Intra-abdominal infections (IAIs) are among the leading causes of septic shock. These patients often experience long-lasting critical illnesses, with persistent inflammation, immunosuppression, and catabolism syndrome (PICS). A personalized and multidisciplinary approach is fundamental for appropriate management of patients with complicated IAI and PICS. Many patients with complicated IAI have no improvement or worsening after appropriate initial management, and this requires careful re-evaluation and may be caused by uncontrolled infection, dysregulated immune response, or side effects of therapies. Uncontrolled infections are often caused by inadequate source control, other sources of infection, or inappropriate antibiotic therapy (molecules/dosages). A dysregulated immune response refers to the inability of a patient’s immune system to eradicate the infection, leading to immune paralysis. Complicated IAIs remain a challenge in critical care, and a personalized interdisciplinary approach is crucial for identifying individual needs to provide comprehensive and tailored interventions encompassing considerations of resuscitative treatments, immunomodulatory therapies, and specific supportive measures.