Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Effect of Amoxicillin/Clavulanate on Gastrointestinal Motility in Children
Gomez, Roberto; Fernandez, Sergio; Aspirot, Ann; Punati, Jaya; Skaggs, Beth; Mousa, Hayat; Di Lorenzo, Carlo
Division of Pediatric Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH.
Address correspondence and reprint requests to Roberto Gomez, MD, Division of Gastroenterology, Hepatology, and Nutrition, Wake Forest University Baptist Medical Hospital, Medical Center Boulevard, Winston Salem, NC 27157 (e-mail: firstname.lastname@example.org).
Received 25 April, 2011
Accepted 13 June, 2011
The authors report no conflicts of interest.
Aim: The aim of the present study was to evaluate the effect of amoxicillin/clavulanate (A/C) on gastrointestinal motility.
Methods: Twenty consecutive pediatric patients referred for antroduodenal manometry received 20 mg/kg of A/C into the small bowel lumen. In 10 patients (group A), A/C was given 1 hour after and in 10 (group B), 1 hour before ingestion of a meal. Characteristics of the migrating motor complex, including presence, frequency, amplitude, and propagation of duodenal phase III and phase I duration and phase II motility index (MI), were evaluated 30 minutes before and after A/C administration.
Results: There were no statistically significant differences in age and sex between the 2 groups. Manometry studies were considered normal in 8 patients in each group. In group A, 2 patients developed duodenal phase III after receiving A/C, and no significant difference was found in the MI before and after the drug administration. In group B, 9 patients developed duodenal phase III (P < 0.05 vs group A). All phase III occurred within a few minutes from the medication administration. Most duodenal phase III contractions were preceded by an antral component during fasting but never after the medication was administered in either of the 2 groups (P < 0.001 vs fasting). In group B, the duration of duodenal phase I was shorter after drug administration (P < 0.05). There was no significant difference in duodenal phase II MI before and after A/C administration for the 2 study groups.
Conclusions: In children, administration of A/C directly into the small bowel before a meal induces phase III-type contractions in the duodenum, with characteristics similar to those present in the fasting state. These data suggest the possible use of A/C as a prokinetic agent. Further studies are needed to clarify its specific mechanism of action and the group of patients most likely to benefit from its use.
Upper gastrointestinal symptoms such as nausea, vomiting, abdominal pain, early satiety, and abdominal distention are highly prevalent in the pediatric population (1). These symptoms frequently are related to the conditions associated with abnormalities in gastrointestinal motility such as gastroparesis and intestinal pseudo-obstruction (2). Postprandial antral hypomotility has been associated with symptoms of gastric stasis (3), and antral hypomotility and duodenal postprandial hypomotility have been documented in children with feeding disorders and gastric emptying delay (4). Antroduodenal manometry has been proven to be a reliable technique for the assessment of foregut motility in children of all ages (5). Despite advances in diagnosis of motility disorders, there continues to be a paucity of medications available for the treatment of upper gastrointestinal tract motor function. Cisapride, a drug that is at present available only on a restricted basis, was used in the past to accelerate gastric emptying (4). The use of metoclopramide has been restricted due to its neurological adverse effects (6,7). Domperidone was never approved for use in the United States (8). Erythromycin increases antral contractility by binding to motilin receptors in the smooth muscle from the antrum but has little, if any, effect in the small and large intestines (9,10). Amoxicillin/clavulanate (A/C) is a widely used antimicrobial agent. Clavulanic acid, a β-lactamase inhibitor, enhances the activity of the amoxicillin. A/C induces diarrhea, as an adverse effect, more frequently than amoxicillin alone (11,12). The mechanism for these adverse effects is not well understood. A/C has been reported to increase small bowel motility in healthy individuals (13). It has been used in the treatment of bacterial overgrowth in patients with chronic diarrhea (14). The present study was designed to test 2 hypotheses: A/C stimulates gastric and duodenal motility in pediatric patients with chronic or recurrent upper gastrointestinal symptoms and A/C induces a motility pattern that is comparable to the baseline antroduodenal motility.
The study was offered to consecutive patients who were scheduled to undergo antroduodenal manometry testing in the Motility Center at Nationwide Children's Hospital and began only after a parent gave informed consent and each patient older than 9 years provided informed assent. The study was approved by the institutional review board at Nationwide Children's Hospital.
The antroduodenal manometry was performed in each patient according to our standard clinical protocol (15,16). In brief, patients stopped all of the medications that potentially affected gastrointestinal motility and antibiotics at least 3 days before the study. We used catheters with 8 radially oriented recording sites, separated 3 to 5 cm from each other to measure pressure changes. The motility catheter was placed by the interventional radiologist under sedation, with 3 pressure sensors in the antrum and 5 in the duodenum. We did not study patients in whom the tip of the motility catheter was not located in at least the third portion of the duodenum and patients who had a previous history of allergy to amoxicillin or clavulanate. After catheter placement, motility was monitored during fasting for at least 3 hours. After the fasting period, patients received an age-appropriate caloric meal and the antroduodenal motility was monitored for at least 1 additional hour.
All of the patients received 1 dose of A/C (Augmentin, GlaxoSmithKline, Philadelphia, PA) 250 mg/12.5 mg/5 mL (20 mg/kg of amoxicillin/1 mg/kg of clavulanate) through the central lumen of the antroduodenal catheter. Patients were divided into 2 groups. In the first group (group A), the medication was administered 1 hour after the meal followed by subsequent monitoring of motility for an additional hour. The second group (group B) received the medication 1 hour before the meal, and motility was monitored for 1 hour before ingestion of the meal.
Interpretation of the study and measurement of all of the study variables were made by an investigator blinded to the time of the medication infusion. For each tracing, the following parameters were calculated and compared: characteristics of the migrating motor complex (MMC), including presence, number, frequency, amplitude, and duration of duodenal phase III, duodenal phase I duration, and duodenal motility index (MI). Presence and number of antral contractions were also determined. All of the parameters were evaluated during the whole fasting period and during the 60 minutes after A/C administration. Phase III was defined as a cluster of repetitive contractions occurring at the maximum rate for that area of the alimentary tract (2–3/minute in the antrum and 10–12/minute in the small intestine), lasting for >2 minutes, propagating faster than 3 cm/minute >6 cm along the duodenum or small intestine (5). MI was defined as the sum of amplitudes from all of the contractions divided by the interval time and by the number of channels analyzed.
Data are presented as means and standard deviations. By using SPSS version 17 (SPSS Inc, Chicago, IL), motility parameters obtained during fasting and after A/C were compared by paired t test. A number of patients developing MMC phase III during fasting and post-A/C were analyzed using Fisher exact test.
Twenty patients (9 girls and 11 boys) participated in the study. There were no significant differences in demographics and clinical characteristics between patients in group A and group B. In 8 of 10 patients in each group, no significant motility abnormalities were identified, and the studies were interpreted as normal. Demographics of patients and manometry results are described in Table 1. All 20 patients had recognizable spontaneous phase III of the MMC. In group A (A/C postmeal), 2 patients developed duodenal phase III after receiving A/C. In group B (A/C premeal), 9 of 10 patients developed duodenal phase III (P < 0.05 vs group A, Table 2). Motor characteristics of phase III did not differ between fasting and post-A/C (Table 3). For both groups, phase III occurred soon after medication administration, 8.8 ± 6.7 minutes (Fig. 1). Duodenal phase III was preceded by an antral component in most instances in both groups during fasting but not after A/C was administered in either of the 2 groups (80% vs 0%; P < 0.05). In group B, the duration of duodenal phase I was shorter after drug administration (531 ± 403 vs 891 ± 193 seconds; P < 0.05). Duodenal phase II MI 30 minutes before and after A/C administration was for group A 2090.6 ± 1871.6 vs 2119.1 ± 1891.1, and for group B 1169 ± 1309.1 vs 1046 ± 88.5 (nonsignificant for either of the 2 study groups).
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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Primary gastrointestinal motility disorders in childhood
Minerva Pediatrica, 64(6):
amoxicillin/clavulanate; children; gastrointestinal motility; motor migrating complex
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