What are the potential interactions between Augmentin (amoxicillin/clavulanate) and methotrexate?

Interaction Between Augmentin (Amoxicillin/Clavulanate) and Methotrexate

Augmentin (amoxicillin/clavulanate) can increase methotrexate toxicity and should be used with extreme caution in patients on methotrexate therapy, requiring close monitoring of methotrexate levels and potential temporary discontinuation of methotrexate during the antibiotic course. 1

Mechanism of Interaction

The interaction between Augmentin and methotrexate occurs through several mechanisms:

1. Protein binding displacement: Penicillins (including amoxicillin) can displace methotrexate from serum albumin binding sites, leading to increased free methotrexate levels 1, 2

2. Reduced renal clearance: Penicillins may reduce the renal clearance of methotrexate, resulting in increased serum concentrations and potential toxicity 2

3. Competition for tubular secretion: Both drugs compete for the common tubular secretion system in the kidneys 3

Clinical Significance and Risk Factors

The severity of this interaction depends on several factors:

• Methotrexate dose: The interaction is more significant with high-dose methotrexate therapy but can still be clinically relevant with low-dose regimens 2

• Renal function: The interaction is more pronounced in patients with reduced renal function, particularly in elderly patients 1, 4

• Duration of therapy: Longer concurrent use increases risk of toxicity 1

Potential Consequences

Concurrent use may lead to:

• Bone marrow suppression
• Pancytopenia
• Mucositis
• Hepatotoxicity
• Renal failure
• Gastrointestinal toxicity

A case report documented severe toxicity including renal failure, myelosuppression, mucositis, nausea, vomiting, fever, and dermatologic abnormalities when amoxicillin was administered during high-dose methotrexate therapy 3.

Management Recommendations

1. For severe infections requiring Augmentin:

   • Temporarily discontinue methotrexate until the antibiotic course is complete and the infection has resolved 1
   • Monitor complete blood count, renal function, and liver function tests more frequently

2. For patients on long-term antibiotics:

   • More frequent monitoring of methotrexate levels and toxicity parameters is required 1

3. For elderly patients or those with renal impairment:

   • Exercise extreme caution as the interaction is more significant due to reduced renal function 4
   • Consider alternative antibiotics when possible

4. If concurrent use cannot be avoided:

   • Consider temporary methotrexate dose reduction
   • Monitor methotrexate levels closely
   • Be prepared to administer leucovorin (folinic acid) rescue if signs of toxicity develop 2

Warning Signs of Toxicity

Monitor for early signs of methotrexate toxicity:

• Mucositis (oral ulcers)
• Unexplained fever
• Diarrhea
• Decreased blood counts
• Elevated liver enzymes
• Skin rash or erythema

Common Pitfalls to Avoid

1. Assuming low-dose methotrexate is safe: Even with low-dose methotrexate regimens used in rheumatoid arthritis or psoriasis, this interaction can be clinically significant 1, 2

2. Overlooking renal function: Patients with even mild renal impairment are at significantly higher risk 4

3. Failure to monitor: Not implementing more frequent monitoring when the combination is used 1

4. Multiple interacting medications: The risk increases when other medications that affect methotrexate metabolism are used concurrently (e.g., NSAIDs, proton pump inhibitors) 1, 2

In summary, the combination of Augmentin and methotrexate requires careful consideration of risks versus benefits, with close monitoring for signs of toxicity if concurrent use cannot be avoided.