Is it safe to prescribe nitrofurantoin (Macrobid) twice daily for five days to a patient taking low‑dose methotrexate 7.5 mg once weekly?

Nitrofurantoin Use with Low-Dose Methotrexate: Safety Considerations

Yes, you can prescribe Macrobid (nitrofurantoin) 100 mg twice daily for 5 days to a patient taking methotrexate 7.5 mg weekly, but you must temporarily discontinue methotrexate during the antibiotic course and until the infection fully resolves.

Primary Recommendation

The British Association of Dermatologists explicitly lists nitrofurantoin as a drug that may increase methotrexate toxicity through folic acid deficiency mechanisms, and recommends stopping methotrexate when antibiotics are given for severe infections or infections not responding to standard treatment until the patient recovers and the antibiotic course is complete. 1

Clinical Decision Algorithm

Step 1: Assess Infection Severity

• For uncomplicated cystitis (dysuria, frequency, urgency without fever >38°C, flank pain, or systemic symptoms): Nitrofurantoin 100 mg twice daily for 5 days is the appropriate first-line choice 2
• If pyelonephritis is suspected (fever, flank pain, costovertebral angle tenderness): Do not use nitrofurantoin; choose a fluoroquinolone or cephalosporin instead 2

Step 2: Verify Renal Function

• Confirm creatinine clearance ≥30 mL/min before prescribing nitrofurantoin 3
• Nitrofurantoin is contraindicated when CrCl <30 mL/min due to inadequate urinary concentrations and increased peripheral neuropathy risk 3
• This is particularly critical because methotrexate is 85% renally excreted, and renal impairment dramatically increases methotrexate toxicity risk 4

Step 3: Temporarily Hold Methotrexate

• Instruct the patient to skip their weekly methotrexate dose during the 5-day nitrofurantoin course 1
• Do not resume methotrexate until the infection has completely resolved and the antibiotic course is finished 1
• This typically means holding methotrexate for 1-2 weeks total

Step 4: Continue Folic Acid Supplementation

• Ensure the patient continues their folic acid supplementation (1-5 mg daily) throughout the antibiotic course and methotrexate hold 4
• Folic acid helps mitigate the antifolate effects of both methotrexate and nitrofurantoin 1

Mechanism of Interaction

The British Association of Dermatologists identifies nitrofurantoin as causing folic acid deficiency, which compounds methotrexate's antifolate mechanism 1. Additionally, one case report documented altered methotrexate clearance when nitrofurantoin was administered concurrently for a urinary tract infection, with clearance returning to baseline after nitrofurantoin discontinuation 5. While this case involved high-dose methotrexate for CNS lymphoma, it demonstrates a pharmacokinetic interaction that warrants caution even at low doses.

Risk Stratification for This Patient

Your patient taking methotrexate 7.5 mg weekly has additional risk factors that make the interaction more clinically significant:

• Advanced age (if elderly): Increases methotrexate toxicity risk and is associated with higher rates of trimethoprim-related immunosuppression in similar antifolate interactions 1
• Any degree of renal impairment: Both drugs rely on renal elimination, and interactions are more significant with reduced renal function 1

Why Not Use Alternative Antibiotics?

Trimethoprim-sulfamethoxazole (Bactrim) is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk from combined antifolate effects 1, 4. The British Association of Dermatologists states that co-trimoxazole and trimethoprim should be avoided in patients taking methotrexate, with most severe cases reported in elderly patients with renal impairment 1.

Other antibiotics (penicillins, tetracyclines, ciprofloxacin) have been shown to increase methotrexate levels with high-dose methotrexate but are not typically problematic in clinical practice with low-dose weekly methotrexate 1. However, the British Association of Dermatologists still recommends stopping methotrexate for severe infections requiring antibiotics 1.

Monitoring After Resuming Methotrexate

• Check complete blood count 1-2 weeks after restarting methotrexate to ensure no delayed myelosuppression 4
• Monitor for early signs of toxicity: unusual fatigue, oral ulcers, fever, or new respiratory symptoms 4
• Watch for macrocytic anemia as an early indicator of folate deficiency before severe toxicity develops 4

Common Pitfalls to Avoid

• Do not continue methotrexate during the nitrofurantoin course simply because the dose is "low" (7.5 mg weekly); the British Association of Dermatologists makes no distinction by methotrexate dose in their antibiotic interaction guidance 1
• Do not use nitrofurantoin if there is any suspicion of upper tract involvement, as it will not treat pyelonephritis effectively and the patient will still require methotrexate discontinuation for a different antibiotic 2
• Do not assume the interaction is negligible because nitrofurantoin is only for 5 days; the case report showed measurable pharmacokinetic changes even with short-term use 5
• Do not stop folic acid supplementation during the methotrexate hold; continue it to help prevent folate depletion 4