Background: While selective use of antibiotics for infected pancreatic necrosis (IPN) in acute pancreatitis (AP) is recommended, studies indicate a high rate of inadequate treatment. Methods: A search of PubMed, Scopus, and Cochrane databases was conducted, focusing on primary research and meta-analyses. Data were categorized based on core concepts, and a narrative synthesis was performed. Results: The search identified a total of 1016 publications. After evaluating 203 full texts and additional sources from the grey literature, 80 studies were included in the review. The answers obtained were: (1) Preventive treatment does not decrease the incidence of IPN or mortality. Given the risks of bacterial resistance and fungal infections, antibiotics should be reserved for highly suspected or confirmed IPN; (2) The diagnosis of IPN does not always require microbiological samples, as clinical suspicion or computed tomography signs can suffice. Early diagnosis and treatment may be improved by using biomarkers such as procalcitonin and novel microbiological methods; (3) When indicated, early initiation of antibiotics is a key determinant in reducing mortality associated with IPN; (4) Antibiotics with good penetration into pancreatic tissue covering Gram-negative and Gram-positive bacteria should be used. Routine antifungal therapy is not recommended; (5) The step-up approach, including antibiotics, is the standard for IPN management; (6) Antibiotic duration should be kept to a minimum and should be based on the quality of source control and patient condition. Conclusions: Early antibiotic therapy is essential for the treatment of IPN, but prophylactic antibiotics are not recommended in AP. High-quality randomized controlled trials are required to better understand the role of antibiotics and antifungals in AP management.
