Background: Infection is one of the important causes of death in patients with severe acute pancreatitis (SAP) , but the bacterial spectrum and antibiotic resistance are constantly changing. Making good use of antibiotics and controlling multi-drug-resistant (MDR) bacterial infections are of vital importance in improving the cure rate of SAP. We conducted a retrospective study in the hope of providing references for antibiotic selection and control of drug-resistant bacteria. Methods: Retrospective analysis was performed on the data of patients hospitalized in our hospital due to acute pancreatitis (AP) in the past 5 years. General data were classified and statistically analyzed. Subsequently, the bacterial spectrum characteristics and the data related to drug-resistant bacterial infection of 569 AP patients were analyzed. Finally, unconditional logistic regression analysis was conducted to analyze the risk factors of MDR infection. Results: A total of 398 patients were enrolled in this study and the hospitalization data and associated results were analyzed. A total of 461 strains of pathogenic bacteria were detected, including 223 (48.4%) gram-negative bacterial strains, 190 (41.2%) gram-positive bacterial strains and 48 (10.4%) fungal strains. The detection rates of resistance in gram-negative and gram-positive bacterial strains were 48.0% (107/223) and 25.3% (48/190), respectively. There were significant differences between the MDR group and the non-MDR group for the factors of precautionary antibiotic use, kinds of antibiotics used, receipt of carbapenem, tracheal intubation, hemofiltration and number of hospitalization days in the intensive care unit. Unconditional logistic regression revealed 2 risk factors for MDR bacterial infection. Conclusions: Our results illustrate that gram-negative bacteria were the most common pathogens in SAP infection, and the proportion of gram-positive bacteria increased notably. The rate of antibiotic resistance was higher than previously reported. Unconditional logistic regression analysis showed that using more types of antibiotics and the number of hospitalization days in the ICU were the risk factors associated with MDR bacterial infection.