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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. Results The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks ( P P P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. Conclusions The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period.

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. The patients' discharge diagnoses were identified, categorized, and compared with previously reported clinical mimics categories for 32 patients (1992-2005). Results From 2005 to 2015, 76 clinical mimic illnesses were identified. These illnesses were distributed into the 5 categories previously reported of (1) probable infant botulism lacking confirmatory testing (26.3%); (2) spinal muscular atrophy (19.7%); (3) miscellaneous (15.8%); (4) metabolic disorders (11.8%); and (5) other infectious diseases (10.6%). Of the 76 clinical mimic illnesses, 15.8% had no alternate diagnosis established and were therefore categorized as undetermined. Conclusions Over the 23 years 1992-2015, patients presenting with illnesses so clinically similar to infant botulism that they were treated with BIG-IV had actual diagnoses that were distributed into 5 main categories. These categories and their individual components constitute a working bedside differential diagnosis of infant botulism.

New therapeutic strategies, including immune globulin intravenous, have emerged in the past two decades for the management of botulism. However, impact on outcomes and hospitalization charges among infants (aged ≤1 year) with botulism in the United States is unknown.We analyzed the Kids' Inpatient Database (KID) and National Inpatient Sample (NIS) for in-hospital outcomes and charges for infant botulism cases from 1997 to 2009. Demographics, discharge status, mortality, length of stay, and hospitalization charges were reported from the two databases and compared.Between 1997 and 2009, 504 infant hospitalizations were captured in KID', and 340 hospitalizations from NIS, for comparable years. A significant decrease was observed in mean length of stay for 'KID (P 0.01); a similar decrease was observed for the NIS. The majority of patients were discharged to home. Despite an initial decrease after 1997, an increasing trend was observed for 'KID/NIS mean hospital charges from 2000 to 2009 (from $57,659/$56,309 to $143,171/$106,378; P 0.001/P 0.001). A linear increasing trend was evident when examining mean daily hospitalization charges for both databases. In conducting a subgroup analysis of the 'KID database, the youngest patients with infantile botulism (≤1.9 months) displayed the highest average number of procedures during their hospitalization (P .001) and the highest rate of mechanical ventilation (P .001), compared with their older counterparts.Infant botulism cases have demonstrated a significant increase in hospitalization charges over the years despite reduced length of stay. Additionally, there were significantly higher daily adjusted hospital charges and an increased rate of routine discharges for immune globulin intravenous-treated patients. More controlled studies are needed to define the criteria for cost-effective use of intravenous immune globulin in the population with infant botulism.

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.Cases were defined by laboratory identification of BoNT and/or neurotoxigenic Clostridium species in patients' feces. Parents were interviewed using a structured questionnaire. Descriptive epidemiologic characteristics were compared between 1976-1996 and 1997-2016.From 1976-2016, 1345 cases of infant botulism occurred in 45 of 58 California counties (6.5 cases/100 000 live-births/year) caused by BoNT types A, B, Ba, Bf, and F; 88% of cases were ≤6 months of age and 51% were female. Cases were white (84.2%), Asian (8.9%), other races (3.8%), and African American (2.8%); 29.4% of cases were Hispanic. More than 99% of cases were hospitalized. Case occurrence peaked in summer-fall. Of 8 designated geographic regions, the Central Coast counties had 3 times the statewide incidence in both 20-year time periods. Breast-fed patients (83%) were more than twice as old at onset as formula-fed patients (median, 4.4 vs 1.7 months, respectively; P .001). BoNT/A cases were older at onset than BoNT/B cases (median, 3.8 vs 2.9 months, respectively; P .001).Comprehensive continuous surveillance of infant botulism for 40 years in a large, diversely populated state identified fundamental epidemiologic characteristics of this uncommon illness. Unusual features included greater than 99% case hospitalization, absence of male preponderance, and a distinctive age distribution.

Botulism is a rare neuromuscular condition, and multiple clinical forms are recognized. Infant botulism was first identified in the 1970s, and it typically occurs in infants younger than 1 year of age who ingest Clostridium botulinum spores. A specific treatment for infant botulism, intravenous botulism immunoglobulin (BIG-IV or BabyBIG®), was developed in 2003, and this treatment has substantially decreased both morbidity and hospital costs associated with this illness. This article will review the pathogenesis of infant botulism as well as the epidemiology, clinical manifestations, diagnosis, and treatment of this condition.

Infant botulism is a rare neuroparalytic disease caused by the neurotoxin of Clostridium botulinum. Initial clinical features are constipation, poor feeding, descending hypotonia, drooling, irritability, weak crying and cranial nerve dysfunctions. We describe the clinical progression and the epidemiological investigation carried out in a 3-month-old infant. Better knowledge of the disease should allow faster diagnosis and adequate management. We emphasize the risks associated with honey exposure in children less than one year old and that honey should not be fed to infants under 12 months of age.

Background Infant botulism (IB) is caused by the intestinal colonization by Clostridium botulinum in the first year of life and its subsequent production of neurotoxins. Traditionally, IB has been associated to honey consumption. IB cases tend to cluster in geographic regions. In Europe, IB is a rare disorder. From 1976 through 2006, 65 cases were identified in 13 European countries. In Spain, in the last 15 years, most of the cases have been reported in one region, Andalusia (Southern Spain). A specific treatment for IB type A and type B (BabyBIG) is available outside of the United States since 2005. Methods and aims: We performed a retrospective review of IB cases detected in Andalusia since 1997 and compare them with the cases of IB reported in Europe. Results We identified 11 confirmed cases of IB in Andalusia since 1997, and 14 cases in Spain. Nine out of 11 cases were detected since 2007; none of these infants had been exposed to honey consumption. One case in 1997 and another in 2000 were associated to honey. Two cases were treated with BabyBIG in 2007. In the period 2006–2012 the cases of IB reported in Europe were 54. Conclusions We identified a considerable increase in the incidence of IB since 2006. A tendency to a reduction in the number of cases of IB linked to honey consumption has also been identified. An increase in the exposure to these bacteria from the environment could be presumed. Clinicians should maintain a high index of suspicion for this treatable disorder.

Infant botulism is a serious and life threatening disease and is the commonest form of botulism. Whilst it is rare outside the USA sporadic cases continue to be reported from other parts of the world. It is important to have a high index of suspicion for accurate and early diagnosis as the clinical manifestations are varied. Treatment with botulinum immunoglobulin may modify the outcome of this condition with more rapid recovery from respiratory paralysis and overall decreased intensive care stay.

A 7-week-old boy with flaccid paralysis was diagnosed with infant botulism caused by Clostridium botulinum toxin type A. In this case of infant botulism, untreated well-water was identified as a potential source of this infection.

Infant botulism is caused by the ingestion of spores of Clostridium botulinum and affects newborns and infants under 12 months of age. Ingested spores multiply and produce botulinum toxin in the digestive tract, which then induces clinical symptoms. A single French case was described in the literature prior to 1991. We describe the cases of infant botulism identified in France between 1991 and 2009. All clinical suspicions of botulism must be declared in France. Biological confirmation of the disease is provided by the National reference laboratory for anaerobic bacteria and botulism at the Pasteur Institute. During this period, 7 cases of infant botulism were identified, 1 per year from 2004 to 2008 and 2 in 2009. The median age of affected infants was 119 days and all were female. All infants presented with constipation and oculomotor symptoms. All were hospitalized and required mechanical ventilation. The infants recovered from their botulism. The diagnosis of infant botulism was biologically confirmed for all patients. One 4-month-old infant was treated with a single dose of the human-derived botulism antitoxin specific for infant botulism types A and B (BabyBIG®). The infants all had different feeding habits ranging from exclusive breast feeding to a mix of formula feeding and solid food consumption. The consumption of honey, the only documented risk food for this disease, was reported for 3 of the infants. The honey had been placed on the pacifier of 2 infants and directly in the mouth of the 3rd by the mother. Infant botulism, a form of botulism that was previously rarely recognized in France, has been reported more frequently during the last 6 years. This disease remains rare but nonetheless severe. In light of recent epidemiological data, efforts to raise awareness among parents of infants and health professionals on the danger of infant botulism and particularly, its association with honey consumption seems necessary.

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. Results Five of 30 (17%) PIF samples ingested by patients contained clostridial spores. Spores were also found in 7 of 9 (78%) market-purchased PIF samples. Clostridium sporogenes was isolated most frequently, followed by Clostridium butyricum and at least 10 other soil-dwelling clostridial species. No neurotoxigenic clostridia were isolated. The most probable number of clostridial spores in PIF ranged between 1.1 to >23 per 100 g. Conclusions With the notable exception of production of botulinum neurotoxin, C sporogenes is physiologically comparable with proteolytic strains of C botulinum, and both share the same natural reservoir (soils and dust worldwide). The isolation of C sporogenes and potentially pathogenic clostridia from U.S.-manufactured PIF suggests that neurotoxigenic clostridial spores have the potential to be present in these products.

Three infants presenting with severe cases of infantile botulism, occurring at 17, 30, and 180 days of life, respectively, are described in this report. All three infants presented with areflexive flaccid coma or apnoeas requiring prolonged ventilation. In serum, type B botulinum neurotoxin (BoNT/B) was detected in two cases and BoNT/A in the third case, confirming the diagnosis of infantile botulism. Despite constant nursing and monitoring, the recovery of motility was progressive, but finally complete. Dysautonomia, measured by recording heart rate variability (HRV), persisted beyond observable physical recovery. Dysautonomia was assessed using a time-domain analysis of the continuous electrocardiogram response (via non-invasive weekly 24 h Holters), which included sympathetic (SDNN) and parasympathetic indices (RMS-SD, pNN50). In all three of our patients, we observed an initial hypotonic period and a major decrease in all HRV indices. Despite observable recovery shortly after extubation, HRV time domain indices remained altered for many weeks. Because of the close monitoring afforded by hospitalization, this change in autonomic function was not accompanied by syncope, complications arising from ventricular arrhythmia, or sudden death. Our observations have important clinical implications since they emphasize the importance of pursuing cardiopulmonary monitoring following apparent functional recovery from the BoNTs.

Nowadays, infant botulism is the most important form of human botulism in some countries. This illness affects infants younger than 52 weeks of age. The infection occurs in the intestinal tract; therefore, ingestion of Clostridium botulinum spores with food is proposed. In some countries, people use chamomile tea as a household remedy for intestinal colics and given this tea to infants. Chamomile can be contaminated with C. botulinum and could be a vehicle of its spores. Our aim was to study the prevalence and spore-load of C. botulinum in chamomile. We analysed 200 samples; the 7.5% of them were contaminated with botulinum spores. However, prevalence of these spores was significantly higher in chamomile sold by weight in herbal stores (unwrapped chamomile) than prevalence in chamomile sold in tea bags ( p = 0.0055). The spore-load detected in all positive samples was 0.3–0.4 spores per gram of chamomile. We identified C. botulinum types A, B, and F in the 53.3%, 6.7%, and 13.3%, respectively. Chamomile (principally, unwrapped chamomile) is a potencial vehicle of C. botulinum spores, and ingestion of chamomile tea could represent a risk for infant botulism.

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.

Although botulism is usually an acute, often lethal disease that is caused by the ingestion of botulinum neurotoxin, there are also recognized forms like infant botulism, wound botulism, or "botulism of undefined origin" that are characterized by the fact that Clostridium botulinum colonizes the host and produces its toxin in the host. Evidence is presented here that a disease in cattle and in human care takers of diseased animals that has evolved over the past two decades, may be a chronic, visceral form of C. botulinum infection.

The botulinum neurotoxins are produced by anaerobic, spore-forming bacteria belonging to the Clostridium genus. They are synthesised as a single chain protein (150 kDa), which is not or weakly active. The active form results from a proteolysis cleaving the precursor in a light chain (about 50 kDa) and a heavy chain (about 100 kDa), which are linked by a disulfide bridge. The heavy chain is involved in the recognition of a specific neuronal surface receptor and mediates the internalization of the light chain into the cytosol. The light chain is responsible for the intracellular activity. It catalyses the proteolysis of SNARE proteins, which are involved in the exocytosis of synaptic vesicles containing acetylcholine. Hence, the release of acetylcholine at the neuromuscular junction is blocked, leading to a flaccid paralysis. Human botulism, usually type A, B or E, is associated with intoxination, ingestion of preformed toxin in food, with digestive toxi-infection, mainly in newborns (infant botulism), or with wound contamination (wound botulism). The treatment of botulism is usually symptomatic. The specific treatment is based on the serotherapy or on the use of purified specific antibodies. The vaccination against botulism is efficient. However, since the botulinum neurotoxins are widely used for the treatment of numerous dystonias, a generalised vaccination is not conceivable.

Although food botulism (FB) in Argentina was described by 1911, the first documented outbreak was recorded in 1922. In 1957, an outbreak of type A FB caused by red bell peppers was the first laboratory confirmation of botulism in Argentina. From 1922 to 1997, 70 FB outbreaks affecting 242 persons with 111 deaths (case fatality rate, 46%) were reported in Argentina. Infant botulism (IB) was recognized in 1976 and has been mostly diagnosed in the U.S.A. More than 146 IB cases have been reported in Argentina since 1982. Additional cases may go undiagnosed due to physician inexperience and limited access to diagnostic services. A single laboratory-confirmed case of wound botulism (WB) occurred in Argentina in 1995. The botulinal neurotoxins (BoNTs) identified in Argentina have been types A, B, E, F and Af in FB, and exclusively type A in IB and WB. For the laboratory diagnosis of botulism, serum, gastrointestinal sample, food, and wounds should be tested for BoNT. Gastrointestinal, wound and food sample must also be cultured for toxigenic organisms. When higher volumes of serum were tested, BoNT was found in 61% of IB patients in Mendoza compared with 13% in a previous series from the U.S.A. Reliable typing can only be achieved when the BoNT belongs to a known serotype and the toxin titer is above 4000 LD 50 /mL. When these criteria are not met, as in most clinical samples, bacterial isolation, purification and adequate toxin production in culture are required. Neutralization testing must be performed at not less than three 10-fold doses of toxin because of (1) the existence of subtypes, where a second, minor serotype is present, (2) the sharing of epitopes between certain serotypes, and (3) the occurrence of serological variants. Three basic properties of working antitoxins, specificity, protency and avidity, must be known for BoNT typing. The efficiency index (EI), which expresses the avidity of antitoxins, is an important instrument for recognizing BoNT subtypes.

We report on a 3-month-old girl with culture-confirmed infant botulism caused by a rare double toxin-producing Clostridium botulinum type Ba. This case was not related to honey-feeding. The clinical course was prolonged, with minimal spontaneous improvement at onset, and a period of fluctuating motor weakness and nasogastric feeding dependence afterward. Neurophysiologic studies produced normal results. Human botulism immune globulin was administered empirically on day 23 of presentation, with rapid full recovery. This case highlights the importance of pursuing diagnoses of infant botulism despite normal results of neurophysiologic testing and no history of honey-feeding. Our case also demonstrates a favorable response to human botulism immune globulin, despite the relatively late treatment.

A total of 48 honey samples were analysed for Clostridium botulinum spores. Samples were prepared by direct addition (DA), dilution centrifugation (DC) and supernatant filtration (SF) methods and cultured in cooked meat medium (CMM) and trypticase peptone glucose yeast (TPGY) enrichment broths were used for the isolation of C. botulinum spores. The DC method was found most efficient while CMM enrichment broth was more successful than TPGY. Six of analysed 48 honey samples were C. botulinum positive (12.5%). Results indicated that honey sold in retail markets of Ankara found to be significantly (12.5%) contaminated with C. botulinum.

There is convincing evidence that breast-feeding is protective against gastro-enteritis and diarrhoea, but for other infections the situation is less clear cut. There is evidence that breast-fed infants are at increased risk of one infection (infant botulism). They are probably not significantly protected from upper respiratory tract infections (other than otitis media.), but they may be at a decreased risk of lower respiratory tract infections, particularly those associated with respiratory syncytial virus. There is strong evidence that Haemophilus influenzae B infection is more likely in the bottle-fed infant, and consistent evidence of protection of young children from chronic otitis media with prolonged breast-feeding.

Summary Degenerate oligonucleotide primers, designed to conserved regions of the heavy chain of the botulinum neurotoxin (BoNT), were used to amplify a fragment of approximately 1.1 kb from twenty-five type A Clostridium botulinum strains. These strains were isolated from different geographical locations, from both infant and food-borne botulism. Restriction fragment length polymorphism (RFLP) analysis of the PCR products with Rsa I and Sau3 Al revaled two different groups of BoNT/A genes, designated BoNT/A1 and BoNT/A2. These two groups did not correlate with the origin of the strains, each group containing isolates from infant and food-borne botulism. Organisms isolated from infant botulism in Japan fell into group A2 while all strains examined from the USA, from both infant and food-borne botulism, fell into group A1. Strains from other locations were as follows: food-borne isolates from the UK (groups A1 and A2), Mauritius (group A1) and Venezuela (group A1). In addition, strains encoding BoNT/A1 gave PCR products with primers designated to detect hemagglutinin genes, the products of which form part of the large progenitor toxin complex produced by some strains of C. botulinum , but strains encoding BoNT/A2 gave no such products. In addition, RFLP analysis and probing studies revealed S of the 25 type A strains examined contained unexpressed type B gene sequences.

Ninety samples of honey produced in eastern France, and 26 samples of honey originating from various countries, were analyzed for the presence of Clostridium botulinum spores. Although eight samples were found positive when using the mouse toxicity test, none of the strains isolated from the positive samples were identified as C. botulinum. This result is consistent with the hitherto rare occurrence of cases of infant botulism reported in France.

The neurotoxin gene from a strain of Clostridium botulinum type A causing infant botulism was cloned as a series of overlapping polymerase chain reaction (PCR) fragments generated using primers designed to conserved regions of published botulinal toxin (BoNT) sequences. Translation of the nucleotide sequence derived from cloned PCR fragments demonstrated that the toxin gene encodes a protein of 1,296 amino acid residues. Comparative alignment of the derived infant BoNT/A sequence with those of other published neurotoxins revealed highest sequence relatedness with BoNT/A of classical food-borne botulism. The sequence identity between infant and classical BoNT/A was 94.9% for the light chain (corresponding to 23 amino acid changes) and 87.1% for the heavy chain (corresponding to 109 amino acid changes).

Little has been written about infant botulism in the emergency medicine literature, despite increasing references in the pediatric journals. We describe three cases diagnosed at The Children's Hospital in Denver, Colorado, over an 8-month period. A review of the literature follows, to discuss the clinical manifestations, differential diagnosis, diagnostic workup and treatment of the disease.

Recently, it has been shown that two Clostridium butyricum strains (ATCC 43181 and ATCC 43755), isolated from cases of infant botulism, produce a botulinal neurotoxin type E ( BoNT E ). Here we have determined the nucleotide sequences of the BoNT E genes of these two C. butyricum strains and from C. botulinum E strain Beluga. We show that the sequences of the BoNT E genes from the two C. butyricum strains are identical and differ in only 64 positions resulting in 39 amino acid changes (97% identity at the amino acid level) from that derived from C. botulinum. Our data suggest a transfer of the BoNT E gene from C. botulinum to the originally nontoxigenic C. butyricum strains.

The first cases of infant botulism in Argentina were described in 1982. From 1982 to 1997, 146 cases of infant botulism were diagnosed by the identification of botulinal toxin and Clostridium botulinum in feces. The cases were between 2 and 48 weeks of age: 90% were between 5 and 24 weeks old, and 49% were between 5 and 12 weeks old. Of 93 (64%) patients whose sex was reported, 55 (59%) were male and 38 (41%) were female. By season in which illness occurred, 43 (29%) occurred in winter, 43 (29%) in spring, 36 (25%) in summer and 22 (15%) in autumn. The majority of patients lived in suburban or rural areas. All strains isolated belonged to C. botulinum type A, consistent with the predominance of this type in the soils of Argentina.

Summary Whether spore-forming or non-spore forming, some anaerobes are important pathogens to consider by reason of their presence in the environment and in the human natural cavities. We will discuss new data in clostridia which are characterized by their ubiquity, their ability to survive as spores under adverse conditions and their capacity to produce potent toxins. New toxins have been recently described, i.e. an hemolysin in C. septicm and a larvicidal toxin, of potential interest as an anti-vectorial agent, in C. bifermentans . A C. butyricum strain and a C. barati strain producing botulinal toxins of type E and F, respectively have been isolated in infant botulism; also a C. botulinum strain producing two toxins, A and B has been isolated in a botulism outbreak. Taken together, these observations raise the question of the genetic determinism underlying the occurrence of toxins amongst previously non toxinogenic clostridial species. Infant botulism is an old disease, but a recently described clinical entity. The precise mechanisms underlying this toxi-infection are actually unknown, and probable involve a temporary immunity deficiency in some newbornsk. In C. difficile , several points have been partially solved. There is now a consensus concerning the existence of two toxins of high molecular weight, A and B that cross react against the present available antisera and thus should share common epitopes. Cloning studies suggest that gene(s) coding for both toxins should be very close, if not identical. Both toxins apparently have a similar mode of action (cytotoxic activity), the toxin A having in addition an enterotoxin action. The receptors for each toxin should be different, and should also differ in man and animal. Several questions are presently still unsolved, particularly; (i) the question in C. difficile of additional virulence determinants; (ii) the lack of virulence of C. difficile in newborns: the lack of specific toxin(s) receptors in the newborn has been suggested, but has yet to be confirmed; ( iii ) the role of antibiotic administration in the onset of the disease: if, in some cases, the administered antibiotic may directly select a C. difficile strain resistant to this antibiotic, in other cases, the antibiotic would exert an indirect action by inhibiting bacterial flora involved in resistance to colonization by C. difficile . The role of Clostridia , and particularly of C. butyricum in neonatal enterocolitis (NNE) is presently a matter of controversy. Epidemiological and experimental evidence have raised the question of the potential role of C. butyricum in NNE, but this species was also found in control infants and no specific toxicity determinant of C. butyricum has been shown in experiments with mice or culture cells, except a thermostable factor of low molecular weight identified as butyric acid. An experimental axenic chicken/quail model was then developed. Whether it is possible to extrapolate the chicken/quail model to human is a mute point. Virulence factors of non-spore forming anaerobes are discussed in most of the communications of the present symposium, and they are dealing with adherence, tissu damaging products, and host-protective properties. We wish just to emphasize the recent characterization of enterotoxigenic Bacteroides fragilis strains causing severe diarrhea in man and livestock, and experimentally capable of producing an enteric disease in infant rabbits. Transferable antibiotic resistance in anaerobes, either in Clostridium or in Bacteroides , are now well documented and such resistances may be considered as virulence cofactors. The genetic determinants of the antibiotic resistances are chromosomally-determined, plasmid-borne or localized on transposons. A relatively great variety of mechanisms of horizontal transfer of these genetic determinants have been identified in those anaerobes: self-mobilizing plasmids in C. perfringens and Bacteroides , conjugal Tc R and Tc R Cc R elements, conjugative transposon-like elements, and a conjugal mobilizing transposon in Bacteroides . In other groups, i.e. C. difficile and C. innocuum chromosomally-determined antibiotic resistance are transferable through a mechanism presently uncharacterized. Recent epidemiological data suggest the spreading of antibiotic resistance in other groups, i.e. the anaerobic cocci.

Four strains of Clostridium botulinum type A having been associated with infant botulism in Japan, and another strain isolated from honey not associated with infant botulism, were found to be hemagglutinin (HA) negative. These strains do not produce L (Mr 500 kDa) nor LL toxin (Mr 900 kDa) but M toxin (Mr 300 kDa) only. No marked difference was found between the HA-positive and HA-negative strains in other biochemical properties, but the HA-negative strains tended to colonize more easily in the intestines of infant mice than did HA-positive strains. The toxin of HA-positive strains and that of HA-negative strains differed in the antigenicity of part of the toxic component and that of the nontoxic component, and in the molecular size of the toxic component.

The clinician is often asked to evaluate the floppy infant. Numerous conditions that cause hypotonia in infancy are briefly outlined in this article. These conditions may affect the brain, spinal cord, or motor unit. Several disorders of neuromuscular transmission, including four distinct and recently described congenital myasthenic syndromes and infant botulism, are discussed thereafter.

A clinical case of infant botulism was detected in Portugal. This rare occurrence was detected in a child provided from an immigrant family from Eastern Europe. Apart from breast milk, the parents also gave him honey and chamomile tea. Clostridium botulinum type B was identified after bacterial isolation in child faeces, honey and chamomile herbs samples. The Botulism neurotoxin (BoNT) B was detected in the faeces according to CDC Atlanta specific procedures.

Infant botulism is the intestinal (infectious) toxemia in which swallowed spores of Clostridium botulinum activate in the lumen of the colon and thereby produce botulinum toxin, which after absorption causes flaccid paralysis. Human Botulism Immune Globulin (BIG-IV) neutralizes botulinum toxin types A and B. The US FDA licensed BIG-IV to the California Department of Public Health, its creator and developer, as the public service orphan drug BabyBIG ® in October 2003 (N. Engl. J. Med. 2006;354:462–471). International distribution began on a trial basis in July 2005. This report summarizes the 2003–2007 distribution, efficacy and safety data for BIG-IV. In the US, a total of 333 eventually laboratory-confirmed patients residing in 35 states were treated within 1 week of hospital admission: 142 type A, 188 type B, 2 type Ba and 1 type Bf. Mean length of hospital stay was 2.2±1.5 vs. 5.7±5.1 wks for untreated patients in the 1992–97 BIG-IV randomized clinical trial ( P ® ), its use globally to treat infant botulism patients has demonstrated its continued safety, efficacy and US cost-effectiveness.

Infant botulism occurs in infants between 1 week and 11 months of age and results from the in vivo production of neurotoxin by Clostridium botulinum . The clinical spectrum ranges from asymptomatic carriers, through various degrees of paralysis, to sudden death. The classic clinical presentation is an afebrile child with constipation and generalized weakness manifested by poor head control, poor suck, and weak cry. Symptoms can progress to include cranial nerve palsies, respiratory arrest, and adynamic lleus. Treatment is supportive in an intensive care setting. Antibiotics and antitoxin are not indicated. The morbidity and mortality is less than 3% in hospitalized patients and complete recovery can be expected. The environmental and dietary factors associated with infection are discussed.

The syndrome of infant botulism, characterized by constipation, poor feeding, hypotonia, poor head control, and bulbar involvement, is typically a monophasic disease. We describe a 7-month-old infant with a recurrence of illness 13 days after resolution of the presenting signs. The source of infection was unknown and the only potential risk factors were exclusive breastfeeding and decreased bowel movements, which by themselves cannot explain the recurrence. Although treatment with botulism immunoglobulin is now suggested for the acute phase of infantile botulism, its use for recurrence is controversial.

Clostridium botulinum type B has recently been isolated from food-borne and infant botulism cases. The BoNT/B in these cases was divided into two main subtypes, B1 and B2, based on analysis of the amino acid sequences. The genetic properties of the C. botulinum type B strains in relation to infant botulism in Japan (strains 111, Osaka05 and Osaka06) were analyzed by sequencing of the bont/B and nontoxic component genes (ha70, ha17, ha33, p21 and ntnh), PFGE genotyping and southern blot hybridization with bont/B probe. Strain Osaka05 produced particular BoNT/B, which were grouped to a novel variant on phylogenetic analysis. The substitutions of amino acid residues were concentrated in the heavy chain, especially in the HCC subdomain. Strains 111 and Osaka06 were classified as subtype B2. The nontoxic component gene arrangements within these subtypes were identical to each other. Multiplex PCR method for BoNT/B subtyping (B1, B2 and Osaka05) was newly established based on bont/B nucleotide sequences variability. Three isolates from infant botulism in Japan were identified as different genotypes based on Sma I-digested PFGE. The BoNT/B encoding gene was shown to be located on large plasmids (approximately 150 or 260–280 kbp) for various subtype strains including isolates from infant botulism in Japan using Southern blot hybridization after nondigested PFGE with bont/B probe.

The spontaneous production of botulinum toxin in the infant gut by ingested Clostridium botulinum organisms is the underlying cause of infant botulism, recognised as an infectious disease only in late 1976. Because of the recognition of the pathophysiology of this disease and because the known potency and action of botulinum toxin can lead to rapid respiratory arrest, it appeared possible that the in-vivo production of botulinum toxin could cause the sudden death of some infants. To test this hypothesis, serum, selected tissues, and bowel contents from 280 dead infants were examined for the presence of C. botulinum toxin and/or organsisms. We found C. botulinum organisms in 10 infants, all of whom died suddenly and unexpectedly. 9 of these deaths were classified by the forensic pathologist as sudden infant death syndrome (S.I.D.S. or crib death). In 2 of these 10 sudden deaths both C. botulinum organisms and botulinum toxin were identified, and from the spleen of 1, C. botulinum organisms were isolated. Faecal specimens from 160 age-matched healthy infants who served as controls in studies of inpatient infant botulism cases were negative for both C. botulinum organisms and toxin, except for one specimen that contained only C. botulinum type A organisms. The 9 S.I.D.S. cases with evidence of C. botulinum infection comprised 4.3% of the 211 S.I.D.S. cases examined over 12 months. These findings suggest that intestinal production of botulinum toxin by C. botulinum is one cause of S.I.D.S. The strikingly similar age-distribution of 62 inpatient infant botulism cases and the 211 S.I.D.S. cases is also consistent with this concept. The possibility that in-vivo production of botulinum toxin may account for a larger proportion of S.I.D.S. cases is discussed.

We examined the possibility that human milk and formula milk might differentially affect the severity of the infant botulism because they differ in immunologic composition and in influence on the normal intestinal microflora against which Clostridium botulinum must compete. A beneficial effect of human milk was suggested by the different feeding experiences of the moderate, hospitalized patients and the sudden death cases. Of patients hospitalized in California, 66% (33/50) were still being nursed at onset of illness, a percentage significantly greater than that of matched controls (P less than 0.01). In contrast, all ten California cases of sudden infant death attributable to C. botulinum infection were being fed iron-supplemented formula milk at death) unlike their controls, P less than 0.02) and had received no human milk within ten weeks of death. A beneficial effect of human milk was also observed in differences in mean age at onset; hospitalized breast-fed patients were almost twice as old (13.8 +/- 6.7 weeks) as were hospitalized formula-fed patients (7.6 +/- 2.9 weeks) (P less than 0.01). Human milk (or possibly other factors associated with breast-feeding) appeared to have moderated the severity at onset of infant botulism, allowing time for hospital admission, whereas for some infants with this illness, formula milk (or possibly other factors associated with formula feeding) was linked to sudden unexpected death.

A total of 150 honey, 43 syrup and 40 dry cereal samples were analyzed for Clostridium botulinum spores, each in triplicate quantities of 25 g. The foods were sampled randomly, except for two lots of honey which were potentially associated with illness. Botulinal spores were detected in a sample of honey associated with infant botulism and in a single sample of rice cereal.

Clostridium botulinum and its toxin were identified in the faeces of four infants, aged 6 to 13 weeks, who had symptoms consistent with botulism. Two cases had type-A toxin and two cases had type-B toxin present in their faeces. No toxin was detectable in sera. C. botulinum and toxin could be recovered from faeces more than 8 weeks after admission to hospital. All four cases occurred within a 6-month period. The source of the toxin in these infants may have been in-vivo production from ingested organisms.