Dual-Toxin ("Bivalent") Infant Botulism in California, 1976-2020: Epidemiologic, Clinical, and Laboratory Aspects.

Objective: To assess the consequences of infant botulism that result from Clostridium botulinum strains that produce 2 botulinum toxin serotypes, termed "bivalent."

Study Design: Epidemiologic investigations used a standard questionnaire. Clostridium botulinum strains were isolated by standard methods.

Closed Genome Sequence of Clostridium botulinum Strain IBCA10-7060 Type Bh.

Clostridium botulinum strain IBCA10-7060 was isolated from a stool specimen from an infant botulism patient and is the only Clostridium botulinum strain known that produces botulinum toxin type H. We present here its 4.09-Mbp closed genome sequence.

Descriptive Epidemiology of Infant Botulism in California: The First 40 Years.

Objective: To ascertain the descriptive epidemiology of infant botulism, the flaccid paralysis that results when neurotoxigenic Clostridium species produce botulinum toxin (BoNT) in the infant colon, in its first 40 years following initial recognition in California in 1976.

Study Design: Cases were defined by laboratory identification of BoNT and/or neurotoxigenic Clostridium species in patients' feces. Parents were interviewed using a structured questionnaire.

Seven-Year Case-Control Study in California of Risk Factors for Infant Botulism.

Objective: To ascertain possible risk factors for infant botulism, the intestinal infectious form of human botulism, in the years immediately following its initial recognition in California in 1976.

Study Design: Parents of 159 California laboratory-confirmed cases of infant botulism from 1976 to 1983 and 318 healthy controls were interviewed using a comprehensive (>300 factors) questionnaire. "Neighborhood controls" (n = 184) were matched on date of birth, sex, race/ethnicity, and neighborhood of residence.

The Novel Clostridial Neurotoxin Produced by Strain IBCA10-7060 Is Immunologically Equivalent to BoNT/HA.

Background: Botulinum neurotoxins (BoNTs) comprise seven agreed-on serotypes, A through G. In 2014, a novel chimeric neurotoxin produced by clostridial strain IBCA10-7060 was reported as BoNT/H, with subsequent names of BoNT/FA or BoNT/HA based on sequence homology of the N-terminus to BoNT/F, the C-terminus to BoNT/A and neutralization studies. The purpose of this study was to define the immunologic identity of the novel BoNT.

Antimicrobial Susceptibility of 260 Clostridium botulinum Type A, B, Ba, and Bf Strains and a Neurotoxigenic Clostridium baratii Type F Strain Isolated from California Infant Botulism Patients.

Infant botulism is an infectious intestinal toxemia that results from colonization of the infant large bowel by (or rarely, by neurotoxigenic or ), with subsequent intraintestinal production and absorption of botulinum neurotoxin that then produces flaccid paralysis. The disease is often initially misdiagnosed as suspected sepsis or meningitis, diagnoses that require prompt empirical antimicrobial therapy. Antibiotics may also be needed to treat infectious complications of infant botulism, such as pneumonia or urinary tract infection.

Safety and immunogenicity of investigational recombinant botulinum vaccine, rBV A/B, in volunteers with pre-existing botulinum toxoid immunity.

Objectives: We undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®).

Study Design: A single 0.

Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure.

Objectives: To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism.

Study Design: Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges.

More Clinical Mimics of Infant Botulism.

Objective: To ascertain the actual diagnoses of 76 patients (2005-2015) whose clinical presentations so closely resembled infant botulism that the patients were treated with Human Botulism Immune Globulin Intravenous (BIG-IV; BabyBIG), but whose illnesses subsequently were not laboratory confirmed as infant botulism ("clinical mimics" of infant botulism).

Study Design: The California Department of Public Health produces BIG-IV and distributes it nationwide as a public service (ie, not-for-profit) orphan drug to treat patients hospitalized with suspected infant botulism. During the study period, admission records and discharge summaries for all patients treated with BIG-IV but who lacked a laboratory-confirmed diagnosis of infant botulism were collected and abstracted.

Immunological Characterization and Neutralizing Ability of Monoclonal Antibodies Directed Against Botulinum Neurotoxin Type H.

Background: Only Clostridium botulinum strain IBCA10-7060 produces the recently described novel botulinum neurotoxin type H (BoNT/H). BoNT/H (N-terminal two-thirds most homologous to BoNT/F and C-terminal one-third most homologous to BoNT/A) requires antitoxin to toxin ratios ≥1190:1 for neutralization by existing antitoxins. Hence, more potent and safer antitoxins against BoNT/H are needed.

Molecular epidemiology of infant botulism in California and elsewhere, 1976-2010.

Background: Infant botulism (IB), first identified in California in 1976, results from Clostridium botulinum spores that germinate, multiply, and produce botulinum neurotoxin (BoNT) in the immature intestine. From 1976 to 2010 we created an archive of 1090 BoNT-producing isolates consisting of 1012 IB patient (10 outpatient, 985 hospitalized, 17 sudden death), 25 food, 18 dust/soils, and 35 other strains.

Methods: The mouse neutralization assay determined isolate toxin type (56% BoNT/A, 32% BoNT/B).

Arrangement of the Clostridium baratii F7 toxin gene cluster with identification of a σ factor that recognizes the botulinum toxin gene cluster promoters.

Botulinum neurotoxin (BoNT) is the most poisonous substances known and its eight toxin types (A to H) are distinguished by the inability of polyclonal antibodies that neutralize one toxin type to neutralize any of the other seven toxin types. Infant botulism, an intestinal toxemia orphan disease, is the most common form of human botulism in the United States. It results from swallowed spores of Clostridium botulinum (or rarely, neurotoxigenic Clostridium butyricum or Clostridium baratii) that germinate and temporarily colonize the lumen of the large intestine, where, as vegetative cells, they produce botulinum toxin.

A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins.

Background: Clostridium botulinum strain IBCA10-7060, isolated from a patient with infant botulism, produced botulinum neurotoxin type B (BoNT/B) and another BoNT that, by use of the standard mouse bioassay, could not be neutralized by any of the Centers for Disease Control and Prevention-provided monovalent polyclonal botulinum antitoxins raised against BoNT types A-G.

Methods And Results:  The combining of antitoxins to neutralize the toxicity of known bivalent C. botulinum strains Ab, Ba, Af, and Bf also failed to neutralize the second BoNT.

Molecular characterization of a novel botulinum neurotoxin type H gene.

We sequenced the 2 botulinum toxin gene clusters of Clostridium botulinum strain IBCA10-7060 type Bh. The sequence of bont/H differed substantially from the sequences of the 7 known bont genes for toxin types A-G. The 5' one-third terminus of bont/H that codes for the botulinum toxin light chain differed markedly from the light chain coding sequences of toxin types A-G.

Clostridium botulinum strain Af84 contains three neurotoxin gene clusters: bont/A2, bont/F4 and bont/F5.

Sanger and shotgun sequencing of Clostridium botulinum strain Af84 type Af and its botulinum neurotoxin gene (bont) clusters identified the presence of three bont gene clusters rather than the expected two. The three toxin gene clusters consisted of bont subtypes A2, F4 and F5. The bont/A2 and bont/F4 gene clusters were located within the chromosome (the latter in a novel location), while the bont/F5 toxin gene cluster was located within a large 246 kb plasmid.

Analysis of Clostridium botulinum serotype E strains by using multilocus sequence typing, amplified fragment length polymorphism, variable-number tandem-repeat analysis, and botulinum neurotoxin gene sequencing.

A total of 41 Clostridium botulinum serotype E strains from different geographic regions, including Canada, Denmark, Finland, France, Greenland, Japan, and the United States, were compared by multilocus sequence typing (MLST), amplified fragment length polymorphism (AFLP) analysis, variable-number tandem-repeat (VNTR) analysis, and botulinum neurotoxin (bont) E gene sequencing. The strains, representing environmental, food-borne, and infant botulism samples collected from 1932 to 2007, were analyzed to compare serotype E strains from different geographic regions and types of botulism and to determine whether each of the strains contained the transposon-associated recombinase rarA, involved with bont/E insertion. MLST examination using 15 genes clustered the strains into several clades, with most members within a cluster sharing the same BoNT/E subtype (BoNT/E1, E2, E3, or E6).

Universal and specific quantitative detection of botulinum neurotoxin genes.

Background: Clostridium botulinum, an obligate anaerobic spore-forming bacterium, produces seven antigenic variants of botulinum toxin that are distinguished serologically and termed "serotypes". Botulinum toxin blocks the release of acetylcholine at neuromuscular junctions resulting in flaccid paralysis. The potential lethality of the disease warrants a fast and accurate means of diagnosing suspected instances of food contamination or human intoxication.

Presence of soil-dwelling clostridia in commercial powdered infant formulas.

Objective: Because Clostridium botulinum was isolated from powdered infant formula (PIF) fed to an infant in the United Kingdom who subsequently developed infant botulism and from unopened PIF from the same manufacturer, we tested PIF manufactured in the United States for the presence of clostridial spores.

Study Design: Thirty PIF ingested by 19 California infants with botulism within 4 weeks of onset of illness (48% of all patients fed PIF during study) in 2006-2007 were cultured anaerobically to isolate clostridia. All isolated clostridia were identified to the species level and enumerated with standard microbiologic and molecular methods.

Global occurrence of infant botulism, 1976-2006.

Objective: To summarize the worldwide occurrence of reported infant (intestinal toxemia) botulism cases since first recognition of the disease in 1976.

Patients And Methods: We collected information on infant botulism cases by active and passive surveillance, by provision of therapeutic Human Botulism Immune Globulin to suspected cases, and by searching the medical literature. We defined a case as laboratory-confirmed botulism that occurred in an infant View Article and Find Full Text PDF

Attomolar detection of botulinum toxin type A in complex biological matrices.

Background: A highly sensitive, rapid and cost efficient method that can detect active botulinum neurotoxin (BoNT) in complex biological samples such as foods or serum is desired in order to 1) counter the potential bioterrorist threat 2) enhance food safety 3) enable future pharmacokinetic studies in medical applications that utilize BoNTs.

Methodology/principal Findings: Here we describe a botulinum neurotoxin serotype A assay with a large immuno-sorbent surface area (BoNT/A ALISSA) that captures a low number of toxin molecules and measures their intrinsic metalloprotease activity with a fluorogenic substrate. In direct comparison with the "gold standard" mouse bioassay, the ALISSA is four to five orders of magnitudes more sensitive and considerably faster.

Clinical mimics of infant botulism.

Since 1992, Human Botulism Immune Globulin has been provided by the California Department of Health Services to infants with probable infant botulism, the intestinal toxemia form of human botulism. Human Botulism Immune Globulin became available in California in 1992-1997 within a randomized, controlled, double-blinded, pivotal clinical trial and subsequently became available nationwide in 1998-2003 in an open-label study until its licensure in October 2003 as BabyBIG. Thereafter, Human Botulism Immune Globulin remained available nationwide as an approved orphan-drug product.

Creation and development of the public service orphan drug Human Botulism Immune Globulin.

The public service orphan drug Human Botulism Immune Globulin for the treatment of infant botulism would not have come into existence without the federal Orphan Drug Act and the funding mechanism that it provided to conduct pivotal clinical trials. Nonetheless, creating, developing, and achieving licensure of Human Botulism Immune Globulin took approximately 15 years and approximately $10.6 million (2005 dollars) to accomplish.