Association between selective digestive decontamination and decreased rate of acquired candidemia in mechanically ventilated ICU patients: a multicenter nationwide study.

BACKGROUND: Candidemia is a high-risk complication among intensive care unit (ICU) patients. While selective digestive decontamination (SDD) has been shown to be effective in preventing ICU-acquired bacterial secondary infection, its effects on ICU-acquired candidemia (ICAC) remain poorly explored. Therefore, we sought to assess the effects of SDD on ICAC. METHOD: Using the REA-REZO network, we included adult patients receiving mechanical ventilation for at least 48 h from January 2017 to January 2023. Non-parsimonious propensity score matching with a 1:1 ratio was performed to investigate the association between SDD and the rate of ICAC. RESULTS: A total of 94 437 patients receiving at least 48 h of mechanical ventilation were included throughout the study period. Of those, 3 001 were treated with SDD and 651 patients developed ICAC. The propensity score matching included 2 931 patients in the SDD group and in the standard care group. In the matched cohort analysis as well as in the overall population, the rate of ICAC was lower in patients receiving SDD (0.8% versus 0.3%; p = 0.012 and 0.7% versus 0.3%; p = 0.006, respectively). Patients with ICAC had higher mortality rate (48.4% versus 29.8%; p < 0.001). Finally, mortality rates as well as ICU length of stay in the matched populations did not differ according to SDD (31.0% versus 31.1%; p = 0.910 and 9 days [5-18] versus 9 days [5-17]; p = 0.513, respectively). CONCLUSION: In this study with a low prevalence of ICAC, SDD was associated with a lower rate of ICAC that did not translate to higher survival.

Comparison of simulated candidemia detection during prophylactic antifungal therapy.

BACKGROUND: We investigated the neutralization performance of various automated blood culture systems for antifungal agents with regard to the most commonly isolated Candida species. METHODS: In this study, we evaluated the time to detection (TTD) of simulated candidemia for 6 Candida spp. (C. albicans, C. auris, C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis) in 3 automated blood culture systems (BACTEC™ FX, BACT/ALERT® 3D, and BACT/ALERT® VIRTUO®), with or without trough and peak levels of eight antifungal agents (amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole, micafungin, posaconazole, and voriconazole). RESULTS: Caspofungin and micafungin significantly prolonged the TTDs for most of the tested strains in the 3 blood culture instruments, especially at peak concentrations. CONCLUSION: Peak concentrations of caspofungin and micafungin influence the performance of blood culture detection systems. Therefore, one should be careful about the possibility of prolonged TTDs for candidemia when using the abovementioned antifungal agents.

Epidemiology of candidemia in lung transplant recipients and risk factors for candidemia in the early posttransplant period in the absence of universal antifungal prophylaxis.

BACKGROUND: Lung transplant recipients are at increased risk of candidemia, especially in the early posttransplant period. However, the specific predisposing factors have not been established. The natural history of candidemia after lung transplantation, in the absence of universal antifungal prophylaxis, is not known. METHODS: We retrospectively examined the epidemiology of candidemia at any time posttransplant in patients who underwent lung transplantation at our center between 2016 and 2019. We undertook a case-control study and used logistic regression to evaluate the risk factors for candidemia during the first 30 days posttransplantation. RESULTS: During the study period 712 lung transplants were performed on 705 patients. Twenty-five lung transplant recipients (LTRs) (3.5%) experienced 31 episodes of candidemia. The median time to candidemia was 19.5 days (IQR 10.5-70.5), with 61.2% (n = 19) episodes of candidemia occurring within the first 30 days posttransplantation. Pretransplant hospitalization, posttransplant ECMO, and posttransplant renal replacement therapy were associated with an increased risk of candidemia in the first 30 days posttransplant. Of those with candidemia in the first 30 days, 31.2% died within 30 days of the index positive blood culture. Candidemia was associated with decreased survival within 30 days posttransplant. CONCLUSION: This study highlights the greatest risk period of lung transplant recipients for development of candidemia and identifies several factors associated with increased risk of candidemia. These findings will help guide future studies on antifungal prophylaxis.

Effectiveness of Fluconazole Prophylaxis in a Targeted High-Risk Group in a Surgical Intensive Care Unit.

Background: Candidemia is an important nosocomial infection in intensive care units (ICUs), with total parenteral nutrition (TPN) a well-recognized risk factor. Antifungal prophylaxis may be an effective intervention to prevent candidemia in high-risk patients. In this report, the effectiveness of fluconazole prophylaxis was examined in patients located in a combined surgical-neurosurgical ICU serving an urban Level 1 trauma center who were receiving prolonged courses of TPN. Methods: Fluconazole was administered prophylactically for patients receiving TPN for more than six days. Rates of candidemia during the intervention were compared with those prior to the intervention. Results: During the 27-month pre-intervention period, seven episodes of candidemia occurred during 1,277 days of parenteral nutrition therapy. During the 17-month post-intervention period, there were zero episodes during 852 days of therapy (p = 0.03). Similarly, during the pre-intervention period, there were six episodes of candidemia during 867 high-risk days of therapy, compared with zero during 643 days of high-risk therapy in the post-intervention period (p = 0.04). The rates of bacteremia did not change, and emergence of fluconazole-resistant Candida species was not evident. Conclusions: At our surgical ICU, this fluconazole prophylaxis was associated with a significant decrease in the number of patients with candidemia, without emergence of resistant species.

Preventing Candida albicans from subverting host plasminogen for invasive infection treatment.

Candida albicans is a common fungal pathogen in humans that colonizes the skin and mucosal surfaces of the majority healthy individuals. How C. albicans disseminates into the bloodstream and causes life-threatening systemic infections in immunocompromised patients remains unclear. Plasminogen system activation can degrade a variety of structural proteins in vivo and is involved in several homeostatic processes. Here, for the first time, we characterized that C. albicans could capture and "subvert" host plasminogen to invade host epithelial cell surface barriers through cell-wall localized Eno1 protein. We found that the "subverted" plasminogen system plays an important role in development of invasive infection caused by C. albicans in mice. Base on this finding, we discovered a mouse monoclonal antibody (mAb) 12D9 targeting C. albicans Eno1, with high affinity to the 254FYKDGKYDL262 motif in α-helices 6, ß-sheet 6 (H6S6) loop and direct blocking activity for C. albicans capture host plasminogen. mAb 12D9 could prevent C. albicans from invading human epithelial and endothelial cells, and displayed antifungal activity and synergistic effect with anidulafungin or fluconazole in proof-of-concept in vivo studies, suggesting that blocking the function of cell surface Eno1 was effective for controlling invasive infection caused by Candida spp. In summary, our study provides the evidence of C. albicans invading host by "subverting" plasminogen system, suggesting a potential novel treatment strategy for invasive fungal infections.

Candidaemia in haematological malignancy patients from a SEIFEM study: Epidemiological patterns according to antifungal prophylaxis.

BACKGROUND: Candidaemia is an important infectious complication for haematological malignancy patients. Antifungal prophylaxis reduces the incidence of candidaemia but may be associated with breakthrough candidaemia. OBJECTIVE: To analyse the Candida species' distribution and relative antifungal susceptibility profiles of candidaemia episodes in relation to the use of antifungal prophylaxis among Italian SEIFEM haematology centres. METHODOLOGY: This multicentre retrospective observational SEIFEM study included 133 single-species candidaemia episodes of haematological malignancy patients for whom antifungal susceptibility testing results of blood Candida isolates were available between 2011 and 2015. Each participating centre provided both clinical and microbiological data. RESULTS: Non-Candida albicans Candida (NCAC) species were the mostly isolated species (89, 66.9%), which accounted for C parapsilosis (35, 26.3%), C glabrata (16, 12.0%), C krusei (14, 10.5%), C tropicalis (13, 9.8%) and uncommon species (11, 8.3%). C albicans caused the remaining 44 (33.1%) episodes. Excluding 2 C albicans isolates, 23 of 25 fluconazole-resistant isolates were NCAC species (14 C krusei, 6 C glabrata, 2 C parapsilosis and 1 C tropicalis). Fifty-six (42.1%) of 133 patients developed breakthrough candidaemia. Systemic antifungal prophylaxis consisted of azoles, especially fluconazole and posaconazole, in 50 (89.3%) of 56 patients in whom a breakthrough candidaemia occurred. Interestingly, all these patients tended to develop a C krusei infection (10/56, P = .02) or a fluconazole-resistant isolate's infection (14/50, P = .04) compared to patients (4/77 and 10/77, respectively) who did not have a breakthrough candidaemia. CONCLUSIONS: Optimisation of prophylactic strategies is necessary to limit the occurrence of breakthrough candidaemia and, importantly, the emergence of fluconazole-resistant NCAC isolates' infections in haematological malignancy patients.

Diagnostic usefulness of differential time to positivity in neutropenic cancer patients with suspected catheter-related candidemia.

Methods for distinguishing catheter-related candidemia (CRC) from non-CRC before catheter removal remain limited. We thus evaluated the diagnostic performance of differential time to positivity (DTP) to diagnose CRC in neutropenic cancer patients with suspected CRC. Of the 35 patients enrolled, 15 (43%) with CRC (six definite and nine probable) and 17 (49%) with non-CRC were finally analyzed. Based on the receiver operating characteristic curve, the optimal cutoff value of DTP for diagnosing CRC was ≥1.45 hours with the sensitivity 80% (95% confidence interval [CI], 51-95) and specificity 100% (95% CI, 80-100), respectively.

Diagnosis and Treatment of Candidemia in the Intensive Care Unit.

Candidemia is the fourth most frequent health care-associated bloodstream infection, and the most frequent severe fungal infection developing in critically ill patients in intensive care units (ICUs). Diagnosis of candidemia in ICU patients is a complex task made of both early and late assessments involving both conventional diagnostic methods and novel rapid tests. Management strategies to optimize treatment of candidemia can be challenging and include starting early adequate therapy, use of an adequate dose and duration of therapy, de-escalating treatment whenever possible, and early discontinuation of useless antifungals in those with no definitive diagnosis of fungal infection. Herein, we will discuss recent epidemiological data on candidemia in ICUs and current diagnostic techniques before concentrating on antifungal treatments.

The epidemiology of Candida species in the Middle East and North Africa.

In recent decades, the epidemiology of invasive candidiasis (IC) has progressively changed worldwide. This notably includes emergence of several Candida species. Although some surveillance programs provided global trends in IC epidemiology, data from countries from the Middle East and North Africa (MENA) remain scarce. In this manuscript, we reviewed the existing available data on the epidemiology of Candida species associated with IC, particularly candidemia, in MENA region regarding species distribution. As witnessed worldwide, an evident shift of Candidaalbicans towards non-albicansCandida (NAC) has been observed in the MENA region. The worrying emergence of multi-drug resistant Candida species in MENA calls for a better understanding of their epidemiology. This represents an essential prerequisite for the implementation of effective infection control strategies and surveillance systems to prevent IC among high-risk patients.

Exploiting the vulnerable active site of a copper-only superoxide dismutase to disrupt fungal pathogenesis.

Copper-only superoxide dismutases (SODs) represent a new class of SOD enzymes that are exclusively extracellular and unique to fungi and oomycetes. These SODs are essential for virulence of fungal pathogens in pulmonary and disseminated infections, and we show here an additional role for copper-only SODs in promoting survival of fungal biofilms. The opportunistic fungal pathogen Candida albicans expresses three copper-only SODs, and deletion of one of them, SOD5, eradicated candidal biofilms on venous catheters in a rodent model. Fungal copper-only SODs harbor an irregular active site that, unlike their Cu,Zn-SOD counterparts, contains a copper co-factor unusually open to solvent and lacks zinc for stabilizing copper binding, making fungal copper-only SODs highly vulnerable to metal chelators. We found that unlike mammalian Cu,Zn-SOD1, C. albicans SOD5 indeed rapidly loses its copper to metal chelators such as EDTA, and binding constants for Cu(II) predict that copper-only SOD5 has a much lower affinity for copper than does Cu,Zn-SOD1. We screened compounds with a variety of indications and identified several metal-binding compounds, including the ionophore pyrithione zinc (PZ), that effectively inhibit C. albicans SOD5 but not mammalian Cu,Zn-SOD1. We observed that PZ both acts as an ionophore that promotes uptake of toxic metals and inhibits copper-only SODs. The pros and cons of a vulnerable active site for copper-only SODs and the possible exploitation of this vulnerability in antifungal drug design are discussed.

The epidemiology and management of candidemia in Northern Ireland during 2002-2011, including a 12-month enhanced case review.

In Northern Ireland there are concerns about candidaemia, with rates higher than those reported in England and Wales. Our aim was to explore the epidemiology of candidaemia during a 10 year period and the clinical management upon suspicion of cases during a one year enhanced investigation in Northern Ireland.Candidaemia reports to the Public Health Agency were validated during 2002-2011 and used to examine incidence and antifungal sensitivity trends (during 2007-2011). A clinical proforma was used to collate information for all patients with candidaemia in 2011.The majority (96%) of isolates were captured through voluntary laboratory reporting. There was a year-on-year increase in candidaemia from 2002-2011, from 80 to 131 episodes (incidence rate ratio 1.09 95% CI 1.05-1.13). Rates were highest in males under 1 year and over 75 years. 83/98 (85%) of case notes were available from candidaemia patients during 2011. The most prevalent risk factors were patients on total parenteral nutrition (26 people, 31.3%), surgery in the two months prior to the candidaemia (25 people, 30.1%), significant steroid use in the previous 3 months (24 people, 28.9%) and active neoplastic disease (23 people, 27.7%),This study confirmed an increase in candidaemia rates over time, with the observed incidence in 2011 higher than England and Wales. We identified areas for improvement around the clinical management of candidaemia. We recommend raising the awareness of guidelines for fundoscopy, echocardiography and central venous catheter removal.

Clinical characteristics and predictors of mortality in patients with candidemia: a six-year retrospective study.

Although candidemia has been reported globally, little is known about the differences in candidemia episodes between ICU and surgical wards or the correlation between serum biomarkers and mortality from candidemia. A retrospective study of hospitalized patients with candidemia was conducted in southwest China. A total of 198 non-duplicate candidemia episodes were identified between January 2011 and December 2016. Candida albicans was the leading species causing candidemia (34.9%), and 78.8% of these isolates were susceptible to fluconazole. More than half of candidemic patients were hospitalized in surgical wards, but the incidence of these surgical patients was much lower than that of ICU patients. Compared with surgical patients, patients admitted to ICU were more frequently subjected to extensive invasive procedures, severe clinical presentations, and heavy exposure to antibiotics. In addition, the mortality in ICU was significantly higher than that in surgical wards. Multivariable analysis revealed that ascites, catheter-related candidemia, ICU admission, septic shock, and concomitant bacterial infection were independent factors associated with mortality. Moreover, we observed that high PCT and BDG levels as well as low PLT counts were also associated with mortality from candidemia. Better understanding of the specific predictors in different wards could facilitate the identification of high-risk candidates to receive early antifungal therapy, thus improving the outcomes of critically ill patients with candidemia.

Candidemia in children: Epidemiology, prevention and management.

Candidemia is the leading cause of invasive fungal infections in hospitalised children. The highest rates of candidemia have been recorded in neonates and infants <1 year of age. Candidemia is more frequent in neonates and young infants than in adults, and is associated with better clinical outcomes, but higher inpatient costs. Over the last 10 years, a declining trend has been noted in the incidence of paediatric candidemia in the US and elsewhere due to the hospital-wide implementation of central-line insertion and maintenance bundles that emphasise full sterile barrier precautions, chlorhexidine skin preparation during line insertion, meticulous site and tubing care, and daily discussion of catheter necessity. Additional interventions aiming at reducing gut-associated candidemia are required in immunocompromised and critically ill children.

Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole.

We retrospectively assessed breakthrough invasive fungal infections (b-IFIs) in 100 consecutive patients with leukemia receiving single-agent isavuconazole; 13 had documented b-IFIs (candidiasis in 6, mucormycosis in 4). All b-IFIs were observed in patients with prolonged neutropenia and active leukemia.

The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future.

Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40-50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of "trained immunity" and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens.

Breakthrough Candida guilliermondii (Meyerozyma guilliermondii) fungemia after cord blood transplantation for extranodal NK-cell lymphoma with azole prophylaxis.

Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non-albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long-term azole administration.

Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.

OBJECTIVES: Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. METHODS: A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. RESULTS: 43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p = 0.05), immunosuppression (2.42, 1.03-5.68, p = 0.043), and parenteral nutrition (2.87, 1.44-5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. CONCLUSIONS: Outcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

Analysis on clinical characteristics and drug resistance of Candida parapsilosis bloodstream infections in West China Hospital, China, from 2012 to 2015.

OBJECTIVE OF THE STUDY: Candida parapsilosis has emerged as an important cause of bloodstream infections (BSI) in the health care setting. We aimed to describe the clinical characteristics and drug resistance of C. parapsilosis BSI in West China Hospital of Sichuan University in China and provide the basis for prevention and treatment of this disease. PATIENTS: We retrospectively collected and analyzed patients presented in our hospital reported with C. parapsilosis BSI from January 2012 to January 2015. MATERIALS AND METHODS: Data regarding age, gender, the department distribution, the potential clinical risk factors and the result of clinical treatment and prognosis were retrospectively evaluated. As to the antifungal drugs susceptibility testing, we used Etest method for determining the minimum inhibitory concentrations (MICs) of amphotericin B, fluconazole, voriconazole, caspofungin and flucytosine for all the clinical isolates of C. parapsilosis. Standard quality strains were used as the controls. RESULTS: Most of the patients with C. parapsilosis BSI were over 60-year-old (37.5%) or within 10years old (28.13%). Among patients, 78.13% came from an intensive care unit or had undergone surgery in the past several months. The major risk factors associated with an increased risk of infection included the use of broad-spectrum antibacterial drugs and deep vein indwelling. The overall mortality of patients with C. parapsilosis BSI was 31.25%. The drug sensitivity tests revealed that all isolates were sensitive to amphotericin B and flucytosine. Two and 1 isolates were found susceptible to fluconazole and voriconazole in a dose-dependent manner, respectively. Only 1 isolate was resistant to fluconazole. 4 isolates (12.5%) were medium sensitive to caspofungin, but no one showed drug resistance. CONCLUSION: In summary, elders and newborns were more vulnerable to C. parapsilosis infections. C. parapsilosis was found frequently as pathogens leading to BSI in patients admitted to ICU and departments of surgery and often causing a high mortality rate. C. parapsilosis rarely showed drug resistance at present, so common antifungal drugs could be used for treatment. Recommendations for using of antifungal drugs focused on paying close attention to possible drug resistance trend.

[Candidemia and invasive candidiasis approach in critically ill patients: role of the echinocandins]. / Abordaje de la candidemia y la candidiasis invasiva en el paciente crítico: papel de las equinocandinas.

OBJECTIVE: Invasive infections caused by Candida spp. in critically ill patients may significantly worsen their prognosis, so it is of great importance to establish an early detection and a suitable therapeutic strategy. The objective of this study was to define the differential role of echinocandins in treating certain critical patient profiles. METHODS: A scientific committee of 9 experts in infectious diseases, critical care, microbiology, and hospital pharmacy reviewed the existing evidence on the treatment of candidemia and invasive candidiasis in critically ill patients. After that, a questionnaire with 35 items was elaborated to be agreed by 26 specialists in the aforementioned disciplines using a modified Delphi method. RESULTS: After two rounds of evaluation, a consensus was reached in terms of agreement in 66% of the items. Some of the consensuses achieved included: it is not necessary to adjust the dose of echinocandins during renal replacement therapy; the echinocandins are the empirical and/or directed treatment of choice for candidemia and invasive candidiasis associated with biofilms; these drugs may be used in the antifungal prophylaxis of high-risk liver transplantation. In the absence of additional clinical data, it should be noted that micafungin is the echinocandin with the most available scientific evidence. CONCLUSIONS: The experts consulted showed a high degree of agreement on some of the most controversial aspects regarding the management of candidemia and invasive candidiasis in critical patients, which could inform of practical recommendations for their treatment.