Erythromycin thiocyanate: Synthesis, Efficacy and Safety

Introduction

Erythromycin thiocyanate is one of several treatment options that has been evaluated for gastroparesis in adults and for feeding intolerance in the neonatal population but there are limited studies performed in pediatric patients outside of the neonatal intensive care unit (NICU) population. Erythromycin thiocyanate is a macrolide antibiotic, and the proposed mechanism of action for treatment of gastroparesis is that it increases motility by acting on the motilin receptor, consequently regulating phase 3 of the migrating motor complex and creating peristaltic activity in the antrum and duodenum. The use of erythromycin for motility has been evaluated in 5 pediatric studies outside of the NICU.4–8 Most previous studies focused on using intravenous (IV) erythromycin as a diagnostic drug for motility testing using a -time IV dose of 3 mg/kg.[1]

Synthesis

Preparation of erythromycin thiocyanate trihydrate: In a three-necked flask, 50ml of water and 0g erythromycin were added and stirred, then added with equimolar 2M lactic acid aqueous solution to erythromycin, and stirred at 5-40°C. After complete reaction, the mixture was filtered, 0% sodium thiocyanate solution in a molar ratio to erythromycin of :-.2 was added dropwise, cooled to a temperature between -5°C and 0°C, the resultant solid was washed with water, filtered under a reduced pressure and dried at room temperature for 48h to obtain an off-white crystal powder. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 86.6 % (the theoretical value: 86.65%); melting point: 6.9-65.°C (not corrected), water content measured by Karl Fischer method was 6.42% (the theoretical value: 6.38%), thermogram TG-DTA: weight loss before 40°C was about 6.39%, which was in the error range of the sample with 3 crystal water (see ), MS(ESI, FAB) m/z:793, 792, 734, 733, 59, 58. Element analysis: found: C 53.95, H 8.88, N 3.39, S 3.70; calculated: C 53.88, H 8.8, N 3.3, S 3.79.[2]

The Efficacy and Safety of Erythromycin thiocyanate

Comparative Analysis

Forty patients, accounting for 59.7% of the study population, experienced an improvement in gastroparesis symptoms. This outcome is notably more robust when compared to the findings of a survey study conducted by Rodriguez et al, where only 2 out of 37 respondents, equivalent to 5.4%, reported a resolution in symptoms among 40 patients who utilized Erythromycin thiocyanate. The remaining four studies, which focused on infants and children not in the NICU, centered on antroduodenal manometry to evaluate gastrointestinal motility, making direct comparisons with this study challenging due to significant disparities in study design and primary outcomes.[3]

Patient-specific factors, such as concurrent diseases and the severity of illness, may influence the effectiveness of Erythromycin thiocyanate. Our study encompassed approximately 40% of patients with congenital heart disease. Prior research has indicated that infants and children with congenital heart defects often exhibit poor feeding tolerance and struggle with full gastric feeds due to hypoxemia, reduced sensory input, and/or ischemic injury to the gastrointestinal tract. Our findings align with these studies, as a higher proportion of patients in the no improvement group had congenital heart disease. Additionally, our study included 3 children who began Erythromycin thiocyanate treatment in the PICU or CICU, with the majority, 22 patients or 84.6%, also having congenital heart disease. Numerous studies have observed that critical illness can elevate the risk of feeding intolerance, potentially due to a range of factors including diminished gastric motility. A recent study by Solana et al highlighted that children with cardiac disease were more prone to experience interruptions in enteral nutrition compared to those without cardiac disease. Given that our study only included 4 patients with congenital heart disease who initiated Erythromycin thiocyanate outside the PICU or CICU, we were unable to conduct further analyses to ascertain the impact of both congenital heart disease and illness severity on the response to Erythromycin thiocyanate due to the small sample size.

Dosing and Duration of Erythromycin Thiocyanate

The median dose of Erythromycin thiocyanate for patients who experienced improvement was .5 mg/kg/day, administered in divided doses every 8 hours. In contrast, Rodriguez et al found varying doses ranging from 2 to 40 mg/kg/day in divided doses every 6 hours among the 40 patients who received Erythromycin thiocyanate. They did not specify the median dose these patients received but noted that the mean duration of Erythromycin thiocyanate was 4. ± 3.6 months. The median duration of Erythromycin thiocyanate in this study was significantly shorter compared to that of Rodriguez et al. The median duration for those with symptom improvement was 4 days. This suggests that providers might observe improvements within the initial days of Erythromycin thiocyanate treatment and could consider alternative interventions, such as increasing the dose of Erythromycin thiocyanate or adding other motility agents, if gastroparesis symptoms do not improve within 5 to 7 days. However, this could also indicate tachyphylaxis due to the downregulation of motilin receptors with the prolonged use of Erythromycin thiocyanate.

Cardiac and Interaction Profiles of Erythromycin Thiocyanate

Previous studies have not assessed the occurrence of cardiac dysrhythmias or the use of QTc prolonging medications alongside Erythromycin thiocyanate. As previously mentioned, most studies involving Erythromycin thiocyanate in infants and children outside the NICU included only a single dose and did not monitor for adverse events. Rodriguez et al noted that 4 (0%) children experienced adverse events from Erythromycin thiocyanate, including abdominal pain, headaches, and behavioral changes. Despite the majority of their patients receiving Erythromycin thiocyanate for an average of 4 months, they did not evaluate QTc prolongation through electrocardiograms. In this study, we examined the number of patients exhibiting a prolonged QTc interval (defined as a QTc of 450 ms or a ≥25% increase from baseline) and those on potential QTc prolonging medications. The majority, 58.2%, received at least one QTc prolonging medication in addition to Erythromycin thiocyanate. Based on this study's definition, 4 (6.0%) patients had a prolonged QTc. Determining the actual incidence of prolonged QTc was challenging because only 6 (23.9%) had both baseline and follow-up electrocardiograms. Prior research in adults has identified risk factors for QTc prolongation, including cardiac defects, concurrent QTc prolonging medications, and electrolyte imbalances, such as hypokalemia and hypomagnesemia. Given these risk factors are prevalent among hospitalized patients, it is advisable for providers to obtain a baseline electrocardiogram for those on at least one concurrent QTc prolonging medication and to regularly monitor electrolyte levels when initiating Erythromycin thiocyanate.

Several patients in this study were also on medications known to interact with Erythromycin thiocyanate. Previous pediatric studies on Erythromycin thiocyanate for gastroparesis did not assess drug-drug interactions or report on other medications these patients were taking. We found that 94% of patients had at least one medication with a Class C, D, or X drug-drug interaction. These results align with those of Antoon et al, who reported that 49% of all hospitalized patients and 75% of PICU patients in US children’s hospitals were exposed to agents with potential for significant drug-drug interactions. In this study, all medications identified for potential drug-drug interactions with Erythromycin thiocyanate were due to Erythromycin thiocyanate’s inhibition of the metabolism of the other agents. Because of the retrospective nature of the study, we could not evaluate the clinical significance of these interactions. However, it remains uncertain what impact these interactions had on Erythromycin thiocyanate’s efficacy, as all interactions affected the metabolism of the other agent rather than the metabolism of Erythromycin thiocyanate itself.

References

[1] Febo-Rodriguez L, Chumpitazi BP, Shulman RJ. Childhood gastroparesis is a unique entity in need of further investigation. Neurogastroenterol Motil. 2020;32((3)):e13699.

[2] Mansi Y, Abdelaziz N, Ezzeldin Z, Ibrahim R. Randomized controlled trial of a high dose of oral erythromycin for the treatment of feeding intolerance in preterm infants. Neonatology. 2011;100((3)):290–294.

[3] Cucchiara S, Minella R, Scoppa A, et al. Antroduodenal motor effects of intravenous erythromycin in children with abnormalities of gastrointestinal motility. J Pediatr Gastroenterol Nutr. 1997;24((4)):411–4188.

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