Contextualizing On-Therapy Resistance Development With Novel Antibiotics: Interplay Between Timing of Therapy Initiation and Critical Illness–Linked Pharmacokinetic/Pharmacodynamic Unpredictability

To the Editor—We read with interest the case report by Dorazio et al [1]. The authors describe an important case highlighting challenges in tackling a recalcitrant pseudomonal infection in a high-risk patient. However, the context suggests that the emergence of resistance to novel antibiotics when their deployment was delayed is consistent with the well-characterized behavior of Pseudomonas aeruginosa under conditions of prolonged, sequential, and suboptimal antimicrobial exposure in high-risk patients. The patient in question was critically ill with necrotizing pneumonia, septic shock, and acute respiratory distress syndrome requiring mechanical ventilation and venoarterial extracorporeal membrane oxygenation (ECMO), and experienced multiple episodes of nosocomial infection over a 131-day hospitalization. Following appropriate ceftriaxone therapy for initial pneumococcal bacteremia, the patient developed P aeruginosa pneumonia, which surprisingly worsened on meropenem (9 days), assuming that index isolate was (reliably) susceptible to meropenem. What ensued was an extended cascade of novel antipseudomonal therapies—ceftolozane–tazobactam (13 days), imipenem–relebactam (19 days), cefiderocol (26 days), retreatment with imipenem–relebactam (15 days), and finally cefepime–zidebactam (28 days). At each step, the isolate acquired resistance to the preceding agent.