high-concentration cosmetic or therapeutic injections of toxin (iatrogenic botulism). In addition, concerns have been raised about the possibility of a bioterrorism event involving toxin exposure through intentional contamination of food or drink or through aerosolization. Neurologic symptoms are similar regardless of exposure route. Treatment involves supportive care, intubation and mechanical ventilation when necessary, and administration of botulinum antitoxin. Certain neurological diseases (e.g., myasthenia gravis and Guillain-Barré syndrome) have signs and symptoms that overlap with botulism. Before the publication of these guidelines, no comprehensive clinical care guidelines existed for treating botulism. These evidence-based guidelines provide health care providers with recommended best practices for diagnosing, monitoring, and treating single cases or outbreaks of foodborne, wound, and inhalational botulism and were developed after a multiyear process involving several systematic reviews and expert input.

Introduction

Background

These evidence-based guidelines provide health care personnel with recommended best practices for diagnosing, monitoring, and treating botulism in the settings of conventional, contingency, and crisis standards of care. The following syndromes are described: foodborne botulism (exposure to botulinum neurotoxin in food), wound botulism (exposure to botulinum neurotoxin from a wound colonized with the bacteria), inhalational botulism (exposure to aerosolized botulinum neurotoxin, which could be caused intentionally), and iatrogenic botulism (exposure to botulinum neurotoxin by injection of high-concentration botulinum toxin for cosmetic or therapeutic purposes). These guidelines do not address syndromes of botulism caused by intestinal colonization by botulinum-toxin–producing Clostridia species (i.e., infant botulism and adult colonization botulism), which are inherently sporadic and have not occurred in outbreaks. Therefore, throughout the text, terms such as "botulism" and "patient with suspected botulism" refer to syndromes other than intestinal colonization.

Contamination of foods with botulinum neurotoxin can occur unintentionally when botulinum spores germinate under appropriate conditions and produce toxin, or intentionally, when toxin is added directly to foods. Foodborne botulism outbreaks usually affect few persons. However, because large outbreaks are possible ("epidemic potential"), foodborne botulism is a public health emergency. Contamination of wounds with Clostridium botulinum and subsequent in situ botulinum toxin production is typically (in the United States) caused by unsanitary injection of a particular type of heroin (black tar heroin) subcutaneously or subdermally; although common-source heroin containing clostridial spores might affect groups of injectors, wound botulism does not have the epidemic potential of foodborne botulism.^[1] Purified botulinum toxin, produced and weaponized by military biological warfare programs of various countries, could be dispersed as an aerosol and cause inhalational botulism. This form of botulism, which does not occur naturally and has been reported once in a laboratory worker, could affect many persons.^[2]

Diagnosis of botulism depends on high clinical suspicion and a thorough neurologic examination. The timeliness of diagnosis is crucial to successful treatment because botulinum antitoxin, the only specific therapy for botulism, must be administered to patients as quickly as possible. In the United States, botulinum antitoxin (to treat suspected botulism, other than infant botulism) is available emergently and free of charge from the federal government. Health departments and CDC provide emergency clinical consultations 24 hours per day and facilitate rapid antitoxin delivery for treatment of suspected botulism, other than infant botulism. For suspected cases of infant botulism, the California Department of Public Health Infant Botulism Treatment and Prevention Program provides clinical consultation and access to the specific antitoxin licensed for treatment of infant botulism.

The recommendations in these guidelines address the conventional standard of care, in which medical resources are not limited, as well as settings of contingency and crisis standards of care, with limited medical resources. These guidelines focus on clinical management in the acute phase of illness and do not address long-term care, epidemiologic investigations, antitoxin for postexposure prophylaxis, and management of routine medical issues that are not specific to botulism. Clinicians, hospital administrators, state and local health officials, and planners can use the recommendations in these guidelines to assist in developing crisis protocols for national preparedness for botulism events ranging from sporadic (single) cases to large outbreaks.

Pathophysiology of Botulism

Botulism is caused by toxins formed by the anaerobic, gram-positive bacterium C. botulinum and, rarely, by strains of closely related species (C. baratii and C. butyricum).^[3] These organisms form spores that are ubiquitous in the environment and capable of indefinitely surviving most naturally occurring conditions as well as boiling and other routine cooking practices. Spores are routinely ingested by humans but do not normally germinate in the intestine.^[4] Toxin is produced only when the spores germinate; this occurs under a rare confluence of circumstances that include anaerobic conditions, low acidity (pH >4.5), low salt and sugar content, and temperatures of 37°F–99°F (3°C–37°C), depending on the serotype. Botulinum toxins are the most potent biologic toxins known. Although the precise lethal dose for humans is unknown, extrapolations have been made from primate studies. The lethal doses for purified crystalline botulinum toxin type A for a 154-lb (70-kg) man are estimated to be 70 μg when introduced orally and 0.80–0.90 μg when inhaled.^[2] Lower doses were proposed in older studies.^[5–7]

Seven antigenically distinct botulinum toxins have been identified (A, B, C, D, E, F, and G), all during 1919–1970;^[3] most strains of C. botulinum produce only a single toxin, although strains producing two toxin types have been identified.^[8] In addition, two novel botulinum-toxin–like proteins have been identified from gene sequences and assembled: one from a C. botulinum isolate and one from an Enterococcus faecium isolate.^[9–11] All botulinum toxin types share a similar structure, consisting of a zinc-endopeptidase protein formed by a heavy chain of approximately 100,000 daltons and a light chain of approximately 50,000 daltons. Botulinum neurotoxin enters the vascular circulation (through ingestion, absorption from colonized wound or intestine, inhalation, or injection) and is transported to peripheral cholinergic nerve terminals, including neuromuscular junctions, postganglionic parasympathetic nerve endings, and peripheral ganglia.^[12] All toxin types produce a similar clinical syndrome of cranial nerve palsies followed by descending symmetric flaccid paralysis of variable severity and extent through similar pharmacological mechanisms at the neuromuscular junction.^[12–14]

The sequence of botulinum neurotoxin activity at the neuromuscular junction includes heavy-chain binding to a neuronal cell followed by internalization by means of receptor-mediated endocytosis, translocation to the cytosol, and cleavage of the proteins (specific for each serotype) involved in the release of the neurotransmitter acetylcholine.^[4] The characteristic flaccid paralysis results from blocking acetylcholine transmission across the neuromuscular junction by inhibition of acetylcholine release from the presynaptic motor neuron terminal.^[12] The large molecular size of the botulinum toxin likely precludes its crossing the blood-brain barrier to the central nervous system.^[4] Botulinum toxin might be transported to the central nervous system axonally, similar to tetanus toxin, which it resembles, although direct effects on the central nervous system have not been documented in humans.^[15] Recovery, which takes weeks to months, occurs after sprouting of new nerve terminals.

Toxin serotypes A, B, E, and (more rarely) F cause human disease. Toxin type A produces the most severe syndrome, with the highest proportion of patients requiring mechanical ventilation.^[14,16,17] Toxin type B usually causes milder disease than type A.^[14,16,17] Only two cases of illness in humans from toxin type C and one outbreak caused by toxin type D have been reported, all in the 1950s.^[18,19] Although toxin type C blocks neuromuscular transmission in human tissue in laboratory experiments, this toxin type might not be absorbed in the human gastrointestinal tract.^[20,21] In studies of human tissue, toxin type D has been reported not to block neuromuscular transmission.^[20] No cases in humans have been reported from toxin type G.^[3] Toxin type E, usually associated with consumption of foods of aquatic origin, produces a syndrome of variable severity, which frequently includes gastrointestinal symptoms.^[17,22,23] Type F cases are rare and characterized by rapid progression, extensive paralysis, and respiratory failure but with earlier recovery.^[24,25] All toxin types readily produce botulism in experimental animal models.

Page 1 of 11

Methods

CME / ABIM MOC / CE Information

References

Table 1.

Table 2.

Table 3.

Table 4.

Table 5.

Table 6.

Box 1.

Box 2.

References

Faculty and Disclosures

Faculty

Agam K. Rao, MD

Jeremy Sobel, MD

Kevin Chatham-Stephens, MD

Carolina Luquez, PhD

CME Author

Laurie Barclay, MD

CME Reviewer/Nurse Planner

Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

CME / ABIM MOC / CE

Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021

Target Audience and Goal Statement

Disclosures

Faculty

Agam K. Rao, MD

Jeremy Sobel, MD

Kevin Chatham-Stephens, MD

Carolina Luquez, PhD

CME Author

Laurie Barclay, MD

CME Reviewer/Nurse Planner

Hazel Dennison, DNP, RN, FNP-BC, CHCP, CPHQ, CNE

Accreditation Statements

For Physicians

For Nurses

For Pharmacists

Instructions for Participation and Credit

Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021

Abstract and Introduction

Abstract

Introduction

Pathophysiology of Botulism

Table of Contents