What are the infection risks and management strategies for patients with a history of cancer, autoimmune diseases, or severe psoriasis taking methotrexate (MTX)?

Methotrexate-Associated Infection: Risk and Management

Methotrexate increases infection risk, particularly pneumonia, skin/soft tissue infections, and urinary tract infections, with most infections occurring within the first 18 months of treatment; temporarily discontinue MTX during severe infection or when infection fails to respond to standard treatment, and permanently discontinue if opportunistic infections develop. 1

Infection Risk Profile

Low-dose methotrexate carries a documented 7% infection rate in controlled trials, comparable to other immunosuppressants like azathioprine. 1 The infection risk is not uniform throughout treatment:

• Highest risk period: First 18 months of therapy, when the majority of infections occur 1, 2
• Opportunistic infections: Can occur at any time but typically manifest within the first 12 weeks, with risk persisting throughout the entire treatment course 1
• Most common infections: Pneumonia, skin/soft tissue infections, and urinary tract infections 1

The FDA label confirms decreased resistance to infection as a known adverse effect, with potentially fatal opportunistic infections reported, particularly Pneumocystis jirovecii pneumonia. 3

Management Algorithm for Active Infection

Immediate Actions

Temporarily discontinue methotrexate when encountering: 1, 4

• Severe infection of any type
• Any infection not responding to standard antimicrobial treatment

Permanently discontinue methotrexate if: 1, 4

• Opportunistic infections develop (including P. jirovecii pneumonia, disseminated herpes simplex, cytomegalovirus, cryptococcosis, histoplasmosis, or nocardiosis) 3

Monitoring During Infection

Obtain complete blood count with differential urgently to assess for: 4, 5

• Neutropenia or other cytopenias that increase infection severity
• Bone marrow suppression requiring filgrastim (5 mcg/kg daily subcutaneously) 1

Monitor renal function closely, as decreased renal clearance increases methotrexate levels and toxicity, creating a dangerous cycle during infection. 4

Monitor carefully for signs of sepsis during any infection, as MTX overdose and toxicity carry high mortality risk. 1

Restarting Therapy

Methotrexate can be restarted once the infection has completely cleared, resuming the regular monitoring schedule. 1, 4

Prophylactic Strategies

Pre-Treatment Screening

Before initiating methotrexate: 6

• Screen for hepatitis B and C
• Check varicella zoster virus (VZV) serology if no chickenpox history
• Consider VZV vaccination for seronegative patients (must stop immunosuppressants 6 months before administering live vaccine)

During Treatment Prophylaxis

For non-vaccinated or high-risk patients: 6

• Antiviral prophylaxis: Acyclovir or valacyclovir for all patients, especially those with prior herpes simplex or varicella zoster infection
• PCP prophylaxis: Strongly recommended when CD4 counts are low or patient receives high-dose corticosteroids with methotrexate
• Annual influenza vaccination (inactivated vaccine) 6

Critical caveat: Immunization with live virus vaccines is contraindicated during methotrexate therapy, as immunization may be ineffective and disseminated vaccinia infections have been reported. 3

Drug Interaction Hazards

Antibiotic Combinations to Avoid

Co-trimoxazole (trimethoprim-sulfamethoxazole) is particularly dangerous when combined with methotrexate, causing potentially fatal bone marrow suppression, mucocutaneous ulceration, leukopenia, and renal insufficiency through additive antifolate effects. 1, 4, 7 This combination should be avoided entirely. 4

Other problematic antibiotics include trimethoprim alone and other antifolate drugs, which increase toxicity through reduced protein binding or decreased renal elimination. 1, 4

NSAIDs

NSAIDs can reduce renal elimination of methotrexate, leading to toxicity, with case reports of significant morbidity and mortality following co-prescription of naproxen, diclofenac, ibuprofen, and indomethacin. 1 However, these cases often involved concurrent use of other interacting drugs, and the risk appears highest in elderly patients with baseline renal impairment. 1

Special Populations at Higher Risk

Methotrexate should be used with extreme caution in: 4, 3

• Patients with diabetes (increased infection risk)
• HIV or hepatitis patients
• Elderly patients with any degree of renal impairment
• Patients with overt or laboratory evidence of immunodeficiency syndromes (usually contraindicated) 3

Monitoring Schedule

Regular complete blood count monitoring is essential: 6

• Every 7-14 days for the first month
• Every 2-3 months once therapy is stabilized

Educate patients to immediately report: 5

• Fever, chills, or signs of infection
• Cough or dyspnea (consider P. jirovecii pneumonia when pulmonary symptoms develop) 3
• Mucositis, diarrhea, or other signs of toxicity