Association between gastric Candida colonization and surgical site infections after high-level hepatobiliary pancreatic surgeries: the results of prospective observational study

High-level hepatobiliary pancreatic (HBP) surgeries such as major hepatectomy and pancreaticoduodenectomy (PD) are associated with a high incidence of morbidity and mortality despite advanced surgical techniques and postoperative care [1, 2]. A large portion of the morbidity was constituted by postoperative infectious complications: pancreatic fistula, biliary fistula, intra-abdominal abscess, and wound infection [3‐6]. Several reports have focused on the association between microorganisms and the postoperative infections, in which bacteriobilia caused by preoperative biliary drainage was significantly associated with wound infection, intra-abdominal abscess, and sepsis [7‐11]. In such cases, we have focused on the association between Candida colonization and postoperative complications.

Candida colonization in the human gastrointestinal tract is generally recognized as inapparent infection but sometimes develops to Candida infection of candidemia and Candida peritonitis in patients recovering from abdominal surgeries, in which Candida species invade from mucosal defects and the amount of Candida species increases in non-functioning bowels [12, 13]. Recent reports revealed that the presence of a high amount of Candida species is related to invasive Candida infection and inflammatory disease, which implies that Candida colonization might have a negative influence on the clinical course [14, 15]. Previously, we clarified that biliary candidiasis could be the independent cause of surgical site infections (SSIs) after PD, in which biliary candidiasis was recognized as inapparent infection from the upper gastrointestinal tract to hepaticojejunostomy [10, 11]. Bacterial and fungal species in the upper gastrointestinal tract may have a significant impact on postoperative infectious complications. To date, however, there have been no reports regarding the impact of gastric Candida colonization on postoperative infectious complications in high-level HBP surgeries.

In the present study, we aimed to clarify the influence of gastric Candida colonization on SSIs in patients who underwent high-level HBP surgeries.

Of the 70 patients originally enrolled in the current study, 4 were excluded as subjects: two died of non-infectious complications within 5 days of the operation, and the other two had too little gastric juice to perform a fungal and bacterial culture. Therefore, the total number of subjects was 66 patients. Table 1 shows the background of the subjects including pre- and intraoperative variables. There were 41 males and 25 females. Their median age was 69 years (23–91 years). Their preoperative diagnoses were PDAC in 30 patients, intraductal papillary mucinous neoplasm (IPMN) in 8, biliary tract cancer (BCD) in 10 (distal cholangiocarcinoma in 5, perihilar cholangiocarcinoma in 3, ampullary carcinoma in 1, and intrahepatic cholangiocarcinoma in 1), hepatocellular carcinoma in 6, and the other diseases in 12 (liver metastasis from colon cancer in 2, congenital biliary dilatation in 2, refractory cholangitis after operation for congenital biliary dilatation in 2, hepatectomy for living donor liver transplant in 2, intraductal papillary neoplasm of the bile duct in 1, refractory cholangitis after Kasai’s operation for biliary atresia in 1, papillary adenoma of the ampulla in 1, and pancreatic neuroendocrine tumor in 1). Operative procedures included pancreatectomies in 50 patients (PD in 42, distal pancreatectomy in 6, and total pancreatectomy in 2), hepatectomies in 13 (major hepatectomy in 6, anatomical sectionectomy in 4, anatomical subsectionectomy in 3), and 3 other procedures (transhepatic hilar bile duct resection in 1, common bile duct resection for congenital biliary disease in 1, and living donor liver transplant in 1).

In the present study, we newly elucidated the following insights: (1) Asymptomatic gastric Candida colonization is preoperatively found in approximately 30% of patients for whom high-level HBP surgery was proposed. (2) In such patients, the risk of SSIs and postoperative morbidity was notably higher after high-level HBP surgery. (3) These results were consistent regardless of the type of procedure (with or without enterotomy and PD or non-PD).

Candida species are commonly considered to colonize the human gut as a component of the resident microbiota. Their presence is usually regarded as benign. However, high-level Candida colonization is reported to be associated with gastrointestinal tract diseases including Crohn’s disease, ulcerative colitis, and gastric ulcer [25‐27]. However, there have been no studies that prospectively assess the fungal and bacterial flora of the stomach, and this is the first study focusing on the resident microbiota in the stomach and the association between Candida colonization and SSIs after HBP surgeries.

The rate of Candida infection tends to increase with increasing age and is significantly high especially in those with age over 60 because their immune systems are weaker and their participation in outdoor activities is not low [28]. In critically ill patients recovering from abdominal surgery, 5–10% of them have a probability of developing invasive Candida infection of candidemia and Candida peritonitis by exposure to an increasing amount of Candida species in non-functioning bowel, prolonged antibiotic therapy, and organ support of central venous catheters, intubation tubes, Foley catheters, and nasogastric tubes [13, 14]. Therefore, we hypothesized that patients with compromising factors like malignant disease, diabetes mellitus, or poor nutritional status had asymptomatic fungal colonization of the digestive tract, and therefore highly developed postoperative infectious complications. In the present study, however, gastric Candida colonization was not related to patients’ compromised status such as age, PS, cachexia, primary disease, preoperative biliary drainage, and chemoradiotherapy, but was a unique significant risk factor of SSIs. According to previous reports, gastrointestinal Candida colonization is linked to poor oral hygiene and a western diet with increased consumption of purified wheat flour in healthy people [29‐32]. Candida species colonized preoperatively in the gastrointestinal tract might increase after invasive procedures of high-level HBP surgeries and might cause infectious complications.

High-level HBP surgeries continue to be accompanied by postoperative complications despite the improvement in surgical techniques and perioperative care. The morbidity following PD ranges from 30 to 70%, and postoperative mortality rates remain approximately between 1 and 5% even in high-volume centers [3‐5]. Major hepatectomy also has high morbidity rates of 24–70%, and perioperative mortality rates range from 1.8 to 8.4% [1, 6]. In such clinical courses, complications are highly associated with infection by microorganisms. Preoperative biliary drainage and instrumentations are associated with postoperative infectious complications of wound infection and intra-abdominal abscess, and microorganisms in the bile show a concordance of 100% and 69% of microorganisms in intra-abdominal abscess and wound infection [7, 8]. Therefore, perioperative use of specific antibiotics based on bile culture is recommended for preventing infectious complications [9], whereas few studies are focusing on SSI and fungal infection. Kato et al. [10, 11] reported a negative impact of biliary candidiasis on postoperative complications after PD. A total of 66.7% of patients with biliary candidiasis developed an intra-abdominal abscess, 14.3% sepsis, 14.3% PV thrombosis, and 9.5% abdominal hemorrhage. Moreover, the incidence of leakage in pancreatojejunostomy (grade B or C) was significantly higher in patients with biliary candidiasis compared with those without it (38.1% vs. 5.7%, p = 0.019). In the present study, a highly significant number of the patients with gastric Candida colonization experienced postoperative complications of organ or space SSIs, C-D grade of IIIa or higher, prolonged hospital stays, and readmission, compared with those without gastric Candida colonization in high-level HBP surgeries. Candida colonization is a significant issue to be addressed for decreasing morbidity and mortality rates in HBP surgery fields, although it remains underestimated as compared with other infectious diseases [33, 34].

The underlining mechanism that gastric Candida colonization increases SSIs regardless of the operative procedures has yet to be addressed. Candida species in gastric juice might develop contamination of the peritoneum by opening bowel flora, invasion into tissues from mucosal defects, and translocation into pancreatic juice or bile juice, causing the serious complications of postoperative massive ascites, pancreatic fistula, biliary fistula, and cholangitis. According to previous studies, fungal–bacterial coinfection might be associated with SSIs. Candida albicans initially adheres to and invades an epithelial cell, causing fungal recognition and the formation of hyphae. Hypha formation causes epithelial cell damage and activates the immune system through the secretion of a cytolytic peptide toxin called Candidalysin. Activated epithelial cells lead to the production of proinflammatory cytokines, chemokines, and antimicrobial peptides to recruit neutrophil and macrophage [35, 36]. The organ wall damage caused by Candida species allows bacteria to penetrate more easily in mouse models [37, 38]. Furthermore, Candida albicans produces a biofilm of a heterogeneous mixture of other microbial species and directly stimulates the growth of the species in vitro, causing resistance to antibiotic therapy [37]. In the current study, the same Candida species were identified in 27.3% of specimens from infected sites in group GC, whereas Candida species were not identified from infected sites in group NGC. Bacteria detection rates from infected sites tended to be higher in group GC than in group NGC although there was no significant difference. The results of the subgroup analysis show that the incidence of SSIs was significantly higher not only in the GC group receiving surgery accompanied by enterotomy but also in those without enterotomy, suggesting that Candida species in gastric juice not only cause direct damage to the organs but also accelerate other bacterial infections.

In the present study, the concordance rate of microorganisms between gastric juice and infected sites was low. Candida species can proliferate in the stomach by adjusting the thickness of the outer cell wall layer [39]. However, the majority of bacterial species are influenced by low pH in the stomach [40]. Major SSIs in high-level HBP surgeries were pancreatic fistula, biliary fistula, and intra-abdominal abscess. In such situations, bacterial species in the intestinal tract are different from those in gastric juice and might play a significant role in the development of SSIs, although Candida species can survive in the gastrointestinal tract. Preoperative biliary drainage, which is widely accepted as a risk factor of postoperative complications, had no association with SSIs. In cases with preoperative biliary drainage, perioperative antibiotics were selected based on the culture of the bile obtained by the drainage. We consider that such perioperative management contributed to decreasing the influence of preoperative biliary drainage on SSIs.

The potential limitation of this study is the small case number, one institutional and observational study. Therefore, the results might be confounded by institution-specific factors such as surgical technique and postoperative management. Moreover, we did not perform and validate Candida’s real-time polymerase chain reaction tests to evaluate Candida colonization in gastric juice and SSIs. To confirm the legitimacy of our results, multi-institutional prospective surveillance would be required. Currently, we propose a randomized control study (preoperative Candida eradication vs. no treatment) to apply our results to the clinical setting.

In conclusion, gastric Candida colonization is highly associated with SSIs after high-level HBP surgeries. Therefore, preoperative gastric Candida detection could be useful for predicting the development of SSIs after high-level HBP surgery, allowing us to pay maximum attention to SSIs and other complications.