The 2016 Infectious Diseases Society of America (IDSA) guidelines recommend considering empiric antifungal therapy in patients with clinical evidence of intra-abdominal infection and significant risk factors for invasive candidiasis, particularly recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis (strong recommendation; moderate-quality evidence). The guidelines identify recurrent gastroduodenal perforation as a particularly high-risk condition and suggest that patients with gastroduodenal perforation who are deteriorating despite antibacterial therapy may benefit from empiric antifungals, even without Candida isolation. When antifungal therapy is indicated, an echinocandin is generally preferred, while fluconazole may be an alternative in selected patients. Experts emphasize that adequate source control through drainage or debridement is essential, and treatment duration should be guided by clinical response and adequacy of source control. [1]
The 2017 European Association for Cardio-Thoracic Surgery (EACTS) expert consensus statement addresses the management of mediastinitis associated with esophageal perforation, including spontaneous, iatrogenic, and traumatic perforations. The statement recommends intravenous broad-spectrum antibiotics covering aerobic and anaerobic bacteria, while antifungal coverage is advised only in selected patients, particularly those who are immunosuppressed or were receiving broad-spectrum antibiotics before the perforation. The authors emphasize that esophageal perforation can result in contamination of the mediastinum with saliva and gastric contents, potentially leading to mediastinitis and severe infection. Management therefore requires prompt antimicrobial treatment, restoration of esophageal integrity, and control of contamination through appropriate drainage or surgical intervention. However, the consensus statement does not provide comparative clinical data demonstrating improved outcomes with empiric antifungal therapy, nor does it establish specific antifungal agents, treatment durations, or criteria for routine administration. Thus, its support for empiric antifungal coverage is limited to selected higher-risk patients rather than all patients with esophageal perforation. [2]
The 2020 World Society of Emergency Surgery (WSES) guidelines suggest against routine empiric antifungal therapy in patients with perforated peptic ulcers, recommending its use in patients at high risk for fungal infection, including those who are immunocompromised, elderly, have significant comorbidities, experience prolonged intensive care unit stays, or have unresolved intra-abdominal infections (weak recommendation; low-quality evidence). The guidelines recommend obtaining intraoperative samples for bacterial and fungal cultures to guide antimicrobial therapy. Although fungal isolation from peritoneal fluid has been associated with longer hospital stays, higher surgical site infection rates, and increased mortality, these associations do not establish a benefit from antifungal treatment. Specifically, the guidelines cite a retrospective study (see Table 1) of 133 patients with peptic ulcer perforation that found no statistically significant survival difference between patients who received antifungal therapy and those who did not; shock on admission and an Acute Physiology and Chronic Health Evaluation (APACHE) score greater than 20 were independently associated with poor outcomes. When antifungal treatment is indicated, the guidelines describe fluconazole as an option for selected patients with community-acquired Candida peritonitis and low risk of fluconazole resistance, while echinocandins are preferred for high-risk patients and invasive Candida infections in critically ill patients. Overall, the guidelines favor individualized antifungal treatment based on infection risk, clinical severity, microbiological findings, and response to treatment rather than routine empiric administration. These recommendations specifically address perforated peptic ulcers and do not directly evaluate esophageal perforation. [3]
A 2019 review article evaluated the role of empiric antifungal therapy in patients with perforated peptic ulcers. The review identified five studies, including one randomized trial involving various intra-abdominal perforations, one prospective observational study, and three retrospective studies. No randomized trials specifically evaluating empiric antifungal therapy in patients with perforated peptic ulcers were identified. Although Candida species were frequently isolated from peritoneal fluid and fungal-positive cultures were associated with worse outcomes in some studies, the clinical benefit of empiric antifungal treatment remained uncertain. Two retrospective studies specifically involving perforated peptic ulcers found no significant improvements in mortality, hospital or intensive care unit length of stay, intra-abdominal abscesses, or other evaluated outcomes with antifungal therapy. Notably, the review included the retrospective study of 133 patients with community-acquired perforated peptic ulcer-associated peritonitis and Candida-positive peritoneal cultures, previously discussed in the 2020 WSES guidelines, which found no significant improvement in 30-day mortality or secondary outcomes with antifungal therapy after propensity-score matching (see Table 1). A randomized trial involving 109 patients with intra-abdominal perforations found that a single intraoperative dose of fluconazole did not significantly reduce mortality compared with placebo (7.5% vs 14.3%; p= 0.059), although the study was not adequately powered to evaluate perforated peptic ulcers specifically (see Table 2). Conversely, observational studies involving broader populations with intra-abdominal candidiasis or postoperative intra-abdominal sepsis reported associations between earlier antifungal treatment and improved survival, but their heterogeneous populations and nonrandomized designs limit applicability to perforated peptic ulcers. The authors concluded that available evidence did not establish improved clinical outcomes with routine empiric antifungal therapy in perforated peptic ulcers and cautioned against its routine use, while acknowledging that further research is needed to identify patients who may benefit, particularly those with greater illness severity or significant comorbidities. [4]
A 2022 review discusses management of esophageal perforation in the emergency department based on available evidence. Given the risk of gastrointestinal microorganism spillage into the finite potential spaces within the neck, mediastinum, and peritoneum, broad-spectrum antibiotics should be administered upon suspicion of esophageal perforation to ensure adequate coverage for Gram-positive, Gram-negative, and anaerobic bacteria. On the other hand, empiric antifungal coverage is recommended for high-risk patient populations, including those with a history of an immunocompromised state, esophageal lesions or infections, prolonged proton pump inhibitor use, or other factors associated with fungal infection. In such cases, use of intravenous antifungal agents, such as fluconazole or caspofungin, may be considered along with infectious diseases consultation. Instead of being given as a universal empiric regimen, antifungal agents may be used as adjunctive therapies for esophageal perforation in select patients. [5]
A 2025 systematic review and meta-analysis of 8 retrospective studies representing 1,802 adults with perforated peptic ulcers assessed whether empiric antifungal therapy reduces 30-day mortality. Empiric antifungals were given to 19.6%, most commonly fluconazole, and nearly all patients received surgical repair of the causative perforation. Intraoperative cultures were obtained in 73.7% of patients and blood cultures in 54.5%; cultures were positive for fungal organisms in 44% of surgical and 5.6% of blood cultures. Positive intraoperative fungal cultures were significantly associated with diabetes mellitus (odds ratio [OR] 1.55, 95% confidence interval [CI] 1.05 to 2.30), history of malignancy (OR 2.80, 95% CI 1.22-6.45), active steroid therapy (OR 5.13, 95% CI 1.37 to 19.3), and increased mortality (OR 2.49, 95% CI 1.67 to 3.70). Empiric antifungal therapy did not significantly decrease mortality rates (OR 1.45, 95% CI 0.33 to 6.41), and, while detection of fungi in the peritoneal fluid was associated with increased risk of death, it was not affected by administration of empiric antifungal therapy. [6]