The promise of immunogenomics at the bedside: genetic risk of intra-abdominal candidiasis*.
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ABSTRACT:
SUBMITTER: Panackal AA
PROVIDER: S-EPMC3970113 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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The promise of immunogenomics at the bedside: genetic risk of intra-abdominal candidiasis*.
Panackal Anil A AA Williamson Peter R PR
Critical care medicine 20140401 4
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Project description: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.
| S-EPMC8960530 | biostudies-literature
Project description:BackgroundThe understanding of high mortality associated with intra-abdominal candidiasis (IAC) remains limited. While Candida is considered a harmless colonizer in the digestive tract, its role as a true pathogen in IAC is still debated. Evidence regarding Candida virulence in the human peritoneal fluid are lacking. We hypothesized that during IAC, Candida albicans develops virulence factors to survive to new environmental conditions. The objective of this observational exploratory monocentric study is to investigate the influence of peritoneal fluid (PF) on the expression of C. albicans virulence using a multimodal approach.Materials and methodsA standardized inoculum of a C. albicans (3.106 UFC/mL) reference strain (SC5314) was introduced in vitro into various PF samples obtained from critically ill patients with intra-abdominal infection. Ascitic fluids (AFs) and Sabouraud medium (SBD) were used as control groups. Optical microscopy and conventional culture techniques were employed to assess the morphological changes and growth of C. albicans. Reverse transcriptase qPCR was utilized to quantify the expression levels of five virulence genes. The metabolic production of C. albicans was measured using the calScreener™ technology.ResultsA total of 26 PF samples from patients with secondary peritonitis were included in the study. Critically ill patients were mostly male (73%) with a median age of 58 years admitted for urgent surgery (78%). Peritonitis was mostly hospital-acquired (81%), including 13 post-operative peritonitis (50%). The infected PF samples predominantly exhibited polymicrobial composition. The findings revealed substantial variability in C. albicans growth and morphological changes in the PF compared to ascitic fluid. Virulence gene expression and metabolic production were dependent on the specific PF sample and the presence of bacterial coinfection.ConclusionsThis study provides evidence of C. albicans virulence expression in the peritoneal fluid. The observed variability in virulence expression suggests that it is influenced by the composition of PF and the presence of bacterial coinfection. These findings contribute to a better understanding of the complex dynamics of intra-abdominal candidiasis and advocate for personalized approach for IAC patients. Trial registration https://clinicaltrials.gov/ (NCT05264571; February 22, 2022).
| S-EPMC10542081 | biostudies-literature
Project description:Intra-abdominal candidiasis (IAC) is poorly understood compared to candidemia. We described the clinical characteristics, microbiology, treatment and outcomes of IAC, and identified risk factors for mortality. We performed a retrospective study of adults diagnosed with IAC at our center in 2012-2013. Risk factors for mortality were evaluated using multivariable logistic regression. We identified 163 patients with IAC, compared to 161 with candidemia. Types of IAC were intra-abdominal abscesses (55%), secondary peritonitis (33%), primary peritonitis (5%), infected pancreatic necrosis (5%), and cholecystitis/cholangitis (3%). Eighty-three percent and 66% of secondary peritonitis and abscesses, respectively, stemmed from gastrointestinal (GI) tract sources. C. albicans (56%) and C. glabrata (24%) were the most common species. Bacterial co-infections and candidemia occurred in 67% and 6% of patients, respectively. Seventy-two percent of patients underwent an early source control intervention (within 5 days) and 72% received early antifungal treatment. 100-day mortality was 28%, and highest with primary (88%) or secondary (40%) peritonitis. Younger age, abscesses and early source control were independent predictors of survival. Younger age, abscesses and early antifungal treatment were independently associated with survival for IAC stemming from GI tract sources. Infectious diseases (ID) consultations were obtained in only 48% of patients. Consulted patients were significantly more likely to receive antifungal treatment. IAC is a common disease associated with heterogeneous manifestations, which result in poor outcomes. All patients should undergo source control interventions and receive antifungal treatment promptly. It is important for the ID community to become more engaged in treating IAC.
| S-EPMC4849645 | biostudies-literature
Project description: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.
| S-EPMC7075487 | biostudies-literature
Project description:Intra-abdominal candidiasis (IAC) is one of the most common of invasive candidiasis observed in critically ill patients. It is associated with high mortality, with up to 50% of deaths attributable to delays in source control and/or the introduction of antifungal therapy. Currently, there is no comprehensive guidance on optimising antifungal dosing in the treatment of IAC among the critically ill. However, this form of abdominal sepsis presents specific pharmacokinetic (PK) alterations and pharmacodynamic (PD) challenges that risk suboptimal antifungal exposure at the site of infection in critically ill patients. This review aims to describe the peculiarities of IAC from both PK and PD perspectives, advocating an individualized approach to antifungal dosing. Additionally, all current PK/PD studies relating to IAC are reviewed in terms of strength and limitations, so that core elements for the basis of future research can be provided.
| S-EPMC10659066 | biostudies-literature
Project description:The pathogenesis of Candida glabrata infections is poorly understood. We studied the pathogenesis of intra-abdominal candidiasis (IAC) in mice that were infected intraperitoneally with C. glabrata and sterile feces. C. glabrata BG2 (5 × 10(8) CFU) caused a 100% mortality rate. Sublethal inocula of BG2 (1 × 10(8) or 1 × 10(7) CFU) caused peritonitis that progressed to abscesses. Three clinical C. glabrata strains (5 × 10(8) CFU) caused 80 to 100% mortality rates, while a fourth (strain 346) caused a 29% mortality rate. Following sublethal inocula (1 × 10(7) CFU), the intra-abscess burdens of virulent strain 356 were ∼1 log greater than those of strain 346. A C. glabrata Δplb1-2 mutant (phospholipase B genes disrupted) killed mice as well as BG2 did. When sublethal inocula were used, however, the Δplb1-2 mutant was associated with more rapid abscess resolution and lower intra-abscess burdens; these findings were reversed by PLB1 and PLB2 reinsertion. The Δplb1-2 mutant was also more susceptible than BG2 to killing by human neutrophils in vitro. BG2 and the Δplb1-2 mutant were indistinguishable during hematogenously disseminated candidiasis. C. albicans SC5314 was more virulent than C. glabrata BG2 during IAC, causing a 100% mortality rate following a challenge with 5 × 10(7) CFU. In contrast, a sublethal inoculum (1 × 10(7) CFU) of BG2 caused less neutrophil infiltration and greater burdens in peritoneal fluid than SC5314 did and abscesses that persisted longer and contained greater burdens. In conclusion, a mouse model of C. glabrata IAC mimics disease in humans and distinguishes the relative virulence of clinical and gene disruption strains. C. glabrata differed from C. albicans during IAC by being less lethal and eliciting dampened neutrophil responses but resulting in more persistent peritonitis and abscesses.
| S-EPMC4097615 | biostudies-literature
Project description:BackgroundThe pathogenesis of intra-abdominal candidiasis is poorly understood.MethodsMice were intraperitoneally infected with Candida albicans (1 × 10(6) colony-forming units) and sterile stool. nanoString assays were used to quantitate messenger RNA for 145 C. albicans genes within the peritoneal cavity at 48 hours.ResultsWithin 6 hours after infection, mice developed peritonitis, characterized by high yeast burdens, neutrophil influx, and a pH of 7.9 within peritoneal fluid. Organ invasion by hyphae and early abscess formation were evident 6 and 24 hours after infection, respectively; abscesses resolved by day 14. nanoString assays revealed adhesion and responses to alkaline pH, osmolarity, and stress as biologic processes activated in the peritoneal cavity. Disruption of the highly-expressed gene RIM101, which encodes an alkaline-regulated transcription factor, did not impact cellular morphology but reduced both C. albicans burden during early peritonitis and C. albicans persistence within abscesses. RIM101 influenced expression of 49 genes during intra-abdominal candidiasis, including previously unidentified Rim101 targets. Overexpression of the RIM101-dependent gene SAP5, which encodes a secreted protease, restored the ability of a rim101 mutant to persist within abscesses.ConclusionsA mouse model of intra-abdominal candidiasis is valuable for studying pathogenesis and C. albicans gene expression. RIM101 contributes to persistence within intra-abdominal abscesses, at least in part through activation of SAP5.
| S-EPMC3789567 | biostudies-literature
Project description: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.
| S-EPMC8097442 | biostudies-literature
Project description:This study aimed to develop and validate a nomogram based on lymphocyte subtyping and clinical factors for the early and rapid prediction of Intra-abdominal candidiasis (IAC) in septic patients. A prospective cohort study of 633 consecutive patients diagnosed with sepsis and intra-abdominal infection (IAI) was performed. We assessed the clinical characteristics and lymphocyte subsets at the onset of IAI. A machine-learning random forest model was used to select important variables, and multivariate logistic regression was used to analyze the factors influencing IAC. A nomogram model was constructed, and the discrimination, calibration, and clinical effectiveness of the model were verified. High-dose corticosteroids receipt, the CD4+T/CD8+ T ratio, total parenteral nutrition, gastrointestinal perforation, (1,3)-β-D-glucan (BDG) positivity and broad-spectrum antibiotics receipt were independent predictors of IAC. Using the above parameters to establish a nomogram, the area under the curve (AUC) values of the nomogram in the derivation and validation cohorts were 0.822 (95% CI 0.777-0.868) and 0.808 (95% CI 0.739-0.876), respectively. The AUC in the derivation cohort was greater than the Candida score [0.822 (95% CI 0.777-0.868) vs. 0.521 (95% CI 0.478-0.563), p < 0.001]. The calibration curve showed good predictive values and observed values of the nomogram; the Decision Curve Analysis (DCA) results showed that the nomogram had high clinical value. In conclusion, we established a nomogram based on the CD4+/CD8+ T-cell ratio and clinical risk factors that can help clinical physicians quickly rule out IAC or identify patients at greater risk for IAC at the onset of infection.
| S-EPMC11747989 | biostudies-literature
Project description:BackgroundThe prognostic role of what a surgeon observes in the abdomen of patients with complicated intra-abdominal infection (cIAI) is largely unknown. The aim of this prospective study was to systemically analyze components of the intra-abdominal view (IAV) and their association to severe complicated intra-abdominal sepsis (SCIAS) or mortality.MethodsThe study cohort consisted of adult patients with cIAI. The operating surgeon filled a paper form describing the intra-abdominal view. Demographics, operative details, and preoperative physiological status were collected. Descriptive, univariate, and multivariate statistical analyses were performed, and a new score was developed based on regression coefficients. The primary outcome was a composite outcome of SCIAS or 30-day mortality, in which SCIAS was defined as organ dysfunctions requiring intensive care unit admission.ResultsA total of 283 patients were analyzed. The primary outcome was encountered in 71 (25%) patients. In the IAV, independent risk factors for the primary outcome were fecal or bile as exudate (odds ratio (OR) 1.98, 95% confidence interval 1.05-3.73), diffuse peritonitis (OR 2.15, 1.02-4.55), diffuse substantial redness of the peritoneum (OR 5.73, 2.12-15.44), and a non-appendiceal source of cIAI (OR 11.20, 4.11-30.54). Based on these factors, an IAV score was developed and its performance analyzed. The area under the receiver operating characteristic for the IAV score was 0.81. The IAV score also correlated significantly with several outcomes and organ dysfunctions.ConclusionsThe extent of peritonitis, diffuse substantial redness of the peritoneum, type of exudate, and source of infection associate independently with SCIAS or mortality. A high IAV score associates with mortality and organ dysfunctions, yet it needs further external validation. Combining components of IAV into comprehensive scoring systems for cIAI patients may provide additional value compared to the current scoring systems.Trial registrationThe study protocol was retrospectively registered on April 4, 2016, right after the first enrolled patient at Clinicaltrials.gov database (NCT02726932).
| S-EPMC6441193 | biostudies-literature