Can Azithromycin Cause Delirium?: Understanding a Rare Drug Side Effect

October 13, 2025 •

4 min read

Studies analyzing the FDA Adverse Event Reporting System (FAERS) have found a statistically significant association between azithromycin and reported delirium. While uncommon, it is important to understand the risk factors and recognize the symptoms of this serious neuropsychiatric side effect, particularly among vulnerable populations.

Quick Summary

Azithromycin, a macrolide antibiotic, has been associated with a rare risk of delirium, especially in elderly or compromised patients. Reports detail temporary mental confusion and agitation that resolve upon discontinuing the drug.

Key Points

Rare but Documented Side Effect: Azithromycin, though less likely than other macrolides, has been associated with rare cases of delirium confirmed by case reports and large-scale pharmacovigilance studies.
At-Risk Populations: Elderly patients and those with renal impairment, pre-existing cognitive issues, or critical illness are at higher risk for experiencing delirium while on azithromycin.
Symptoms Can Fluctuate: Delirium manifests as an acute, fluctuating disturbance in attention and awareness, which can be either hyperactive (agitation, hallucinations) or hypoactive (lethargy, apathy).
Timely Detection is Key: Recognizing the sudden onset of confusion and other cognitive changes is vital for prompt management and improved patient outcomes.
Resolution Follows Discontinuation: In most cases, the delirium resolves after the azithromycin is discontinued, although the process may take longer than for other macrolide-induced CNS effects.
Management is Straightforward: The primary treatment involves stopping the azithromycin, substituting a different antibiotic, and providing supportive care to manage symptoms.

Can Azithromycin Cause Delirium? The Evidence

Yes, azithromycin can cause delirium, though it is considered a rare adverse drug reaction. While macrolide antibiotics like azithromycin are primarily known for their efficacy against bacterial infections, they have also been linked to neuropsychiatric side effects. Historically, azithromycin was believed to have a lower risk of these effects compared to other macrolides like clarithromycin, but case reports and large-scale pharmacovigilance studies have confirmed the potential association.

Documented Case Reports and Findings

Several studies and case reports provide evidence for azithromycin-induced delirium:

Geriatric Patients: In 2003, researchers reported significant delirium in two elderly patients receiving conventional doses of azithromycin for lower respiratory tract infections. The delirium developed within 72 hours of starting the drug and resolved 48–72 hours after discontinuation. Interestingly, the resolution time was slower than typically seen with clarithromycin-induced CNS symptoms.
Pediatric Cases: Delirium has also been observed in children. In 2014, a report detailed delirium in a pediatric patient following therapeutic doses of azithromycin. The symptoms subsided within 48 hours after the drug was stopped. A 2011 report also documented azithromycin-induced agitation and choreoathetosis in a child, which resolved upon discontinuing the antibiotic.
FAERS Database Analysis: A large-scale pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) confirmed a statistically significant association between azithromycin and reported delirium. The study identified azithromycin, along with other macrolides, as having an increased risk of reporting delirium compared to the broader population. The analysis also found that older patients (over 65) had a higher reporting odds ratio for delirium associated with macrolide antibiotics.

Understanding the Mechanism

The precise mechanism by which azithromycin causes delirium is not fully understood, but it is thought to involve the drug's effect on the central nervous system (CNS). Unlike some other antibiotics, azithromycin has limited penetration into the blood-brain barrier, which may explain why CNS effects are rare. However, in susceptible individuals, some penetration may be sufficient to cause adverse effects. Hypotheses for macrolide-induced neurotoxicity include:

GABA Receptor Antagonism: Similar to other antibiotics like beta-lactams and fluoroquinolones, some macrolides may exert a competitive antagonism effect on GABA-A receptors, a key inhibitory neurotransmitter system in the brain. This could lead to a state of neuronal hyperexcitability and contribute to symptoms like confusion and seizures.
Drug Interactions: Concurrent use of other medications, especially those metabolized by the cytochrome P450 enzyme system, can potentially elevate macrolide levels in the body, increasing the risk of toxicity.
Neuroinflammation: Infection and the associated inflammatory response can also contribute to delirium, potentially interacting with or exacerbating the antibiotic's effects on the brain.

Risk Factors for Azithromycin-Induced Delirium

While this side effect is uncommon, certain patient characteristics can increase the risk of developing delirium with azithromycin.

Advanced Age: Elderly patients are particularly vulnerable to drug-induced delirium due to age-related changes in metabolism, polypharmacy, and a higher prevalence of cognitive issues.
Renal Impairment: Reduced kidney function can lead to higher-than-normal drug concentrations in the body, increasing the likelihood of toxicity.
Pre-existing CNS Conditions: Patients with prior brain injury, dementia, or other neurological or psychiatric disorders are more susceptible to cognitive changes induced by medications.
Critical Illness: Sepsis, severe infections, and other critical medical conditions place stress on the body and brain, making patients more prone to delirium.

Recognizing Delirium: Symptoms and Characteristics

Delirium is a serious condition requiring immediate medical attention. It is characterized by an acute, fluctuating disturbance in attention, awareness, and cognition. The key to identifying it is recognizing a change from the patient's baseline mental state. Symptoms can be categorized into three types:

Delirium Symptom Categories

Hyperactive: Characterized by restlessness, agitation, aggression, mood swings, and hallucinations.
Hypoactive: The more common but often missed type, involving lethargy, drowsiness, apathy, and decreased responsiveness.
Mixed: Patients fluctuate between hyperactive and hypoactive states, making the condition unpredictable.


Feature	Delirium	Dementia
Onset	Acute, over hours to days	Gradual, over months to years
Course	Fluctuating, often worse at night	Progressive decline, generally stable throughout the day
Attention	Significantly impaired; easily distracted	Initially preserved, declines as disease progresses
Awareness	Reduced or altered	Generally clear
Reversibility	Often reversible with treatment of underlying cause	Irreversible and progressive

Management and Outlook

If azithromycin-induced delirium is suspected, the management strategy is straightforward: discontinue the offending drug immediately. The medical team can then switch to an alternative, non-neurotoxic antibiotic to treat the underlying infection. In many reported cases, symptoms begin to subside shortly after the azithromycin is stopped, although full resolution may take several days, particularly in elderly patients.

Steps for Management

Discontinue Azithromycin: Remove the drug identified as the likely cause of the delirium.
Substitute Antibiotic: Replace with a suitable antibiotic from a different class to treat the infection.
Symptom Management: Supportive care is crucial. This includes maintaining a calm, predictable environment and ensuring adequate hydration and nutrition. In cases of severe agitation or psychosis, medications like antipsychotics may be used cautiously, especially in elderly patients.
Follow-up: Continuous monitoring is necessary to ensure the delirium resolves completely and to prevent future episodes.

Conclusion

While azithromycin is generally a safe and well-tolerated antibiotic, its potential to cause delirium should not be overlooked, especially in at-risk populations like the elderly or those with underlying CNS or renal issues. The existence of multiple case reports and documented associations in pharmacovigilance data confirms that azithromycin can cause delirium. Timely recognition of the symptoms and swift discontinuation of the medication are crucial for preventing negative patient outcomes. Healthcare providers should be mindful of this rare but serious side effect when prescribing macrolides and vigilantly monitor patients for any signs of cognitive change during treatment. Patients and caregivers should also be aware of the possibility and promptly report any unusual changes in mental status to a medical professional.

Frequently Asked Questions

Delirium caused by azithromycin is rare but documented. It is less common than other macrolides like clarithromycin, but it has been confirmed through case reports and analyses of adverse event databases, particularly in vulnerable populations.

The onset of delirium linked to azithromycin is typically rapid, often appearing within a few days of starting the medication. Case reports have described onset within 72 hours of initiating therapy.

Key symptoms include acute confusion, disorientation, agitation, hallucinations, and fluctuating levels of consciousness. The patient's behavior represents a clear and rapid change from their normal baseline.

Yes, elderly patients are at a significantly higher risk for drug-induced delirium. Factors such as age-related changes in metabolism, polypharmacy, and the presence of underlying health conditions contribute to this increased vulnerability.

If you or someone you know is experiencing symptoms of delirium while on azithromycin, it is crucial to seek immediate medical attention. The drug will likely need to be discontinued and potentially replaced with an alternative antibiotic.

The main treatment is to stop the azithromycin. Medical staff will provide supportive care and may use other medications to manage severe symptoms. The delirium often resolves after the drug is stopped, though complete recovery may take time.

No, azithromycin-induced delirium is typically a temporary condition. It usually resolves once the medication is discontinued, and the underlying infection is treated, though the duration of resolution can vary.