What is the severity of the interaction between amoxicillin and methotrexate?

Severity of Amoxicillin-Methotrexate Interaction

The amoxicillin-methotrexate interaction is considered clinically significant and potentially serious, particularly with high-dose methotrexate, but appears to be less problematic with low-dose methotrexate regimens commonly used in dermatology and rheumatology practice.

Mechanism and Clinical Significance

The interaction occurs through reduced renal elimination of methotrexate, as amoxicillin (a penicillin) competes with methotrexate at the renal tubular secretion system, specifically the organic anion transport pathways 1, 2. This competition can lead to:

• Prolonged and elevated methotrexate serum levels 2
• Decreased total plasma clearance of methotrexate 2
• Secondary methotrexate-induced renal impairment 2

Evidence Quality and Context

The strongest evidence comes from high-dose methotrexate scenarios (≥1 g/m²), where a documented case showed severe toxicity when amoxicillin was co-administered, resulting in renal failure, myelosuppression, mucositis, and dermatologic abnormalities 2. However, this involved chemotherapy-level dosing, not the low-dose methotrexate (typically 7.5-25 mg weekly) used for inflammatory conditions.

For low-dose methotrexate, the British Association of Dermatologists guidelines acknowledge that penicillins can increase methotrexate levels when high-dose methotrexate is used, but explicitly state "this does not appear to be an issue in clinical practice" for low-dose regimens 1. A large case-control study of 73 patients receiving high-dose methotrexate found no significant association between presence of interacting drugs (including antibiotics) and delayed methotrexate clearance 3.

Risk Stratification

High-risk scenarios where this interaction becomes more clinically significant include:

• Renal impairment: Interactions are substantially more likely in patients with reduced kidney function 1
• Elderly patients: Age-related decline in renal function increases methotrexate accumulation risk 1, 4
• High-dose methotrexate: Chemotherapy regimens (≥1 g/m²) carry the highest interaction risk 2
• Concurrent use of other interacting drugs: NSAIDs, trimethoprim, proton pump inhibitors 1

Lower-risk scenarios:

• Low-dose methotrexate (7.5-25 mg weekly) in patients with normal renal function 1
• Short-course antibiotic therapy in otherwise healthy patients 1

Clinical Management Algorithm

For patients already on methotrexate who require antibiotics:

1. Assess renal function before prescribing amoxicillin 1, 5
2. For severe infections or infections not responding to standard treatment: Stop methotrexate until the patient recovers and the antibiotic course is complete 1
3. For routine infections in low-risk patients: Continue methotrexate with enhanced monitoring 1
4. Consider alternative antibiotics when feasible, though the British guidelines note penicillins are generally acceptable in low-dose methotrexate scenarios 1

Monitoring recommendations when co-prescribing:

• Monitor CBC and liver function tests every 2-4 weeks initially if both drugs are used together 4, 5
• Check renal function (BUN and creatinine) every 2-3 months, or more frequently if risk factors present 4, 5
• For high-dose methotrexate: Monitor serum methotrexate levels at 24,48, and 72 hours 2

Patient education on toxicity signs:

• Unusual bruising or bleeding (myelosuppression) 4
• Mouth sores (mucositis) 4, 2
• Severe nausea/vomiting 4
• Dark urine or signs of renal dysfunction 4
• Fever or signs of infection 2

Important Caveats

The interaction severity is dose-dependent and context-dependent. While documented case reports show serious toxicity with high-dose methotrexate 2, the British Association of Dermatologists explicitly states this is not a clinical issue with low-dose methotrexate in routine practice 1. However, never dismiss this interaction in elderly patients or those with renal impairment, as these populations are at substantially higher risk 1, 4.

Avoid confusing this with the trimethoprim-methotrexate interaction, which is far more serious due to synergistic antifolate effects and should be absolutely avoided 1, 6. Amoxicillin's mechanism is purely pharmacokinetic (reduced renal clearance), not pharmacodynamic 2.