Skull base osteomyelitis (SBO) is a life-threatening condition in patients with underlying comorbidities. Ear infections may spread through normal skull base fissures in this group of patients. However, its diagnosis is frequently delayed due to the unspecific clinical findings at onset, such as headache, with diverse cranial neuropathies later as the disease progresses. We present the case of a patient with otogenic skull base osteomyelitis complicated with retropharyngeal extension, treated with surgical drainage and broad-spectrum antibiotics directed toward extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, with recurrence of the infection three months later. With this case study, we aim to stress the importance of antimicrobial resistance and how it can preclude an otherwise favorable prognosis.Copyright © 2022, Jacobo-Pinelli et al.