Concomitant use of low-dose methotrexate and trimethoprim-sulfamethoxazole and the 30-day risk of all-cause mortality among older adults: A population-based cohort study

Background: The interaction between trimethoprim-sulfamethoxazole (TMP-SMX) and methotrexate can result in severe additive antifolate effects, alter methotrexate pharmacokinetics, and lead to toxicity or death.

Objective: To characterize the risk of death in older adults co-prescribed low-dose methotrexate and TMP-SMX versus low-dose methotrexate and a cephalosporin.
Design, Setting, and Participants: Retrospective, population-based, new-user cohort study in Ontario, Canada (2002–2022) using linked administrative healthcare data.
Older adults taking low-dose methotrexate who were newly co-prescribed TMP-SMX (n=1602) were matched 1:1 with those who were newly co-prescribed a cephalosporin.
Exposure: Older adults taking low-dose methotrexate newly co-prescribed TMP-SMX versus those who were newly co-prescribed a cephalosporin.
Main Outcome and Measure: The primary outcome was all-cause mortality within 30 days of the antibiotic dispensing date. Secondary outcomes included all-cause hospitalization, a hospital visit (i.e., an emergency department visit or a hospital admission) with myelosuppression (defined as a diagnosis of aplastic anemia, neutropenia, thrombocytopenia, or pancytopenia) and infection (defined as a hospital admission with any infection as the main diagnosis). Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RR) were obtained using modified Poisson regression and risk differences (RD) using binomial regression.

Results: In a propensity-score matched cohort of 3204 adults taking low-dose methotrexate (78% women; median age 75 [IQR 70-81]), the 30-day risk of death was similar in adults co-prescribed TMP-SMX versus a cephalosporin (14/1602 [0.87%] vs 15/1602 [0.94%]; RR, 0.93 (95% CI, 0.45 to 1.93); RD, -0.06% [95% CI, -0.72% to 0.60%]). The risk of all-cause hospitalization (RR, 1.49 [95% CI, 1.13 to 1.97]; RD, 2.37% [95% CI, 0.75% to 3.99%] and infection (RR, 2.78 [95% CI, 1.30 to 5.95]; RD, 1.00% [95% CI, 0.29% to 1.71%]) was higher in adults treated with TMP-SMX than those treated with cephalosporins.
Conclusion and Relevance: In older adults taking low-dose methotrexate, co-prescription of TMP-SMX versus a cephalosporin was not associated with a higher 30-day risk of death but was associated with a higher 30-day risk of all-cause hospitalization and infection. Physicians should balance the risks and benefits of co-prescribing TMP-SMX and low-dose methotrexate.