Drug-induced liver injury (DILI) is a potentially severe and underestimated condition that can occur in patients exposed to multiple broad-spectrum antimicrobial regimens for prolonged periods. DILI poses a diagnostic challenge due to the lack of specific biomarkers and the multiplicity of possible causative agents. Early recognition is essential to prevent severe outcomes.

A 61-year-old male with hypertension, poorly controlled diabetes, and a history of left lower-limb amputation for diabetic foot was initially admitted with otitis externa that progressed to otomastoiditis caused by carbapenemase-producing Pseudomonas aeruginosa (IMP). After failure of previous antimicrobial regimens (ciprofloxacin, ceftazidime, and cefepime), therapy with ceftazidime-avibactam plus aztreonam was initiated according to microbiological susceptibility. A few days after starting treatment, a marked elevation of hepatic enzymes (transaminases and cholestatic enzymes) was observed, showing a mixed-pattern DILI. The antimicrobials and other potentially hepatotoxic drugs were discontinued. After transient improvement, re-exposure led to a new enzyme peak, confirming positive re-exposure. Subsequent attempts with meropenem and polymyxin B also resulted in transaminase elevation, limiting safe and effective antimicrobial options. With surgical intervention deferred due to structural constraints and progression to skull-base osteomyelitis, treatment decisions were discussed with hepatology and palliative-care teams. Prednisone (1 mg/kg/day) and ursodeoxycholic acid (14 mg/kg/day) were initiated, and ceftazidime-avibactam plus aztreonam were cautiously reintroduced with close laboratory monitoring. The patient tolerated therapy well, completing 12 weeks of treatment with satisfactory clinical response.

This case underscores the importance of pharmacovigilance, causality assessment in DILI, and multidisciplinary collaboration among infectious-disease, hepatology, and clinical-pharmacy teams to ensure therapeutic safety in complex infectious scenarios.