Intra-abdominal Candidiasis Research Articles

Synergetic action of atorvastatin and fluconazole against fluconazole-resistant Candida albicans in vitro and in a murine model for intra-abdominal Candidiasis / Ação sinérgica da atorvastatina e fluconazol contra Candida albicans resistente ao fluconazol in vitro e em um modelo murino contra Candidíase intra-abdominal

Introduction: Candida albicans is the most common causative agent of Intra-abdominal Candidiasis (IAC) and it is resistant to most antifungal drugs currently available. Here we investigated atorvastatin in vitro and in vivo antifungal activities against a fluconazole-resistant C. albicans strain as a potential repurposed drug. The following tests were carried out: antifungal susceptibility tests to determine minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), determination of time-kill curve, biofilm assays, Candida albicans yeast-hyphae transition inhibition assay, murine model of Intra-abdominal candidiasis, survival curve, fungal load quantification, histopathology analysis, quantification of TNF-α and IL-17 cytokines, quantification of N-acetyl-β-D-glucosaminidase. In vitro assays showed the synergetic action of atorvastatin and fluconazole against C. albicans growth and biofilm maturation while the time-kill curve assay revealed their fungicidal effect after 24 h of treatment. When yeast-to-hyphae transition was assessed, the synergetic effect of atorvastatin and fluconazole reduced C. albicans filamentation significantly. In vivo tests showed that one of the most noticeable signs of IAC is the intense systemic inflammation. However, our survival curve test showed that despite being ill, animals exhibited little to no clinical signs of systemic inflammation when treatment included a combination of atorvastatin and fluconazole. Altogether, these findings suggest that atorvastatin could be feasibly used in the treatment fluconazole-resistant C. albicans strains, showing that drug repurposing is an important strategy when considering the limited number of antifungal drugs available for treatment in addition to financial hardship experienced in research and development of new antifungal drugs.

Is ß-d-glucan Relevant for the Diagnosis and Follow-Up of Intensive Care Patients with Yeast-Complicated Intra-Abdominal Infection?

The usefulness of (1,3)-ß-d-glucan (BDG) detection for the diagnosis of intra-abdominal candidiasis and treatment monitoring is unknown. A prospective, single-center study of consecutive patients admitted to an ICU with complicated intra-abdominal infection (IAI) over a 2-year period was conducted. BDG was measured in the peritoneal fluid and serum between day 1 (D1) and D10. Patients with a positive peritoneal fluid yeast culture (YP) were compared to those with a negative yeast culture (YN). The evolution of serum BDG was compared in the two groups. Seventy patients were included (sixty-five analyzed): YP group (n = 19) and YN group (n = 46). Median peritoneal BDG concentration during surgery was 2890 pg.mL−1 [IQR: 942–12,326] in the YP group vs. 1202 pg.mL−1 [IQR: 317–4223] in the YN group (p = 0.13). Initial serum BDG concentration was 130 pg.mL−1 [IQR: 55–259] in the YP group vs. 88 pg.mL−1 [IQR: 44–296] in the YN group (p = 0.78). No difference in evolution of serum BDG concentrations was observed between the groups (p = 0.18). In conclusion, neither peritoneal BDG nor serum BDG appear to be good discriminating markers for the diagnosis of yeast IAI. In addition, monitoring the evolution of serum BDG in yeast IAI did not appear to be of any diagnostic value.

Fluconazole versus micafungin for initial antifungal prophylaxis against Candida in pancreas transplant recipients: A comparative study of two consecutive periods.

Invasive fungal infection, particularly intraabdominal candidiasis, exerts a negative impact on the outcome of pancreas transplant recipients (PTRs). Optimal antifungal prophylaxis in this context remains unclear. We performed a single-centre retrospective study to compare the incidence of invasive candidiasis during the first 6 post-transplant months in a cohort of 218 PTRs over two periods in which different agents for antifungal prophylaxis were used: fluconazole (Fluco-Px) from March 1995 to June 2012, and micafungin followed by fluconazole (Mica-Px) from July 2012 to December 2018. A total of 152 and 66 PTRs received Fluco-Px and Mica-Px. Mean age was 39.7±7.8years, 56.4% (123/218) were males, and 85.3% (186/218) underwent simultaneous pancreas-kidney transplantation. Invasive candidiasis occurred in 21.7% (33/152) of PTRs under Fluco-Px compared to 24.2% (16/66) of those under Mica-Px (p-value=.681). Median time from transplantation to infection was 8days (interquartile range [IQR]: 6-16) under Fluco-Px versus 6.5 (IQR: 3.3-15.8) under Mica-Px (p-value=.623). Non-albicans Candida species comprised 27.5% (11/40) and 25.0% (4/16) of episodes under Fluco-Px and Mica-Px respectively (p-value=.849). Surgical site infection was the most common form in both groups (82.5% [33/40] and 87.5% [14/16]; p-value=.954). Multivariable analysis identified cold ischaemia time of the pancreas and kidney grafts, surgical reintervention and insulin requirement after transplantation as risks factor for invasive candidiasis. This retrospective study did not reveal a significant benefit from the initial use of micafungin-based antifungal prophylaxis over fluconazole among PTRs in terms of invasive candidiasis.

Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study.

IntroductionIntra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10–30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU.MethodsWe performed a case–control study in 26 European ICUs during the period January 2015–December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study.ResultsDuring the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65–72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98–21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73–25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04–17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32–10.52, p = 0.01) were independently associated with IAC.ConclusionsGastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00585-6.

T2Candida Assay in the Diagnosis of Intraabdominal Candidiasis: A Prospective Multicenter Study.

The T2Candida magnetic resonance assay is a direct-from-blood pathogen detection assay that delivers a result within 3–5 h, targeting the most clinically relevant Candida species. Between February 2019 and March 2021, the study included consecutive patients aged >18 years admitted to an intensive care unit or surgical high-dependency unit due to gastrointestinal surgery or necrotizing pancreatitis and from whom diagnostic blood cultures were obtained. Blood samples were tested in parallel with T2Candida and 1,3-β-D-glucan. Of 134 evaluable patients, 13 (10%) were classified as having proven intraabdominal candidiasis (IAC) according to the EORTC/MSG criteria. Two of the thirteen patients (15%) had concurrent candidemia. The sensitivity, specificity, positive predictive value, and negative predictive value, respectively, were 46%, 97%, 61%, and 94% for T2Candida and 85%, 83%, 36%, and 98% for 1,3-β-D-glucan. All positive T2Candida results were consistent with the culture results at the species level, except for one case of dual infection. The performance of T2Candida was comparable with that of 1,3-β-D-glucan for candidemic IAC but had a lower sensitivity for non-candidemic IAC (36% vs. 82%). In conclusion, T2Candida may be a valuable complement to 1,3-β-D-glucan in the clinical management of high-risk surgical patients because of its rapid results and ease of use.

A Case of Surgical Drainage for Intra-abdominal Candidiasis after Peritonitis due to a Perforated Duodenal Ulcer

術後合併症としてのintra-abdominal candidiasis（IAC）は，稀であるが予後不良な病態である．十二指腸穿孔性汎発性腹膜炎術後のカンジダ性多発腹腔内膿瘍に対して再手術を行った1例を報告する．症例は65歳の男性．十二指腸穿孔性汎発性腹膜炎，敗血症性ショックの診断で緊急開腹ドレナージ，大網充填術を行った．敗血症性ショックからは回復したが，術後6日目に発熱，CRP再上昇を認めた．術中採取した感染性腹水からCandida albicansが同定され，抗真菌薬加療を開始した．発熱等の症状は改善せず，術後10日目の腹部造影CTで多数の腹腔内膿瘍を認めたため，再開腹ドレナージ術を行った．術後十二指腸潰瘍穿孔部からの腸液の再流出を認めたが，抗真菌薬は計28日投与し，IACは軽快した．緊急手術術後IACにはドレナージ術が有効であるが，再手術はリスクを伴うため，適切な時期や適応に関する検討が今後の課題である．

Candida glabrata MSH2 deletion increases antifungal tolerance in vitro and during intra-abdominal candidiasis (IAC), it does not impact pathogenesis of peritonitis or intra-abdominal abscesses

Background: IAC is the second most common type of invasive Candidiasis, but its pathogenesis is poorly understood. We have shown that Candida albicans DNA damage response genes are strongly induced within intra-abdominal abscesses. Deletion of C. glabrata MSH2, A DNA mismatch repair (MMR) gene, results in a mutator phenotype that facilitates multidrug resistance in vitro and in mouse gastrointestinal tracts. Our goal was to determine if CGMSH2 Contributed to pathogenesis or resistance to the new antifungal rezafungin during IAC. Methods: We createdΔMSH2 in BG2 using SAT-Flipper, and tested virulence and rezafungin responses in a mouse model of IAC. Results: ΔMSH2 displayed no growth defects at 30°C in liquid (YPD, Ypglycerol) or solid media (YPD+0.02% MMS, 1MM H2O2, 1M NACL, 20 UG/ML CW, 250 UG/ML OR 0.02% SDS). ΔMSH2 longevity in YPD was comparable to BG2. Caspofungin-, Rezafungin- and Fluconazole-resistant mutants arose 24-, 16- and 3-fold more often, respectively, for ΔMSH2 than BG2 (108-106 CFU overnight in YPD, selected on 8XMIC-Containing plates). However, respective minimum inhibitory concentrations (MICS) were not different, nor were rezafungin time-kills.ΔMSH2 was comparable to BG2 in peritonitis and abscess burdens in mouse IAC.ΔMSH2 demonstrated significantly greater caspofungin- and fluconazole-tolerance than BG2 in abscesses. Rezafungin reduced peritonitis and abscess burdens ofΔMSH2,BG2 ANDFKS mutant strains to similar extents. Conclusions: CgMSH2 deletionincreased the frequency of spontaneously-arising echinocandin- and fluconazole-resistant colonies in vitro and tolerance in intra-abdominal abscesses, but it did not attenuate virulence or rezafungin responses during IAC.

Deciphering the epidemiology of invasive candidiasis in the intensive care unit: is it possible?

Invasive candidiasis (IC) has emerged in the last decades as an important cause of morbidity, mortality, and economic load in the intensive care unit (ICU). The epidemiology of IC is still a difficult and unsolved enigma for the literature. Accurate estimation of the true burden of IC is difficult due to variation in definitions and limitations inherent to available case-finding methodologies. Candidemia and intra-abdominal candidiasis (IAC) are the two predominant types of IC in ICU. During the last two decades, an increase in the incidence of candidemia has been constantly reported particularly in the expanding populations of elderly or immunosuppressed patents, with a parallel change in Candida species (spp.) distribution worldwide. Epidemiological shift in non-albicans spp. has reached worrisome trends. Recently, a novel, multidrug-resistant Candida spp., Candida auris, has globally emerged as a nosocomial pathogen causing a broad range of healthcare-associated invasive infections. Epidemiological profile of IAC remains imprecise. Though antifungal drugs are available for Candida infections, mortality rates continue to be high, estimated to be up to 50%. Increased use of fluconazole and echinocandins has been associated with the emergence of resistance to these drugs, which affects particularly C. albicans and C. glabrata. Crucial priorities for clinicians are to recognize the epidemiological trends of IC as well as the emergence of resistance to antifungal agents to improve diagnostic techniques and strategies, develop international surveillance networks and antifungal stewardship programmes for a better epidemiological control of IC.

Protocol for the pBDG2 Study: Prospective Evaluation of 1.3-β-D-Glucan in the Peritoneal Fluid for the Diagnosis of Intra-Abdominal Candidiasis in Critically Ill Patients

Background: The delayed diagnosis of the presence of Candida in severe intra-abdominal infections exposes patients to an increased risk of mortality. The prevalence of intra-abdominal candidiasis (IAC) varies with the type of intra-abdominal infection, the underlying conditions and the presence of risk factors for Candida infection. This study aims to evaluate the interest of the measure of 1.3-β-D-glucan (BDG) in the peritoneal fluid for the early diagnosis of IAC. Methods and analysis: This is a prospective multicenter (n = 5) non-interventional study, focusing on all critically ill patients with an intra-abdominal infection requiring intra-abdominal surgery. The primary objective is to assess the diagnostic performance of the BDG measured in the peritoneal fluid for the early detection of IAC using the Candida culture as the gold standard. The secondary objective is to report the prevalence of IAC in the selected population. This study aims to enroll 200 patients within 48 months. By estimating the prevalence of IAC in the selected population at 30%, 50 patients with IAC (cases) are expected. These 50 IAC cases will be matched with 50 non-IAC patients (as a control group). The peritoneal BDG will be measured a posteriori in all of these 100 selected patients. This article presents the protocol and the current status of the study. Only the prevalence of IAC is reported as preliminary result.

Immune Resolution Dilemma: Host Antimicrobial Factor S100A8/A9 Modulates Inflammatory Collateral Tissue Damage During Disseminated Fungal Peritonitis.

Intra-abdominal infection (peritonitis) is a leading cause of severe disease in surgical intensive care units, as over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of the immune system is to return to homeostasis after combating infection. S100A8/A9 (calprotectin) is an antimicrobial and pro-inflammatory protein complex used as a biomarker for diagnosis of numerous inflammatory disorders. Here we describe the role of S100A8/A9 in inflammatory collateral tissue damage (ICTD). Using a mouse model of disseminated intra-abdominal candidiasis (IAC) in wild-type and S100A8/A9-deficient mice in the presence or absence of S100A9 inhibitor paquinimod, the role of S100A8/A9 during ICTD and fungal clearance were investigated. S100A8/A9-deficient mice developed less ICTD than wild-type mice. Restoration of S100A8/A9 in knockout mice by injection of recombinant protein resulted in increased ICTD and fungal clearance comparable to wild-type levels. Treatment with paquinimod abolished ICTD and S100A9-deficient mice showed increased survival compared to wild-type littermates. The data indicates that S100A8/A9 controls ICTD levels and antimicrobial activity during IAC and that targeting of S100A8/A9 could serve as promising adjunct therapy against this challenging disease.

Therapeutic Potential of Fosmanogepix (APX001) for Intra-abdominal Candidiasis: from Lesion Penetration to Efficacy in a Mouse Model.

Intra-abdominal candidiasis (IAC) is one of the most common yet underappreciated forms of invasive candidiasis. IAC is difficult to treat, and therapeutic failure and drug-resistant breakthrough infections are common in some institutions despite the use of echinocandins as first-line agents. Fosmanogepix (FMGX, formerly APX001) is a first-in-class antifungal prodrug that can be administered both intravenously and orally. FMGX is currently in phase 2 clinical development for the treatment of life-threatening invasive fungal infections. To explore the pharmacological properties and therapeutic potential of FMGX for IAC, we evaluated both drug penetration and efficacy of the active moiety manogepix (MGX, formerly APX001A) in liver tissues in a clinically relevant IAC mouse model infected with Candida albicans Matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed absolute drug quantitation were employed to evaluate drug penetration into liver abscess lesions both spatially and quantitatively. The partitioning of MGX into lesions occurred slowly after a single dose; however, robust accumulation in the lesion was achieved after 3 days of repeated dosing. Associated with this drug penetration pattern, reduction in fungal burden and clearance in the liver were observed in mice receiving the multiday FMGX regimen. In comparison, administration of micafungin resulted in marginal reduction in fungal burden at the end of 4 days of treatment. These results suggest that FMGX is a promising candidate for the treatment of IAC.

The burden of serious fungal infections in Azerbaijan.

Background:Azerbaijan is an upper middle-income country in South Caucasus with an area of 86,600 km2 and a total population of 10 million people and gross domestic product of US $4480 per capita. The aim of this research is to estimate fungal infection burden and highlight the problem at national and international levels.Methods:Fungal infection burden was estimated using data from epidemiological papers and population at risk and LIFE (Leading International Fungal Education) modelling.Results:The number of people living with human immunodeficiency virus (PLHIV) in 2018 was 6193, 29% of them not receiving antiretroviral therapy. Based on 90% and 20% rates of oral and oesophageal candidiasis in patients with CD4 cell count <200 µl–1 we estimate 808 and 579 patients with oral and oesophageal candidiasis, respectively. The annual incidences of cryptococcal meningitis and Pneumocystis pneumonia are 5 and 55 cases, respectively. We estimated 2307 cases of chronic pulmonary aspergillosis (CPA), 4927 patients with allergic bronchopulmonary aspergillosis (ABPA), and 6504 with severe asthma with fungal sensitization (SAFS). Using data on chronic obstructive pulmonary diseases (COPD), lung cancer, acute myeloid leukaemia rates, and number of transplantations, we estimated 693 cases of invasive aspergillosis following these conditions. Using a low-European rate for invasive candidiasis, we estimated 499 and 75 patients with candidemia and intra-abdominal candidiasis respectively. The number of adult women (15–55 years) in Azerbaijan is ~2,658,000, so it was estimated that 159,490 women suffer from recurrent vulvovaginal candidiasis (rVVC).Discussion:In total, the estimated number of people suffering from fungal diseases in Azerbaijan is 225,974 (2.3% of the population). However, the fungal rate is underestimated due to lack of epidemiological data. The most imminent need is improvement in diagnostic capabilities. This aim should be achieved via establishing a reference laboratory and equipping major clinical centers with essential diagnostics assays.

Design, synthesis, and biodistribution studies of new analogues of marine alkaloids: Potent invitro and invivo fungicidal agents against Candida spp.

Invasive candidiasis, such as intra-abdominal candidiasis (IAC), is a significant cause of morbidity and mortality worldwide. IAC is still poorly understood, and its treatment represents a challenge for public health. In this study, we showed the invitro anti-Candida activity of four alkaloid synthetic derivatives and their antifungal potential in a murine model of IAC. The biological effects of alkaloids were evaluated against Candida spp. through the determination of the minimum inhibitory concentration (MIC). For the alkaloids that showed antifungal activity, the fungicidal concentration, time-kill curve, synergism with azoles and polyenes, phenotypic effects, and the effect against virulence factors were also determined. The most active alkaloids were selected for invivo assays. The compounds 6a and 6b were active against C.albicans, C.glabrata, and C.tropicalis (MIC 7.8μg/mL) and showed promising antifungal activity against C.krusei (MIC 3.9μg/mL). The compound 6a presented a potent fungicidal effect invitro, eliminating the yeast C.albicans after 8h of incubation at MIC. An important invitro synergistic effect with ketoconazole was observed for these two alkaloids. They also induced the lysis of fungal cells by binding to the ergosterol of the membrane. Besides that, 6a and 6b were able to reduce yeast-to-hyphal transition in C.albicans, as well as inhibit the biofilm formation of this pathogen. In the in vivo assay, the compound 6a did not show acute toxicity and was mainly absorbed by the liver, spleen, and lung after a parenteral administration. Also, this analogue significantly reduced the fungal load of C. albicans on the kidney and spleen of animals with IAC. Therefore, these results showed that the compound 6a is a potent anti-Candida agent invitro and invivo.

Evaluation of Invasive Intra-abdominal Candidiasis in Crohn Disease at the Time of Surgery.

PurposeThe aim of this study was to determine whether a connection exists between Crohn disease and fungi, specifically Candida albicans, because one possible cause of disease is thought to be the presence of fungi in the intra-abdominal cavity. The diagnosis of invasive candidiasis is difficult due to the lack of specific clinical manifestations of the disease. A retrospective evaluation of the presence of invasive candidiasis was done in a group of 54 patients with Crohn disease and in a group of 31 patients who received surgery primarily for right-sided cancer of the colon.MethodsCulture samples were obtained from the wall of the extraluminal portion of the terminal ileum and the adjacent mesenterium, and then sent to the microbiology laboratory for further investigation. Sabouraud agar (SGC2) and chromID Candida agar (CAN2) were used for both short-term (48 hours) and long-term (10 days) cultivation.ResultsPearson chi-square test revealed a statistically significant difference in the prevalence of fungi and yeast between the 2 groups of patients (χ2 = 4.3873, P < 0.05).ConclusionPatients with Crohn disease had a significantly higher prevalence of fungi and yeasts in the intra-abdominal cavity compared with cancer patients.

Performance of the T2Candida Panel for the Diagnosis of Intra-abdominal Candidiasis

Performance of T2Candida for detecting intra-abdominal candidiasis (IAC) was assessed in 48 high-risk patients. T2Candida sensitivity/specificity and positive/negative predictive values were 33%/93% and 71%/74%, respectively. IAC was present in 100% of cases with concordant positive T2Candida/1,3-beta-d-glucan and absent in 90% of concordant negative results. Combination T2Candida/1,3-beta-d-glucan may help guide treatment decisions.

Penetration of Ibrexafungerp (Formerly SCY-078) at the Site of Infection in an Intra-abdominal Candidiasis Mouse Model.

Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.

Appropriate Source Control and Antifungal Therapy are Associated with Improved Survival in Critically Ill Surgical Patients with Intra-abdominal Candidiasis

BackgroundIntra-abdominal candidiasis (IAC) is the predominant type of invasive candidiasis with high mortality in surgical intensive care patients. The purpose of this study was to investigate the impact of appropriate source control and antifungal therapy on the outcomes of critically ill surgical patients with IAC.MethodsThis was a retrospective single-center cohort study. Adult surgical patients who were admitted to the intensive care unit and diagnosed with IAC from January 1, 2003, to December 31, 2016, were enrolled. The patients’ data including risk factors of IAC, infection-related information, antifungal treatment and 30-day outcomes were collected. The primary endpoint was 30-day mortality. A COX proportional hazards model was used to analyze the association between appropriate treatment and 30-day survival.ResultsA total of 82 patients were included in the analysis. Of these, 45 (54.9%) were complicated with septic shock at IAC diagnosis. Types of IAC included peritonitis (61.0%), intra-abdominal abscesses (23.2%) and biliary tract infections (15.9%). Of the included patients, 53 (64.6%) received appropriate source control and 44 (53.7%) appropriate antifungal therapy. Compared with patients with neither of these treatments, appropriate source control (HR 0.08, 95% CI 0.02–0.30; P < 0.001), appropriate antifungal therapy (HR 0.14, 95% CI 0.04–0.55; P = 0.005), and a combination of these treatments (HR 0.02, 95% CI 0.00–0.08; P < 0.001) were associated with reduced risk of death within 30 days after IAC diagnosis.ConclusionFor critically ill surgical patients with IAC, both appropriate source control and appropriate antifungal therapy were associated with reduced risk of 30-day mortality, and the protective effects of the two appropriate treatments were additive.

Roles of the multiplex real-time PCR assay and β-D-glucan in a high-risk population for intra-abdominal candidiasis (IAC).

Multiplex quantitative real-time PCR (MRT-PCR) using blood can improve the diagnosis of intra-abdominal candidiasis (IAC). We prospectively studied 39 patients with suspected IAC in the absence of previous antifungal therapy. Blood cultures, MRT-PCR, and β-D-glucan (BDG) in serum were performed in all patients. IAC was defined according to the 2013 European Consensus criteria. For MRT-PCR, the probes targeted the ITS1 or ITS2 regions of ribosomal DNA. Candidaemia was confirmed only in four patients (10%), and IAC criteria were present in 17 patients (43.6%). The sensitivity of MRT-PCR was 25% but increased to 63.6% (P=.06) in plasma obtained prior to volume overload and transfusion; specificity was above 85% in all cases. BDG performance was improved using a cutoff>260 pg/ml, and improvement was not observed in samples obtained before transfusion. In this cohort of high risk of IAC and low rate of bloodstream infection, the performance of non-culture-based methods (MRT-PCR or BDG) was moderate but may be a complementary tool given the limitations of diagnostic methods available in clinical practice. Volume overload requirements, in combination with other factors, decrease the accuracy of MRT-PCR in patients with IAC.

Risk factors of invasive candidiasis in critical cancer patients after various gastrointestinal surgeries: A 4-year retrospective study.

For early diagnosis and treatment of invasive candidiasis (IC), the well-known risk factors may not apply in the intensive care unit (ICU). This retrospective study identified the risk factors predicting IC and candidemia in cancer patients under intensive care after gastrointestinal surgery.Enrolled were 229 cancer patients admitted to our oncology surgical ICU after gastrointestinal surgery between January 1, 2010 and October 31, 2014.The most common types of solid gastrointestinal cancers were gastric (49.8%), colon (20.1%), and esophageal (18.3%). The percentage of patients with corrected Candida colonization index (CCI) ≥0.4 was 31.9%. IC was confirmed in 19 patients (8.3%), and the ICU mortality was 15.8%. Candida albicans accounted for 52.6% of the total number of pathogenic Candida isolates. Among patients with CCI ≥0.4, the cancers with the highest prevalence were cardiac (45%) and gastric (36%), with ICU mortalities of 20% and 4.9%, respectively. For the diagnosis of candidemia, (1-3)-β-D-glucan (BDG) ≥80 pg/mL showed a sensitivity and specificity of 25% and 82.7%, respectively, positive and negative predictive values 6.7% and 95.7%, and area under the receiver operating characteristic curve 0.512. CCI ≥0.4 was the only significant predictor of IC, and number of organ failures was the only predictor of candidemia (P = .000 and .026).CCI ≥0.4 was the only significant risk factor predicting IC, with greater prediction of intra-abdominal candidiasis but failure to predict candidemia. Blood culture and BDG detection are recommended to supplement diagnosis. Patients may have multifocal and high-grade Candida colonization after cardiac surgery, and; therefore, are at high risk of IC, which should be taken seriously.

2887. Identifying Candida albicans Transcription Factors (TFs) That Regulate Pathogenesis of Intra-abdominal Candidiasis (IAC) by Screening a Deletion Mutant Library

BackgroundIAC is a common manifestation of invasive candidiasis, but its pathogenesis is poorly understood. We developed a mouse model of C. albicans IAC, in which disease progresses from peritonitis to abscesses (IAA) in a manner that recapitulates human infection. Our goal was to use the model to identify C. albicans TFs that regulate virulence during IAC.MethodsWe screened a signature-tagged library (48 unique oligonucleotide markers) of homozygous deletion mutants for 165 C. albicans TF genes, created in duplicate in strain SC5314 (S. Noble). Mice were infected intra-peritoneally in triplicate with pools of 24 mutants and wild-type, and strains harvested at 72 hours in IAA.ResultsTwenty-one TF mutants were significantly attenuated for virulence in both libraries, and 2 TF mutants were significantly more virulent in both libraries, as measured by tissue burdens (figure). Biologic processes over-represented among attenuated mutants were regulation of pH responses, biofilm, hyphal formation, echinocandin responses, and copper metabolism. pH responses are likely to be crucial to pathogenesis of IAC, as C. albicans transitions from pH 8 during peritonitis to pH 6.8 within IAA. 9 pH response regulators contributing to virulence included RIM101, STP2 (alkaline), ASH1, SFL1, SFL2 (neutral), MNL1, SKO1, PHO4 (weak acid), and CSR1 (acid). We created rim101 null mutant and reconstitution strains, and demonstrated that the gene was essential for complete virulence during peritonitis and IAA. Transcriptional profiling of strains by RT-PCR during peritonitis and in vitro showed both conserved and rewired Rim101 targets. SAP5, which encodes an aspartyl protease, is a major Rim101 target in vivo and in vitro; over-expression of SAP5 in rim101 restored virulence during IAA at 3, 7, and 10 days, but not during peritonitis. Other pH regulatory TF genes are currently being validated as virulence determinants, and pathway relationships between MNL1, SKO1, and PHO4 during IAA formation are being explored through epistasis approaches.ConclusionScreening of a C. albicans TF mutant library identified pH responses and other biologic processes as important during pathogenesis of IAC. Rim101, an alkaline pH response regulator, contributes to both peritonitis and IAA, the latter at least in part through its effects on Sap5. Disclosures All Authors: No reported Disclosures.