Christopher A. Guidry MD MS, Robert G. Sawyer MD No Difference in Outcomes of Fungal Intra-Abdominal Infection with a 4-day Treatment Regimen Nathan R. Elwood MD, Christopher A. Guidry MD MS, Robert G. Sawyer MD Department of Surgery, University of Virginia Health System, Charlottesville VA

No conflicts of interest I have no conflicts of interest to disclose

Background Complicated intra-abdominal infection (IAI) is a common problem with significant morbidity Fungal organisms are present in approximately 10-40% of IAI1 Candida in IAI is associated with significant morbidity and mortality2 Mortality of Candidal peritonitis reaches 20-40% in ICU patients; higher in patients presenting in shock3,4 -Complicated intraabdominal infection is a common problem, with significant attendant morbidity and mortality -Fungal organisms are present in 10-40% of IAI, depending on the source of infection. Patients with gastroduodenal perforation, anastomotic leaks, and necrotizing pancreatitis are are particularly high risk for fungal infection -The presence of yeast in IAI is associated with increased morbidity and mortality, with mortality reaching 40% in studies of ICU patients with Candidal peritonitis, and in patients who present with hemodynamic changes this number is significantly higher

Treatment of Fungal IAI Most common organisms are C. albicans, C. glabrata, C. krusei Resuscitation Source control Antifungal therapy 5,6 -The most common organism in fungal IAI is Candida albicans, accounting for 50-60% of fungal IAI, followed by Candida glabrata, candida krusei, and several other non-albicans Candida species -As with any IAI, resuscitation, prompt source control, and appropriate antimicrobial therapy are the fundamental components of treatment -Guidelines for treatment of IAI in general call for a treatment course of 4-7 days, while 2016 guidelines from the Infectious Diseases Society of America for treatment of Candidal IAI do not recommend a specific duration of treatment, but call for the length of antifungal therapy to be based on clinical response and adequacy of source control -However, given the potential negative effects of antimicrobial therapy, there have been efforts to minimize the duration of treatment in IAI

STOP-IT Trial Patients receiving a fixed 4-day course of antibiotics had no difference in outcomes compared to the control group -Clinical outcomes were similar between these two groups, indicating that a shorter duration of antibiotics is not associated with higher rates of treatment failure -Based on this result, we questioned if this finding applies to patients with a fungal component to their infection, which would generally be considered harder to treat and associated with worse outcomes

STOP-IT Trial Patients receiving a fixed 4-day course of antibiotics had no difference in outcomes compared to the control group Does this apply to patients with more complex infections such as fungal IAI? -Clinical outcomes were similar between these two groups, indicating that a shorter duration of antibiotics is not associated with higher rates of treatment failure -Based on this result, we questioned if this finding applies to patients with a fungal component to their infection, which would generally be considered harder to treat and associated with worse outcomes

Methods Post-hoc subgroup analysis of patients with fungal isolates Analyzed in 2 ways: Based on original randomization to control or experimental arms Comparison to patients without a fungal isolate Wilcoxon rank-sum test for continuous variables Chi square or Fisher’s exact test for categorical variables -To evaluate this question, we performed a post-hoc analysis of prospectively collected data from the STOP-IT trial in order to see if the results held true in patients with a fungal IAI We first analyzed patients who had positive fungal cultures based on their original randomization to the control or experimental arms to see if there were any differences in clinical outcomes with a shorter treatment duration We then compared patients with fungal IAI to those without a fungal component to their infection to evaluate differences between these two patient populations

Demographics and Comorbidities There were 58 patients with positive fungal cultures, of which 31 were in the control group, and 27 were in the experimental group These two groups were similar in demographics and comorbidities There was a trend toward patients in the experimental group being older, but this was not statistically significant

Results Between the control and experimental groups there were no differences in clinical outcomes including the composite outcome, mortality, recurrent IAI, surgical site infection, hospital days, or days to the resumption of enteral feeding The only difference between the groups was the number of days of antimicrobial therapy, as expected given that this was the intervention, with a median of 5 days compared to 8 days of therapy

Results Between the control and experimental groups there were no differences in clinical outcomes including the composite outcome, mortality, recurrent IAI, surgical site infection, hospital days, or days to the resumption of enteral feeding The only difference between the groups was the number of days of antimicrobial therapy, as expected given that this was the intervention, with a median of 5 days compared to 8 days of therapy

Source of Infection We then compared patients with fungal isolates to those without a fungal component to their infection When compared to patients without fungal infection, those with fungal isolates were more likely to have malignancy and coronary artery disease, but were otherwise similar. Fungal infections were more likely to originate from the duodenum and small bowel, and fungi were never isolated from infections of biliary origin There were trends toward fungi being more likely to be isolated from gastric sources, and less likely isolated from appendiceal IAI, but these did not reach statistical significance

Source of Infection We then compared patients with fungal isolates to those without a fungal component to their infection When compared to patients without fungal infection, those with fungal isolates were more likely to have malignancy and coronary artery disease, but were otherwise similar. Fungal infections were more likely to originate from the duodenum and small bowel, and fungi were never isolated from infections of biliary origin There were trends toward fungi being more likely to be isolated from gastric sources, and less likely isolated from appendiceal IAI, but these did not reach statistical significance

Results (cont) -Comparing clinical outcomes between patients with and without fungal infection, patients with fungal IAI had more days to enteral feeding and longer hospital stays, but there was no difference in mortality, recurrent IAI, surgical site infection, or the composite outcome

Results (cont) -Comparing clinical outcomes between patients with and without fungal infection, patients with fungal IAI had more days to enteral feeding and longer hospital stays, but there was no difference in mortality, recurrent IAI, surgical site infection, or the composite outcome

Discussion A fixed 4 day treatment regimen is not associated with worse outcomes in fungal IAI Supports the results of the STOP-IT trial in a population which would be expected to have harder to treat infection Patients with fungal IAI may have more complicated infections overall, evidenced by longer admissions and more days to enteral feeding In contrast to other studies, there was no increased mortality in patients with fungal IAI Possibly because many other studies focus on critically ill patients Critically ill patients also more likely to have nosocomial infection -In this study population of patients with fungal IAI, a fixed 4-day treatment regimen was not associated with worse outcomes -Patients with fungal IAI may have more complicated infections overall -However these differences could also be due to clinician choices to be more conservative with patients who have fungal IAI 6.

Prospectively collected multi-center data Strengths Prospectively collected multi-center data Well-matched control and experimental groups Limitations Small sample size Post-hoc analysis Not all patients adhered to protocol This could bias toward a finding of equivalence -Stengths of this study included the use of prospectively collected multi-center data to evaluate a clinically important entity, and the presence of well matched control and experimental arms -A limitation of this study is the small sample size, with only 58 patients having positive fungal cultures. -As a post-hoc analysis of a trial not initially designed to investigate fungal IAI, these results are inherently limited -Furthermore, not all patients adhered to protocol, and even in the experimental group the median duration of antimicrobial therapy was 5 days rather than 4. This would tend to make the two groups more similar and bias toward a finding of equivalence. -However, one reason for this is likely the way in which duration of therapy was accounted for. Many patients were not started empirically on antifungals, which were only initiated once culture results became available, generally on day 2 or 3 of therapy. Antifungal therapy was then initiated and continued for 4 full days, leading to a total duration of therapy that was longer than 4 days.

Conclusions A 4-day course of antifungal therapy was not associated with a higher rate of treatment failure Patients with fungal IAI had longer admissions, but no difference in treatment failure Even in more complex infections, we may be able to spare patients the negative effects of prolonged antimicrobial therapy

References Sandven, Per, et al. "Significance of Candida recovered from intraoperative specimens in patients with intra-abdominal perforations." Critical care medicine 30.3 (2002): 541-547. Montravers, Philippe, et al. "Candida as a risk factor for mortality in peritonitis." Critical care medicine 34.3 (2006): 646-652 Montravers, Philippe, et al. "A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive‐care units." Clinical Microbiology and Infection 17.7 (2011): 1061-1067 Kollef, Marin, et al. "Septic shock attributed to Candida infection: importance of empiric therapy and source control." Clinical infectious diseases 54.12 (2012): 1739-1746. Solomkin, Joseph S., et al. "Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America." Clinical infectious diseases 50.2 (2010): 133-164. 6. Pappas, Peter G., et al. "Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America." Clinical Infectious Diseases (2015): civ933.

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