In the present study, we report for the first time the possible benefit on gastrointestinal motility of A/C given enterally in children. We demonstrated the occurrence of duodenal phase III of the MMC after the administration of A/C in most of the study subjects in the first 10 minutes after its administration. The characteristics of duodenal phase III triggered by A/C were similar to phase III generated during fasting. This response was evident when A/C was given before a meal; however, it was obtained less reliably at the doses we used when the medication was given after the meal. This response suggests that A/C is able to induce a duodenal preprandial motility pattern but may not be able to disrupt the duodenal postprandial motility pattern. Despite the use of a population of patients referred for the evaluation of a variety of different symptoms and with different associated comorbidities, there was fair homogeneity in the characteristics of the gastroduodenal motility in the study patients. The fact that the majority of the manometry studies were interpreted as normal decreases the chance of a possible bias related to an underlying motility disorders.
Inducing preprandial duodenal phase III may accelerate small bowel transit, influence the gut microbiome, and play a role in preventing the development of small bowel bacterial overgrowth. Bacterial overgrowth is a condition highly prevalent in patients with alterations of duodenal phase III and chronic symptoms of intestinal pseudo obstruction and irritable bowel syndrome (17). The use of an agent such as A/C, which can both stimulate motility and treat bacterial overgrowth, may be particularly beneficial in this clinical scenario.
The intrinsic mechanisms by which A/C induces the interdigestive phase III are not known. The immediacy of the motor response suggests a local receptor–mediated affinity or a paracrine receptor stimulation by the amoxicillin or clavulanate components of the medication. Due to the pharmacokinetics of A/C, it is improbable that any of the prodrug can achieve a serum concentration that would have triggered the motility response. The gut absorption of amoxicillin is constant and depends on the dose used. When orally administered, it reaches its Tmax at 1.14 ± 0.4 hours. For the clavulanic acid, the absorption varies more among patients reaching its Tmax at 1.24 ± 0.48 hours (18,19).
Several mechanisms are known to play a role in the generation of the interdigestive gastroduodenal motor pattern; however, none of them may clearly explain how A/C affects the antroduodenal interdigestive motility. It is unlikely that A/C stimulates the motilin receptor because of its lack of effect on the antral component of the MMC. Motilin reaches plasma peak level during the interdigestive phase III in the antrum and duodenum, inducing a greatly efficient motor stimulation at these 2 levels (20,21). Vagal nerve–mediated acetylcholine receptor stimulation is also unlikely because it shares the same principle, inducing mainly an antral phase III without affecting the duodenal interdigestive motor pattern, which was the main effect of A/C in the present study (20,21). A neuroendocrine effect by 5′-hydroxytryptamine, stored in the enterochromaffin cells, is unlikely because it induces a duodenal phase II followed by gastric and duodenal phase III. This response occurs even in the postprandial or digestive phase of the MMC (22,23).
The duodenal motor response obtained with A/C is comparable with the one observed after administration of octreotide, another medication known to induce duodenal phase III. It produces an attenuation of the antral electrical and motor response while reliably inducing a duodenal phase III–like cluster of contractions (24). Octreotide is helpful in the treatment of patients with motility disorders and has been used to decrease bacterial overgrowth by inducing small bowel phase III in patients with pseudoobstruction secondary to scleroderma (16,25,26).
Because the main effect of A/C seems to be in the small bowel, its use may be ideal if combined with a gastrokinetic agent when the child is fed orally or through gastrostomy. Several gastrokinetic agents have been used with the aim of alleviating symptoms secondary to altered antroduodenal motility. Central and peripheral dopaminergic receptor agonists, metoclopramide and domperidone, known to increase antroduodenal motility and decrease symptoms in patients with gastroparesis, are not advisable for widespread use in children due to their adverse effects of tardive dyskinesia and lack of approval from regulatory agencies in the United States, respectively (7,27). Erythromycin is a potent motilin agonist (9,28), and it has been shown that it can accelerate antroduodenal flow by increasing antral and duodenal phase III contractions and decrease pyloric resistance (29–31). This medication may represent a helpful therapeutic option if given in combination with A/C, which seems to exert most of its effects on the small bowel. Another future potential combination may be the use of A/C with the recently discovered ghrelin receptor agonists, which seem to accelerate gastric emptying (32). Use of A/C may be ideal in those children fed directly into the small bowel with gastrojejunal or nasojejunal feeding tubes or surgical jejunostomy.
The possible obvious downsides of using A/C as a prokinetic agent include the induction of bacterial resistance, especially from Gram-negative bacteria such as Escherichia coli and Klebsiella (33–35). Antibiotic-associated diarrhea is a known adverse effect from clavulanic acid and has been described for both preparations containing clavulanic acid, A/C, and ticarcillin/clavulanate (34,36). Indeed, Clostridium difficile–associated diarrhea and yeast infection are dreaded complications of any long-term antibiotic use. Although other mechanisms can explain diarrhea in some of the patients using antibiotics, it is possible that increased motility could play a role in the development of antibiotic-associated diarrhea. Clavulanic acid in its noncombined form is not available; therefore, its use is limited as a prokinetic agent. Nevertheless, the paucity of presently available therapeutic options may justify the use of A/C in patients with severe forms of small bowel dysmotility, in whom other interventions have not been efficacious. Future studies should aim at evaluating its clinical and long-term benefit in such clinical situations.
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