We present a case of a male Italian patient of 66 years with a history of kidney transplantation in treatment with cyclosporine and methylprednisolone. He visited an ENT clinic and was diagnosed as chronic left purulent otitis media. He began at-home antibiotic therapy with poor benefit. On 09/13/18, he was admitted to the hospital "S. Maria "of Terni for persistence of left ear pain and complete hearing loss. Magnetic resonance imaging (MRI) of the brain showed "in correspondence of the petrous rock and the mastoid…presence of flogistic tissue." Auricular swabs and later surgical drainage of the purulent material were performed and both were positive for extensively drug-resistant (XDR) Pseudomonas aeruginosa sensitive only to colistin in absence of synergism with rifampin. The patient underwent antibiotic therapy with ceftolozane-tazobactam, a new generation cephalosporin with anti-Pseudomonas activity and a β-lactamase inhibitor, that currently is indicated for the treatment of complicated urinary tract infections and complicated intra-abdominal infections, with complete healing. In literature, it is described a series of 12 patients with severe MDR (multidrug-resistant) Pseudomonas aeruginosa infections (6 pneumonia) who received salvage therapy with ceftolozane-tazobactam after inappropriate empirical and/or suboptimal treatment. This study included a case of a male patient of 45 years, affected by Burkitt lymphoma and severe neutropenia, who presented with otitis and mastoiditis, and isolation of Pseudomonas aeruginosa in surgical drainage of the purulent material of the ear (blood cultures were negative). He underwent antibiotic therapy with ceftolozane-tazobactam at a dosage of 3 g/8 h for 21.3 days. The patient was healed, but a late recurrence was described because of isolation of ceftolozane-tazobactam-resistant Pseudomonas after therapy. The possibility of acquiring resistance to ceftolozane-tazobactam should be considered in patients with previous exposure to beta-lactams and with poor response to these antibiotics.