Botulinum Antitoxin Research Articles

First case of infant botulism in Sicily—case report

BackgroundBotulism is a rare and life-threatening disease caused by the potent botulinum neurotoxin (BoNT), which can be produced by Clostridium botulinum (C. botulinum) and related bacteria. Clinical manifestations, which include a symmetrical, descending muscular paralysis, generalized hypotonia, and potentially respiratory failure, are non-specific and diagnosis is challenging, especially when anamnesis does not reveal any typical risk factor, like honey consumption.Case PresentationWe present what is, to the best of our knowledge, the first documented case of infant botulism (IB) in Sicily and discuss its peculiarities and the challenges faced in the diagnostic-therapeutic process. The infant was exclusively breastfed and no history of consumption of possibly contaminated foods, like honey, was found. The signs observed at presentation included poor suction, hypotonia, and hyporeactivity. A detailed anamnesis motivated the suspicion of botulism, due to the occurrence of constipation and exposure to dust from home renovation works during the days before the onset of symptoms. The botulinum antitoxin was administered and the diagnosis was confirmed through fecal examination, detecting toxin-producing C. botulinum.ConclusionIB should be considered in every infant with rapidly progressing hypotonia and a history of constipation. However rarely, transmission could occur through inhalation of dust particles containing the toxin, therefore it is important to explore all possible sources of exposure. In the case described, timely diagnosis and treatment determined the successful outcome, which highlights the importance of early intervention in managing IB.

Случай тяжелого пищевого ботулизма у ребенка: трудности диагностики и тактика терапии

Practitioners’ alertness of botulism in children decreases due to the rarity of its cases. Early diagnosis is based on clinical symptoms though the clinical manifestations may also escalate rapidly and further lead to misdiagnosis. Patients with suspected botulism require immediate hospitalization due to the high risk for paralysis of respiratory muscles and the need for mechanical ventilation. The timely administration of the antitoxin is crucial. However, maximum allowable time of its administration counting from the onset is still a subject to discussion among physicians. Authors represent a clinical case of late diagnosis of severe foodborne botulism in a 5 y/o pediatric patient with the development of tetraplegia, paralysis of cranial nerves, mechanical ventilation for 148 days, the beginning of motor recovery on the 10th day and antitoxin administration on the 18th day counting from the onset of paralysis that all let to the full motor recovery after 20 months. The difficulties of diagnosis in the acute period and both laboratory and instrumental studies are described. The questions of the duration and the necessity of the administration of botulinum antitoxin in this particular clinical case of late diagnosis are discussed as well.

Neurotropic Effect of Botulinum Toxin and the Potential of Specific Serum Therapy in Botulism (Review)

INTRODUCTION. The outbreak of foodborne botulism that occurred in Russia in June 2024 once again demonstrated the danger of this rather rare but severe infectious disease caused by ingesting botulinum neurotoxin. The only aetiological treatment for botulism is currently the administration of antitoxins against various serotypes of botulinum toxin. However, antitoxins do not provide rapid regression of neurological symptoms, which may raise doubts about the effectiveness of the selected treatment option. It is impossible to assess the potential of specific treatment without understanding the mechanisms of action of botulinum toxin and antitoxin.AIM. This study aimed to systemise information on the mechanism underlying the damaging effect of botulinum neurotoxin, aetiological antitoxin treatment, and the patient recovery process.DISCUSSION. The mechanism underlying the damaging effect of botulinum neurotoxin consists in the destruction of SNARE proteins in presynaptic cholinergic nerve terminals, which disrupts the release of acetylcholine into the synaptic cleft and the transmission of excitation between neurons. The lack of acetylcholine at the neuromuscular junction results in a distinctive form of persistent flaccid paralysis. The specific mechanism of action of botulinum toxin determines the treatment strategy, which includes a set of life-sustaining measures and the earliest possible antiserum administration. If used within 48 hours from the onset of symptoms, botulinum antitoxin binds botulinum toxin circulating in the blood, which stops the progression of paralysis and prevents further disorders in patients. However, botulinum antitoxin cannot neutralise the effect of the toxin that has already bound to nerve receptors, so clinical symptoms may worsen within 12 hours after antiserum administration. Restoration of normal neuronal transmission occurs through the formation of new axonal sprouts and can take a long time.CONCLUSIONS. Antitoxin administration is effective and irreplaceable in the aetiological treatment of botulism. Nevertheless, the duration of recovery depends on the speed of reinnervation and restoration of transmission at the neuromuscular junction.

Functional prediction and assignment of Clostridium botulinum type A1 operome: A quest for prioritizing drug targets

Clostridium botulinum strain Hall produces potent botulinum neurotoxin type A1, which causes food-borne, infant, and wound botulism in humans. Antibiotics and botulinum antitoxins can control growth and prevent botulinum toxicity. However, limited information on a protein with an unknown function hinders the discovery of new drug targets for this disease. In this study, a combined bioinformatics approach with literature support was applied to predict, assign, and validate operome functions. Our functional annotation scheme was based on sequence motifs, conserved domains, structures, protein folds, and evolutionary relationships. Approximately 14.62 % of the operome exhibited sequence similarity to known proteins, with 6.65 % predicted functions for 293 proteins, including 121 proteins exclusive to C. botulinum. Structural analysis revealed a significant presence of the Rossmann fold (26 %) and miscellaneous folds (43 %) among the operome. Transporters (>85) and transcriptional regulators (>45) were prevalent, underscoring their importance in C. botulinum adaptive strategies. The newly identified operome contributed to the diverse cellular and metabolic processes of this organism. The function of its operome was involved in amino acid metabolism and botulinum neurotoxin biosynthesis. In this study, we identified and characterized 13 new virulence proteins from the operome to determine their structure–function relationships. These new metabolic and virulence proteins allow the organism to colonize and interact with the human gastrointestinal tract. This study provides a quest for new drugs and targets for treating the underlying diseases of C. botulinum in humans.

Foodborne botulism outbreak with potential new management options.

To shed some light on a potential therapeutic modality that may facilitate resolution of botulism symptoms, namely 3,4-diaminopyridine (3,4-DAP). In Riyadh, Saudi Arabia, we recently encountered a foodborne botulism outbreak that, luckily, was discovered early. In Prince Sultan Military Medical city, we admitted, during a period of approximately 3 weeks, 15 probable cases, 2 of which were excluded due to more likely alternative diagnoses. We report in this case series 13 highly suspected cases of botulism that we encountered during the outbreak. A total of 12 out of 13 patients required intensive care unit (ICU) admission, one of which required intubation. Symptoms included cranial nerve palsies, gastrointestinal symptoms, limb and respiratory muscle weakness. Patients showed clinical improvement when received botulinum antitoxin and 3,4-DAP if given early in the course of the disease. Early admisntration of 3,4-DAP may facilitate recovery and prevent disease progression. Larger prospective trials should be carried out to confirm that.

A rare symptom of foodborne botulism: dysgeusia. Case report and clinical review

Clostridium botulinum has become one of the most well-known microorganisms in medical history, thanks to both fatal botulism epidemics and the recent medical use of botulinum neurotoxin. It is a Gram-positive, anaerobic, spore-forming bacterium that causes classic foodborne botulism, infant botulism, wound botulism, and intestinal colonization botulism, a serious neuroparalytic disease. The most common type of botulism is foodborne botulism, which is caused by eating botulinum toxin-contaminated foods. Just a few micrograms of toxin are enough to cause symptoms and, if untreated, death. Rapid diagnosis of the condition is critical to avoiding fatal outcomes. This article describes a clinical case of a patient who presented to us in June with typical symptoms of botulism. Early clinical diagnosis is based on a thorough medical history, including a meticulous reconstruction of the patient's food history in the days preceding symptom onset, as well as a careful physical examination, which can be highly suggestive of botulinum intoxication. Botulism treatment consists of symptom control, mechanical respiratory support, and Botulinum Antitoxin (BAT) administered intravenously. Epidemiological investigation is critical for quickly identifying the food vehicle causing the intoxication.

Clinical characteristics and prognosis of 8 cases of severe infant botulism

Objective: To summarize the clinical characteristics and prognosis of severe infant botulism and evaluate the therapeutic effect of botulinum antitoxin in the pediatric intensive care unit (PICU). Methods: The clinical data of 8 cases diagnosed with infantile botulism were retrospectively analyzed in the PICU of Beijing Children's Hospital from October 2019 to August 2023. Data of basic demographic information, clinical manifestations, laboratory tests, treatment and prognosis of each child were collected and analyzed using descriptive statistical methods. Results: Eight laboratory-confirmed cases of infant botulism were included in this study, all of which were male infants with an age of 6.0 (3.3,6.8) months. Three of the children were from Inner Mongolia Autonomous Region, 2 of them were from Hebei, and the other 3 were from Beijing, Shandong and Xinjiang Uyghur Autonomous Region, respectively. All the patients were previously healthy. In 4 of these cases, the possible cause was the ingestion of either honey and its products or sealed pickled food by the mother or child before the onset of the disease. The first symptom was poor milk intake (4 cases), followed by shallow shortness of breath (7 cases), limb weakness (7 cases) and so on. The typical signs were bilateral dilated pupils (8 cases) and decreased limb muscle strength (8 cases). The main subtype was type B (7 cases), and only 1 case was classified as type A. Six of the children were treated with antitoxin therapy for a duration of 24 (19, 49) d. Seven of them had invasive mechanical ventilation. All the patients survived upon discharge with a follow-up period of 29 d to 3 years and 8 months. Six patients had fully recovered, and 2 recently discharged patients were gradually recovering. Conclusions: For infants with suspected contact or ingestion of botulinum and presented with bilateral pupillary paralysis, muscle weakness and clear consciousness, the stool should be collected for diagnostic testing using a mouse bioassay as soon as possible. Type B was the most common type. The antitoxin treatment was effectiveness and the prognosis was well.

Standardization of the Japanese National Standard, Equine Botulinum Antitoxin Type A, and Factors Affecting Standardization.

Equine botulinum antitoxin is one of the most popular countermeasures for human botulism. The unitage of the antitoxin product is defined according to national minimum requirement or pharmacopoeia in each country by referring to national standard antitoxins for four types (A, B, E, and F). With the expected depletion of the national standard antitoxins, replacement national standard antitoxins are produced and standardized through collaboration of the National Control Laboratory and other participants, including manufacturer(s). Therefore, Japanese National Standard Botulinum Antitoxin Type A, Equine, was replaced according to the results of a collaborative study involving the National Institute of Infectious Diseases and KM Biologics Co., Ltd. The unitage of the replacement material was determined through mouse neutralization tests, which involved toxin-antitoxin mixture injection at pH 7.0. Potency value of 440 units/vial was obtained. However, the Japanese Minimum Requirement for Biological Products was revised, and the neutralization reactions were repeated at pH 6.0, for which considerably different potency value (656 units/vial) and survival profile of mice were obtained. In September 2021, the replacement material, Japanese National Standard Botulinum Antitoxin Type A, Equine, lot 2, was established with potency value of 656 Units/vial. The impact of pH-dependent change in potency on antitoxin quality control is discussed.

A human bispecific antibody neutralizes botulinum neurotoxin serotype A

Botulinum neurotoxin (BoNT) shows high lethality and toxicity, marking it as an important biological threat. The only effective post-exposure therapy is botulinum antitoxin; however, such products have great potential for improvement. To prevent or treat BoNT, monoclonal antibodies (mAbs) are promising agents. Herein, we aimed to construct a bispecific antibody (termed LUZ-A1-A3) based on the anti-BoNT/A human monoclonal antibodies (HMAb) A1 and A3. LUZ-A1-A3 binds to the Hc and L-HN domains of BoNT/A, displaying potent neutralization activity against BoNT/A (124 × higher than that of HMAb A1 or HMAb A3 alone and 15 × higher than that of the A1 + A3 combination). LUZ-A1-A3 provided effective protection against BoNT/A in an in vivo mouse model. Mice were protected from infection with 500 × LD50 of BoNT/A by LUZ-A1-A3 from up to 7 days before intraperitoneal administration of BoNT/A. We also demonstrated the effective therapeutic capacity of LUZ-A1-A3 against BoNT/A in a mouse model. LUZ-A1-A3 (5 μg/mouse) neutralized 20 × LD50 of BoNT/A at 3 h after intraperitoneal BoNT/A administration and complete neutralized 20 × LD50 of BoNT/A at 0.5 h after intraperitoneal BoNT/A administration. Thus, LUZ-A1-A3 is a promising agent for the pre-exposure prophylaxis and post-exposure treatment of BoNT/A.

Successful treatment of a 15 years-old obese adolescent patient with botulinum anti-toxin after gastric Botox and systemic botulism findings: a case report

Obesity is an increasingly common public health problem in children. The main goal in the fight against obesity is to prevent the development of obesity by healthy eating, increasing physical activity and reducing screen time. Patients with obesity should be treated in a multidisciplinary manner in accordance with the guidelines. In children and adolescents, applications such as gastric Botox, which are not included in the guidelines and for which there is insufficient literature information, should be avoided. Obese patients with Botulism side effects should be questioned about this application and Botulism antitoxin should be administered in appropriate cases. In this case report, we present a 15-year-old adolescent girl who developed botulism after gastric Botox administration in another medical institution and was successfully treated with Botulism antitoxin and prostigmine.

A Three-Monoclonal Antibody Combination Potently Neutralizes BoNT/G Toxin in Mice.

Equine-derived antitoxin (BAT®) is the only treatment for botulism from botulinum neurotoxin serotype G (BoNT/G). BAT® is a foreign protein with potentially severe adverse effects and is not renewable. To develop a safe, more potent, and renewable antitoxin, humanized monoclonal antibodies (mAbs) were generated. Yeast displayed single chain Fv (scFv) libraries were prepared from mice immunized with BoNT/G and BoNT/G domains and screened with BoNT/G using fluorescence-activated cell sorting (FACS). Fourteen scFv-binding BoNT/G were isolated with KD values ranging from 3.86 nM to 103 nM (median KD 20.9 nM). Five mAb-binding non-overlapping epitopes were humanized and affinity matured to create antibodies hu6G6.2, hu6G7.2, hu6G9.1, hu6G10, and hu6G11.2, with IgG KD values ranging from 51 pM to 8 pM. Three IgG combinations completely protected mice challenged with 10,000 LD50s of BoNT/G at a total mAb dose of 6.25 μg per mouse. The mAb combinations have the potential for use in the diagnosis and treatment of botulism due to serotype G and, along with antibody combinations to BoNT/A, B, C, D, E, and F, provide the basis for a fully recombinant heptavalent botulinum antitoxin to replace the legacy equine product.

Foodborne botulism and the importance of recognizing the disease in the emergency department: a case report

BackgroundBotulism is a rare neuroparalytic disease that has only presented itself 19 times in the last 30 years in Belgium. Patients present to emergency services with a wide range of complaints. Foodborne botulism is a forgotten yet life-threatening disease.Case presentationWe describe a case of a Caucasian female in her 60s that presented to the emergency with reflux with nausea and spasmodic epigastric pain, no vomiting, dry mouth, and weakness in both legs. The symptoms started after ingestion of Atlantic wolffish. After exclusion of other more common causes, foodborne botulism was suspected. The patient was admitted to the intensive care unit for mechanical ventilation. Following treatment with trivalent botulinum antitoxin, she made a full neurologic recovery.ConclusionIt is important to rapidly recognize the possible diagnosis of botulism even if the neurological symptoms are not dominant. Rapid neurologic dysfunction and respiratory difficulties starts between 6 and 72 hours after ingestion. The decision to administer antitoxins should, however, be based on the presumptive clinical diagnosis and diagnosis should not delay therapy.

Use of Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine) (BAT®) in Clinical Study Subjects and Patients: A 15-Year Systematic Safety Review.

Botulism is a rare, sometimes fatal paralytic illness caused by botulinum neurotoxins. BAT® (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)—(Equine)) is an equine-derived heptavalent botulinum antitoxin indicated for the treatment of symptomatic botulism in adult and pediatric patients. This review assesses the cumulative safety profile for BAT product from 2006 to 2020, using data received from clinical studies, an expanded-access program, a post-licensure registry, spontaneous and literature reports. The adverse event (AE) incidence rate for BAT product was calculated conservatively using only BAT product exposures for individuals with a record (512) and was alternatively estimated using all BAT product exposure data, including post-licensure deployment information (1128). The most frequently reported BAT product-related AEs occurring in greater than 1% of the 512–1128 BAT product-exposed individuals were hypersensitivity, pyrexia, tachycardia, bradycardia, anaphylaxis, and blood pressure increase reported in 2.3–5.1%, 1.8–3.9%, 1.0–2.2%, 0.89–2.0%, 0.62–1.4%, and 0.62–1.4%, respectively. For patients properly managed in an intensive care setting, the advantages of BAT product appear to outweigh potential risks in patients due to morbidity and mortality of botulism. AEs of special interest, including bradycardia, hemodynamic instability, hypersensitivity, serum sickness, and febrile reactions in the registry, were specifically solicited.

Current status and development trend of botulinum antitoxin

Botulism is a rare, potentially fatal disease caused by botulinum toxin, a strongest biotoxin produced by Clostridium botulinum. Botulinum antitoxin is the only specific treatment for botulism. Early administration of botulinum antitoxin is essential for the therapeutic effect of botulism. At present, almost all the approved botulinum antitoxins are equine plasma derived products, which have the potential risk of adverse reactions, including allergic reactions. This paper summarizes the current status of production technique, quality control and clinical application of botulinum antitoxin both at home and abroad, and introduce the application prospect of botulinum antitoxin.

Outbreak of foodborne botulism in Alexandria, Egypt: modulating indications for administration of heptavalent botulinum antitoxin

In October 2019, ninety-four patients were admitted into Alexandria Poison Center (APC) with a history of ingestion of Feseekh (salted fish). In an attempt to allocate the resources, not all patients were given HBAT (botulism antitoxin heptavalent (A, B, C, D, E, F, G) equine immediately. The current study aimed to portray the clinical characteristics of the cases, explore the possible relation between these characteristics and necessity of HBAT administration, explore the reliability of mouse lethal test, and establish a clinical guide for management including preservation of resources. The current prospective study included 94 patients who were admitted to Alexandria Poison Center (APC) in the period from the 29th of September to the 27th of October 2019. The patients' data were recorded using a checklist that includes: personal data, past medical history, clinical assessment, investigations, treatment, and the outcome. The checklist was carried out to assess and follow up each patient. Hospitalized patients were categorized according to symptoms consistent with botulism. The equine HBAT, made by Emergent BioSolutions Canada Inc. (formerly Cangene Corporation), was used in the treatment. HBAT was given to thirty-four patients (36.2%) only out of the total admission. However, eighty-two (87.2%) of patients were completely cured, whereas ten patients (10.6%) were discharged with mild neurological sequels and death occurred only in two cases (2.2%). Sixty cases (63.8%) with suspected foodborne botulism could be managed by supportive treatment only with no need for HBAT, while patients with evident neurological signs received HBAT immediately.

Suspected botulism outbreak after the consumption of vegetarian pâté in the south of Viet Nam

Botulism and other botulinum neurotoxins-producing clostridia are potentially life-threatening diseases caused by toxins produced by Clostridium botulinum. Here we reported a case series of six patients who presented with botulism following ingestion of commercially made pâté. The key features of presentation were acute onset of bilateral cranial nerve palsies and symmetrical descending weakness in the absence of fever resulting in the need for mechanical ventilation in all six patients. The clinical diagnosis of botulism was confirmed through the identification of C. botulinum from the suspected food source. Given that botulinum antitoxin was not available in Vietnam at the time, and their severe status, all patients received a trial of plasma exchange therapy, but no clear benefit was seen. Due to its rarity, diagnosing botulism is a challenge, demanding high clinical suspicion. Successful outcomes depend upon early recognition and rapid initiation of specific treatment with botulinum antitoxin. There is a need to improve global access to antitoxin. These cases, the first in Viet Nam, serve as a reminder of the need to maintain the highest possible food hygiene and preservation practices.

Clinical Guidelines for Diagnosis and Treatment of Botulism, 2021.

SummaryBotulism 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.

An investigation of a botulism poisoning event in Urumqi, Xinjiang

Objective To investigate the pathogenic factors and causes of a botulism poisoning event and provide evidence for the prevention and control of the similar events in the future. Methods Field epidemiological survey was conducted through consulting medical records, interviewing relevant doctors and household survey, Laboratory test was done after collecting case stool samples and residual food samples for the detection of Clostridium botulinum. Results Two poisoning cases were confirmed and admitted to hospital. After botulinum antitoxin A and B treatment, the symptoms were significantly alleviated. C. botulinum was isolated, which was identified as type A C. botulinum after detection of type A toxin gene by real time quantitative PCR. Type A botulinum toxin was detected in mouse experiments. Conclusion This poisoning event was caused by homemade tempeh contaminated by C. botulinum type A. It is recommended to strengthen health education about the prevention of contamination in food production and storage. Medical institutions should prepare emergency medicines for food poisoning. Antitoxin serum should be used for the treatment of botulism poisoning.

Management of an outbreak of botulism with benign clinical presentation

Botulism is a life-threatening presynaptic disorder of the neuromuscular transmission produced by the neurotoxin elaborated by the botulinum neurotoxin-producing clostridia. We describe the management of a case series of 14 patients, members of 5 different families that were exposed to home-canned tuna and developed symptoms compatible with a mild clinical presentation of foodborne botulism. The electrophysiological study of the index case represented a reliable diagnostic test as it demonstrated a slight presynaptic dysfunction of the neuromuscular junction. Definite diagnosis was later confirmed by microbiological tests. Out of 14, only 3 patients presenting with a shorter period from symptom onset and with signs of multiple cranial neuropathies received botulinum antitoxin. All the patients remained stable and recovered progressively. Treatment with antitoxin may not be necessary in patients with late-presenting disease and mild and stable clinical picture.

Botulism outbreak after the consumption of vegetarian pâté in the south of Viet Nam

Botulism is a potentially life-threatening disease caused by toxins produced by Clostridium botulinum. Here we reported a case series of six patients who presented with botulism following ingestion of commercially made pâté. The key features of presentation were acute onset of bilateral cranial nerve palsies and symmetrical descending weakness in the absence of fever resulting in the need for mechanical ventilation in all six patients. The clinical diagnosis of botulism was confirmed through the identification of C. botulinum from the suspected food source. Given that botulinum antitoxin was not available in Vietnam at the time, and their severe status, all patients received a trial of plasma exchange therapy, but no clear benefit was seen. Due to its rarity, diagnosing botulism is a challenge, demanding high clinical suspicion. Successful outcomes depend upon early recognition and rapid initiation of specific treatment with botulinum antitoxin. There is a need to improve global access to antitoxin. These cases, the first in Viet Nam, serve as a reminder of the need to maintain the highest possible food hygiene and preservation practices.