Erythromycin has motilin receptor agonist activity, which improves gastric-emptying rates by stimulating enteric contractility. It causes pyloric relaxation and is a potent gastric-emptying stimulant. However, its use is limited by many drug interactions and adverse effects, including QT-interval prolongation. As a result, azithromycin has been studied as a potential alternative to erythromycin for treating gastroparesis because it has fewer adverse effects and drug interactions than erythromycin. [1]
Azithromycin is assumed to have prokinetic characteristics similar to those of erythromycin. In one study, small-bowel manometric data of 30 patients with chronic digestive problems or documented refractory gastroparesis revealed that azithromycin and erythromycin has a similar effect on antral activity when the same dosage of 250 mg is administered intravenously (IV). Another study using gastric-emptying scintigraphy showed that azithromycin’s effect on accelerating gastric emptying in adult patients with gastroparesis is equivalent to that of erythromycin. A review of articles on the use of azithromycin for gastroparesis treatment from 1966 to 2012 found that just two observational studies (performed during testing procedures) support its use. Since the prokinetic effects and safety profile of azithromycin are controversial, further research is required to evaluate the drug’s long-term efficacy and safety, and randomized, blinded, controlled studies should be performed before azithromycin is considered for gastroparesis treatment. [1]
This review concludes that the use of IV azithromycin to treat gastroparesis is questionable and risky because of the lack of reliable randomized, blinded, controlled studies to confirm its long-term efficacy and safety. It is even riskier to administer azithromycin at an interval of every 12 hours instead of every 24 hours since the drug continues to accumulate with each 12-hour interval, leading to an increased risk of QTc-interval prolongation. Additionally, because inappropriate use of azithromycin results in long-term antibiotic resistance, IV azithromycin should be reserved for the treatment of community-acquired pneumonia or other serious bacterial infections. [1]
The 2022 American Gastroenterological Association clinical practice update on the management of medically refractory gastroparesis addressed the use of azithromycin as a potential treatment option for gastric emptying. Azithromycin, as well as erythromycin, were recognized as agents that accelerate gastric emptying in gastroparesis but its use is limited due to its increased risk of cardiac arrhythmias and potential to prolong the QT interval. Similarly, the 2022 American College of Gastroenterology gastroparesis guidelines addressed the use of motilin agonists (i.e., azithromycin) as short-term treatments for gastroparesis, but due to limited clinical trial data, no recommendation for use was provided. [2], [3]
A 2017 review outlined management strategies for the treatment of gastroparesis. Treatments targeting motilin receptors are one of the strategies mentioned. Macrolide antibiotics have agonistic effects on motilin receptors and help with gastric emptying. Studies on the prokinetic effects of erythromycin have been positive, even when compared against metoclopramide. The drawbacks to motilin medications are the down-regulation of motilin receptors, with the effect of tachyphylaxis. The lowest effective doses are recommended. Problems with cytochrome P450 interactions can also limit the use of the medication and cause more symptoms, and carry a risk of sudden cardiac death as well. Azithromycin has been shown to be equally effective as erythromycin but without the cardiac risk and cytochrome interactions. Studies with azithromycin have shown increased antral contractility with the medication and a longer half-life than erythromycin. There is a need for further investigation of chronic use of azithromycin for use in gastroparesis. [4]
A 2018 clinical investigation retrospectively evaluated the prokinetic efficacy of intravenous azithromycin compared to erythromycin in pediatric patients undergoing antroduodenal manometry. Conducted at a single tertiary care center, the analysis included data from two adolescent females (both age 15) who received 1 mg/kg IV azithromycin due to an erythromycin shortage, and two age- and symptom-matched female controls who received 1 mg/kg IV erythromycin. All patients exhibited symptoms consistent with gastroparesis including abdominal pain, vomiting, and nausea; three had previously demonstrated delayed gastric emptying on scintigraphy, although all four demonstrated normal antroduodenal manometry patterns based. According to data extracted from high-resolution motility catheter tracings, administration of IV azithromycin elicited migrating motor complexes (MMCs) in both the stomach and small intestine that were nearly identical in amplitude, frequency, and duration to those induced by erythromycin. Specifically, gastric contraction amplitudes averaged 259 mm Hg with azithromycin and 241 mm Hg with erythromycin, while small intestinal MMC amplitudes measured 68 mm Hg and 72 mm Hg for azithromycin and erythromycin, respectively. Contraction frequencies in the stomach (3–4/min) and intestine (11–13/min), as well as contraction durations (stomach: 12–14 minutes), demonstrated close concordance between treatment arms. Propagation of phase III activity from the antrum to the duodenum was observed in both groups, confirming preserved neuromuscular function. These proximate findings support the hypothesis that azithromycin may serve as a viable alternative to erythromycin for inducing diagnostically relevant MMCs in pediatric patients, especially given azithromycin’s more favorable cardiac and pharmacokinetic profile. [5]
A 2013 experimental investigation evaluated whether azithromycin exhibits agonist activity at the human motilin receptor and assessed its ability to facilitate cholinergic activity in the human stomach. Using CHO-K1 cells stably expressing the human motilin receptor, radiolabeled ligand binding assays demonstrated that azithromycin displaced [125I]-motilin in a concentration-dependent manner, achieving a 52 ± 7% inhibition at 100 µM, which was comparable to erythromycin’s displacement of 58 ± 18% at 30 µM. Functional calcium flux assays revealed that azithromycin, erythromycin, and motilin each induced transient increases in intracellular calcium concentrations, with half maximal effective concentration (EC50) values of 2.9 µM, 0.92 µM, and 36 nM, respectively. Peak calcium responses declined rapidly in all cases (t½ = 34–39 seconds), highlighting a short-lived activation of the receptor in this recombinant system. Notably, the intrinsic activities of azithromycin and erythromycin were similar and approximated that of motilin at maximal concentrations. In parallel, ex vivo functional assays utilizing circular muscle strips from the human gastric antrum showed that both azithromycin and erythromycin lactobionate, at concentrations of 30–300 µM, potentiated cholinergically mediated contractions evoked by electrical field stimulation (EFS). Azithromycin at 300 µM elicited an apparent Emax of 2,007 ± 396% relative to baseline EFS-evoked contraction amplitude, with a delayed onset (~45 minutes) and irregular fade (t½ ~22 minutes). This facilitation was independent of direct muscle contractility, as submaximal carbachol-induced contractions remained unaffected. Higher concentrations also induced transient muscle contractions, separated temporally from the sustained cholinergic facilitation. The pharmacodynamic profile of azithromycin was comparable to that of erythromycin lactobionate, which similarly enhanced EFS-induced contractions (Emax 1,924 ± 1,375%) and produced modest, short-lived muscle contractions. These findings support the motilin receptor agonist activity of azithromycin in native human gastric tissue and suggest a mechanistic basis for its prokinetic effects observed in clinical settings. [6]
Only one randomized clinical trial comparing azithromycin and erythromycin for the symptomatic treatment of gastroparesis is registered via ClinicalTrials.gov. However, the study was terminated in 2014 because the original investigator left the institution, and the replacement investigator retired. [7]