Candida albicans and Non-C. albicans Candida Species: Comparison of Biofilm Production and Metabolic Activity in Biofilms, and Putative Virulence Properties of Isolates from Hospital Environments and Infections

Candida albicans and, more recently, non-C. albicans Candida spp. are considered the most frequent fungi in hospitals. This study analyzed Candida spp. isolates and compared the frequency of different species, that is, C. albicans and non-C. albicans Candida spp., and the origins of isolates, that is, from hospital environments or infections. Yeast virulence factors were evaluated based on biofilm production and metabolic activity. Hemolysin production and the antifungal susceptibility profiles of isolates were also evaluated. Candida spp. were highly prevalent in samples collected from hospital environments, which may provide a reservoir for continuous infections with these yeasts. There were no differences in the biofilm productivity levels and metabolic activities of the environmental and clinical isolates, although the metabolic activities of non-C. albicans Candida spp. biofilms were greater than those of the C. albicans biofilms (p < 0.05). Clinical samples had higher hemolysin production (p < 0.05) and lower susceptibility to fluconazole (p < 0.05). Non-C. albicans Candida spp. predominated in samples collected from hospital environments and infections (p < 0.05). These species had a lower susceptibility to fluconazole and amphotericin B, and their biofilms had higher metabolic activities than those produced by C. albicans, which may explain the increased incidence of fungal infections with these yeasts during recent years.     

Evaluation of Antifungal Susceptibility Testing with Microdilution and Etest Methods of <Emphasis Type="Italic">Candida</Emphasis> Blood Isolates

Candida species that show an increasing number of clinical and/or microbiological resistance to several antifungals and are the most common agents of invasive fungal infections. The aim of this study was to investigate the in vitro susceptibility of Candida blood isolates to antifungal agents (amphotericin B, fluconazole, itraconazole, and voriconazole) by comparative use of the CLSI reference microdilution method and Etest. Four hundred Candida blood isolates (215 Candida albicans, 185 non-albicans Candida strains) were included in the study. The broth microdilution test was performed according to the CLSI M27 A2 document. Etest was carried out according to the manufacturer’s instructions. The MIC results obtained with reference microdilution were compared with those obtained with the Etest by using percent and categorical agreements. According to MIK₉₀ values, voriconazole was the most active and itraconazole was the least active drug in vitro against all Candida species. Other than voriconazole, statistically significant differences were found when the susceptibility of Candida albicans and non-albicans Candida spp. to amphotericin B, fluconazole, and itraconazole were compared. These antifungal agents were found to be more active to C. albicans. Among the non-albicans Candida species, the lowest MIC values were obtained for Candida parapsilosis isolates. When the standard method was compared with Etest, the total agreement was higher for C. albicans than for non-albicans species, especially for fluconazole and voriconazole. In view of the findings, it was concluded that itraconazole showed the lowest activity against all Candida species. Etest could be an alternative method in assessing the in vitro antifungal susceptibility of Candida spp., but it is more convenient to use the microdilution method for studying in vitro susceptibility of non-albicans species, in particular for those possessing high MIC values against azoles.     

Antifungal Activity of Naphthoquinoidal Compounds In Vitro against Fluconazole-Resistant Strains of Different Candida Species: A Special Emphasis on Mechanisms of Action on Candida tropicalis

In recent decades, the incidence of candidemia in tertiary hospitals worldwide has substantially increased. These infections are a major cause of morbidity and mortality; in addition, they prolong hospital stays and raise the costs associated with treatment. Studies have reported a significant increase in infections by non-albicans Candida species, especially C. tropicalis. The number of antifungal drugs on the market is small in comparison to the number of antibacterial agents available. The limited number of treatment options, coupled with the increasing frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. The objective of this study was to evaluate and compare the antifungal activities of three semisynthetic naphthofuranquinone molecules against fluconazole-resistant Candida spp. strains. These results allowed to us to evaluate the antifungal effects of three naphthofuranquinones on fluconazole-resistant C. tropicalis. The toxicity of these compounds was manifested as increased intracellular ROS, which resulted in membrane damage and changes in cell size/granularity, mitochondrial membrane depolarization, and DNA damage (including oxidation and strand breakage). In conclusion, the tested naphthofuranquinones (compounds 1–3) exhibited in vitro cytotoxicity against fluconazole-resistant Candida spp. strains.     

Candidal urinary tract infections caused by non-<Emphasis Type="Italic">albicans Candida</Emphasis> species

The incidence of non-albicans Candida and non-Candida species isolated from the urine of patients admitted to various departments of theFaculty Hospital of the Medical Faculty of Šafárik University in Košice was examined. From a total of 94 samples of analyzed urine 58 strains ofC. albicans and 36 strains of yeasts belonging to 6 species of non-albicans Candida and non-Candida spp. were detected:C. parapsilosis (n=23), C. tropicalis (6), C. krusei (3), C. robusta (2), C. catenulata (1) andCryptococcus neoformans (1). In relation to the diagnosis, the yeasts were isolated from patients suffering from a kidneys disease, epididymitis, diabetes, neoplastic diseases, urogenital anomalies, obstructive uropathy, cystitis, prostatitis, hemolytic-uremic syndrome, and others.     

Geographic Trends in Invasive Candidiasis

Candida species are one of the most important causes of bloodstream infection (BSI) in tertiary-care hospitals worldwide. The incidence of candidemia and the Candida species causing these infections may vary geographically. Although C. albicans remains the species most commonly isolated, there is clear evidence showing increasing rates of BSI caused by Candida non-albicans species around the world. C. glabrata is the second most common cause of candidemia in North America, but it is less frequently isolated in Latin America. On the other hand, C. parapsilosis complex represents the second or the third most common species found in Latin American and Iberian countries, while C. tropicalis has emerged as a frequent agent of BSI in Latin America and Asia-Pacific regions. In this context, a complex set of clinical aspects and biologic factors may contribute to the geographic trends in the epidemiology of candidemia.     

Antifungal Therapy for Invasive Fungal Diseases in Allogeneic Stem Cell Transplant Recipients: An Update

Invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in allogeneic stem cell transplant (SCT) recipients. While the most common pathogens are Candida spp. and Aspergillus spp., the incidence of infections caused by non-albicans Candida species as well as molds such as Zygomycetes has increased. For many years, amphotericin B deoxycholate (AMB-D) was the only available antifungal for the treatment of IFDs. Within the past decade, there has been a surge of new antifungal agents developed and added to the therapeutic armamentarium. Lipid-based formulations of amphotericin B provide an effective and less nephrotoxic alternative to AMB-D. Voriconazole has now replaced AMB-D as first choice for primary therapy of invasive aspergillosis (IA). Another extended-spectrum triazole, posaconazole, also appears to be a promising agent in the management of zygomycosis, refractory aspergillosis, and for prophylaxis. Members of the newest antifungal class, the echinocandins, are attractive agents in select infections due to their safety profile, and are a more attractive option compared to AMB-D as initial treatment for invasive candidiasis and (based on one study) challenge fluconazole for superiority in management with this mycoses. However, challenges do exist among these newer agents in very high-risk individuals like allogeneic SCT recipients, which may include adverse drug events, drug–drug interactions, variability in oral absorption, and availability of alternative formulations. The addition of newer agents has also stimulated interest in the potential application of combination therapy in serious, life-threatening infections. However, adequate studies are not available for most IFDs; thus, the clinical use of combination therapy is not evidenced based on most cases and preciseness in its use is uncertain. Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses.     

Species diversity of yeast in oral colonization of insulin-treated diabetes mellitus patients

The aim of this study was to investigate oral yeast colonization, antifungal susceptibility and strain diversity in insulin-dependent diabetes mellitus patients (175), as well as to evaluate the influence of dental prostheses. Oral rinse samples were cultured on selective media, in order to isolate, count and identify the yeasts recovered. More than half of the diabetic subjects (53%) carried significant amounts of Candida cells in the buccal cavity and these organisms were recovered at higher densities in diabetics wearing dentures. A total of 93 yeast strains were isolated from these patients, including: Candida spp. (n = 89); Pichia (n = 02); Trichosporon (n = 1), and Geotrichum (n = 1). C. albicans represented 56% of these strains, non-albicans Candida 39.8%, and other genera of yeast 4.3%. C. albicans was prevalent, followed by C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. rugosa and C. guilliermondii. Agar disk-diffusion tests of the susceptibility of non-albicans Candida and other genera of yeast to fluconazole showed resistance in 21.9%, mainly in C. rugosa (100%), C. glabrata (57%) and C. krusei (50%). Local oral factors, such as the presence of dentures, in association with diabetes, seemed to have the effect of increasing the amount and variety of Candida species in the oral cavities, mainly those with lower drug susceptibilities.     

Fungal diseases of the respiratory tract

The proportion ofCandida and non-Candida species in the clinical material from patients. with respiratory-tract diseases was determined.C. albicans was isolated in 102 cases. An additional 89 strains of yeasts, isolated in association with respiratory diseases, belonged to 10 non-albicans Candida spp. andCryptococcus spp. The prevailing species, which occurred in 47 cases, wasC. parapsilosis. C. tropicalis, C. glabrata, andC. guilliermondii were isolated in 12, 10, and 9 cases, respectively. Four strains ofC. krusei and three strains ofC. lusitaniae and one strain each ofC. freyschussii, C. robusta, C. zeylanoides, andCryptococcus neoformans were also isolated.     

Is There Still a Place for Conventional Amphotericin B in the Treatment of Neonatal Fungal Infections?

Neonatal invasive fungal infections (IFIs) remain an increasing problem associated with high rates of morbidity and mortality, as well as late-onset neurodevelopmental implications. Invasive candidiasis remains the leading neonatal IFI. Candida albicans is the fungal species most often affecting this population, although a changing epidemiologic incidence to non-albicans Candida species is reported in some neonatal intensive care units. Many treatment recommendations are extrapolated from adult populations, emphasizing the need to establish the optimal antifungal agent, dosage, and duration of therapy in neonates. Historically, conventional amphotericin B has been considered an efficient and safe treatment approach for most neonatal IFIs. More recently, lipid formulations of amphotericin B have been studied, used alone or in combination with other antifungal agents such as azoles or echinocandins. The aim of this article is to review the published experience in the use of amphotericin B formulations to treat neonatal IFIs.     

Candidemia in the Pediatric Intensive Care Unit: What’s Different from Candidemia in Adults?

Candida species bloodstream infections have been associated with high morbidity and mortality, especially in patients hospitalized in a pediatric intensive care unit (PICU). The incidence of such infections is rising because of malignancies, prolonged PICU stay, and the use of broad-spectrum antibiotics. Although Candida albicans remains the most frequently isolated species, non-albicans Candida species have shown an increased frequency. Treatment with fluconazole or an echinocandin should be considered in patients at high risk for candidemia or as initial treatment for non-neutropenic patients with candidemia, in addition to the removal of intravascular catheters. Treatment with a lipid formulation of amphotericin B or caspofungin is suggested for neutropenic patients. Early diagnosis, prompt therapy, and prevention are the cornerstones of controlling infection and improving outcome. Although there are some differences between children and adults with candidemia, especially in antifungal drug therapy and outcome, in general the incidence, risk factors, species variation, diagnostic methods, and management are similar.     

The role of second-generation triazole antifungal agents voriconazole and posaconazole in patients with hematologic malignancies

The second-generation triazoles, voriconazole and posaconazole, have found important roles in the management of invasive fungal infections in high-risk patients. Both agents are more active against Candida albicans and the non-albicans Candida species than the first-generation triazoles. They are active against Aspergillus species, including those species less susceptible to polyenes, and against a variety of non-Aspergillus molds. In contrast to posaconazole, voriconazole has no activity against the zygomycetes, and breakthrough infections have been observed. Both are well absorbed, but considerable intra- and interpatient pharmacokinetic variability has raised the question of therapeutic drug monitoring. Both inhibit hepatic cytochrome P450 isoenzymes, which are important in the metabolism of various drugs coadministered in the management of high-risk patients. Clinical trials have demonstrated the safety and efficacy of both agents for antifungal prophylaxis and treatment in invasive candidiasis, invasive aspergillosis, and in invasive fungal infections caused by a variety of non-Aspergillus molds. Posaconazole is the only triazole approved for use in the treatment of invasive zygomycosis. Voriconazole is the accepted standard first-line therapy for invasive aspergillosis.     

Epidemiología de las candidiasis invasoras en población pediátrica y adulta

BackgroundInvasive candidiasis (IC) is the most frequent fungal disease in children and adults.AimsTo critically review and update the current epidemiology of Candida spp. disease in neonates, children and adults (critically ill patients and in oncohematologic patients and in solid organ transplant recipients).MethodsWe searched the PubMed/Medline, discussing the current data.Results and conclusionsIC is associated with high attributable morbimortality and increased healthcare costs. In the last decades the incidence of invasive Candida spp. disease has increased in critically ill patients, has decreased in oncohematologic patients, although currently the involvement of non-albicans Candida species in the etiology of this disease is increasing steadily.     

Invasive Candidiasis in the Neutropenic Cancer Patient

Invasive candidiasis (IC) is an important complication among cancer patients with neutropenia, as it is associated with significant mortality. Despite the introduction of the new antifungals in clinical practice and their widespread use as treatment or prophylaxis, the incidence of IC and the predominance of non-albicans Candida species remain unchanged, and mortality rates remain as high as in previous periods. New techniques have been developed to decrease the time to Candida species identification from blood cultures. Nonculture diagnostic methods and molecular diagnostic tests for detection of Candida are promising but have not been validated in neutropenic patients. Recently, voriconazole was proved to be as effective as fluconazole for prophylaxis in neutropenic recipients of hematopoietic stem cell transplants and in patients with graft-versus-host disease. Despite the lack of randomized studies of the treatment of IC among neutropenic patients, it seems that the success rates of antifungal therapy do not differ from those in non-neutropenic patients.     

Treatment of breakthrough fungal infections: Is there one best drug strategy?

Widespread use of antifungal drugs in prophylactic and therapeutic settings is associated with breakthrough infections primarily due to Aspergillus and non-Aspergillus molds and non-albicans Candida. Reasons for breakthrough include worsening of initial infection, superinfection, and co-infection; subtherapeutic drug levels, emergence of antifungal resistance, and host factors may contribute to progression of the initial infection. Establishing an etiologic diagnosis is crucial because clinical and radiological features are nonspecific, and empirically chosen drug(s) may not provide appropriate antimicrobial coverage. Evidence-based data do not exist for the management of breakthrough infection. Current treatment strategies include switching therapy to a drug of another class, dose optimization, and combinations of drugs. Dosage adjustment of triazoles guided by serum concentrations may ensure optimal efficacy and avoidance of toxicity. A combination of an echinocandin plus a triazole or polyene appears to be synergistically effective against invasive aspergillosis. The treatment strategy needs to be individualized. For an optimal outcome, reversal of immunosuppression is essential.     

Role of cell-mediated immunity in the resistance to experimental sporotrichosis in mice

The in vitro activity of several new imidazoles, cloconazole, sulconazole, butoconazole, isoconazole and fenticonazole, were compared with those of amphothericin B, flucytosine, and three azoles: econazole, miconazole and ketoconazole against isolates of pathogenic Candida. A total of 186 clinical isolates of 10 species of the genus Candida and two culture collection strains were tested by an agar-dilution technique. Isoconazole was the most active azole, followed by butoconazole and sulconazole. Differences between some of the species in their susceptibility to the antifungal agents were noted. Sulconazole and cloconazole had the highest activity in vitro against 106 isolates of C. albicans. Butoconazole and isoconazole were also very active against isolates of C. albicans, and were the most active azole compounds against 80 isolates of Candida spp.     

Enfermedades invasoras por hongos levaduriformes en pacientes neutropénicos

Invasive fungal diseases caused by yeasts still play an important role in the morbidity and mortality in neutropenic patients with haematological malignancies. Although the overall incidence of invasive candidiasis has decreased due to widespread use of antifungal prophylaxis, the incidence of non-Candida albicans Candida species is increasing compared with that of C. albicans, and mortality of invasive candidiasis continues to be high. In addition, there has been an increase in invasive infections caused by an array of uncommon yeasts, including species of the genus Malassezia, Rhodotorula, Trichosporon and Saprochaete, characterised by their resistance to echinocandins and poor prognosis.     

How to diagnose and treat fungal infections in chronic prostatitis

Epidemiologic changes that include immune-compromised patients and drug-resistant fungi have caused an increase in nosocomial infections by Candida albicans and non-albicans Candida species. Other fungi, aspergilla and Cryptococcus (environmental contaminants), are opportunistic invaders of the immune-compromised (transplant, HIV) patients. The environmental fungi Coccidioides immitis (dry arid areas), Histoplasma capsulatum (Avian-infested areas), and Blastomyces dermatitidis (aquatic areas) can cause infections in immune-competent and immune-deficient patients. Each fungus can cause changes in the prostate that mimic bacterial infection, benign prostatic hypertrophy, or neoplasm. Diagnosis can be established by urine cultures or needle biopsy of the prostate. Prostate surgery for carcinoma or benign enlargement may detect latent fungal infection. Different fungal species can have divergent clinical manifestations and require different treatment. In some cases, asymptomatic, localized, fungal prostatitis can be cured by removal of the infected gland. Symptomatic and disseminated infection may require prostatectomy and systemic antifungal therapy.     

2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole analogues: Antifungal activity in vitro against <Emphasis Type="Italic">Candida</Emphasis> species

The antifungal activity in vitro of the newly synthesized and previously reported compounds of 5-substituted 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole series was evaluated. Their structures were confirmed by elemental analyses and IR, ¹H and ¹³C NMR and mass spectra. The azole-resistant clinical isolates of Candida albicans and no-albicans Candida spp. were used in the antifungal tests. Some compounds exhibit higher activities than the comparatively studied antifungal drugs. Amino-1,3,4-thiadiazole derivatives exhibited higher (than other analogues) antifungal effects against Candida no-albicans spp. than against C. albicans. Derivatives with strong antifungal activity have a narrow range of lipophilicity values determined by the Villar approach.     

Epidemiology and Microbiologic Characterization of Nosocomial Candidemia from a Brazilian National Surveillance Program

Candidemia is a growing problem in hospitals all over the world. Despite advances in the medical support of critically ill patients, candidiasis leads to prolonged hospitalization, and has a crude mortality rate around 50%. We conducted a multicenter surveillance study in 16 hospitals distributed across five regions of Brazil to assess the incidence, species distribution, antifungal susceptibility, and risk factors for bloodstream infections due to Candida species. From June 2007 to March 2010, we studied a total of 2,563 nosocomial bloodstream infection (nBSI) episodes. Candida spp. was the 7^th most prevalent agent. Most of the patients were male, with a median age of 56 years. A total of 64 patients (46.7%) were in the ICU when candidemia occurred. Malignancies were the most common underlying condition (32%). The crude mortality rate of candidemia during the hospital admission was 72.2%. Non-albicans species of Candida accounted for 65.7% of the 137 yeast isolates. C. albicans (34.3%), Candida parapsilosis (24.1%), Candida tropicalis (15.3%) and Candida glabrata (10.2%) were the most prevalent species. Only 47 out of 137 Candida isolates were sent to the reference laboratory for antifungal susceptibility testing. All C. albicans, C. tropicalis and C. parapsilosis isolates were susceptible to the 5 antifungal drugs tested. Among 11 C. glabrata isolates, 36% were resistant to fluconazole, and 64% SDD. All of them were susceptible to anidulafungin and amphotericin B. We observed that C. glabrata is emerging as a major player among non-albicans Candida spp. and fluconazole resistance was primarily confined to C. glabrata and C. krusei strains. Candida resistance to echinocandins and amphotericin B remains rare in Brazil.Mortality rates remain increasingly higher than that observed in the Northern Hemisphere countries, emphasizing the need for improving local practices of clinical management of candidemia, including early diagnosis, source control and precise antifungal therapy.     

Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species

Invasive Candida infections have increased fivefold over the past 20 years. During this time, the incidence of antifungal resistance and infection due to non-albicans species has risen with the increasing use of broad spectrum antifungals. As few new antifungal agents are in development, strategies to improve outcomes in the treatment of Candida infections are sorely needed. The use of immunotherapy to augment the host immune response as an adjunctive treatment for Candida infections is a potentially robust and promising approach. The purpose of this review is to focus on new developments in the use of adjunctive immunotherapy for the treatment of Candida infections, and discuss the potential impact of antifungal resistance on the host immune response.