Trimethoprim and Methotrexate Injection: Interaction Details

a) Guidelines (British Association of Dermatology): Coadministration of sulfamethoxazole/trimethoprim is an absolute contraindication with methotrexate therapy (strength of recommendation C; level of evidence 2+). Evidence for this interaction comes mostly from concomitant use of sulfamethoxazole/trimethoprim with low-dose methotrexate resulting in bone marrow suppression and case reports of immunosuppression mainly in older adults who often have renal impairment ².

b) In a propensity-score matched cohort of 3204 adults taking low-dose methotrexate (MTX), the 30-day risk of death was similar in adults coadministered sulfamethoxazole/trimethoprim (SMX/TMP) vs a cephalosporin.(0.87% vs 0.94%; RR, 0.93; 95% CI, 0.45 to 1.93). The risk of all-cause hospitalization (RR, 1.49; 95% CI, 1.13 to 1.97) and infection (RR, 2.78; 95% CI, 1.3 to 5.95) was higher in adults treated with SMX/TMP than those treated with a cephalosporin. Sulfamethoxazole/trimethoprim use was not associated with a hospital visit with myelosuppression. In the matched cohort, the median age was 75 years and 78% were female. Diagnoses included rheumatoid arthritis (82%), urinary tract infection (24%), ear, nose and throat-related infections (5%), skin infection (4%), other bacterial infections (4%) and concurrent use of folic acid medications (65%). The minimum overlap between the most recent low-dose MTX prescription and the new antibiotic prescription was 3 days. The median overlap was 7 days (interquartile range [IQR] 7 to 10). The median MTX dose was 15 mg/week ⁵.

c) In a retrospective review of patients receiving methotrexate (MTX) with or without a prophylactic dose of sulfamethoxazole/trimethoprim (SMX/TMP), prophylactic SMX/TMP use was not associated with an increased risk of cytopenia (Hb decreased by more than 2 g/dL, platelet count of less than 150,000/mm(3), or WBC less than 3500/mm(3)). Among 175 patients administered MTX with or without SMX/TMP, 9 developed cytopenia. Three patients developed anemia, 4 patients developed leukopenia, and 2 patients developed thrombocytopenia. The median dose of MTX was 10 (8.8 to 13.8) mg/week. Two patients had underlying chronic liver disease. Drugs coadministered with MTX included mycophenolate mofetil (n=1), leflunomide (n=1), NSAIDs (n=5), prophylactic dose of SMX/TMP (n=2), aspirin (n=1) and cefpodoxime (n=1). The median creatinine level was 0.63 (0.51 to 0.9) mg/dL, and the mean corpuscular volume was 89.5 (87.2 to 93.3) femtoliters. The median time from administration of MTX to the development of cytopenia was 70 (34 to 102.5) days ⁴.

d) In a retrospective case-control study assessing the risk association between drug interactions and high-dose methotrexate (MTX; 1 g/m(2) or greater), sulfamethoxazole/trimethoprim (SMX/TMP) was not associated with delayed MTX clearance. Study participants included adult oncology patients who received high-dose MTX. Patients were classified as cases or controls based on their MTX levels. Cases had delayed MTX clearance defined as 0.1 micromol/L or greater at 72 hours after the start of MTX infusion, and controls were patients who did not experience a delay in MTX clearance (less than 0.1 micromol/L at 72 hours). The primary endpoint was the frequency of presence of interacting drugs at the start of MTX infusion and for 72 hours after between cases and controls. Secondary endpoints included the occurrence of myelosuppression, nephrotoxicity, hepatotoxicity, and mucositis. Of the 73 patients included in the study, 23 (31.5%) were defined as cases. Interacting drugs were not significantly associated with delayed MTX clearance. Three patients (13%) in the case group received SMX/TMP compared to 15 (30%) in the control group. Furthermore, after adjusting for MTX dose, the most frequently observed drugs (allopurinol, proton pump inhibitors, and SMX/TMP) were not associated with delayed MTX clearance. Cases experienced more anemia (Grade 2.52 vs 1.68) and higher rates of mucositis (65.2% vs 20%) ⁶.

e) A 70-year-old woman was taking long-term, low-dose methotrexate for psoriasis. After diagnosing acute bronchitis, her general practitioner prescribed sulfamethoxazole/trimethoprim for her. She developed severe pancytopenia with concurrent use of methotrexate and sulfamethoxazole/trimethoprim ⁷.

f) A pharmacokinetic study found a 66% increase in systemic exposure to methotrexate when given concurrently with sulfamethoxazole/trimethoprim. Methotrexate concentrations were measured in nine children with acute lymphoblastic leukemia during methotrexate dosing alone and during coadministration with sulfamethoxazole/trimethoprim. The free methotrexate fraction increased from 37.4% to 52.2% when sulfamethoxazole/trimethoprim was added to methotrexate therapy, and free methotrexate renal clearance decreased from 12.1 to 5.6 mL/kg/min during multidrug administration. Serum concentrations of sulfamethoxazole/trimethoprim and the percentage decrease in renal clearance of free methotrexate were closely correlated ⁸.

g) An 81-year-old woman stabilized on methotrexate for rheumatoid arthritis was diagnosed with inoperable cancer of the bladder, and was placed on trimethoprim 100 mg daily with an indwelling catheter. Two months later, she was readmitted with severe pancytopenia after her general practitioner increased her trimethoprim dose to 200 mg daily for symptoms of a urinary tract infection. Despite aggressive treatment with granulocyte colony stimulating factor, the patient's bone marrow did not recover and she died of bronchopneumonia ⁹.

h) An 80-year-old female was started on intramuscular methotrexate therapy for deteriorating psoriasis. Blood counts were normal prior to the sixth injection of methotrexate, but five days later she presented with painful, ulcerated areas and contact bleeding over her thighs, buttocks, back, and upper chest. Blood work revealed severe neutropenia (white cell count 0.9 x 10(9)/L, neutrophils 0.3 x 10(9)/L). Five days prior to the sixth injection of methotrexate, the patient had been started on trimethoprim 200 mg twice daily for a urinary tract infection. Her skin ulcerations and leukopenia were attributed to an interaction between methotrexate and trimethoprim ¹⁰.

i) A case report describes a patient who developed megaloblastic pancytopenia secondary to methotrexate and sulfamethoxazole/trimethoprim (SMX/TMP). A 58-year-old male with a history of rheumatoid arthritis presented with symptoms of prostatitis. He was started on a 6-week regimen of SMX/TMP. Four weeks later, symptoms of prostatitis resolved, but he had hematuria, fatigue, decreased appetite, and orthostatic dizziness. A CBC demonstrated Hb of 72 g/L, HCT of 0.21, leukocyte count of 2,000,000/L, and platelet count of 50,000/L with macrocytic red cells, absence of reticulocytes, and markedly hypersegmented neutrophils on a peripheral smear. All drugs were discontinued and he was hospitalized for transfusion of platelets and packed red blood cells. The bone marrow revealed hypocellularity with megaloblastic red-cell precursors and hypersegmented polyps. He was diagnosed with megaloblastic pancytopenia, secondary to methotrexate and SMX/TMP. He received leucovorin 25 mg every 6 hours and within 96 hours, his CBC showed Hb of 104 g/L, HCT of 0.32, leukocyte count of 7,100,000/L, and platelet count of 218 x 10(9)/L. Clinicians should be aware of the possibility of life-threatening pancytopenia when methotrexate is used concomitantly with TMP ¹¹.