Is diarrhea the primary side effect of amoxicillin at higher doses, such as 1 gram three times a day (TID)?

Diarrhea as a Side Effect of High-Dose Amoxicillin

Yes, diarrhea is the main side effect of amoxicillin at higher doses such as 1 gram three times daily (TID), particularly when combined with clavulanate. 1

Evidence on Amoxicillin and Diarrhea

• According to the FDA label, diarrhea is listed as one of the most common adverse reactions (greater than 1%) observed in clinical trials of amoxicillin 1
• The risk of diarrhea is significantly higher with amoxicillin-clavulanate compared to amoxicillin alone, with diarrhea being the most frequently reported adverse event 1, 2
• In clinical trials, patients receiving dual therapy with amoxicillin and lansoprazole experienced diarrhea at a rate of 8%, while those receiving triple therapy (amoxicillin/clarithromycin/lansoprazole) experienced diarrhea at a rate of 7% 1
• A systematic review and meta-analysis found that diarrhea was significantly associated with amoxicillin-clavulanate (Peto odds ratio 3.30) but not with amoxicillin alone 2

Dose-Related Gastrointestinal Effects

• Higher doses of amoxicillin are associated with increased rates of gastrointestinal side effects, particularly diarrhea 3, 4
• In a randomized clinical trial comparing high-dose versus standard-dose amoxicillin-clavulanate, severe diarrhea was reported in 15.8% of high-dose immediate-release amoxicillin patients compared to 4.8% in standard-dose patients (p=0.048) 4
• When the clavulanate dose exceeds approximately 10 mg/kg per day, diarrhea becomes more problematic 5

Mechanism and Management

• Antibiotic-associated diarrhea can occur through two primary mechanisms: disruption of normal gut flora and, more seriously, Clostridioides difficile-associated diarrhea (CDAD) 1, 6
• CDAD has been reported with use of nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis 1
• For mild diarrhea associated with amoxicillin, maintaining hydration with clear liquids (8-10 large glasses daily) is recommended 7
• Dietary modifications for mild diarrhea include eliminating lactose-containing products, avoiding alcohol, and eating small, frequent meals of bland foods 7
• Loperamide may be considered for mild diarrhea, with an initial dose of 4 mg followed by 2 mg after every loose stool (not exceeding 16 mg per day) 7

Other Notable Side Effects

• Besides diarrhea, other common adverse reactions to amoxicillin include rash, vomiting, and nausea 1
• Candidiasis is significantly associated with amoxicillin use (Odds Ratio 7.77) 2
• Serious but less common side effects include hypersensitivity reactions, severe cutaneous adverse reactions, and blood disorders 1

Clinical Implications

• When prescribing high-dose amoxicillin (1 gram TID), patients should be counseled about the increased risk of diarrhea 1, 4
• For moderate to severe diarrhea, or diarrhea persisting more than 2-3 days, medical evaluation is necessary to rule out CDAD 7, 1
• If CDAD is suspected or confirmed, appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated 1

High-dose amoxicillin therapy requires careful monitoring for gastrointestinal side effects, with diarrhea being the most common adverse event that may impact patient adherence and treatment success.