- USES: Azithromycin, clarithromycin, and erythromycin are macrolide antibiotics used for a variety of infections. Fidaxomicin is indicated in adults for the treatment of Clostridium difficile-associated diarrhea. PHARMACOLOGY: This class of antibiotics are named the macrolide antibiotics by virtue of their chemical structure which possesses a macrocyclic lactone ring. The macrolide antibiotics act by binding to the 50 S ribosomal subunits of susceptible bacteria, thereby suppressing bacterial protein synthesis. These drugs are bacteriostatic at low concentrations and bacteriocidal at high concentrations. Azithromycin is the prototype of a subclass of macrolide antibiotics known as the azalides. This agent differs structurally from erythromycin by insertion of a methyl-substituted nitrogen at position 9a in the lactone ring, creating a 15-membered macrolide. Fidaxomicin is a locally-acting bactericidal macrolide antibiotic derived from fermentation of Actinomycete Dactylosporangium aurantiacum, and is primarily active against Clostridia species including Clostridium difficile via inhibition of RNA polymerases. EPIDEMIOLOGY: Overdose is rare. OVERDOSE: Significant toxicity following acute overdose is uncommon. Severe epigastric pain, nausea, vomiting, and pancreatitis have been reported following erythromycin (base) overdose. An infant was inadvertently administered IV azithromycin (a 5 to 10-fold overdose) instead of the prescribed ceftriaxone, and quickly became unresponsive, cyanotic, and pulseless. The cardiac monitor showed wide-complex bradycardia, with a prolonged QTc interval, and third-degree atrioventricular block. The patient survived but with significant anoxic encephalopathy. ADVERSE EFFECTS: 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. COMMON: Nausea, vomiting and abdominal pain. The incidence of GI reactions may vary with the erythromycin salt preparation, and/or dosing regimen. Diarrhea may occur due to increased gastrointestinal motility caused by erythromycin. LESS FREQUENT OR RARE: Pancreatitis, pyloric stenosis, dynamic ileus, pseudomembranous colitis, sensorineural hearing loss, cholestasis, cholestatic hepatitis, acute hepatitis, hepatic failure, agranulocytosis, thrombocytopenia, hemolytic anemia, hypothermia, hypovolemic shock and hypotension, personality changes, nightmares, leukocytoclastic vasculitis, acute respiratory distress following an allergic reaction, Schonlein-Henoch syndrome, candidal esophagitis, gingival hyperplasia, contact dermatitis, fixed drug eruptions, toxic pustuloderma, and toxic epidermal necrolysis, interstitial nephritis, glomerulonephritis, thrombophlebitis (after IV administration), ventricular dysrhythmias (after IV administration). In general, the risk of dysrhythmias is increased when these agents are administered in combination with other drugs that prolong the QT interval.
Range of Toxicity:
- TOXICITY: In general, the macrolide antibiotics are of a low order toxicity. However, side effects can occur even within the therapeutic range of dosing. ERYTHROMYCIN: Adverse gastrointestinal effects are infrequent with the use of 1 gram per day orally in divided doses. Adverse gastrointestinal effects are more frequent and severe with 2 grams/day or more of any erythromycin formulation. ADULT: A woman who acutely ingested approximately 6.6 grams of erythromycin base developed severe epigastric pain, nausea and vomiting 3 hours later. PEDIATRIC: A 15-year-old girl developed nausea, vomiting, epigastric pain and tenderness, with an elevated serum lipase after ingesting 16 tablets (333 mg) of erythromycin base. An infant was inadvertently administered IV azithromycin (a 5 to 10-fold overdose) instead of the prescribed ceftriaxone, and quickly became unresponsive, cyanotic, and pulseless. The cardiac monitor showed wide-complex bradycardia, with a prolonged QTc interval, and third-degree atrioventricular block. The patient survived but with significant anoxic encephalopathy. THERAPEUTIC DOSE: Dosing varies by agent and indication. Refer to Dosing and Administration section.
- Support: MANAGEMENT OF MILD TO MODERATE TOXICITY: Toxicity following an acute overdose is uncommon. Treatment is symptomatic and supportive. Treat significant vomiting and diarrhea with IV fluids; administer antiemetics, as needed. Manage mild hypotension with IV fluids. MANAGEMENT OF SEVERE TOXICITY: Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Dysrhythmias should be treated with standard antiarrhythmic drugs, if necessary. SEIZURES: Administer IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. HYPERSENSITIVITY REACTION: Administer antihistamines, with or without inhaled beta agonists, corticosteroids or epinephrine.
- Decontamination: PREHOSPITAL: Severe toxicity is unusual after ingestion; prehospital decontamination is generally NOT necessary. HOSPITAL: GI decontamination is unlikely to be necessary, administer activated charcoal if the ingestion is recent and toxic coingestants are involved.
- Airway management: Airway management is unlikely to be needed following an overdose; however, ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias or severe acute allergic reactions.
- Antidote: None.
- Torsades de pointes: Prolongation of the QT interval has been associated with macrolide antibiotics, including azithromycin, and cases of torsade de pointes have been reported during postmarketing surveillance of azithromycin. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
- Monitoring of patient: Plasma levels of macrolide antibiotics are not clinically useful in overdose situations. Monitor vital signs and mental status following significant overdose. Monitor CBC with differential and platelet count, renal function and liver enzymes following a significant overdose. Leukopenia, agranulocytosis, and thrombocytopenia have been reported. Monitor serum electrolytes in patients with significant vomiting and/or diarrhea. Obtain an ECG, and institute continuous cardiac monitoring following significant overdose. Monitor pancreatic enzyme levels if the patient presents with severe epigastric pain or other clinical evidence of pancreatitis.
- Enhanced elimination procedure: Erythromycin is not removed significantly by either peritoneal dialysis or hemodialysis. It is unknown if hemodialysis would be effective in overdose of other agents.
- Patient disposition: HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home. OBSERVATION CRITERIA: Patients who are symptomatic need to be monitored until they are clearly improving and clinically stable. ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.