C53-13 Methotrexate and Trimethoprim-Sulfamethoxazole Interaction Causing Severe Pancytopenia

Abstract Methotrexate (MTX) is a cornerstone therapy for inflammatory and neoplastic conditions, but its use is limited by toxicities such as pancytopenia. These risks are magnified by drug interactions, particularly with trimethoprim-sulfamethoxazole (TMP-SMX), a sulfonamide antibiotic with overlapping antifolate activity and inhibition of renal MTX clearance. Even at low doses, this combination can cause life-threatening hematologic complications. A 60-year-old woman with seropositive rheumatoid arthritis treated with chronic MTX and monthly abatacept infusions presented with progressive encephalopathy, mucositis, and pancytopenia. Two weeks earlier she had been prescribed TMP-SMX for a urinary tract infection. She subsequently developed unsteadiness, cough, and worsening confusion, and was admitted to the ICU with hypoxemic respiratory failure, acute kidney injury, and shock. Initial evaluation revealed profound pancytopenia (WBC 1.9 ×109/L, hemoglobin 7.8 g/dL, platelets 55 ×109/L), severe oral mucositis, and evidence of invasive candidemia with mucosal sloughing causing airway obstruction. She required intubation, vasopressors, and antifungal therapy. Bone marrow biopsy demonstrated markedly hypocellular marrow with preserved trilineage hematopoiesis, consistent with drug-induced suppression. Folate level was critically low (3.8 ng/mL); high-dose intravenous folate was initiated along with empiric antimicrobials, filgrastim, and transfusion support. Despite aggressive care, her course was complicated by refractory septic shock and multiorgan failure, and she died. Her presentation was attributed to the synergistic myelotoxicity of MTX and TMP-SMX. TMP-SMX both impairs MTX clearance via renal tubular inhibition and augments its antifolate effect, predisposing patients to marrow failure, mucositis, and opportunistic infection. This case highlights the catastrophic potential of MTX-TMP-SMX coadministration in immunosuppressed patients. The synergistic antifolate toxicity can rapidly precipitate marrow failure, mucosal injury, and multiorgan dysfunction requiring intensive care management. In the ICU, prompt discontinuation of both agents, high-dose folate rescue, hematologic growth factor support, and broad antimicrobial coverage are essential. Close hemodynamic and respiratory monitoring are critical, as mucosal sloughing and infection can quickly lead to airway compromise and septic shock. Early collaboration between critical care, hematology, and infectious disease teams is vital for stabilization. Given the frequent outpatient use of both medications, clinicians must maintain vigilance and ensure careful risk assessment, laboratory monitoring, and timely escalation to ICU-level care when systemic toxicity develops. Preventive awareness of this avoidable interaction remains the most effective strategy to reduce morbidity and mortality. This abstract is funded by: None