What are the potential adverse effects of taking antibiotics while on methotrexate (25mg) for Rheumatoid Arthritis (RA), given a 5-day history of sore throat and mildly swollen lymph nodes with negative test results for Influenza A and B, COVID-19 (Coronavirus Disease 2019), and Streptococcus (Strep) infections?

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From the Guidelines

I strongly advise against taking antibiotics without consulting your rheumatologist, as they may interact with methotrexate and increase the risk of adverse effects, particularly bone marrow suppression, liver damage, and kidney problems. The main concern is that both methotrexate and certain antibiotics (particularly trimethoprim-sulfamethoxazole, penicillins, and some cephalosporins) can affect folate metabolism and kidney function, potentially increasing methotrexate toxicity 1. Since your tests for common infections came back negative, it's unclear if antibiotics are necessary, as they won't help viral infections.

Key Considerations

  • The potential for increased methotrexate toxicity when combined with certain antibiotics is a significant concern, and temporary folate supplementation may be necessary to mitigate this risk 1.
  • Some antibiotics, such as azithromycin or doxycycline, may have fewer interactions with methotrexate, and your doctor may consider these alternatives if antibiotics are deemed necessary 1.
  • It's essential to stay well-hydrated and monitor for unusual symptoms like unusual bruising, severe fatigue, or yellowing of skin while taking antibiotics and methotrexate concurrently 1.
  • The American College of Physicians and the Centers for Disease Control and Prevention recommend reserving antibiotic treatment for acute rhinosinusitis for patients with persistent symptoms or severe symptoms, and not prescribing antibiotics for patients with the common cold 1.

Recommendations

  • Consult with your rheumatologist before taking antibiotics to discuss potential interactions with methotrexate and determine the best course of action.
  • If antibiotics are necessary, ensure your doctor knows you're on methotrexate 25mg weekly and consider temporary folate supplementation.
  • Monitor for unusual symptoms and stay well-hydrated while taking antibiotics and methotrexate concurrently.

From the FDA Drug Label

Infection - There have been case reports of sometimes fatal opportunistic infections in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases. The most frequently reported adverse reactions include... decreased resistance to infection. Blood and Lymphatic System Disorders - suppressed hematopoiesis, anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, thrombocytopenia, agranulocytosis, eosinophilia, lymphadenopathy and lymphoproliferative disorders (including reversible).

The potential adverse effects of taking antibiotics while on methotrexate (25mg) for Rheumatoid Arthritis (RA) include:

  • Increased risk of infection: Methotrexate can decrease resistance to infection, and the use of antibiotics may further increase this risk.
  • Suppressed hematopoiesis: Methotrexate can cause bone marrow suppression, which can lead to decreased production of blood cells, including white blood cells that fight infection.
  • Lymphadenopathy and lymphoproliferative disorders: Methotrexate can cause swelling of the lymph nodes and increase the risk of lymphoproliferative disorders. It is essential to closely monitor patients on methotrexate therapy for signs of infection and toxicity, especially when taking antibiotics 2.

From the Research

Potential Adverse Effects of Taking Antibiotics with Methotrexate

  • The use of antibiotics in patients taking methotrexate for Rheumatoid Arthritis (RA) may increase the risk of adverse effects, particularly those related to immunosuppression and bone marrow suppression 3, 4.
  • Methotrexate is known to have adverse effects common to all immunosuppressants, including gastrointestinal and haematological disorders 5.
  • The combination of methotrexate and certain antibiotics may increase the risk of severe adverse effects, such as bone marrow suppression and opportunistic infections 3, 4.
  • Patients taking methotrexate are at risk for opportunistic infections, despite normal leukocyte counts 4.

Considerations for Patients with Sore Throat and Swollen Lymph Nodes

  • The presence of a sore throat and mildly swollen lymph nodes, with negative test results for common infections, may indicate a viral or bacterial infection that requires antibiotic treatment.
  • However, the use of antibiotics in patients taking methotrexate should be done with caution, as it may increase the risk of adverse effects 3, 4.
  • The decision to use antibiotics in patients taking methotrexate should be based on a thorough evaluation of the potential benefits and risks, and should be made in consultation with a healthcare professional.

Immunosuppression and Infection Risk

  • Methotrexate is an immunosuppressive agent that can increase the risk of infections, particularly opportunistic infections 4.
  • The risk of infection may be increased in patients taking methotrexate, particularly those with a history of immunosuppression or underlying medical conditions 6, 4.
  • However, a recent study suggests that methotrexate may not predispose patients to severe COVID-19, and may even be associated with a milder disease course 7.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

4
Research

Opportunistic infection during treatment with low dose methotrexate.

American journal of respiratory and critical care medicine, 1994

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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