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PubMed1980

Susceptibility of Clostridium botulinum to thirteen antimicrobial agents.

A total of 224 strains of Clostridium botulinum (including isolates from 14 patients with infant botulism and 4 with wound botulism) and 15 strains of C. sporogenes were tested by agar dilution for susceptibility to tetracycline, metronidazole, erythromycin, penicillin, rifampin, chloramphenicol, clindamycin, cephalothin, cefoxitin, vancomycin, sulfamethoxazole-trimethoprim, nalidixic acid, and gentamicin. At least 90% of the C. botulinum strains tested (except for nonproteolytic strains of toxin type F with penicillin) were susceptible to all drugs except sulfamethoxazole-trimethoprim, nalidixic acid, and gentamicin. Minimal inhibitory concentrations for strains from patients with infant and wound botulism were similar to those for other C. botulinum strains.

Anti-Bacterial Agents↗
PubMed1998

Clinical evidence of extraocular muscle fiber-type specificity of botulinum toxin.

OBJECTIVE: To compare the effects of botulinum toxin on static and dynamic aspects of eye movements, and thereby elucidate the mechanisms of its action on eye muscles. BACKGROUND: Laboratory evidence indicates that static alignment and saccades are subserved by different extraocular muscle fiber types, and botulinum toxin may cause specific dysfunction of the fibers controlling static alignment. Diplopia is a well-known side effect of periorbital botulinum toxin injections in humans, and may be a clinical correlate of the laboratory findings. METHODS: Search coil recording of eye movements was performed in one patient with systemic botulism, and in three patients with diplopia following periorbital injection of botulinum toxin A. RESULTS: In the patient with acute botulism, eye movement alignment, range, and saccadic velocity profiles were abnormal. In three patients with iatrogenic diplopia, static alignment was abnormal but movement range and saccadic velocities were within normal limits. Edrophonium improved the range of movements and saccadic velocities in the patient with systemic botulism but was ineffective in reversing ocular misalignment in the one iatrogenic patient to whom it was administered. CONCLUSIONS: Precise alignment is subserved by orbital singly innervated muscle fibers, and the effects of botulinum toxin are greatest on these fibers. This predilection is apparent when the toxin dose is very small, as must have been the case in our patients with iatrogenic diplopia. The lack of a response to edrophonium probably reflects structural damage to muscle fibers. In contrast, larger doses of toxin produce an acute dysfunction of all extraocular muscle fiber types, which is responsive to edrophonium and consequently reflects partial blockade at the neuromuscular junction.

Adult↗
PubMed1993

Seasonal prevalence of Clostridium botulinum type C in sediments of a northern California wetland.

The prevalence of Clostridium botulinum type C (% of positive sediment samples) was determined in 10 marshes at Sacramento National Wildlife Refuge (SNWR), located in the Central Valley of California (USA), where avian botulism epizootics occur regularly. Fifty-two percent of 2,200 sediment samples collected over an 18-mo period contained C. botulinum type C (both neurotoxic and aneurotoxic) which was present throughout the year in all 10 marshes. The prevalence of C. botulinum type C was similar in marshes with either high or low botulism losses in the previous 5 yr. Marshes with avian botulism mortality during the study had similar prevalences as marshes with no mortality. However, the prevalence of C. botulinum type C was higher in marshes that remained flooded all year (permanent) compared with marshes that were drained in the spring and reflooded in the fall (seasonal). The prevalence of C. botulinum type C declined in seasonal marshes during the dry period. Similar declines did not occur in the permanently flooded marshes.

Animals↗
PubMed2006

A review of WHO International Standards for botulinum antitoxins.

Clostridium botulinum produces the most potent known toxins, with seven distinct serotypes currently defined (A-G). These toxins can cause a life threatening systemic toxicity whether through natural causes such as food poisoning, infant botulism, wound botulism, or through use as bio-terror agents (e.g. inhalational botulism). It was realised early on that standard reference botulinum antitoxins were required to reduce the variation between assays and ensure a consistent potency of therapeutic antitoxins and vaccines, and to define the serotype. This led to the International Unit being defined by the World Health Organisation (WHO) in the 1960s with the establishment of the first International Standards (IS) for serotypes A-F. Since then botulinum antitoxin ISs have been used world wide as the 'yard stick' to measure the neutralising potency of antitoxins. These primary WHO ISs are used to calibrate in house working reagents that are more extensively utilised. A definition of the International Unit for serotype G antitoxin has yet to be defined or accepted by the WHO and urgently needs addressing. However, before September 11th 2001 there was very little interest in botulinum antitoxin IS and as a result stocks of most of the original preparations are now completely exhausted or depleted and replacements long overdue. We have reviewed the extensive history and availability of the primary WHO ISs and interim materials. All type A and B antitoxin materials were recently assayed and their relative activities confirmed against the original IS preparations. The recent increase in demand for these materials has further exacerbated the shortage. We describe here the production and characterization of stable freeze dried potential candidate replacements along with a new prospective first IS for type G antitoxin. Available toxin A reference preparations are also briefly reviewed.

Animals↗
PubMed2002

Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.

The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A) in vivo. Although no single mAb significantly neutralized toxin, a combination of three mAbs (oligoclonal Ab) neutralized 450,000 50% lethal doses of BoNT/A, a potency 90 times greater than human hyperimmune globulin. The potency of oligoclonal Ab was primarily due to a large increase in functional Ab binding affinity. The results indicate that the potency of the polyclonal humoral immune response can be deconvoluted to a few mAbs binding nonoverlapping epitopes, providing a route to drugs for preventing and treating botulism and diseases caused by other pathogens and biologic threat agents.

Animals↗
PubMed2000

Genetic analysis of type E botulinum toxin-producing Clostridium butyricum strains.

Type E botulinum toxin (BoNT/E)-producing Clostridium butyricum strains isolated from botulism cases or soil specimens in Italy and China were analyzed by using nucleotide sequencing of the bont/E gene, random amplified polymorphic DNA (RAPD) assay, pulsed-field gel electrophoresis (PFGE), and Southern blot hybridization for the bont/E gene. Nucleotide sequences of the bont/E genes of 11 Chinese isolates and of the Italian strain BL 6340 were determined. The nucleotide sequences of the bont/E genes of 11 C. butyricum isolates from China were identical. The deduced amino acid sequence of BoNT/E from the Chinese isolates showed 95.0 and 96.9% identity with those of BoNT/E from C. butyricum BL 6340 and Clostridium botulinum type E, respectively. The BoNT/E-producing C. butyricum strains were divided into the following three clusters based on the results of RAPD assay, PFGE profiles of genomic DNA digested with SmaI or XhoI, and Southern blot hybridization: strains associated with infant botulism in Italy, strains associated with food-borne botulism in China, and isolates from soil specimens of the Weishan lake area in China. A DNA probe for the bont/E gene hybridized with the nondigested chromosomal DNA of all toxigenic strains tested, indicating chromosomal localization of the bont/E gene in C. butyricum. The present results suggest that BoNT/E-producing C. butyricum is clonally distributed over a vast area.

Amino Acid Sequence↗
PubMed1983

Fluorescent-antibody reagents for the identification of Clostridium botulinum.

Fluorescent-antibody reagents were prepared against vegetative cells of representative strains of each physiological group and toxin type of Clostridium botulinum known to have caused botulism in humans. A fluorescent-antibody reagent was also prepared for C. botulinum type G, which has been isolated from autopsy specimens but which has not clearly been implicated in botulism. These fluorescent-antibody reagents were evaluated against 200 strains of C. botulinum and 64 strains of other clostridia. Each reagent reacted with at least a 2+ intensity with all of the strains in its same toxin type and physiological group. Ninety-seven percent of the strains gave at least a 3+ reaction with the homologous group or toxin type reagent. Some cross-reactions occurred with reagents against different toxin type strains within a physiological group; there was less cross-reaction between physiological groups and very little reactivity of C. botulinum reagents with nontoxigenic organisms. Absorption of cross-reacting antibodies was not successful. Certain reagents could be used for presumptive laboratory identification of C. botulinum strains causing botulism, especially in infants. The type G reagent provided a good means of identifying C. botulinum type G, which lacks the lipase marker and whose toxigenicity may be more difficult to demonstrate in mixed cultures. There was a serological relationship between C. botulinum type G and some strains of Clostridium subterminale. This relationship provided evidence of differences between strains of C. botulinum type G isolated in two different countries.

Antibodies, Bacterial↗
PubMed1997

In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches.

Human exposure to botulinum toxin typically occurs in two settings: 1) as an etiologic agent in the disease botulism and 2) as a therapeutic agent for the treatment of dystonia. Epidemiologic studies on botulism suggest that the human nervous system is susceptible to five toxin serotypes (A, B, E, F and G) and resistant to two (C and D). In the past, these epidemiologic findings have been used as the basis for selecting serotypes that should be tested as therapeutic agents for dystonia. Epidemiologic data have been utilized because there are no studies of botulinum neurotoxin action on isolated human nerves. In the present study, electrophysiologic techniques were used to monitor toxin effects on neuromuscular transmission in surgically excised human pyramidalis muscles, ligand binding studies were done to detect and characterize toxin receptors in human nerve membrane preparations, and molecular biologic techniques were used to isolate and sequence a human gene that encodes a substrate for botulinum neurotoxin. The results demonstrated that stable resting membrane potentials (-61.5 mV; S.E.M. +/- 0.7) were maintained in individual fibers of pyramidalis muscle for up to 6 hr at 33 degrees C. The rate of spontaneous miniature endplate potentials was low in physiologic solution (0.14 sec(-1)) but increased in response to elevations in extracellular potassium concentration. In keeping with epidemiologic findings, botulinum toxin type A (10(-8) M) paralyzed transmission in human preparations (ca. 90 min). In contrast to epidemiologic findings, serotype C (10(-8) M) also paralyzed human tissues (ca. 65 min). Iodinated botulinum toxin displayed high-affinity binding to receptors in human nerve membrane preparations (serotype A high-affinity site: K(d) = 0.3 nM, B(max) = 0.78 pmol/mg protein; serotype C high-affinity site: K(d) = 1.96 nM, B(max) = 8.9 pmol/mg protein). In addition, the human nervous system was found to encode polypeptides that are substrates for botulinum neurotoxin types A (synaptosomal-associated protein of M(r) 25,000) and C (syntaxin 1A). These data have important implications bearing on: 1) the development and administration of vaccines against botulism and 2) the testing of toxin serotypes for the treatment of dystonia.

Botulinum Toxins↗
PubMed2001

Botulinum toxin as a biological weapon: medical and public health management.

OBJECTIVE: The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population. PARTICIPANTS: The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine. EVIDENCE: The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960-March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement. CONSENSUS PROCESS: The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members. CONCLUSIONS: An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.

Antitoxins↗
PubMed2004

Roads from vaccines to therapies.

Over the past decade, we have demonstrated that various recombinant fragments of botulinum neurotoxin are highly immunogenic, stimulating notable levels of protective antibodies in mice, guinea pigs, and nonhuman primates. One of the fragments evaluated, the fragment C, is a potential next-generation vaccine candidate to replace the current pentavalent botulinum toxoid vaccine. Synthetic genes encoding the carboxyl-terminal regions (approximately 50 kDa) of toxin types A, B, C1, E, and F were expressed in Pichia pastoris, and manufacturing processes were developed for producing highly purified vaccines. These vaccines were shown to be safe, highly efficacious, stable, and amenable to high-level industrial production. Recombinant vaccines are now being produced in accordance with current Good Manufacturing Practices for use in future clinical trials. As our discovery-based program on vaccine development is diminishing, it is concurrently being replaced with a program focused on developing therapeutic interventions to botulism. Synthetic genes encoding the light chains of botulinum toxin have been expressed in Escherichia coli, and purified. These proteolytically active light chains are being used in high-throughput assays to screen for inhibitors of its catalytic activity. Other resources developed as part of the vaccine initiative, likewise, are finding utility in the quest to develop therapies for botulism.

Animals↗
PubMed1986

Disorders of neuromuscular transmission in infants and children.

Disorders of neuromuscular transmission in infants and children can be divided into two groups. The first group includes conditions similar to those seen in adults: autoimmune myasthenia gravis, Lambert-Eaton myasthenic syndrome, and botulism. The second includes several disorders that are unique to this age group, such as the congenital myasthenias and infantile botulism. This review discusses the diseases of neuromuscular transmission found in the pediatric population, with emphasis on electrodiagnosis. The distinctive clinical and electrophysiologic features allow the clinician to identify these illnesses correctly, so that appropriate treatment can be instituted or further specialized investigation can be undertaken.

Autoimmune Diseases↗
PubMed1996

Mapping of the antibody-binding regions on botulinum neurotoxin H-chain domain 855-1296 with antitoxin antibodies from three host species.

Botulism due to food poisoning is caused mainly by protein toxins, botulinum neurotoxins (BoNTs), produced by Clostridium botluinum in seven known immunological serotypes. These are the most potent toxins and poisons known. BoNT effects blockade of neuromuscular transmission by preventing neurotransmitter release. Human botulism is most frequently caused by types A, B, and E. Recent studies have shown that immunization with a 43-kDa C-terminal fragment (Hc, residues 860-1296) of BoNT/A affords excellent protection against BoNT/A poisoning. We raised antibodies (Abs) against BoNT/A in horse, and against pentavalent toxoid (BoNTs A, B, C, D, E) in human volunteers and outbred mice. Thirty-one 19-residue peptides that started at residue 855, overlapped consecutively by 5 residues, and encompassed the entire length of the Hc of BoNT/A were synthesized and used for mapping the Ab-binding regions recognized by the anti-BoNT/A antisera. Horse Abs against BoBT/A were bound by peptides 855-873, 939-957, 1079-1097/1093-1111 overlap, 1191-1209/1205-1223 overlap, 1261-1279 and 1275-1296. In addition, peptides 883-901, 911-929, 995-1013, 1023-1041/1037-1055 overlap, 1121-1139, and 1149-1167 gave low, but significant and reproducible, binding. With human antisera, high amounts of Abs were bound by peptides 869-887, 925-943, 981-999, 995-1013, 1051-1069, and 1177-1195. In addition, lower amounts of Abs were bound by peptides 911-929, 939-957, 967-985, and the overlaps 1121-1139/1135-1153 and 1247-1265/1261-1279/1275-1296. With outbred mouse antisera, high amounts of Abs were bound by peptides 869-887, 1051-1069, and 1177-1195, while peptides 939-957, 995-1013, 1093-1111, and 1275-1296 bound lower amounts of Abs. The results indicate that horse antiserum against BoNT/A or human and mouse (outbred) antisera against the toxoid recognized similar regions on BoNT/A, but exhibited some boundary frame shifts and differences in immunodominance of these regions among the antisera. Selected synthetic epitopes will be used as immunogens to stimulate active or passive (by Ab transfer) immunity against toxin poisoning.

Amino Acid Sequence↗
PubMed2002

[Botulinum toxin--the dose controls the poison. A historical sketch].

Botulism, a potentially lethal form of paralytic food poisoning, was described as early as 1793. Basic research, especially in the late nineteenth and early twentieth centuries, revealed that botulism is caused by exotoxins. Further biochemical work around and after the Second World War gave insight into the molecular structure of seven different serotypes of botulinum toxin (BT/A-G) as well as into its acetylcholine blocking mode of action. In 1977, Scott treated patients with strabism by injecting minute amounts of purified BT/A. In short sequence, BT proved effective in blepharospasm, cervical dystonia, and various off-label indications. In the near future, registration of these new indications, marketing of new serotypes (BT/B), and availability of more practical antibody tests can be expected. The first applications of BT were performed by Roggenkaemper, Dressler, and Benecke in Germany and by Poewe and Auff in Austria. According to a worldwide trend, a rapid expansion regarding BT users and indications followed. Formation of BT competence centers in both countries aims at maintaining high standards in BT research and education.

Austria↗
PubMed1986

Effect of 3,4-diaminopyridine on the survival of mice injected with botulinum neurotoxin type A, B, E, or F.

To determine the efficacy of 3,4-diaminopyridine (3,4-DAP) as a potential treatment for botulism, its effect on the survival times of mice injected with type A, B, E, or F botulinum toxin (Bo Tx) was examined. Mice were injected ip with 10, 20, or 40 LD50 of Bo Tx. Three hours later, when the mice displayed signs of botulism, half of each group of mice was treated with 3,4-DAP, an agent which increases nerve-evoked transmitter release. At each dose of type A Bo Tx tested, 3,4-DAP definitely prolonged survival. In contrast, treatment with the drug did not significantly increase the survival time of mice injected with type B, E, or F Bo Tx. The differences in efficacy of 3,4-DAP against the four serotypes of Bo Tx together with previously reported variations in specific toxicity and duration of paralysis may reflect differences in the pharmacological activity of these neurotoxins.

4-Aminopyridine↗
PubMed2004

Isolation and characterization of a neutralizing antibody specific to internalization domain of Clostridium botulinum neurotoxin type B.

Botulinum neurotoxins (BoNTs), the causative agents for life-threatening human disease botulism, have been recognized as biological warfare agents. In this study, a neutralizing mouse monoclonal antibody against botulinum neurotoxin serotype B (BoNT/B), named BTBH-N1, was developed from mice immunized with BoNT/B toxoid without non-toxic components, which are generally associated with the toxin. Western blot analysis, using recombinant toxin fragments containing light (L), N-terminal half of heavy (HN) and C-terminal half of heavy chains, indicated that BTBH-N1 recognizes linear epitopes located on the HN domain. An in vivo neutralization assay with mice, was conducted to characterize the neutralization capacity of the BTBH-N1. Only 10 microg of BTBH-N1 completely neutralized 20 units (1 unit = one 50% lethal dose) of BoNT/B. Even though the Mab (up to 100 microg) failed to protect mice challenged with 100 units, it significantly prolonged the time to death in a dose dependent manner. BTBH-N1, the first neutralizing antibody against BoNT/B, could be further developed as effective biological therapeutics for preventing and treating botulism, as well as other diseases caused by BoNT/B.

Animals↗
PubMed1982

Clostridium botulinum type C in the Mersey estuary.

Nineteen of 98 samples of mud or sand taken from the Mersey estuary in 1981 contained Clostridium botulinum type C, the organism almost always responsible for botulism in water birds. In the Dungeon and Score Bank areas, where many dead and dying birds were found during the period September-December 1979, almost half the samples contained type C. Most of the positive samples were essentially muddy rather than sandy. The findings do not prove that botulism contributed to the 1979 mortality but are nonetheless thought-provoking, particularly because type C--unlike type B--is by no means ubiquitous in Britain. Type B was present in 12.2% of samples from the Mersey estuary.

Animals↗
PubMed1987

A food-poisoning incident caused by Clostridium botulinum toxin A in Japan.

Food poisoning caused by Clostridium botulinum toxin A occurred in Japan. Eleven (31%) of 36 patients from 14 different areas died of botulism. Most of the patients had eaten commercial fried lotus-rhizome solid mustard without heating. The food, which implicated one of the special local products used for gifts in Kumamoto, was found to have been produced by a manufacturer in Kumamoto prefecture. In Fukuoka prefecture, two of three patients died on days 4 and 8 after eating the food; they had typical symptoms of botulism. A total of 42 packages of the food bought as gifts was collected from different districts in Fukuoka prefecture for examination for both organism and toxin. Thirteen of these (31%) were contaminated with the organism, and in 11 (26%) a small amount of toxin A had been produced.

Botulinum Toxins↗