The continuous changes in the aetiology and epidemiology of invasive candidiasis: from familiar <Emphasis Type="Italic">Candida albicans</Emphasis> to multiresistant <Emphasis Type="Italic">Candida auris</Emphasis>

Recent changes in the aetiology and epidemiology of invasive candidiasis have serious implications for current and future diagnosis, treatment and prognosis. The aim of the current review was to discuss the epidemiology of invasive candidiasis, the distribution of Candida species in different regions of the world, the medical concerns of the changing aetiology and the emergence of antifungal resistance. Overall burden of invasive candidiasis remains high, especially in vulnerable persons, such as the elderly, immunosuppressed or debilitated patients. Moreover, there is a progressive shift in the aetiology of invasive candidiasis from Candida albicans to other species of Candida, probably related to the increased use of azole drugs with a clear trend towards increased antifungal resistance. Finally, the emergence and rise of multiresistant species, such as Candida auris or Candida glabrata, is a major threat making necessary invasive candidiasis worldwide surveillances. These changes have serious implications for the diagnosis, treatment and prognosis of invasive candidiasis. Updated knowledge of the current local epidemiology of invasive candidiasis is critical for the clinical management.     

Polymerase Chain Reaction (PCR)–Based Diagnostic Assays for Invasive Candidiasis

Candidemia and other types of invasive candidiasis are associated with mortality rates as high as 40% despite antifungal therapy. In part, the poor outcomes stem from the inadequacies of diagnostic tests for invasive candidiasis. The current gold standard is blood culture, which is negative in 50% of autopsy-proven cases. As such, development of novel diagnostics is a top priority. Assays for invasive candidiasis based on polymerase chain reaction (PCR) are potentially attractive because of their high sensitivity, rapid turnaround time, capacity for speciation, and ability to quantitate the candidal burden. Research has refined PCR methods and performance parameters to the point that diagnostic assays for invasive candidiasis are approaching the clinic. Overall, optimized PCR assays have sensitivities and specificities for candidemia and proven or probable invasive candidiasis that exceed 90%. Studies are now needed to determine the precise clinical roles of PCR diagnostic assays and their impact on patient outcomes.     

Risk factors in invasive candidiasis: stratification

Risk factors of invasive candidiasis in the setting of non neutropenic critical patients are well known, although currently there is a need to define and validate in prospective multicenter studies risk assessment strategies that would predict accurately the likelihood of invasive candidiasis. The clinical application in order to define which patients should be treated with antifungal prophylaxis and which groups or subgroups of patients should be assessed prospectively during the risk period in order to validate the new diagnostic microbiological indirect techniques for invasive candidiasis and preemptive treatment should be based in these strategies.     

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.     

Value of serum arabinitol for the management of Candida infections in clinical practice

To determine the value of serum arabinitol concentrations in clinical practice, we identified all patients at the University of Utah Medical Center for whom a serum arabinitol determination had been requested by the attending physician or housestaff to assist in the management of candidiasis. The patient populaton was divided into three categories on the basis of clinical and pathological findings: (1) superficial candidiasis, (2) possible deep, invasive candidiasis, and (3) definite, deep invasive candidiasis. Abnormal renal function was associated with elevated concentrations of serum arabinitol in proportion to the degree of renal dysfunction. Both the serum arabinitol concentration and the arabinitol/creatinine ratio were increased in the combined patient population with candidiasis relative to normal uninfected controls (p=0.06 and 0.001, respectively). However, neither of these tests reliably distinguished patients with invasive candidiasis from those with only superficial candidal disease.     

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.     

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.     

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.     

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.     

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.     

Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice

Neutrophils (PMNs) constitute the main mechanism of host defense against acute invasive and disseminated candidiasis. Recent studies have demonstrated that tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF) play an important role in the recruitment of PMNs at the site of invasive Candida infection. In the absence of either TNFalpha or IL-6, the course of experimental disseminated candidiasis is more severe, due to defective PMN recruitment. Treatment of mice with recombinant G-CSF (rG-CSF) leads to a significantly reduced mortality during disseminated candidiasis. The outgrowth of Candida albicans from the organs of rG-CSF-treated mice is significantly decreased. Treatment with the combination of rG-CSF and fluconazole has an additive effect on the reduction of fungal load in the organs. In subacute or chronic disseminated Candida infection, rG-CSF is less effective, indicating that neutrophil recruitment and activation are crucial in acute, life-threatening candidiasis, whereas other host defense mechanisms control the outcome of less overwhelming invasive Candida infection.     

Diagnosis of invasive candidiasis by enzyme-linked immunosorbent assay using the N-terminal fragment of <Emphasis Type="Italic">Candida albicans</Emphasis> hyphal wall protein 1

Background  

The diagnosis of invasive candidiasis is difficult because there are no specific clinical manifestations of the disease and colonization and infection are difficult to distinguish. In the last decade, much effort has been made to develop reliable tests for rapid diagnosis of invasive candidiasis, but none of them have found widespread clinical use.     

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.     

Utilidad clínica de la micafungina en el tratamiento de las candidiasis invasoras en el paciente oncohematológico

BackgroundInvasive candidiasis is a severe infection among onco-hematological patients, with an attributable mortality around 40%. Micafungin has shown efficacy in antifungal prophylaxis among hematopoietic stem cell transplant recipients and in the treatment of esophageal candidiasis.AimsTo assess the role of micafungin in the treatment of invasive candidiasis among onco-hematological patients.MethodsLiterature review.ResultsIn a study on 126 patients with candidemia treated with micafungin, an overall response rate of 83% was reported. A double-blind study of 531 patients with invasive candidiasis comparing micafungin (100 mg/day) versus liposomal amphotericin B (3 mg/kg/day) reported success in 90% of patients in both arms, with a more favorable safety profile with micafungin. Other double blind randomized, phase III study compared two doses of micafungin (100 mg/day and 150 mg/day) with standard doses of caspofungin (70 mg loading dose, then 50 mg/day) in adults with invasive candidiasis. Overall success rate was 74% for micafungin 100 mg/day, 70% for micafungin 150 mg/day, and 71% for caspofungin. A double blind randomized study compared micafungin (2 mg/kg/day) to liposomal amphotericin B (3 mg/kg/day) in the treatment of invasive candidiasis in children with a predominance of infections with non-albicans Candida spp. Overall success rate was similar (73% for micafungin and 76% for liposomal amphotericin B).ConclusionsComparative phase III studies have demonstrated non-inferiority of micafungin compared to standard antifungal agents for invasive candidiasis. Micafungin is safe and effective in the treatment of children and adults with invasive candidiasis. Effectivity in invasive infections caused by non-albicans Candida spp is especially relevant in onco-hematological patients receiving fluconazole prophylaxis.     

Use of 65-kDa mannoprotein gene primers for real-time identification of Candida albicans

Invasive candidiasis is associated with high morbidity and mortality, especially in immunocompromised patients. Early diagnosis is often difficult because most clinical signs and symptoms are nonspecific and blood cultures are often negative or become positive too late. Consequently, effective treatment is often delayed. Therefore, there has been an increased interest in the development of molecular-based technology in the diagnosis of invasive candidiasis. In this review, we compare molecular diagnostic tests currently adopted and those under evaluation. We highlight the advantages and the limitations of these methods for the diagnosis of invasive candidiasis. We also describe recent methods based on real time with primers of a gene coding for a 65-kDa mannoprotein of Candida albicans.     

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.     

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

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

Microbiological non-culture methods for the diagnosis of invasive candidiasis: usefulness of surrogate markers

The usefulness of surrogate markers in the diagnosis of invasive candidiasis is based on their ability to detect the infection caused by the different Candida spp. and to differentiate when the fungus is a colonizer or it is causing an invasive disease. This differentiation has been tried by detecting antigens, antibodies and other Candida components in the patient's sera. In this paper we will review the antigens, antibodies and other Candida components which may be useful in the laboratory diagnosis of invasive candidiasis in the non-neutropenic critically ill patient.     

白念珠菌耐药的分子机制研究进展

近年来,免疫受损人群不断增多,该人群念珠菌病发病率呈上升趋势。随着抗真菌药物的广泛应用,临床分离到的白念珠菌耐药株增多,有关白念珠菌对抗真菌药物的耐药机制的研究又有了进一步的进展。就白念珠菌对唑类、多烯类、5-氟胞嘧啶、棘白菌素类等抗真菌药物的耐药机制方面的研究进展,作了介绍。