Erythromycin and Congeners: A Toxicologist’s Perspective.

Erythromycin and its congeners including erythromycin, azithromycin and clarithromycin belong to the antibiotic class called macrolides.  

Macrolide antibiotics are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections.  

First-line indications for macrolides include the treatment of atypical community acquired pneumonia, H. Pylori (as part of triple therapy), chlamydia, pertussis (by Bordetella pertussis) and acute non-specific urethritis.  

Clarithromycin and azithromycin (2nd generation macrolides) have a better pharmacokinetic profile and are more active than erythromycin against target organisms.  

Macrolides are also a useful alternative for people with penicillin and cephalosporin allergy. 

Macrolides also have immunomodulatory and anti-inflammatory effects, which can be beneficial in some situations, e.g. when they are used in the treatment of cystic fibrosis 

Adverse effects of macrolides 

  • In general, macrolide antibiotics are considered to have fewer, less severe toxic effects than most other antimicrobial agents. These effects are usually reversible upon discontinuation of the drug.  
  • The most common adverse effects associated with macrolides are dose dependent gastrointestinal effects such as abdominal discomfort and cramp, nausea, vomiting and diarrhoea. The symptoms are more common in children. 
  • Erythromycin is associated with a higher incidence of gastrointestinal adverse effects than 2nd generation macrolides. More frequent daily dosing (i.e divided doses) may alleviate these gastrointestinal effects.  
  • Macrolides, particularly erythromycin and clarithromycin,induce prolongation of the QT interval due to their interference with the delayed rectifier potassium current (IKr) that leads to accumulation of potassium ions in cardiac myocytes and delayed cardiac repolarization.  
  • Other studies suggest that macrolide-induced oxidative stress consequent to inhibition of the mitochondrial electron transport chain contributes to altered kinetics of potassium channel conductance.  
  • The risk of prolongation of the QT interval may be increased by simultaneous administration of other drugs that prolong the QT interval (eg Tricyclic antidepressants) or reduce the rate of macrolide clearance (itraconazole, ketoconazole, ritonavir, and verapamil) 
  • The single most important concern with drug-induced QT prolongation is risk for fatal polymorphic ventricular tachycardia, or torsades de pointes. However, a Life-threatening bradyarrhythmia after massive azithromycin overdose has been reported. 
  • Of significance, however, is that prolongation of QT interval is not associated with remarkable clinically related outcomes such as arrhythmia or cardiac mortality. 
  • Erythromycin and clarithromycin are associated with increased risk of MI compared to azithromycin. Thus, macrolides should be prescribed with great caution in patients with preexisting cardiac disease, those with atherosclerosis or other ischemic heart diseases. 
  • Infants aged under three months treated with erythromycin are at increased risk of developing pyloric stenosis. They should be avoided in this group. 
  • Clarithromycin, and much less erythromycin, have been reported to cause neurotoxicity, mostly in the form of acute delirium or psychosis including visual hallucination of worm infestation, ‘antibiomania (the feeling of ‘leaving the planet’), and cat-like screeching. The risk for neurotoxicity is highest in patients with a history of psychiatric illness. 
  • A self-limited liver injury (cholestatic hepatitis and acute hepatitis) has been described for all four of the orally absorbed agents days after starting therapy.  Symptoms include fatigue, dark urine and jaundice, often with right upper quadrant pain and fever.  
  • Other rare adverse effects include hypersensitivity (e.g. anaphylaxis, fixed drug eruptions, Stevens-Johnson syndrome and interstitial nephritis), pancreatitis, Clostridium difficile-associated infection, blood dyscrasias (e.g. blood thrombocytopenia), and ototoxicity (reversible if the diagnosis is made early). 

Drug-drug interactions 

  • Macrolides are potent hepatic cytochrome P450 enzyme inhibitors, inhibitors of transporter proteins, alters gastrointestinal flora and accelerates gastric emptying. These actions have the potential to cause adverse interactions with other medicines. 
  • Erythromycin and clarithromycin are substrates and also strong inhibitors of CYP3A4 enzymes, and thus lead to the accumulation of drugs that require CYP3A4 for their metabolism such as statins (mainly simvastatin and atorvastatin) whose accumulation result in an increased risk of myopathy and rhabdomyolysis; calcium-channel blockers may potentially cause hypotension-induced nephrotoxicity. Consider a different antibiotic or temporarily stop the CYP3A4-metabolized statin during erythromycin or clarithromycin administration in all patients. 
  • Although a small fraction (less than 7.5%) of erythromycin appears in urine as unchanged drug, and thus kidney diseases are theoretically expected to have a minimal impact on its disposition, clinical observation shows that there are elevated erythromycin concentrations (associated with reversible hearing loss) in patients with end-stage renal disease. This is thought to arise from altered drug metabolism due to uraemia-induced downregulation of cytochrome P450 enzymes and alterations in the transporter system (of drugs into or out of the liver). 
  • Clarithromycin, on the other hand, is metabolized by CYP 3A4 to an active metabolite which is primarily excreted renally. Thus, the risk for prolonged elimination half-life and accumulation to toxic effects is more likely to occur in patients with kidney disease (but not those with hepatic impairment).  
  • Nonetheless, macrolides are generally metabolized in the liver and therefore should be avoided in people with severe liver impairment. 
  • Macrolides (clarithromycin is +++) are also known to inhibit the P-glycoprotein transport system that functions as an efflux pump in the intestines and the liver. Inhibition of this system limits absorption of orally administered drugs as well as their excretion into the bile. Because P-glycoprotein is involved in the transport of many other drugs, erythromycin and clarithromycin participate in drug-drug interactions. Drug substrates to P-glycoprotein transporter (eg pravastatin and simvastatin,colchicine and digoxin) if co-administered may increase their uptake and concentrations to toxic levels by inhibiting their efflux. 
  • Azithromycin is a weak substrate for CYP3A4, to be minimally metabolized by the enzyme, and to neither induce nor inhibit CYP3A4 activity. Thus, azithromycin does not interact with CP3A4 metabolized drugs nor require dose modification in patients with kidney disease. 

Treatment of overdose 

  • Monitor and correct vital signs, electrolytes, blood counts, renal function and liver enzymes following a significant overdose.  
  • Obtain an ECG, and institute continuous cardiac monitoring following significant overdose.  
  • Decontaminate the gut with activated charcoal if the ingestion is recent  
  • Treat significant vomiting and diarrhea with IV fluids; administer antiemetics, as needed.  
  • Manage hypotension with IV fluids with IV 0.9% NaCl at 1020 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.          
  • Electrical cardioversion and defibrillation may be used to manage arrhythmias. Treat stable patients with magnesium (first-line agent).  
  • Beta receptor blocking agents may be useful in decreasing risk of stress-induced arrhythmias. 
  • Bradycardia may be managed with atropine 
  • Administer potassium supplements to raise potassium levels which then shortens the action potential and may minimize the occurrence of arrhythmias.  
  • Sodium channel blocking drugs such as mexiletine have been used to prevent arrhythmias in long QT syndrome. 
  • Administer IV benzodiazepines; barbiturates or propofol if seizures persist or recur.   
  • Administer antihistamines, with or without inhaled beta agonists, corticosteroids or epinephrine for hypersensitivity reactions. 
  • Antioxidants may be administered to reduce oxidative stress associated with myocardial toxicity, QT interval prolongation and arrhythmias. 

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