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Infant botulism is an acute life-threatening condition and diagnosis is frequently delayed. Therefore, the best time window to administer specific antibodies, at present the only etiology-based therapy, is often missed, entailing long periods of hospitalization in the PICU. Here we present a 3-month-old boy with infant botulism and respiratory failure, who quickly and favorably responded to thiamine supplementation. From the feces we isolated Clostridium botulinum serotype A2. In addition to producing botulinum neurotoxin A, this strain carried the thiaminase I gene and produced thiaminase I. Accordingly, the child’s feces were positive for thiaminase I activity. Because C botulinum group I strains are capable of producing thiaminase I, we speculate that thiamine degradation might further aggravate the paralytic symptoms caused by botulinum neurotoxins in infant botulism. Thus, supportive supplementation with thiamine could be beneficial to speed up recovery and to shorten hospitalization in some patients with infant botulism.

Fifty-seven patients with infant botulism were cared for at The Children's Hospital of Philadelphia between 1976 and 1987. The ages of the children ranged from 18 days to slightly more than 7 months. The average duration of hospitalization was 44 +/- 34 days, with the average intensive care unit stay lasting 29 +/- 25 days (54 of 57 patients). The majority (77%) of the patients were ultimately intubated and mechanically ventilated (68%). The principal indication for intubation was loss of protective airway reflexes and not hypercarbia or hypoxemia. In those patients who required mechanical ventilation the average duration was 23 +/- 22 days, with the 10 most severely affected patients (greater than or equal to 28 days of mechanical ventilation) averaging 53 +/- 25 days. Excluding patients ventilated for more than a month, those who underwent tracheostomy were hospitalized nearly twice as long as those who were managed by nasotracheal intubation only (33.5 days vs 63.2 days). The use of continuous nasogastric feedings has supplied most infants with sufficient enteral feedings to avoid weight loss and the need for central intravenous alimentation.

OBJECTIVE. To report a tertiary care hospital's 30-year experience with the diagnosis, treatment, and outcome of infant botulism in the PICU before and after the availability of Botulism Immune Globulin Intravenous.METHODS. This was a retrospective medical chart review of the 67 patients who had received a diagnosis of infant botulism and were admitted to the ICU from 1976 to 2005. The ages on presentation, length of hospital stay, length of ICU stay, length of mechanical ventilation, and type of botulism toxin were recorded and compared for patients who had received Botulism Immune Globulin Intravenous and those who had not. On the basis of our results, conclusions were drawn regarding the effect of Botulism Immune Globulin Intravenous on the morbidity of infant botulism.RESULTS. Sixty-seven patients’ charts were reviewed; 23 male and 29 female patients did not receive Botulism Immune Globulin Intravenous. Of patients who did not receive Botulism Immune Globulin Intravenous, the median age at presentation was 71 days, median length of hospital stay was 35 days, ICU stay was 24 days, and duration of mechanical ventilation was 17 days. A total of 40% had type A toxin, and 60% had type B toxin. There was a significant difference between patients with toxin types A and B in length of hospital stay but not length of ICU stay or mechanical ventilation. Patients with type A toxin were significantly older than patients with type B toxin. Fifteen children received Botulism Immune Globulin Intravenous. There were statistically significant differences in length of hospital stay, length of ICU stay, and length of mechanical ventilation between patients who received Botulism Immune Globulin Intravenous and those who did not.CONCLUSIONS. The use of Botulism Immune Globulin Intravenous significantly decreased the length of ICU stay, length of mechanical ventilation, and overall hospital stay in children with infant botulism.

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. Use of Human Botulism Immune Globulin to treat patients with infant botulism has resulted thus far in more than 30 years of avoided hospital stay and more than $50 million (2005 dollars) of avoided hospital costs. To provide a possible paradigm for others, the circumstances that enabled a state public health department to create, test, license, and distribute an orphan drug are described here.

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. To achieve prompt neutralization of circulating botulinum toxin, the decision to treat with Human Botulism Immune Globulin has been based on clinical criteria that include a consistent history and physical findings of bulbar palsies, hypotonia, and weakness. After licensure, the charts of patients who did not have laboratory-confirmed infant botulism were reviewed to identify their actual diagnoses. The ∼5% of 681 patients treated with Human Botulism Immune Globulin who did not have infant botulism fell into 5 categories: spinal muscular atrophy, metabolic disorders, other infectious diseases, miscellaneous, and probable infant botulism lacking laboratory confirmation.

Three infants with infant botulism are presented to illustrate how atypical, early, and severe features may obscure or delay diagnosis. Two boys aged 6 weeks and 20 days, respectively, presented with rapid deterioration after brief periods of poor feeding, one with an apparent life-threatening event at home and the other with a full cardiopulmonary arrest. Initial abnormal laboratory findings of coagulopathy suggested sepsis in the first infant. In the second infant, severe acidosis and hypoglycemia suggested an underlying metabolic disorder. A third infant, aged 1 month, was hospitalized originally with an admitting diagnosis of “pharyngitis” resulting from his inability to take adequate feedings. He received intravenous fluids and antibiotics. One week later he suffered a respiratory arrest. Laboratory findings of severe hyponatremia and acidosis at the time of his arrest suggested a metabolic etiology. Even retrospectively, none of these infants had the typical initial complaint of constipation, and none were noted to have ptosis or facial weakness before catastrophic collapse. However, in each case, the parent had initially brought the child to the physician for “poor feeding” or “poor suck,” which was not recognized by medical personnel as a result of bulbar weakness. Ultimately, all 3 infants were found to have infant botulism. All 3 had received antibiotics before catastrophic collapse, possibly contributing to the rapidity of the deterioration. Each recovered, although the delay in diagnosis made them ineligible for treatment with botulism immunoglobulin.

The majority of the almost 400 confirmed cases of infant botulism in the United States have occurred in California, Pennsylvania, and Utah. In Pennsyvania, 44 of 53 (83%) cases occurred within a geographic area of Southeastern Pennsylvania which represents one tenth of the Commonwealth's area and one third of the population at risk for infant botulism. In Southeastern Pennsylvania, a map of the residences of cases circumscribes a discrete ring around Philadelphia. A case-control study performed to seek host-related risk factors, identifies the significant associations of botulism with infants who are white, breast-fed, and born at term into two-parent families with hospitalization insurance. County control studies were performed to identify differences in host-related factors between areas of high and low prevalence of botulism. Although some "protection" could be afforded Philadelphia infants by their feeding and family characteristics, the differences in case rates between Philadelphia and the botulism "ring counties" cannot be explained entirely by host-related factors. Further, the absence of botulism in counties just outside of the botulism "ring," where infants were found to have identical potential risk factors, suggests that an uneven distribution of botulinal spores in the environment is the most significant determinant of case rate.

A child with infant botulism became apneic and died while receiving ampicillin and gentamicin therapy. As aminoglycosides have been implicated in the induction and/or exacerbation of neuromuscular blockade, we used an animal model to test the hypothesis that aminoglycosides potentiate neuromuscular blockade of botulinum toxin. In the range of aminoglycoside doses utilized in these experiments, both gentamicin and tobramycin enhance neuromuscular impairment and death of botulinum toxin-exposed mice. These results support recently published clinical observations that aminoglycosides may potentiate neuromuscular weakness caused by botulinum toxin, and suggest that these antibiotics should be used with caution in suspected cases of infant botulism.