What are the side effects of co-amoxiclav (amoxicillin-clavulanate)?

Side Effects of Co-Amoxiclav (Amoxicillin-Clavulanate)

Co-amoxiclav commonly causes gastrointestinal side effects, with diarrhea/loose stools being the most frequent adverse reaction, occurring in approximately 9% of patients, followed by nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%). 1

Common Adverse Reactions

Gastrointestinal Effects

• Diarrhea and loose stools are the predominant side effects, occurring in 9% of patients overall 1
• The incidence of diarrhea increases significantly with higher doses—in pediatric sinusitis trials, adverse events occurred in 44% of patients on high-dose amoxicillin-clavulanate versus 14% on placebo 2
• Other GI effects include nausea (3%), abdominal discomfort, flatulence, and vomiting (1%) 1
• Less than 3% of patients discontinue therapy due to drug-related adverse reactions 1

Dermatologic Reactions

• Skin rashes and urticaria occur in approximately 3% of patients 1
• Meta-analyses show approximately 5% increased rate of adverse events, particularly diarrhea and rash, compared to placebo 2
• Mild erythematous rash has been reported in comparative studies 3

Other Common Effects

• Vaginitis occurs in 1% of patients 1
• Headache occurs in less than 1% of patients 1

Serious Adverse Reactions

Hypersensitivity and Anaphylaxis

• Co-amoxiclav is the most frequently identified cause of severe drug-induced anaphylaxis in perioperative settings 4
• Anaphylactic reactions can occur even in patients with previous tolerant exposures to the antibiotic 5
• Other hypersensitivity reactions include pruritus, angioedema, serum sickness-like reactions, erythema multiforme, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and toxic epidermal necrolysis 1

Hepatic Dysfunction

• Hepatic dysfunction, including hepatitis and cholestatic jaundice, has been reported with co-amoxiclav 1
• This occurs more commonly in elderly patients, males, or those on prolonged treatment 1
• Onset of hepatic dysfunction may occur during therapy or several weeks after discontinuation 1
• The hepatic dysfunction may be severe but is usually reversible; deaths have been reported 1

Hematologic Effects

• Anemia (including hemolytic anemia), thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported 1
• These reactions are usually reversible upon discontinuation and are believed to be hypersensitivity phenomena 1
• Increased prothrombin time has been reported in patients receiving co-amoxiclav with concurrent anticoagulant therapy 1

Renal Effects

• Interstitial nephritis, hematuria, and crystalluria have been reported 1

Gastrointestinal Complications

• Clostridium difficile-associated diarrhea (CDAD) and pseudomembranous colitis can occur 1
• Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment 1
• Other serious GI effects include enterocolitis and hemorrhagic colitis 1

Central Nervous System Effects

• Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported 1

Comparative Tolerability

Versus Other Antibiotics

• Co-amoxiclav has higher rates of gastrointestinal intolerance compared to macrolides alone 4
• In comparative studies with ciprofloxacin, co-amoxiclav was associated with similar overall adverse event rates but different profiles: nausea (10.6% vs 13%), diarrhea (6.7% vs 4.3%), and abdominal pain (7.3% vs 7.6%) 6
• Ciprofloxacin was better tolerated than co-amoxiclav in one study, with only 12.4% reporting adverse events versus 25% with co-amoxiclav 4

Pediatric Considerations

• Tooth discoloration (brown, yellow, or gray staining) has been reported, most commonly in pediatric patients 1
• Discoloration was reduced or eliminated with brushing or dental cleaning in most cases 1
• In pediatric otitis media trials, treatment-related side effects occurred in 8% of azithromycin patients versus 4% of co-amoxiclav patients 3

Long-Term and Microbiome Effects

• Growing evidence suggests early-life antibiotic exposures may disrupt microbial balance, potentially contributing to inflammatory bowel disease, obesity, eczema, and asthma 2
• Antibiotics are responsible for the largest number of unplanned medical visits for medication-related adverse events among children, exceeding 150,000 per year 2

Clinical Implications

When prescribing co-amoxiclav, the American Academy of Otolaryngology-Head and Neck Surgery notes that side effects include rash, upset stomach, nausea, vomiting, allergic reactions, and promotion of resistant bacteria 4. The number needed to harm is approximately 8, meaning for every 8 patients treated with antibiotics, one will experience an adverse event 4. Shorter courses of therapy (5-7 days versus 10 days) reduce adverse event rates while maintaining efficacy 4.