Management strategies: prophylaxis, empirical and preemptive treatment of established invasive candidiasis in the critically ill non-neutropenic patient

In critically ill non neutropenic patients there are four broad approaches for the management of antifungal treatment for invasive candidiasis: prophylaxis, empirical, preemptive therapy and treatment of established infections. All these approaches in relationship with risk strategies and microbiological indirect laboratory techniques for establishing invasive candidiasis will be discussed.     

Enfermedades invasoras por hongos levaduriformes en el receptor de un trasplante de órgano sólido

Invasive yeast diseases are uncommon nowadays in solid organ transplant recipients. Invasive candidiasis (2%) usually presents during the first month after transplantation in patients with risk factors. Both common and transplant-specific risk factors have been identified, allowing very efficacious targeted prophylaxis strategies. The most common clinical presentations are fungaemia and local infections near the transplantation area. Cryptococcosis is usually a late infection. Its incidence remains stable and the specific risk factors have not been identified. When cryptococcosis is detected very early, transmission with the allograft should be considered. The most common clinical presentations include meningitis, pneumonia, and disseminated infection. Intracranial hypertension and immune reconstitution syndrome have to be considered.No therapeutic clinical trials have been conducted in solid organ transplant recipients, thus treatment recommendations are derived from data obtained from the general population. It is particularly important to consider the possibility of drug-drug interactions, mainly between azoles and calcineurin inhibitors. Both invasive candidiasis and cryptococcosis increase the mortality significantly in solid organ transplant recipients.     

Prevention of invasive candidiasis in the critically ill non neutropenic patient

Prevention of invasive candidiasis (IC) in the setting of critically ill non neutropenic patients should be based on evidenced-based recommendations, namely improved hand hygiene, optimal catheter care, and rational and reduced use of broad-spectrum antibiotics. Concomitant interventions aimed at reducing risk factors are important to decrease IC.     

Laboratory aids in the diagnosis of invasive candidiasis

The laboratory diagnosis of candidiasis continues to be problematic; however, there have been several advances in the past decade which promise to enhance our ability to identify patients at high risk for infection and/or to document invasive candidiasis in critically ill and immunocompromised patients. The introduction of commercially available biphasic blood culture medium and subsequently the lysiscentrifugation procedure has markedly improved the ability of laboratories to detect fungemia. Although serologic methods have not been very successful in diagnosing candidiasis in immunocompromised patients, several antigen detection methods are now under investigation. In addition, detection of fungal metabolites such as D-arabinitol remains promising. Finally, application of the techniques of molecular biology for typing and detection of fungal pathogens has expanded our understanding of candidal infections and may offer the most sensitive and specific means of diagnosing invasive candidiasis.     

The patient with candidemia: Treatment choices and algorithms

Candidemia and other forms of invasive candidiasis have become increasingly important health care-associated infections. Risk factors are easily identified in patients with this disease, and about one half are residents of an ICU. In recent years, the treatment of candidemia and invasive candidiasis has significantly evolved from amphotericin B-based regimens to the echinocandins and fluconazole. A strategy of “step-down” therapy from an echinocandin to fluconazole in selected non-neutropenic patients with candidemia has been commonly practiced but not well studied. The approach to candidemia in the neutropenic patient is similar, but a lipid formulation of amphotericin B or voriconazole is often preferred because of the risk of concomitant mold infection. The biggest therapeutic challenge remaining to clinicians is the intensive care unit patient with multiple risk factors and a clinical suspicion of invasive candidiasis. Because optimal therapy in these patients is unknown, well-designed clinical trials and the continued development of non-culture-based diagnostic assays are crucial.     

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

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

Invasive Fungal Infection in Primary Immunodeficiencies Other Than Chronic Granulomatous Disease

Purpose of review

We aimed to review invasive fungal infections complicating primary immunodeficiencies (PID).

Recent findings

Several PID predisposing to fungal infections were recently deciphered. CARD9 deficiency selectively predisposes to fungal infections including candidiasis, aspergillosis, deep dermatophytosis, and phaeohyphomycosis, with frequent central nervous system location, especially after Candida infection. Patients with heterozygous STAT1 gain-of-function mutations are mostly predisposed to chronic mucocutaneous candidiasis but may also display, even though less frequently, invasive fungal infections. Aspergillosis complicating STAT3 deficiency is also a major concern in patients with lung cavities. Antifungal prophylaxis is recommended in this first group of patients. Previously well-reported PID are known to predispose to fungal infections, such as genetic defects impairing the IL-12/IFN-γ axis can predispose to cryptococcosis, and dimorphic fungal infections.

Summary

Patients developing invasive fungal infections including candidiasis, aspergillosis, cryptococcosis, phaeohyphomycosis, pneumocystosis, or disseminated infections caused by dimorphic fungi, without known underlying risk factors, should be explored immunogenetically in order to diagnose primary immunodeficiencies, even in the absence of previous other infectious episodes.

     

Utilidad clínica de la micafungina en el tratamiento de las candidiasis invasoras en el neonato

BackgroundIn neonatal intensive care units, deep fungal disease due to Candida spp. are an important clinical problem, partly due to the increasing prevalence of Candida disease and also to the high associated and constant morbimortality; both factors are independently maintained though there has been a significant improvement in the management of neonatal patients.AimsTo define the therapeutic use of micafungin for the treatment of neonatal invasive candidiasis.MethodsWe use a review of biomedic data bases namely Medline and EMBASE.ConclusionsMicafungin is the latest introduced echinocandin. It has a wide spectrum of activity and covers Candida albicans and non-albicans Candida species. It has scarce drugs interactions and is devoid of toxicity, being an attractive approach for the treatment of invasive candidiasis (without meningitis, endocarditis and endophthalmitis). Althought the European Medicines Agency approved in 2008 the use of Micafungin for the treatment of invasive candidiasis in children, the available clinical experience is limited and currently more clinical studies are warranted to define its efficacy and safety in neonates.     

多发性骨髓瘤并发上消化道侵袭性念珠菌病2例报道及文献复习

目的 探讨多发性骨髓瘤(Multiple myeloma,MM)并发上消化道侵袭性念珠菌病的临床特点,提高诊治该病的水平.方法 回顾分析我科2例多发性骨髓瘤并发上消化道侵袭性念珠菌病的诊治过程,分析、总结治疗经验,并结合文献复习骨髓瘤并发上消化道侵袭性念珠菌感染的易感因素、临床表现、诊断和鉴别诊断及治疗.结果 MM患者1,女性,异基因造血干细胞移植术后4个月发生腹泻伴腹部隐痛,抗移植物抗宿主病(graftversus host disease,GVHD)治疗无效,经胃镜诊断上消化道念珠菌病,予卡泊芬净治愈出院.MM患者2,男性,化疗过程中疾病进展,并出现腹胀、腹痛,对症处理改善,再次化疗时上述症状加重并发肺部念珠菌病,发生急性心、肾功能不全,经胃镜诊断上消化道念珠菌病,予伊曲康唑、米卡芬净治疗,最终因肺部真菌感染加重,治疗无效死亡.结论 多发性骨髓瘤并发上消化道侵袭性念珠菌病易发生误诊、漏诊.临床医生需提高对该病的认识,首选电子胃镜明确诊断、判断疗效.     

EPICO 2.0 project. Development of educational therapeutic recommendations using the DELPHI technique on invasive candidiasis in critically ill adult patients in special situations

BackgroundAlthough there has been an improved management of invasive candidiasis in the last decade, still controversial issues remain, especially in different therapeutic critical care scenarios.AimsWe sought to identify the core clinical knowledge and to achieve high agreement recommendations required to care for critically ill adult patients with invasive candidiasis for antifungal treatment in special situations and different scenarios.MethodsSecond prospective Spanish survey reaching consensus by the DELPHI technique, conducted anonymously by electronic e-mail in the first phase to 23 national multidisciplinary experts in invasive fungal infections from five national scientific societies including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious disease specialists, answering 30 questions prepared by a coordination group after a strict review of literature in the last five years. The educational objectives spanned four categories, including peritoneal candidiasis, immunocompromised patients, special situations, and organ failures. The agreement among panelists in each item should be higher than 75% to be selected. In a second phase, after extracting recommendations from the selected items, a meeting was held with more than 60 specialists in a second round invited to validate the preselected recommendations.Measurements and main resultsIn the first phase, 15 recommendations were preselected (peritoneal candidiasis (3), immunocompromised patients (6), special situations (3), and organ failures (3)). After the second round the following 13 were validated: Peritoneal candidiasis (3): Source control and early adequate antifungal treatment is mandatory; empirical antifungal treatment is recommended in secondary nosocomial peritonitis with Candida spp. colonization risk factors and in tertiary peritonitis. Immunocompromised patients (5): consider hepatotoxicity and interactions before starting antifungal treatment with azoles in transplanted patients; treat candidemia in neutropenic adult patients with antifungal drugs at least 14 days after the first blood culture negative and until normalization of neutrophils is achieved. Caspofungin, if needed, is the echinocandin with most scientific evidence to treat candidemia in neutropenic adult patients; caspofungin is also the first choice drug to treat febrile candidemia; in neutropenic patients with candidemia remove catheter. Special situations (2): in moderate hepatocellular failure, patients with invasive candidiasis use echinocandins (preferably low doses of anidulafungin and caspofungin) and try to avoid azoles; in case of possible interactions review all the drugs involved and preferably use anidulafungin. Organ failures (3): echinocandins are the safest antifungal drugs; reconsider the use of azoles in patients under renal replacement therapy; all of the echinocandins to treat patients under continuous renal replacement therapy are accepted and do not require dosage adjustment.ConclusionsTreatment of invasive candidiasis in ICU patients requires a broad range of knowledge and skills as summarized in our recommendations. These recommendations may help to optimize the therapeutic management of these patients in special situations and different scenarios and improve their outcome based on the DELPHI methodology.     

The role of antifungal susceptibility testing in the management of patients with invasive mycoses

The availability of standardized antifungal susceptibility testing methodologies as well as the definition of interpretative breakpoints have made possible the establishment of useful correlations between in vitro testing data and clinical results with antifungal drugs such as fluconazole and itraconazole in patients with oropharyngeal candidiasis. The results obtained in these studies, however, can not be extrapolated to other organisms or clinical syndromes. Although there has been some recent progress, the interpretations of in vitro and in vivo results obtained in patients suffering cryptococcosis or invasive candidiasis needs to be further defined in order to establish meaningful clinical-laboratory correlations. Furthermore, the method needs to be fully standardized in case of filamentous fungi. It can be anticipated that the development, standardization and validation of in vitro antifungal susceptibility testing will guide clinicians in the management of patients with invasive mycoses.     

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

Purpose of Review

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

Recent Findings

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

Summary

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

     

Is there a role for antibody testing in the diagnosis of invasive candidiasis?

During the last decades, the use of antibody tests for the diagnosis of invasive mycoses has declined as a consequence of the general belief that they are insensitive and non-specific. However, there is a clear evidence that antibodies can be detected in highly immunodeficient patients (such as bone marrow transplant recipients), and that those antibodies are useful for the diagnosis. Antibody tests are currently in use as diagnostic tools for some primary mycoses, such as the endemic mycoses, aspergilloma, allergic bronchopulmonary aspergilosis and sporothrichosis. For invasive candidiasis, diagnostic methods must differentiate Candida colonization of mucous membranes or superficial infection from tissue invasion by this microorganism. Substantial progress has been made in diagnosis of invasive candidiasis with the development of a variety of methods for the detection of antibodies and antigens. However, no single test has found widespread clinical use and there is a consensus that diagnosis based on a single specimen lacks sensitivity. It is necessary to test sequential samples taken while the patient is at greatest risk for developing invasive candidiasis to optimize the diagnosis. Results obtained from a panel of diagnostic tests in association with clinical aspects will likely be the most useful strategy for early diagnosis and therapy.     

Candidiasis of the Central Nervous System in Neonates and Children With Primary Immunodeficiencies

Purpose of review

Candida infections of the central nervous system (CNS) are a life-threatening complication of invasive infections that most often affect vulnerable groups of patients, including neonates and children with primary immunodeficiency disorders (PID). Here, we review the currently known risk factors for CNS candidiasis, focusing predominantly on the PID caused by biallelic mutations in CARD9.

Recent findings

How the CNS is protected itself against fungal invasion is poorly understood. CARD9 promotes neutrophil recruitment and function, and is the only molecule shown to be critical for protection against CNS candidiasis in humans thus far.

Summary

Fundamental insights into the pathogenesis of CNS candidiasis gained from studying rare CARD9-deficient patients has significant implications for other patients at risk for this disease, such as CARD9-sufficient neonates. These findings will be important for the development of adjunctive immune-based therapies, which are urgently needed to tackle the global burden of invasive fungal diseases.

     

Evaluation of three serological tests for detection of anti-candidal antibodies in diagnosis of invasive candidiasis

Immunoblot detection of antibody against 47 KD cytoplasmic antigen ofCandida albicans was evaluated in diagnosis of invasive candidiasis and compared to whole cell agglutination and gel diffusion tests for detection of anticandidal antibody in 64 patients. The patients included 17 with culture proved candidemia, 34 with significant candiduria (more than 10,000 colony forming units per ml of urine) and 13 with nonsignificant candiduria. Antibody against 47 KD antigen was found to be the best indicator for diagnosis of invasive candidiasis even in patients with malignancy. The sensitivity of this procedure was 82.4%, specificity 86.7%, positive predictive value 77.8%, negative predictive value 89.7% and efficacy 85.1%. The gel diffusion procedure lacked in sensitivity whereas whole cell agglutination lacked in specificity. Detection of antibody against 47 KD antigen proved to be a valuable adjunct in the diagnosis of invasive candidiasis.     

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

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

Epitope mapping human heat shock protein 90 with sera from infected patients

Abstract Epitope mapping with sera from a range of infected patients showed that antibodies are commonly produced which cross-react with a number of epitopes on human heat shock protein 90 (HSP 90). Such autoreactive antibodies were particularly frequent in patients suffering from systemic candidiasis (9 patients), invasive aspergillosis (6 patients), ABPA (2 patients), a patient with aspergilloma and one with malaria. The patient with malaria recognised similar epitopes to those with invasive aspergillosis and candidiasis including the highly conserved epitope LKVIRKVIRK and an epitope NNLGTI which was otherwise only recognised by patients with candidiasis. Crossreacting antibodies to relatively few epitopes occurred in patients with Enterococcus faecalis and Corynebacterium jeikeium endocarditis. This was contrasted with the results from 6 patients with systemic lupus erythematosus (SLE) who were positive on immunoblot against fungal HSP 90. These did not react with the above epitopes but reacted with other areas within human HSP 90.     

Opciones terapéuticas para el tratamiento antifúngico en el paciente crítico

Invasive fungal infections, especially in the critical care setting, have become an excellent target for prophylactic, empiric, and pre-emptive therapy interventions due to their associated high morbidity, mortality rate, increased incidence, and healthcare costs. For these reasons, new studies and laboratory tests have been developed over the last few years in order to formulate an early therapeutic intervention strategy in an attempt to reduce the high mortality rate associated with these infections. In recent years, evidencebased studies have shown the roles that the new antifungal drugs play in the treatment of invasive mycosis in seriously ill and complex patients, although data from critically ill patients are more limited. New antifungal agents have been analyzed in different clinical situations in critical care units, and the increasing number of non-Candida albicans species suggest that the application of early echinocandin therapy in critically ill patients with invasive candidiasis is a good option. Voriconazole should be recommended for invasive aspergillosis as a first line option.     

Farmacoeconomía del tratamiento de las candidiasis invasoras

BackgroundInvasive candidiasis episodes have increased during last years and they have been related with high rates of crude mortality. Invasive candidiasis-related deaths have not diminished significantly with the introduction of antifungals in the past decade. Finantial managers are worried about extra costs from acquisition of new antifungal agents.AimThis review includes the main studies age-stratified to assess different variables related to the economic burden of invasive candidiasis.MethodsSystematic review of biomedic databases including Medline, PubMed and EMBASE.ResultsThe studies show hospital stay as the main variable related with higher impact in the increase of invasive candidiasis costs. Acquisition costs of antifungals have a very low impact in the invasive candidiasis costs.ConclusionsPharmacoeconomics applied in candidiasis invasive therapy must avoid assessing acquisition costs of antifungals exclusively, needing to include both direct and indirect costs associated with this fungal infection. The cost of antifungal acquisition represents a low impact in the overall economic burden of this fungal infection. Further pharmacoeconomics evaluations should be performed including similar definitions to decrease the possible bias in results interpretation.     

Antibodies to Candida albicans germ tubes in two intensive care patients with invasive candidiasis

Two cases of invasive candidiasis in intensive care patients are presented to illustrate the usefulness of detection of antibodies to Candida albicans germ tubes in the diagnosis of invasive candidiasis and in monitoring the efficacy of the antifungal treatment.