Erythromycin


Article Author:
Khashayar Farzam


Article Editor:
Judy Quick


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
11/20/2019 11:09:40 PM

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] 


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Erythromycin - Questions

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Which of the following drugs binds to motilin receptors?



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Which of the following organisms is not well covered by the macrolide erythromycin?



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A 6-week-old infant presents with the insidious onset of cough and tachypnea. On examination the infant is afebrile with rales on pulmonary auscultation. You suspect chlamydia trachomatis pneumonia that is supported by a chest radiograph demonstrating interstitial infiltrates. Erythromycin is prescribed. What is the most common adverse reaction of erythromycin in infants?



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A 65-year-old patient is diagnosed with community-acquired pneumonia and started on an oral antibiotic. Two days later, he returns complaining of abdominal pain, nausea, and vomiting, which caused him to stop taking the antibiotic. What drug was the patient likely taking?



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For treatment of gastroparesis, erythromycin acts by?



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Erythromycin acts by inhibiting which of the following?



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Which of the following has been associated with erythromycin esolate?



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Which of the following drugs is absorbed from the gastrointestinal system?



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A patient is treated with a broad-spectrum bacteriostatic drug, but the bacteria became resistant by methylation of the 23S rRNA. Select the most likely medication.



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Which type of erythromycin is associated adverse reaction of cholestatic hepatitis with fever and jaundice?



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A 65-year-old male with a past medical history of diabetes mellitus and indigestion presents to the clinic complaining of recurrent vomiting after meals. He is diagnosed with gastroparesis and prescribed erythromycin. Four days later, the patient presents to the emergency room after losing consciousness. Electrocardiogram shows no ST segment changes and a QTc of 514 ms with a heart rate of 67. Minutes later, the patient loses consciousness again. What is the most likely cause of the patient's syncope?



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Which of the following is used for prophylaxis of neonatal conjunctivitis?



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A 71-year-old male with a past medical history of osteoarthritis, atrial fibrillation, and diabetes mellitus is currently on warfarin. He also uses Ibuprofen daily for pain control due to his arthritis. He presents to the clinic complaining of vomiting after meals and indigestion. The provider prescribes erythromycin in an attempt to improve his gastric motility. For what is this patient at risk?



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Erythromycin - References

References

Antibiotics for prolonged wet cough in children., Marchant JM,Petsky HL,Morris PS,Chang AB,, The Cochrane database of systematic reviews, 2018 Jul 31     [PubMed]
Amsden GW, Erythromycin, clarithromycin, and azithromycin: are the differences real? Clinical therapeutics. 1996 Jan-Feb     [PubMed]
Schmidt N,Gans EH, Tretinoin: A Review of Its Anti-inflammatory Properties in the Treatment of Acne. The Journal of clinical and aesthetic dermatology. 2011 Nov     [PubMed]
Morgan JA,Cooper DB, Pregnancy, Group B Streptococcus null. 2018 Jan     [PubMed]
Camilleri M,Parkman HP,Shafi MA,Abell TL,Gerson L, Clinical guideline: management of gastroparesis. The American journal of gastroenterology. 2013 Jan     [PubMed]
Kanoh S,Rubin BK, Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical microbiology reviews. 2010 Jul     [PubMed]
Tenson T,Lovmar M,Ehrenberg M, The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome. Journal of molecular biology. 2003 Jul 25     [PubMed]
Liang JH,Han X, Structure-activity relationships and mechanism of action of macrolides derived from erythromycin as antibacterial agents. Current topics in medicinal chemistry. 2013     [PubMed]
Gaillard T,Dormoi J,Madamet M,Pradines B, Macrolides and associated antibiotics based on similar mechanism of action like lincosamides in malaria. Malaria journal. 2016 Feb 12     [PubMed]
Guo MT,Yuan QB,Yang J, Insights into the amplification of bacterial resistance to erythromycin in activated sludge. Chemosphere. 2015 Oct     [PubMed]
Varaldo PE,Montanari MP,Giovanetti E, Genetic elements responsible for erythromycin resistance in streptococci. Antimicrobial agents and chemotherapy. 2009 Feb     [PubMed]
Maganti K,Onyemere K,Jones MP, Oral erythromycin and symptomatic relief of gastroparesis: a systematic review. The American journal of gastroenterology. 2003 Feb     [PubMed]
Albarellos GA,Montoya L,Landoni MF, Pharmacokinetics of erythromycin after intravenous, intramuscular and oral administration to cats. Veterinary journal (London, England : 1997). 2011 Jan     [PubMed]
Carter BL,Woodhead JC,Cole KJ,Milavetz G, Gastrointestinal side effects with erythromycin preparations. Drug intelligence     [PubMed]
Hancox JC,Hasnain M,Vieweg WV,Gysel M,Methot M,Baranchuk A, Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity. Therapeutic advances in infectious disease. 2014 Apr     [PubMed]
Mason JW, Antimicrobials and QT prolongation. The Journal of antimicrobial chemotherapy. 2017 May 1     [PubMed]
Li X,Wang M,Liu G,Zhou L,Wang Z,Li C, Macrolides use and the risk of sudden cardiac death. Expert review of anti-infective therapy. 2016 Jun     [PubMed]
Williams DA, Stevens-Johnson syndrome after erythromycin therapy while deployed at sea. Military medicine. 2000 Aug     [PubMed]
Akiyoshi T,Ito M,Murase S,Miyazaki M,Guengerich FP,Nakamura K,Yamamoto K,Ohtani H, Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. Drug metabolism and pharmacokinetics. 2013     [PubMed]

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