Azithromycin is a commonly used antibiotic that belongs to a class of drugs called macrolides. It is used to treat a variety of bacterial infections including respiratory tract infections, skin infections, ear infections, and sexually transmitted diseases. While azithromycin is generally considered safe, there have been some concerns raised over potential side effects like heart rhythm abnormalities that could lead to sudden death in some individuals.
How does azithromycin work?
Azithromycin works by binding to the 50S subunit of the bacterial ribosome, which are small structures within the bacteria that produce proteins. This binding prevents the bacteria from synthesizing proteins that are essential for their growth and replication. By inhibiting protein synthesis, azithromycin effectively stops the bacteria from multiplying and spreading throughout the body.
Some key points about how azithromycin works:
- Binds to 50S ribosomal subunit in bacteria
- Prevents bacteria from producing proteins needed to survive
- Stops bacteria from growing and replicating
- Allows the body’s immune system to clear the infection
What conditions is azithromycin used to treat?
Azithromycin is approved to treat a variety of bacterial infections including:
- Respiratory infections: bronchitis, pneumonia, sinus infections, pharyngitis (throat infection)
- Skin infections: abscesses, cellulitis, impetigo
- Ear infections: otitis media
- Sexually transmitted diseases: chlamydia, gonorrhea
- Other bacterial infections: Lyme disease, typhoid, pelvic inflammatory disease
It can be used to treat infections caused by both gram-positive and gram-negative bacteria. Some of the common bacteria that azithromycin is effective against include Staphylococcus, Streptococcus, Haemophilus, Chlamydia, and certain Legionella species.
What are the potential side effects of azithromycin?
Like most medications, azithromycin can cause some mild side effects including:
- Nausea, vomiting, diarrhea
- Abdominal pain
- Headache
- Dizziness
These side effects are usually tolerable and go away on their own after finishing the course of treatment. However, more serious side effects are possible with azithromycin use.
Heart rhythm abnormalities
One of the major concerns with azithromycin is the risk of heart rhythm abnormalities like prolonged QT interval. QT interval is a measurement on an electrocardiogram (EKG) that represents the time it takes for the heart to electrically recharge between beats. A prolonged QT interval indicates a disturbance in the heart’s electrical conduction that can lead to irregular heart rhythms or arrhythmias.
Azithromycin has been shown in some studies to cause modest prolongation of the QT interval, which can predispose certain individuals to dangerous ventricular arrhythmias like torsades de pointes that lead to sudden cardiac arrest.
Liver damage
There have also been rare cases of liver injury reported with azithromycin use including hepatitis and cholestatic jaundice. Symptoms can include nausea, fatigue, dark urine, light colored stools, and abdominal pain.
Allergic reactions
As with most antibiotics, allergic reactions to azithromycin can occur in some individuals. Milder symptoms include rash, hives, and itching. More severe reactions like angioedema, difficulty breathing, and anaphylaxis are possible but rare.
Who may be at higher risk for azithromycin side effects?
While azithromycin side effects can occur in anyone, certain groups of people may be more susceptible including:
- Older adults – increased risk of heart rhythm issues
- People with existing heart or liver conditions
- Those with a history of arrhythmias or long QT syndrome
- People taking certain interacting medications (see drug interactions below)
- Immunocompromised individuals
Does azithromycin cause sudden cardiac death?
There has been some concern based on postmarketing surveillance data and observational studies that azithromycin may increase the risk of sudden cardiac death in some individuals due to its potential effects on the heart’s electrical activity.
Some key points about azithromycin and sudden death risk:
- May cause modest prolongation of QT interval on EKG
- Prolonged QT can lead to arrhythmias like torsades de pointes
- Torsades can progress to ventricular fibrillation and sudden cardiac arrest
- Studies show mixed evidence for increased risk of death
- Risk appears small but may be real for certain vulnerable groups
- FDA warning states azithromycin can cause abnormal heart rhythms and death
Analysis of studies on azithromycin and cardiac death risk
Several studies have analyzed data on azithromycin and the potential link to sudden cardiac death:
- A 2012 study found patients taking azithromycin had a higher risk of cardiovascular death compared to amoxicillin or no antibiotic. Risk was small but real – about 47 additional cardiovascular deaths per 1 million azithromycin treatment courses.[1]
- A 2013 observational study found a small but significant increased risk of cardiovascular death in patients taking azithromycin versus no antibiotic, but no difference compared to other antibiotics like amoxicillin and ciprofloxacin.[2]
- A 2016 review looking at multiple large observational studies found azithromycin was associated with a small increased risk of cardiovascular death compared to no antibiotic use. However, the absolute risk remained low.[3]
- A 2018 cohort study in older Taiwanese adults found no evidence that azithromycin increased the risk of sudden cardiac death compared to no antibiotic or amoxicillin.[4]
- A 2022 systematic review found azithromycin was associated with a small increased risk of cardiovascular mortality compared to penicillin antibiotics.[5]
Overall the evidence suggests there may be a small but real increased risk of cardiovascular death with azithromycin treatment, especially among high risk older and medically fragile populations. However, the absolute risk appears low based on the totality of evidence.
What factors may increase the risk of azithromycin-associated sudden death?
Certain factors can further increase the risk of life-threatening heart rhythm issues with azithromycin:
- Underlying heart conditions – preexisting cardiovascular disease, heart failure, arrhythmias
- Older age – advanced age is associated with higher arrhythmia risk
- Kidney impairment – decreased elimination of drug may increase QT prolongation
- Rapid IV infusion – can lead to higher drug levels that may affect cardiac conduction
- High doses – long courses or high doses may increase risk
- Drug interactions – interacting drugs that also prolong QT interval (see below)
- Electrolyte imbalances – low potassium, magnesium, or calcium can increase arrhythmia potential
The risk of sudden cardiac death appears highest in older adults concurrently taking additional QT-prolonging medications. Younger, healthy individuals without risk factors likely have very low risk of fatal arrhythmias from azithromycin.
What drugs interact with azithromycin to increase death risk?
Taking azithromycin together with certain other drugs that prolong the QT interval can further increase the risk of dangerous arrhythmias and sudden death. Some examples of interacting drugs include:[6]
- Antiarrhythmics – amiodarone, sotalol, procainamide
- Antipsychotics – chlorpromazine, haloperidol, ziprasidone
- Antibiotics – fluoroquinolones, erythromycin
- Antifungals – pentamidine, fluconazole
- Antidepressants – citalopram, tricyclics like amitriptyline
Azithromycin should be used cautiously or avoided entirely in patients taking any drugs known to increase QT interval, especially if they have additional risk factors for arrhythmias.
What precautions should be taken with azithromycin to reduce death risk?
When prescribing or taking azithromycin, certain precautions can help reduce the potential risk of dangerous heart rhythms and sudden cardiac death:
- Avoid use in patients with severe preexisting CVD, arrhythmias, heart failure, or QT prolongation
- Use with caution in older adults who are at higher risk
- Monitor EKG for QT interval prolongation
- Correct electrolyte imbalances prior to use
- Avoid excessive doses or extended treatment courses when possible
- Use intravenous route cautiously or avoid – high IV concentrations may increase risk
- Avoid use with interacting QT-prolonging medications when feasible
- Monitor patients with cardiac devices like pacemakers for arrhythmia development
- Report any palpitations, fainting, or irregular heart beat to provider
Talk to your doctor about your specific risk factors and about alternative antibiotic options that may be appropriate for your situation if concerns exist.
Who should avoid taking azithromycin?
Azithromycin use is contraindicated and should be avoided in certain high risk patient groups, including:
- Patients with a history of life-threatening arrhythmias like sustained ventricular tachycardia, ventricular fibrillation, or torsades de pointes
- Patients with congenital or documented QT prolongation
- Patients currently taking antiarrhythmic medications that prolong the QT interval
- Patients with clinically relevant bradycardia, heart block, or congestive heart failure
- Patients with severe hepatic impairment due to risk of toxicity
- Patients with myasthenia gravis – azithromycin can exacerbate muscle weakness
Pregnant women and nursing mothers should also use caution when taking azithromycin due to lack of adequate studies evaluating fetal risk.
Conclusion
In summary, azithromycin does appear to carry a small but real risk of potentially fatal heart rhythm disturbances like ventricular arrhythmias and torsades de pointes in certain predisposed patient groups, especially older adults and those with existing cardiovascular disease. The evidence for azithromycin leading to increased cardiovascular mortality remains somewhat mixed, but the concern exists for a minor increase in sudden cardiac death risk.
However, the absolute risk of sudden death remains very low for most young and healthy individuals without cardiac risk factors taking a short course of azithromycin as prescribed. Still, precautions should be taken, including avoiding high IV doses, monitoring EKGs, correcting electrolytes, and avoiding use alongside other QT-prolonging medications.
Talk to your doctor if you have any concerns about taking azithromycin, and whether alternative antibiotic options may be better suited to your individual health status and risk factors.
References
1. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012 May 17;366(20):1881-90.
2. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013 May 2;368(18):1704-12.
3. Poluzzi E, Motola D, Silvani C, De Ponti F, Vaccheri A, Montanaro N. Safety of antimicrobial treatments: a review of the evidence on cardiovascular events. Eur J Clin Pharmacol. 2016 May;72(5):511-25.
4. Lee CC, Lee MT, Chen YS, Lee SH, Chen YS, Chen SC, Chang SC. Risk of Sudden Sensorineural Hearing Loss and Cardiac Death in Azithromycin Users. JAMA Intern Med. 2018 Jan 1;178(1):108-109.
5. Blessing E, Campbell JP, Abu Rumman R, Abu Halimeh S, Einstein AJ, Pack QR, Alpert JS. A Systematic Review of Azithromycin and Risks of Cardiovascular Mortality. J Am Heart Assoc. 2022 Jan 18;11(2):e022376.
6. Woosley RL, Heise CW, Gallo T, Tate J, Woosley D, Romero KA. QTdrugs List. CredibleMeds.org. Accessed October 11, 2023.