Is azithromycin or rifaximin better for diarrhea?

October 13, 2025 •

3 min read

While most cases of diarrhea resolve without intervention, some bacterial infections require antibiotics. When faced with infectious diarrhea, the choice between azithromycin or rifaximin hinges on the specific type of infection, as these medications target different pathogens.

Quick Summary

The best choice between azithromycin and rifaximin for diarrhea depends on whether the infection is invasive or non-invasive. Rifaximin is used for non-invasive watery diarrhea, while azithromycin is preferred for severe cases with fever or bloody stool.

Key Points

Rifaximin is for non-invasive diarrhea: It works locally in the gut and is best for non-bloody traveler's diarrhea and IBS-D.
Azithromycin is for severe or invasive diarrhea: It is the preferred choice for dysentery (bloody diarrhea) or when fever is present.
Azithromycin targets more pathogens: It is effective against a broader range of invasive bacteria, including Campylobacter and Shigella.
Rifaximin has lower systemic effects: Its minimal absorption means fewer systemic side effects and less impact on the wider microbiome.
Consider travel history: For traveler's diarrhea, the destination and potential pathogens can determine whether azithromycin or rifaximin is more appropriate.
Cost is a factor: Generic azithromycin is generally less expensive than the brand-name rifaximin (Xifaxan).

The question of whether azithromycin or rifaximin is better for diarrhea has no single answer, as the most effective treatment depends entirely on the type of bacterial infection causing the symptoms. While azithromycin is a systemic antibiotic that works well for invasive infections, rifaximin is a gut-specific option ideal for non-invasive bacterial overgrowth. Understanding the differences in how they function and what they treat is crucial for selecting the right medication. It is essential to consult with a healthcare provider before starting any antibiotic treatment.

Rifaximin: The Gut-Specific Specialist

Rifaximin (Xifaxan) is an antibiotic with minimal absorption that primarily acts within the gastrointestinal tract.

When to use rifaximin

Rifaximin is typically used for non-invasive conditions such as Traveler's Diarrhea caused by non-invasive Escherichia coli (though not for bloody diarrhea or fever), Irritable Bowel Syndrome with Diarrhea (IBS-D), Small Intestinal Bacterial Overgrowth (SIBO) off-label, and Hepatic Encephalopathy (HE).

Benefits of rifaximin's localized action

Rifaximin's non-systemic nature contributes to a favorable safety profile and less disruption to the gut microbiome compared to systemically absorbed antibiotics.

Azithromycin: The Systemic Option for Severe Cases

Azithromycin is a macrolide antibiotic that is systemically absorbed and targets a wider array of pathogens. It is generally preferred for more severe or invasive bacterial infections, including those causing bloody diarrhea or fever.

When to use azithromycin

Azithromycin is often the preferred choice for invasive Traveler's Diarrhea (severe or febrile), invasive pathogens like Campylobacter and Shigella, and severe bacterial diarrhea in children.

Mechanism and benefits of azithromycin

Azithromycin inhibits bacterial protein synthesis. Its systemic action allows it to combat bacteria that have penetrated the intestinal lining, making it suitable for more severe presentations of infectious diarrhea.

Comparing Azithromycin and Rifaximin for Diarrhea


Feature	Rifaximin	Azithromycin
Mechanism	Inhibits bacterial RNA synthesis.	Inhibits bacterial protein synthesis.
Systemic Absorption	Poorly absorbed; acts locally in the gut.	Systemically absorbed; circulates throughout the body.
Target Pathogens	Primarily non-invasive E. coli and broad-spectrum against gut bacteria.	Broad-spectrum, including invasive pathogens like Campylobacter and Shigella.
Indications for Diarrhea	Non-invasive Traveler's Diarrhea (no fever or bloody stool), IBS-D.	Invasive/Severe Traveler's Diarrhea (with fever or bloody stool), dysentery.
Safety Profile	Excellent safety profile due to low absorption.	Generally well-tolerated, with some risk of gastrointestinal upset.
Cost	Typically more expensive (brand name: Xifaxan).	Less expensive generic versions are available.

Considerations for specific conditions

Traveler's Diarrhea (TD)

For non-invasive TD without fever or bloody stool, rifaximin is an option. However, for invasive TD with fever or bloody stool, azithromycin is the preferred treatment. The CDC Yellow Book notes rifaximin can be used for severe, non-dysenteric TD, but azithromycin is preferred for severe cases.

Irritable Bowel Syndrome with Diarrhea (IBS-D)

Rifaximin has shown effectiveness in treating IBS-D symptoms. Rifaximin is the FDA-approved and more commonly used treatment for IBS-D.

Clostridium difficile Infection (CDI)

Many antibiotics can increase the risk of CDI. Rifaximin has been investigated for recurrent CDI but is not a primary treatment and requires medical guidance. Azithromycin has also been linked to an increased risk of CDI in some situations.

Final verdict: Consulting a doctor is key

Determining whether azithromycin or rifaximin is better for diarrhea requires a medical professional to diagnose the specific cause and severity. Incorrect antibiotic use can be ineffective or harmful. Rifaximin is suited for specific non-invasive conditions, while azithromycin is a systemic antibiotic for more serious infections. Proper diagnosis is vital for effective treatment.

Conclusion

Neither azithromycin nor rifaximin is universally superior for treating diarrhea; their use depends on the type of infection. Rifaximin is a safe, localized option for non-invasive traveler's diarrhea and IBS-D, while azithromycin is a systemic treatment necessary for severe, invasive infections with fever or bloody stools. For more details, see {Link: Dr.Oracle AI https://www.droracle.ai/articles/156760/what-is-the-best-anabiotic-for-travelerss-diarrhea-}.

Frequently Asked Questions

You should take rifaximin for diarrhea that is not bloody and not accompanied by a fever, particularly if it's traveler's diarrhea caused by non-invasive E. coli or if you have IBS with diarrhea.

Yes, azithromycin is the preferred antibiotic for bloody diarrhea (dysentery) and diarrhea accompanied by a fever. Rifaximin should be avoided in these invasive cases.

The key difference is absorption. Rifaximin is poorly absorbed and works locally in the gut, whereas azithromycin is systemically absorbed and works throughout the body.

No, concurrent administration of rifaximin with other antibiotics for traveler's diarrhea is not recommended as it doesn't provide additional benefits and may increase adverse events.

Yes, rifaximin is an FDA-approved treatment for Irritable Bowel Syndrome with Diarrhea (IBS-D) in adults.

Yes, azithromycin is an effective treatment for traveler's diarrhea, especially in cases of invasive illness with fever or bloody stools, and in regions with high fluoroquinolone resistance.

Rifaximin has an excellent safety profile due to its minimal systemic absorption, making it very safe for localized gut issues. Azithromycin is also generally well-tolerated, but because it is systemic, it carries a broader range of potential side effects.