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Introduction Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli represents an escalating global antimicrobial threat. ESBL enzymes confer resistance to penicillins, third-generation cephalosporins, and aztreonam, frequently limiting therapy to carbapenems or newer β-lactam/β-lactamase inhibitor combinations. While ESBL infections are increasingly reported in urinary and bloodstream infections, central nervous system (CNS) involvement remains extremely rare in adults. Reported cases of ESBL meningitis or ventriculitis most commonly occur in neonates or following neurosurgical instrumentation. Hematogenous CNS invasion has been attributed to sustained bacteremia with receptor-mediated endothelial transcytosis and blood-brain barrier disruption. We present a fatal case of ESBL E. coli ventriculitis occurring in the setting of bacteremia and external ventricular drain (EVD) placement, highlighting dual pathogenic mechanisms and therapeutic challenges.Case Presentation A 64-year-old male with prior subarachnoid hemorrhage requiring burr hole and EVD placement, multiple ischemic strokes, intracranial stenting, embolized cerebellar AVM, pulmonary embolism (not anticoagulated), and metastatic pancreatic carcinoma presented with septic shock secondary to urinary tract infection. Blood cultures grew ESBL-producing E. coli, prompting escalation from piperacillin/tazobactam to ertapenem. His course was complicated by hypoxic respiratory failure, hydrocephalus, and imaging-confirmed ventriculitis requiring intubation and EVD placement with transfer to neurocritical care. CSF cultures subsequently grew ESBL E. coli, confirming ventriculitis in the setting of active bacteremia and ventricular instrumentation. Antimicrobial therapy was transitioned to a 14-day course of ceftazidime-avibactam in coordination with infectious disease and neurosurgery. Despite aggressive management, he developed refractory status epilepticus requiring multiple antiseizure agents and continuous sedation. Neurologic function progressively deteriorated, culminating in loss of brainstem reflexes off sedation. Following goals-of-care discussions, compassionate extubation was performed, and the patient expired.Discussion ESBL CNS infections in adults are rare, with most literature limited to case reports and small series. Zeiler et al. described postoperative ESBL E. coli ventriculitis requiring combined intraventricular and intravenous therapy for microbiologic clearance. Similarly, Cascio et al. reported carbapenemase-producing ventriculitis successfully treated only after intraventricular colistin following failure of systemic therapy alone. Elaldi et al. demonstrated persistent ESBL E. coli meningitis requiring prolonged carbapenem-based regimens, emphasizing high mortality and delayed clearance. These reports underscore three key principles: (1) limited CSF penetration of systemic antibiotics, (2) the frequent need for intraventricular therapy in hardware-associated infection, and (3) high morbidity despite appropriate treatment. Mortality rates in reported ESBL meningitis cases approach 30-40%, particularly in medically complex or elderly patients. Our case is distinctive for probable dual pathogenesis—hematogenous seeding during sustained ESBL bacteremia compounded by EVD-associated infection risk in a patient with prior neurosurgical interventions. Unlike several reported cases achieving microbiologic clearance, our patient experienced rapid neurologic decline, reflecting host vulnerability and disease severity.Conclusion ESBL E. coli ventriculitis remains an uncommon but devastating neurocritical complication. This case highlights the intersection of bacteremia, ventricular instrumentation, and multidrug resistance. Rising ESBL prevalence necessitates early recognition, rapid susceptibility-guided therapy, and multidisciplinary coordination. However, outcomes remain guarded in high-risk neurocritical populations, reinforcing the importance of infection prevention strategies and vigilance in patients with bacteremia and ventricular hardware.Disclosures S. Vyas: None. S. Kumar: None. J. Krantz: None. M. Hasham: None.