Invasive Candidiasis in Patients with Implants

Implantable device infections are an important cause of invasive candidiasis and carry high rates of morbidity and mortality. Central vascular access catheters are by far the most commonly infected type of device. Infections associated with peritoneal dialysis catheters, cardiac devices, prosthetic joints, and other implantable devices are much less common but can have devastating consequences for affected patients. Central to the pathogenesis of these infections is the interplay between altered anatomic barriers due to device implantation, host immune factors, and the tendency of Candida to form biofilms upon inanimate surfaces. Once infection develops, current treatment options nearly always necessitate removal of the device, so major efforts are under way to prevent infection by implementing innovative infection control strategies and developing implants that are less susceptible to biofilm formation. This review focuses on recent developments in our understanding of the epidemiology, pathogenesis, treatment options, and prevention of implant-associated invasive candidiasis.     

Invasive Candidiasis in the Neutropenic Cancer Patient

Invasive candidiasis (IC) is an important complication among cancer patients with neutropenia, as it is associated with significant mortality. Despite the introduction of the new antifungals in clinical practice and their widespread use as treatment or prophylaxis, the incidence of IC and the predominance of non-albicans Candida species remain unchanged, and mortality rates remain as high as in previous periods. New techniques have been developed to decrease the time to Candida species identification from blood cultures. Nonculture diagnostic methods and molecular diagnostic tests for detection of Candida are promising but have not been validated in neutropenic patients. Recently, voriconazole was proved to be as effective as fluconazole for prophylaxis in neutropenic recipients of hematopoietic stem cell transplants and in patients with graft-versus-host disease. Despite the lack of randomized studies of the treatment of IC among neutropenic patients, it seems that the success rates of antifungal therapy do not differ from those in non-neutropenic patients.     

Current Epidemiology and Management of Invasive Candidiasis in Infants

Invasive candidiasis (IC) is common in premature infants and is associated with significant morbidity and mortality. Although the incidence of IC in infants is decreasing, there is marked variability in number of cases by center and geographical region, and current methods for diagnosis are suboptimal. Nonabsorbable antifungals, probiotics, and systemic antifungals have been shown to decrease IC in select populations. Although empirical antifungal therapy may provide benefit to infants with IC, prediction of the disease is difficult. While available antifungal agents appear to be effective in the treatment of IC in infants, knowledge of the optimal type, dose, and duration of antifungal therapy is limited by the low number of available infant studies.     

Rapid Species Diagnosis for Invasive Candidiasis Using Mass Spectrometry

Background

Matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI TOF-MS) allows the identification of most bacteria and an increasing number of fungi. The potential for the highest clinical benefit of such methods would be in severe acute infections that require prompt treatment adapted to the infecting species. Our objective was to determine whether yeasts could be identified directly from a positive blood culture, avoiding the 1–3 days subculture step currently required before any therapeutic adjustments can be made.

Methodology/Principal Findings

Using human blood spiked with Candida albicans to simulate blood cultures, we optimized protocols to obtain MALDI TOF-MS fingerprints where signals from blood proteins are reduced. Simulated cultures elaborated using a set of 12 strains belonging to 6 different species were then tested. Quantifiable spectral differences in the 5000–7400 Da mass range allowed to discriminate between these species and to build a reference database. The validation of the method and the statistical approach to spectral analysis were conducted using individual simulated blood cultures of 36 additional strains (six for each species). Correct identification of the species of these strains was obtained.

Conclusions/Significance

Direct MALDI TOF-MS analysis of aliquots from positive blood cultures allowed rapid and accurate identification of the main Candida species, thus obviating the need for sub-culturing on specific media. Subsequent to this proof-of-principle demonstration, the method can be extended to other clinically relevant yeast species, and applied to an adequate number of clinical samples in order to establish its potential to improve antimicrobial management of patients with fungemia.     

Kinetics of Anti-Mannan Antibodies Useful in Confirming Invasive Candidiasis in Immunocompromised Patients

In studying the anti-mannan antibodies longitudinally in serial serum samples of three immunocompromised patients, it was observed that anti-mannan antibodies started to increase shortly after the moment that cultures of deep-tissue sites became positive with Candida albicans. The mean anti-mannan antibody titers determined in a group of 36 immunocompromised patients with invasive candidiasis increased within two weeks after the probable onset of invasive candidiasis. In contrast, anti-mannan antibody levels in serial serum samples of 14 immunocompromised patients who were only colonized with C. albicans remained stable or decreased over time. The HA test measuring the anti-mannan antibodies was 64% sensitive and 89% specific in determining invasive candidiasis. In contrast, antibodies specific for candidal cytoplasmic antigens or enolase alone were of little value in confirming invasive candidiasis in these immunocompromised patients.     

The Role of Genetics in Host Responses to Mucosal and Invasive Candidiasis

The development of mucosal and invasive candidiasis depends upon a variety of innate and acquired risk factors. The number of genes known to be important for immunity against candidiasis has been increasing. Studies of variants of these genes are facilitating our knowledge of host predisposition to infection. Insights gleaned from genetic variants identified in patients with primary immunodeficiency syndromes such as chronic mucocutaneous candidiasis have further aided in this process. This article reviews data from genomic association studies in patients with such syndromes and in broader patient populations. These studies are placed within the framework of our current understanding of antifungal host defenses.     

Impact of New Diagnostic Approaches for Invasive Candidiasis on Antifungal Stewardship

Background

Invasive candidiasis (IC) including candidemia and deep-seated candidiasis is associated with up to 50 % overall mortality and up to $80,000 in attributable cost (2015 US$). Rapid diagnostic tests (RDTs) for Candida have been developed. However, whether RDTs along with real-time decision support translate to better attainment of stewardship goals—improve clinical outcomes, minimize unintended consequences of antifungal use, and reduce healthcare costs—is unknown. The purpose of this systematic review was to provide an up-to-date review of recently published studies that have assessed how RDTs for IC impact attainment of these goals.

Methods

Three electronic bibliographic databases were searched using a pre-defined search strategy evaluating the impact of RDTs for IC on attainment of antifungal stewardship goals. Quality assessments were performed by two reviewers using established study methodology metrics.

Results and Conclusions

Eight studies were identified of which five had sufficient information to be included in the review. Despite the limitations of the various studies and the different methodologies employed, the studies all produced similar conclusions. Compared to conventional methods and baseline stewardship activities, the integration of RDTs for IC and real-time decision support, mainly through antifungal stewardship, was associated with decreased mortality, more optimal use of antifungals, and reduced healthcare costs. However, larger clinical studies are needed to confirm these trends.

     

Chemokine Receptor Ccr1 Drives Neutrophil-Mediated Kidney Immunopathology and Mortality in Invasive Candidiasis

Invasive candidiasis is the 4^th leading cause of nosocomial bloodstream infection in the US with mortality that exceeds 40% despite administration of antifungal therapy; neutropenia is a major risk factor for poor outcome after invasive candidiasis. In a fatal mouse model of invasive candidiasis that mimics human bloodstream-derived invasive candidiasis, the most highly infected organ is the kidney and neutrophils are the major cellular mediators of host defense; however, factors regulating neutrophil recruitment have not been previously defined. Here we show that mice lacking chemokine receptor Ccr1, which is widely expressed on leukocytes, had selectively impaired accumulation of neutrophils in the kidney limited to the late phase of the time course of the model; surprisingly, this was associated with improved renal function and survival without affecting tissue fungal burden. Consistent with this, neutrophils from wild-type mice in blood and kidney switched from Ccr1^lo to Ccr1^high at late time-points post-infection, when Ccr1 ligands were produced at high levels in the kidney and were chemotactic for kidney neutrophils ex vivo. Further, when a 1∶1 mixture of Ccr1^+/+ and Ccr1^−/− donor neutrophils was adoptively transferred intravenously into Candida-infected Ccr1^+/+ recipient mice, neutrophil trafficking into the kidney was significantly skewed toward Ccr1^+/+ cells. Thus, neutrophil Ccr1 amplifies late renal immunopathology and increases mortality in invasive candidiasis by mediating excessive recruitment of neutrophils from the blood to the target organ.     

Geographic and Temporal Trends in Amazonian Knowledge Production

The presence of researchers from Western (i.e., developed world) institutions in Amazonia has frequently been contentious due to fears of ‘scientific imperialism’ or suspicions that they may be exerting undue influence over research agendas and knowledge production to the detriment of local researchers. Such negative perceptions are widespread, but not well substantiated. A more nuanced understanding of these issues requires information on who is conducting research in Amazonia and how knowledge production has changed over time. We performed a bibliometric analysis on Thomson Reuters'ISI Web of Science of all research articles about the Amazon published in three time periods: 1986–1989, 1996–1999, and 2006–2009. We found that the number of articles published and the diversity of countries involved in Amazonian research increased dramatically over the three time periods. The representation of several Amazonian countries—especially Brazil—increased, while the proportion of articles without a single author from an Amazonian country also increased. The results indicate that the research capacity of Amazonian countries has increased, but that leadership of high‐impact projects may still largely reside with researchers from developed countries.     

Chronic Invasive Sinus Aspergillosis in Immunocompetent Hosts: A Geographic Comparison

Purpose  

To investigate potential differences in clinical presentation, histopathology, and outcomes of chronic invasive sinus aspergillosis (CISA) based on geographic region and species of Aspergillus isolated.     

Untargeted Antifungal Treatment Strategies for Invasive Candidiasis in Non-neutropenic Critically Ill Patients: Current Evidence and Insights

Purpose of Review

The purpose of this study was to provide an overview and insights on important new concepts on untargeted antifungal treatment strategies, namely prophylaxis pre-emptive and empiric treatments for the management of invasive candidiasis (IC) in non-neutropenic critically ill patients.

Recent Findings

Recently, clinical practice guidelines provided recommendation for the management of IC. However, results from recent trials and systematic reviews questioned the effect of untargeted antifungal treatment strategies, especially in terms of survival benefits in non-neutropenic patients, even with septic shock.

Summary

Widespread use of untargeted antifungal treatment strategies seems not to be justified anymore. Future research should evaluate comprehensive diagnostic-therapeutic approaches, including the implementation of de-escalation. In the meanwhile, clinicians should take into account all available sources of information including clinical evaluation, risk factor assessment, scores, and surrogate biomarkers to tailor antifungal treatment before definitive microbiological diagnosis.

     

Invasive Candidiasis in Brescia,Italy: Analysis of Species Distribution and Antifungal Susceptibilities During Seven Years

The aims of this study were to evaluate the epidemiology of nosocomial candidemia in a large teaching hospital in Brescia, Italy, and the in vitro antifungal susceptibility of isolates. We analyzed 196 isolates causing fungemia in patients admitted in our hospital, between January 2009 and December 2015. Strains were identified by VITEK 2 and MALDI-TOF MS. MICs were determined by Sensititre Yeast One_TM. The resistance was defined by using the revised CLSI breakpoints/epidemiological cutoff values to assign susceptibility or wild type to systemic antifungal agents. Most infections were caused by Candida albicans (60%), Candida parapsilosis (15%), Candida glabrata (12%) and Candida tropicalis (6%). The susceptibility rate for fluconazole was 96.5%. Non-Candida species isolates exhibited full susceptibilities to echinocandins according to CLSI breakpoints. Amphotericin B demonstrated excellent activity against all Candida species. Local epidemiological and antifungal susceptibility studies are necessary in order to improve empirical treatment guidelines.     

Biomarkers for Diagnosis and Follow-Up of Invasive Candidiasis: A Brief Review of the ECIL Recommendations

The main biomarkers for rapid and non-invasive diagnosis of invasive candidiasis include 1,3-beta-D-glucan (BG), mannan antigen (Mn), anti-mannan antibodies (A-Mn) and various molecular methods. BG, Mn and A-Mn assays are standardized, and data on BG are the most extensive. For haematology and oncology population, its performance is characterised by suboptimal sensitivity but excellent specificity. For these populations, the experts from the third European Conference on Infections in Leukemia (ECIL-3) recommended BG for detection of invasive fungal infections with grading BII, and combined Mn/A-Mn detection for the diagnosis of candidemia and hepatosplenic candidiasis, with grading CII and BIII, respectively. While very promising, PCR lacks standardization and thus could not be formally recommended. There is limited and contradictory data on the performance of BG for the monitoring of outcome in patients with invasive candidiasis, although a trend of decline or increase of BG levels was found to be associated with, respectively, a successful response or failure.     

Prediction of the Clinical Outcome in Invasive Candidiasis Patients Based on Molecular Fingerprints of Five Anti-Candida Antibodies in Serum

Better prognostic predictors for invasive candidiasis (IC) are needed to tailor and individualize therapeutic decision-making and minimize its high morbidity and mortality. We investigated whether molecular profiling of IgG-antibody response to the whole soluble Candida proteome could reveal a prognostic signature that may serve to devise a clinical-outcome prediction model for IC and contribute to known IC prognostic factors. By serological proteome analysis and data-mining procedures, serum 31-IgG antibody-reactivity patterns were examined in 45 IC patients randomly split into training and test sets. Within the training cohort, unsupervised two-way hierarchical clustering and principal-component analyses segregated IC patients into two antibody-reactivity subgroups with distinct prognoses that were unbiased by traditional IC prognostic factors and other patients-related variables. Supervised discriminant analysis with leave-one-out cross-validation identified a five-IgG antibody-reactivity signature as the most simplified and accurate IC clinical-outcome predictor, from which an IC prognosis score (ICPS) was derived. Its robustness was confirmed in the test set. Multivariate logistic-regression and receiver-operating-characteristic curve analyses demonstrated that the ICPS was able to accurately discriminate IC patients at high risk for death from those at low risk and outperformed conventional IC prognostic factors. Further validation of the five-IgG antibody-reactivity signature on a multiplexed immunoassay supported the serological proteome analysis results. The five IgG antibodies incorporated in the ICPS made biologic sense and were associated either with good-prognosis and protective patterns (those to Met6p, Hsp90p, and Pgk1p, putative Candida virulence factors and antiapoptotic mediators) or with poor-prognosis and risk patterns (those to Ssb1p and Gap1p/Tdh3p, potential Candida proapoptotic mediators). We conclude that the ICPS, with additional refinement in future larger prospective cohorts, could be applicable to reliably predict patient clinical-outcome for individualized therapy of IC. Our data further provide insights into molecular mechanisms that may influence clinical outcome in IC and uncover potential targets for vaccine design and immunotherapy against IC.Despite recent advances in antifungal therapy, invasive candidiasis (IC)1 remains a leading infectious cause of morbidity and mortality in cancer, postsurgical, and intensive care patients (1–3). Its significant impact on patient clinical outcome, as reflected in its increased attributable mortality (10%–49%), length of hospital stay (3–30 days per patient), and healthcare costs (US $ 6214–92,266 per episode), could however be ameliorated if early and appropriate antifungal therapeutic strategies were administered (1, 4). This precondition highlights the need to search for prognostic features that may reliably predict the clinical outcome in IC patients at presentation to tailor and individualize therapeutic decision-making accordingly and, as a result, to minimize the burden of the invasive infections caused by Candida spp. (commonly Candida albicans (1)).Several factors have classically been reported to adversely influence the clinical outcome of IC patients (3, 5–7). Nonetheless, the prognostic potential of some of these traditional factors for IC is controversial (8, 9) and overall these have a limited prognostic power. For this reason, alternative laboratory tests based on measurement of Candida d-arabinitol/creatinine ratio, Candida antigen titer, or anti-Candida antibody levels (10–15) have been developed to explore their prognostic usefulness in IC. However, none of them has yet been validated for routine clinical practice. Furthermore, these few biomarkers may lack sensitivity for individual prediction of clinical outcomes in the first stages of infection and/or are not yet sufficiently accurate to attain widespread clinical use. In the light of these limitations, and considering the heterogeneity and intricacy of the host responses and molecular mechanisms underlying IC pathogenesis, it is likely that optimally combined multiple biomarkers may cover a broader range of IC patients and pathogenicity-related issues and more reliably predict IC prognosis in an early stage.Serological proteome analysis (SERPA) may be a promising tool in this context because this global profiling technique enables the simultaneous assessment of reactivities of antibodies to a large panel of immunogenic proteins (i.e. the immunome of a (micro)organism (16)) in one experimental approach (17–21). This strategy has widely been applied to antibody-reactivity profiling for diagnostic and therapeutic purposes in cancers, autoimmune disorders, allergies, and infectious diseases (including IC (13, 15, 22, 23)) (18, 24–30). Despite that attractive clinical value, little is known, however, about the potential of this immunoproteomic method to identify antibody-reactivity patterns or signatures (18, 31) that may have utility in predicting the prognosis of individual patients with these pathologies. These prognostic signatures might further offer insights into IC pathogenesis and uncover potential targets for molecular therapies against IC. This approach could also profit from bioinformatics to search for hidden trends within generated multidimensional data and derive useful new knowledge (models, algorithms or rules) (32, 33).Here, we examined the reactivity profiles of serum antibodies to the whole soluble Candida immunome at an early stage of IC by using SERPA and data-mining procedures in order to determine whether these could be indicative of distinct clinical outcomes in IC patients at presentation. We investigated whether these patterns could further reveal a prognostic signature that may serve to create a robust and consistent molecular predictor of clinical outcome for IC applicable to clinical practice and contribute to the traditional prognostic factors for IC. We then developed a multiplexed immunoassay to simultaneously and rapidly measure this simplified molecular fingerprint in each serum specimen and evaluate whether this could be a useful method for individual prediction of clinical outcomes in IC. We also explored whether this prognostic signature could yield biologic insights into molecular mechanisms that confer protection against IC and provide potential molecular targets for the design of novel vaccine- and/or immunotherapy-based strategies to prevent and control IC.