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Why does erythromycin cause increased gastrointestinal side effects, including risk of diarrhea?


  • GI toxicity is the most common side effect of erythromycin therapy.
  • In the acidic environment of the stomach, erythromycin is degraded to a hemiketal intermediate that serves as a motilin-receptor agonist. 
  • Motilin stimulates a G-protein coupled pathway in smooth muscle cells of the GI tract leading to contractions.
  • Motilin-stimulated contractions are a component of a cyclic process known as the migrating motor complex.
  • Activation of the motilin pathway by erythromycin leads to adverse GI effects.

Author: Sarah White, PharmD
Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editors:
Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP and Sabrina W. Cole, PharmD, BCPS
Last Reviewed:
August 2015


  • Erythromycin is a macrolide antibiotic that was first identified as a byproduct of Streptomyces erythraeus in 1952.  The erythromycin molecule is comprised of a 14-membered lactone ring with two deoxy sugar groups.1,2  The most common side effects of erythromycin therapy are gastrointestinal (GI) in nature and consist of diarrhea, nausea, vomiting and abdominal cramping.3

    Erythromycin has poor stability in acidic environments and is rapidly degraded into intermediate metabolites after oral administration.3  One of these metabolites, 8,9-anhydro-6,9-hemiketal intermediate, serves as a motilin-receptor agonist.4  Motilin is a natural GI peptide hormone that is responsible for amplifying migrating motor complex activity within the upper alimentary tract.  The migrating motor complex is a series of neural impulses and smooth muscle contractions that stimulates caudal propulsion of GI contents during periods of fasting.  Motilin stimulates smooth muscle contractions through a series of downstream effects that are depicted below.4

    Activation of this pathway with erythromycin therapy leads to excessive contractile activity that is largely responsible for GI toxicity.2,5  At low doses (40-80 mg), side effects may also be mediated by cholinergic facilitation, although the exact mechanism of this effect is unknown.6  Adverse effects of erythromycin are observed at normal doses of the oral base preparation (ie, 250-500 mg every 6-12 hours).  Doses exceeding 3 mg/kg may stimulate forceful smooth muscle contractions that can lead to dumping of gastric contents into the duodenum.6  For many years, GI side effects have limited patient tolerability to erythromycin, prompting research for novel agents with more favorable safety profiles.


    1. MacDougall C. Chapter 55. Protein Synthesis Inhibitors and Miscellaneous Antibacterial Agents. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. 
    2. Deck DH, Winston LG, Winston LG. Chapter 44. Tetracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Oxazolidinones. In: Katzung BG, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12nd ed. New York: McGraw-Hill; 2012.
    3. Zuckerman JM, Qamar F, Bono BR. Macrolides, ketolides, and glycylcyclines: azithromycin, clarithromycin, telithromycin, tigecycline. Infect Dis Clin North Am. 2009 Dec;23(4):997-1026. 
    4. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005 Oct;17(5):643-53.
    5. Abu-Gharbieh E, Vasina V, Poluzzi E, De Ponti F. Antibacterial macrolides: a drug class with a complex pharmacological profile. Pharmacol Res. 2004 Sep;50(3):211-22.
    6. Sharkey KA, Wallace JL. Chapter 46. Treatment of Disorders of Bowel Motility and Water Flux; Anti-Emetics; Agents Used in Biliary and Pancreatic Disease. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. Accessed May 13, 2013.
    7. Blondeau JM. The evolution and role of macrolides in infectious diseases. Expert Opin Pharmacother. 2002 Aug;3(8):1131-51.

MESH Terms & Keywords

  • Erythromycin, motilin, GI, diarrhea