Could one of the most widely prescribed antibiotics amoxicillin/clavulanate “augmentin™” be a risk factor for autism?

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Summary

Autism is an ever increasing problem in the United States. Characterized by multiple deficits in the areas of communication, development, and behavior; autistic children are found in every community in this country and abroad. Recent findings point to a significant increase in autism which can not be accounted for by means such as misclassification. The state of California recently reported a 273% increase in the number of cases between 1987 and 1998. Many possible causes have been proposed which range from genetics to environment, with a combination of the two most likely. Since the introduction of clavulanate/amoxicillin in the 1980s there has been the increase in numbers of cases of autism.

In this study 206 children under the age of three years with autism were screened by means of a detailed case history. A significant commonality was discerned and that being the level of chronic otitis media. These children were found to have a mean number 9.96 bouts of otitis media (with a standard error of the mean of ±1.83). This represents a sum total for all 206 children of 2052 bouts of otitis media. These children received a mean number of 12.04 courses of antibiotics (standard error of the mean of ±.125). The sum total number of courses of antibiotics given to all 206 children was 2480. Of those 893 courses were Augmentin. with 362 of these Augmentin courses administered under the age of one year.

A proposed mechanism whereby the production of clavulanate may yield high levels of urea/ammonia in the child is presented. Further an examination of this mechanism needs to be undertaken to determine if a subset of children are at risk for neurotoxicity from the use of clavulanic acid in pharmaceutical preparations.

Section snippets

History of autism

Autism is an ever increasing problem in the United States. Characterized by multiple deficits in the areas of communication, development, and behavior; autistic children are found in every community in this country and abroad. Estimates now hover around the 4–20 per 100,000 children [1], [2], [3], [4]. Recent findings from the MIND Institute at the University of California Davis states that: “the unprecedented increase in autism in California is real and cannot be explained away by artificial

Etiologies

Many causes of autism have been postulated. They range from environmental to toxicological causes. The most current thinking including that of some in Congress is that vaccination and more specifically the mercury based preservative in the vaccination is causing brain damage in children resulting in autism [6]. Other theories such as that of Andrew Wakefield a pediatric gastroenterologist who found the measles virus in the biopsied small intestines of autistic children on whom he performed

Examining the time-line

In looking at temporal factors which may be connected to the onset of the increase in autism, one needs to examine what types of medication, and/or drug introductions have been made to coincide with the onset of autism. One such potential causative factor which fits the time-line test is amoxicillin/clavulanate. Introduced in the early 1980s use of this preparation for otitis media began to appear in the literature in the mid to late 1980s [11], [12], [13], [14]. It appears that no other new

Clinical findings

206 children with autism not related to a known genetic condition, birth trauma, or known neurological disease was seen in the office and a detailed case history was obtained. The 206 children had a mean number 9.96 bouts of otitis media (standard error of the mean of ±1.83). This represented a sum total for the 206 children under the age of three years of 2052 bouts of otitis media. These children received a mean number of 12.04 courses of antibiotics. (The standard error of the mean of

Mechanism of clavanic acid/amoxicillin

Clavulanic acid (CA) is a β-lactamase inhibitor is used commercially as a component of a pharmaceutical formulation, generally in the form of a salt, especially potassium clavulanate. CA is produced commercially by culturing the microorganism streptomyces clavuligerus. CA and its alkali metal salts and esters are active inhibitors of β-lactamase produced by some gram positive as well as gram negative micro-organisms. Additionally, CA and its alkali metal salts also have a synergistic action

Manufacturing clavulanate/amoxicillin

Clavulanic acid and its derivatives such as potassium clavulanate are extremely moisture sensitive, and its formation must be carried out under conditions of relatively low humidity. When CA is prepared, it is done so by the process of adding urea or an available ammonia source to a fermentation broth. The fermentation process for producing CA are particularly sensitive to concentrations of ammonia in the system. While ammonia is needed to catalyze the fermentation system, it needs to be kept

Urea nitrogen poisoning

Urea and nitrogen poisoning is well known in the agriculture literature. While much has been written about nitrate and nitrite poisoning in livestock, little is written about it in humans. There is generally a two-fold effect of urea poisoning: (1) the neurotoxic effect on brain tissue, and (2) the highly alkaline corrosive effects of NH3 levels in the digestive tract. Moderate to acute signs of urea poisoning include abdominal colic, bloating, diarrhea, muscle tremor, incoordination, weakness,

Conclusion

In light of these findings, It is important that further studies be undertaken. Such studies could include endoscopic studies pre and post administration of Augmentin™ as well other neurotoxicological studies which would measure the potential residue of CA in the GI systems of children, especially in infants and toddlers. Since Augmentin™ is one of the most widely prescribed drugs for children and that its introduction into the marketplace for use in the treatment of childhood illnesses

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