Cause Of Invasive Fungal Infections Research Articles

In vitro susceptibility testing in fungi: a global perspective on a variety of methods

Candida and Aspergillus species are the most common causes of invasive fungal infections in immunocompromised patients. The introduction of new antifungal agents and recent reports of resistance emerging during treatment have highlighted the need for in vitro susceptibility testing. For some drugs, there is a supporting in vitro-in vivo correlation available from studies of clinical efficacy. Both intrinsic and emergent antifungal drug resistance are encountered. Various testing procedures have been proposed, including macrodilution and microdilution, agar diffusion, disk diffusion and Etest. Early recognition of infections caused by pathogens that are resistant to one or more antifungals is highly warranted to optimise treatment and patient outcome.

Invasive Fungal Infections

Invasive fungal infections (IFIs) are being increasingly recognized as a major threat in critically ill adult and paediatric patients. They can range widely in severity and can be life threatening in some patients. Candida and Aspergillus species are the most common causes of IFIs, but other yeasts and filamentous fungi are emerging pathogens. C. albicans, the most significant pathogenic species, is seen in almost all of the 17% of patients treated in the intensive care unit (ICU) who develop IFIs, and is associated with significant morbidity and mortality. Non-albicans spp. are becoming more common, particularly in neutropenic patients and those on existing azole therapy. Early diagnosis is challenging due to delays in, and low sensitivity of, confirmatory blood cultures, and difficulty in discriminating colonization from invasive candidiasis. Once diagnosed, early initiation of appropriate antifungal therapy is essential for reducing morbidity and mortality. Amphotericin B deoxycholate and azoles, once standard therapy, have been largely superseded in the ICU by broad-spectrum azoles, liposomal amphotericin B and the newer echinocandin agents with improved efficacy/tolerability profiles. The echinocandins (caspofungin, micafungin and anidulafungin) exhibit fungicidal activity against Candida spp. and fungistatic activity against Aspergillus spp. Echinocandins have demonstrated clinical efficacy, broad spectrum of activity and favourable pharmacological properties, and are, therefore, likely to replace fluconazole as the initial antifungal agent of choice among critically ill patients. Current evidence supports echinocandin empirical therapy for candidaemia or invasive candidiasis in ICU patients with or without neutropenia, and as rescue therapy in patients with life-threatening IFIs caused by strains resistant to other antifungals. Anidulafungin represents a new advance in the treatment of IFIs and is approved for treatment of candidaemia, intra-abdominal abscesses, peritonitis and oesophageal candidiasis.

Antifungal activity againstScedosporiumspecies and novel assays to assess antifungal pharmacodynamics against filamentous fungi

The saprophytic moulds Scedosporium prolificans and Scedosporium apiospermum/Pseudallescheria boydii are an increasing cause of invasive fungal infections in immunocompromised hosts. The growing importance and high mortality rates of invasive disease caused by these fungi necessitates the search for newer treatment strategies. However, clinically available antifungal agents have modest to minimal activity against these organisms that has been confirmed by suboptimal responses in the clinic. Due to this limited in vitro activity and poor clinical response, antifungal combinations and high-dose regimens are frequently recommended to treat these refractory infections. However, development of a pharmacodynamic basis for antifungal dosing in scedosporiosis has been hampered by the limitations in the application of traditional microbiological techniques and endpoints for Scedosporium species. Newer quantitative and qualitative assays have demonstrated utility for measuring drug lethality in filamentous fungi, including Scedosporium species, and may aid in the development of new treatment strategies to improve patient outcomes

Aspergillus to Zygomycetes: Causes, Risk Factors, Prevention, and Treatment of Invasive Fungal Infections

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality, particularly in patients with underlying risk factors (e.g., neutropenia, cancer chemotherapy, transplantation, AIDS). Although Candida species remain a relevant cause of IFI, other organisms (particularly moulds) have become increasingly prevalent. In particular, Aspergillus species are the leading cause of mould infections although other moulds including Fusarium species and Zygomycetes are increasing in frequency, and are associated with a high mortality rate. Options available for the prevention and treatment of these infections include standard and liposomal formulations of amphotericin B, but toxicity concerns limit their use; fluconazole is effective for the prevention and treatment of candidiasis but its inactivity against moulds and increasing resistance are limiting factors. Newer azoles, particularly voriconazole and posaconazole, have an enhanced spectrum of activity that includes Candida species, Aspergillus species, Cryptococcus species, dimorphic fungi, Fusarium species, and, for posaconazole, Zygomycetes. Recent data suggest that these agents are highly effective in a variety of clinical settings. Echinocandins have good activity against Candida species and Aspergillus species but their spectrum generally does not include Fusarium species, Cryptococcus species, Trichosporon species, Zygomycetes, and dematiaceous moulds. While these agents are unlikely to exhibit crossresistance with polyenes or azoles, they must be administered intravenously. Knowledge of the pathogenesis of IFIs and the activity, efficacy, and limitations of available treatment options will allow the selection of an appropriate antifungal agent for individual patients.

Aspergillus to Zygomycetes: Causes, Risk Factors, Prevention, and Treatment of Invasive Fungal Infections

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality, particularly in patients with underlying risk factors (e.g., neutropenia, cancer chemotherapy, transplantation, AIDS). Although Candida species remain a relevant cause of IFI, other organisms (particularly moulds) have become increasingly prevalent. In particular, Aspergillus species are the leading cause of mould infections although other moulds including Fusarium species and Zygomycetes are increasing in frequency, and are associated with a high mortality rate. Options available for the prevention and treatment of these infections include standard and liposomal formulations of amphotericin B, but toxicity concerns limit their use; fluconazole is effective for the prevention and treatment of candidiasis but its inactivity against moulds and increasing resistance are limiting factors. Newer azoles, particularly voriconazole and posaconazole, have an enhanced spectrum of activity that includes Candida species, Aspergillus species, Cryptococcus species, dimorphic fungi, Fusarium species, and, for posaconazole, Zygomycetes. Recent data suggest that these agents are highly effective in a variety of clinical settings. Echinocandins have good activity against Candida species and Aspergillus species but their spectrum generally does not include Fusarium species, Cryptococcus species, Trichosporon species, Zygomycetes, and dematiaceous moulds. While these agents are unlikely to exhibit crossresistance with polyenes or azoles, they must be administered intravenously. Knowledge of the pathogenesis of IFIs and the activity, efficacy, and limitations of available treatment options will allow the selection of an appropriate antifungal agent for individual patients.

Development of an Immunochromatographic Lateral-Flow Device for Rapid Serodiagnosis of Invasive Aspergillosis

Aspergillus fumigatus is a cosmopolitan saprotrophic fungus that is second only to Candida species as a cause of invasive fungal infections in immunocompromised humans. Current immunodiagnostic tests for invasive aspergillosis (IA) are based on the detection of circulating galactomannan (GM) in a patient's serum by using a rat monoclonal antibody (MAb), EB-A2, that binds to tetra (1-->5)-beta-D-galactofuranoside, the immunodominant epitope in GM. The potential cross-reactivity of MAb EB-A2 with non-Aspergillus fungi, with contaminating GM in beta-lactam antibiotics and foodstuffs, and with bacterial lipoteichoic acids has prompted efforts to discover non-GM antigens that can act as surrogate markers for the diagnosis of IA. This paper describes the development of a mouse MAb, JF5, that binds to a protein epitope present on an extracellular glycoprotein antigen secreted constitutively during the active growth of A. fumigatus. The MAb was used to develop an immunochromatographic lateral-flow device (LFD) for the rapid (15-min) detection of Aspergillus antigens in human serum. The test is highly specific, reacting with antigens from Aspergillus species but not with antigens from a large number of clinically important fungi, including Candida species, Cryptococcus neoformans, Fusarium solani, Penicillium marneffei, Pseudallescheria boydii, and Rhizopus oryzae. The LFD was able to detect circulating antigen in serum samples from patients suspected of having or shown to have IA on the basis of their clinical symptoms and results from tests for GM and fungal (1-->3)-beta-D-glucan. The ease of use of the LFD provides a diagnostic platform for the routine testing of vulnerable patients who have an elevated risk of IA.

A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V(max) values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

Antifungal therapy for neonatal candidiasis

This review focuses on recent data regarding antifungal prophylaxis and antifungal treatment of neonatal candidiasis. Candida species are the leading cause of invasive fungal infection in the neonatal intensive care unit, and are the third most common blood culture isolates recovered from cases of late-onset sepsis in the neonatal intensive care unit. Neonatal candidemia is associated with significant morbidity and mortality. Risk factors for neonatal candidiasis have been elucidated, and prophylaxis of high-risk infants has been found to be effective, particularly in neonatal intensive care units with a high incidence of candidemia. Amphotericin B has been the mainstay of antifungal therapy for candidemia in the neonatal intensive care unit but newer agents such as echinocandins and azoles are currently being evaluated. Neonatal candidiasis is a serious infection especially in extremely low-birthweight infants and prophylaxis has been shown to be effective in preventing candidiasis in high-risk infants. Newer pharmacokinetic, safety and efficacy data for both older and newer antifungal agents are emerging in neonates, and these data may help us achieve more effective management of neonatal candidiasis.

A prospective randomized trial of itraconazole vs fluconazole for the prevention of fungal infections in patients with acute leukemia and hematopoietic stem cell transplant recipients

Fluconazole antifungal prophylaxis is standard care in allogeneic hematopoietic stem cell transplant (HSCT) recipients, but this drug lacks anti-Aspergillus activity, the primary cause of invasive fungal infection (IFI) in many transplantation centers. We performed a randomized trial to compare itraconazole vs fluconazole, for prevention of IFIs in patients with acute leukemia (AL) and HSCT recipients. One hundred and ninety-five patients were randomly assigned to either fluconazole or itraconazole antifungal prophylaxis, after stratification into high-risk and low-risk groups. Antifungal prophylaxis was started at the beginning of chemotherapy and continued until resolution of neutropenia, or until amphotericin B treatment was started. IFI occurred in 11 (11%) of itraconazole, and in 12 (12%) fluconazole recipients. Invasive candidiasis (IC) developed in two (2%) itraconazole and one (1%) fluconazole recipients, while invasive aspergillosis (IA) developed in nine (9%) itraconazole and 11(11%) fluconazole recipients. There was no difference in the incidence of total IFI, IC and IA between the two study arms. However, there was a nonsignificant trend towards reduced mortality among patients who developed IA while receiving itraconazole prophylaxis (3/9=33% vs 8/11=73%, P=0.095).

Deoxycholate amphotericin B and amphotericin B lipid complex exert additive antifungal activity in combination with pulmonary alveolar macrophages against Fusarium solani

Fusarium spp. have emerged as important causes of invasive fungal infections in immunocompromised patients. Rabbit pulmonary alveolar macrophages (PAMs) exhibited fungicidal activity against conidia of Fusarium solani and achieved a time-dependent increase in killing. Neither deoxycholate amphotericin B (DAMB) nor amphotericin B lipid complex (ABLC) exerted a suppressive effect on PAMs by decreasing their conidiocidal activity against F. solani. On the contrary, at a concentration of 0.125 microg ml(-1), ABLC and, to a lesser degree, DAMB additively augmented the fungicidal activity of pulmonary alveolar macrophages against conidia of Fusarium solani.

The Epidemiology and Attributable Outcomes of Candidemia in Adults and Children Hospitalized in the United States: A Propensity Analysis

Candida species are the fourth most common cause of bloodstream infection and are the leading cause of invasive fungal infection among hospitalized patients in the United States. However, the frequency and outcomes attributable to the infection are uncertain. This retrospective study set out to estimate the incidence of candidemia in hospitalized adults and children in the United States and to determine attributable mortality, length of hospital stay, and hospital charges related to candidemia. We used the Nationwide Inpatient Sample 2000 for adult patients and the Kids' Inpatient Database 2000 for pediatric patients. We matched candidemia-exposed and candidemia-unexposed patients by the propensity scores for the probability of candidemia exposure, which were derived from patient characteristics. Attributable outcomes were calculated as the differences in estimates of outcomes between propensity score-matched patients with and without candidemia. In the United States in 2000, candidemia was diagnosed in an estimated 1118 hospital admissions of pediatric patients and 8949 hospital admissions of adult patients, yielding a frequency of 43 cases per 100,000 pediatric admissions (95% confidence interval [CI], 35-52 cases per 100,000 pediatric admissions) and 30 cases per 100,000 adult admissions (95% CI, 26-34 cases per 100,000 adult admissions). In pediatric patients, candidemia was associated with a 10.0% increase in mortality (95% CI, 6.2%-13.8%), a mean 21.1-day increase in length of stay (95% CI, 14.4-27.8 days), and a mean increase in total per-patient hospital charges of 92,266 dollars (95% CI, 65,058 dollars-119,474 dollars). In adult patients, candidemia was associated with a 14.5% increase in mortality (95% CI, 12.1%-16.9%), a mean 10.1-day increase in length of stay (95% CI, 8.9-11.3 days), and a mean increase in hospital charges of 39,331 dollars (95% CI, 33,604 dollars-45,602 dollars). The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment of candidemia in adults and children.

Prevention, Diagnosis, and Treatment of Invasive Fungal Infections in Patients with Cancer and Neutropenia

Invasive fungal infections are a major cause of morbidity and mortality in patients with prolonged neutropenia and in allogeneic hematopoietic stem cell transplant recipients. The degree and duration of neutropenia influence the risk of opportunistic fungal infections. Because Candida and Aspergillus species are the major causes of invasive fungal infections in neutropenic patients, the fungal section of the NCCN guidelines focus on these two pathogens. Effective prevention and therapy of invasive fungal pathogens is a priority in highly immunocompromised patients with cancer. Three strategies in preventing and treating patients at high risk for fungal infection will be considered: (1) prophylaxis; (2) empirical therapy; and (3) treatment for probable or proven fungal infection. In addition to more effective antifungal agents, growing interest has been noted in novel non-culture detection methods to facilitate early diagnosis of invasive fungal infections.

Interactions of human phagocytes with mouldsFusariumspp. andVerticilliumnigrescenspossessing different pathogenicity1

Fusarium spp. are emerging as important causes of invasive fungal infections. They tend to have decreased susceptibility to antifungal agents, making host defences very important. The ability of human phagocytes to cause damage to hyphae of Fusarium solani, F. oxysporum and Verticillium nigrescens, a mould with very low pathogenicity, was assessed using the 2,3-bis[2-methoxy-4-nitro-5-sulphophenyl]2H-tetrazolium-5-carboxanilide (XTT) metabolic assay. The oxidative burst, evidenced as superoxide anion (O2-) production, of phagocytes in response to hyphae was also investigated, as well as phagocytosis of conidia by monocyte (MNC)-derived macrophages (MDM). Hyphal damage by polymorphonuclear leukocytes (PMNL) and MNC showed a linear trend increasing with effector cell:target cell (E:T) ratio. Although no significant differences were observed for PMNL, MNC-induced damage to F. solani hyphae was lower than that seen with F. oxysporum hyphae at an E:T ratio of 20:1 and with V. nigrescens hyphae at ratios of 1:1, 5:1 and 20:1 (P < 0.05). In contrast, levels of O2- production by phagocytes in response to F. oxysporum were lower than those induced in response to the other fungi (P < 0.01). The average number of V. nigrescens conidia ingested by MDM was higher than that of conidia of the other fungi (P < 0.01). Phagocytes respond to the test fungi differentially, with F. solani being the least susceptible to damage by MNC. This may correlate with the observation that, compared to the other fungi studied, it causes a relatively high incidence of infections in neutropenic patients.