Methotrexate is a versatile medication used for a variety of indications. It's use for rheumatoid arthritis specifically, is widespread as the medication appears to slow disease progression and is relatively inexpensive.


While effective, it is well known to have several dangerous drug interactions. In addition, methotrexate has a fairly narrow therapeutic index, meaning that there is a slim margin between safe and toxic dosages.


Methotrexate Antibiotic Interaction

Many of the concerning drug interactions involve a potential increase in methotrexate levels in the body. A variety of drugs can affect how quickly methotrexate is absorbed or metabolized. Below, are the common antibiotics that can interact with methotrexate:

  • Penicillin
  • Ciprofloxacin
  • Amoxicillin
  • Dapsone
  • Neomycin
  • Bactrim (sulfamethoxazole/trimethoprim)


Many of the antibiotics above (specifically ciprofloxacin and penicillin), affect how methotrexate is metabolized by the kidney. They can reduce the renal clearance of methotrexate. Reduced renal clearance can potentially increase concentrations of methotrexate in the body, leading to toxic levels which could cause an increased risk of drug associated side effects such as hematologic and GI toxicity. 


With regard to Levaquin, it is in the same class of antibiotics as ciprofloxacin, but it typically isn't considered an interacting drug with methotrexate. However, as Levaquin and Cipro are similar, many practitioners recommend avoiding Levaquin and methotrexate co-administration. Interestingly enough, some studies have shown benefit in treating the symptoms of rheumatoid arthritis using methotrexate AND Levaquin together.


Methotrexate is commonly dosed once weekly. To avoid the potential interaction between methotrexate and other drugs, they should be dosed at least 12 hours apart from one another. Data indicates that the majority of methotrexate is eliminated renally during the first 12 hours after administration. There rarely is a need to wait longer than 12 hours. Therefore, per your question, you are OK to dose your antibiotic the day after methotrexate administration.


Having stated the above, methotrexate is transported and retained in our cells well after it has been eliminated from the blood. At this point, the decreased renal drug clearance due to the potential drug interaction discussed above isn't as significant. However, it would still be prudent to be aware of the side effects of toxic methotrexate levels including:

  • Sore throat
  • Leukopenia
  • Thrombocytopenia
  • Skin ulcerations


If you are experiencing side effects, be sure to speak with your doctor.