Gastrointestinal fistula is an abnormal connection between the gastrointestinal tract and the abdominal cavity, body surface, or other organs. It can be primarily classified into types such as gastrointestinal fistula, enteric-cutaneous fistulas, enteric-internal fistulas, and entero-atmospheric fistulas (EAF) (Gribovskaja-Rupp and Melton, 2016; Lee and Loi, 2024). Surgical procedures are the main cause of gastrointestinal fistulas; however, other significant triggers include radiation therapy, inflammatory bowel disease, malignant tumors, and certain medications (Chiarello et al., 2022a, b; Zheng et al., 2020), The dangers of gastrointestinal fistulas primarily stem from the leakage of digestive fluids. On one hand, this can lead to severe electrolyte and acid-base imbalances; on the other hand, the digestive enzymes in these fluids can erode the surrounding tissue, potentially causing massive hemorrhage either in the abdominal cavity or the gastrointestinal tract. Furthermore, the leaked digestive fluids contain bacteria that may lead to infections in affected organs or regions, such as intra-abdominal infections, retroperitoneal infections, necrotizing fasciitis of the abdominal wall, urinary tract infections due to enterovesical fistulas, and reproductive system infections resulting from enterovaginal fistulas. Thus, gastrointestinal fistulas remain a challenging issue in clinical practice. A systematic review that included 3,078 patients with gastrointestinal fistulas revealed a high healing rate of 89%; however, the mortality rate reached 8.5%. Notably, gastrointestinal fistulas accompanied by severe intra-abdominal infections had a mortality rate close to 30% (Gefen et al., 2022). As research progresses, it has become increasingly clear that intra-abdominal infections associated with gastrointestinal fistulas are often the starting point for multiple high-risk factors leading to death. Anastomotic leaks are the most common cause of postoperative intra-abdominal infections, usually resulting from mixed infections by various microorganisms, including Enterococcus species, Enterobacteriaceae, Bacteroides, and fungi. Additionally, the prolonged use of broad-spectrum antibiotics has resulted in many bacteria exhibiting multidrug resistance, complicating clinical management of gastrointestinal fistula patients (Mücke et al., 2017; Liu et al., 2017; Wu et al., 2015). Current guidelines recommend empirical antibiotic treatment strategies that only partially cover resistant microorganisms, making infections caused by multidrug-resistant bacteria often complex and challenging to treat. Consequently, clinicians face difficulties in selecting effective antimicrobial treatment strategies (Roson-Calero et al., 2023).

The treatment methods for gastrointestinal fistulas have been progressively improved and refined through clinical exploration. Staged treatment strategies have been validated in clinical practice, benefiting patients with gastrointestinal fistulas. The overall treatment of gastrointestinal fistulas can be broadly divided into three phases: the early phase of infection control and resuscitation, the non-surgical treatment phase, and the elective definitive surgery phase. Significant advances in technologies such as vacuum-assisted closure (VAC), over the scope clip (OTSC), dual-lumen drainage devices, and enteral and parenteral nutrition have supported non-surgical management. However, many fistulas continue to persist without healing spontaneously. When conditions such as the release of abdominal adhesions, improved nutritional status, and restoration of organ function are met, definitive surgery can be implemented. This underscores the importance of surgical intervention as a critical approach in the treatment of gastrointestinal fistulas (Jeong et al., 2023).

Therefore, it is crucial to investigate the prevalence of multidrug-resistant (MDR) infections in the perioperative period of patients with gastrointestinal fistulas. However, there is currently a lack of relevant data for this population. Through a retrospective study, we assessed the specifics of MDR bacterial and fungal infections, their resistance patterns, and conducted a thorough analysis of associated risk factors. We aimed to effectively integrate this information to establish a risk prediction nomogram, providing a foundation and reference for the diagnosis and treatment of MDR bacterial and fungal infections in patients with gastrointestinal fistulas during the perioperative period.

Gastrointestinal fistula is a common and severe complication of abdominal surgery. It represents a complex pathophysiological process associated with a range of serious complications and high mortality rates. In the 1970s, the mortality rate of gastrointestinal fistulas was approximately 50.0% to 60.0%. However, with ongoing research into the mechanisms of fistula formation and advancements in treatment methods, as well as improvements in medical technology, the current mortality rate has decreased to between 5.3% and 21.3% (Draus et al., 2006; Pepe et al., 2024). Studies have shown that patients with gastrointestinal fistulas often experience severe infections. This is primarily due to the disruption of intestinal integrity, which exposes a diverse array of microorganisms from the gut. Additionally, factors such as prolonged antibiotic use, extended hospital stays, long-term ICU admissions, and various invasive procedures significantly increase the risk of bacterial infections (Doerken et al., 2021). Bacterial infections are inextricably linked to the integrity of the intestinal mucosal barrier. However, enteral nutrition (EN) is superior to parenteral nutrition (PN) in maintaining the integrity of the intestinal mucosal barrier and regulating immune function (Grillo-Ardila et al., 2024; Shao et al., 2023). Patients with gastrointestinal fistulas, particularly those with high-output fistulas, often cannot receive EN early and must rely on PN management (Ortiz et al., 2017). During this period, the function of the intestinal mucosa is compromised to varying degrees, further heightening the risk of bacterial translocation and enteric infections (Casaer et al., 2011). Following severe infections, patients may exhibit related symptoms that adversely affect liver and kidney function, exacerbate malnutrition, and potentially lead to septic shock, creating a vicious cycle. In recent years, the application of numerous new technologies has enabled a significant number of patients suffering from gastrointestinal fistulas to improve with conservative treatment (Rabel et al., 2023). Nonetheless, surgical intervention remains critically important in the management of fistulas. Some patients can benefit from conservative treatment to improve their clinical and nutritional status, but complete fistula relief usually requires surgery (Huang et al., 2022). Furthermore, in the case of a duodenal or high jejunal fistula, aggressive surgical intervention is essential to prevent the exacerbation of infection or the risk of uncontrollable intra-abdominal hemorrhage caused by the corrosive output of the fistula, which can pose a serious threat to the patient’s life. This study focuses for the first time on the analysis of multidrug-resistant bacteria and fungi in patients with gastrointestinal fistulas during the perioperative period and aims to develop a risk prediction nomogram that assists clinicians in effectively assessing the risk of multidrug-resistant infections in patients requiring surgery. Treatment of infections caused by multidrug-resistant microorganisms can be enhanced by predicting infection by potential pathogens and selecting antibiotics based on drug sensitivity results.

In this study, we found that, the predominant pathogens associated with gastrointestinal fistula-related multi-drug resistant bacteria and fungal infections were Gram-negative bacilli, consistent with previous research (Liu et al., 2017). Among the Gram-negative bacteria, the leading strains identified were Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli. Notably, Klebsiella pneumoniae has now surpassed Escherichia coli to become the most prevalent strain, exhibiting the highest proportion of resistance mechanisms, including positivity for CRE (Carbapenem-resistant Enterobacteriaceae) and ESBL (Extended-Spectrum Beta-lactamases) at 80.7%. This trend necessitates significant clinical attention. The second most common strain was Escherichia coli, a typical member of the intestinal flora; however, a concerning proportion of these infections exhibited CRE or ESBL resistance mechanisms, reaching 59.2%. Additionally, the prevalence of CR-PA (Carbapenem-resistant Pseudomonas aeruginosa) and CR-AB (Carbapenem-resistant Acinetobacter baumannii) was notably high, at 45.9% and 80.6%, respectively. In recent years, carbapenem resistance has been linked to high mortality rates and has emerged as a global concern, increasing the treatment burden for infection control (Giacobbe et al., 2023; Boattini et al., 2023). Antimicrobial susceptibility testing revealed that the average antibiotic resistance rates for Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli were 49.34%, 50.16%, and 38.52%, respectively. The rates of resistance to meropenem among carbapenemase-producing Enterobacteriaceae were alarmingly high, with Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli showing resistance rates of 82.5%, 87.1%, and 81.6%, respectively, significantly exceeding previous reports (Sid Ahmed et al., 2023; Chang et al., 2023). Furthermore, we observed a concerning proportion of resistant strains to tigecycline, polymyxin B, and ceftazidime-avibactam in Klebsiella pneumoniae. This may be attributed to the fact that most of our patients were transferred from other hospitals and had already received several days of antibiotic treatment, which is a known risk factor for the development of carbapenem resistance (López-Cubillos et al., 2023). In terms of Gram-positive bacteria, the most common strain identified was Enterococcus faecium, accounting for 34%. We also discovered one case of methicillin-resistant Staphylococcus aureus (MRSA), two cases of methicillin-resistant coagulase-negative staphylococci (MRSCON), and one case of beta-lactamase-producing Staphylococcus. Among the cocci, the average resistance rates of Enterococcus faecium and hemolytic Staphylococcus to the tested antibiotics exceeded 30%. The resistance rate to penicillin in Gram-positive cocci exceeded 85%, and the resistance rate to the broad-spectrum antibiotic levofloxacin was also notably high. Thus far, there have been no observed resistance cases against linezolid or vancomycin among Gram-positive cocci; however, careful monitoring for related complications is warranted during their use. Fungal infections were relatively infrequent, comprising about 10% of cases, and no drug-resistant fungi were identified. Nonetheless, fungal infections can be clinically challenging to detect, and delays in antifungal treatment, prolonged use of antifungal medications, and substantial side effects pose significant difficulties in managing fungal infections associated with gastrointestinal fistula. Overall, this study highlights that in the perioperative period, patients with gastrointestinal fistula predominantly present with multidrug-resistant Gram-negative bacteria, particularly carbapenem-resistant Enterobacteriaceae, with Klebsiella pneumoniae emerging as a critical concern that requires heightened attention.

Through univariate analysis, we found significant differences in multiple indicators between the positive and negative groups of multidrug-resistant bacteria in the training cohort. We assessed the relevant indicators and discarded those with more than 20% missing values. Subsequently, we performed multivariate logistic regression, which included six indicators: secondary surgery, hospital stays, preoperative white blood cell (WBC) count, preoperative neutrophil count (N), postoperative WBC count, and postoperative C-reactive protein (CRP). Using these indicators, we constructed a diagnostic model that demonstrated good overall performance, with AUC values of 0.905 and 0.793 for the training and validation Cohort, respectively. The calibration curve indicated that the predicted values were in good agreement with the actual values. Decision curve analysis revealed that in both cohorts, the net benefit of treatment based on this model exceeded that of alternative strategies with threshold probabilities ranging from 0 to 1.

Reoperation (Secondary surgery) is a necessary intervention for managing severe complications that may arise after surgical procedures; however, it imposes a significant burden on patients. Multiple studies indicate that unexpected reoperations are predictive factors for prolonged hospital stays, increased complications, and reduced short-term survival rates (Xu et al., 2023; Luo et al., 2023; Zhuang et al., 2022). Patients with gastrointestinal fistulas usually experience unavoidable complications after surgery and may be forced to undergo a second surgical intervention shortly after the initial surgery. The reasons that led to the patient’s secondary surgery can be summarized in two points. On the one hand, the existing treatment of gastrointestinal fistulae is unsatisfactory, which may be due to poor initial abdominal drainage, leading to the possibility of severe intra-abdominal infection. On the other hand, salvage therapy is indispensable when patients experience life-threatening complications such as uncontrolled intra-abdominal hemorrhage. The need for a second surgery is a considerable setback for patients, often heralding adverse clinical outcomes, and consequently, it has become an independent risk factor for multidrug-resistant bacterial and fungal infections. Previous studies have found that the reoperation rate for patients with intestinal fistulas is approximately 15%, while the readmission rate ranges from 15% to 30%, which reflect the complexity of this condition and the challenges associated with its treatment (Christensen et al., 2021; Hatchimonji et al., 2020). Hospital stays for patients with gastrointestinal fistulas tend to be prolonged, often involving extended periods in the intensive care unit (ICU). This lengthy hospitalization undoubtedly provides a conducive environment for the establishment of multidrug-resistant bacteria, thereby serving as an independent risk factor for both multidrug-resistant bacterial and fungal infections, consistent with prior research (Shen et al., 2023). Preoperative white blood cell (WBC) counts, neutrophil counts (N), and postoperative WBC levels reflect the overall inflammatory status of the body. Previous studies have indicated a close relationship between these markers and the occurrence of multidrug-resistant bacterial infections (Yan et al., 2022). Both WBCs and neutrophils play critical roles in angiogenesis, hematopoiesis, wound healing, and inflammatory processes associated with infectious diseases (Carnevale et al., 2023). Procalcitonin (PCT) and C-reactive protein (CRP) are commonly used biological markers for inflammation and sepsis (Tian et al., 2023). Under normal physiological conditions, serum PCT concentrations are extremely low. PCT is synthesized in monocytes and the liver, and its production is stimulated by lipopolysaccharides and cytokines (Pournaghi et al., 2024). Conversely, CRP is produced by the liver in response to interleukin-6 (IL-6), which is generated during infection and inflammation. Studies show that in patients who develop postoperative infections, CRP levels increase rapidly. In patients responsive to antibiotic treatment, CRP levels typically decrease within 48 hours post-surgery. A CRP level exceeding 250 mg/L often indicates poorer clinical outcomes (Perrella et al., 2021). As significant indicators of inflammation, the combined use of CRP and PCT can effectively enhance the diagnostic efficiency for intra-abdominal infections (Song and Lu, 2021). In this study, univariate analysis demonstrated that both preoperative and postoperative PCT and CRP levels were significant; however, due to a certain proportion of missing data for preoperative PCT and CRP, these were not included in the multivariate analysis. The multivariate analysis revealed that postoperative CRP is an independent risk factor for predicting multidrug-resistant bacterial and fungal infections.

Our study has several limitations. First, as a retrospective study, it may be subject to some degree of selection bias. We obtained a limited number of case observations from a small sample size and a single center. Second, although our study was divided into a training cohort and a validation cohort, further prospective studies are necessary to validate the accuracy of our nomogram before widespread clinical application. Third, we did not include antibiotic use as a factor in our analysis due to the complexity of the information regarding antibiotic therapy. Many patients had already been on antibiotics for a period before transferring to our hospital, making statistical evaluation challenging. Consequently, we plan to conduct prospective randomized controlled studies for further exploration.

Our study indicate that in patients with gastrointestinal fistulas, perioperative infections are predominantly caused by multidrug-resistant Gram-negative bacteria, with carbapenemase-producing Enterobacteriaceae and multidrug-resistant Klebsiella pneumoniae emerging as particularly concerning issues. The independent risk factors for multidrug-resistant bacterial and fungal infections during the perioperative period in these patients include secondary surgery, prolonged hospital stays, preoperative white blood cell (WBC) counts, preoperative neutrophil counts, postoperative WBC counts, and postoperative C-reactive protein (CRP) levels. Developing a predictive model based on these indicators demonstrates good clinical applicability and high predictive accuracy, which can inform effective prevention and treatment strategies, facilitate rational antibiotic use, and improve patient outcomes.