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    Challenging diagnosis of chronic cerebral fungal infection: Value of (1→3)-ß-D-glucan and mannan antigen testing in cerebrospinal fluid and of cerebral ventricle puncture. Hobson Claire A,Desoubeaux Guillaume,Carvalho-Schneider Claudia,Destrieux Christophe,Cottier Jean-Philippe,Garot Denis,Le Brun Cécile,Maakaroun Zoha,Lemaignen Adrien,Bailly Éric,Bernard Louis Medical mycology Primary fungal infection of the central nervous system (CNS) is rare but often associated with severe prognosis. Diagnosis is complicated since cerebrospinal fluid (CSF) samples obtained from lumbar puncture usually remain sterile. Testing for fungal antigens in CSF could be a complementary diagnostic tool. We conducted such measurements in CSF from patients with CNS fungal infection and now discuss the usefulness of ventricular puncture. Mannan and (1→3)ß-D-glucan (BDG) testing were retrospectively performed in CSF samples from three patients with proven chronic CNS fungal infection (excluding Cryptococcus), and subsequently compared to 16 controls. Results from lumbar punctures and those from cerebral ventricles were confronted. BDG detection was positive in all the CSF samples (from lumbar and/or ventricular puncture) from the three confirmed cases. In case of Candida infection, mannan antigen measurement was positive in 75% of the CSF samples. In the control group, all antigen detections were negative (n = 15), except for one false positive. Faced with suspected chronic CNS fungal infection, measurement of BDG levels appears to be a complementary diagnostic tool to circumvent the limitations of mycological cultures from lumbar punctures. In the event of negative results, more invasive procedures should be considered, such as ventricular puncture. 10.1093/mmy/myaa035
    Analysis of pathogens and risk factors of secondary pulmonary infection in patients with COVID-19. Tang Haicheng,Zhao Zhangyan,Zhang Xiaolin,Pan Lei,Wu Qingguo,Wang Mei,Zhang Yunbin,Li Feng Microbial pathogenesis To investigate the distribution and risk factors of pathogens in secondary pulmonary infection in patients with COVID-19.142 patients with confirmed COVID-19 from Shanghai Public Health Clinical Center were collected, and 32 patients with pulmonary infection were taken as the infection group. The distribution of pathogens in the sputum specimens was applied for retrospective analysis. Meanwhile, 110 patients diagnosed with COVID-19, but without pulmonary infection were regarded as the asymptomatic group. The risk factors of pulmonary infection were analyzed with generalized linear models and logistic regression. The pathogens in the lung infection group were mainly gram-negative bacteria (22, 68.8%), especially Klebsiella pneumoniae. Gram-positive bacteria and fungi accounted for 13 (40.6%), mainly Staphylococcus aureus, and 11 (34.4%), mainly Candida albicans. There were 14 cases (43.8%) infected with two or more pathogens. The comparison between the two groups found that, patients with elder age, underlying diseases, more lung lesions and low protein contents, were more likely to develop lung infections. At last, univariate analysis showed that 6 factors, including indwelling gastric catheter, the number of deep vein catheters, tracheal intubation tracheotomy, invasive mechanical ventilation, hormonal application, and the use of more than three antibacterial drugs, are risk factors for COVID-19 secondary pulmonary infection. Generalized linear models and logistic regression analysis showed antimicrobial use as an independent risk factor for COVID-19 secondary lung infection. There are many risk factors for secondary lung infection in severe COVID-19 patients, and it is recommended to use antibiotics reasonably. 10.1016/j.micpath.2021.104903
    Roles of the multiplex real-time PCR assay and β-D-glucan in a high-risk population for intra-abdominal candidiasis (IAC). Fortún J,Buitrago M J,Gioia F,Gómez-Gª de la Pedrosa E,Alvarez M E,Martín-Dávila P,Pintado V,Cobeta P,Martinez-Castro N,Soriano C,Moreno I,Corral S,Muñoz P,Moreno-Jimenez G,Cuenca-Estrella M,Moreno-Guillen S Medical mycology 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. 10.1093/mmy/myz123
    Fungal Infection in Lung Transplantation. Kennedy Cassie C,Pennington Kelly M,Beam Elena,Razonable Raymund R Seminars in respiratory and critical care medicine Invasive fungal infections threaten lung transplant outcomes with high associated morbidity and mortality. Pharmacologic prophylaxis may be key to prevent posttransplant invasive fungal infections, but cost, adverse effects, and absorption issues are barriers to effective prophylaxis. Trends in fungal infection diagnostic strategies utilize molecular diagnostic methodologies to complement traditional histopathology and culture techniques. While lung transplant recipients are susceptible to a variety of fungal pathogens, spp. and spp. infections remain the most common. With emerging resistant organisms and multiple novel antifungal agents in the research pipeline, it is likely that treatment strategies will continue to evolve. 10.1055/s-0041-1729173
    Managing Fungal Infections in Cystic Fibrosis Patients: Challenges in Clinical Practice. Magee Lauren C,Louis Mariam,Khan Vaneeza,Micalo Lavender,Chaudary Nauman Infection and drug resistance Cystic Fibrosis (CF) is an autosomal recessive disease characterized by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Impairment of the CFTR protein in the respiratory tract results in the formation of thick mucus, development of inflammation, destruction of bronchial tissue, and development of bacterial or fungal infections over time. CF patients are commonly colonized and/or infected with fungal organisms, or , with prevalence rates ranging from 5% to 78% in the literature. Risk factors for acquiring fungal organisms include older age, coinfection with , prolonged use of oral and inhaled antibiotics, and lower forced expiratory volume (FEV). There are limited data available to differentiate between contamination, colonization, and active infection. Furthermore, the pathogenicity of colonization is variable in the literature as some studies report a decline in lung function associated with fungal colonization whereas others showed no difference. Limited data are available for the eradication of fungal colonization and the treatment of active invasive aspergillosis in adult CF patients. In this review article, we discuss the challenges in clinical practice and current literature available for laboratory findings, clinical diagnosis, and treatment options for fungal infections in adult CF patients. 10.2147/IDR.S267219
    Quantification of anidulafungin and micafungin in human body fluids by high performance-liquid chromatography with UV-detection. Welte René,Oberacher Herbert,Schwärzler Bernhard,Joannidis Michael,Bellmann Romuald Journal of chromatography. B, Analytical technologies in the biomedical and life sciences The echinocandins anidulafungin (ANID) and micafungin (MICA) are recommended for treatment of invasive Candida infections. As target-site concentrations of antimicrobial agents are crucial for eradication of pathogens, we established and validated high-performance liquid chromatography-UV detection (HPLC-UV) assays for quantification of ANID and MICA in human plasma, ascites fluid, pleural effusion, and in cerebrospinal fluid (CSF). Sample pre-purification was performed by protein precipitation with acetonitrile followed by solid phase extraction. For both assays, intra- and interday precision, and accuracy fulfilled the requirements for bioanalytical methods issued by the European Medicine Agency (EMA). The lower limit of quantification was 0.01 mg/L for both drugs. At 25 °C, ANID and MICA concentrations declined by up to 70% within 24 h. Concentrations remained stable over 24 h at 4 °C and over four weeks at -80 °C. In conclusion, the developed methods are fit for the assessment of target-site pharmacokinetics of ANID and MICA in clinical studies. 10.1016/j.jchromb.2019.121937
    The synergistic fungicidal effect of low-frequency and low-intensity ultrasound with amphotericin B-loaded nanoparticles on C. albicans in vitro. Yang Min,Xie Shuang,Adhikari Vishnu Prasad,Dong Yu,Du Yonghong,Li Dairong International journal of pharmaceutics It is difficult to effectively eradicate C. albicans using traditional antifungal agents, mainly because the low permeability of the C. albicans cell wall creates strong drug resistance. The aim of this study was to investigate the synergistic fungicidal effect and the underlying mechanisms of low-frequency and low-intensity ultrasound combined with a treatment of amphotericin B-loaded nanoparticles (AmB-NPs) against C. albicans. AmB-NPs were prepared by a poly(lactic-co-glycolic acid) (PLGA) double emulsion method. C. albicans was treated by AmB-NPs combined with 42 kHz ultrasound irradiation at an intensity of 0.30 W/cm for 15 min. The results demonstrate that the application of ultrasound enhanced the antibacterial effectiveness of AmB-NPs (P < 0.01), and the antifungal efficiency increased significantly with increasing AmB concentration of drug-loaded nanoparticles under ultrasonic irradiation. Additionally, the mycelial morphology of C. albicans suffered from the most severe damage and loss of normal microbial morphology after the combined treatment of AmB-NPs and ultrasound, as revealed by electron microscope. Furthermore, we verified the safe use of low-frequency ultrasound on exposed skin and discussed the potential mechanism of ultrasound enhanced fungicidal activity. The results reveal that the mechanism may be associated with the ultrasound cavitation effect and an increase in intracellular reactive oxygen species. 10.1016/j.ijpharm.2018.03.033
    Antifungal Therapy: New and Evolving Therapies. Nivoix Yasmine,Ledoux Marie-Pierre,Herbrecht Raoul Seminars in respiratory and critical care medicine Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug-drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug-drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections. 10.1055/s-0039-3400291
    Pharmacokinetics and Antifungal Activity of Echinocandins in Ascites Fluid of Critically Ill Patients. Welte René,Oberacher Herbert,Gasperetti Tiziana,Pfisterer Hartwig,Griesmacher Andrea,Santner Tobias,Lass-Flörl Cornelia,Hörtnagl Caroline,Leitner-Rupprich Sandra,Aigner Maria,Lorenz Ingo,Schmid Stefan,Edlinger Michael,Eller Philipp,Dankl Daniel,Joannidis Michael,Bellmann Romuald Antimicrobial agents and chemotherapy The pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida albicans and Candida glabrata at concentrations of 0.03 to 16.00 μg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata. Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication. 10.1128/AAC.02565-20
    Leukotriene B4-Mediated Neutrophil Recruitment Causes Pulmonary Capillaritis during Lethal Fungal Sepsis. Lee Esther K S,Gillrie Mark R,Li Lu,Arnason Jason W,Kim Jung Hwan,Babes Liane,Lou Yuefei,Sanati-Nezhad Amir,Kyei Stephen K,Kelly Margaret M,Mody Christopher H,Ho May,Yipp Bryan G Cell host & microbe Candida albicans bloodstream infection causes fungal septicaemia and death in over half of afflicted patients. Polymorphonuclear leukocytes (PMN) mediate defense against invasive candidiasis, but their role in protection versus tissue injury and sepsis is unclear. We observe PMN intravascular swarming and subsequent clustering in response to C. albicans yeast in a lethal septic mouse and human pulmonary circulation model. Live C. albicans sequester to the endothelium and are immediately captured by complement-dependent PMN chemotaxis, which is required for host survival. However, complement activation also leads to Leukotriene B4 (LTB4)-mediated intravascular PMN clustering and occlusion, resulting in capillaritis with pulmonary hemorrhage and hypoxemia. This clustering is unique to fungi and triggered by fungal cell wall components. PMN clustering is absent in mice lacking LTB4-receptor, and capillaritis is attenuated upon pharmacological LTB4 blockade without affecting phagocytosis. Therefore, therapeutically disrupting infection-induced capillaritis may limit organ injury without impairing host defense during fungal sepsis. 10.1016/j.chom.2017.11.009
    The Emerging Threat of Antifungal Resistance in Transplant Infectious Diseases. Schwartz Ilan S,Patterson Thomas F Current infectious disease reports PURPOSE OF REVIEW:The global emergence of antifungal resistance among Candida spp. and Aspergillus spp. will disproportionately affect transplantation recipients, who are prone to invasive fungal disease. RECENT FINDINGS:Invasive candidiasis is increasingly caused by non-albicans Candida species with reduced susceptibility to first-line antifungals. Echinocandin resistance in Candida glabrata is increasing in some settings. Candida auris has rapidly emerged as a global concern due to multidrug resistance and efficient nosocomial spread in healthcare settings. Azole-resistant Aspergillus fumigatus is already an important concern in some European countries and is increasingly reported elsewhere, possibly driven by agricultural use of triazole fungicides. Antifungal resistance is anticipated to expand among these and other common fungal pathogens. Culture-independent detection methods will become more important for rapid diagnosis and to guide empiric therapy. Antifungal stewardship is of critical importance to conserve our limited antifungal armamentarium for transplantation recipients and other vulnerable patients. 10.1007/s11908-018-0608-y
    Delivering on Antimicrobial Resistance Agenda Not Possible without Improving Fungal Diagnostic Capabilities. Denning David W,Perlin David S,Muldoon Eavan G,Colombo Arnaldo Lopes,Chakrabarti Arunaloke,Richardson Malcolm D,Sorrell Tania C Emerging infectious diseases Antimicrobial resistance, a major public health concern, largely arises from excess use of antibiotic and antifungal drugs. Lack of routine diagnostic testing for fungal diseases exacerbates the problem of antimicrobial drug empiricism, both antibiotic and antifungal. In support of this contention, we cite 4 common clinical situations that illustrate this problem: 1) inaccurate diagnosis of fungal sepsis in hospitals and intensive care units, resulting in inappropriate use of broad-spectrum antibacterial drugs in patients with invasive candidiasis; 2) failure to diagnose chronic pulmonary aspergillosis in patients with smear-negative pulmonary tuberculosis; 3) misdiagnosis of fungal asthma, resulting in unnecessary treatment with antibacterial drugs instead of antifungal drugs and missed diagnoses of life-threatening invasive aspergillosis in patients with chronic obstructive pulmonary disease; and 4) overtreatment and undertreatment of Pneumocystis pneumonia in HIV-positive patients. All communities should have access to nonculture fungal diagnostics, which can substantially benefit clinical outcome, antimicrobial stewardship, and control of antimicrobial resistance. 10.3201/eid2302.152042
    Risk factors for candidemia: a prospective matched case-control study. Poissy Julien,Damonti Lauro,Bignon Anne,Khanna Nina,Von Kietzell Matthias,Boggian Katia,Neofytos Dionysios,Vuotto Fanny,Coiteux Valérie,Artru Florent,Zimmerli Stephan,Pagani Jean-Luc,Calandra Thierry,Sendid Boualem,Poulain Daniel,van Delden Christian,Lamoth Frédéric,Marchetti Oscar,Bochud Pierre-Yves, , Critical care (London, England) BACKGROUND:Candidemia is an opportunistic infection associated with high morbidity and mortality in patients hospitalized both inside and outside intensive care units (ICUs). Identification of patients at risk is crucial to ensure prompt antifungal therapy. We sought to assess risk factors for candidemia and death, both outside and inside ICUs. METHODS:This prospective multicenter matched case-control study involved six teaching hospitals in Switzerland and France. Cases were defined by positive blood cultures for Candida sp. Controls were matched to cases using the following criteria: age, hospitalization ward, hospitalization duration, and, when applicable, type of surgery. One to three controls were enrolled by case. Risk factors were analyzed by univariate and multivariate conditional regression models, as a basis for a new scoring system to predict candidemia. RESULTS:One hundred ninety-two candidemic patients and 411 matched controls were included. Forty-four percent of included patients were hospitalized in ICUs, and 56% were hospitalized outside ICUs. Independent risk factors for candidemia in the ICU population included total parenteral nutrition, acute kidney injury, heart disease, prior septic shock, and exposure to aminoglycoside antibiotics. Independent risk factors for candidemia in the non-ICU population included central venous catheter, total parenteral nutrition, and exposure to glycopeptides and nitroimidazoles. The accuracy of the scores based on these risk factors is better in the ICU than in the non-ICU population. Independent risk factors for death in candidemic patients included septic shock, acute kidney injury, and the number of antibiotics to which patients were exposed before candidemia. DISCUSSION:While this study shows a role for known and novel risk factors for candidemia, it specifically highlights important differences in their distribution according to the hospital setting (ICU versus non-ICU). CONCLUSION:This study provides novel risk scores for candidemia accounting for the hospital setting and recent progress in patients' management strategies and fungal epidemiology. 10.1186/s13054-020-2766-1
    Penetration of echinocandins into wound secretion of critically ill patients. Gasperetti Tiziana,Welte René,Oberacher Herbert,Marx Jana,Lorenz Ingo,Schellongowski Peter,Staudinger Thomas,Burgmann Karin,Eller Philipp,Santner Tobias,Griesmacher Andrea,Pfisterer Hartwig,Eschertzhuber Stephan,Aigner Maria,Joannidis Michael,Bellmann Romuald Infection PURPOSE:Wound infections caused by Candida are life-threatening and difficult to treat. Echinocandins are highly effective against Candida species and recommended for treatment of invasive candidiasis. As penetration of echinocandins into wounds is largely unknown, we measured the concentrations of the echinocandins anidulafungin (AFG), micafungin (MFG), and caspofungin (CAS) in wound secretion (WS) and in plasma of critically ill patients. METHODS:We included critically ill adults with an indwelling wound drainage or undergoing vacuum-assisted closure therapy, who were treated with an echinocandin for suspected or proven invasive fungal infection. Concentrations were measured by liquid chromatography with UV (AFG and MFG) or tandem mass spectrometry detection (CAS). RESULTS:Twenty-one patients were enrolled. From eight patients, serial WS samples and simultaneous plasma samples were obtained within a dosage interval. AFG concentrations in WS amounted to < 0.025-2.25 mg/L, MFG concentrations were 0.025-2.53 mg/L, and CAS achieved concentrations of 0.18-4.04 mg/L. Concentrations in WS were significantly lower than the simultaneous plasma concentrations and below the MIC values of some relevant pathogens. CONCLUSION:Echinocandin penetration into WS displays a high inter-individual variability. In WS of some of the patients, concentrations may be sub-therapeutic. However, the relevance of sub-therapeutic concentrations is unknown as no correlation has been established between concentration data and clinical outcome. Nevertheless, in the absence of clinical outcome studies, our data do not support the use of echinocandins at standard doses for the treatment of fungal wound infections, but underline the pivotal role of surgical debridement. 10.1007/s15010-021-01604-x
    Micafungin use in a UK tertiary referral hospital. Enoch David A,Murphy Michael E,Micallef Christianne,Yang Huina,Brown Nicholas M,Aliyu Sani H Journal of global antimicrobial resistance OBJECTIVES:Here we sought to describe the real-life usage of micafungin in a UK tertiary referral hospital. METHODS:A prospective, non-interventional, observational surveillance study was performed. RESULTS:Micafungin was commenced in 174 courses involving 148 patients to treat invasive candidiasis and candidaemia (132 courses) and aspergillosis in situations where alternatives such as voriconazole or liposomal amphotericin B could not be used (42 courses). Fungal infection was defined as proven as per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines in 84 courses (48.3%). Micafungin was well tolerated; 10 patients (6.8%) developed a rise in alanine aminotransferase (ALT) and only 1 patient stopped therapy due to this. Therapy was rationalised to fluconazole in 77 courses (44.3%). There were no differences in intensive care unit admission or deaths when comparing all 174 courses where patients received micafungin for Aspergillus and Candida infection, respectively [49% vs. 42% (P=0.82) and 24% vs. 15% (P=0.186)]. One patient developed disseminated mucormycosis and four patients had recurrent candidaemia (attributed to poor source control) while receiving micafungin. CONCLUSIONS:Micafungin was clinically effective for the treatment of invasive Candida and Aspergillus infections, and usage did not increase the risk of liver dysfunction even in patients with abnormal ALT at baseline. 10.1016/j.jgar.2018.06.009
    Candidemia in children: Epidemiology, prevention and management. Mantadakis Elpis,Pana Zoe Dorothea,Zaoutis Theoklis Mycoses 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. 10.1111/myc.12792
    Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies. Open forum infectious diseases BACKGROUND:There are no clear criteria for antifungal de-escalation after initial empirical treatments. We hypothesized that early de-escalation (ED) (within 5 days) to fluconazole is safe in fluconazole-susceptible candidemia with controlled source of infection. METHODS:This is a multicenter post hoc study that included consecutive patients from 3 prospective candidemia cohorts (2007-2016). The impact of ED and factors associated with mortality were assessed. RESULTS:Of 1023 candidemia episodes, 235 met inclusion criteria. Of these, 54 (23%) were classified as the ED group and 181 (77%) were classified as the non-ED group. ED was more common in catheter-related candidemia (51.9% vs 31.5%;  = .006) and episodes caused by , yet it was less frequent in patients in the intensive care unit (24.1% vs 39.2%;  = .043), infections caused by (0% vs 9.9%;  = .016), and candidemia from an unknown source (24.1% vs 47%;  = .003). In the ED and non-ED groups, 30-day mortality was 11.1% and 29.8% ( = .006), respectively. Chronic obstructive pulmonary disease (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.48-10.61), Pitt score > 2 (OR, 4.39; 95% CI, 1.94-9.20), unknown source of candidemia (OR, 2.59; 95% CI, 1.14-5.86), candidemia caused by (OR, 3.92; 95% CI, 1.48-10.61), and prior surgery (OR, 0.29; 95% CI, 0.08-0.97) were independent predictors of mortality. Similar results were found when a propensity score for receiving ED was incorporated into the model. ED had no significant impact on mortality (OR, 0.50; 95% CI, 0.16-1.53). CONCLUSIONS:Early de-escalation is a safe strategy in patients with candidemia caused by fluconazole-susceptible strains with controlled source of bloodstream infection and hemodynamic stability. These results are important to apply antifungal stewardship strategies. 10.1093/ofid/ofab250
    Echinocandins for management of invasive candidiasis in patients with liver disease and liver transplantation. Yeoh Siang Fei,Lee Tae Jin,Chew Ka Lip,Lin Stephen,Yeo Dennis,Setia Sajita Infection and drug resistance species remains one of the most important causes of opportunistic infections worldwide. Invasive candidiasis (IC) is associated with considerable morbidity and mortality in liver disease (LD) patients if not treated promptly. Echinocandins are often recommended as a first-line empirical treatment for managing IC and can especially play a critical role in managing IC in LD patients. However, advanced LD patients are often immunocompromised and critically ill. Hence altered pharmacokinetics, drug interactions as well as tolerance issues of antifungal treatments are a concern in these patients. This comprehensive review examines the epidemiology, risk factors and diagnosis of IC in patients with LD and evaluates differences between three available echinocandins for treating this group of patients. 10.2147/IDR.S165676
    Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: New leadership is about working together. Hoenigl Martin,Gangneux Jean-Pierre,Segal Esther,Alanio Alexandre,Chakrabarti Arunaloke,Chen Sharon C-A,Govender Nelesh,Hagen Ferry,Klimko Nikolaj,Meis Jacques F,Pasqualotto Alessandro C,Seidel Danila,Walsh Thomas J,Lagrou Katrien,Lass-Flörl Cornelia,Cornely Oliver A, Mycoses Invasive mycoses present a global challenge with expansion into new hosts, emergence of new pathogens, and development of multidrug resistance. In parallel, new antifungal agents and advanced laboratory diagnostic systems are being developed. In response to these evolving challenges, the European Confederation of Medical Mycology (ECMM) is committed to providing international expertise, guidance, and leadership with the key objectives of improving diagnosis, treatment, outcome, and survival of persons with invasive fungal diseases. Representing 25 affiliated National Medical Mycology Societies, the ECMM has developed several major ways to achieving these critical objectives: (a) tasking specific medical mycology working groups; (b) founding the ECMM Academy and Fellow program (FECMM); (c) expanding the goals of ECMM beyond the European region; (d) implementing the ECMM Excellence Centre Initiative in Europe; and (e) the ECMM Global Guidelines and Neglected Orphan Disease Guidance Initiatives focusing on mucormycosis, rare mould diseases, rare yeast diseases, and endemic mycoses. We believe that these important initiatives and other strategies of the ECMM will advance the field of medical mycology and improve the outcome of patients with invasive mycoses worldwide. 10.1111/myc.12836
    Antifungal Prevention of Systemic Candidiasis in Immunocompetent ICU Adults: Systematic Review and Meta-Analysis of Clinical Trials. Dupont Hervé,Mahjoub Yazine,Chouaki Taieb,Lorne Emmanuel,Zogheib Elie Critical care medicine OBJECTIVES:The aim of this study was to identify the impact of antifungal prevention in critically ill immunocompetent adult patients on mortality and subsequent infection. DATA SOURCES:A systematic review and meta-analysis of randomized controlled trials comparing any antifungal use versus placebo to prevent candidiasis in ICU patients were performed. STUDY SELECTION:Searches were performed on PubMed, Embase, Scopus, main conference proceedings, and ClinicalTrials.gov, as well as reference lists. DATA EXTRACTION:The primary outcomes were mortality and invasive candidiasis. The secondary outcome was the rate of Candida albicans and nonalbicans strains after treatment. A random effect model was used, and sensitivity analysis was performed for both outcomes. Results are expressed as risk ratios and their 95% CIs. DATA SYNTHESIS:Nineteen trials (10 with fluconazole, four with ketoconazole, one with itraconazole, three with micafungin, and one with caspofungin) including 2,792 patients were identified. No individual trial showed a decreased mortality rate. Combined analysis showed that preventive antifungal did not decrease mortality (risk ratio, 0.88; 95% CI, 0.74-1.04; p = 0.14) but significantly decreased secondary fungal infections by 50% (risk ratio, 0.49; 95% CI, 0.35-0.68; p = 0.0001). No shift across nonalbicans strains was observed during treatment (risk ratio, 0.62; 95% CI, 0.19-1.97; p = 0.42). However, publication biases preclude any definite conclusions for prevention of infection. CONCLUSIONS:Antifungal prevention of systemic candidiasis in immunocompetent critically ill adults did not reduce mortality and may have decreased secondary fungal infection rates. However, significant publication bias was present. 10.1097/CCM.0000000000002698
    Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010-16. Whitney Laura,Al-Ghusein Hasan,Glass Stephen,Koh Mickey,Klammer Matthias,Ball Jonathan,Youngs Jonathan,Wake Rachel,Houston Angela,Bicanic Tihana The Journal of antimicrobial chemotherapy Background:The need for antifungal stewardship is gaining recognition with increasing incidence of invasive fungal infection (IFI) and antifungal resistance alongside the high cost of antifungal drugs. Following an audit showing suboptimal practice we initiated an antifungal stewardship programme and prospectively evaluated its impact on clinical and financial outcomes. Patients and methods:From October 2010 to September 2016, adult inpatients receiving amphotericin B, echinocandins, intravenous fluconazole, flucytosine or voriconazole were reviewed weekly by an infectious diseases consultant and antimicrobial pharmacist. Demographics, diagnosis by European Organization for Research and Treatment of Cancer (EORTC) criteria, drug, indication, advice, acceptance and in-hospital mortality were recorded. Antifungal consumption and expenditure, and candidaemia species and susceptibility data were extracted from pharmacy and microbiology databases. Results:A total of 432 patients were reviewed, most commonly receiving AmBisome® (35%) or intravenous fluconazole (29%). Empirical treatment was often unnecessary, with 82% having no evidence of IFI. Advice was given in 64% of reviews (most commonly de-escalating or stopping treatment) and was followed in 84%. Annual antifungal expenditure initially reduced by 30% (£0.98 million to £0.73 million), then increased to 20% above baseline over a 5 year period; this was a significantly lower rise compared with national figures, which showed a doubling of expenditure over the same period. Inpatient mortality, Candida species distribution and rates of resistance were not adversely affected by the intervention. Conclusions:Provision of specialist input to optimize antifungal prescribing resulted in significant cost savings without compromising on microbiological or clinical outcomes. Our model is readily implementable by hospitals with high numbers of at-risk patients and antifungal expenditure. 10.1093/jac/dky389
    T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study. Muñoz Patricia,Vena Antonio,Machado Marina,Gioia Francesca,Martínez-Jiménez María Carmen,Gómez Elia,Origüen Julia,Orellana María Ángeles,López-Medrano Francisco,Fernández-Ruiz Mario,Merino Paloma,González-Romo Fernando,Frías Isabel,Pérez-Granda María-Jesús,Aguado José María,Fortún Jesús,Bouza Emilio, The Journal of antimicrobial chemotherapy Objectives:We assessed the potential role of T2Candida MR (T2MR) and serological biomarkers [β-d-glucan (BDG) or Candida albicans germ tube antibodies (CAGTA)], alone or in combination with standard cultures, for identifying patients with suspected invasive candidiasis (IC), who may benefit from maintaining antifungal therapy. Methods:Prospective observational multicentre study including all adult patients receiving empirical antifungal therapy for suspected IC, from January to June 2017. CAGTA, BDG and T2MR were determined at baseline and at +2 and +4 days after enrolment. Primary endpoint was the diagnostic value of CAGTA, BDG and T2MR, alone or in combination with standard culture, to predict diagnosis of IC and/or mortality in the first 7 days after starting antifungal therapy (poor outcome). Results:Overall, 14/49 patients (28.6%) had a poor outcome (7 died within the first 7 days of antifungal therapy, whereas 7 ended with a diagnosis of IC). CAGTA [3/14 (21.4%) versus 8/35 (22.9%), P = 1] and BDG [8/14 (57.1%) versus 17/35 (48.6%), P = 0.75] results were similar in poor- and good-outcome patients. Conversely, a positive T2MR was associated with a higher risk of poor outcome [5/14 (35.7%) versus 0/35 (0.0%) P = 0.0001]. Specificity and positive predictive value of a positive T2MR for predicting poor outcome were both 100%, with a negative predictive value of 79.6%. After testing the combinations of biomarkers/standard cultures and T2MR/standard cultures, the combination of T2MR/standard cultures showed a high capacity to discriminate patients with poor outcome from those with good clinical evolution. Conclusions:T2MR may be of significant utility to identify patients who may benefit from maintaining antifungal therapy. 10.1093/jac/dky047
    Advances in the diagnosis of fungal pneumonias. Kelly Bryan T,Pennington Kelly M,Limper Andrew H Expert review of respiratory medicine INTRODUCTION:Fungal infections are increasingly encountered in clinical practice due to more favorable environmental conditions and increasing prevalence of immunocompromised individuals. The diagnostic approach for many fungal pathogens continues to evolve. Herein, we outline available diagnostic tests for the most common fungal infections with a focus on recent advances and future directions. AREAS COVERED:We discuss the diagnostic testing methods for angioinvasive molds ( spp. and spp.), invasive yeast ( spp. and ssp.), Pneumocystis, and endemic fungi ( sp., Coccidioides sp., and Hitoplasma sp.). The PubMed-NCBI database was searched within the past 5 years to identify the most recent available literature with dates extended in cases where literature was sparse. Diagnostic guidelines were utilized when available with references reviewed. EXPERT OPINION:Historically, culture and/or direct visualization of fungal organisms were required for diagnosis of infection. Significant limitations included ability to collect specimens and delayed diagnosis associated with waiting for culture results. Antigen and antibody testing have made great strides in allowing quicker diagnosis of fungal infections but can be limited by low sensitivity/specificity, cross-reactivity with other fungi, and test availability. Molecular methods have a rich history in some fungal diseases, while others continue to be developed. 10.1080/17476348.2020.1753506
    Anidulafungin Pharmacokinetics in Ascites Fluid and Pleural Effusion of Critically Ill Patients. Welte R,Eller P,Lorenz I,Joannidis M,Bellmann R Antimicrobial agents and chemotherapy Anidulafungin concentrations were quantified with high-pressure liquid chromatography (HPLC) and UV detection of the ascites fluid and pleural effusion of 10 adult critically ill patients. Samples were collected from ascites fluid and from pleural drains or during paracentesis and thoracentesis, respectively. Anidulafungin levels in ascites fluid (0.12 to 0.99 μg/ml) and in pleural effusion (0.32 to 2.02 μg/ml) were below the simultaneous levels in plasma (1.04 to 7.70 and 2.48 to 13.36 μg/ml, respectively) and below the MIC values for several pathogenic strains. 10.1128/AAC.02326-17
    Population pharmacokinetics of micafungin over repeated doses in critically ill patients: a need for a loading dose? Kapralos Iasonas,Mainas Efstratios,Neroutsos Efthymios,Apostolidi Stella,Siopi Maria,Apostolopoulou Olympia,Dimopoulos George,Sambatakou Helen,Valsami Georgia,Meletiadis Joseph,Dokoumetzidis Aristides The Journal of pharmacy and pharmacology OBJECTIVES:To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens. METHODS:An HPLC-fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens. KEY FINDINGS:A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains. CONCLUSIONS:A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment. 10.1111/jphp.13353
    CD8 T cell survival in lethal fungal sepsis was ameliorated by T-cell-specific mTOR deletion. Wang Hao,Han Wen,Guo Ran,Bai Guangxu,Chen Jianwei,Cui Na International journal of medical sciences Lethal fungal sepsis causes high morbidity and mortality in intensive care patients. Fungal infections have an immunological basis, and it has been shown in recent studies that decreased CD8 T-cell count in fungal infections is related to prognosis, while the underlying mechanism is still unclear. Here, a lethal fungal sepsis model induced by candidemia was created and we found a decreased CD8 T-cell count and exaggerated apoptosis. Simultaneously, expression of light chain (LC)3B in CD8 T cells increased, along with increased autophagosomes and accumulation of p62 in infected mice. We regulated the activity of the mammalian target of rapamycin (mTOR) pathway using T-cell-specific mTOR/ TSC1 deletion mice. We observed increased number of autophagosomes and expression of LC3B in CD8T cells after T-cell-specific mTOR knockout, while accumulation of p62 was not ameliorated, and there was no increase in the number of autolysosomes. Apoptosis rate and expression of , a pro-apoptotic gene, decreased in CD8 T cells in mTOR-deletion mice but increased in TSC1-deletion mice. Our results showed increased CD8 T-cell death in spleen of lethal fungal sepsis mice, and decreased expression of mTOR ameliorated CD8 T-cell survival. mTOR may be a possible target to reverse CD8 T-cell immune dysfunction in lethal fungal sepsis. 10.7150/ijms.55592
    Global epidemiological burden of fungal infections in cirrhosis patients: A systematic review with meta-analysis. Verma Nipun,Singh Shreya,Singh Manvi,Chauhan Anil,Pradhan Pranita,Jaiswal Nishant,Chakrabarti Arunaloke,Singh Meenu Mycoses BACKGROUND AND AIMS:Fungal infections (FIs) have serious implications, yet understated in cirrhosis. Therefore, we reviewed the epidemiology and trends of FIs among cirrhotics. METHODS:Four electronic databases were searched for full-text articles describing prevalence of FIs in cirrhosis. Studies from post-transplant, malignancy and classical-immuno-deficiency patients were excluded. A random-effects meta-analysis was done to pool estimates of FIs (overall, and by type and infection-site), and their variation(I ) was explored on moderator-analysis and meta-regression. Risk of bias and asymmetry in estimates was assessed by a checklist and Egger's regression, respectively.(CRD42019142782). RESULTS:Thirty-four low-risk and four moderate-risk studies (31 984 cirrhotics) were included. Pooled estimates of overall FIs (17 studies), invasive fungal infections (IFIs; 17 studies), invasive candidiasis (23 studies) and invasive aspergillosis (16 studies) in cirrhosis were 10.2%(6.0-16.9), 9.5%(5.4-16.2), 4.0%(2.0-8.0) and 2.8%(1.5-5.3), respectively (I  > 90%;each). Site of FIs in decreasing order of pooled prevalence was pulmonary, urinary tract, bloodstream, peritoneal, oesophageal and cerebral. Geographic differences in these estimates were remarkable, with highest burden of overall FIs from Belgium, the United States and India. Non-albicans-Candida and Aspergillus infections have increased over the last decade in cirrhosis. Intensive-care-unit (ICU)-admitted and acute-on-chronic liver failure (ACLF) patients had the highest prevalence of IFIs. MELD score(cases), bias score and sample size across studies were the predictors of variance in overall FI estimates. Diabetes, steroid and broad-spectrum antibiotic-exposure, and multiple organ failures were the common predispositions reported in patients with FIs. CONCLUSIONS:FIs impose a substantial burden in cirrhosis. ACLF and ICU admission should be considered as a host factor for defining IFIs. Epidemiology of FIs can guide interpretation of biomarkers and antifungal treatment in cirrhosis. 10.1111/myc.13387
    A novel approach to candidemia? The potential role of checkpoint inhibition. Mellinghoff Sibylle C,von Bergwelt-Baildon Michael,Schößer Hans A,Cornely Oliver A Medical mycology Infections with Candida spp. cause significant morbidity and mortality despite intensive treatment with antifungal agents. Novel treatment options are urgently needed. Predominately immunocompromised patients are affected. This warrants the conclusion that strengthening host immunity may have the potential to improve outcome. Recent studies imply a potential benefit of checkpoint inhibition reversing hyporesponsiveness of innate and adaptive immunity during invasive fungal infections and invasive candidiasis in particular. We here give a brief overview of first preclinical data in vitro and in vivo and clinical evidence in selected cases. 10.1093/mmy/myy089
    Risk factors for early invasive fungal infections in paediatric liver transplant recipients. Pasternak Yehonatan,Rubin Shiri,Bilavsky Efraim,Mozer-Glassberg Yael,Levy Itzhak,Nahum Elhanan,Rom Eran,Gurevich Michael,Ben-Zvi Haim,Ashkenazi-Hoffnung Liat Mycoses Invasive fungal infections (IFIs) postliver transplantation are a frequent cause of morbidity and mortality; however, studies reporting on these infections in the paediatric population are scarce. To investigate the incidence and risk factors of IFIs in paediatric liver transplant recipients during the early posttransplantation period (≤3 months). Data were collected for all paediatric liver transplant recipients registered in a national transplantation center from 2004 to 2014. Using a stepwise logistic regression to identify independent risk factors for IFIs, a predictive model was formulated. Ten IFIs were identified in 81 liver transplant recipients (12.3%) all occurring during the first month posttransplantation. Candida species were responsible for nine cases (90%), of which four were non-albicans Candida (44%). Significant risk factors were identified; recipient of multiple blood product transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two clinical parameters to define high-risk patients: a living donor transplantation and duration of IV antibiotic treatment (area under the ROC curve 0.918). IFIs are a significant complication occurring in the first month posttransplantation. Future studies are required to assess efficacy of targeted antifungal prophylaxis in high risk patients. 10.1111/myc.12784
    Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies. Epstein David J,Seo Susan K,Brown Janice M,Papanicolaou Genovefa A The Journal of antimicrobial chemotherapy Antifungal prophylaxis is the standard of care for patients undergoing intensive chemotherapy for haematological malignancy or haematopoietic cell transplantation (HCT). Prophylaxis with azoles reduces invasive fungal infections and may reduce mortality. However, breakthrough infections still occur, and the use of azoles is sometimes complicated by pharmacokinetic variability, drug interactions, adverse events and other issues. Echinocandins are highly active against Candida species, including some organisms resistant to azoles, and have some clinical activity against Aspergillus species as well. Although currently approved echinocandins require daily intravenous administration, the drugs have a favourable safety profile and more predictable pharmacokinetics than mould-active azoles. Clinical data support the efficacy and safety of echinocandins for antifungal prophylaxis in haematology and HCT patients, though data are less robust than for azoles. Notably, sparse evidence exists supporting the use of echinocandins as antifungal prophylaxis for patients with significant graft-versus-host disease (GvHD) after HCT. Two drugs that target (1,3)-β-d-glucan are in development, including an oral glucan synthase inhibitor and an echinocandin with unique pharmacokinetics permitting subcutaneous and weekly administration. Echinocandins are a reasonable alternative to azoles and other agents for antifungal prophylaxis in patients undergoing intensive chemotherapy for haematological malignancy or those receiving HCT, excluding those with significant GvHD. 10.1093/jac/dkx450
    Procalcitonin for the diagnosis of invasive candidiasis: what is the evidence? Raineri Santi Maurizio,Cortegiani Andrea,Vitale Filippo,Iozzo Pasquale,Giarratano Antonino Journal of intensive care Procalcitonin is a widely used marker for the evaluation of infection and sepsis and to guide antibiotic therapy. During the last decade, several studies evaluated its role and diagnostic performance as a surrogate marker for the identification of spp. in suspected invasive candidiasis. A low serum level and a favorable negative predictive value are the main findings for procalcitonin in this setting. The aim of this report is to provide an updated brief summary of the evidence supporting the use of PCT for the management of invasive candidiasis. 10.1186/s40560-017-0252-x
    Correction to: P-42 Distribution and antifungal susceptibility of Candida isolates in a Tunisian burn unit. Sonia Trabelsi,Majdi Hanachi,Meriam Bouchekoua,Dorsaf Aloui,Sarra Cheikhrouhou,Samira Khaled,Allah Messadi Amen,Lamia Thabet Annals of intensive care INTRODUCTION:Burned patients are at high risk of yeast colonization and thus of invasive fungal infections, particularly to Candida (C.) spp., leading to an increase in morbidity and mortality. While pre-emptive antifungal therapy has improved survival, it may lead to an increase in antifungal resistance. The objectives of this work were to describe Candida species distribution and to determine the antifungal susceptibility of Candida isolates acquired in a burn unit. 10.1186/s13613-019-0555-2
    Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction. Lin Xiao-Bin,Lui Ka Yin,Guo Peng-Hao,Liu Xiao-Man,Liang Tao,Hu Xiao-Guang,Tong Li,Wu Jing-Jing,Xia Yan-Zhe,Chen Pan,Zhong Guo-Ping,Chen Xiao,Cai Chang-Jie Pharmacotherapy STUDY OBJECTIVES:This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN:Prospective pharmacokinetics study. SETTING:The intensive care unit in a tertiary-care medical center. PATIENTS:A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS:Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (C ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS:A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the C target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma C monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS:For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients. 10.1002/phar.2634
    Synergistic Antifungal Effect of Amphotericin B-Loaded Poly(Lactic-Co-Glycolic Acid) Nanoparticles and Ultrasound against Candida albicans Biofilms. Yang Min,Du Kaiyue,Hou Yuru,Xie Shuang,Dong Yu,Li Dairong,Du Yonghong Antimicrobial agents and chemotherapy is a human opportunistic pathogen that causes superficial and life-threatening infections. An important reason for the failure of current antifungal drugs is related to biofilm formation, mostly associated with implanted medical devices. The present study investigated the synergistic antifungal efficacy of low-frequency and low-intensity ultrasound combined with amphotericin B (AmB)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (AmB-NPs) against biofilms. AmB-NPs were prepared by a double-emulsion method and demonstrated lower toxicity than free AmB. We then established biofilms and treated them with ultrasound and AmB-NPs separately or jointly and The results demonstrated that the activity, biomass, and proteinase and phospholipase activities of biofilms were decreased significantly after the combination treatment of AmB-NPs with 42 kHz of ultrasound irradiation at an intensity of 0.30 W/cm for 15 min compared with the controls, with AmB alone, or with ultrasound treatment alone ( < 0.01). The morphology of the biofilms was altered remarkably after joint treatment based on confocal laser scanning microscopy (CLSM), especially in regard to reduced thickness and loosened structure. Furthermore, the same synergistic effects were found in a subcutaneous catheter biofilm rat model. The number of CFU from the catheter exhibited a significant reduction after joint treatment with AmB-NP and ultrasound for seven continuous days, and CLSM and scanning electron microscopy (SEM) images revealed that the biofilm on the catheter surface was substantially eliminated. This method may provide a new noninvasive, safe, and effective therapy for biofilm infection. 10.1128/AAC.02022-18
    Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients. Märtson Anne-Grete,van der Elst Kim C M,Veringa Anette,Zijlstra Jan G,Beishuizen Albertus,van der Werf Tjip S,Kosterink Jos G W,Neely Michael,Alffenaar Jan-Willem Antimicrobial agents and chemotherapy The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for , , and , respectively. The final 2-compartment model included weight as a covariate on volume of distribution (). The mean of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant ( ) was 0.09 (SD, 0.04) h, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients. 10.1128/AAC.00905-20
    Characteristics, outcome and risk factors for mortality of paediatric patients with ICU-acquired candidemia in India: A multicentre prospective study. Chakrabarti Arunaloke,Sood Prashant,Rudramurthy Shivaprakash M,Chen Sharon,Jillwin Joseph,Iyer Ranganathan,Sharma Ajanta,Harish Belgode Narasimha,Roy Indranil,Kindo Anupma J,Chhina Deepinder,Savio Jayanthi,Mendiratta Deepak,Capoor Malini R,Das Shukla,Arora Anita,Chander Jagdish,Xess Immaculata,Boppe Appalaraju,Ray Ujjwayini,Rao Ratna,Eshwara Vandana Kalwaje,Joshi Sangeeta,Patel Atul,Sardana Raman,Shetty Anjali,Pamidimukkala Umabala, Mycoses BACKGROUND:The epidemiology, clinical profile and outcome of paediatric candidemia vary considerably by age, healthcare settings and prevalent Candida species. Despite these differences, few comprehensive studies are undertaken. This nationwide study addresses this knowledge gap. METHODS:487 children who contracted ICU-acquired candidemia at 23 Indian tertiary care centres were assessed for 398 variables spanning demography, clinical characteristics, microbiology, treatment and outcome. RESULTS:Both neonates (5.0 days; range = 3.0-9.5) and non-neonatal children (7.0 days; range = 3.0-13.0) developed candidemia early after ICU admission. Majority of neonates were premature (63.7%) with low birthweight (57.1%). Perinatal asphyxia (7.3%), pneumonia (8.2%), congenital heart disease (8.4%) and invasive procedures were common comorbidities, and antibiotic use (94.1%) was widespread. C tropicalis (24.7%) and C albicans (20.7%) dominated both age groups. Antifungal treatment (66.5%) and removal of central catheters (44.8%) lagged behind. Overall resistance was low; however, emergence of resistant C krusei and C auris needs attention. The 30-day crude mortality was 27.8% (neonates) and 29.4% (non-neonates). Logistic regression identified admission to public sector ICUs (OR = 5.64), mechanical ventilation (OR = 2.82), corticosteroid therapy (OR = 8.89) and antifungal therapy (OR = 0.22) as independent predictors of 30-day crude mortality in neonates. Similarly, admission to public sector ICUs (OR = 3.62), mechanical ventilation (OR = 3.13), exposure to carbapenems (OR = 2.18) and azole antifungal therapy (OR = 0.48) were independent predictors for non-neonates. CONCLUSIONS:Our findings reveal a distinct epidemiology, including early infection with a different spectrum of Candida species, calling for appropriate intervention strategies to reduce candidemia morbidity and mortality. Independent factors identified in our regression models can help tackle these challenges. 10.1111/myc.13145
    Invasive Candidiasis Species Distribution and Trends, United States, 2009-2017. Ricotta Emily E,Lai Yi Ling,Babiker Ahmed,Strich Jeffrey R,Kadri Sameer S,Lionakis Michail S,Prevots D Rebecca,Adjemian Jennifer The Journal of infectious diseases BACKGROUND:Invasive candidiasis (IC) is a growing concern among US healthcare facilities. A large-scale study evaluating incidence and trends of IC in the United States by species and body site is needed to understand the distribution of infection. METHODS:An electronic medical record database was used to calculate incidence and trends of IC in the United States by species and infection site from 2009 through 2017. Hospital incidence was calculated using total unique inpatient hospitalizations in hospitals reporting at least 1 Candida case as the denominator. IC incidence trends were assessed using generalized estimating equations with exchangeable correlation structure to fit Poisson regression models, controlling for changes in hospital characteristics and case mix over time. RESULTS:Candida albicans remains the leading cause of IC in the United States, followed by Candida glabrata. The overall incidence of IC was 90/100 000 patients, which did not change significantly over time. There were no changes in incidence among C. albicans, C. glabrata, C. parapsilosis, or C. tropicalis; the incidence of other Candida spp. as a whole increased 7.2% annually. While there was no change in candidemia 2009-2017, abdominal and nonabdominal sterile site IC increased significantly. CONCLUSIONS:Nonbloodstream IC is increasing in the United States. Understanding the epidemiology of IC should facilitate improved management of infected patients. 10.1093/infdis/jiaa502
    Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital. Rautemaa-Richardson R,Rautemaa V,Al-Wathiqi F,Moore C B,Craig L,Felton T W,Muldoon E G The Journal of antimicrobial chemotherapy Objectives:A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker [serum β-1-3-d-glucan (BDG)] was developed in 2013 by an antifungal stewardship (AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). Methods:All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed. Results:The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016. Conclusions:The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis. 10.1093/jac/dky360
    Candida infection of membrane oxygenator during ECMO therapy. Schilcher Gernot,Eisner Florian,Hackl Gerald,Eller Philipp,Valentin Thomas,Zollner-Schwetz Ines,Krause Robert,Brcic Luka The Journal of infection 10.1016/j.jinf.2018.08.011
    ICU Patients' Antibiotic Exposure and Triazole-Resistance in Invasive Candidiasis: Parallel Analysis of Aggregated and Individual Data. Wang Yan,Zhang Ying,McGuire Treasure M,Hollingworth Samantha A,Van Driel Mieke L,Cao Lu,Wang Xue,Dong Yalin Frontiers in pharmacology The relationship between antibiotic use and the incidence of triazole-resistant phenotypes of invasive candidiasis (IC) in critically ill patients is unclear. Different methodologies on determining this relationship may yield different results. A retrospective multicenter observational analysis was conducted to investigate exposure to antibiotics and the incidence of non-duplicate clinical isolates of spp. resistant to fluconazole, voriconazole, or both during November 2013 to April 2018, using two different methodologies: group-level (time-series analysis) and individual-patient-level (regression analysis and propensity-score adjusting). Of 393 identified spp. from 388 critically ill patients, there were three phenotypes of IC identified: fluconazole-resistance (FR, 63, 16.0%); voriconazole-resistance (VR, 46, 11.7%); and cross-resistance between fluconazole and voriconazole (CR, 32, 8.1%). Exposure to several antibacterial agents with activity against the anaerobic gastrointestinal flora, especially third-generation cefalosporins (mainly cefoperazone/sulbactam and ceftriaxone), but not triazoles, have an immediate effect (time lag = 0) on subsequent ICU-acquired triazole-resistant IC in the group-level ( < 0.05). When the same patient database was analyzed at the individual-patient-level, we found that exposure to many antifungal agents was significantly associated with triazole-resistance (fluconazole [adjusted odds ratio (aOR) = 2.73] or caspofungin [aOR = 11.32] on FR, voriconazole [aOR = 2.87] on CR). Compared to the mono-triazole-resistant phenotype, CR IC has worse clinical outcomes (14-days mortality) and a higher level of resistance. Group-level and individual-patient-level analyses of antibiotic-use-versus-resistance relations yielded distinct but valuable results. Antibacterials with antianaerobic activity and antifungals might have "indirect" and "direct" effect on triazole-resistant IC, respectively. 10.3389/fphar.2021.586893
    Caspofungin pharmacokinetics and probability of target attainment in ICU patients in China. Li Fangyi,Zhou Minggen,Jiao Zheng,Zou Zijun,Yu Erqian,He Zhijie Journal of global antimicrobial resistance OBJECTIVES:Effective antifungal therapy is important to reduce mortality in patients with invasive fungal infections (IFIs). Numerous factors affect pharmacokinetic/pharmacodynamic (PK/PD) parameters in critically-ill patients. To guide individualised administration in critically-ill patients, it is of great significance to determine the population pharmacokinetics of caspofungin. METHODS:A prospective study in 42 ICU patients with IFIs was conducted in China. A population pharmacokinetic model of caspofungin was established using a non-linear mixed-effects model, which was utilised to investigate the effects of demographic indices, liver function and kidney function on pharmacokinetics. Additionally, appropriate dosages of caspofungin under various scenarios were determined based on MICs and probability of target attainment (PTA) at specific dosages. RESULTS:In critically-ill Chinese patients, clearance (CL), volume of distribution (V) and area under the curve at steady-state (AUC) of caspofungin were 0.32 L/h, 6.77 L and 135.47 mg•h/L, respectively. Blood albumin and total bilirubin levels were factors affecting CL, while body weight was the only factor affecting V among Chinese people with relatively low weight compared with other populations. A maintenance dose of 50 mg caspofungin achieved a high PTA for treating IFIs caused by Candida albicans (MIC ≤ 0.06 mg/L) and Candida glabrata (MIC ≤ 0.125 mg/L). The maintenance dose of caspofungin should be adjusted to 70-200 mg for IFIs caused by C. albicans (MIC, 0.06-0.125 mg/L). For IFIs caused by Candida parapsilosis, an MIC > 0.03 mg/L is associated with a very low PTA, but higher doses of caspofungin or alternative antifungals need to be further studied. CONCLUSION:The population pharmacokinetic model established here described well the PK/PD characteristics of caspofungin in critically-ill Chinese patients. These results could guide the formulation of individualised caspofungin dosing regimens for critically-ill patients. 10.1016/j.jgar.2021.03.011
    Dectin-1 Facilitates IL-18 Production for the Generation of Protective Antibodies Against . Shen Hui,Yu Yuetian,Chen Si-Min,Sun Juan-Juan,Fang Wei,Guo Shi-Yu,Hou Wei-Tong,Qiu Xi-Ran,Zhang Yu,Chen Yuan-Li,Wang Yi-Da,Hu Xin-Yu,Lu Liangjing,Jiang Yuan-Ying,Zou Zui,An Mao-Mao Frontiers in microbiology Invasive candidiasis (IC) is one of the leading causes of death among immunocompromised patients. Because of limited effective therapy treatment options, prevention of IC through vaccine is an appealing strategy. However, how to induce the generation of direct candidacidal antibodies in host remains unclear. mutant is an avirulent strain that exposes cell wall β-(1,3)-glucans. Here, we found that vaccination with the mutant strain could protect mice against invasive candidiasis caused by and non- spp. The protective effects induced by mutant relied on long-lived plasma cells (LLPCs) secreting protective antibodies against . Clinically, we verified a similar profile of IgG antibodies in the serum samples from patients recovering from IC to those from mutant-vaccinated mice. Mechanistically, we found cell wall β-(1,3)-glucan of mutant facilitated Dectin-1 receptor dependent nuclear translocation of non-canonical NF-κB subunit RelB in macrophages and subsequent IL-18 secretion, which primed protective antibodies generation . Together, our study demonstrate that Dectin-1 engagement could trigger RelB activation to prime IL-18 expression and established a new paradigm for consideration of the link between Dectin-1 mediated innate immune response and adaptive humoral immunity, suggesting a previously unknown active vaccination strategy against spp. infection. 10.3389/fmicb.2020.01648
    Economic evaluation of micafungin versus liposomal amphotericin B (LAmB) for treating patients with candidaemia and invasive candidiasis (IC) in Turkey. Neoh Chin Fen,Senol Esin,Kara Ates,Dinleyici Ener Cagri,Turner Stuart J,Kong David C M European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome. 10.1007/s10096-018-3312-9
    Burden and treatment patterns of invasive fungal infections in hospitalized patients in the Middle East: real-world data from Saudi Arabia and Lebanon. Alothman Adel F,Althaqafi Abdulhakeem O,Matar Madonna J,Moghnieh Rima,Alenazi Thamer H,Farahat Fayssal M,Corman Shelby,Solem Caitlyn T,Raghubir Nirvana,Macahilig Cynthia,Charbonneau Claudie,Stephens Jennifer M Infection and drug resistance OBJECTIVES:The objective of this study was to document the burden and treatment patterns associated with invasive fungal infections (IFIs) due to and species in Saudi Arabia and Lebanon. METHODS:A retrospective chart review study was conducted using data recorded from 2011 to 2012 from hospitals in Saudi Arabia and Lebanon. Patients were included if they had been discharged with a diagnosis of IFI due to or , which was culture proven or suspected based on clinical criteria. Hospital data were abstracted for a random sample of patients to capture demographics, treatment patterns, hospital resource utilization, and clinical outcomes. Descriptive results were reported. RESULTS:Five hospitals participated and provided data on 102 patients with IFI (51 from Lebanon and 51 from Saudi Arabia). The mean age of the patients was 55 years, and 55% were males. Comorbidities included diabetes (41%), coronary artery disease (24%), leukemia (19%), moderate-to-severe renal disease (16%), congestive heart failure (15%), and chronic obstructive pulmonary disease (15%). Twenty percent of patients received corticosteroids prior to admission and 26% had received chemotherapy in the past 90 days. Inpatient mortality was 42%, and the mean hospital length of stay was 32.4±28.6 days. Fifty-five percent of patients required intensive care unit admission (17.2±14.1 days), 37% required mechanical ventilation (13.7±13.2 days), and 11% required dialysis (14.6±14.2 days). The most commonly used first-line antifungal was fluconazole. CONCLUSION:Patients with IFI in Saudi Arabia and Lebanon frequently have multiple medical comorbidities and may not have traditionally observed IFI risk factors. Efforts to increase use of rapid diagnostic tests and appropriate antifungal treatments may impact the substantial mortality and high length of stay observed in these patients. 10.2147/IDR.S97413
    New approaches for the detection of invasive fungal diseases in patients following liver transplantation-results of an observational clinical pilot study. Decker Sebastian O,Krüger Albert,Wilk Henryk,Grumaz Silke,Vainshtein Yevhen,Schmitt Felix C F,Uhle Florian,Bruckner Thomas,Zimmermann Stefan,Mehrabi Arianeb,Mieth Markus,Weiss Karl Heinz,Weigand Markus A,Hofer Stefan,Sohn Kai,Brenner Thorsten Langenbeck's archives of surgery PURPOSE:Despite antifungal prophylaxis following liver transplantation (LTX), patients are at risk for the development of subsequent opportunistic infections, such as an invasive fungal disease (IFD). However, culture-based diagnostic procedures are associated with relevant weaknesses. METHODS:Culture and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of ß-D-glucan (BDG), galactomannan (GM), interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A and mid-regional proadrenomedullin (MR-proADM) were evaluated in 93 patients at 6 consecutive time points within 28 days following LTX. RESULTS:A NGS-based diagnostic approach was shown to be suitable for the early identification of fungal pathogens in patients following LTX. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with an IFD. CONCLUSION:Plasma measurements of MR-proADM and IL-17A as well as a NGS-based diagnostic approach were shown to be attractive methodologies to attenuate the weaknesses of routinely used culture-based diagnostic procedures for the determination of an IFD in patients following LTX. However, an additional confirmation within a larger multicenter trial needs to be recommended. TRIAL REGISTRATION:German Clinical Trials Register: DRKS00005480 . 10.1007/s00423-019-01769-y
    Diagnostic accuracy of fungal PCR and β-d-glucan for detection of candidaemia: a preliminary evaluation. McKeating Cara,White P Lewis,Posso Raquel,Palmer Michael,Johnson Elizabeth,McMullan Ronan Journal of clinical pathology AIMS:Although treatment for candidaemia is time critical, culture-based tests prolong turnaround times and may promote underdiagnosis. Non-culture-based tests have the potential to overcome these difficulties but are in limited clinical use. The aim of this work was to undertake an initial evaluation of two non-culture-based tests for diagnosis of candidaemia. METHODS:Patients with candidaemia were identified prospectively over a 4-month period. Sera drawn from case (candidaemic) and control (non-candidaemic) patients on the same day as the positive blood culture were tested with both the Renishaw RenDx Fungiplex test and a commercial β-d-glucan (BDG) assay (Fungitell, Associates of Cape Cod). Sensitivity and specificity were calculated independently and in combination, using paired blood culture as the reference standard. RESULTS:There were 10 eligible case patients and 39 negative controls. PCR sensitivity and specificity were found to be 44.4% (95% CI 18.9% to 73.3%) and 87.2% (72.8% to 94.8%), respectively. BDG sensitivity and specificity were 80% (47.9% to 95.4%) and 89.7% (75.9% to 96.5%), respectively. When combining PCR and BDG, sensitivity was 90% (95% CI 57.4% to 100%) and specificity was 79.5% (64.2% to 89.5%). When two sequential specimens were tested, PCR sensitivity increased to 60% (95% CI 31.2% to 83.3%) and BDG sensitivity to 90% (54.7% to 100%). CONCLUSION:A combination of tests, or a single test at multiple time points, may be preferable to relying on one test at a single time point. This should be accounted for in design of future diagnostic accuracy studies of tests for invasive candidosis. 10.1136/jclinpath-2017-204692
    Suboptimal Dosing of Fluconazole in Critically Ill Patients: Time To Rethink Dosing. Muilwijk Eline W,de Lange Dylan W,Schouten Jeroen A,Wasmann Roeland E,Ter Heine Rob,Burger David M,Colbers Angela,Haas Pieter J,Verweij Paul E,Pickkers Peter,Brüggemann Roger J Antimicrobial agents and chemotherapy Fluconazole is frequently used for the treatment of invasive infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target AUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.). 10.1128/AAC.00984-20
    Epidemiology, clinical characteristics, resistance, and treatment of infections by . Cortegiani Andrea,Misseri Giovanni,Fasciana Teresa,Giammanco Anna,Giarratano Antonino,Chowdhary Anuradha Journal of intensive care spp infections are a major cause of morbidity and mortality in critically ill patients. is an emerging multi-drug-resistant fungus that is rapidly spreading worldwide. Since the first reports in 2009, many isolates across five continents have been identified as agents of hospital-associated infections. Independent and simultaneous outbreaks of are becoming a major concern for healthcare and scientific community. Moreover, laboratory misidentification and multi-drug-resistant profiles, rarely observed for other non-albicans species, result in difficult eradication and frequent therapeutic failures of infections. The aim of this review was to provide an updated and comprehensive report of the global spread of , focusing on clinical and microbiological characteristics, mechanisms of virulence and antifungal resistance, and efficacy of available control, preventive, and therapeutic strategies. 10.1186/s40560-018-0342-4
    Efficacy of anidulafungin in 539 patients with invasive candidiasis: a patient-level pooled analysis of six clinical trials. Kullberg Bart Jan,Vasquez José,Mootsikapun Piroon,Nucci Marcio,Paiva José-Artur,Garbino Jorge,Yan Jean Li,Aram Jalal,Capparella Maria Rita,Conte Umberto,Schlamm Haran,Swanson Robert,Herbrecht Raoul The Journal of antimicrobial chemotherapy Objectives:To evaluate the efficacy of anidulafungin for the treatment of candidaemia and invasive candidiasis in a large dataset, including patients with deep-seated tissue candidiasis, neutropenia and infection due to non- albicans Candida species. Methods:Data were pooled from six prospective, multicentre, multinational studies: four open-label, non-comparative studies of anidulafungin and two double-blind, double-dummy, randomized studies of anidulafungin versus caspofungin (clinical trial registrations: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351 and NCT00805740; ClinicalTrials.gov). In all studies, patients with culture-confirmed invasive candidiasis received a single intravenous (iv) loading dose of anidulafungin 200 mg on day 1, followed by 100 mg once-daily. Switch to oral fluconazole or voriconazole was permitted after 5-10 days of iv treatment in all studies except one. Antifungal treatment (iv plus oral therapy if applicable) was maintained for ≥14 days after the last positive Candida culture. The primary endpoint was successful global response at end of iv therapy (EOivT) in the modified ITT (mITT) population. Results:In total, 539 patients were included (mITT population). The most common baseline Candida species were Candida albicans (47.9%), Candida glabrata (21.0%), Candida tropicalis (13.7%), Candida parapsilosis (13.2%) and Candida krusei (3.5%). Median duration of anidulafungin iv treatment was 10.0 days. The global response success rate at EOivT was 76.4% (95% CI 72.9%-80.0%). All-cause mortality was 13.0% on day 14 and 19.1% on day 28. Adverse events (AEs) were consistent with the known AE profile for anidulafungin. Conclusions:These data demonstrate that anidulafungin is effective for treatment of candidaemia and invasive candidiasis in a broad patient population. 10.1093/jac/dkx116
    Prospective evaluation of lymphocyte subtyping for the diagnosis of invasive candidiasis in non-neutropenic critically ill patients. Zhang Jiahui,Cui Na,Long Yun,Wang Hao,Han Wen,Li Yuanfei,Xiao Meng International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases OBJECTIVES:This study aimed to investigate the distinguishing ability of lymphocyte subtyping for Invasive candidiasis (IC) diagnosis and prognosis in non-neutropenic critically ill patients. METHODS:We assessed the quantitative changes in key parameters of lymphocyte subtyping at the onset of clinical signs of infection in non-neutropenic critically ill patients and their potential influence on diagnosis and outcome of IC. The primary outcome was 28-day mortality. RESULTS:Among the 182 consecutive critically ill patients, 22 (12.1%) were in the IC group. The CD28CD8 T-cell counts (AUC 0.863, 95%CI 0.804-0.909, P<0.001) had greater diagnostic value for IC than other parameters had. Adding CD28CD8 T to Candida score significantly improved the predictive value of Candida score (P=0.039). Multivariate logistic regression analysis identified CD28CD8 T-cell counts≤78 cells/mm (OR 24.544, 95%CI 6.461-93.236, P<0.001) as an independent predictor for IC diagnosis. CD28CD8 T-cell counts could also predict 28-day mortality. Kaplan-Meier survival analysis provided evidence that CD28CD8 T-cell count <144cells/mm (log-rank test; P=0.03) were associated with lower survival probabilities. CONCLUSIONS:CD28CD8 T-cell counts play an important role in early diagnosis of IC. Low counts are associated with early mortality in non-neutropenic critically ill patients. These results suggest the potential usefulness of measuring CD28CD8 T-cell lymphocyte levels in the early recognition and diagnosis of IC. TRIAL REGISTRATION:ChiCTR-ROC-17010750. Registered 28 February 2017. 10.1016/j.ijid.2018.10.028
    Candidemia Diagnosis With T2 Nuclear Magnetic Resonance in a PICU: A New Approach. Cendejas-Bueno Emilio,Falces-Romero Iker,Laplaza-González María,Escosa-García Luis,Schuffelmann-Gutierrez Cristina,Romero-Gómez María P,Verdú-Sánchez Cristina,Calderón-Llopis Belén,Amores-Hernández Irene,Pemán Javier,Gómez-Zamora Ana,Río-García Miguel,Menéndez-Suso Juan José,Rodríguez-Álvarez Diego,Durán-Lorenzo Iría,Pérez-Acosta Elena,Rubio Miguel Rodríguez,Álvarez-Rojas Elena,Martínez-Romillo Paloma Dorao,Goded-Rambaud Federico,de Lorenzo Abelardo García,Maseda Emilio,Mingorance Jesús,de la Oliva Pedro,García-Rodríguez Julio Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies OBJECTIVES:Early diagnosis of invasive Candida infections is a challenge for pediatricians, intensivists, and microbiologists. To fill this gap, a new nanodiagnostic method has been developed using manual application of T2 nuclear magnetic resonance to detect Candida species. The aim of this study was to evaluate, prospectively, the usefulness as a tool diagnosis of the T2Candida panel in pediatric patients admitted at the PICU compared with blood culture. DESIGN:This is a prospective, observational, and unicentric study to compare T2Candida results with simultaneous blood cultures for candidemia diagnose. SETTING:This study was carried out in a 1,300-bed tertiary care hospital with a 16-bed medical-surgical PICU. PATIENTS:Sixty-three patients from 0 to 17 years old were enrolled in this study, including those undergoing solid organ transplantation (kidney, liver, pulmonary, multivisceral, intestinal, and heart) and hematopoietic stem cell transplantation. MEASUREMENTS AND MAIN RESULTS:Seven patients were positive by the T2Candida test. Only two of them had the simultaneous positive blood culture. T2Candida yielded more positive results than blood cultures. CONCLUSIONS:T2Candida might be useful for the diagnosis of candidemia in PICUs. The prevalence of candidemia might be underestimated in this pediatric population. The use of this diagnostic tool in these units may help clinicians to start adequate and timely antifungal treatments. 10.1097/PCC.0000000000002548
    Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on continuous venovenous haemodiafiltration. Pérez-Pitarch Alejandro,Ferriols-Lisart Rafael,Aguilar Gerardo,Ezquer-Garín Carlos,Belda F Javier,Guglieri-López Beatriz International journal of antimicrobial agents INTRODUCTION:The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS:Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS:Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION:The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection. 10.1016/j.ijantimicag.2017.05.013
    Comparative Genomics of Serial Isolates and the Rapid Acquisition of Echinocandin Resistance during Therapy. Barber Amelia E,Weber Michael,Kaerger Kerstin,Linde Jörg,Gölz Hanna,Duerschmied Daniel,Markert Antonie,Guthke Reinhard,Walther Grit,Kurzai Oliver Antimicrobial agents and chemotherapy The opportunistic pathogen shows a concerning increase in drug resistance. Here, we present the analysis of two serial bloodstream isolates, obtained 12 days apart. Both isolates show pan-azole resistance and echinocandin resistance was acquired during the sampling interval. Genome sequencing identified nine nonsynonymous SNVs between the strains, including a S663P substitution in FKS2 and previously undescribed SNVs in and , offering insight into how acquires drug resistance and adapts to a human host. 10.1128/AAC.01628-18
    Optimisation of fluconazole therapy for the treatment of invasive candidiasis in preterm infants. Archives of disease in childhood INTRODUCTION:Fluconazole is an important antifungal in the prevention and treatment of invasive infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a population pharmacokinetic study on fluconazole in preterm neonates in order to optimise dosing through the identified predictive patient characteristics. METHODS:Fluconazole concentrations obtained from preterm infants from two studies were pooled and analysed using NONMEM V.7.3. The developed model was used to evaluate current dosing practice. A therapeutic dosing strategy aiming to reach a minimum target exposure of 400 and 200 mg×hour/L per 24 hours for fluconazole-susceptible meningitis and other systemic infections, respectively, was developed. RESULTS:In 41 preterm neonates with median (range) gestational age 25.3 (24.0-35.1) weeks and median postnatal age (PNA) at treatment initiation 1.4 (0.2-32.5) days, 146 plasma samples were collected. A one-compartment model described the data best, with an estimated clearance of 0.0147 L/hour for a typical infant of 0.87 kg with a serum creatinine concentration of 60 µmol/L and volume of distribution of 0.844 L. Clearance was found to increase with 16% per 100 g increase in actual body weight, and to decrease with 12% per 10 µmol/L increase in creatinine concentration once PNA was above 1 week. Dose adjustments based on serum creatinine and daily dosing are required for therapeutic target attainment. CONCLUSION:In preterm neonates, fluconazole clearance is best predicted by actual body weight and serum creatinine concentration. Therefore, fluconazole dosing should not only be based on body weight but also on creatinine concentration to achieve optimal exposure in all infants. ETHICS STATEMENT:The Erasmus MC ethics review board approved the protocol of the DINO Study (MEC-2014-067) and the Radboud UMC ethics review board waived the need for informed consent for cohort 2 (CMO-2021-8302). Written informed consent from parents/legal guardians was obtained prior to study initiation. 10.1136/archdischild-2021-322560
    Invasive Fungal Infection After Lung Transplantation: Epidemiology in the Setting of Antifungal Prophylaxis. Baker Arthur W,Maziarz Eileen K,Arnold Christopher J,Johnson Melissa D,Workman Adrienne D,Reynolds John M,Perfect John R,Alexander Barbara D Clinical infectious diseases : an official publication of the Infectious Diseases Society of America BACKGROUND:Lung transplant recipients commonly develop invasive fungal infections (IFIs), but the most effective strategies to prevent IFIs following lung transplantation are not known. METHODS:We prospectively collected clinical data on all patients who underwent lung transplantation at a tertiary care academic hospital from January 2007-October 2014. Standard antifungal prophylaxis consisted of aerosolized amphotericin B lipid complex during the transplant hospitalization. For the first 180 days after transplant, we analyzed prevalence rates and timing of IFIs, risk factors for IFIs, and data from IFIs that broke through prophylaxis. RESULTS:In total, 156 of 815 lung transplant recipients developed IFIs (prevalence rate, 19.1 IFIs per 100 surgeries, 95% confidence interval [CI] 16.4-21.8%). The prevalence rate of invasive candidiasis (IC) was 11.4% (95% CI 9.2-13.6%), and the rate of non-Candida IFIs was 8.8% (95% CI 6.9-10.8%). First episodes of IC occurred a median of 31 days (interquartile range [IQR] 16-56 days) after transplant, while non-Candida IFIs occurred later, at a median of 86 days (IQR 40-121 days) after transplant. Of 169 IFI episodes, 121 (72%) occurred in the absence of recent antifungal prophylaxis; however, IC and non-Candida breakthrough IFIs were observed, most often representing failures of micafungin (n = 16) and aerosolized amphotericin B (n = 24) prophylaxis, respectively. CONCLUSIONS:Lung transplant recipients at our hospital had high rates of IFIs, despite receiving prophylaxis with aerosolized amphotericin B lipid complex during the transplant hospitalization. These data suggest benefit in providing systemic antifungal prophylaxis targeting Candida for up to 90 days after transplant and extending mold-active prophylaxis for up to 180 days after surgery. 10.1093/cid/ciz156
    Biomarker-based strategy for early discontinuation of empirical antifungal treatment in critically ill patients: a randomized controlled trial. Rouzé Anahita,Loridant Séverine,Poissy Julien,Dervaux Benoit,Sendid Boualem,Cornu Marjorie,Nseir Saad, Intensive care medicine PURPOSE:The aim of this study was to determine the impact of a biomarker-based strategy on early discontinuation of empirical antifungal treatment. METHODS:Prospective randomized controlled single-center unblinded study, performed in a mixed ICU. A total of 110 patients were randomly assigned to a strategy in which empirical antifungal treatment duration was determined by (1,3)-β-D-glucan, mannan, and anti-mannan serum assays, performed on day 0 and day 4; or to a routine care strategy, based on international guidelines, which recommend 14 days of treatment. In the biomarker group, early stop recommendation was determined using an algorithm based on the results of biomarkers. The primary outcome was the percentage of survivors discontinuing empirical antifungal treatment early, defined as a discontinuation strictly before day 7. RESULTS:A total of 109 patients were analyzed (one patient withdraw consent). Empirical antifungal treatment was discontinued early in 29 out of 54 patients in the biomarker strategy group, compared with one patient out of 55 in the routine strategy group [54% vs 2%, p < 0.001, OR (95% CI) 62.6 (8.1-486)]. Total duration of antifungal treatment was significantly shorter in the biomarker strategy compared with routine strategy [median (IQR) 6 (4-13) vs 13 (12-14) days, p < 0.0001). No significant difference was found in the percentage of patients with subsequent proven invasive Candida infection, mechanical ventilation-free days, length of ICU stay, cost, and ICU mortality between the two study groups. CONCLUSIONS:The use of a biomarker-based strategy increased the percentage of early discontinuation of empirical antifungal treatment among critically ill patients with suspected invasive Candida infection. These results confirm previous findings suggesting that early discontinuation of empirical antifungal treatment had no negative impact on outcome. However, further studies are needed to confirm the safety of this strategy. This trial was registered at ClinicalTrials.gov, NCT02154178. 10.1007/s00134-017-4932-8
    Healthcare-associated fungal outbreaks: New and uncommon species, New molecular tools for investigation and prevention. Bougnoux Marie-Elisabeth,Brun Sophie,Zahar Jean-Ralph Antimicrobial resistance and infection control Outbreaks of healthcare-associated fungal infections have repeatedly been described over recent years, often caused by new or uncommon species. , a recently described multidrug-resistant yeast species, is certainly the most worrisome species having caused several severe healthcare outbreaks of invasive infections, on four continents. Also, large nosocomial outbreaks due to uncommon fungal species such as and , were both linked to contamination of medical products, however the source of another outbreak, caused by , remains unresolved. Furthermore, these outbreaks identified new populations under threat in addition to those commonly at risk for invasive fungal infections, such as immunosuppressed and intensive care unit patients. All of these outbreaks have highlighted the usefulness of a high level of awareness, rapid diagnostic methods, and new molecular typing tools such as Whole Genome Sequencing (WGS), prompt investigation and aggressive interventions, including notification of public health agencies. This review summarizes the epidemiological and clinical data of the majority of healthcare-associated outbreaks reported over the last 6 years caused by uncommon or new fungal pathogens, as well as the contribution of WGS as support to investigate the source of infection and the most frequent control measures used. 10.1186/s13756-018-0338-9
    Erratum to: Contribution of Candida biomarkers and DNA detection for the diagnosis of invasive candidiasis in ICU patients with severe abdominal conditions. León Cristóbal,Ruiz-Santana Sergio,Saavedra Pedro,Castro Carmen,Loza Ana,Zakariya Ismail,Úbeda Alejandro,Parra Manuel,Macías Desirée,Tomás José Ignacio,Rezusta Antonio,Rodríguez Alejandro,Gómez Frederic,Martín-Mazuelos Estrella, Critical care (London, England) 10.1186/s13054-017-1686-1
    Antifungal Drugs for Invasive Candida Infections (ICI) in Neonates: Future Perspectives. Bersani Iliana,Piersigilli Fiammetta,Goffredo Bianca Maria,Santisi Alessandra,Cairoli Sara,Ronchetti Maria Paola,Auriti Cinzia Frontiers in pediatrics Fungal infections may complicate the neonatal clinical course, and the spectrum of therapies for their treatment in the perinatal period is limited. Polyenes, Azoles and Echinocandins represent the three classes of antifungal drugs commonly used in the neonatal period. The present review provides an overview about the most recent therapeutic strategies for the treatment of fungal infections in neonates. 10.3389/fped.2019.00375
    The risk and clinical outcome of candidemia depending on underlying malignancy. Lortholary Olivier,Renaudat Charlotte,Sitbon Karine,Desnos-Ollivier Marie,Bretagne Stéphane,Dromer Françoise, Intensive care medicine PURPOSE:To assess the risk factors and outcomes associated with fungemia caused by the six most commonly occurring Candida species in patients with and without malignancies. METHODS:Analysis of the episodes of fungemia due to common Candida species in adults, based on an active hospital-based surveillance program (Paris area, France, 2002 to 2014). RESULTS:Of the 3417 patients (3666 isolates), 1164 (34.1%) had a solid tumor (45.7% digestive tract) and 586 (17.1%) a hematological malignancy (41.8% lymphoma, 33.5% acute leukemia). The hematology patients were significantly younger, more often pre-exposed to antifungals, more often infected by C. tropicalis, C. krusei, or C. kefyr, and more often treated in the first instance with an echinocandin. Compared with inpatients who were not in ICU at the time of fungemia, those in ICU were less frequently infected by C. parapsilosis (p < 0.02), had more recent surgery (p < 0.03), and died more frequently before day 8 and day 30 (p < 0.0001). An increase in crude mortality over time in ICU was observed only in oncology patients (p < 0.04). For all patients, lack of prescription of antifungals despite knowledge of positive blood culture increased the risk of death. The odds of being infected by a given Candida species compared with C. albicans were uneven regarding age, gender, type of malignancy, hospitalization in ICU, central venous catheter, HIV status, intravenous drug addiction, and previous exposure to antifungal drugs. Compared with C. albicans, C. glabrata (OR = 0.69 [0.54-0.89]) and C. parapsilosis (OR = 0.49 [0.35-0.67]) were associated with a decreased risk of death by day 8 and day 30. CONCLUSION:The clinical context of underlying malignancy and hospitalization in ICU may be relevant to the initial management of candidemia. 10.1007/s00134-017-4743-y
    : An Overview of How to Screen, Detect, Test and Control This Emerging Pathogen. Fasciana Teresa,Cortegiani Andrea,Ippolito Mariachiara,Giarratano Antonino,Di Quattro Orazia,Lipari Dario,Graceffa Domenico,Giammanco Anna Antibiotics (Basel, Switzerland) The multidrug-resistant yeast is associated with invasive infections in critically ill patients and has been isolated in different countries worldwide. Ease of spread, prolonged persistence in the environment and antifungal drug resistance pose a significant concern for the prevention of transmission and management of patients with infections. Early and correct identification of patients colonized with is critical in containing its spread. However, this may be complicated by strains being misidentified as other phylogenetically related pathogens. In this review, we offer a brief overview highlighting some of the critical aspects of sample collection, laboratory culture-dependent and independent identification and the susceptibility profile of . 10.3390/antibiotics9110778
    Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets. Gong Ying,Li Tao,Yu Cuixiang,Sun Shujuan Frontiers in cellular and infection microbiology In recent decades, the incidence of invasive fungal infections has increased notably. , a common opportunistic fungal pathogen that dwells on human mucosal surfaces, can cause fungal infections, especially in immunocompromised and high-risk surgical patients. In addition, the wide use of antifungal agents has likely contributed to resistance of to traditional antifungal drugs, increasing the difficulty of treatment. Thus, it is urgent to identify novel antifungal drugs to cope with infections. Heat shock proteins (Hsps) exist in most organisms and are expressed in response to thermal stress. In , Hsps control basic physiological activities or virulence via interaction with a variety of diverse regulators of cellular signaling pathways. Moreover, it has been demonstrated that Hsps confer drug resistance to . Many studies have shown that disrupting the normal functions of Hsps inhibits fungal growth or reverses the tolerance of to traditional antifungal drugs. Here, we review known functions of the diverse Hsp family, Hsp-associated intracellular signaling pathways and potential antifungal targets based on these pathways in . We hope this review will aid in revealing potential new roles of Hsps in addition to canonical heat stress adaptions and provide more insight into identifying potential novel antifungal targets. 10.3389/fcimb.2017.00520
    Evaluation of the (1,3)-β-D-glucan assay for the diagnosis of neonatal invasive yeast infections. Cornu Marjorie,Goudjil Sabrina,Kongolo Guy,Leke André,Poulain Daniel,Chouaki Taieb,Sendid Boualem Medical mycology Most newborns in the neonatal intensive care unit (NICU) are premature and at risk of invasive fungal infections (IFIs). Invasive yeast infections (IYIs) are the most common fungal infections in this population. These infections are difficult to diagnose because symptoms are nonspecific, and the sensitivity of blood cultures is low. The serum (1,3)-β-D-glucan (BDG) assay provides a reliable marker for the diagnosis of IFIs in adults with haematological malignancies. We assessed the diagnostic performance of this test in neonatal IYIs and its contribution to the monitoring of antifungal treatment. A retrospective study was performed in the NICU of the French University Hospital of Amiens from February 2012 to February 2014. Forty-seven neonates (33 males, 14 females) with a median gestational age of 30 weeks (IQR: 27-31) and median birth weight of 1200 g (IQR: 968-1700) were included and divided into three groups: 21 control neonates (CTRL), 20 neonates with probable IYI (PB), and six with proven IYI (PV). Median BDG levels were significantly higher in the global IYI group (PB + PV): 149 pg/ml (IQR: 85-364) vs. CTRL group: 39 pg/ml (IQR: 20-94) (P < .001). The optimal cut-off was 106 pg/ml (sensitivity 61.5%; specificity 81%). BDG levels decreased with antifungal treatment. BDG was detectable in cerebrospinal fluid, but the interest of this for diagnostic purposes remains unclear. Our results suggest that the BDG assay may be useful for the early identification of IYIs in neonates and for monitoring antifungal therapy efficacy. 10.1093/mmy/myx021
    The Epidemiology and Prevention of Candida auris. Snyder Graham M,Wright Sharon B Current infectious disease reports PURPOSE OF REVIEW:Candida auris has recently emerged as a pathogen with the potential for nosocomial transmission and outbreaks. The aim of this review is to summarize the global dissemination of this pathogen, characterize patient and facility characteristics associated with infection and outbreaks, and outline evidence to support interventions to prevent of transmission in the healthcare setting. RECENT FINDINGS:C. auris has emerged separately in four clades, with international spread within a decade of its first identification and report. Acquisition and infection have predominantly been identified as healthcare-associated events. The presence of invasive devices, intensive care, and broad-spectrum antibiotic and antifungal use may be important risk factors for the development of infection due to C. auris. Nosocomial transmission is likely associated with colonization density and suboptimal infection prevention practices. The optimal strategy for reducing transmission from the environment requires further study. Candida auris is a recently emerging fungal pathogen that may cause nosocomial infections and outbreaks. Based on observed transmission patterns and interventions, key prevention measures outlined in the review include case finding and surveillance, hand hygiene, and environmental disinfection. 10.1007/s11908-019-0675-8
    Congenital Cutaneous Candidiasis: Prompt Systemic Treatment Is Associated With Improved Outcomes in Neonates. Kaufman David A,Coggins Sarah A,Zanelli Santina A,Weitkamp Jörn-Hendrik Clinical infectious diseases : an official publication of the Infectious Diseases Society of America BACKGROUND:Congenital cutaneous candidiasis (CCC) is a challenging diagnosis due to various rash presentations. Inadequate early treatment is associated with high rates of dissemination and death. The effects of early diagnosis, dermatologic presentation, and antifungal treatment on outcomes are lacking. METHODS:CCC cases were reviewed from 2 academic neonatal intensive care units (NICUs) from 2004 to 2015. We defined CCC as a diffuse rash involving the body, extremities, face or scalp, and/or funisitis, presenting in the first week (≤7 days), with identification of Candida species from skin or mucous membrane cultures, and/or by culture or staining of the placenta or umbilical cord. RESULTS:CCC occurred in 0.1% of all NICU admissions (21 of 19 303) and 0.6% of infants <1000 grams birth weight. Median gestational age of CCC infants was 26 3/7 (range, 23 0/7-40 4/7) weeks. Skin findings were commonly present on the day of birth [median (range): 0 (0-6) days], appearing most frequently as a desquamating, maculopapular, papulopustular, and/or erythematous diffuse rash. When systemic antifungal therapy was started empirically at the time of rash presentation and continued for a median (interquartile range) of 14 (14-15) days, all patients survived and none developed dissemination. Delaying systemic treatment, exclusive use of nystatin, and treating for <10 days was associated with Candida bloodstream dissemination. CONCLUSIONS:CCC is an invasive infection that presents as a diffuse rash in preterm and term infants. Prompt systemic antifungal treatment at the time of skin presentation for ≥14 days prevents dissemination and Candida-related mortality. 10.1093/cid/cix119
    Candidemia in Colombia Cortés Jorge Alberto,Ruiz José Franklin,Melgarejo-Moreno Lizeth Natalia,Lemos Elkin V Biomedica : revista del Instituto Nacional de Salud In Colombia, especially in intensive care units, candidemia is a frequent cause of infection, accounting for 88% of fungal infections in hospitalized patients, with mortality ranging from 36% to 78%. Its incidence in Colombia is higher than that reported in developed countries and even higher than in other Latin American countries. First, the patient’s risk factors should be considered, and then clinical characteristics should be assessed. Finally, microbiological studies are recommended and if the evidence supports its use, molecular testing.In general, American, Latin American, and European guides place the echinocandins as the first-line treatment for candidemia and differ in the use of fluconazole based on evidence, disease severity, previous exposure to azoles, and prevalence of Candida non-albicans. Taking into account the high incidence of this disease in our setting, it should be looked for in patients with risk factors to start a prompt empirical anti-fungal treatment. 10.7705/biomedica.4400
    Clinical characteristics and predictors of mortality in patients with candidemia: a six-year retrospective study. Jia Xiaojiong,Li Congya,Cao Ju,Wu Xianan,Zhang Liping European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 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. 10.1007/s10096-018-3304-9
    ICU-acquired candidaemia in France: Epidemiology and temporal trends, 2004-2013 - A study from the REA-RAISIN network. Baldesi Olivier,Bailly Sébastien,Ruckly Stéphane,Lepape Alain,L'Heriteau François,Aupee Martine,Boussat Sandrine,Bervas Caroline,Machut Anais,Berger-Carbonne Anne,Savey Anne,Timsit Jean François, The Journal of infection OBJECTIVE:Candidaemia is a life-threatening infectious disease, associated with septic shock, multiple organ failure, and a high mortality rate. In France, reported data on the incidence of ICU-acquired candidaemia and the causative Candida species are scarce. The objective of this study was to determine temporal trends in epidemiology and risk factors of intensive care unit-acquired candidaemia (ICU-Cand) and ICU mortality among a very large population of ICU patients. METHOD:Demographics, patient risk factors, invasive device exposure and nosocomial infection in ICU patient were collected from 2004 to 2013 in a national network of 213 ICUs: REA-RAISIN. Incidence and risk factors for candidaemia and ICU mortality were assessed. RESULTS:Out of 246,459 ICU patients, 851 developed an ICU-cand, representing 0.3 per 1000 patients-days. The incidence rose sharply over time. Candida albicans was the main species. The overall and ICU mortality was 52.4% in ICU-cand patients. The main risk factors of ICU-cand were length of stay, severity of illness and antimicrobial therapy at ICU admission, immune status and use of invasive procedure. ICU-cand was an independent risk factor of mortality (OR: 1.53; 95%CI [1.40-1.70]); in a sub-group analysis, independent effects on mortality were observed with C. albicans (OR: 1.45 [1.23-1.71]), Candida tropicalis (OR: 2.11 [1.31-3.39]) and "other" Candida species (OR: 1.64 [1.09-2.45]). CONCLUSION:ICU candidaemia ranked sixth among bloodstream infections, and its average annual incidence was 0.3 per 1000 patients days. Despite of new therapy and international recommendation, the incidence rose sharply during the study period, and ICU mortality remained high. 10.1016/j.jinf.2017.03.011
    A Rapid, Visible, and Highly Sensitive Method for Recognizing and Distinguishing Invasive Fungal Infections via CCP-FRET Technology. Yang Qiong,He Binghong,Chen Chong,Wang Haitao,Li Wanjie,Xue Xiuhua,Qiu Tian,Hao Xiaoran,Lv Fengting,Wang Shu ACS infectious diseases Invasive fungal infection (IFI) is one of the leading causes of death in the intensive care unit (ICU) due to its high morbidity and mortality among immunocompromised patients. Early diagnosis of IFI is typically infeasible because of the lack of clinical signs and symptoms. By virtue of the cationic conjugated polymer-based fluorescence resonance energy transfer (CCP-FRET) technology, we develop a rapid, visible, simple, and sensitive method for simultaneous detection and discrimination of three types of pathogens, including (), (), and (). The CCP-FRET system contains a CCP fluorescent probe and pathogen-specific DNA labeled with fluorescent dyes. These two components spontaneously self-assemble into the complex under electrostatic attraction, resulting in an efficient FRET from CCP to fluorescent dyes when irradiated with a 380 nm ultraviolet (UV) light. The CCP-FRET method can specifically identify the DNA molecules that are extracted from culture pathogen strains or blood samples via PCR and single base extension (SBE) reactions, without any cross-reactions on the DNA of nonspecific strains. In particular, the sensitivity of this method is down to 0.03125 ng, which is ten times higher than that of real-time PCR. We further evaluate its detection efficiency by testing 15 blood samples from neonatal patients who suffer from pathogen infections, in which some of them have undergone antipathogen treatments. Using the CCP-FRET method, 33.3% (5/15) of samples tested positive for and/or infections, whereas no pathogen DNAs are recognized with real-time PCR, despite using the same primers. Interestingly, the CCP-FRET method can output unique fluorescent color as well as RGB patterns to different types of pathogen infections, by which the infection type can be conveniently determined. Collectively, the CCP-FRET method is a sensitive and reliable detection platform for rapid identification of fungal and bacterial multiple infections, holding great promise for uses in clinical testing. 10.1021/acsinfecdis.1c00393
    Usefulness of ß-D-glucan for diagnosis and follow-up of invasive candidiasis in onco-haematological patients. Guitard J,Isnard F,Tabone M-D,Antignac M,Brissot E,Senghor Y,Petit A,Leverger G,Hennequin C The Journal of infection OBJECTIVES:Definitive diagnosis of invasive candidiasis (IC) may be difficult to achieve in patients with haematological malignancy (PHM). We aimed to evaluate the performance of BDG for the diagnosis and the follow-up of IC in PHM. PATIENTS AND METHODS:We retrospectively reviewed the serological data of BDG assay in adult and paediatric PHM, who developed candidemia or chronic disseminated candidiasis (CDC) through a 4-year period. Sensitivity and kinetics of BDG were determined for both clinical forms. RESULTS:In a panel of 3027 PHM, incidence rates of candidemia and CDC ranged between 0.74 and 0.77 and 0.30 and 0.44 according to the group of patients. At the time of diagnosis, 43.5% and 73% of cases of candidemia and CDC had a positive BDG assay, respectively. We found a significant correlation between the level of BDG at diagnosis and the outcome of candidemia (p = 0.022). In all cases of CDC, BDG negative results were obtained 2 to 6 months before recovery of the CT-scan lesions. CONCLUSIONS:BDG exhibits a low sensitivity to detect IC in PHM, but its kinetics correlates the clinical outcome. Additional studies are warranted in patients with CDC to evaluate the interest of monitoring BDG levels to anticipate the discontinuation of antifungal maintenance therapy. 10.1016/j.jinf.2018.01.011
    Performance of Repeated Measures of (1-3)-β-D-Glucan, Mannan Antigen, and Antimannan Antibodies for the Diagnosis of Invasive Candidiasis in ICU Patients: A Preplanned Ancillary Analysis of the EMPIRICUS Randomized Clinical Trial. Dupuis Claire,Le Bihan Clément,Maubon Daniele,Calvet Laure,Ruckly Stéphane,Schwebel Carole,Bouadma Lila,Azoulay Elie,Cornet Muriel,Timsit Jean-Francois, Open forum infectious diseases Background:We aimed to assess the prognostic value of repeated measurements of serum (1-3)-β-D-glucan (BDG), mannan-antigen (mannan-Ag), and antimannan antibodies (antimannan-Ab) for the occurrence of invasive candidiasis (IC) in a high-risk nonimmunocompromised population. Methods:This was a preplanned ancillary analysis of the EMPIRICUS Randomized Clinical Trial, including nonimmunocompromised critically ill patients with intensive care unit-acquired sepsis, multiple colonization, and multiple organ failure who were exposed to broad-spectrum antibacterial agents. BDG (>80 and >250 pg/mL), mannan-Ag (>125 pg/mL), and antimannan-Ab (>10 AU) were collected repeatedly. We used cause-specific hazard models. Biomarkers were assessed at baseline in the whole cohort (cohort 1). Baseline covariates and/or repeated measurements and/or increased biomarkers were then studied in the subgroup of patients who were still alive at day 3 and free of IC (cohort 2). Results:Two hundred thirty-four patients were included, and 215 were still alive and free of IC at day 3. IC developed in 27 patients (11.5%), and day 28 mortality was 29.1%. Finally, BDG >80 pg/mL at inclusion was associated with an increased risk of IC (CSHR[IC], 4.67; 95% CI, 1.61-13.5) but not death (CSHR[death], 1.20; 95% CI, 0.71-2.02). Conclusions:Among high-risk patients, a first measurement of BDG >80 pg/mL was strongly associated with the occurrence of IC. Neither a cutoff of 250 pg/mL nor repeated measurements of fungal biomarkers seemed to be useful to predict the occurrence of IC. The cumulative risk of IC in the placebo group if BDG >80 pg/mL was 25.39%, which calls into question the efficacy of empirical therapy in this subgroup. 10.1093/ofid/ofab080
    Delivery strategies of amphotericin B for invasive fungal infections. Wang Xiaochun,Mohammad Imran Shair,Fan Lifang,Zhao Zongmin,Nurunnabi Md,Sallam Marwa A,Wu Jun,Chen Zhongjian,Yin Lifang,He Wei Acta pharmaceutica Sinica. B Invasive fungal infections (IFIs) represent a growing public concern for clinicians to manage in many medical settings, with substantial associated morbidities and mortalities. Among many current therapeutic options for the treatment of IFIs, amphotericin B (AmB) is the most frequently used drug. AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance. In this review, we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs. We have also discussed the mechanism of actions of AmB, rationale for treating IFIs, and recent advances in formulating AmB for clinical use. Finally, this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs. 10.1016/j.apsb.2021.04.010
    Characteristics and Management of Candidaemia Episodes in an Established Outbreak. Mulet Bayona Juan V,Tormo Palop Nuria,Salvador García Carme,Herrero Rodríguez Paz,Abril López de Medrano Vicente,Ferrer Gómez Carolina,Gimeno Cardona Concepción Antibiotics (Basel, Switzerland) The multi-resistant yeast has become a global public health threat because of its ease to persist and spread in clinical environments, especially in intensive care units. One of the most severe manifestations of invasive candidiasis is candidaemia, whose epidemiology has evolved to more resistant non- species, such as . It is crucial to establish infection control policies in order to control an outbreak due to nosocomial pathogens, including the implementation of screening colonisation studies. We describe here our experience in managing a outbreak lasting more than two and a half years which, despite our efforts in establishing control measures and surveillance, is still ongoing. A total of 287 colonised patients and 47 blood stream infections (candidaemia) have been detected to date. The epidemiology of those patients with candidaemia and the susceptibility of isolates are also reported. Thirty-five patients with candidaemia (74.5%) were also previously colonised. Forty-three patients (91.5%) were hospitalised (61.7%) or had been hospitalised (29.8%) in the ICU before developing candidaemia. Antifungal therapy for candidaemia consisted of echinocandins in monotherapy or in combination with amphotericin B or isavuconazole. The most common underlying disease was abdominal surgery (29.8%). The thirty-day mortality rate was 23.4% and two cases of endophtalmitis due to were found. All isolates were resistant to fluconazole and susceptible to echinocandins and amphotericin B. One isolate became resistant to echinocandins two months after the first isolate. Although there are no established clinical breakpoints, minimum inhibitory concentrations for isavuconazole were low (≤ 1 μg/mL). 10.3390/antibiotics9090558
    Morbidity and mortality of candidaemia in Europe: an epidemiologic meta-analysis. Koehler P,Stecher M,Cornely O A,Koehler D,Vehreschild M J G T,Bohlius J,Wisplinghoff H,Vehreschild J J Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases OBJECTIVES:Candidaemia is a serious hazard to hospitalized patients, but European epidemiological data are restricted to national studies focusing on Northern Europe, population-based surveillance programmes or studies conducted in distinct local areas. The aim was to provide current data on the overall burden and epidemiological development of candidaemia in Europe. METHODS:A Web of Knowledge™ search was carried out from January 2000 to February 2019. Appropriate data were collected on total cases, study duration, incidence, species distribution and/or mortality rates. Meta-analysis was performed to pool individual studies. Heterogeneity was examined using the I statistic. Calculations of pooled incidence and mortality rates, subgroup analysis by geographical origin, study period and scenarios were carried out. Daily candidaemia incidence and mortality rates in Europe were extrapolated. Systematic review and meta-analysis were used to determine incidence and mortality of candidaemia in the UN European region. Complete datasets were categorized into population-based and hospital-based epidemiological studies and were analysed separately. Subgroup analyses were performed for geographic distributions and time-dependent developments. RESULTS:In population-based studies, 43 799 cases of candidaemia were diagnosed in 1 885 271 885 person-years, revealing an overall pooled incidence rate of 3.88/100 000. The highest pooled incidence rate was observed in intensive care units (5.5/1000 admissions, Day 30 mortality rate 37%), followed by tertiary care centres (0.96/1000 admissions, pooled Day 30 mortality rate 38%) and the mixed group of teaching and general hospitals (0.52/1000 admissions, pooled Day 30 mortality rate 37%). European incidence of candidaemia was extrapolated to approximately 79 cases per day, of which an estimated 29 patients might have fatal outcome at Day 30. CONCLUSIONS:Pooled incidence rates, species distribution and outcome of candidaemia differ considerably between clinical groups, European regions and over time. We observed an increasing overall pooled incidence rate of candidaemia and a higher proportion of Candida spp. other than C. albicans in the current decade in population-based data. 10.1016/j.cmi.2019.04.024
    In vitro synergy of isavuconazole in combination with colistin against Candida auris. Schwarz Patrick,Bidaud Anne-Laure,Dannaoui Eric Scientific reports The in vitro interactions of isavuconazole with colistin were evaluated against 15 clinical Candida auris isolates by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing and by agar diffusion using isavuconazole gradient concentration strips with or without colistin incorporated RPMI agar. Interpretation of the checkerboard results was done by the fractional inhibitory concentration index and by response surface analysis based on the Bliss model. By checkerboard, combination was synergistic for 93% of the isolates when interpretation of the data was done by fractional inhibitory concentration index, and for 80% of the isolates by response surface analysis interpretation. By agar diffusion test, although all MICs in combination decreased compared to isavuconazole alone, only 13% of the isolates met the definition of synergy. Essential agreement of EUCAST and gradient concentration strip MICs at +/- 2 log dilutions was 93.3%. Antagonistic interactions were never observed for any technique or interpretation model used. 10.1038/s41598-020-78588-5
    Molecular Characterization of by Microsatellite Typing and Emergence of Clonal Antifungal Drug Resistant Strains in a Multicenter Surveillance in China. Zhang Li,Yu Shu-Ying,Chen Sharon C-A,Xiao Meng,Kong Fanrong,Wang He,Ning Ya-Ting,Lu Min-Ya,Sun Tian-Shu,Hou Xin,Zhou Meng-Lan,Kang Wei,Zhang Ge,Duan Si-Meng,Xu Ying-Chun Frontiers in microbiology is an important species causing invasive candidiasis (IC) in China. The present survey was a national multicenter study of the molecular epidemiology and antifungal susceptibility profiles of . Non-duplicate isolates were collected from 10 hospitals across China in the CHIF-NET program 2016-2017. Isolates were genotyped using four highly polymorphic microsatellite markers, and susceptibility profiles determined using Sensititre YeastOne YO10. A total of 319 from separate patients with IC were studied; 49.2, 17.9, and 10.3% isolates were from patients in surgical departments, general intensive care units (ICUs) and neonatal ICUs (NICU), respectively. showed good susceptibility to nine antifungal drugs. Microsatellite analysis identified 122 microsatellite (MT) types. Most MT types had sporadic distribution. However, we identified 32 clusters across 10 hospitals; seven clusters were caused by seven endemic genotypes involving five or more isolates in hospitals designated as H01, H02, H06, and H10. These clusters mainly affected surgical departments and ICUs, except for genotype MT42 which was seen in 22 patients from NICU (hospital H06). Of 16 fluconazole-resistant isolates, seven from hospital H02 shared the same genotype MT70, and three from hospital H04 were of genotype MT47. For 37 isolates with non-wild type MICs to 5-flucytosine, 29 were from hospital H01 (genotype MT48). Here we present the first nationwide molecular epidemiology study of in China, identified several previously unrecognized clusters, which included antifungal drug resistant isolates. These findings provide important data for control of IC in China. 10.3389/fmicb.2020.01320
    Association of Immune Cell Subtypes and Phenotype With Subsequent Invasive Candidiasis in Patients With Abdominal Sepsis. Arens Christoph,Kramm Timo,Decker Sebastian,Spannenberger Jens,Brenner Thorsten,Richter Daniel Christoph,Weigand Markus Alexander,Uhle Florian,Lichtenstern Christoph Shock (Augusta, Ga.) BACKGROUND:In nonneutropenic intensive care unit (ICU) patients, current risk stratification scores lack specificity to reliably predict the risk of a prospective invasive candidiasis (IC). We aimed to explore possible associations of distinct immunological markers with different degrees of Candida affection in patients with abdominal sepsis. METHODS:The presented explorative, noninterventional diagnosis study recruited patients admitted to the surgical ICU at Heidelberg University Hospital with abdominal sepsis. Over 5 days, we determined white blood cell count, 1,3-β-D-glucan, and HLA-DR expression; the amount of Th1, Th17, regulatory T, T helper, and cytotoxic T cells; Dectin-1 and TLR2-expression; the amount of T, B, and NK cells; the ex vivo secretion of IL-8 upon stimulation with LPS, flagellin, and zymosan; and the distribution of distinct T-cell cytokines in a daily manner. On day 21, patients' Candida infection status was stratified in no colonization or IC, colonization or IC. RESULTS:A total of 26 patients were included. On day 21, five patients showed no colonization or IC, in 13 patients a colonization was detected, and eight patients were diagnosed with IC. On study inclusion, the stratification groups showed comparable values in standard laboratory parameters and morbidity scores. Decreased B and NK cell counts, as well as reduced IL-8 secretion after ex vivo stimulation with LPS or flagellin seemed to be associated with a higher risk of subsequent Candida colonization. Even lower values could distinguish the therapy-relevant difference between prospective IC from colonization alone. CONCLUSIONS:We were able to show distinct immune system impairments in early abdominal sepsis by specific immune-based measurements. A possible association of these impairments with a subsequent Candida affection is shown. 10.1097/SHK.0000000000001251
    Impact of mTOR signaling pathway on CD8+ T cell immunity through Eomesodermin in response to invasive candidiasis. Zhang Jiahui,Cui Na,Wang Hao,Han Wen,Bai Guangxu,Cheng Wei Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi BACKGROUND:We investigated the effect of the mammalian target of rapamycin (mTOR) pathway on CD8+ T cell immunity through Eomesodermin (Eomes) in intensive care unit (ICU) patients with invasive candidiasis (IC) and in a mouse model. METHODS:We evaluated quantitative changes in parameters of the mTOR/phosphorylated ribosomal S6 kinase (pS6K) pathway and immune system at the onset of infection in ICU patients. The study was registered on 28 February 2017 at chictr.org.cn (ChiCTR-ROC-17010750). We also used a mouse model of Candida infection and constructed T-cell-specific mTOR and T-cell-specific tuberous sclerosis complex (TSC) 1 conditional knockout mice to elucidate the molecular mechanisms. RESULTS:We enrolled 88 patients, including 8 with IC. The IC group had lower CD8+ T cell counts, higher serum levels of mTOR, pS6K, Eomes and interleukin (IL)-6. The mouse model with IC showed results consistent in the clinical study. The CD8+ T cell immune response to IC seemed to be weakened in TSC1 knockout mice compared with wild-type IC mice, demonstrating that mTOR activation resulted in the impaired CD8+ T cell immunity in IC. CONCLUSIONS:In IC, the mTOR activation may play a vital role in impaired CD8+ T cell immunity through enhancing expression of Eomes. The study was registered on 28 February 2017 at chictr.org.cn (identifier ChiCTR-ROC-17010750). 10.1016/j.jmii.2021.03.021
    (1→3)-β-D-glucan testing for the detection of invasive fungal infections in immunocompromised or critically ill people. White Sandra K,Schmidt Robert L,Walker Brandon S,Hanson Kimberly E The Cochrane database of systematic reviews BACKGROUND:Invasive fungal infections (IFIs) are life-threatening opportunistic infections that occur in immunocompromised or critically ill people. Early detection and treatment of IFIs is essential to reduce morbidity and mortality in these populations. (1→3)-β-D-glucan (BDG) is a component of the fungal cell wall that can be detected in the serum of infected individuals. The serum BDG test is a way to quickly detect these infections and initiate treatment before they become life-threatening. Five different versions of the BDG test are commercially available: Fungitell, Glucatell, Wako, Fungitec-G, and Dynamiker Fungus. OBJECTIVES:To compare the diagnostic accuracy of commercially available tests for serum BDG to detect selected invasive fungal infections (IFIs) among immunocompromised or critically ill people. SEARCH METHODS:We searched MEDLINE (via Ovid) and Embase (via Ovid) up to 26 June 2019. We used SCOPUS to perform a forward and backward citation search of relevant articles. We placed no restriction on language or study design. SELECTION CRITERIA:We included all references published on or after 1995, which is when the first commercial BDG assays became available. We considered published, peer-reviewed studies on the diagnostic test accuracy of BDG for diagnosis of fungal infections in immunocompromised people or people in intensive care that used the European Organization for Research and Treatment of Cancer (EORTC) criteria or equivalent as a reference standard. We considered all study designs (case-control, prospective consecutive cohort, and retrospective cohort studies). We excluded case studies and studies with fewer than ten participants. We also excluded animal and laboratory studies. We excluded meeting abstracts because they provided insufficient information. DATA COLLECTION AND ANALYSIS:We followed the standard procedures outlined in the Cochrane Handbook for Diagnostic Test Accuracy Reviews. Two review authors independently screened studies, extracted data, and performed a quality assessment for each study. For each study, we created a 2 × 2 matrix and calculated sensitivity and specificity, as well as a 95% confidence interval (CI). We evaluated the quality of included studies using the Quality Assessment of Studies of Diagnostic Accuracy-Revised (QUADAS-2). We were unable to perform a meta-analysis due to considerable variation between studies, with the exception of Candida, so we have provided descriptive statistics such as receiver operating characteristics (ROCs) and forest plots by test brand to show variation in study results. MAIN RESULTS:We included in the review 49 studies with a total of 6244 participants. About half of these studies (24/49; 49%) were conducted with people who had cancer or hematologic malignancies. Most studies (36/49; 73%) focused on the Fungitell BDG test. This was followed by Glucatell (5 studies; 10%), Wako (3 studies; 6%), Fungitec-G (3 studies; 6%), and Dynamiker (2 studies; 4%). About three-quarters of studies (79%) utilized either a prospective or a retrospective consecutive study design; the remainder used a case-control design. Based on the manufacturer's recommended cut-off levels for the Fungitell test, sensitivity ranged from 27% to 100%, and specificity from 0% to 100%. For the Glucatell assay, sensitivity ranged from 50% to 92%, and specificity ranged from 41% to 94%. Limited studies have used the Dynamiker, Wako, and Fungitec-G assays, but individual sensitivities and specificities ranged from 50% to 88%, and from 60% to 100%, respectively. Results show considerable differences between studies, even by manufacturer, which prevented a formal meta-analysis. Most studies (32/49; 65%) had no reported high risk of bias in any of the QUADAS-2 domains. The QUADAS-2 domains that had higher risk of bias included participant selection and flow and timing. AUTHORS' CONCLUSIONS:We noted considerable heterogeneity between studies, and these differences precluded a formal meta-analysis. Because of wide variation in the results, it is not possible to estimate the diagnostic accuracy of the BDG test in specific settings. Future studies estimating the accuracy of BDG tests should be linked to the way the test is used in clinical practice and should clearly describe the sampling protocol and the relationship of time of testing to time of diagnosis. 10.1002/14651858.CD009833.pub2
    Evaluation of the updated " score" with Sepsis 3.0 criteria in critically ill patients. Annals of translational medicine BACKGROUND:The score proposed in 2009 was calculated on the definition of "severe sepsis", which was removed in the Sepsis 3.0 definition. This study investigated the clinical relevance of score with the updated Sepsis 3.0 definition (CS-3.0) instead of severe sepsis (CS-2009) in the new admitted critically ill patients. METHODS:We performed a retrospective analysis on a single center public database. All patients with ICU stay ≥72 hours were included in this study. The score was calculated based on the data collected on ICU admission. The incidence of invasive candidiasis was determined and its relationship with the CS-2009 and CS-3.0 was studied. RESULTS:A total of 17,666 patients were identified after screening 58,976 hospital admissions, and 436 cases (2.5%) were diagnosed with invasive candidiasis. In the infection group, the number of patients who met the Sepsis 3.0 criteria was greater than the number of patients with severe sepsis (81.2% 78.4%, P<0.005). The area under curve of the CS-2009 was 0.789 (95% CI: 0.765-0.813) and the CS-3.0 was 0.804 (95% CI: 0.782-0.827). CONCLUSIONS:Our study confirmed the clinical relevance and comparative superiority of the updated score model, using the Sepsis 3.0 definition, compared with the classic sepsis/severe sepsis model, in assessment of critically ill patients. Considering the clinical importance of organ dysfunction in ICI, the Sepsis 3.0 should be used as the basis for prediction of invasive candidiasis. 10.21037/atm-20-995
    Clinical characteristics and predictors of mortality in cirrhotic patients with candidemia and intra-abdominal candidiasis: a multicenter study. Bassetti Matteo,Peghin Maddalena,Carnelutti Alessia,Righi Elda,Merelli Maria,Ansaldi Filippo,Trucchi Cecilia,Alicino Cristiano,Sartor Assunta,Toniutto Pierluigi,Wauters Joost,Laleman Wim,Tascini Carlo,Menichetti Francesco,Luzzati Roberto,Brugnaro Pierluigi,Mesini Alessio,Raviolo Stefania,De Rosa Francesco G,Lagunes Leonel,Rello Jordi,Dimopoulos George,Colombo Arnaldo L,Nucci Marcio,Vena Antonio,Bouza Emilio,Muñoz Patricia,Tumbarello Mario,Losito Raffaella,Martin-Loeches Ignacio,Viscoli Claudio Intensive care medicine PURPOSE:The aim of the study was to describe the characteristics of cirrhotic patients with candidemia and intra-abdominal candidiasis (IAC) and to evaluate the risk factors associated with 30-day mortality. METHODS:A multicenter multinational retrospective study including all consecutive episodes of candidemia and IAC in adult patients with liver cirrhosis in 14 European hospitals during the period 2011-2013 was performed. RESULTS:A total of 241 episodes (169 candidemia, 72 IAC) were included. Most Candida infections were acquired in hospital (208, 86.3%), mainly in the intensive care unit (ICU) (121, 50.2%). At clinical presentation, fever was seen in 60.6% of episodes (146/241) and septic shock in 34.9% (84/241). C. albicans was the most common species (found in 131 episodes, 54.4%), followed by C. glabrata (35, 14.5%) and C. parapsilosis (34, 14.1%). Overall, the 30-day mortality was 35.3%. Multivariable analysis identified candidemia (OR 2.2, 95% CI 1.2-4.5) and septic shock (OR 3.2, 95% CI 1.7-6) as independent factors associated with 30-day mortality. Adequate antifungal treatment (OR 0.4, 95% CI 0.3-0.9) was associated with survival benefit. CONCLUSIONS:A shift towards increasing prevalence of C. glabrata and C. parapsilosis species in patients with liver disease was documented. Candidemia and IAC were associated with significant mortality in cirrhotic patients. Thirty-day mortality was associated with candidemia and severe clinical presentation, whereas adequate antifungal treatment improved the prognosis. 10.1007/s00134-017-4717-0
    Fungal infections in adult patients on extracorporeal life support. Cavayas Yiorgos Alexandros,Yusuff Hakeem,Porter Richard Critical care (London, England) BACKGROUND:Patients on extracorporeal membrane oxygenation (ECMO) are often among the most severely ill in the intensive care unit. They are often receiving broad-spectrum antibiotics; they have multiple entry points for pathogens; and their immune system is impaired by blood circuit interaction. These factors are thought to predispose them to fungal infections. We thus aimed to evaluate the prevalence, risk factors, and prognosis of fungal infections in adults on ECMO. METHODS:We conducted a retrospective cohort study using the Extracorporeal Life Support Organization registry, which compiles data on ECMO use from hundreds of international centers. We included all adult patients from 2006 to 2016 on any mode of ECMO with either a diagnosis of fungal infection or a positive fungal culture. RESULTS:Our study comprised 2129 adult patients (10.8%) with fungal colonization or infection. Aspergillus involvement (colonization or infection) was present in 272 patients (1.4%), of whom 35.7% survived to hospital discharge. There were 245 patients (1.2%) with Candida invasive bloodstream infection, with 35.9% survival. Risk factors for Aspergillus involvement included solid organ transplant (OR 1.83; p = 0.008), respiratory support (OR 2.75; p < 0.001), and influenza infection (OR 2.48; p < 0.001). Risk factors for candidemia included sepsis (OR 1.60; p = 0.005) and renal replacement therapy (OR 1.55; p = 0.007). In multivariable analysis, Aspergillus involvement (OR 0.40; p < 0.001) and candidemia (OR 0.47; p < 0.001) were both independently associated with decreased survival. CONCLUSIONS:The prevalence of Aspergillus involvement and Candida invasive bloodstream infection were not higher in patients on ECMO than what has been reported in the general intensive care population. Both were independently associated with a reduced survival. Aspergillus involvement was strongly associated with ECMO for respiratory support and influenza. 10.1186/s13054-018-2023-z
    What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead. Bassetti Matteo,Righi Elda,Montravers Philippe,Cornely Oliver A The Journal of antimicrobial chemotherapy The treatment of invasive candidiasis has changed greatly in the past decade and must continue to evolve if we are to improve outcomes in this serious infection. A review of recent history may provide insights for the future. The morbidity and mortality of invasive candidiasis remain difficult to measure despite an obvious clinical burden. Current treatment guidelines now recommend echinocandins as first-line empirical treatment, with fluconazole as an acceptable alternative for selected patients, reflecting the efficacy demonstrated by echinocandins and increasing resistance observed with fluconazole. The selection of antifungal therapy now must consider not only resistance but also the shift in predominance from Candida albicans to non-albicans species, notably Candida glabrata. The recent emergence of Candida auris has been met with great interest, although the longer-term implications of this phenomenon remain unclear. The broad goal of treatment continues to be administration of safe, efficacious antifungal therapy as soon as possible. Diagnostic methods beyond traditional blood culture present an opportunity to shorten the time to an accurate diagnosis, and earlier treatment initiation based on prophylactic and empirical or pre-emptive strategies seeks to ensure timely therapeutic intervention. In addition, there are novel agents in the antifungal pipeline. These developments, as well as ongoing studies of dosing, toxicity and resistance development, are important items on the current research agenda and may play a role in future changes to the treatment of invasive candidiasis. 10.1093/jac/dkx445
    Hospital outbreak of fluconazole-resistant : arguments for clonal transmission and long-term persistence. Fekkar Arnaud,Blaize Marion,Bouglé Adrien,Normand Anne-Cécile,Raoelina Audrey,Kornblum Dimitri,Kamus Laure,Piarroux Renaud,Imbert Sébastien Antimicrobial agents and chemotherapy The worldwide emergence of multidrug-resistant pathogenic fungi is a threat to human health. At this very moment, an emergence of isolates harbouring a resistance to fluconazole, one of the most popular antifungal drugs, is being described in several countries. We seek to better understanding the epidemiology, pathogenicity and transmission of resistant Faced with an outbreak of invasive infections due to resistant isolates of , we performed a 7-year retrospective and prospective analysis of 283 isolates collected in 240 patients, among who 111 had invasive candidiasis. Study included review of hospital records, genotyping analysis and susceptibility testing that allow determining the type and outcome of infections, as well as the spatial and temporal spread of clusters. Overall the incidence of azole resistance was 7.5%. Genotyping analysis unveiled several previously undetected outbreaks and clonal spread of susceptible and resistant isolates over a long period of time. In comparison with susceptible isolates, resistant ones have a more restricted genetic diversity and seem to be more likely to spread and more frequently associated with invasive infections. In intensive care units, patients with invasive infections due to resistant isolates had poorer outcome (overall mortality at day 30 of 40%; 4/10) than susceptible ones (overall mortality at day 30 of 26.5%; 9/34). Our results suggest that the propensity of to spread on an epidemic fashion is underestimated, which warrants reinforced control and epidemiological survey of this species. 10.1128/AAC.02036-20
    Conventional amphotericin B must be avoided in Candida infections. Martin-Loeches I,De Waele J J,Timsit J F,Bassetti M Intensive care medicine 10.1007/s00134-019-05784-x
    The Epidemiology and Susceptibility of Candidemia in Jerusalem, Israel. Israel Sarah,Amit Sharon,Israel Ariel,Livneh Ayalah,Nir-Paz Ran,Korem Maya Frontiers in cellular and infection microbiology Invasive infections pose a major public health problem worldwide and is a major cause of nosocomial bloodstream infection. Our aim was to assess dynamics in incidence, species distribution and antifungal susceptibility of candidemia episodes in Jerusalem, to better understand the epidemiology of invasive isolates and to better direct therapy. We analyzed the incidence dynamics, species distribution and susceptibility pattern of 899 candidemia episodes during 2005-2016 in Jerusalem. The overall incidence of candidemia was relatively low of 0.62 per 1,000 admissions. was the leading pathogen (39.4%); however, there was a shift toward non- species, with predominating among them (40%). As expected, more than one-third of candidemias occurred in intensive care units. However, the distribution between species varied and was the leading pathogen in hematology-oncology patients. The susceptibility of isolates to antifungals remained stable throughout the years. Only a minority of isolates were non-susceptible to fluconazole (3.3%), however, an unexpectedly high resistance rate (37.8%) was observed in isolates. We found an alarming rate of caspofungin resistance in (33.6%) and (67%); this may reflect misclassification of resistance by the -test method. This is the first comprehensive candidemia analysis in the Jerusalem area that should serve as a basis for decision-making regarding appropriate antifungal treatment in the hospital setting. The exceptional high resistance rate amongst emphasizes the importance of antifungal susceptibility monitoring in medical centers serving large urban areas to better direct appropriate treatment. 10.3389/fcimb.2019.00352
    Factors determining the mortality in cirrhosis patients with invasive candidiasis: A systematic review and meta-analysis. Medical mycology The impact of invasive candidiasis (IC) on the outcomes in the non-conventional high-risk cirrhosis population is poorly characterized. Therefore, we reviewed the outcomes and their influencing factors in cirrhosis patients with IC. PubMed, Embase, Ovid, CINHAL, and Web of Science were searched for full-text observational studies describing mortality due to IC in cirrhosis. We did a systematic review and random-effects meta-analysis to pool the point-estimate and comparative-odds of mortality. The estimate's heterogeneity was explored on sub-groups, outliers-test, and meta-regression. We evaluated the asymmetry in estimates on funnel plot and Eggers regression. Quality of studies was assessed on the New-Castle Ottawa scale. Of 3143 articles, 13 studies (611 patients) were included (good/fair quality: 6/7). IC patients were sick with a high model for end-stage liver disease (MELD: 27.0) and long hospital stay (33.2 days). The pooled-mortality was 54.7% (95% CI: 41.3--67.5), I2: 80%, P < 0.01. Intensive care unit (ICU) admission (P < 0.001), site of infection; viz. peritonitis and candidemia (P = 0.014) and high MELD of cases (P = 0.029) were predictors of high mortality. The odds of mortality due to IC was 4.4 times higher than controls and was 8.5 and 3.3 times higher than non-infected, and bacterially-infected controls. Studies in ICU-admitted (OR: 5.0) or acute-on-chronic liver failure (ACLF, OR: 6.3) patients had numerically higher odds of mortality than all-hospitalized cirrhosis patients (OR: 4.0). In conclusion, substantially high mortality is reported in cirrhosis patients with IC. ICU admission, ACLF, high MELD, peritonitis, and candidemia are key factors determining high mortality in cirrhosis patients with IC. LAY SUMMARY:We report a high mortality rate of 55% in patients with liver cirrhosis and invasive candidiasis. Higher odds (4.4 times) of death, especially in patients with ACLF (6.3 times) or ICU admission (5.0 times) were seen. Candida peritonitis and candidemia are associated with high mortality in cirrhosis. HIGHLIGHTS: 10.1093/mmy/myab069
    Continual Decline in Azole Susceptibility Rates in Over a 9-Year Period in China. Frontiers in microbiology BACKGROUND:There have been reports of increasing azole resistance in , especially in the Asia-Pacific region. Here we report on the epidemiology and antifungal susceptibility of causing invasive candidiasis in China, from a 9-year surveillance study. METHODS:From August 2009 to July 2018, isolates ( = 3702) were collected from 87 hospitals across China. Species identification was carried out by mass spectrometry or rDNA sequencing. Antifungal susceptibility was determined by Clinical and Laboratory Standards Institute disk diffusion (CHIF-NET10-14, = 1510) or Sensititre YeastOne (CHIF-NET15-18, = 2192) methods. RESULTS:Overall, 22.2% (823/3702) of the isolates were resistant to fluconazole, with 90.4% (744/823) being cross-resistant to voriconazole. In addition, 16.9 (370/2192) and 71.7% (1572/2192) of the isolates were of non-wild-type phenotype to itraconazole and posaconazole, respectively. Over the 9 years of surveillance, the fluconazole resistance rate continued to increase, rising from 5.7 (7/122) to 31.8% (236/741), while that for voriconazole was almost the same, rising from 5.7 (7/122) to 29.1% (216/741), with no significant statistical differences across the geographic regions. However, significant difference in fluconazole resistance rate was noted between isolates cultured from blood (27.2%, 489/1799) and those from non-blood (17.6%, 334/1903) specimens (-value < 0.05), and amongst isolates collected from medical wards (28.1%, 312/1110) versus intensive care units (19.6%, 214/1092) and surgical wards (17.9%, 194/1086) (Bonferroni adjusted -value < 0.05). Although echinocandin resistance remained low (0.8%, 18/2192) during the surveillance period, it was observed in most administrative regions, and one-third (6/18) of these isolates were simultaneously resistant to fluconazole. CONCLUSION:The continual decrease in the rate of azole susceptibility among strains has become a nationwide challenge in China, and the emergence of multi-drug resistance could pose further threats. These phenomena call for effective efforts in future interventions. 10.3389/fmicb.2021.702839
    Pathogenic Effects of IFIT2 and Interferon-β during Fatal Systemic Candida albicans Infection. Stawowczyk Marcin,Naseem Shamoon,Montoya Valeria,Baker Darren P,Konopka James,Reich Nancy C mBio A balanced immune response to infection is essential to prevent the pathology and tissue damage that can occur from an unregulated or hyperactive host defense. Interferons (IFNs) are critical mediators of the innate defense to infection, and in this study we evaluated the contribution of a specific gene coding for IFIT2 induced by type I IFNs in a murine model of disseminated Invasive candidiasis is a frequent challenge during immunosuppression or surgical medical interventions, and is a common culprit that leads to high rates of mortality. When IFIT2 knockout mice were infected systemically with , they were found to have improved survival and reduced fungal burden compared to wild-type mice. One of the mechanisms by which IFIT2 increases the pathological effects of invasive appears to be suppression of NADPH oxidase activation. Loss of IFIT2 increases production of reactive oxygen species by leukocytes, and we demonstrate that IFIT2 is a binding partner of a critical regulatory subunit of NADPH oxidase, p67 Since the administration of IFN has been used therapeutically to combat viral infections, cancer, and multiple sclerosis, we evaluated administration of IFN-β to mice prior to infection. IFN-β treatment promoted pathology and death from infection. We provide evidence that IFIT2 increases the pathological effects of invasive and that administration of IFN-β has deleterious effects during infection. The attributable mortality associated with systemic infections in health care settings is significant, with estimates greater than 40%. This life-threatening disease is common in patients with weakened immune systems, either due to disease or as a result of therapies. Type I interferons (IFN) are cytokines of the innate defense response that are used as immune modulators in the treatment of specific cancers, viral infections, and multiple sclerosis. In this study, we show using a murine model that the loss of a specific IFN-stimulated gene coding for IFIT2 improves survival following systemic infection. This result infers a harmful effect of IFN during infection and is supported by our finding that administration of IFN-β prior to invasive infection promotes fatal pathology. The findings contribute to our understanding of the innate immune response to , and they suggest that IFN therapies present a risk factor for disseminated candidiasis. 10.1128/mBio.00365-18
    De-escalation of antifungal treatment in critically ill patients with suspected invasive Candida infection: incidence, associated factors, and safety. Jaffal Karim,Poissy Julien,Rouze Anahita,Preau Sébastien,Sendid Boualem,Cornu Marjorie,Nseir Saad Annals of intensive care BACKGROUND:Antifungal treatment is common in critically ill patients, but only a small proportion of patients receiving antifungals have a proven fungal infection. However, antifungal treatment has side effects such as toxicity, emergence of resistance, and high cost. Moreover, empirical antifungal treatment is still a matter for debate in these patients. Our study aimed to determine the incidence, associated factors, and safety of de-escalation of antifungals in critically ill patients. METHODS:This retrospective study was conducted in a 30-bed mixed ICU, from January 2012 through January 2013. Patients hospitalized for > 5 days and treated with antifungals for first suspected or proven invasive Candida infection were included. Exclusion criteria were prophylactic antifungals, suspected invasive aspergillosis, and neutropenia. De-escalation was defined as switch from initial systemic antifungals (except fluconazole) to triazoles, or stopping initial drugs within the 5 days following their initiation. RESULTS:One hundred and ninety patients were included. Antifungal treatment was empirical, preemptive, and targeted in 55, 27, and 24% of study patients, respectively. Caspofungin (53%), fluconazole (43%), voriconazole (4%), and liposomal amphotericin B (0.5%) were the more frequently used antifungals. De-escalation was performed in 38 (20%) patients. Invasive mechanical ventilation was independently associated with lower rates of de-escalation (OR 0.25 [95% CI 0.08-0.85], p = 0.013). Total duration of antifungal treatment was significantly shorter in patients with de-escalation, compared with those with no de-escalation (med [IQR] 6 (5, 18) vs. 13 days (7, 25), p = 0.023). No significant difference was found in duration of mechanical ventilation (22 [5-31] vs. 20 days [10-35], p = 0.43), length of ICU stay (25 [14-40) vs. 25 days [11-40], p = 0.99), ICU mortality (45 vs. 59%, p = 0.13), or 1-year mortality (55 vs. 64%, p = 0.33) between patients with de-escalation and those with no de-escalation, respectively. CONCLUSIONS:De-escalation was performed in 20% of patients receiving systemic antifungals for suspected or proven invasive Candida infection. Mechanical ventilation was independently associated with lower rates of de-escalation. De-escalation of antifungal treatment seems to be safe in critically ill patients. 10.1186/s13613-018-0392-8
    Candida: Platelet Interaction and Platelet Activity in vitro. Eberl Claudia,Speth Cornelia,Jacobsen Ilse D,Hermann Martin,Hagleitner Magdalena,Deshmukh Hemalata,Ammann Christoph G,Lass-Flörl Cornelia,Rambach Günter Journal of innate immunity Over the last 2 decades, platelets have been recognized as versatile players of innate immunity. The interaction of platelets with fungal pathogens and subsequent processes may critically influence the clinical outcome of invasive mycoses. Since the role of platelets in Candida infections is poorly characterized and controversially discussed, we studied interactions of human platelets with yeast cells, (pseudo-)hyphae, biofilms and secretory products of human pathogenic Candida species applying platelet rich plasma and a whole blood model. Incubation of Candida with platelets resulted in moderate mutual interaction with some variation between different species. The rate of platelets binding to -Candida (pseudo-) hyphae and candidal biofilm was comparably low as that to the yeast form. Candida-derived secretory products did not affect platelet activity - neither stimulatory nor inhibitory. The small subset of platelets that bound to Candida morphotypes was consequently activated. However, this did not result in reduced growth or viability of the different Candida species. A whole blood model simulating in vivo conditions confirmed platelet activation in the subpopulation of Candida-bound platelets. Thus, the inability of platelets to efficiently react on Candida presence might favor fungal survival in the blood and contribute to high morbidity of Candida sepsis. 10.1159/000491030
    Investigation of Candida parapsilosis virulence regulatory factors during host-pathogen interaction. Tóth Renáta,Cabral Vitor,Thuer Ernst,Bohner Flóra,Németh Tibor,Papp Csaba,Nimrichter Leonardo,Molnár Gergő,Vágvölgyi Csaba,Gabaldón Toni,Nosanchuk Joshua D,Gácser Attila Scientific reports Invasive candidiasis is among the most life-threatening infections in patients in intensive care units. Although Candida albicans is the leading cause of candidaemia, the incidence of Candida parapsilosis infections is also rising, particularly among the neonates. Due to differences in their biology, these species employ different antifungal resistance and virulence mechanisms and also induce dissimilar immune responses. Previously, it has been suggested that core virulence effecting transcription regulators could be attractive ligands for future antifungal drugs. Although the virulence regulatory mechanisms of C. albicans are well studied, less is known about similar mechanisms in C. parapsilosis. In order to search for potential targets for future antifungal drugs against this species, we analyzed the fungal transcriptome during host-pathogen interaction using an in vitro infection model. Selected genes with high expression levels were further examined through their respective null mutant strains, under conditions that mimic the host environment or influence pathogenicity. As a result, we identified several mutants with relevant pathogenicity affecting phenotypes. During the study we highlight three potentially tractable signaling regulators that influence C. parapsilosis pathogenicity in distinct mechanisms. During infection, CPAR2_100540 is responsible for nutrient acquisition, CPAR2_200390 for cell wall assembly and morphology switching and CPAR2_303700 for fungal viability. 10.1038/s41598-018-19453-4
    Impact of echinocandin on prognosis of proven invasive candidiasis in ICU: A post-hoc causal inference model using the AmarCAND2 study. Bailly Sébastien,Leroy Olivier,Azoulay Elie,Montravers Philippe,Constantin Jean-Michel,Dupont Hervé,Guillemot Didier,Lortholary Olivier,Mira Jean-Paul,Perrigault Pierre-François,Gangneux Jean-Pierre,Timsit Jean-François, The Journal of infection OBJECTIVE:guidelines recommend first-line systemic antifungal therapy (SAT) with echinocandins in invasive candidiasis (IC), especially in critically ill patients. This study aimed at assessing the impact of echinocandins compared to azoles as initial SAT on the 28-day prognosis in adult ICU patients. METHODS:From the prospective multicenter AmarCAND2 cohort (835 patients), we selected those with documented IC and treated with echinocandins (ECH) or azoles (AZO). The average causal effect of echinocandins on 28-day mortality was assessed using an inverse probability of treatment weight (IPTW) estimator. RESULTS:397 patients were selected, treated with echinocandins (242 patients, 61%) or azoles (155 patients, 39%); septic shock: 179 patients (45%). The median SAPSII was higher in the ECH group (48 [35; 62] vs. 43 [31; 58], p = 0.01). Crude mortality was 34% (ECH group) vs. 25% (AZO group). After adjustment on baseline confounders, no significant association emerged between initial SAT with echinocandins and 28-day mortality (HR: 0.95; 95% CI: [0.60; 1.49]; p = 0.82). However, echinocandin tended to benefit patients with septic shock (HR: 0.46 [0.19; 1.07]; p = 0.07). CONCLUSION:Patients who received echinocandins were more severely ill. Echinocandin use was associated with a non-significant 7% decrease of 28-day mortality and a trend to a beneficial effect for patient with septic shock. 10.1016/j.jinf.2016.12.016
    Recognition and diagnosis of invasive fungal infections in neonates. Calley Joanne L,Warris Adilia The Journal of infection Fungal infections largely caused by Candida species are responsible for a significant disease burden in neonates and invasive candidiasis in hospitalised neonates has high associated morbidity and mortality. Early initiation of antifungal treatment improves outcome but the recognition and diagnosis of systemic fungal infection in this population is difficult due to the non-specific clinical presentation and the high false negative rate of cultures. There is a need for a practical, sensitive and rapid diagnostic test to enhance identification and early treatment. Serum detection of (1,3)-β-d-glucan and Candida PCR are promising candidates but at present limited data exists for their use in the neonatal intensive care setting. Until such investigations are validated, early initiation of antifungal treatment on the basis of risk factor profile and clinical features remains the safest practical approach. 10.1016/S0163-4453(17)30200-1
    Use of T2MR in invasive candidiasis with and without candidemia. Zacharioudakis Ioannis M,Zervou Fainareti N,Mylonakis Eleftherios Future microbiology The mortality associated with invasive candidiasis remains unacceptably high. The T2 magnetic resonance (T2MR) assay is a novel US FDA-approved molecular diagnostic assay for the diagnosis of candidemia that can rapidly detect the five most commonly isolated Candida spp. In clinical trials, T2MR has exhibited good clinical sensitivity and specificity. Potential benefits from the adoption of T2MR technology in the diagnostic and therapeutic algorithms for invasive candidiasis can arise from timely diagnosis of disease, increased case detection, tailored therapy and decrease in empiric antifungal treatment. As everyday clinical experience with the assay is evolving, we discuss the utility of T2MR in invasive candidiasis with and without candidemia based on the currently available evidence regarding its performance. 10.2217/fmb-2018-0079
    Diagnostic Performance of T2Candida Among ICU Patients With Risk Factors for Invasive Candidiasis. Open forum infectious diseases BACKGROUND:Invasive candidiasis (IC) comprises candidemia and deep-seated candidiasis. Blood culture (BC) is the gold standard test, but sensitivity is low. T2Candida is a new diagnostic test. We investigated the performance of T2Candida, BC, and mannan antigen (MAg) for detection of IC in a high-risk intensive care unit (ICU) population. METHODS:One-hundred twenty-six ICU patients at high risk of IC with sepsis despite 3 days of broad-spectrum antibiotics were included. Paired BC, T2Candida, and MAg were obtained twice weekly (334 sets). Patients were classified into proven, likely, possible, or unlikely IC based on patient record review. RESULTS:At enrollment, 92 (77%) patients were receiving antifungal therapy (mainly fluconazole 66%). Fifteen (11.9%) patients were positive by BC (n = 4), T2Candida (n = 11), or MAg (n = 10). The T2Candida species distribution at inclusion ( /: 8/11 [72.3%] and /: 3/11 [27.3%]) was supported by the identification of BC or colonizing isolates in 10/11 cases. Patients were classified with proven (11), likely (6), possible (11), and unlikely (98) IC. Defining IC as proven/proven&likely/proven&likely&possible, respectively, the sensitivity was as follows: T2Candida (55%/59%/39%), BC (45%/29%/ 8%), and MAg (36%/41%/32%). The negative predictive value was similar across the tests for proven vs others and proven/likely vs others (94%-96% and 90%-95%, respectively). For test combinations including T2Candida, the sensitivity increased to 64%-65%, without hampering the positive predictive value. CONCLUSIONS:In conclusion, although the diagnostic performance was modest for all the tests, the combination of T2Candida and BC seemed to have the best diagnostic performance, and thus implementation of T2Candida may improve the diagnosis of IC. 10.1093/ofid/ofz136
    Candida albicans infection and intestinal immunity. Tong Yiqing,Tang Jianguo Microbiological research Fungal infections cause high rates of morbidity and mortality in intensive care and immunocompromised patients, and can represent a life-threatening disease. As a microorganism commonly found in the intestine, Candida albicans (C. albicans) can invade the gut epithelium barrier via microfold cells and enter the bloodstream. The defensive potential of the intestinal barrier against invasive C. albicans is dependent on innate and adaptive immune responses which enable the host to eliminate pathogenic fungi. The lamina propria layer of the intestine contains numerous immune cells capable of inducing an innate cellular immune response against invasive fungi. This review focuses on the immune response triggered by a C. albicans infection in the intestine. 10.1016/j.micres.2017.02.002
    Invasive fungal tracheobronchitis in mechanically ventilated critically ill patients: underlying conditions, diagnosis, and outcomes. Lin Chun-Yu,Liu Wei-Lun,Chang Che-Chia,Chang Hou-Tai,Hu Han-Chung,Kao Kuo-Chin,Chen Ning-Hung,Chen Ying-Jen,Yang Cheng-Ta,Huang Chung-Chi,Dimopoulos George Annals of intensive care BACKGROUND:Invasive fungal tracheobronchitis (IFT) is a severe form of pulmonary fungal infection that is not limited to immunocompromised patients. Although respiratory failure is a crucial predictor of death, information regarding IFT in critically ill patients is limited. METHODS:In this retrospective, multicenter, observational study, we enrolled adults diagnosed as having IFT who had been admitted to the intensive care unit between January 2007 and December 2015. Their demographics, clinical imaging data, bronchoscopic and histopathological findings, and outcomes were recorded. RESULTS:This study included 31 patients who had been diagnosed as having IFT, comprising 24 men and 7 women with a mean age of 64.7 ± 13.7 years. All patients developed respiratory failure and received mechanical ventilation before diagnosis. Eighteen (58.1%) patients had diabetes mellitus, and 12 (38.7%) had chronic lung disease. Four (12.9%) patients had hematologic disease, and none of the patients had neutropenia. Twenty-five (80.6%) patients were diagnosed as having proven IFT, and the remaining patients had probable IFT. Aspergillus spp. (61.3%) were the most common pathogenic species, followed by Mucorales (25.8%) and Candida spp. (6.5%). The diagnoses in six (19.4%) patients were confirmed only through bronchial biopsy and histopathological examination, whereas their cultures of bronchoalveolar lavage fluid were negative for fungi. The overall in-hospital mortality rate was 93.5%. CONCLUSIONS:IFT in critically ill patients results in a high mortality rate. Diabetes mellitus is the most prevalent underlying disease, followed by chronic lung disease. In addition to Aspergillus spp., Mucorales is another crucial pathogenic species. Bronchial lesion biopsy is the key diagnostic strategy. 10.1186/s13613-016-0230-9
    A high-throughput and rapid method for accurate identification of emerging multidrug-resistant Candida auris. Ahmad Ausaf,Spencer Jonathan E,Lockhart Shawn R,Singleton Sabrina,Petway David J,Bagarozzi Dennis A,Herzegh Owen T Mycoses Candida auris is an emerging multidrug-resistant yeast associated with invasive infection in healthcare settings. Recently, C auris cases in the United States have been detected in 11 states with the majority of cases in New York, New Jersey and Illinois. Rapid and accurate identification of C auris is critical for patient care and the implementation of public health measures to control the spread of infection. Our aim was to develop and validate a rapid DNA extraction method using the Roche MagNA Pure 96 instrument and a TaqMan real-time PCR assay for reliable, high-throughput identification of C auris. We evaluated 247 patient dermal swab samples previously analysed by culture/MALDI-TOF. The diagnostic sensitivity and specificity were 93.6% and 97.2%, respectively. The assay was highly reproducible with a detection limit of 1 C auris CFU/10 μL. A receiver operating characteristic curve analysis of the real-time PCR data showed an area of 0.982 under the curve, with a C cut-off value of ≤37.0. The turnaround time from DNA extraction to real-time PCR results was approximately 200 samples/day. In conclusion, we successfully validated a rapid and high-throughput method for accurate and reproducible identification of C auris with a significantly reduced turnaround time compared to culture/MALDI-TOF based methods. 10.1111/myc.12907
    Cloth Lanyards as a Source of Intermittent Transmission of Candida auris on an ICU. Patterson Charlotte A,Wyncoll Duncan,Patel Amita,Ceesay Yusupha,Newsholme William,Chand Meera,Mitchell Hannah,Tan Mark,Edgeworth Jonathan D Critical care medicine OBJECTIVES:Candida auris has been implicated in ICU outbreaks worldwide and is notable for being difficult to identify and treat, its resilience in the environment, and significant patient mortality associated with invasive disease. Here, we describe a small C. auris outbreak and how it was terminated. DESIGN:Single-center, observational. SETTING:Two general adult ICUs at an urban U.K. teaching hospital. PATIENTS:All patients positive for C. auris during the 5-month outbreak were included (n = 7). INTERVENTIONS:Stepwise implementation of enhanced infection prevention and control precautions was introduced including twice-weekly screening, contact tracing, isolation precautions, and environmental decontamination. A detailed environmental screen was performed to identify potential reservoirs. This included the patient bed space and clinical equipment and a frequently handled cloth lanyard attached to a key used to access controlled drugs. Personal possessions such as mobile phones, lanyards, and identification badges were also screened. MEASUREMENTS AND MAIN RESULTS:The index case and six linked acquisitions were identified. Four of six (67%) patients were identified after discharge of all known previous C. auris cases from ICU, highlighting potential for an environmental reservoir. Environmental screening identified C. auris from a patient bed space following deep cleaning, prompting review and enhancement of cleaning procedures. The controlled drug cloth lanyard was positive for C. auris, which prompted removal and culture of all staff lanyards. C. auris was identified on 1/100 staff lanyards (1%). No mobile phones or identification badges were positive for C. auris. The outbreak terminated following withdrawal of lanyards from ICU. CONCLUSIONS:This outbreak further implicates environmental reservoirs as sustaining C. auris ICU outbreaks. Identification of C. auris on cloth lanyards highlights the need to identify commonly handled moveable objects during an outbreak. We suggest that ICUs with a C. auris outbreak should investigate similar infrequently cleaned items as potential reservoirs and review their policies on lanyard use. 10.1097/CCM.0000000000004843
    Empyema Thoracis at Two Academic Medical Centers: New Insights Into Treatment and Outcomes. Senger Suheyla S,Thompson George R,Samanta Palash,Ahrens Jillian,Clancy Cornelius J,Nguyen M Hong Open forum infectious diseases Background: empyema thoracis (pleural empyema) is an uncommon manifestation of invasive candidiasis, for which optimal treatment is unknown. Methods:This is a retrospective study of patients with empyema at 2 academic medical centers from September 2006 through December 2015. Results:We identified 81 patients with empyema (median age, 62 years; 68% men). Sixty-five percent of patients underwent surgery or an invasive intervention of the thorax or abdomen within the preceding 90 days. empyema originated from intrathoracic (51%) or intra-abdominal sources (20%), spontaneous esophageal rupture (12%), pleural space manipulation (9%), and pneumonia (6%). Eighty-four percent and 41% of patients were intensive care unit residents and in septic shock, respectively, within 3 days of diagnosis. Causative species were (65%), (26%), (11%), (4%), (2%), and (1%). Bacteria were recovered from empyemas in 51% of patients. Concurrent candidemia was diagnosed in only 2% of patients. Management included pleural drainage and antifungal treatment in 98% and 85% of patients, respectively. Mortality at 100 days was 27%, and it was highest for cases stemming from esophageal rupture (67%). Spontaneous esophageal rupture and echinocandin rather than fluconazole treatment were independent risk factors for death at 100 days ( = .003 and .04, respectively); receipt of antifungal therapy was an independent predictor of survival ( = .046). Conclusions: empyema mortality rates were lower than reported previously. Optimal management included pleural drainage and fluconazole treatment. Superiority of fluconazole over echinocandins against empyema needs to be confirmed in future studies. 10.1093/ofid/ofaa656
    Breakthrough invasive fungal infections: Who is at risk? Jenks Jeffrey D,Cornely Oliver A,Chen Sharon C-A,Thompson George R,Hoenigl Martin Mycoses The epidemiology of invasive fungal infections (IFIs) in immunocompromised individuals has changed over the last few decades, partially due to the increased use of antifungal agents to prevent IFIs. Although this strategy has resulted in an overall reduction in IFIs, a subset of patients develop breakthrough IFIs with substantial morbidity and mortality in this population. Here, we review the most significant risk factors for breakthrough IFIs in haematology patients, solid organ transplant recipients, and patients in the intensive care unit, focusing particularly on host factors, and highlight areas that require future investigation. 10.1111/myc.13148
    Isolation of Candida auris from 9 patients in Central America: Importance of accurate diagnosis and susceptibility testing. Araúz Ana Belen,Caceres Diego H,Santiago Erika,Armstrong Paige,Arosemena Susan,Ramos Carolina,Espinosa-Bode Andres,Borace Jovanna,Hayer Lizbeth,Cedeño Israel,Jackson Brendan R,Sosa Nestor,Berkow Elizabeth L,Lockhart Shawn R,Rodriguez-French Amalia,Chiller Tom Mycoses Candida auris is an emerging multidrug-resistant (MDR) fungus associated with invasive infections and high mortality. This report describes 9 patients from whom C. auris was isolated at a hospital in Panama City, Panama, the first such cases in Central America, and highlights the challenges of accurate identification and methods for susceptibility testing. 10.1111/myc.12709
    Candida albicans - Biology, molecular characterization, pathogenicity, and advances in diagnosis and control - An update. Dadar Maryam,Tiwari Ruchi,Karthik Kumaragurubaran,Chakraborty Sandip,Shahali Youcef,Dhama Kuldeep Microbial pathogenesis Candida albicans is an emerging multidrug-resistant fungal pathogen representing an important source of invasive disease in humans and generating high healthcare costs worldwide. This fungus is frequently found in different anatomical sites of healthy persons and could induce systemic and superficial infections under optimal environmental conditions. Invasive candidiasis (IC) is an important nosocomial infection with high morbidity and mortality rates in hospitalized children. It represents a major source of prolonged infections in intensive care unit (ICU), particularly in immunosuppressed or elderly patients. Clinical diagnosis of candidiasis could be difficult because of the lack of specific symptoms and clinical signs. Although C. albicans is the most frequently isolated Candida species in IC, non-albicans Candida (NAC) species are also commonly detected. Multilocus enzyme electrophoresis (MLEE), fragment length polymorphism (RFLP), electrophoretic karyotyping (EK), and random amplified polymorphic DNA (RAPD), multilocus sequence typing (MLST) are known as an efficient technique used for molecular typing of Candida species. The efficacy of antifungal treatment against candidiasis has been evaluated and discussed in the context of large epidemiological studies. The present review highlights the etiology, epidemiology, molecular typing, commensalism and virulence factors, along with the appropriate prevention and control strategies regarding this widespread pathogen. 10.1016/j.micpath.2018.02.028
    Strain Distribution and Drug Susceptibility of Invasive Fungal Infection in Clinical Patients With Systemic Internal Diseases. Zeng Xuehua,Peng Mengran,Liu Guirong,Huang Yongqing,Zhang Tingting,Wen Jing,Lai Wei,Zheng Yue Frontiers in bioengineering and biotechnology Background:Patients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated. Objective:This work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases. Methods:Samples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents. Results:A total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were (90.50%), (8.93%), and (0.56%). The infective candida subgroups were (70.95%), (6.15%), (5.59%), (3.91%), and (3.91%). The susceptibility of non- fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for , 98.43 and 100% for , and 100% for both drugs for , , and . The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for , 20 and 20% for , and 57.14 and 57.14% for . The resistance rate of for both fluconazole and itraconazole was 41.43%. Conclusion:Patients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. , especially , was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non- fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases. 10.3389/fbioe.2020.625024
    Mind the gaps: challenges in the clinical management of invasive candidiasis in critically ill patients. Peçanha-Pietrobom Paula M,Colombo Arnaldo Lopes Current opinion in infectious diseases PURPOSE OF REVIEW:Strict adherence to clinical practice guidelines is recognized to improve outcomes but the inconvenient truth is that only a small subset of what is done in medicine has been tested in appropriate, well designed studies. In this article, we aim to review controversial aspects of the clinical management of invasive candidiasis recommended by guidelines. RECENT FINDINGS:Despite still being recommended by guidelines, we fail to identify a single randomized clinical trial documenting that the use of antifungal drugs in high-risk critically ill patients without microbiologic documentation of Candida infection decreases mortality. Regarding deep-seated Candida infections, most cohort studies of patients with candidemia found less than 5% of patients developed endophthalmitis and endocarditis. In this scenario, it is reasonable to reconsider routine universal screening of both complications in candidemic patients. Finally, a large number of studies have shown that critically ill patients usually have lower echinocandin exposure when compared with other populations. We need more data on the clinical relevance of this finding. SUMMARY:We need robust studies to validate new strategies for the clinical management of candidemia in ICU, including: the use of fungal biomarkers in the early initiation or interruption of antifungal therapy in high-risk patients to replace the conventional empirical antifungal therapy driven by predictive rules; validation of targeted screening of eye infection and endocarditis with the aid of fungal biomarkers only in high-risk patients; we should clarify if higher doses of candins are necessary to treat invasive candidiasis in critically ill patients, especially in the case of intra-abdominal infections where drug penetration is suboptimal. 10.1097/QCO.0000000000000684
    Genetic and behavioral adaptation of Candida parapsilosis to the microbiome of hospitalized infants revealed by in situ genomics, transcriptomics, and proteomics. Microbiome BACKGROUND:Candida parapsilosis is a common cause of invasive candidiasis, especially in newborn infants, and infections have been increasing over the past two decades. C. parapsilosis has been primarily studied in pure culture, leaving gaps in understanding of its function in a microbiome context. RESULTS:Here, we compare five unique C. parapsilosis genomes assembled from premature infant fecal samples, three of which are newly reconstructed, and analyze their genome structure, population diversity, and in situ activity relative to reference strains in pure culture. All five genomes contain hotspots of single nucleotide variants, some of which are shared by strains from multiple hospitals. A subset of environmental and hospital-derived genomes share variants within these hotspots suggesting derivation of that region from a common ancestor. Four of the newly reconstructed C. parapsilosis genomes have 4 to 16 copies of the gene RTA3, which encodes a lipid translocase and is implicated in antifungal resistance, potentially indicating adaptation to hospital antifungal use. Time course metatranscriptomics and metaproteomics on fecal samples from a premature infant with a C. parapsilosis blood infection revealed highly variable in situ expression patterns that are distinct from those of similar strains in pure cultures. For example, biofilm formation genes were relatively less expressed in situ, whereas genes linked to oxygen utilization were more highly expressed, indicative of growth in a relatively aerobic environment. In gut microbiome samples, C. parapsilosis co-existed with Enterococcus faecalis that shifted in relative abundance over time, accompanied by changes in bacterial and fungal gene expression and proteome composition. CONCLUSIONS:The results reveal potentially medically relevant differences in Candida function in gut vs. laboratory environments, and constrain evolutionary processes that could contribute to hospital strain persistence and transfer into premature infant microbiomes. Video abstract. 10.1186/s40168-021-01085-y
    Increasing morbidity and mortality of candidemia over one decade in a Swiss university hospital. Battistolo Julien,Glampedakis Emmanouil,Damonti Lauro,Poissy Julien,Grandbastien Bruno,Kalbermatter Laetitia,Pagani Jean-Luc,Eggimann Philippe,Bochud Pierre-Yves,Calandra Thierry,Marchetti Oscar,Lamoth Frederic, Mycoses BACKGROUND:The epidemiology of candidemia is evolving with raising concern about the emergence of intrinsically resistant non-albicans Candida species and acquisition of antifungal resistance. In addition to microbiological surveys, epidemiological studies including clinical data are needed to assess the impact of candidemia on morbidity and mortality. OBJECTIVES:To assess the clinical and microbiological trends of candidemia in a Swiss university hospital. PATIENTS/METHODS:This single-centre retrospective study compared the incidence of candidemia, Candida species distribution, antifungal resistance profiles, clinical characteristics and outcomes between two periods separated by one decade. RESULTS:A total of 170 candidemic episodes were included (68 from period 1, 2004-2006, and 102 from period 2, 2014-2017). Incidence of candidemia (0.85 to 0.97 episode/10,000 patient-days), species distribution (55%-57% C albicans) and antifungal susceptibilities remained unchanged. During period 2, candidemia was more frequently observed in intensive care units (ICU, 38% vs 19% in period 1, P = .01) and amongst older patients (median age 68 vs 59 years old, P < .01) with more immunosuppressive conditions (24% vs 9%, P = .01). Candidemia in period 2 was more frequently followed by septic shock (23% vs 7% in period 1, P = .01) and ICU admission (42% vs 12%, P < .01) and was associated with higher mortality (34% vs 18%, P = .03). Overall, factors associated with mortality in multivariate analyses included cirrhosis, solid malignancies and ICU stay at the time of candidemia. CONCLUSIONS:Despite stable incidence, species distribution and antifungal resistance of candidemia, an epidemiological shift of the disease towards older and more critically ill patients was observed, with higher mortality rates. 10.1111/myc.13376
    Changes in the relative prevalence of candidaemia due to non-albicans Candida species in adult in-patients: A systematic review, meta-analysis and meta-regression. Giacobbe Daniele Roberto,Maraolo Alberto Enrico,Simeon Vittorio,Magnè Federica,Pace Maria Caterina,Gentile Ivan,Chiodini Paolo,Viscoli Claudio,Sanguinetti Maurizio,Mikulska Malgorzata,Fiore Marco,Bassetti Matteo Mycoses BACKGROUND:Candidaemia remains associated with high mortality and increased costs worldwide. OBJECTIVE:To assess the changes over time in the relative prevalence of non-albicans candidaemia (NAC). METHODS:A systematic review, meta-analysis and meta-regression were performed. Observational studies investigating the epidemiology of consecutive, non-selected, candidaemia episodes were included. Two separated analyses were conducted: (a) whole hospital analysis and (b) intensive care unit (ICU) analysis. RESULTS:Starting from an initial total of 7726 records, 220 studies fulfilled inclusion criteria. The pooled prevalence of NAC in whole hospital analysis was 49.5% (95% confidence intervals [CI] 48.0-51.1, I 93.1%), while the pooled prevalence in ICU analysis was 50.6% (95% CI 46.6-54.6; I 86.7%). In meta-regression, a progressive increase in NAC prevalence was observed in whole hospital analysis, although it explained only a small portion of between-study variance (estimated yearly prevalence change +0.3%, 95% CI from +0.1% to +0.5%, P = .003; adjusted R 3.42%) and was observed only in some continents in subgroup analyses. No relevant changes over time were observed in NAC prevalence for ICU studies. CONCLUSIONS:We registered an increasing trend in the relative prevalence of NAC, which, nonetheless, seems to be limited to some continents and to contribute only minimally to explain the observed differences in NAC prevalence across studies. 10.1111/myc.13054
    Candida infanticola and Candida spencermartinsiae yeasts: Possible emerging species in cancer patients. Shokohi Tahereh,Aslani Narges,Ahangarkani Fatemeh,Meyabadi Masoumeh Fatahi,Hagen Ferry,Meis Jacques F,Boekhout Teun,Kolecka Anna,Badali Hamid Microbial pathogenesis Opportunistic infections due to Candida species occur frequently in intensive care settings. We investigated the prevalence of Candida species among 65 clinical specimens obtained from 200 cancer patients by phenotypic and molecular (ITS sequencing and AFLP) methods. Among the 65 yeast isolates, Candida albicans was the most commonly isolated species (n = 34, 52.3%), whereas other Candida species comprised 47.7% (n = 31) and consisted of Candida glabrata (n = 14, 21.5%), Candida tropicalis (n = 5, 7.7%) and uncommon Candida species (n = 12, 18.5%) such as Candida pelliculosa (n = 3, 4.6%), Pichia kudriavzevii (= Candida krusei, n = 2, 3.1%), Candida orthopsilosis (n = 2, 3.1%), Candida parapsilosis (n = 1, 1.5%), Candida infanticola (n = 2, 3.1%), Candida spencermartinsiae (n = 1, 1.5%), and Kluyveromyces marxianus (=Candida kefyr, n = 1, 1.5%). Candida infanticola and Candida spencermartinsiae were recovered from oral lesions of cancer patients. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) easily confirmed these isolates as less common Candida isolates (4.6%). The in vitro antifungal susceptibilities of C. spencermartinsiae and the two strains of C. infanticola were determined according to CLSI guidelines (M27-A3). MIC results among these isolates showed they were susceptible to isavuconazole, posaconazole and voriconazole, however, fluconazole and caspofungin had high MIC values. These Candida species that may occur more commonly in infections remain unnoticed using commonly used phenotypical methods in routine microbiology laboratories. MALDI-TOF MS proved to be a more fast and robust diagnostic technique for identification of the yeasts isolated from different clinical specimens of cancer patients. 10.1016/j.micpath.2017.12.069
    Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment. Arendrup Maiken Cavling,Patterson Thomas F The Journal of infectious diseases Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. 10.1093/infdis/jix131
    Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in a teaching hospital in China. Xiao Zengli,Wang Qi,Zhu Fengxue,An Youzhong Antimicrobial resistance and infection control Background:Candidemia is still a common life-threatening disease and causes significant morbidity and mortality, especially in critically ill patients. We conducted this study to analyze the epidemiology, clinical characteristics, species distribution, antifungal susceptibility and mortality risk factors of candidemia in an intensive care unit. Methods:We retrospectively analyzed patients with candidemia in the intensive care unit of our hospital from 2011 to 2017. The clinical characteristics, including clinical and laboratory data, antibiotic therapies, underlying conditions, and invasive procedures and outcomes, were analyzed. We also performed a logistic regression analysis to identify the independent risk factors for mortality. Results:In this six-year retrospective study, we identified 82 patients with candidemia. The median age of the patients was 76 years (range, 26 years to 91 years), and 50 of the patients (61%) were male. was the most common fungal species (38/82, 46.3%), followed by (16/82, 19.5%), (13/82, 15.9%), and (12/82, 14.6%). Most isolates were susceptible to the antifungal agents. The all-cause mortality rate was 51.2%. In binary logistic regression analysis, the worst Glasgow coma score (GCS), PaO/FiO ratio (P/F ratio), and mean arterial pressure (MAP) within three days after admission were independent risk factors for mortality. Conclusions: was the most frequently isolated fungal species. Most isolates were susceptible to the antifungal agents. The worst GCS score, P/F ratio, and MAP within three days after admission were independent risk factors for mortality due to candidemia in critically ill patients. 10.1186/s13756-019-0534-2
    Investigation of a healthcare-associated Candida tropicalis candidiasis cluster in a haematology unit and a systematic review of nosocomial outbreaks. Barac Aleksandra,Cevik Muge,Colovic Natasa,Lekovic Danijela,Stevanovic Goran,Micic Jelena,Rubino Salvatore Mycoses BACKGROUND:Non-albicans Candida spp. are an emerging cause of hospital-acquired bloodstream infections, associated with high mortality due to the challenges in diagnosis and delayed treatment. OBJECTIVES:We aimed to investigate a cluster of healthcare-associated invasive candidiasis caused by C tropicalis and review the literature of healthcare-associated outbreaks or clusters caused by C tropicalis. METHODS:An investigation was performed to determine clinical presentation, treatment outcomes and the factors contributing to C tropicalis candidemia occurrence. We searched the Medline database via PubMed and Ovid using the keywords of "Candida tropicalis" combined with "outbreak" or "clustering" or "clusters," and we limited the search to studies conducted from January 1989 to January 2019. RESULTS:We report two related cases of C tropicalis candidemia among patients with AML following a period of neutropenia, who had erythematous skin rash as a first manifesting sign of candidiasis. C tropicalis was isolated from blood and skin cultures of both patients, which were identical by pulsed-field gel electrophoresis typing. Our systematic review of outbreaks caused by C tropicalis suggests that (a) most reported outbreaks have occurred in neonatal and adult ICUs; (b) patients who receive total parenteral therapy, antibiotics and those who have indwelling catheters and recent surgery are at high risk of infection; and (c) environmental and healthcare personnel surveillance suggest that cross-contamination is a major risk factor. CONCLUSION:Control of nosocomial outbreaks caused by C tropicalis should include better infection control measures, education of healthcare professionals especially working in adult and neonatal intensive care and haematology units. 10.1111/myc.13048
    Characteristics and outcomes of patients with postoperative Candida versus bacterial mediastinitis: a case-matched comparative study. Moyon Quentin,Lebreton Guillaume,Huang Florent,Demondion Pierre,Desnos Cyrielle,Chommeloux Juliette,Hékimian Guillaume,Bréchot Nicolas,Nieszkowska Ania,Schmidt Matthieu,Leprince Pascal,Combes Alain,Luyt Charles-Edouard,Pineton de Chambrun Marc European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery OBJECTIVES:Postoperative mediastinitis, a feared complication after cardiac surgery, is associated with high mortality, especially of critically ill patients. Candida species infections are rare and severe, with poorly known outcomes. We conducted a case-control study to describe the characteristics, management and outcomes of patients with postoperative Candida mediastinitis. METHODS:This French, monocentre, retrospective study included all patients with postoperative Candida mediastinitis (January 2003-February 2020) requiring intensive care unit admission. Candida mediastinitis patients (henceforth cases) were matched 1:1 with postoperative bacterial mediastinitis (henceforth control), based on 3 factors during mediastinitis management: age >40 years, cardiac transplantation and invasive circulatory device used. The primary end point was the probability of survival within 1 year after intensive care unit (ICU) admission. RESULTS:Forty cases were matched to 40 controls. The global male/female ratio was 2.1, with mean age at admission 47.9 ± 13.8 years. Candida species were: 67.5% albicans, 17.5% glabrata, 15% parapsilosis, 5.0% tropicalis, 2.5% krusei and 2.5% lusitaniae. The median duration of mechanical ventilation was 23, 68.8% of patients received renal replacement therapy and 62.5% extracorporeal membrane oxygenation support. The probability of survival within the first year after ICU admission was 40 ± 5.5% and was significantly lower for cases than for controls (43 ± 8% vs 80 ± 6.3%, respectively; Log-rank test: P < 0.0001). The multivariable Cox proportional hazards model retained only renal replacement therapy [hazard ratio (HR) 3.7, 95% confidence interval (CI) 1.1-13.1; P = 0.04] and Candida mediastinitis (HR 2.4, 95% CI 1.1-5.6; P = 0.04) as independently associated with 1-year mortality. CONCLUSIONS:Candida mediastinitis is a serious event after cardiac surgery and independently associated with 1-year mortality. Further studies are needed to determine whether deaths are directly attributable to Candida mediastinitis. 10.1093/ejcts/ezab437
    Candida auris Cell Wall Mannosylation Contributes to Neutrophil Evasion through Pathways Divergent from Candida albicans and Candida glabrata. Horton Mark V,Johnson Chad J,Zarnowski Robert,Andes Brody D,Schoen Taylor J,Kernien John F,Lowman Douglas,Kruppa Michael D,Ma Zuchao,Williams David L,Huttenlocher Anna,Nett Jeniel E mSphere Candida auris, a recently emergent fungal pathogen, has caused invasive infections in health care settings worldwide. Mortality rates approach 60% and hospital spread poses a public health threat. Compared to other spp., C. auris avoids triggering the antifungal activity of neutrophils, innate immune cells that are critical for responding to many invasive fungal infections, including candidiasis. However, the mechanism underpinning this immune evasion has been largely unknown. Here, we show that C. auris cell wall mannosylation contributes to the evasion of neutrophils and in a zebrafish infection model. Genetic disruption of mannosylation pathways ( and ) diminishes the outer cell wall mannan, unmasks immunostimulatory components, and promotes neutrophil engagement, phagocytosis, and killing. Upon examination of these pathways in other spp. (Candida albicans and Candida glabrata), we did not find an impact on neutrophil interactions. These studies show how C. auris mannosylation contributes to neutrophil evasion though pathways distinct from other common spp. The findings shed light on innate immune evasion for this emerging pathogen. The emerging fungal pathogen Candida auris presents a global public health threat. Therapeutic options are often limited for this frequently drug-resistant pathogen, and mortality rates for invasive disease are high. Previous study has demonstrated that neutrophils, leukocytes critical for the antifungal host defense, do not efficiently recognize and kill C. auris. Here, we show how the outer cell wall of C. auris promotes immune evasion. Disruption of this mannan polysaccharide layer renders C. auris susceptible to neutrophil killing and in a zebrafish model of invasive candidiasis. The role of these mannosylation pathways for neutrophil evasion appears divergent from other common species. 10.1128/mSphere.00406-21
    The Clinical Outcome of Postoperative Invasive Fungal Infections Complicating Laparoscopic Sleeve Gastrectomy. Bichovsky Yoav,Koyfman Leonid,Friger Michael,Kirshtein Boris,Borer Abraham,Sebbag Gilbert,Frank Dmitry,Frenkel Amit,Peiser Jochanan G,Klein Moti,Brotfain Evgeni Obesity surgery PURPOSE:Peritonitis is a major complication of bariatric surgery due to direct damage to the natural barriers to infection. Most such secondary peritoneal infections are caused by Gram-negative microorganisms; however, under certain conditions, Candida species can infect the peritoneal cavity following bariatric surgery. MATERIALS AND METHODS:We retrospectively analyzed the clinical and microbiological data of morbidly obese patients who suffered infectious complications following laparoscopic sleeve gastrectomy (LSG) at the Soroka Medical Center between January 2010 and June 2015. RESULTS:Out of 800 patients who underwent LSG, 43 (5.3%( developed secondary peritonitis and were admitted to our General Intensive Care Unit during the study period. Intraperitoneal leaks, intraabdominal abscesses and pleural effusions were significantly more common in patients with fungal infection than in those with non-fungal infections (p values 0.027, < 0.001, and < 0.014, respectively). Leaks situated at the suture line of gastro-esophageal area occurred much more frequently in the fungal infection group than in the non-fungal infection group (94.7 vs 41.7%, p < 0.001). Microbiological analysis of the abdominal and pleural fluids of patients with invasive fungal infectious complications showed the presence of commensal polymicrobial bacterial infections-mainly Streptoccocus constellatus and coagulase negative Staphylococcus spp. Leakage at the suture line of gastro-esophageal area (upper suture part) and administration of parenteral nutrition were found to be independent predictors for invasive fungal infections after LSG. CONCLUSION:Our study demonstrates that invasive fungal infection is a significant postoperative infectious complication of bariatric LSG surgery in morbidly obese patients. 10.1007/s11695-018-3347-0
    (1,3)-β-D-Glucan-based empirical antifungal interruption in suspected invasive candidiasis: a randomized trial. De Pascale Gennaro,Posteraro Brunella,D'Arrigo Sonia,Spinazzola Giorgia,Gaspari Rita,Bello Giuseppe,Montini Luca Maria,Cutuli Salvatore Lucio,Grieco Domenico Luca,Di Gravio Valentina,De Angelis Giulia,Torelli Riccardo,De Carolis Elena,Tumbarello Mario,Sanguinetti Maurizio,Antonelli Massimo Critical care (London, England) BACKGROUND:(1,3)-β-D-Glucan has been widely used in clinical practice for the diagnosis of invasive Candida infections. However, such serum biomarker showed potential to guide antimicrobial therapy in order to reduce the duration of empirical antifungal treatment in critically ill septic patients with suspected invasive candidiasis. METHODS:This was a single-centre, randomized, open-label clinical trial in which critically ill patients were enrolled during the admission to the intensive care unit (ICU). All septic patients who presented invasive Candida infection risk factors and for whom an empirical antifungal therapy was commenced were randomly assigned (1:1) in those stopping antifungal therapy if (1,3)-β-D-glucan was negative ((1,3)-β-D-glucan group) or those continuing the antifungal therapy based on clinical rules (control group). Serum 1,3-β-D-glucan was measured at the enrolment and every 48/72 h over 14 days afterwards. The primary endpoint was the duration of antifungal treatment in the first 30 days after enrolment. RESULTS:We randomized 108 patients into the (1,3)-β-D-glucan (n = 53) and control (n = 55) groups. Median [IQR] duration of antifungal treatment was 2 days [1-3] in the (1,3)-β-D-glucan group vs. 10 days [6-13] in the control group (between-group absolute difference in means, 6.29 days [95% CI 3.94-8.65], p < 0.001). Thirty-day mortality was similar (28.3% [(1,3)-β-D-glucan group] vs. 27.3% [control group], p = 0.92) as well as the overall rate of documented candidiasis (11.3% [(1,3)-β-D-glucan group] vs. 12.7% [control group], p = 0.94), the length of mechanical ventilation (p = 0.97) and ICU stay (p = 0.23). CONCLUSIONS:In critically ill septic patients admitted to the ICU at risk of invasive candidiasis, a (1,3)-β-D-glucan-guided strategy could reduce the duration of empirical antifungal therapy. However, the safety of this algorithm needs to be confirmed in future, multicentre clinical trial with a larger population. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03117439 , retrospectively registered on 18 April 2017. 10.1186/s13054-020-03265-y
    Antifungal susceptibility testing in species: current methods and promising new tools for shortening the turnaround time. Knabl Ludwig,Lass-Flörl Cornelia Expert review of anti-infective therapy INTRODUCTION:Invasive fungal diseases (IFDs) have received attention as an emerging public health threat, are difficult to diagnose and to treat, and are associated with substantial morbidity and mortality. The standard of care in IFD management requires an early and targeted antifungal treatment, hence covers - amongst others - species identification and antifungal susceptibility testing (AFST). AREAS COVERED:This review gives an overview of methods currently applied in AFST and highlights promising new tools for shortening the turnaround time focusing on species. EXPERT OPINION:The performance of the broth microdilution reference methods for AFST is not suitable for daily laboratory practice as they are too labor-intensive and time-consuming. Other conventional approaches such as disk diffusion assays, epsilometer tests, colorimetric or automated approaches are easier in handling, and in part, show good correlations with the reference methods. Promising results for shortening the turnaround time in providing MIC data or resistance detection include matrix-assisted laser desorption/ionization-time of flight mass spectrometer (MALDI-TOF MS) assisted AFST, molecular-based techniques and modified conventional approaches applying direct inoculation methods. These underlying AFST concepts are promising but in part completely different, have their own advantages and disadvantages, and need further clinical validation. 10.1080/14787210.2020.1760841
    Molecular mechanisms of azole resistance in Candida tropicalis isolates causing invasive candidiasis in China. Fan X,Xiao M,Zhang D,Huang J-J,Wang H,Hou X,Zhang L,Kong F,Chen S C-A,Tong Z-H,Xu Y-C Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases OBJECTIVE:We investigated molecular mechanisms responsible for azole resistance in Candida tropicalis isolates. METHODS:We studied 507 C. tropicalis isolates causing invasive candidiasis from ten hospitals over 5 years. Antifungal susceptibility was determined by broth microdilution methods. Point mutations in the C. tropicalis ERG11 gene that may confer azole resistance were explored and verified. The expression levels of ERG11, CYTb, MDR1 and CDR1 genes were compared in 20 fluconazole-susceptible and 20 fluconazole-resistant isolates. RESULTS:Fluconazole-susceptible, -susceptible dose-dependent and -resistant strains accounted for 76.7% (389/507), 10.5% (53/507) and 12.8% (65/507) of C. tropicalis isolates, respectively. The ERG11 mutation A395T/W occurred in 10.7% (54/507) of isolates, all of which were resistant to fluconazole. The nucleotide mutation C461T/Y was the second most common (50/507 isolates, 9.9%), and all isolates carrying C461T/Y also had the mutation A395T/W. However, the presence of C461T did not contribute to the azole-resistant phenotype. Substitutions V125A, Y257H and G464S (<2% of isolates), which were reported for the first time in C. tropicalis, also conferred fluconazole non-susceptible phenotypes. Compared with fluconazole susceptible isolates, fluconazole-resistant isolates had higher ERG11 (fold expression level 1.42 versus 0.79, p < 0.01) but lower CYTb (fold expression level 1.26 versus 2.67, p < 0.01) gene expression levels. Three azole-resistant isolates carrying the wild-type ERG11 gene had higher levels of CDR1 and MDR1 expression. CONCLUSIONS:ERG11 missense mutations were the major mechanism responsible for azole resistance in C. tropicalis isolates, but overexpression of ERG11, CDR1 and MDR1, as well as reduced expression of CYTb, also contributed to resistance. 10.1016/j.cmi.2018.11.007
    Invasive Fungal Infection. von Lilienfeld-Toal Marie,Wagener Johannes,Einsele Hermann,Cornely Oliver A,Kurzai Oliver Deutsches Arzteblatt international BACKGROUND:The incidence of invasive fungal infection is approximately 6 cases per 100 000 persons per year. It is estimated that only half of such infections are detected during the patient's lifetime, making this one of the more common overlooked causes of death in intensive-care patients. The low detection rate is due in part to the complexity of the diagnostic work-up, in which the clinical, radiological, and microbiological findings must be considered. Fungi with resistance to antimycotic drugs have been found to be on the rise around the world. METHODS:This review is based on pertinent publications retrieved from a selective search in PubMed, with special attention to guidelines on the diagnosis and treatment of invasive fungal infections caused by Candida spp., Aspergillus spp., Mucorales, and Fusarium spp. RESULTS:The clinical risk factors for invasive fungal infection include, among others, congenital immune deficiency, protracted (>10 days) marked granulocytopenia (<0.5 x 109/L), allogeneic stem-cell transplantation, and treatment with immunosuppressive drugs or corticosteroids. High-risk groups include patients in intensive care and those with structural pulmonary disease and/or compli- cated influenza. The first line of treatment, supported by the findings of randomized clinical trials, consists of echinocandins for in- fections with Candida spp. (candidemia response rates: 75.6% for anidulafungin vs. 60.2% for fluconazole) and azole antimycotic drugs for infections with Aspergillus spp. (response rates: 52.8% for voriconazole vs. 31.6% for conventional amphotericin B). The recommended first-line treatment also depends on the local epidemiology. This challenge should be met by interdisciplinary collaboration. Therapeutic decision-making should also take account of the often severe undesired effects of antimycotic drugs (including impairment of hepatic and/or renal function) and the numerous interactions that some of them have with other drugs. CONCLUSION:Invasive fungal infections are often overlooked in routine hospital care. They should be incorporated into antimicro- bial stewardship programs as an essential component. There is also a pressing need for the development of new classes of antimycotic drug. 10.3238/arztebl.2019.0271
    Candida auris Biofilm Colonization on Skin Niche Conditions. Uppuluri Priya mSphere , an emerging multidrug-resistant yeast, has recently been associated with outbreaks of invasive infections in health care facilities worldwide. Its success as a nosocomial pathogen lies in its capability to sustain for prolonged periods in the intensive care unit (ICU), adeptly colonize skin, and spread among patients. Little is known of the mechanism behind the predilection of for skin or the extent of its resilience on it. Now, M. V. Horton, C. J. Johnson, J. F. Kernien, T. D. Patel, et al. (mSphere 5:e00910-19, 2020, https://doi.org/10.1128/mSphere.00910-19) demonstrate that in synthetic sweat medium designed to mimic axillary skin conditions, can grow into multilayers of cells called biofilms that can resist desiccation. ' propensity to form biofilms was further elaborated using a novel porcine skin model of skin colonization. These studies provide early evidence that biofilm cells persisting on skin could serve as source of continuing outbreaks in health care facilities. Interventions blocking biofilm growth on skin will help control the spread of this pathogen. 10.1128/mSphere.00972-19
    Tracing the Evolutionary History and Global Expansion of Candida auris Using Population Genomic Analyses. Chow Nancy A,Muñoz José F,Gade Lalitha,Berkow Elizabeth L,Li Xiao,Welsh Rory M,Forsberg Kaitlin,Lockhart Shawn R,Adam Rodney,Alanio Alexandre,Alastruey-Izquierdo Ana,Althawadi Sahar,Araúz Ana Belén,Ben-Ami Ronen,Bharat Amrita,Calvo Belinda,Desnos-Ollivier Marie,Escandón Patricia,Gardam Dianne,Gunturu Revathi,Heath Christopher H,Kurzai Oliver,Martin Ronny,Litvintseva Anastasia P,Cuomo Christina A mBio has emerged globally as a multidrug-resistant yeast that can spread via nosocomial transmission. An initial phylogenetic study of isolates from Japan, India, Pakistan, South Africa, and Venezuela revealed four populations (clades I, II, III, and IV) corresponding to these geographic regions. Since this description, has been reported in more than 30 additional countries. To trace this global emergence, we compared the genomes of 304 isolates from 19 countries on six continents. We found that four predominant clades persist across wide geographic locations. We observed phylogeographic mixing in most clades; clade IV, with isolates mainly from South America, demonstrated the strongest phylogeographic substructure. isolates from two clades with opposite mating types were detected contemporaneously in a single health care facility in Kenya. We estimated a Bayesian molecular clock phylogeny and dated the origin of each clade within the last 360 years; outbreak-causing clusters from clades I, III, and IV originated 36 to 38 years ago. We observed high rates of antifungal resistance in clade I, including four isolates resistant to all three major classes of antifungals. Mutations that contribute to resistance varied between the clades, with Y132F in as the most widespread mutation associated with azole resistance and S639P in for echinocandin resistance. Copy number variants in predominantly appeared in clade III and were associated with fluconazole resistance. These results provide a global context for the phylogeography, population structure, and mechanisms associated with antifungal resistance in In less than a decade, has emerged in health care settings worldwide; this species is capable of colonizing skin and causing outbreaks of invasive candidiasis. In contrast to other species, is unique in its ability to spread via nosocomial transmission and its high rates of drug resistance. As part of the public health response, whole-genome sequencing has played a major role in characterizing transmission dynamics and detecting new introductions. Through a global collaboration, we assessed genome evolution of isolates of from 19 countries. Here, we described estimated timing of the expansion of each clade and of fluconazole resistance, characterized discrete phylogeographic population structure of each clade, and compared genome data to sensitivity measurements to describe how antifungal resistance mechanisms vary across the population. These efforts are critical for a sustained, robust public health response that effectively utilizes molecular epidemiology. 10.1128/mBio.03364-19
    Comparative Evaluations of the Pathogenesis of Candida auris Phenotypes and Candida albicans Using Clinically Relevant Murine Models of Infections. Vila Taissa,Montelongo-Jauregui Daniel,Ahmed Hussian,Puthran Taanya,Sultan Ahmed S,Jabra-Rizk Mary Ann mSphere The newly emerged species is associated with an exponential rise in life-threatening invasive disease in health care facilities worldwide. Unlike other species, exhibits a high level of transmissibility, multidrug resistance, and persistence in the environment, yet little is known about its pathogenesis largely due to limited data from animal models. Based on biofilm evaluations and confocal laser scanning microscopy, phenotypes with different biofilm-forming abilities were identified, indicating potential clinical implications. Using clinically relevant murine models of implanted catheter, oral, and intraperitoneal infections, we comparatively evaluated the host site-specific pathogenic potential of phenotypes and Based on the results of microbial recovery and scanning electron microscopy analysis of explanted catheters, compared to , more avidly adhered and formed biofilms on catheters. However, although adhered to oral tissue , unlike , it failed to colonize the oral cavity , as demonstrated by microbial recovery and tissue histopathology analysis. In contrast, recovery from peritoneal lavage fluid and kidneys during time course experiments demonstrated that persisted longer in the peritoneal cavity and kidneys. Although there were clear niche-specific differences in pathogenic features between and , no significant differences were noted between the phenotypes The combined findings highlight unique niche-specific pathogenic traits for warranting further investigations. Understanding the factors contributing to the rise of as a nosocomial pathogen is critical for controlling the spread of this species. The newly emerged species has been associated with an exponential rise in invasive disease in health care facilities worldwide with a mortality rate approaching 60%. exhibits a high level of transmissibility, multidrug resistance, and persistence in hospital environments, yet little is known about its pathogenesis largely due to limited data from animal studies. We used clinically relevant murine models of infection to comparatively evaluate the host niche-specific pathogenic potential of and Findings demonstrated that adheres more avidly, forming robust biofilms on catheters implanted in mice. However, although adhered to oral tissue , it failed to colonize the oral cavity In contrast, in the intraperitoneal infection model, persisted longer in the peritoneal cavity and kidneys. Understanding the host-pathogen factors contributing to the rise of as a nosocomial pathogen is critical for controlling the spread of this species. 10.1128/mSphere.00760-20
    Controlling a possible outbreak of Candida auris infection: lessons learnt from multiple interventions. Biswal M,Rudramurthy S M,Jain N,Shamanth A S,Sharma D,Jain K,Yaddanapudi L N,Chakrabarti A The Journal of hospital infection BACKGROUND:Multidrug-resistant Candida auris infection has been reported from five continents in recent years. The prevalence of C. auris invasive infection has been estimated at 5.3% for intensive-care-acquired candidaemia in India. The transmission of the organism between the patients and from environment to patients is rapid. AIM:To understand the intra-hospital dynamics of C. auris transmission and to determine the possible interventions to prevent its spread. METHODS:Surveillance of intensive care units was carried out to assess patient colonization, environmental contamination and hand carriage of the yeast among healthcare workers. Interventions including chlorhexidine washing of patients and decontamination of environmental surfaces with stabilized hydrogen peroxide disinfectant (Ecoshield) were undertaken. We further evaluated the effectiveness of frequently used disinfectants in the hospital against C. auris on various inanimate surfaces, and its persistence on hospital fabrics. FINDINGS:Three cases of C. auris bloodstream infection were detected over a period of three months. Many patients admitted at the same time, in the same area, were colonized by C. auris. Surveillance detected C. auris contamination of environmental surfaces and hands of healthcare workers. Interventions such as chlorhexidine washing and appropriate use of disinfectants could eradicate C. auris from patients and hospital environment. CONCLUSION:The frequently used disinfectants in our hospital and current hand hygiene practices were efficient against C. auris if proper contact time and procedures were followed. Evaluation of possible persistence of C. auris on dry fabrics showed that they can persist for up to seven days. 10.1016/j.jhin.2017.09.009
    Invasive Infections during a COVID-19 Case Surge. Hanson Blake M,Dinh An Q,Tran Truc T,Arenas Sebastian,Pronty Darryl,Gershengorn Hayley B,Ferreira Tanira,Arias Cesar A,Shukla Bhavarth S Antimicrobial agents and chemotherapy Clinical cases of C. auris noted during a COVID-19 surge led to an epidemiological, clinical, and genomic investigation. Evaluation identified a close genetic relationship but inconclusive epidemiologic link between all cases. Prolonged hospitalization due to critical illness from COVID-19 and use of antimicrobials may have contributed to clinical infections. 10.1128/AAC.01146-21
    Development of Candida auris Short Tandem Repeat Typing and Its Application to a Global Collection of Isolates. de Groot Theun,Puts Ynze,Berrio Indira,Chowdhary Anuradha,Meis Jacques F mBio is a pathogenic yeast that causes invasive infections with high mortality. Infections most often occur in intensive care units of health care facilities. It is crucial to trace the source and prevent further spread of during an outbreak setting; therefore, genotyping of is required. To enable fast and cost-effective genotyping, we developed a short tandem repeat (STR) typing assay for STRs in were identified, and from an initial selection of 23 STRs, 12 were used to develop a STR typing assay. Having shown that the STR typing assay was reproducible and specific, a robust set of 444 isolates was investigated to identify genotypic diversity. In concordance with whole-genome sequencing (WGS) analysis, we identified five major different clusters of South American, South Asian, African, East Asian, and Iranian origin. Overall, a total of 40 distinct genotypes were identified, with the largest variety in the South Asian clade. Comparison with WGS demonstrated that isolates with <20 single nucleotide polymorphisms (SNPs) are mostly not differentiated by STR analysis, while isolates with 30 or more SNPs usually have differences in one or more STR markers. Altogether, a highly reproducible and specific STR typing assay for was developed; this assay distinguishes the five different clades in identical fashion to WGS, while most isolates differing by >30 SNPs, as determined via WGS, are also separated. This new -specific genotyping technique is a rapid, reliable, and cost-effective alternative to WGS analysis to investigate outbreaks. is an emerging fungal pathogen now recognized as a threat to public health. The pathogen has spread worldwide and causes mainly hospital-associated outbreaks. To track and trace outbreaks and to relate them to new introductions from elsewhere, whole-genome sequencing and amplified fragment length polymorphism (AFLP) have been used for molecular typing. Whole-genome sequencing is costly and available only at a few centers, and AFLP is a complicated technique and hard to interpret. We describe a novel simple STR genotyping technique based on short tandem repeats in the genome. We also show that the performance of this STR-based genotyping technique has proven comparable to that of WGS. Overall, this work provides a novel, rapid, reliable, and cost-effective method of molecular outbreak investigations of . 10.1128/mBio.02971-19
    Candida infections in severe acute pancreatitis: we need to do more in order to distinguish invasive infection from simple colonization. Honore Patrick M,Mugisha Aude,Kugener Luc,Redant Sebastien,Attou Rachid,Gallerani Andrea,De Bels David Critical care (London, England) 10.1186/s13054-020-02873-y
    Candida spp bloodstream infections in a Latin American Pediatric Oncology Reference Center: Epidemiology and associated factors. Paixao de Sousa da Silva Adriana Maria,de Moraes-Pinto Maria Isabel,Teofilo Pignati Luara,Barbosa Teixeira Bruno,Cordeiro Lima Ana Paula,Costa Pimentel Germano Priscila,Petrilli Antonio Sergio,Marques Leticia Maria Acioli,Carlesse Fabianne Mycoses BACKGROUND:Invasive fungal disease is a significant cause of morbidity and mortality in immunosuppressed children. The recognition of patients at risk for candidaemia is paramount to a better prognosis. OBJECTIVES:To characterize Candida spp bloodstream infections (BSI) in a reference centre for paediatric oncology and to describe the most prevalent risk factors associated with candida infections. PATIENTS/METHODS:This is a retrospective cohort study carried out with paediatric patients followed up with at the Institute of Pediatric Oncology, Brazil, who presented positive blood culture for Candida spp from January 2004 to December 2016. RESULTS:Ninety episodes of candidaemia were analysed; patients had a median age of 4.5 years, and 57.8% were males, with a diagnosis of solid tumours in 54.5% of cases. The most common Candida species were C albicans (35.6%), C parapsilosis (30.0%) and C tropicalis (16.7%). C tropicalis BSI was associated with neutropenia and skin lesions. Therapy was successful in 67.1% of the episodes. Older age and thrombocytopenia were associated with therapeutic failure. Death within 30 days occurred in 24.4% of patients; predictive factors were older age and admission to an ICU C parapsilosis candidaemia was a protective factor for death when compared to C albicans. CONCLUSION:The main species isolated were C albicans, C parapsilosis and C tropicalis. C tropicalis BSI was associated with neutropenia and skin lesions. The death rate was significant, and a worse prognosis was associated with older age, thrombocytopenia and admission to an ICU C parapsilosis infection proved to be a protective factor against mortality. 10.1111/myc.13106
    [First Case of COVID-19 Positive Candida auris Fungemia in Turkey]. Bölükbaşı Yasemin,Erköse Genç Gonca,Orhun Günseli,Kuşkucu Mert Ahmet,Çağatay Atahan,Önel Mustafa,Öngen Betigül,Ağaçfidan Ali,Esen Figen,Erturan Zayre Mikrobiyoloji bulteni Candida auris is a species of fungus that has gained importance in recent years owing to its ability to cause hospital infections and epidemics, resistant to antifungal agents and disinfection processes and frequently misidentified by commercial systems. Hospital outbreaks caused by C.auris have been reported from some countries. It has been determined that C.auris has lower virulence than Candida albicans; however, it is associated with high mortality rates in immunocompromised individuals. An increase in the incidence of invasive fungal infections which can lead to serious complications and death, has been identified in severe coronavirus-2019 (COVID-19) patients or immunocompromised individuals with underlying disease. Studies demonstrated an increase in the frequency of C.auris isolation in COVID-19 patients with candidemia. In this report, the first case of COVID-19 positive C.auris fungemia detected in Turkey was presented. A 71-year-old male patient with a history of myocardial infarction, diabetes mellitus, donation of a single kidney and lobectomy surgery due to lung cancer was hospitalized in the pandemic thoracic surgery service due to the findings consistent with viral pneumonia on thoracic computed tomography. Favipiravir 2 x 600 mg and intravenous dexamethasone 1 x 6 mg therapy was administered. The patient tested positive for SARS-CoV-2 polymerase chain reaction, and severe involvement of the left lung was detected in the following days. Antibiotics were administered, followed by insertion of a right jugular vein catheter and initation of tocilizumab. The patient was transferred to the intensive care unit due to increased respiratory distress. Yeast growth was detected in the patient's hemoculture. The yeast strain could not be identified using API ID 32C (bioMerieux, France) (Sacchromyces kluyveri, Candida sake, unacceptable profile), but was identified as C.auris using the VITEK MALDI TOF MS (bioMerieux, France) (99.9%) system and confirmed by sequencing. The minimum inhibitor concentration values were detected as 3 µg/ml for amphotericin B; > 256 µg/ml for fluconazole; 0.19 µg/ml for voriconazole; 0.19 µg/ml for itraconazole; 0.016 µg/ml for posaconazole; 1 µg/ml for caspofungin and 0.094 µg/ml for anidulafungin by using the antibiotic gradient method. The patient's initial treatment comprised meropenem 3 x 1 g, vancomycin 2 x 1 g, caspofungin 1 x 70 mg, and continued as caspofungine 1 x 50 mg after the loading dose, and vancomycin 1 x 1 g/48 hours from the third day of treatment. The patient died on the ninth day after developing candidemia. The present case is the first case of fungemia caused by C.auris in a COVID-19 positive patient in Turkey, and it emphasizes the need of caution for fungemia due to C.auris in intensive care units in our country which has a high COVID-19 incidence. 10.5578/mb.20219716
    Invasive Fungal Disease in Critically Ill Patients at High Risk: Usefulness of Lymphocyte Subtyping. Journal of intensive care medicine OBJECTIVES:This study aimed to investigate the distinguishing ability of lymphocyte subtyping for diagnosis and prognosis of invasive fungal disease (IFD). METHODS:We assessed lymphocyte subtyping and evaluated the quantitative changes in key immunological parameters at intensive care unit (ICU) admission in critically ill patients at high risk and their potential influence on diagnosis and outcome of IFD. The primary outcome was 28-day mortality. RESULTS:Among the 124 critically ill patients with mean Candida score 3.89 (0.76), 19 (15.3%) were in the IFD group. CD28CD8 T-cell counts (area under the curve [AUC] 0.899, 95% confidence interval [CI], 0.834-0.964, < .001) had better distinguishing ability than other immune parameters for IFD diagnosis. The cutoff value of CD28CD8 T-cell counts at ICU admission for IFD diagnosis was 59.5 cells/mm, with 83.3% sensitivity and 86.4% specificity. Multivariate logistic regression analysis identified CD28CD8 T-cell count <59.5 cells/mm (odds ratio 59.7, 95% CI, 7.33-486.9, < .001) as an independent predictor for IFD diagnosis. CD28CD8 T-cell counts could also predict 28-day mortality (AUC 0.656, 95% CI, 0.525-0.788, = .045). Kaplan-Meier survival analysis provided evidence that natural killer cell count <76.0 cells/mm (log-rank test; = .001), CD8 T-cell count <321.5 cells/mm (log-rank test; = .04), and CD28CD8 T-cell count <129.0 cells/mm (log-rank test; = .02) at ICU admission were associated with lower survival probabilities. CONCLUSION:CD28CD8 T-cell counts play an important role in early diagnosis of IFD. Low counts are associated with early mortality in critically ill patients at high risk of IFD. Our findings add evidence to the utility of lymphocyte subtyping in a diagnostic algorithm to better define IFD in critically ill patients at high risk. 10.1177/0885066618800690
    Pharmacokinetic Properties of Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis. Boonstra J M,van der Elst K C,Veringa A,Jongedijk E M,Brüggemann R J,Koster R A,Kampinga G A,Kosterink J G,van der Werf T S,Zijlstra J G,Touw D J,Alffenaar J W C Antimicrobial agents and chemotherapy The estimated attributable mortality rate for invasive candidiasis (IC) in the intensive care unit (ICU) setting varies from 30 to 40%. Physiological changes in critically ill patients may affect the distribution and elimination of micafungin, and therefore, dosing adjustments might be mandatory. The objective of this study was to determine the pharmacokinetic parameters of micafungin in critically ill patients and assess the probability of target attainment. Micafungin plasma concentrations were measured to estimate the pharmacokinetic properties of micafungin. MIC values for isolates were determined to assess the probability of target attainment for patients. Data from 19 patients with suspected or proven invasive candidiasis were available for analysis. The median area under the concentration-time curve from 0 to 24 h at steady state (AUC) was 89.6 mg · h/liter (interquartile range [IQR], 75.4 to 113.6 mg · h/liter); this was significantly lower than the median micafungin AUC values of 152.0 mg · h/liter (IQR, 136.0 to 162.0 mg · h/liter) and 134.0 mg · h/liter (IQR, 118.0 to 148.6 mg · h/liter) in healthy volunteers ( = <0.0001 and = <0.001, respectively). All isolates were susceptible to micafungin, with a median MIC of 0.016 mg/liter (IQR, 0.012 to 0.023 mg/liter). The median AUC/MIC ratio was 5,684 (IQR, 4,325 to 7,578), and 3 of the 17 evaluable patients (17.6%) diagnosed with proven invasive candidiasis did not meet the AUC/MIC ratio target of 5,000. Micafungin exposure was lower in critically ill patients than in healthy volunteers. The variability in micafungin exposure in this ICU population could be explained by the patients' body weight. Our findings suggest that healthier patients (sequential organ failure assessment [SOFA] score of <10) weighing more than 100 kg and receiving 100 mg micafungin daily are at risk for inappropriate micafungin exposure and potentially inadequate antifungal treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT01716988.). 10.1128/AAC.01398-17
    Molecular characterisation and clinical outcomes of Candida auris infection: Single-centre experience in Saudi Arabia. Almaghrabi Reem S,Albalawi Rashed,Mutabagani Maysoon,Atienza Edwin,Aljumaah Suliman,Gade Lalitha,Forsberg Kaitlin,Litvintseva Anastasia,Althawadi Sahar Mycoses BACKGROUND:Candida auris is a difficult-to-diagnose multidrug-resistant yeast that can cause invasive infections with high mortality. Since emerging in 2009, this pathogen has been associated with numerous outbreaks around the world. Whole genome sequencing (WGS) is instrumental for understanding the emergence and local transmission of this pathogen. OBJECTIVES:To describe the clinical, molecular characteristics of Candida auris infection and clinical outcome in our centre. PATIENTS AND METHODS:Patients with positive cultures for Candida auris were identified in a microbiology database. Clinical characteristics and antifungal susceptibility were obtained. Isolates were sent to the US CDC for whole genome sequencing. RESULTS:Seven unique patients with eight different isolates were identified. Seven isolates were sent to the US CDC for whole genome sequencing. None of the patients had bloodstream infection. Thirty-day mortality was higher in infected patients compared with those who were colonised. Seven of the eight isolates were resistant to both fluconazole, and five were resistant to amphotericin B. WGS analysis demonstrated that the seven isolates belonged to the South Asian clade but formed two distinct subclades suggesting two independent introductions and ongoing transmission within the facility. CONCLUSIONS:Candida auris is associated with a high mortality rate in infected patients. Strict infection control measures and surveillance for asymptomatic cases are warranted to halt ongoing transmission. 10.1111/myc.13065
    Candida spp. co-infection in COVID-19 patients with severe pneumonia: Prevalence study and associated risk factors. Segrelles-Calvo Gonzalo,de S Araújo Glauber R,Llopis-Pastor Estefanía,Carrillo Javier,Hernández-Hernández Marta,Rey Laura,Melean Nestor Rodríguez,Escribano Inés,Antón Esther,Zamarro Celia,García-Salmones Mercedes,Frases Susana Respiratory medicine BACKGROUND:Invasive fungal infections (IFI) are increasing in prevalence in recent years. In the last few months, the rise of COVID-19 patients has generated a new escalation in patients presenting opportunistic mycoses, mainly by Aspergillus. Candida infections are not being reported yet. OBJECTIVES:We aimed to determine the prevalence of systemic candidiasis in patients admitted to ICUs due to severe pneumonia secondary to SARS-CoV-2 infection and the existence of possible associated risk factors that led these patients to develop candidiasis. PATIENTS/METHODS:We designed a study including patients with a confirmed diagnosis of COVID-19. RESULTS:The prevalence of systemic candidiasis was 14.4%, and the main isolated species were C. albicans and C. parapsilosis. All patients that were tested positive for Candida spp. stayed longer in the ICU in comparison to patients who tested negative. Patients with candidiasis had higher MuLBSTA score and mortality rates and a worse radiological involvement. In our study, Candida spp. isolates were found in patients that were submitted to: tocilizumab, tocilizumab plus systemic steroids, interferon type 1β and Lopinavir-Ritonavir. CONCLUSIONS:Results suggested a high prevalence of systemic candidiasis in severe COVID-19-associated pneumonia patients. Patients with Candidiasis had the worst clinical outcomes. Treatment with tocilizumab could potentialize the risk to develop systemic candidiasis. 10.1016/j.rmed.2021.106619
    Comparison of four commercially available chromogenic media to identify Candida albicans and other medically relevant Candida species. Scharmann Ulrike,Kirchhoff Lisa,Chapot Valerie le Saout,Dziobaka Jan,Verhasselt Hedda Luise,Stauf Raphael,Buer Jan,Steinmann Joerg,Rath Peter-Michael Mycoses BACKGROUND:The number of invasive Candida infections has significantly increased in recent decades. For the successful treatment of fungal infections, rapid identification at the species level, particularly in polyfungal infections, is a key factor. In this study, four commercially available chromogenic media, CandiSelect™ 4 (CS4), chromID™ Candida Agar (CCA), BBL™ CHROMagar™ Candida Medium (BBL) and Brilliance™ Candida Agar (BCA) were evaluated for Candida identification. MATERIAL/METHODS:Overall, 181 bronchial secretion samples from intensive care patients were analysed prospectively. In addition, 18 primarily sterile materials, previously tested positive for Candida, were investigated retrospectively. All samples were cultured as recommended by the manufacturer and visually inspected after 24 and 48 hours by three independent investigators. As a control, colonies were identified by MALDI-TOF MS. Specificity and sensitivity were determined for C albicans identification prospectively. RESULTS:CS4 and BCA showed the best overall consensus with the identification results reached by MALDI-TOF MS for Candida albicans and species. A clear differentiation between the species could be ascertained via easily identifiable, species-specific coloration in contrast to BBL and CCA. Sensitivity for C albicans (n = 73) identification varied between 32% (BCA) and 69% (CS4 and CCA) after 24 hours and 68% (BBL) and 82% (BCA) after 48 hours incubation, while specificity ranged between 62% (BBL) and 81% (CCA) after 24 hours and 82% (BBL) and 85% (CS4) after 48 hours. CONCLUSION:CS4 and BCA are recommended for routine identification of Candida species in human samples. 10.1111/myc.13119
    ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Martin-Loeches Ignacio,Antonelli Massimo,Cuenca-Estrella Manuel,Dimopoulos George,Einav Sharon,De Waele Jan J,Garnacho-Montero Jose,Kanj Souha S,Machado Flavia R,Montravers Philippe,Sakr Yasser,Sanguinetti Maurizio,Timsit Jean-Francois,Bassetti Matteo Intensive care medicine INTRODUCTION:The term invasive candidiasis (IC) refers to both bloodstream and deep-seated invasive infections, such as peritonitis, caused by Candida species. Several guidelines on the management of candidemia and invasive infection due to Candida species have recently been published, but none of them focuses specifically on critically ill patients admitted to intensive care units (ICUs). MATERIAL AND METHODS:In the absence of available scientific evidence, the resulting recommendations are based solely on epidemiological and clinical evidence in conjunction with expert opinion. The task force used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the recommendations and assign levels of evidence. The recommendations and their strength were decided by consensus and, if necessary, by vote (modified Delphi process). Descriptive statistics were used to analyze the results of the Delphi process. Statements obtaining > 80% agreement were considered to have achieved consensus. CONCLUSIONS:The heterogeneity of this patient population necessitated the creation of a mixed working group comprising experts in clinical microbiology, infectious diseases and intensive care medicine, all chosen on the basis of their expertise in the management of IC and/or research methodology. The working group's main goal was to provide clinicians with clear and practical recommendations to optimize microbiological diagnosis and treatment of IC. The Systemic Inflammation and Sepsis and Infection sections of the European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) therefore decided to develop a set of recommendations for application in non-immunocompromised critically ill patients. 10.1007/s00134-019-05599-w
    Polymerase Chain Reaction Versus Blood Culture to Detect Candida Species in High-Risk Patients with Suspected Invasive Candidiasis: The MICAFEM Study. Nieto Mercedes,Robles Juan Carlos,Causse Manuel,Gutiérrez Leticia,Cruz Perez Maria,Ferrer Ricard,Xercavins Mariona,Herrero Eugenio,Sirvent Elia,Fernández Cristina,Anguita Paloma,Merino Paloma, Infectious diseases and therapy INTRODUCTION:We evaluated the diagnostic reliability of serum polymerase chain reaction (PCR) versus blood culture, abdominal fluid or both (composite measure) in patients receiving empirical antifungal treatment for suspected invasive candidiasis. METHODS:This observational, prospective, non-interventional, multicentre study in Spain enrolled 176 critically ill patients admitted to the intensive care unit. Separate blood samples for culture and serum PCR were taken before the start of antifungal therapy. Patient assessment was performed according to each site's usual clinical practice. The primary end point was concordance between serum PCR and blood culture. Secondary end points were concordance between serum PCR and a positive abdominal fluid sample or the composite measure. Quality indices included sensitivity, specificity, positive/negative predictive values (PPV/NPV) and kappa indices. RESULTS:Among 175 evaluable patients, rates of Candida detection were similar for serum PCR (n = 16/175, 9.1%) versus blood culture (n = 14/175, 8.0%). Quality indices for serum PCR relative to blood culture were: sensitivity 21.4%; specificity 91.9%; PPV 18.8%; NPV 93.1%; kappa index 0.125. Thirty-two abdominal fluid samples were positive. Quality indices for serum PCR versus abdominal fluid were: sensitivity 31.3%; specificity 83.0%; PPV 15.6%; NPV 92.3%; kappa index 0.100. Quality indices for serum PCR versus the composite measure were: sensitivity 15.8%; specificity 92.7%; PPV 37.5%; NPV 79.9%; kappa index 0.107. CONCLUSION:The sensitivity of serum PCR for Candida detection was low and the rate of concordance was low between serum PCR and the other diagnostic techniques used to identify Candida infections. Hospital-based diagnostic tests need optimising to improve outcomes in patients with suspected invasive candidiasis. FUNDING:Astellas Pharma Inc. 10.1007/s40121-019-0248-z
    Systematic review on the first line treatment of amphotericin B in critically ill adults with candidemia or invasive candidiasis. Keane Sean,Geoghegan Pierce,Povoa Pedro,Nseir Saad,Rodriguez Alejandro,Martin-Loeches Ignacio Expert review of anti-infective therapy INTRODUCTION:Invasive candidiasis is the most common fungal infection affecting critically ill adults. International guidelines provide differing recommendations for first-line antifungal therapy, with echinocandins considered first-line in the majority. Amphotericin B has broad activity and low minimum inhibitory concentration resistance patterns across most Candida species and guidance away from its use should be supported by the available evidence. Areas Covered: A systematic literature review was conducted from August to September 2017 to determine whether treatment with echinocandins or other available drugs, namely voriconazole, confers a therapeutic or survival benefit over amphotericin B in critically ill adults with invasive candidiasis. Inclusion criteria were: (1) studies describing critically ill adults with invasive candidiasis, (2) studies describing therapeutic benefit or survival as an outcome, and (3) studies comparing amphotericin B, deoxycholate or lipid preparations, with any newer antifungal agent. Eight studies were included in the final review, incorporating 2352 unique patients. No difference in treatment efficacy or mortality outcomes in critically ill patients with invasive candidiasis receiving an amphotericin B formulation compared with those receiving an echinocandin or voriconazole was shown. Expert Commentary: We conclude that in the existing literature, there is no evidence that choice between echinocandins, voriconazole, or amphotericin B formulations as first-line therapy for critically ill adults with invasive candidiasis is associated with a therapeutic or survival benefit. Clinicians must therefore consider other factors in the selection of first-line therapy. 10.1080/14787210.2018.1528872
    Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study. Bailly Sébastien,Gautier-Veyret Elodie,Lê Minh P,Bouadma Lila,Andremont Olivier,Neuville Mathilde,Mourvillier Bruno,Sonneville Romain,Magalhaes Eric,Lebut Jordane,Radjou Aguila,Smonig Roland,Wolff Michel,Massias Laurent,Dupuis Claire,Timsit Jean-François Antimicrobial agents and chemotherapy This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC) divided by the MIC (AUC/MIC) of 250, 450, and 865 and maximal concentration ( ) divided by the MIC ( /MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V = 9.0 ± 1.2 liters and V = 11.9 ± 2.9 liters. Observed and simulated CAS AUC were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and /MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.). 10.1128/AAC.01545-20
    Species distribution and antifungal susceptibility profile of Candida isolates from blood and other normally sterile foci from pediatric ICU patients in Tehran, Iran. Mirhendi Hossein,Charsizadeh Arezoo,Eshaghi Hamid,Nikmanesh Bahram,Arendrup Maiken Cavling Medical mycology As data on pediatric invasive candidiasis (IC) and the antifungal susceptibility pattern of associated isolates are scarce in Iran, this study aimed to determine species distribution and antifungal susceptibility profile of Candida species isolated from pediatric patients with suspected or documented IC. A total of 235 yeast strains recovered from normally sterile body fluids of patients admitted at the intensive care units of Children's Medical Centre, Tehran, Iran, were identified using CHROMagar Candida, molecular methods (ITS PCR-RFLP and sequencing), and MALDI-TOF. Susceptibility to amphotericin B, fluconazole, voriconazole, micafungin, and anidulafungin was determined according to the European on Antimicrobial Susceptibility testing reference microdilution method (EUCAST E.Def 7.3.1). Candida albicans (53.6%), C. parapsilosis (24.7%), and C. tropicalis (8.5%) were the most common species, followed by C. lusitaniae (4.3%), C. glabrata (3.0%), C. guilliermondii and C. orthopsilosis (each 1.7%), C. kefyr (1.3%), C. dubliniensis (0.8%), and C. intermedia (0.4%). Amphotericin B MICs were ≤1 mg/l for all Candida isolates. C. albicans isolates were susceptible to all five antifungal agents. All C. parapsilosis isolates categorised as intermediate to micafungin and anidulafungin, except two isolates that had the MICs >2 mg/l for micafungin. MIC50, MIC90, and MIC range for fluconazole were 0.25 mg/l, 1 mg/l, and 0.125 - ≥32 mg/l, respectively. Fluconazole and voriconazole showed 100% activity against the most prevalent Candida species. The low resistance rate, favorable safety profile and low cost of fluconazole make it a reasonable choice for treatment of candidemia/invasive candidemia in Iran. 10.1093/mmy/myz047
    A Cluster of Neonatal Infections Caused by Candida auris at a Large Referral Center in Colombia. Alvarado-Socarras Jorge L,Vargas-Soler José A,Franco-Paredes Carlos,Villegas-Lamus Katty Carolina,Rojas-Torres Juan Pablo,Rodriguez-Morales Alfonso J Journal of the Pediatric Infectious Diseases Society BACKGROUND:Globally, Candida auris is an emerging pathogen that poses an essential threat in healthcare settings presenting as outbreaks requiring significant allocation of infection control interventions to curb transmission. This fungal pathogen was initially identified in 2009 in Japan, but it has spread to all continents. Candida auris poses significant diagnostic and treatment challenges. Conventional microbiology laboratories often misidentify this pathogen as Candida haemulonii or as other Candida spp., Rhodoturola glutinis, and even with some bacterial pathogens, including Neisseria meningitidis serogroup A. Furthermore, C. auris displays distinct mechanisms of antifungal resistance to azoles and amphotericin B formulations. Most of the case series and outbreak reports have included invasive infections in adult populations. METHODS:Herein, we present a cluster of neonatal infections caused by Candida auris at a large referral center in Colombia. RESULTS:We report a case series of 8 neonates and infant patients who were seen at a large referral center in Colombia and who develop invasive infections caused by C. haemulonii and C. auris. DISCUSSION:Our report highlights the diagnostic challenges in identifying this fungal pathogen correctly, its clinical spectrum of disease, recommendations for empiric antifungal therapy, and it is not always associated with a high case fatality rate. 10.1093/jpids/piaa152
    Spleen Tyrosine Kinase Is a Critical Regulator of Neutrophil Responses to Species. mBio Invasive fungal infections constitute a lethal threat, with patient mortality as high as 90%. The incidence of invasive fungal infections is increasing, especially in the setting of patients receiving immunomodulatory agents, chemotherapy, or immunosuppressive medications following solid-organ or bone marrow transplantation. In addition, inhibitors of spleen tyrosine kinase (Syk) have been recently developed for the treatment of patients with refractory autoimmune and hematologic indications. Neutrophils are the initial innate cellular responders to many types of pathogens, including invasive fungi. A central process governing neutrophil recognition of fungi is through lectin binding receptors, many of which rely on Syk for cellular activation. We previously demonstrated that Syk activation is essential for cellular activation, phagosomal maturation, and elimination of phagocytosed fungal pathogens in macrophages. Here, we used combined genetic and chemical inhibitor approaches to evaluate the importance of Syk in the response of neutrophils to species. We took advantage of a Cas9-expressing neutrophil progenitor cell line to generate isogenic wild-type and Syk-deficient neutrophils. Syk-deficient neutrophils are unable to control the human pathogens , , and Neutrophil responses to species, including the production of reactive oxygen species and of cytokines such as tumor necrosis factor alpha (TNF-α), the formation of neutrophil extracellular traps (NETs), phagocytosis, and neutrophil swarming, appear to be critically dependent on Syk. These results demonstrate an essential role for Syk in neutrophil responses to species and raise concern for increased fungal infections with the development of Syk-modulating therapeutics. Neutrophils are recognized to represent significant immune cell mediators for the clearance and elimination of the human-pathogenic fungal pathogen The sensing of fungi by innate cells is performed, in part, through lectin receptor recognition of cell wall components and downstream cellular activation by signaling components, including spleen tyrosine kinase (Syk). While the essential role of Syk in macrophages and dendritic cells is clear, there remains uncertainty with respect to its contribution in neutrophils. In this study, we demonstrated that Syk is critical for multiple cellular functions in neutrophils responding to major human-pathogenic species. These data not only demonstrate the vital nature of Syk with respect to the control of fungi by neutrophils but also warn of the potential infectious complications arising from the recent clinical development of novel Syk inhibitors for hematologic and autoimmune disorders. 10.1128/mBio.02043-19
    Defining standards of CARE for invasive fungal diseases in the ICU. Cuenca-Estrella Manuel,Kett Daniel H,Wauters Joost The Journal of antimicrobial chemotherapy The aim of this article is to review the current recommendations for the diagnosis and treatment of invasive fungal infection in the ICU setting and to explore whether there are standards of care for this patient population. The text focuses mainly on the two most common invasive fungal diseases that afflict non-neutropenic patients: candidaemia and invasive candidosis (IC), and invasive pulmonary aspergillosis (IPA). 10.1093/jac/dkz038
    Candida and invasive mould diseases in non-neutropenic critically ill patients and patients with haematological cancer. Colombo A L,de Almeida Júnior J N,Slavin Monica A,Chen Sharon C-A,Sorrell Tania C The Lancet. Infectious diseases Critically ill patients and patients with haematological cancer are HIV-negative populations at high risk of invasive fungal infections. In intensive-care units, candidaemia and intra-abdominal candidiasis predominate, but aspergillosis has emerged as a lethal, under-recognised cause of pneumonia. In patients with haematological malignancies or who have undergone stem-cell transplantations, pulmonary disease due to aspergillus and other mould diseases predominate. In this Series paper, we provide an update on risk assessment, new diagnostic strategies, and therapeutic approaches. New concepts have emerged for use of risk prediction rules and an evidence base now exists for inclusion of biomarkers (eg, galactomannan, 1,3-β-D-glucan, and PCR assays for Aspergillus spp) into early diagnostic and therapeutic strategies. Imaging techniques remain helpful for early diagnosis of pulmonary mould diseases, with PET techniques offering potential improvements in diagnostic specificity and evaluation of clinical response. Echinocandins and triazoles have been validated extensively for prophylaxis, empirical therapy, and targeted therapy, but an increase in intrinsically resistant fungi and emergence of secondary resistance as a result of drug-induced selection pressure are of major concern. Echinocandins remain a major component of treatment of invasive candidiasis and new triazoles are the best alternative for prophylaxis and therapy of invasive aspergillosis. 10.1016/S1473-3099(17)30304-3
    The impact of real life treatment strategies for Candida peritonitis-A retrospective analysis. Dubler S,Laun M,Koch C,Hecker A,Weiterer S,Siegler B H,Röhrig R,Weigand M A,Lichtenstern C Mycoses Candida species are commonly detected isolates from abdominal foci. The question remains as to who would benefit from early empiric treatment in cases of Candida peritonitis. This study collected real-life data on critically ill patients with Candida peritonitis to estimate the relevance of the chosen treatment strategy on the outcome of these patients. One hundred and thirty-seven surgical intensive care unit (ICU) patients with intra-abdominal invasive Candidiasis were included in the study. Fifty-six patients did not get any antifungal agent. Twenty-nine patients were empirically treated, and 52 patients were specifically treated. In the group without, with empiric and with specific antifungal treatment, the 30-day mortality rate was 33.9, 48.3 and 44.2 respectively. Candida albicans was the most frequently found species. Seven patients in the specific treatment group and one patient in the empiric treatment group emerged with candidaemia. Age, leucocyte count, APACHE II Score and acute liver failure were independent predictors of 30-day mortality in patients with Candida peritonitis. Not all patients with Candida peritonitis received antifungal treatment in real clinical practice. Patients with higher morbidity more often got antifungals. Early empirical therapy has not been associated with a better 30-day mortality. 10.1111/myc.12615
    Monocyte human leukocyte antigen-DR but not β-D-glucan may help early diagnosing invasive Candida infection in critically ill patients. Jung Boris,Le Bihan Clément,Portales Pierre,Bourgeois Nathalie,Vincent Thierry,Lachaud Laurence,Chanques Gerald,Conseil Matthieu,Corne Philippe,Massanet Pablo,Timsit Jean François,Jaber Samir Annals of intensive care BACKGROUND:Precision medicine risk stratification is desperately needed to both avoid systemic antifungals treatment delay and over prescription in the critically ill with risk factors. The aim of the present study was to explore the combination of host immunoparalysis biomarker (monocyte human leukocyte antigen-DR expression (mHLA-DR)) and Candida sp wall biomarker β-D-glucan in risk stratifying patients for secondary invasive Candida infection (IC). METHODS:Prospective observational study. Two intensive care units (ICU). All consecutive non-immunocompromised septic shock patients. Serial blood samples (n = 286) were collected at day 0, 2 and 7 and mHLA-DR and β-D-glucan were then retrospectively assayed after discharge. Secondary invasive Candida sp infection occurrence was then followed at clinicians' discretion. RESULTS:Fifty patients were included, 42 (84%) had a Candida score equal or greater than 3 and 10 patients developed a secondary invasive Candida sp infection. ICU admission mHLA-DR expression and β-D-glucan (BDG) failed to predict secondary invasive Candida sp infection. Time-dependent cause-specific hazard ratio of IC was 6.56 [1.24-34.61] for mHLA-DR < 5000 Ab/c and 5.25 [0.47-58.9] for BDG > 350 pg/mL. Predictive negative value of mHLA-DR > 5000 Ab/c and BDG > 350 pg/mL combination at day 7 was 81% [95% CI 70-92]. CONCLUSIONS:This study suggests that mHLA-DR may help predicting IC in high-risk patients with septic shock. The added value of BDG and other fungal tests should be regarded according to the host immune function markers. 10.1186/s13613-021-00918-1
    An Azole-Resistant Outbreak: Clonal Persistence in the Intensive Care Unit of a Brazilian Teaching Hospital. Thomaz Danilo Yamamoto,de Almeida João Nobrega,Lima Glaucia Moreira Espindola,Nunes Maína de Oliveira,Camargo Carlos Henrique,Grenfell Rafaella de Carvalho,Benard Gil,Del Negro Gilda M B Frontiers in microbiology The incidence of candidemia by the complex has increased considerably in recent decades, frequently related to use of indwelling intravascular catheters. The ability of this pathogen to colonize healthcare workers (HCW)' hands, and to form biofilm on medical devices has been associated with the occurrence of nosocomial outbreaks and high mortality rates. Fluconazole has been the leading antifungal drug for the treatment of invasive candidiasis in developing countries. However, azole-resistant isolates are emerging worldwide, including in Brazil. Few studies have correlated outbreak infections due to with virulence factors, such as biofilm production. We thus conducted a microbiological investigation of complex isolates from a Brazilian teaching hospital. Additionally, we identified a previously unrecognized outbreak caused by a persistent azole-resistant () clone in the intensive care unit (ICU), correlating it with the main clinical data from the patients with invasive candidiasis. The molecular identification of the isolates was carried out by PCR-RFLP assay; antifungal susceptibility and biofilm formation were also evaluated. The genotyping of all () was performed by microsatellite analysis and the presence of mutations was assessed in the azole non-susceptible isolates. Fourteen () isolates were recovered from patients with invasive candidiasis, eight being fluconazole and voriconazole-resistant, and two intermediate only to fluconazole (FLC). All non-susceptible isolates showed a similar pattern of biofilm formation with low biomass and metabolic activity. The A395T mutation in was detected exclusively among the azole-resistant isolates. According to the microsatellite analysis, all azole non-susceptible isolates from the adult ICU were clustered together indicating the occurrence of an outbreak. Regarding clinical data, all patients infected by the clonal non-susceptible isolates and none of the patients infected by the susceptible isolates had been previously exposed to corticosteroids (p = 0.001), while the remaining characteristics showed no statistical significance. The current study revealed the persistence of an azole non-susceptible clone with low capacity to form biofilm over two years in the adult ICU. These results reinforce the need of epidemiological surveillance and monitoring antifungal susceptibility of isolates in hospital wards. 10.3389/fmicb.2018.02997
    Risk factors and outcomes of deep tissue Candida invasion in neonates with invasive candidiasis. Eisi Hanin,Ibraheem Shohood,Hisham Tooba,Al-Harbi Aziza,Saidy Khalid,Ali Ismail,Nour Islam,Nasef Nehad Mycoses BACKGROUND:Deep tissue Candida invasion represents a special entity among neonates with invasive candidiasis. We aimed to explore the risk factors and clinical outcomes for deep tissue Candida invasion among neonates with invasive candidiasis. METHODS:A retrospective data review of neonates admitted to NICU of Madinah maternity and children hospital, KSA from January 2012 to December 2019 was done. Data were analysed between infants with or without deep tissue candidiasis among infants with invasive candidiasis. Invasive candidiasis was defined as positive blood or catheter collected urine culture for Candida. Deep tissue Candida invasion was defined as an infection of the central nervous system, eyes, heart, skeletal system, lungs, liver or kidneys. RESULT:A total of 14 (11%) out of 130 neonates with invasive candidiasis had deep tissue Candida invasion. Persistent positive blood culture for Candida [OR 15.2, 95% CI (2.0-114), p = .01], prematurity [OR 7.6, 95% CI (1.04-56.4), p = .04] and prolonged antibiotic duration [OR 1.3, 95% CI (1.02-1.6), p = .03] are independent risk factors for deep tissue Candida invasion. Deep tissue Candida invasion was associated with significantly higher rates of cerebral palsy, hydrocephalus, heart failure and longer length of hospital stay compared to infants without deep tissue invasion. CONCLUSION:Persistent Candida growth in blood cultures, prematurity and long-term antibiotic use are significant risk factors for deep tissue Candida invasion. Deep tissue Candida invasion is associated with prolonged hospital stay and higher neonatal morbidity. 10.1111/myc.13395
    Fluconazole Doses Used for Prophylaxis of Invasive Fungal Infection in Neonatal Intensive Care Units: A Network Meta-Analysis. Leonart Letícia Paula,Tonin Fernanda Stumpf,Ferreira Vinicius Lins,Tavares da Silva Penteado Suelem,de Araújo Motta Fábio,Pontarolo Roberto The Journal of pediatrics OBJECTIVES:To evaluate the safety and efficacy of different doses of fluconazole used for invasive prophylaxis of fungal infection in neonates. STUDY DESIGN:A systematic search was conducted with PubMed, Scopus, and Web of Science. A manual search was performed as well. Only randomized controlled trials of neonates in a neonatal intensive care unit (NICU) who received fluconazole prophylaxis for invasive fungal infection, regardless of the dose or therapeutic regimen, were included in this review. Data on baseline characteristics, outcomes incidence of proven invasive Candida infection, overall mortality, and invasive Candida infection-related mortality were extracted. RESULTS:Eleven studies were included in the review, with fluconazole doses of 3, 4, or 6?mg/kg. When the incidence of invasive Candida and invasive Candida-related mortality were considered as outcomes, the 3 and 6?mg/kg fluconazole doses were found to be statistically superior to placebo (OR, 5.48 [95% credible interval, 1.81-18.94] and 2.63 [1.18-7.02], respectively, and 15.32 [1.54-54.31] and 9.14 [1.26-142.7], respectively), but data for the 3 doses were not statistically significantly different. CONCLUSIONS:Use of the lowest fluconazole dose (3?mg/kg) should be recommended for Candida prophylaxis in neonates, given that increasing the fluconazole dose is not associated with higher efficacy and has greater potential for toxicity and increased cost. 10.1016/j.jpeds.2017.02.039
    Low Caspofungin Exposure in Patients in Intensive Care Units. van der Elst Kim C M,Veringa Anette,Zijlstra Jan G,Beishuizen Albertus,Klont Rob,Brummelhuis-Visser Petra,Uges Donald R A,Touw Daan J,Kosterink Jos G W,van der Werf Tjip S,Alffenaar Jan-Willem C Antimicrobial agents and chemotherapy In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in intensive care unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands from November 2013 to October 2015. Patients received standard caspofungin treatment, and the exposure was determined on day 3 of treatment. An area under the concentration-time curve from 0 to 24 h (AUC) of 98 mg · h/liter was considered adequate exposure. In case of low exposure (i.e., <79 mg · h/liter, a ≥20% lower AUC), the caspofungin dose was increased and the exposure reevaluated. Twenty patients were included in the study, of whom 5 had a positive blood culture. The median caspofungin AUC at day 3 was 78 mg · h/liter (interquartile range [IQR], 69 to 97 mg · h/liter). A low AUC (<79 mg · h/liter) was seen in 10 patients. The AUC was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg · h/liter (IQR, 103.2 to 143.5 mg · h/liter). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with that in healthy volunteers and other (non)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution. (This study has been registered at ClinicalTrials.gov under registration no. NCT01994096.). 10.1128/AAC.01582-16
    An outbreak due to Candida auris with prolonged colonisation and candidaemia in a tertiary care European hospital. Ruiz-Gaitán Alba,Moret Ana M,Tasias-Pitarch María,Aleixandre-López Ana I,Martínez-Morel Héctor,Calabuig Eva,Salavert-Lletí Miguel,Ramírez Paula,López-Hontangas José L,Hagen Ferry,Meis Jacques F,Mollar-Maseres Juan,Pemán Javier Mycoses Multidrug-resistant Candida auris has emerged as a cause of insidious hospital outbreaks and complicated infections. We present the analysis of an ongoing C. auris outbreak including the largest published series of C. auris bloodstream infection. All C. auris-positive patients from April-2016 to January-2017 were included. Environmental, clinical and microbiological data were recorded. Definitive isolate identification was performed by ITS-rDNA sequencing, and typing by amplified fragment length polymorphism fingerprinting. One hundred and forty patients were colonised by C. auris during the studied period (68% from surgical intensive care). Although control measures were implemented, we were not able to control the outbreak. Forty-one invasive bloodstream infections (87.8% from surgical intensive care) were included. Clinical management included prompt intravascular catheter removal and antifungal therapy with echinocandins. All isolates were fluconazole- and voriconazole-resistant, but echinocandin- and amphotericin B-susceptible. Thirty-day mortality rate was 41.4%, and severe septic metastasis as spondylodiscitis and endocarditis were observed in 5 patients (12%). C. auris was also recovered from inanimate patient surroundings and medical equipment. Despite antifungal treatment, high mortality and late complication rates were recorded. Molecular typing suggested a clonal outbreak different from those previously published. 10.1111/myc.12781
    Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients. Martial Lisa C,Ter Heine Rob,Schouten Jeroen A,Hunfeld Nicole G,van Leeuwen Henk J,Verweij Paul E,de Lange Dylan W,Pickkers Peter,Brüggemann Roger J Clinical pharmacokinetics OBJECTIVE:To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS:Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. RESULTS:A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V and V were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. CONCLUSIONS:The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study. 10.1007/s40262-017-0509-5
    Microbial epidemiology of candidaemia in neonatal and paediatric intensive care units at the Children's Medical Center, Tehran. Charsizadeh Arezu,Mirhendi Hossein,Nikmanesh Bahram,Eshaghi Hamid,Makimura Koichi Mycoses Invasive candidiasis is a major cause of morbidity and mortality in children. However, limited data are available on the epidemiology of this infection in paediatric settings in Iran. The aim of this study was to determine the prevalence, microbial epidemiology, risk factors and clinical outcomes associated with candidaemia in intensive care units at the Children's Medical Center, Tehran, Iran. All blood and other normally sterile specimen cultures positive for Candida species were included. Isolates were identified by morphological and molecular methods. Unidentified/doubtful yeast isolates were subjected to ITS sequencing. A total of 156 episodes of invasive candidiasis, with an overall incidence of 15.2 per 1000 ICU admissions, was recorded. Risk factors included presence of central venous lines (89.1%), mechanical ventilation (55.8%) and parenteral nutrition (51.3%). Candida albicans (57.1%) and Candida parapsilosis (24.4%) were the most commonly isolated species. Candida orthopsilosis, Candida glabrata, Candida dubliniensis, Candida lusitaniae, Candida kefyr and Candida intermedia accounted for about 11% of the cases. The overall mortality rate was 42.5%. Non-albicans Candida species accounted for nearly half of the cases of paediatric candidaemia. This is the first prospective study of candidaemia in paediatric settings in Iran and serves to inform necessary interventions for the prevention of candidaemia. 10.1111/myc.12698
    Health care-associated invasive Candida infections in children. Öncü Bahaettin,Belet Nurşen,Emecen Ahmet Naci,Birinci Asuman Medical mycology The aims of the study were to examine the distribution of Candida spp. isolated from sterile body sites, the antifungal susceptibility of the isolates to amphotericin B, and fluconazole, risk factors and clinical outcomes associated with invasive health care-associated Candida infections in neonates and children. Between January 2007 and January 2012, the patients with invasive candidiasis were detected from microbiology laboratary records and medical records were examined retrospectively. Candida spp. were isolated from sterile body sites in 94 patients. The most common underlying diseases were prematurity in neonates and surgery in children. Parenteral nutrition, stay in intensive care unit (ICU), and mechanical ventilation (MV) were major risk factors in neonates. Hospitalization before infection and immunosuppressant therapy were significantly more frequent in children. Of Candida infection episodes, 29.8% was due to C. albicans and 70.2% was due to non-albicans Candida spp. The most common isolated species was C. parapsilosis. Of the Candida species, 90.8% were sensitive, and 9.2% were resistant to fluconazole. The rate of amphotericin B resistant was 1.3%; 23.4% of the patients died in the first 30 days. The main variables associated with mortality were neonates, prematurity, stay in the ICU, parenteral nutrition, MV, length of stay, amphotericin B susceptibility, and high levels of C-reactive protein. 10.1093/mmy/myz005
    Candida colonization as a predictor of invasive candidiasis in non-neutropenic ICU patients with sepsis: A systematic review and meta-analysis. Alenazy Hameid,Alghamdi Amenah,Pinto Ruxandra,Daneman Nick International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases BACKGROUND:Candida colonization is a risk factor for the development of invasive candidiasis. This study sought to estimate the magnitude of this association, and determine if this information can be used to guide empirical antifungal therapy initiation in critically ill septic patients. METHODS:PubMed/MEDLINE and Embase were systematically reviewed for all published studies evaluating predictors of invasive candidiasis in ICU patients with sepsis. Meta-analysis was used to determine the pooled odds ratio for invasive candidiasis among colonized versus non-colonized patients. Sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (+LR, -LR) were then calculated by considering the presence/absence of Candida colonization as the diagnostic test, and the presence/absence of invasive candidiasis as the disease of interest. RESULTS:Out of 9825 patients in the 10 eligible studies, 3886 (40%) were colonized with Candida and 462 patients (4.7%) developed invasive candidiasis. Meta-analysis indicated that critically ill patients with sepsis who are colonized with candida are more likely to develop invasive candidiasis (odds ratio 3.32; 95% CI 1.68-6.58) compared with non-colonized patients. The pooled SN was 75.2% (95% CI 59.6-86.2%), while the pooled SP was 49.2% (95% CI 33.2-65.3%).The NPV of Candida colonization was high (96.9%; 95% CI 92.0-98.9%), but the PPV was low (9.1%; 95% CI 5.5-14.6%). CONCLUSION:Candida colonization is strongly associated with the likelihood of invasive candidiasis among ICU patients with sepsis. Available data argue against initiating empirical antifungal treatment in non-neutropenic septic patients without prior documented Candida colonization. 10.1016/j.ijid.2020.10.092
    A Candida auris Outbreak and Its Control in an Intensive Care Setting. Eyre David W,Sheppard Anna E,Madder Hilary,Moir Ian,Moroney Ruth,Quan T Phuong,Griffiths David,George Sophie,Butcher Lisa,Morgan Marcus,Newnham Robert,Sunderland Mary,Clarke Tiphanie,Foster Dona,Hoffman Peter,Borman Andrew M,Johnson Elizabeth M,Moore Ginny,Brown Colin S,Walker A Sarah,Peto Tim E A,Crook Derrick W,Jeffery Katie J M The New England journal of medicine BACKGROUND:Candida auris is an emerging and multidrug-resistant pathogen. Here we report the epidemiology of a hospital outbreak of C. auris colonization and infection. METHODS:After identification of a cluster of C. auris infections in the neurosciences intensive care unit (ICU) of the Oxford University Hospitals, United Kingdom, we instituted an intensive patient and environmental screening program and package of interventions. Multivariable logistic regression was used to identify predictors of C. auris colonization and infection. Isolates from patients and from the environment were analyzed by whole-genome sequencing. RESULTS:A total of 70 patients were identified as being colonized or infected with C. auris between February 2, 2015, and August 31, 2017; of these patients, 66 (94%) had been admitted to the neurosciences ICU before diagnosis. Invasive C. auris infections developed in 7 patients. When length of stay in the neurosciences ICU and patient vital signs and laboratory results were controlled for, the predictors of C. auris colonization or infection included the use of reusable skin-surface axillary temperature probes (multivariable odds ratio, 6.80; 95% confidence interval [CI], 2.96 to 15.63; P<0.001) and systemic fluconazole exposure (multivariable odds ratio, 10.34; 95% CI, 1.64 to 65.18; P=0.01). C. auris was rarely detected in the general environment. However, it was detected in isolates from reusable equipment, including multiple axillary skin-surface temperature probes. Despite a bundle of infection-control interventions, the incidence of new cases was reduced only after removal of the temperature probes. All outbreak sequences formed a single genetic cluster within the C. auris South African clade. The sequenced isolates from reusable equipment were genetically related to isolates from the patients. CONCLUSIONS:The transmission of C. auris in this hospital outbreak was found to be linked to reusable axillary temperature probes, indicating that this emerging pathogen can persist in the environment and be transmitted in health care settings. (Funded by the National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance at Oxford University and others.). 10.1056/NEJMoa1714373
    Caspofungin: a review of its characteristics, activity, and use in intensive care units. Hashemian Seyed MohammadReza,Farhadi Tayebeh,Velayati Ali Akbar Expert review of anti-infective therapy INTRODUCTION:Candidemia is the fourth frequent reason of healthcare-related bloodstream infections in critically ill patients. For initial management of (suspected) invasive candidiasis in critically ill patients, usage of an echinocandin, e.g. caspofungin, has been recommended. AREAS COVERED:In this study, characteristics of caspofungin and its use in intensive care unit (ICU) patients are reviewed based on an electronic search using PubMed and Google scholar. EXPERT OPINION:Caspofungin is a semisynthetic derivative from pneumocandin B and the first member of the echinocandins that was approved by the U.S. Food and Drug Administration (FDA) to fight fungal infection. Caspofungin inhibits the enzyme β(1,3)-D-glucan synthase of the fungal cell wall resulted in inhibition of the synthesis of β(1,3)-D-glucan. For critically ill patients, inter- and intraindividual variations affect the caspofungin concentration. The incidence rates and densities of candidemia in surgical ICUs may be higher than medical ICUs resulting in a higher burden of candidemia in surgical ICUs. However, the mortality rate in surgical ICU patients with candidemia is higher than that medical ICU patients due to differences in their underlying conditions. 10.1080/14787210.2020.1794817
    Risk Factors for Invasive Candida Infection in Critically Ill Patients: A Systematic Review and Meta-analysis. Thomas-Rüddel Daniel O,Schlattmann Peter,Pletz Mathias,Kurzai Oliver,Bloos Frank Chest BACKGROUND:Current guidelines recommend empirical antifungal therapy in patients with sepsis with high risk of invasive Candida infection. However, many different risk factors have been derived from multiple studies. These risk factors lack specificity, and broad application would render most ICU patients eligible for empirical antifungal therapy. RESEARCH QUESTION:What risk factors for invasive Candida infection can be identified by a systematic review and meta-analysis? STUDY DESIGN AND METHODS:We searched PubMed, Web of Science, ScienceDirect, Biomed Central, and Cochrane and extracted the raw and adjusted OR for each risk factor associated with invasive Candida infection. We calculated pooled ORs for risk factors present in more than one study. RESULTS:We included 34 studies in our meta-analysis resulting in the assessment of 29 possible risk factors. Risk factors for invasive Candida infection included demographic factors, comorbid conditions, and medical interventions. Although demographic factors do not play a role for the development of invasive Candida infection, comorbid conditions (eg, HIV, Candida colonization) and medical interventions have a significant impact. The risk factors associated with the highest risk for invasive Candida infection were broad-spectrum antibiotics (OR, 5.6; 95% CI, 3.6-8.8), blood transfusion (OR, 4.9; 95% CI, 1.5-16.3), Candida colonization (OR, 4.7; 95% CI, 1.6-14.3), central venous catheter (OR, 4.7; 95% CI, 2.7-8.1), and total parenteral nutrition (OR, 4.6; 95% CI, 3.3-6.3). However, dependence between the various risk factors is probably high. INTERPRETATION:Our systematic review and meta-analysis identified patient- and treatment-related factors that were associated with the risk for the development of invasive Candida infection in the ICU. Most of the factors identified were either related to medical interventions during intensive care or to comorbid conditions. 10.1016/j.chest.2021.08.081
    Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units. Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project. Bassetti Matteo,Scudeller Luigia,Giacobbe Daniele R,Lamoth Frederic,Righi Elda,Zuccaro Valentina,Grecchi Cecilia,Rebuffi Chiara,Akova Murat,Alastruey-Izquierdo Ana,Arikan-Akdagli Sevtap,Azoulay Elie,Blot Stijn I,Cornely Oliver A,Lass-Flörl Cornelia,Koehler Philipp,Cuenca-Estrella Manuel,de Lange Dylan W,De Rosa Francesco G,De Waele Jan J,Dimopoulos George,Garnacho-Montero José,Hoenigl Martin,Kanj Souha S,Maertens Johan,Martin-Loeches Ignacio,Muñoz Patricia,Kullberg Bart J,Agvald-Ohman Christina,Poulakou Garyphallia,Rello Jordi,Sanguinetti Maurizio,Taccone Fabio S,Timsit Jean-François,Torres Antoni,Vazquez Jose A,Calandra Thierry, , , , Mycoses BACKGROUND:The reliability of diagnostic criteria for invasive fungal diseases (IFD) developed for severely immunocompromised patients is questionable in critically ill adult patients in intensive care units (ICU). OBJECTIVES:To develop a standard set of definitions for IFD in critically ill adult patients in ICU. METHODS:Based on a systematic literature review, a list of potential definitions to be applied to ICU patients will be developed by the ESCMID Study Group for Infections in Critically Ill Patients (ESGCIP) and the ESCMID Fungal Infection Study Group (EFISG) chairpersons. The proposed definitions will be evaluated by a panel of 30 experts using the RAND/UCLA appropriateness methods. The panel will rank each of the proposed definitions on a 1-9 scale trough a dedicated questionnaire, in two rounds: one remote and one face-to-face. Based on their median rank and the level of agreement across panel members, selected definitions will be organised in a main consensus document and in an executive summary. The executive summary will be made available online for public comments. CONCLUSIONS:The present consensus project will seek to provide standard definitions for IFD in critically ill adult patients in ICU, with the ultimate aims of improving their clinical outcome and facilitating the comparison and generalizability of research findings. 10.1111/myc.12869
    Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project. Bassetti Matteo,Giacobbe Daniele R,Vena Antonio,Trucchi Cecilia,Ansaldi Filippo,Antonelli Massimo,Adamkova Vaclava,Alicino Cristiano,Almyroudi Maria-Panagiota,Atchade Enora,Azzini Anna M,Carannante Novella,Carnelutti Alessia,Corcione Silvia,Cortegiani Andrea,Dimopoulos George,Dubler Simon,García-Garmendia José L,Girardis Massimo,Cornely Oliver A,Ianniruberto Stefano,Kullberg Bart Jan,Lagrou Katrien,Le Bihan Clement,Luzzati Roberto,Malbrain Manu L N G,Merelli Maria,Marques Ana J,Martin-Loeches Ignacio,Mesini Alessio,Paiva José-Artur,Peghin Maddalena,Raineri Santi Maurizio,Rautemaa-Richardson Riina,Schouten Jeroen,Brugnaro Pierluigi,Spapen Herbert,Tasioudis Polychronis,Timsit Jean-François,Tisa Valentino,Tumbarello Mario,van den Berg Charlotte H S B,Veber Benoit,Venditti Mario,Voiriot Guillaume,Wauters Joost,Montravers Philippe Critical care (London, England) BACKGROUND:The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS:A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS:During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS:The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions. 10.1186/s13054-019-2497-3
    Changes in the distribution of colonising and infecting Candida spp. isolates, antifungal drug consumption and susceptibility in a French intensive care unit: A 10-year study. Sasso Milène,Roger Claire,Sasso Magali,Poujol Hélène,Barbar Saber,Lefrant Jean-Yves,Lachaud Laurence Mycoses Monitoring fungal ecology and resistance to antifungal agents within intensive care units (ICU) is essential for the management of invasive fungal infections. Therefore, a retrospective descriptive study was carried in the ICU of Nimes University Hospital, France, from 2007 to 2016. As the majority of invasive fungal infections in ICU are caused by Candida species, the study objectives were to describe Candida species distribution, to assess candidaemia incidence and to monitor the antifungal drug susceptibility of Candida isolates and the consumption of antifungal agents. Among the recorded invasive Candida infections (n=244), 43% were intra-abdominal and 22% bloodstream infections. Candida albicans was the most frequent species (55.8%), followed by Candida glabrata (14.1%), Candida tropicalis (10%), Candida parapsilosis (8%) and Candida krusei (5.3%). Candidaemia incidence was 4.49 per 1000 admissions. The mean consumption of antifungal agents was of 170.5 defined daily doses (DDD) for 1000 hospital days (HD) per year. Changes in antifungal drug consumption were observed, with an increased use of echinocandins (from 17.96 DDD/1000 HD in 2007 to 48.76 DDD/1000 HD in 2016), and the total treatment cost tripled during the study period. No significant change in fungal ecology or in the emergence of resistant species was observed; indeed, only 1.1% of isolates presented an unusual resistance to antifungal agents. 10.1111/myc.12661
    Initial therapeutic strategy of invasive candidiasis for intensive care unit patients: a retrospective analysis from the China-SCAN study. Cui Na,Wang Hao,Su Longxiang,Qiu Haibo,Li Ruoyu,Liu Dawei, BMC infectious diseases BACKGROUND:To investigate the impact of initial antifungal therapeutic strategies on the prognosis of invasive Candida infections (ICIs) in intensive care units (ICUs) in China. METHODS:A total of 306 patients with proven ICIs in the China-SCAN study were analyzed retrospectively. Empiric, pre-emptive, and targeted therapy were adopted based on starting criteria including clinical, microbiological, and other conventional prediction rules. The primary outcome was hospital mortality and the secondary endpoints were duration days in ICU and duration days in hospital. The global responses (clinical and microbiological) at the end of the empirical therapy were also assessed. RESULTS:A total of 268/306 (87.6%) ICI patients received antifungal therapy, including 142/268 (53.0%) initial empirical therapy, 53/268 (19.8%) initial pre-emptive therapy, and 73/268 (27.2%) initial targeted therapy. Compared with the initial empirical antifungal therapy and targeted antifungal therapy, patients with initial pre-emptive antifungal therapy had significantly less clinical remission [11/53 (21.2%) vs. 61/142 (43.3%) vs. 22/73 (30.1%), P = 0.009], higher ICU [26/53 (57.8%) vs. 42/142 (32.2%) vs. 27/73 (43.5%), P = 0.008] and hospital mortality [27/53 (60.0%) vs. 43/142 (32.8%) vs. 29/73 (46.8%), P = 0.004] and more microbiological persistence [9/53 (17.0%) vs. 6/142 (4.2%) vs. 9/73 (12.3%), P = 0.011]. Kaplan-Meier survival analysis revealed that ICI patients with initial pre-emptive antifungal therapy and targeted antifungal therapy were associated with reduced hospital duration compared with patients with initial empirical antifungal therapy after confirmation of fungal infection (log-rank test: P = 0.021). Multivariate regression analysis provided evidence that initial empirical antifungal therapy was an independent predictor for DECREASING the hospital mortality in ICI patients on ICU admission and at ICI diagnosis (odds ratio 0.327, 95% confidence interval 0.160-0.667, P = 0.002; odds ratio 0.351, 95% confidence interval 0.168-0.735, P = 0.006). CONCLUSIONS:The initial therapeutic strategy for invasive candidiasis was independently associated with hospital mortality. Prompt empirical antifungal therapy could be critical to decrease early hospital mortality. TRIAL REGISTRATION:Clinicaltrials.gov NCT01253954 (retrospectively registration date: December 3, 2010). 10.1186/s12879-017-2207-1
    COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave. Bretagne Stéphane,Sitbon Karine,Botterel Françoise,Dellière Sarah,Letscher-Bru Valérie,Chouaki Taieb,Bellanger Anne-Pauline,Bonnal Christine,Fekkar Arnault,Persat Florence,Costa Damien,Bourgeois Nathalie,Dalle Frédéric,Lussac-Sorton Florian,Paugam André,Cassaing Sophie,Hasseine Lilia,Huguenin Antoine,Guennouni Nadia,Mazars Edith,Le Gal Solène,Sasso Milène,Brun Sophie,Cadot Lucile,Cassagne Carole,Cateau Estelle,Gangneux Jean-Pierre,Moniot Maxime,Roux Anne-Laure,Tournus Céline,Desbois-Nogard Nicole,Le Coustumier Alain,Moquet Olivier,Alanio Alexandre,Dromer Françoise, Microbiology spectrum The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) ( < 10). For CAPA, the presence of several mycological criteria was associated with death ( < 10). Serum galactomannan was rarely positive (<20%). The mortality rates were 76.7% (23/30) in patients with host factors for invasive fungal disease, 45.2% (14/31) in those with a preexisting pulmonary condition, and 36.6% (34/93) in the remaining patients ( = 0.001). Antimold treatment did not alter prognosis ( = 0.370). Candida albicans was responsible for 59.3% of CA-fungemias, with a global mortality of 45.7%. For CA-PCP, 58.8% of the episodes occurred in patients with known host factors of PCP, and the mortality rate was 29.5%. CAPA may be in part hospital acquired and could benefit from antifungal prescription at the first positive biomarker result. CA-fungemia appeared linked to ICU stay without COVID-19 specificity, while CA-PCP may not really be a concern in the ICU. Improved diagnostic strategy for fungal markers in ICU patients with COVID-19 should support these hypotheses. To diagnose fungal coinfections in patients with COVID-19 in the intensive care unit, it is necessary to implement the correct treatment and to prevent them if possible. For COVID-19-associated pulmonary aspergillosis (CAPA), respiratory specimens remain the best approach since serum biomarkers are rarely positive. Timing of occurrence suggests that CAPA could be hospital acquired. The associated mortality varies from 36.6% to 76.7% when no host factors or host factors of invasive fungal diseases are present, respectively. Fungemias occurred after 2 weeks in ICUs and are associated with a mortality rate of 45.7%. Candida albicans is the first yeast species recovered, with no specificity linked to COVID-19. Pneumocystosis was mainly found in patients with known immunodepression. The diagnosis occurred at the entry in ICUs and not afterwards, suggesting that if Pneumocystis jirovecii plays a role, it is upstream of the hospitalization in the ICU. 10.1128/Spectrum.01138-21
    Deciphering the epidemiology of invasive candidiasis in the intensive care unit: is it possible? Soulountsi Vasiliki,Schizodimos Theodoros,Kotoulas Serafeim Chrysovalantis Infection 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. 10.1007/s15010-021-01640-7
    Invasive Infections in a Pediatric Intensive Care Unit in Turkey: Evaluation of an 11-Year Period. Aslan Nagehan,Yildizdas Dincer,Alabaz Derya,Horoz Ozden Ozgur,Yontem Ahmet,Kocabas Emine Journal of pediatric intensive care The aim of this study was to evaluate the species, predisposing factors, antifungal treatment approaches, and clinical outcomes of invasive infections (ICIs) in a tertiary pediatric intensive care unit (PICU). A retrospective study was performed from January 2008 to January 2019 including 102 children with ICIs who were admitted to a university hospital in southeastern Turkey. Positive blood cultures were detected in 43 (42.1%) patients, and positive urine cultures were detected in 59 (57.8%). According to our results, (42.2%) was the most common species for all isolates followed by (17.6%). In our patient population, non- species were dominant (57.8%) in all isolates. The most common facilitating factor in our study was the use of mechanical ventilator support (87.3%). The mortality rate of our patients with ICIs was 13.7%. was found to have the highest mortality rate among all species (30.7%). When we compared patients with and those with non- species in terms of risk factors, we detected a significant difference between the two groups for total parenteral nutrition use (  = 0.027). Fluconazole was the most preferred (58.8%) treatment option in our PICU for ICIs. Our results showed an increased trend in micafungin use in recent years. ICIs are a significant problem due to the high mortality and morbidity rates in critically ill pediatric patients in PICUs. In recent years, an increase in infections caused by non- species has been reported. Multicenter prospective studies are needed to determine the risk factors for ICIs. 10.1055/s-0039-1695061
    Diagnostic surveillance by Candida albicans germ tube antibody in intensive care unit patients. Trovato Laura,Astuto Marinella,Castiglione Giacomo,Scalia Guido,Oliveri Salvatore Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi BACKGROUND:The diagnosis of Invasive Candidiasis (IC) presents serious problems, mainly associated with the absence of pathognomonic symptoms of the disease and the difficulty of isolating the fungus in blood culture. Candida albicans germ tube antibody (CAGTA) provides a rapid and simple test for diagnosis of IC. The aim of this study was to evaluate the diagnostic role of the CAGTA in the monitoring of critically-ill patients at risk of developing IC. METHODS:During diagnostic surveillance in the intensive care units (ICU) CAGTA was performed twice a week if predetermined risk factors were present and a positive result was considered when a serum titer ≥1/160 was detected in at least one sample. RESULTS:Seventy critically ill patients were included in the study. Twenty-three patients with proven/probable IC were identified. The sensitivity, specificity, PPV, and NPV of CAGTA for the diagnosis of proven/probable IC in all 70 patients were 91.3%, 68.1%, 58.3%, and 94.1%, respectively. Statistically significant highest titers were found in patients with proven/probable IC as well as increasing titers more than 1/160. CONCLUSIONS:Our results suggest that detection of CAGTA could be a useful biomarker for the diagnosis of proven and probable IC in critical patients during prolonged ICU stay. During the monitoring it is opportune to evaluate the titers kinetics since the clinical diagnosis of proven/probable IC coincided with increase titer from negative (<1/160) to more than 1/160. 10.1016/j.jmii.2019.02.001
    Intensive care medicine research agenda on invasive fungal infection in critically ill patients. Bassetti Matteo,Garnacho-Montero Jose,Calandra Thierry,Kullberg Bartjan,Dimopoulos George,Azoulay Elie,Chakrabarti Arunaloke,Kett Daniel,Leon Cristobal,Ostrosky-Zeichner Luis,Sanguinetti Maurizio,Timsit Jean-Francois,Richardson Malcom D,Shorr Andrew,Cornely Oliver A Intensive care medicine PURPOSE:To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting. METHODS:A systematic review of the medical literature taking account of national and international guidelines and expert opinion. RESULTS:Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3-19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [β-1 → 3-D-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment. CONCLUSIONS:Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed. 10.1007/s00134-017-4731-2
    Invasive Candidiasis in Critically Ill Patients: A Prospective Cohort Study in Two Tertiary Care Centers. Journal of intensive care medicine BACKGROUND:Invasive candidiasis is not uncommon in critically ill patients but has variable epidemiology and outcomes between intensive care units (ICUs). This study evaluated the epidemiology, characteristics, management, and outcomes of patients with invasive candidiasis at 6 ICUs of 2 tertiary care centers. METHODS:This was a prospective observational study of all adults admitted to 6 ICUs in 2 different hospitals between August 2012 and May 2016 and diagnosed to have invasive candidiasis by 2 intensivists according to predefined criteria. The epidemiology of isolated and the characteristics, management, and outcomes of affected patients were studied. Multivariable logistic regression analyses were performed to identify the predictors of versus infection and hospital mortality. RESULTS:Invasive candidiasis was diagnosed in 162 (age 58.4 ± 18.9 years, 52.2% males, 82.1% medical admissions, and admission Acute Physiology and Chronic Health Evaluation II score 24.1 ± 8.4) patients at a rate of 2.6 cases per 100 ICU admissions. On the diagnosis day, the Candida score was 2.4 ± 0.9 in invasive candidiasis compared with 1.6 ± 0.9 in colonization ( < .01). The most frequent species were (38.3%), (16.7%), (16%), and (13.6%). In patients with candidemia, antifungal therapy was started on average 1 hour before knowing the culture result (59.6% of therapy initiated after). Resistance to fluconazole, caspofungin, and amphotericin B occurred in 27.9%, 2.9%, and 3.1%, respectively. The hospital mortality was 58.6% with no difference between and infections (61.3% and 54.9%, respectively; = .44). The independent predictors of mortality were renal replacement therapy after invasive candidiasis diagnosis (odds ratio: 5.42; 95% confidence interval: 2.16-13.56) and invasive candidiasis leading/contributing to ICU admission versus occurring during critical illness (odds ratio: 2.87; 95% confidence interval: 1.22-6.74). CONCLUSIONS:In critically ill patients with invasive candidiasis, was responsible for most cases, and mortality was high (58.6%). Antifungal therapy was initiated after culture results in 60% suggesting low preclinical suspicion. Study registration: NCT01490684; registered in ClinicalTrials.gov on February 11, 2012. 10.1177/0885066618767835
    Multidrug-Resistant Fungemia in Critical Care Units: Experience from a Tertiary Care Hospital in India. Bajpai Vijeta,Govindaswamy Aishwarya,Sagar Sushma,Kumar Subodh,Garg Pramod,Xess Immaculata,Malhotra Rajesh,Mathur Purva Microbial drug resistance (Larchmont, N.Y.) , a recently identified multiresistant Candida species, was first reported in Japan in 2009. It is different from other pathogenic yeast species because of its propensity to cause outbreaks and transmits between patients within health care settings. The invasive infections caused by are associated with high mortality rates, approaching 70% particularly in intensive care unit patients. Conventional biochemical methods are inaccurate in identifying this species of Candida. Although is frequently reported as multi-, extended-, or pan drug resistant to antifungal drugs, there is a wide variability in the susceptibility among reports worldwide. In this study we report a case series of five hospitalized patients with multidrug-resistant candidemia caused by in a tertiary hospital in India. Our finding suggests that correct identification followed by therapeutic intervention is necessary for favorable outcome in patients with fungemia. 10.1089/mdr.2019.0021
    Management of invasive candidiasis and candidaemia in critically ill adults: expert opinion of the European Society of Anaesthesia Intensive Care Scientific Subcommittee. O'Leary R-A,Einav S,Leone M,Madách K,Martin C,Martin-Loeches I The Journal of hospital infection OBJECTIVE:The global burden of invasive fungal disease is increasing. Candida albicans remains the leading cause of fungal bloodstream infections, although non-albicans candidal infections are emerging. Areas of controversy regarding diagnosis and management are hampering our ability to respond effectively to this evolving threat. The purpose of this narrative review is to address current controversies and provide recommendations to supplement guidelines. DIAGNOSIS OF INVASIVE CANDIDIASIS:Diagnosis of invasive candidiasis requires a combination of diagnostic tests and patient risk factors. Beta-D glucan and Candida albicans germ tube antibody are both used as biomarkers as adjuncts to diagnosis, although direct culture remains the gold standard. Scoring systems are available to help distinguish between colonization and invasive disease. TREATMENT OF INVASIVE CANDIDIASIS:Echinocandins are recommended as first-line therapy in candidaemia, with de-escalation to fluconazole when clinical stability is achieved. Empirical therapy is highly recommended in high-risk patients, but a more targeted pre-emptive approach is now being favoured. The evidence for prophylactic therapy remains weak. SUMMARY:Mortality attributable to invasive candidiasis may be as high as 70%. Prompt diagnosis and treatment, in conjunction with source control, are the key to improving outcomes. 10.1016/j.jhin.2017.11.020
    Epidemiology and Mycology of Candidaemia in non-oncological medical intensive care unit patients in a tertiary center in the United States: Overall analysis and comparison between non-COVID-19 and COVID-19 cases. Macauley Precious,Epelbaum Oleg Mycoses The epidemiology and mycology of invasive candidiasis in the ICU is well-described in certain types of critically ill patients but not in others. One population that has been scarcely studied is non-neutropenic patients admitted specifically to medical ICUs. Even less is known about the broader category of medical ICU patients without active oncological disease. This group constitutes a very large share of the patients requiring critical care across the globe, especially in the era of the SARS-CoV-2 pandemic. We analysed medical ICU candidaemia episodes that occurred in non-oncological patients in our tertiary academic centre in the United States from May 2014 to October 2020 to determine the incidence and species distribution of the associated isolates. We then separately considered non-COVID-19 and COVID-19 cases and compared their characteristics. In the non-COVID-19 group, there were 38 cases for an incidence of 1.1% and rate of 11/1000 admissions. In the COVID-19 group, there were 12 cases for an incidence of 5.1% and rate of 51/1000 admissions. In the entire sample, as well as separately in the non-COVID-19 and COVID-19 groups,Candida albicans accounted for a minority of isolates. Compared to non-COVID-19 patients with candidaemia, COVID-19 patients had lower ICU admission SOFA score but longer ICU length of stay and central venous catheter dwell time at candidaemia detection. This study provides valuable insight into the incidence and species distribution of candidaemia cases occurring in non-oncological critically ill patients and identifies informative differences between non-COVID-19 and COVID-19 patients. 10.1111/myc.13258
    Candida auris outbreak involving liver transplant recipients in a surgical intensive care unit. Theodoropoulos Nicole M,Bolstorff Barbara,Bozorgzadeh Adel,Brandeburg Christina,Cumming Melissa,Daly Jennifer S,Ellison Richard T,Forsberg Kaitlin,Gade Lalitha,Gibson Laura,Greenough Thomas,Litvintseva Anastasia P,Mack Deborah A,Madoff Lawrence,Martins Paulo N,McHale Eileen,Melvin Zita,Movahedi Babak,Stiles Tracy,Vallabhaneni Snigdha,Levitz Stuart M American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Candida auris is a yeast that is difficult to eradicate and has caused outbreaks in health care facilities. We report a cluster of 5 patients in 1 intensive care unit who were colonized or infected in 2017. The initial 2 patients were recipients of liver transplants who had cultures that grew C auris within 3 days of each other in June 2017 (days 43 and 30 posttransplant). Subsequent screening cultures identified 2 additional patients with C auris colonization. Respiratory and urine cultures from a fifth patient yielded C auris. All isolates were fluconazole resistant but susceptible to echinocandins. Whole genome sequencing showed the strains were clonal, suggesting in-hospital transmission, and related but distinct from New York/New Jersey strains, consistent with a separate introduction. However, no source or contact was found. Two of the 5 patients died. C auris infection likely contributed to 1 patient death by infecting a vascular aneurysm at the graft anastomosis. Strict infection control precautions were initiated to control the outbreak. Our experience reveals that although severe disease from C auris can occur in transplant recipients, outbreaks can be controlled using recommended infection control practices. We have had no further patients infected with C auris to date. 10.1111/ajt.16144
    Distribution of invasive fungal infections: Molecular epidemiology, etiology, clinical conditions, diagnosis and risk factors: A 3-year experience with 490 patients under intensive care. Borjian Boroujeni Zeinab,Shamsaei Sina,Yarahmadi Mohammad,Getso Muhammad Ibrahim,Salimi Khorashad Alireza,Haghighi Leila,Raissi Vahid,Zareei Mahdi,Saleh Mohammadzade Anita,Moqarabzadeh Vahid,Soleimani Ameneh,Raeisi Farid,Mohseni Moein,Mohseni Maedeh Sadat,Raiesi Omid Microbial pathogenesis Recently, the prevalence of invasive fungal infections (IFIs) is rising. The global mortality rate of IFIs is 10-49%. This study aimed to determine the prevalence, the causative agents, and the risk factors associated with the invasive fungal infections in a tertiary health center to provide valid decision-grounds for healthcare professionals to effectively prevent, control, and treat fungal infections. The current study was conducted on 1477 patients suspected to have systemic fungal infections from different units of the hospital. After screening using routine mycological examination, the patients were confirmed with complementary mycological and molecular methods. Patients were included based on the confirmed diagnosis of IFI and excluded based on lack of a microbiologically and histologically proven diagnosis of IFI. Of the 1477 patients recruited in this study, confirmed cases of fungal infection were 490 (169 proven; 321 cases probable). Among the fungi recovered, Candida species had the highest frequency 337 (68.8%) followed by Aspergillus species 108 (22.1%), Zygomycetes species 21 (4.3%), non-Candida yeast 9 (1.8%). Others were black fungi 5 (1%), mycetoma agents 5 (1%), Fusarium 4 (0.8%), and Trichoderma (0.2%). Hematologic malignancies and diabetes mellitus were the most common underlying diseases among IFI-confirmed patients. This study observed an increased frequency of invasive candidiasis with non-albicans Candida and other invasive saprophytic fungal infections. The increased rate of invasive candidiasis with non-albicans agents highlights a new perspective in the epidemiology and treatment of invasive fungal infections. 10.1016/j.micpath.2020.104616
    Invasive candidiasis in critical care: challenges and future directions. Logan C,Martin-Loeches I,Bicanic T Intensive care medicine Invasive candidiasis is the most common critical care-associated fungal infection with a crude mortality of ~ 40-55%. Important factors contributing to risk of invasive candidiasis in ICU include use of broad-spectrum antimicrobials, immunosuppressive drugs, and total parenteral nutrition alongside iatrogenic interventions which breach natural barriers to infection [vascular catheters, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), surgery]. This review discusses three key challenges in this field. The first is the shift in Candida epidemiology across the globe to more resistant non-albicans species, in particular, the emergence of multi-resistant Candida glabrata and Candida auris, which pose significant treatment and infection control challenges in critical care. The second challenge lies in the timely and appropriate initiation and discontinuation of antifungal therapy. Early antifungal strategies (prophylaxis, empirical and pre-emptive) using tools such as the Candida colonisation index, clinical prediction rules and fungal non-culture-based tests have been developed: we review the evidence on implementation of these tools in critical care to aid clinical decision-making around the prescribing and cessation of antifungal therapy. The third challenge is selection of the most appropriate antifungal to use in critical care patients. While guidelines exist to aid choice, this heterogenous and complex patient group require a more tailored approach, particularly in cases of acute kidney injury, liver impairment and for patients supported by extracorporeal membrane oxygenation. We highlight key research priorities to overcome these challenges in the future. 10.1007/s00134-020-06240-x
    Individual risk factors and critical care unit effects on Invasive Candida Infection occurring in critical care units in the UK: A multilevel model. Patterson Lynsey,McMullan Ronan,Harrison David A Mycoses Geographical variation is observed in invasive candida infection (ICI) and differences between critical care units (CCUs) may contribute. To examine rates, risk factors and individual and unit-level variation of ICI in UK CCUs. Data from the Fungal Infection Risk Evaluation Study was used to examine individuals admitted to 96 CCUs in the UK; July 2009-March 2011. Cases were non-neutropenic individuals aged 18 years and over with ICI identified after admission. Mixed-effects Poisson regression models adjusted for the CCU. There were 225 cases of ICI, a rate of 6.84/10 000 bed days and a threefold variation between the lowest and highest UK regions. Independent risk factors included abdominal surgery (adjusted incidence rate ratio (AIRR) 2.03 95% CI 1.49, 2.76), parenteral nutrition (AIRR 1.89 95% CI 1.33, 2.70), fungal colonisation at two or more sites (AIRR 2.30 95% CI 1.34, 3.95) and indwelling devices. Approximately 4% of the variation in ICI rates could be attributed to the CCU. We identified independent risk factors for ICI and showed, for the first time, that the critical care unit effect was small. Despite this, future studies should consider the hierarchical structure of the data to ensure robust estimates. 10.1111/myc.12956