The present study highlights significantly poorer outcomes in patients with aP who develop invasive infections, as indicated by the detection of pathogens in either blood cultures or other body fluids and pancreatic necroses. Pathogen detection was associated with higher rates of critical illness, prolonged ICU stays and extended in-hospital stays.

It is known that infectious complications in aP, including infected pancreatic necroses and extrapancreatic infections such as pneumonia or bacteremia, contribute to organ failure and increased mortality [7, 28,29,30,31]. Similar findings, particularly in aP patients with extrapancreatic infections, were observed in the retrospective study by Jiang et al. [31]. This underscores the critical importance of initiating early, targeted anti-infective therapy in high-risk patients at the point of care. However, positive microbial identification in clinical practice can be challenging, particularly during the early phase of aP when clear clinical signs of infectious complications or sepsis may not yet be apparent. Early predictors for septic progression at the onset or during the initial phase of aP are largely lacking [13, 18]. Identifying high-risk patients for developing septic complications early in disease progression is crucial for prophylactic antibiotic treatment to prevent septic complications, potentially reducing morbidity, mortality, and prolonged ICU resource utilization and hospital stays [13]. Our multivariable analysis identifies two relevant predictors of bacterial load at the onset of aP: blood leukocytosis and the development of ascites. Both factors are easily assessable in clinical practice and provide strong indicators for initiating appropriate anti-infective therapy.

During the early phase of aP, mortality is often caused by sterile inflammation through SIRS, with organ failure driven by an overwhelming cytokine release [5]. Identifying patients at high risk for infection during the later course of severe aP is crucial, as CARS increases susceptibility to infections due to impaired intestinal barrier function and translocation of gut pathogens [5, 9, 32] into the bloodstream and/or locally into peritoneal fluid and necrotic (peri-) pancreatic tissue [28, 33, 34]. As a result, sepsis with organ failure leads to significant mortality [31, 35].

Prophylactic anti-infective strategies in aP are controversial [7, 13, 36,37,38]. While Ukai et al. and Ding et al. demonstrated lower rates of infected pancreatic necroses [38] and extrapancreatic infections [36], respectively, mortality was not improved in the more recent meta-analysis by Ding et al. [36]. In this context, Montravers et al. analyzed a multicentric cohort of patients admitted to ICU with aP and found that delayed initiation of anti-infective therapy was associated with higher rates of severe septic complications compared to early therapy. Their findings highlight the critical importance of timely intervention in managing infectious complications in aP, particularly in high-risk patient populations [39]. However, these studies did not evaluate early predictors of septic progression and did not stratify aP patients by early risk factors for infection, limiting the generalizability of their findings.

In the present study, we highlight ascitic fluid as an independent risk factor for bacterial load and invasive infection. In this line, ascites has previously been shown to be a negative prognostic factor in aP patients [40, 41]. The pathophysiology of ascites in aP is attributed to the severity of SIRS during the early phase and CARS in the late phase. Contributing factors include capillary leakage, fluid overload, hypoproteinemia, and local complications such as pancreatic duct injury, portal vein thrombosis, and obstructing peripancreatic fluid collections leading to lymphatic leakage [42,43,44]. Additionally, our analysis reveals that the translocation of pathogens, particularly those of gastrointestinal origin, into the abdominal cavity – due to impaired intestinal barrier function during the pathophysiologic course of aP [5, 9, 28, 32,33,34] – is associated with the development of ascites and poorer clinical outcomes. The second early predictor of bacterial load in our analysis was blood leukocytosis at the onset of aP, a well-known indicator of infectious courses, severe local and distant organ complications in aP patients [2, 4, 12, 45].

Our detailed data analysis shows that both predictors from the early onset of aP indicate an infectious complication in patients with aP. This suggests that prophylactic anti-infective therapy for these high-risk patients should be considered at an early stage of the disease, potentially reducing morbidity and mortality thereafter. Therefore, the detailed analysis of pathogens and their drug resistance profiles in the GERM(+) patient cohort, as shown in Fig. 5, holds significant clinical value. It supports the selection of appropriate antimicrobial therapy for high-risk patients and those with infectious complications of aP. The results of our pathogen and antibiotic susceptibility analysis align with findings from the large retrospective study by Wen et al. [46], which reported that early administration of broad-spectrum carbapenems in patients with severe biliary aP was associated with lower length of hospital stay and, most importantly, reduced mortality [46]. As our analysis indicates, a key reason for this could be the high susceptibility of the detected pathogens to carbapenems, which may help to prevent infectious and septic complications at the point of care by ensuring effective early antimicrobial coverage.

Despite its clinical relevance, our study has limitations. Overall, the retrospective, single-center study design limits the generalizability of the results. Furthermore, in our study, post-ERCP was the second most common cause of aP, surpassing biliary etiology. This may be attributed to more complex interventions performed in our tertiary center. The imbalanced patient cohort characteristics necessitating PSM further limit the unrestricted clinical applicability of our findings. Another limitation is the restricted availability of advanced laboratory parameters in this retrospective analysis from clinical routine data, such as procalcitonin [7]. Procalcitonin has been identified in the expert consensus on antibiotic therapy for acute pancreatitis as a potential biomarker to reduce unjustified antibiotic use [18]. Future prospective studies are needed to evaluate its predictive accuracy against our findings, specifically the predictive value of elevated WBC, for guiding early anti-infective decision-making. Nonetheless, our results warrant cautious consideration and verification in larger patient cohorts and form hypotheses for prospectively conduced trials to evaluate improvements in morbidity and mortality through prophylactic anti-infective therapy in high-risk patients, as defined by predictive factors from our multivariable analysis.

In conclusion, our findings underscore the hypothesis that pathogen detection in aP patients is associated with worsened clinical outcomes. Early predictive factors might enable timely initiation of prophylactic anti-infective therapy, potentially preventing septic complications and reducing morbidity and mortality in high-risk aP patients.