Which antibiotic causes most GI upset? A Comprehensive Guide

October 12, 2025 •

4 min read

Approximately one in five people who take antibiotics will experience side effects, with gastrointestinal (GI) issues like diarrhea being the most common [1.9.4]. Understanding which antibiotic causes most GI upset is key to managing treatment and minimizing discomfort.

Quick Summary

A detailed look at the antibiotics most frequently linked to gastrointestinal distress, including broad-spectrum penicillins, clindamycin, and cephalosporins. It explores why this occurs and provides strategies for prevention and management.

Key Points

High-Risk Antibiotics: Clindamycin, amoxicillin-clavulanate, cephalosporins, and fluoroquinolones are most frequently associated with GI upset [1.3.1].
Mechanism of Action: Antibiotics disrupt the natural balance of the gut microbiome, killing beneficial bacteria and allowing harmful ones to overgrow [1.9.2].
C. difficile Risk: A severe consequence of antibiotic use is Clostridioides difficile infection, which causes severe diarrhea and colitis. Clindamycin poses a particularly high risk [1.6.2].
Symptom Prevalence: GI side effects are common, affecting about 1 in 5 people taking antibiotics [1.9.4]. Amoxicillin-clavulanate can cause diarrhea in up to 30% of users [1.5.1].
Management with Probiotics: Taking probiotics like Lactobacillus rhamnosus or Saccharomyces boulardii can significantly reduce the risk of antibiotic-associated diarrhea [1.7.1, 1.7.2].
Diet and Hydration: Staying hydrated and temporarily eating bland foods can help manage symptoms [1.8.3]. Taking certain antibiotics with food may also reduce irritation [1.2.5].
When to Seek Help: Severe, bloody, or persistent diarrhea accompanied by fever or intense cramps requires immediate medical attention [1.4.2].

The Link Between Antibiotics and Digestive Problems

Antibiotics are powerful medications designed to kill harmful bacteria, but they don't distinguish between bad and good bacteria [1.9.2]. The human gastrointestinal tract contains trillions of microorganisms, known as the gut microbiome, which play crucial roles in digestion and immune system regulation [1.9.2]. When antibiotics eliminate beneficial bacteria, this delicate balance is disrupted, a state called dysbiosis. This disruption is a primary reason for antibiotic-associated diarrhea (AAD), nausea, and cramping, affecting up to 30% of patients [1.2.3, 1.9.4].

High-Risk Antibiotics for GI Upset

While nearly all antibiotics can cause GI issues, some carry a significantly higher risk. Broad-spectrum antibiotics, which target a wide variety of bacteria, are most often implicated [1.3.5].

Key Culprits

Clindamycin: Frequently cited as one of the antibiotics most strongly associated with GI side effects, particularly diarrhea [1.3.1, 1.3.2]. It carries a notably high risk for leading to Clostridioides difficile (C. diff) infection [1.6.2].
Amoxicillin-clavulanate (Augmentin): This combination penicillin is well-known for causing GI distress. Studies show diarrhea can occur in 9% to as high as 30% of patients, depending on the dose [1.5.2, 1.5.1].
Cephalosporins: This class, especially second and third-generation versions like cefixime, is frequently associated with diarrhea and other GI issues [1.3.1, 1.10.1].
Macrolides: Erythromycin is particularly known for causing stomach pain, nausea, and diarrhea [1.4.2, 1.4.4]. Newer macrolides like azithromycin and clarithromycin also carry this risk [1.2.2].
Fluoroquinolones: This class of antibiotics is also frequently linked to AAD and an increased risk of C. diff infection [1.3.2].

The Serious Risk of C. difficile Infection

The most severe form of antibiotic-associated diarrhea is caused by the overgrowth of the bacterium Clostridioides difficile [1.2.4]. When antibiotics wipe out competing bacteria in the gut, C. diff can multiply and release toxins that damage the intestinal lining, leading to severe, watery diarrhea, abdominal pain, fever, and a potentially life-threatening condition called pseudomembranous colitis [1.2.3, 1.9.3]. Clindamycin, fluoroquinolones, and cephalosporins are the antibiotics most commonly linked to C. diff infection [1.2.2]. One study noted that clindamycin use was associated with a nearly threefold increased risk of C. diff infection compared to other antibiotics [1.6.1].

Comparison of Common Antibiotics and GI Side Effects


Antibiotic Class	Common Examples	Frequency of GI Upset	Key Considerations
Penicillins	Amoxicillin, Ampicillin	Moderate risk; combination with clavulanate (Augmentin) significantly increases risk [1.5.2, 1.3.1].	Diarrhea rates for Amoxicillin-clavulanate can be up to 30% [1.5.1].
Clindamycin	Clindamycin	High risk [1.3.1]. Diarrhea can occur in up to 21% of patients [1.6.2].	Has one of the highest associations with subsequent C. difficile infection [1.6.2, 1.6.5].
Cephalosporins	Cephalexin, Cefdinir	Frequently associated, especially 2nd and 3rd generation drugs [1.3.1].	Cefixime caused GI disturbances in about 30% of adults in clinical trials [1.10.1].
Macrolides	Erythromycin, Azithromycin	High risk, especially with Erythromycin [1.4.4, 1.3.5].	Taking with food may lessen symptoms, though Erythromycin is best absorbed on an empty stomach [1.4.4].
Fluoroquinolones	Ciprofloxacin, Levofloxacin	Frequently associated with GI upset and C. diff risk [1.3.1].	Risk for C. diff is significant compared to lower-risk antibiotics [1.6.5].
Tetracyclines	Doxycycline, Tetracycline	Lower to moderate risk [1.3.1]. Common side effects include nausea and upset stomach [1.11.1].	Must be taken with plenty of water to avoid esophageal irritation; some cannot be taken with dairy [1.11.2, 1.2.5].

Strategies for Managing and Preventing GI Upset

Managing digestive side effects is crucial for completing your antibiotic course.

1. Take With Food (If Recommended)

For some antibiotics like amoxicillin and doxycycline, taking the medication with food can help reduce stomach irritation [1.2.5]. However, other antibiotics, such as tetracycline, must be taken on an empty stomach for proper absorption. Always check with your doctor or pharmacist for specific instructions [1.2.5].

2. Stay Hydrated

Diarrhea leads to fluid loss. It's important to drink plenty of water, broths, or oral rehydration solutions to replace lost fluids and electrolytes [1.8.1, 1.8.3]. Avoid sugary drinks, alcohol, and caffeine, which can worsen symptoms [1.8.3].

3. Incorporate Probiotics

Probiotics are beneficial live microorganisms that can help restore balance to the gut flora [1.9.1]. Research suggests that taking probiotics during antibiotic therapy can reduce the risk of developing AAD [1.7.1]. A meta-analysis found that probiotics reduced the risk of AAD by 42% [1.7.1]. Strains like Lactobacillus rhamnosus and Saccharomyces boulardii appear to be particularly effective [1.7.2]. It is often recommended to take the probiotic a few hours apart from the antibiotic dose.

4. Adjust Your Diet

Temporarily avoid high-fiber foods, fatty, and spicy foods that can aggravate your digestive system [1.8.2, 1.8.3]. Bland foods may be better tolerated. Once symptoms resolve, you can gradually return to your normal diet.

5. Know When to Contact a Doctor

Mild diarrhea often resolves after the antibiotic course is finished. However, if you experience severe watery or bloody stools, intense abdominal cramping, or fever, contact a healthcare professional immediately, as these could be signs of a C. diff infection [1.4.2, 1.8.2].

Conclusion

While essential for fighting bacterial infections, many antibiotics disrupt the gut's natural environment, leading to GI upset. Broad-spectrum agents like clindamycin, amoxicillin-clavulanate, and certain cephalosporins are most often the answer to 'which antibiotic causes most GI upset?'. Awareness of these risks and proactive management—such as taking probiotics, staying hydrated, and following medication instructions carefully—can help mitigate these common but uncomfortable side effects. Always consult your healthcare provider about any severe or persistent symptoms.

For more information on antibiotic-associated diarrhea, you can visit the Mayo Clinic.

Frequently Asked Questions

Clindamycin is widely recognized for having one of the highest risks of causing antibiotic-associated diarrhea (AAD), including its most severe form, Clostridioides difficile (C. diff) infection [1.3.1, 1.6.2].

You should not take anti-diarrheal medications like loperamide (Imodium) without first consulting your doctor. These drugs can interfere with the body's ability to clear toxins and may worsen a C. diff infection [1.8.2, 1.8.3].

Diarrhea can start within a few days of beginning the antibiotic, but it can also occur up to two months after you have finished your treatment course [1.2.3, 1.4.2].

While probiotics can significantly lower the risk of antibiotic-associated diarrhea, they may not prevent it entirely or alleviate other GI symptoms like nausea or stomach pain [1.7.1]. However, studies show they are beneficial in reducing diarrhea incidence [1.7.1].

Yes. Some antibiotics, like amoxicillin, are better tolerated with food to reduce stomach upset [1.2.5]. Others require an empty stomach for absorption. Always follow the specific instructions from your pharmacist or doctor.

Broad-spectrum antibiotics, which kill a wider range of bacteria, are more disruptive to the gut microbiome than narrow-spectrum ones. This widespread disruption is what leads to a higher incidence of GI side effects [1.3.5].

Yogurt with live active cultures contains probiotics and can be helpful [1.8.4]. However, for preventing AAD, specific probiotic supplements containing strains like Lactobacillus rhamnosus or Saccharomyces boulardii at higher doses (≥ 5 billion CFUs) are often recommended based on clinical studies [1.7.2].