Continuing Education Activity

Erythromycin has traditionally; it has been used for various respiratory infections (i.e., community-acquired pneumonia, Legionnaires disease), prophylaxis of neonatal conjunctivitis, and chlamydia. It is also FDA approved for treating skin infections, intestinal amebiasis, rheumatic fever prophylaxis, syphilis, and pelvic inflammatory disease (PID). If mixed with tretinoin cream or benzoyl peroxide, it is effective for treating acne. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of erythromycin, pertinent for members of the interprofessional team in the treatment of patients with infections and other conditions where this agent is indicated.

Objectives:

• Describe the mechanism of antibacterial action for erythromycin.
• Outline the infectious and non-infectious indications for erythromycin.
• Review the potential adverse events and drug interactions associated with erythromycin.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using erythromycin.

Indications

Erythromycin is a macrolide antibiotic initially discovered in 1952. It is useful for treating various infections and also has an indication for a non-infectious pathology.

Traditionally, its use has been for various respiratory infections (i.e., community-acquired pneumonia, Legionnaires disease),[1] prophylaxis of neonatal conjunctivitis, and chlamydia. It is also FDA approved for treating skin infections, intestinal amebiasis, rheumatic fever prophylaxis, syphilis, and pelvic inflammatory disease (PID).[2] If mixed with tretinoin cream or benzoyl peroxide, it is effective for treating acne.[3] During pregnancy, it can be used for the prevention of Group B streptococcal infection in the newborn.[4] Although some literature shows specific forms of erythromycin may not be fully safe in pregnant women. Erythromycin is also used off-label for treating gastroparesis, also known as delayed gastric emptying. However, the treatment of gastroparesis is a non-FDA approved indication.[5] 

Erythromycin is active against gram-positive bacteria, gram-negative bacteria, and several other organisms. The gram-positive bacteria include Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Listeria monocytogenes, Corynebacterium minutissimum, Corynebacterium diphtheria. The gram-negative bacteria include Legionella pneumophila, Neisseria gonorrhoeae, Haemophilus influenzae, and Bordetella pertussis. Other microorganisms that are covered by erythromycin include Chlamydia trachomatis, Entamoeba histolytica, Mycoplasma pneumoniae, Treponema pallidum, and ureaplasma urealyticum.[2]  

Once erythromycin is orally administered, it is easily absorbed through the gastrointestinal system. It readily diffuses into most bodily fluids. Erythromycin is concentrated in the liver and is then later excreted in bile. Erythromycin administration can also be in intravenous form, topical form, and ophthalmic form.

The side effect profile of erythromycin includes those commonly seen in most antibiotics: nausea, abdominal pain, and diarrhea. As all macrolide antibiotics cause QT prolongation; erythromycin causes the most significant prolongation of the QT interval. Rarely, severe rashes such as Stevens-Johnson syndrome may occur.

Mechanism of Action

Erythromycin is a bacteriostatic antibiotic, which means it prevents the further growth of bacteria rather than directly destroying it. This action occurs by inhibiting protein synthesis. Erythromycin binds to the 23S ribosomal RNA molecule in the 50S subunit of the bacterial ribosome; this causes a blockage in the exiting of the peptide chain that is growing. Given that humans have the 40S and 60S subunits, and do not have 50S subunits, erythromycin does not affect protein synthesis in human tissues.[6][7][8][9]

Resistance can develop against erythromycin. This occurs via modification of the 23S rRNA found in the 50S rRNA. The erythromycin cannot bind to the ribosome, and the bacteria can continue the process of protein synthesis.[10][11]

Aside from being a bacteriostatic macrolide antibiotic, erythromycin is a pro-motility drug. It is an agonist to motilin, which increases motility in the gut.[12]

Once erythromycin is orally administered, it gets deactivated by gastric acid. Oral tablets must either contain an ester or stable salt as part of the molecular structure or be enteric-coated. Following absorption via the gastrointestinal system, it diffuses into various tissues and phagocytes. As phagocytes circulate the blood and induce phagocytosis of harmful bacteria, erythromycin gets released during this process.

The liver metabolizes most of the administered erythromycin. It undergoes demethylation through the cytochrome P450 system, specifically the enzyme CYP3A4, and undergoes elimination through bile. A very small percentage of the drug undergoes renal excretion.

Erythromycin has a half-life of 1.5 to 2 hours. Levels of the drug peak 4 hours after intake.[13]

Administration

Erythromycin is available in oral form. It is also available in an intravenous form, topical form for the skin, and as an ophthalmic preparation for the eyes.

The oral form of the medication is available in 250-mg tablets and 500-mg tablets.  For maximal absorption and minimal side effects, the patient should avoid alcohol, take on an empty stomach (1 hour before or 2 hours after meals), take with a full glass of water, and avoid taking with grapefruit juice.

Optimal blood levels are reached when the patient takes it in a fasting state.

Adverse Effects

All antibiotics carry a significant risk of nausea, vomiting, abdominal pain, and diarrhea. Erythromycin is a motilin agonist, and this increases the likelihood of gastrointestinal side effects compared to other antibiotics.[14]

All macrolide antibiotics cause QT prolongation. Azithromycin causes the least QT prolongation, usually clinically insignificant. Clarithromycin causes greater QT prolongation. Erythromycin is known to cause major prolongation of the QT interval and carries a risk of torsades de pointes. This arrhythmia may cease on its own, or it may degenerate into ventricular fibrillation, a deadly heart rhythm.[15][16][17]   

There also exists a risk of rash, allergic reaction, and reversible deafness. Rare side effects include Stevens-Johnson syndrome, toxic epidermal necrolysis, and cholestasis.[18]

Erythromycin comes in various forms. Pregnant women should not use the form of erythromycin estolate as it may cause hepatotoxicity. It may also increase the risk of pyloric stenosis in the newborn.

Erythromycin is a cytochrome P450 inhibitor; this means it carries the potential to interact with broad ranges of medications. Given it is an inhibitor of CYP450, drugs that get metabolized via the cytochrome P450 system would have increased concentrations and hence carry risks of toxicity.[19]

Contraindications

Patients who have a prolonged QT interval on an electrocardiogram (ECG) should not use erythromycin. A normal QTc interval would be less than 440ms in males and less than 460ms in females. Anyone using a medication that prolongs the QT interval should be very cautious and monitored if adding erythromycin. Similarly, patients diagnosed with long QT syndrome (LQTS) should not use erythromycin. Likewise, patients who have had an episode of torsades de pointes in the past should avoid QT-prolonging drugs such as erythromycin.[15]

As erythromycin may cause serious rashes in a small number of patients, anyone who has experienced similar symptoms in the past should avoid future use of the drug. 

Pregnant women should avoid using erythromycin estolate as it may precipitate hepatotoxicity. 

Erythromycin is a cytochrome P450 inhibitor, which means it interacts with an extensive range of medications. Depending on the medication, dosage adjustment may be required. In some cases, erythromycin should be avoided entirely as CYP450 inhibition may induce toxicity of the other medication.[19] 

Monitoring

Erythromycin has significant gastrointestinal side effects (nausea, vomiting, and diarrhea) and may even be used to help patients with impaired motility. Liver enzymes require monitoring because of the potential for rare but serious hepatic failure. QT interval prolongation is a possible adverse effect and requires careful vigilance in patients with heart conditions, or who take antiarrhythmic or interacting drugs. Pseudomembranous colitis has been reported with erythromycin, and may range in severity from mild to life-threatening; the physician should consider this diagnosis in patients present with severe diarrhea after its administration. 

Toxicity

Macrolide antibiotics have varying levels of cardiotoxicity. Erythromycin carries the most prominent risk of cardiotoxicity among the more commonly used macrolide antibiotics. It induces QT prolongation and increases the risk of the potentially deadly heart rhythm known as torsades de pointes. Careful monitoring of the QTc interval on the ECG is recommended to minimize risk. Patients at higher risk should also have their potassium, magnesium, and calcium levels monitored.

There is no known reversal agent for erythromycin.

Enhancing Healthcare Team Outcomes

Erythromycin has a significant gastrointestinal side effect profile that requires monitoring by the interprofessional team. Members should monitor patients for common side-effects, including abdominal pain and diarrhea that may be associated with pseudomembranous colitis. The medication can also rarely induce QT prolongation that requires referral to a cardiologist and discontinuation of the medication. [Level 5]