Clinical predictive models of invasive Candida infection: A systematic literature review.

Clinical predictive models (CPM) serve to identify and categorize patients into risk categories to assist in treatment and intervention recommendations. Predictive accuracy and practicality of models varies depending on methods used for their development, and should be evaluated. The aim of this study was to summarize currently available CPM for invasive candidiasis, analyze their performance, and assess their suitability for use in clinical decision making. We identified studies that described the construction of a CPM for invasive candidiasis from PubMed/MEDLINE, EMBASE, SCOPUS, Web of Science, Cochrane Library databases, and Clinicaltrials.gov. Data extracted included: author, data source, study design, recruitment period, characteristics of study population, outcome types, predictor types, number of study participants and outcome events, modelling method, and list of predictors used in the final model. Calibration and discrimination in the derivative datasets were used to assess the performance of each model. Ten articles were identified in our search and included for full text review. Five models were developed using data from ICUs, and five models included all hospitalized patients. The findings of this review highlight the limitations of currently available models to predict invasive candidiasis, including lack of generalizability, difficulty in everyday clinical use, and overly optimistic performance. There are significant concerns regarding predictive performance and usability in every day practice of existing CPM to predict invasive candidiasis.

Clinical predictive models may assist in early identification of patients at risk for invasive candidiasis to initiate appropriate treatment. The findings of this systematic review highlight the limitations of currently available models to predict invasive candidiasis.

Hyperpigmentation as a cutaneous manifestation of fungal sepsis in neonates: Case series report.

With improved and prolonged survival of very and extremely low birth weight infants, invasive fungal infection has emerged as an important concern in the neonatal intensive care units. Candidiasis is the third leading cause of late onset sepsis in these neonates and is associated with 20-30% mortality. Extreme prematurity, central venous catheters, prolonged antibiotic exposure, parenteral nutrition are important risk factors. Various forms of cutaneous manifestations of candidiasis have been described ranging from local diaper dermatitis and oral thrush to widespread erosive and ulcerative lesions with extensive crusting in invasive fungal dermatitis. We report a series of four cases with cutaneous hyperpigmentation as manifestation of systemic candidiasis.

What´s new in intraabdominal candidiasis in critically ill patients, a review.

A high prevalence of invasive candidiasis has been reported in recent years. Patients admitted to an intensive care unit are at the highest risk for invasive candidiasis, mostly due to the severity of their disease, immune-suppressive states, prolonged length of stay, broad-spectrum antibiotics, septic shock, and Candida colonization. Intraabdominal candidiasis comprises a range of clinical manifestations, from just the suspicion based on clinical scenario to fever, leukocytosis, increase in biomarkers to the isolation of the responsible microorganism. In critically ill patients with IAC prompt treatment and adequate source control remains the ultimate goal.

Isolated Pulmonary Valve Fungal Endocarditis with Candida parapsilosis: Management Considerations of a Rare Case.

Pulmonary valve infections without the involvement of other valves account for only 1.5- 2% of all infective endocarditis cases. Isolated pulmonary valve endocarditis due to fungus is extremely rare. The case is presented of a 36-year-old male who was found to have isolated pulmonary valve endocarditis caused by a very rare organism, Candida parapsilosis, and that was solely managed with medical therapy. The patient was evaluated for three weeks of lowgrade fever, generalized rash and fatigue, and found to have C. parapsilosis in the blood. Transesophageal echocardiography (TEE) demonstrated a 4.5 cm vegetation on the pulmonary valve, without involvement of other valves. The patient was deemed not to be a surgical candidate and was subsequently started on intravenous liposomal amphotericin B and 5-flucytosine, with excellent clinical outcome. Based on these case details, it must be emphasized that in selective cases and if there are no known complications, fungal endocarditis can be managed successfully using anti-fungal agents.

Manejo de la candidiasis invasiva en el paciente no neutropénico / Management of invasive candidiasis in non-neutropenic patient

Entre los agentes etiológicos que con mayor frecuencia producen infección nosocomial se incluye Candida spp. La candidemia cursa con tasas de mortalidad superiores al 30%. La instauración temprana de tratamiento antifúngico es esencial para mejorar el pronóstico. A falta de pruebas microbiológicas que permitan establecer un diagnóstico precoz, el tratamiento debe establecerse necesariamente de forma empírica (AU)

Among the most frequents etiological agents that causing nosocomial infections, there is included Candida spp. Candida’s bloodstream infection mortality rates are over 30%. Antifungal early treatment is essential to improve the prognosis of this type of infection. Because of the lack of fast enough microbiological tests for early diagnosis, treatment must necessarily be initiated empirically (AU)

[Liver dysfunctions in intensive care patients--consequences for the treatment of invasive Candida infections]. / Leberfunktionsstörungen in der Intensivmedizin - Konsequenzen für die Therapie invasiver Candidainfektionen.

Liver dysfunction is common among patients on intensive care units (ICU) due to sepsis, chronic liver disease, ischemic hepatitis, drug toxicity and intensive care measures. Critically ill patients with invasive fungal infections should therefore be treated with antifungals that are not metabolized by the liver. This may help to avoid therapeutic complications by drug accumulation, inadequate dosages or drug-drug interactions. Echinocandins are established as the antifungal class of choice in the treatment of invasive Candida infections. Anidulafungin is not hepatically metabolized and may be used without dose adjustments in patients with severe liver dysfunction. It has no known clinically relevant drug interactions. In the primary endpoint of the randomized pivotal trial in patients with candidemia or invasive candidiasis, anidulafungin was statistically superior versus the former standard therapy (fluconazole), with a favourable overall safety profile. More recent study data particularly in ICU patients confirm the efficacy of anidulafungin for these patient groups. Therefore, anidulafungin is an important antifungal treatment option for patients with liver dysfunction.

Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later.

INTRODUCTION: For decades, clinicians dealing with immunocompromised and critically ill patients have perceived a link between Candida colonization and subsequent infection. However, the pathophysiological progression from colonization to infection was clearly established only through the formal description of the colonization index (CI) in critically ill patients. Unfortunately, the literature reflects intense confusion about the pathophysiology of invasive candidiasis and specific associated risk factors. METHODS: We review the contribution of the CI in the field of Candida infection and its development in the 20 years following its original description in 1994. The development of the CI enabled an improved understanding of the pathogenesis of invasive candidiasis and the use of targeted empirical antifungal therapy in subgroups of patients at increased risk for infection. RESULTS: The recognition of specific characteristics among underlying conditions, such as neutropenia, solid organ transplantation, and surgical and nonsurgical critical illness, has enabled the description of distinct epidemiological patterns in the development of invasive candidiasis. CONCLUSIONS: Despite its limited bedside practicality and before confirmation of potentially more accurate predictors, such as specific biomarkers, the CI remains an important way to characterize the dynamics of colonization, which increases early in patients who develop invasive candidiasis.

What's new in the clinical and diagnostic management of invasive candidiasis in critically ill patients.

Invasive candidiasis (IC) is a severe complication in the ICU setting. A high proportion of ICU patients become colonized with Candida species, but only 5-30 % develop IC. Progressive colonization and major abdominal surgery are well-known risk factors for Candida infection. IC is difficult to predict and early diagnosis remains a major challenge. In addition, microbiological documentation often occurs late in the course of infection. Delays in initiating appropriate treatment have been associated with increased mortality. In an attempt to decrease Candida-related mortality, an increasing number of critically ill patients without documented IC receive empirical systemic antifungal therapy, leading to concern for antifungal overuse. Scores/predictive rules permit the stratification and selection of IC high-risk patients who may benefit from early antifungal therapy. However, they have a far better negative predictive value than positive predictive value. New IC biomarkers [mannan, anti-mannan, (1,3)-ß-D-glucan, and polymerase chain reaction] are being increasingly used to enable earlier diagnosis and, ideally, to provide prognostic information and/or therapeutic monitoring. Although reasonably sensitive and specific, these techniques remain largely investigational, and their clinical usefulness has yet to be established.

Proyecto épico: formulación de unas recomendaciones educativas con metodología DELPHI para pacientes adultos críticos no neutropénicos y con candidiasis invasiva / Épico project. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non-neutropenic critically ill adult patients

Antecedentes: Aunque en la última década ha mejorado el manejo de la candidiasis invasiva, todavía persisten aspectos controvertidos, en especial por lo que respecta a la estrategia diagnóstica y terapéutica. Objetivos: Identificar los conocimientos clínicos esenciales y formular unas recomendaciones con la obtención de un alto grado de consenso, necesarias en la asistencia de pacientes adultos no neutropénicos en estado crítico con candidiasis invasiva. Métodos: Se preparó una encuesta prospectiva cuyo texto se redactó en español, y se obtuvo un consenso mediante técnica DELPHI (un método de reestructuración de un proceso de comunicación con el que se obtiene un grado de consenso de los especialistas sobre el problema planteado). En primer término, se envió de forma anónima por correo electrónico a 25 especialistas nacionales de diferentes disciplinas médicas, expertos en infecciones fúngicas invasivas, de 5 sociedades científicas nacionales, incluidos intensivistas, anestesistas, microbiólogos, farmacólogos e infectólogos, que respondieron a 47 preguntas preparadas por el grupo de coordinación, tras una revisión exhaustiva de los estudios publicados durante los 5 últimos años. Los objetivos educativos contemplaron 5 categorías: epidemiología, instrumentos diagnósticos, scores, estrategias terapéuticas y de desescalada. Para ser seleccionado, el grado de acuerdo alcanzado entre los expertos del panel en cada uno de los ítems debía superar el 75%. En segundo término, después de extraer las recomendaciones de los ítems seleccionados, se celebró una reunión presencial donde se invitó a participar en una segunda ronda a más de 80 especialistas y se les solicitó la validación de las recomendaciones preseleccionadas. Resultados: En primer término, se realizó una preselección de 20 recomendaciones (epidemiología 4, scores 3, diagnóstico de laboratorio 4, tratamiento 6 y desescalada 3). Después de la segunda ronda, se validaron las 12 recomendaciones siguientes... (AU)

Background. Although there has been an improved management of invasive candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches. Aims. We sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with invasive candidiasis. Methods. A prospective Spanish survey reaching consensus by the DELPHI technique was made. It was anonymously conducted by electronic mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious diseases specialists, who answered to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations. Results. In the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, Treatment 6 and De-escalation approaches 3). After the second round, the following 12 were validated: (1) Epidemiology (2 recommendations): think about candidiasis in your Intensive Care Unit (ICU) and do not forget that non-Candida albicans–Candida species also exist. (2) Diagnostic tools (4 recommendations): blood cultures should be performed under suspicion every 2–3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use non-culture based methods as microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. (3) Scores (1 recommendation): as screening tool, use the Candida Score and determine multicolonization in high risk patients. (4) Treatment (4 recommendations): start early. Choose echinocandins. Withdraw any central venous catheter. Fundoscopy is needed. (5) De-escalation (1 recommendation): only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores. Conclusions. The management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations may help to identify the potential patients... (AU)

Time to initiation of antifungal therapy for neonatal candidiasis.

The effect of delayed antifungal therapy in critically ill infants with invasive candidiasis has not been studied. Our objective was to evaluate the effect of time to initiation of antifungal therapy (TIA) on mortality, disseminated disease, and postinfection hospital stay. We conducted a cohort study of critically ill infants with cultures positive for Candida from 1990 to 2008. TIA was defined as the number of hours from the collection of the first positive culture until the start of antifungal therapy. Of 96 infants, 57% were male, the median gestational age was 27 weeks (range, 23 to 41 weeks), and the median birth weight was 956 g (range, 415 to 6,191 g). Most subjects received amphotericin B deoxycholate. TIA was ≤ 24 h for 35% of infants, between 25 and 48 h for 42%, and >48 h for 23%. Eleven subjects died during hospitalization, and 22% had disseminated candidiasis. The median duration of hospital stay postinfection was 53 days (range, 6 to 217 days). Both univariate and multivariate analyses demonstrated that TIA was not associated with mortality, disseminated disease, or hospital stay postinfection. However, ventilator use for >60 days significantly increased the risk of death (odds ratio [OR], 9.5; 95% confidence interval [CI], 2.2 to 66.7; P = 0.002). Prolonged candidemia increased the risk of disseminated disease by 10% per day of positive culture (OR, 1.1; 95% CI, 1.08 to 1.2; P = 0.007), and low gestational age was associated with increased neonatal intensive care unit (NICU) stay after the first positive Candida culture by 0.94 weeks (95% CI, 0.70 to 0.98; P < 0.001). The TIA was not associated with all-cause mortality, disseminated candidiasis, and postinfection length of hospital stay.

Treatment and prophylaxis of invasive candidiasis.

Invasive candidiasis (IC) is a leading cause of morbidity and mortality in preterm infants. Even if successfully treated, IC can cause significant neurodevelopmental impairment. Preterm infants are at increased risk for hematogenous Candida meningoencephalitis owing to increased permeability of the blood-brain barrier, so antifungal treatment should have adequate central nervous system penetration. Amphotericin B deoxycholate, lipid preparations of amphotericin B, fluconazole, and micafungin are first-line treatments of IC. Fluconazole prophylaxis reduces the incidence of IC in extremely premature infants, but its safety has not been established for this indication, and as yet, the product has not been shown to reduce mortality in neonates. Targeted prophylaxis may have a role in reducing the burden of disease in this vulnerable population.

Lung-enriched organisms and aberrant bacterial and fungal respiratory microbiota after lung transplant.

RATIONALE: Long-term survival after lung transplantation is limited by infectious complications and by bronchiolitis obliterans syndrome (BOS), a form of chronic rejection linked in part to microbial triggers. OBJECTIVES: To define microbial populations in the respiratory tract of transplant patients comprehensively using unbiased high-density sequencing. METHODS: Lung was sampled by bronchoalveolar lavage (BAL) and upper respiratory tract by oropharyngeal wash (OW). Bacterial 16S rDNA and fungal internal transcribed spacer sequencing was used to profile organisms present. Outlier analysis plots defining taxa enriched in lung relative to OW were used to identify bacteria enriched in lung against a background of oropharyngeal carryover. MEASUREMENTS AND MAIN RESULTS: Lung transplant recipients had higher bacterial burden in BAL than control subjects, frequent appearance of dominant organisms, greater distance between communities in BAL and OW indicating more distinct populations, and decreased respiratory tract microbial richness and diversity. Fungal populations were typically dominated by Candida in both sites or by Aspergillus in BAL but not OW. 16S outlier analysis identified lung-enriched taxa indicating bacteria replicating in the lower respiratory tract. In some cases this confirmed respiratory cultures but in others revealed enrichment by anaerobic organisms or mixed outgrowth of upper respiratory flora and provided quantitative data on relative abundances of bacteria found by culture. CONCLUSIONS: Respiratory tract microbial communities in lung transplant recipients differ in structure and composition from healthy subjects. Outlier analysis can identify specific bacteria replicating in lung. These findings provide novel approaches to address the relationship between microbial communities and transplant outcome and aid in assessing lung infections.

Candidiasis invasora en el paciente crítico quemado / Invasive candidiasis in severely ill burned patients

Antecedentes. Los avances en el tratamiento del paciente crítico quemado han llevado a una supervivencia mayor, pero, a su vez, a un aumento de las complicaciones sépticas, en especial de las infecciones fúngicas. Debido a la dificultad en el diagnóstico y a la elevada mortalidad asociada, se ha planteado el tratamiento antifúngico profiláctico o anticipado en los pacientes quemados de alto riesgo, aunque estas pautas son aún controvertidas. Por otro lado, el manejo de esta entidad constituye un serio problema en los pacientes críticos con fracaso multiorgánico, entre los que se incluye a los grandes quemados, debido a la escasez de antifúngicos. Sin embargo, en los últimos años han aparecido nuevos agentes que han supuesto un progreso en el tratamiento de la infección fúngica invasiva en esta subpoblación. Caso clínico. Se presenta un caso de una infección fúngica invasiva en un paciente crítico quemado tratado de forma exitosa con una equinocandina. En la discusión se hace referencia a la experiencia publicada y a las pautas de tratamiento actual. Conclusiones. Actualmente persisten importantes lagunas en el diagnóstico y el tratamiento óptimo de la candidiasis invasiva en el paciente crítico quemado. Son necesarios nuevos estudios prospectivos en esta subpoblación para optimizar su manejo y mejorar los resultados en esta entidad de elevada morbimortalidad(AU)

The advances in burn care therapy have extended considerably the survival of seriously burned patients, exposing them to infectious complications, notably fungal infections. Due to the difficulty in the diagnosis of invasive mycoses and their high associated mortality rates, approaches to prophylactic or pre-emptive antifungal therapy in high-risk burned patients have been proposed, although these guidelines remain controversial. On the other hand, the management of these conditions is a serious problem, especially in critically ill patients with multiorgan failure, including severely ill burn patients due to the shortage of available antifungal agents. However, in the last several years, the range of antifungal agents has been significantly extended, which have led to an improvement in the treatment of invasive fungal infection in this population. Clinical case. We report a case of invasive candidiasis in a severelly ill burns patient successfully treated with an echinocandin. In this case report, current treatment options are discussed, and a review of the literature of previously published cases is made. Conclusions. There are still significant gaps in our knowledge of the optimal diagnostic and management approach for invasive candidiasis in burn patients. Prospective studies are needed in this population to optimise management and improve outcomes in this state of high morbidity and mortality(AU)

Austrian clinical practice with anidulafungin in 2008: a multicenter survey.

Anidulafungin had demonstrated favorable efficacy versus fluconazole in a randomized trial on invasive Candida infections. Since patient characteristics in the post-approval use of antifungals likely deviate from clinical trials, we surveyed the use of anidulafungin in clinical routine. We performed a retrospective survey of the post-approval use of anidulafungin in 9 Austrian clinical centers. Anidulafungin was used in 129 critically ill patients with severe comorbidities and multiple risk factors. Indications were suspected invasive fungal infections (IFI) (61%), proven candidemia (19%), and at risk for IFI (prophylaxis, 20%). Candida colonization in conjunction with other risk factors prompted treatment in many patients. predominant pathogens were C. albicans, C. glabrata and C. krusei. Anidulafungin was mostly used for pre-emptive (69%) and first-line treatment (17%) of invasive candidiasis. Treatment response, i.e. complete response/stabilization as determined by investigators (89% in the overall population; 87% for documented candidemia) and survival rates (81% and 75%, respectively) were similar to previous trial data. No breakthrough IFI and few adverse events were reported. Overall, favorable clinical experiences were documented with anidulafungin in the clinical routine setting.

Micafungin use in children.

Invasive fungal infections (IFIs) are one of the major reasons for morbidity and mortality in immunocompromised children. The majority of IFIs are caused by Candida and Aspergillus species. Early diagnosis and prompt initiation of appropriate antifungal therapy is essential for favorable outcome. Micafungin is a member of the echinocandins, a novel class of antifungal agents that target the biosynthesis of ß-1,3-D-glucan, a key fungal cell wall component. It has concentration-dependent fungicidal activity against Candida species and fungistatic activity against Aspergillus species. Although optimal dosing of micafungin in children has not been established, the recommended dosage in children is 2 mg/kg/day (100 mg/day if >40 kg bodyweight) for invasive candidiasis, 1 mg/kg/day (50 mg/day if >40 kg bodyweight) for the prophylaxis of Candida infections in patients with anticipated prolonged and severe neutropenia or in allogeneic hematopoietic stem cell transplantation recipients. Micafungin has a favorable safety and drug-drug interaction profile. The most common adverse effects in children are diarrhea, epistaxis, abdominal pain, headache, nausea, vomiting, fever, chills, elevation of alanine aminotransferase/aspartate aminotransferase values, hypokalemia, thrombocytopenia, mucositis, and rash. Because of its different mechanisms of action, micafungin shows promise as part of the prophylactic and therapeutic management of IFIs, but larger prospective and comparative trials are needed for widespread use in children.

Epidemiology and antifungal resistance in invasive candidiasis.

The epidemiology of Candida infections has changed over the last two decades: The number of patients suffering from such infections has increased dramatically and the Candida species involved have become more numerous as Candida albicans is replaced as an infecting agent by various non-C. albicans species (NAC). At the same time, additional antifungal agents have become available. The different Candida species may vary in their susceptibility for these various antifungals. This draws more attention to in vitro susceptibility testing. Unfortunately, several different test methods exist that may deliver different results. Moreover, clinical breakpoints (CBP) that classify test results into susceptible, intermediate and resistant are controversial between CLSI and EUCAST. Therefore, clinicians should be aware that interpretations may vary with the test system being followed by the microbiological laboratory. Thus, knowledge of actual MIC values and pharmacokinetic properties of individual antifungal agents is important in delivering appropriate therapy to patients.