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Background The opportunistic parasite Toxoplasma causes life-threatening complications in immunocompromised hosts such as hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the agent of choice in preventing Pneumocystis jirovecii pneumonia and Toxoplasma, but bone marrow suppression often precludes its use. Broad-spectrum atovaquone also targets protozoan tachyzoite and cyst forms, but few studies examine its efficacy in prophylaxis among this vulnerable population. We present two HCT patients experiencing breakthrough toxoplasmosis despite compliance with atovaquone prophylaxis. Methods Review of literature and electronic medical records. Results Case 1. A 68-year-oldToxoplasma seropositive woman with myelodysplastic syndrome underwent Flu-Mel-ATG-matched unrelated donor HCT. On day +68 post HCT, she presented with encephalopathy. MRI brain revealed solid and ring-enhancing lesions correlating with positive CSF T. gondii PCR. Serum DNA PCR was negative. She received 12 weeks of sulfadiazine, pyrimethamine, and leucovorin with clinical and radiological improvement. Atovaquone prophylaxis was restarted given pancytopenia intolerance of TMP-SMX. Despite compliance, she experienced recurrent central nervous system toxoplasmosis. Her demise followed an unrelated ischemic cerebrovascular accident. Case 2. A 53-year-old Toxoplasma seropositive woman with CMV viremia and severe aplastic anemia limiting TMP-SMX use presented with pancytopenia on day +46 after HCT. Diagnosed with graft failure, routine screening revealed positive Toxoplasma PCR while on atovaquone prophylaxis. Toxoplasma PCR became negative after preemptive therapy. She underwent a second Flu-Cy-ATG-TBI-matched related donor HCT. 2 months later, medication noncompliance led to readmission with CMV viremia and culture-negative sepsis. Blood Toxoplasma PCR was positive at the time of death. Conclusion Toxoplasmosis prophylaxis failure can occur in allogeneic HCT recipients receiving atovaquone. When possible, TMP-SMX should remain first-line agent for this indication. In those unable to tolerate TMP-SMX, close clinical and Toxoplasma PCR monitoring may help identify reactivation and facilitate early initiation of therapy. Disclosures All authors: No reported disclosures.

2696. Breakthrough Toxoplasmosis While on Atovaquone Prophylaxis Following Allogeneic Hematologic Stem Cell Transplantation