non-Aspergillus Molds Research Articles

Pharmacotherapy of Invasive Fungal Infections with Voriconazole

Voriconazole, a second-generation and broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14-α-sterol demethylase, which is a pivotal step in cell membrane ergosterol synthesis in fungi. CYP2C19, CYP3A4, flavin-containing monooxygenase (FMO), and to a lesser extent CYP2C9 contribute to the oxidative metabolism of voriconazole by human liver microsomes. Clinical trials have demonstrated the safety and efficacy of voriconazole for prophylaxis and treatment in candidiasis, invasive aspergillosis, and in invasive fungal infections (IFIs) caused by a variety of non-Aspergillus molds, such as Fusarium or Scedosporium spp., and was generally well tolerated as primary therapy in adults and children. The availability of both parenteral and oral formulations and the nearly complete absorption (bioavailability of 96% for adults, ca. 40% in children) of the drug after oral administration provide for ease of use and potential cost savings, and ensure that the therapeutic plasma concentrations are maintained when switching from intravenous to oral regimes. It exhibits nonlinear pharmacokinetics in healthy controls and patients at high risk of IFIs, but considerable intra- and interpatient pharmacokinetic variability has raised the question of therapeutic drug monitoring. Most common adverse events are visual disturbances and elevated transaminase levels. The emergence of resistance towards voriconazole has been rarely reported.

Invasive fungal infections in pediatric oncology

Data on the epidemiology and outcome of invasive fungal infections in children with cancer are limited. The aim of the study was to delineate the epidemiologic, clinical features, risk factors, and outcome of invasive fungal infections in this population. The medical records of all children with malignancies diagnosed with an invasive fungal infection in 1998-2006 at a tertiary pediatric medical center were reviewed for demographic, clinical, and laboratory data. Invasive fungal infection was diagnosed according to the latest EORTC/MSG criteria. Of the 1,047 children hospitalized in the hematology/oncology department during the study period, 75 (7.2%) were diagnosed with a proven (n = 16, 21.3%), probable (n = 18, 24%), or possible (n= 41, 54.7%) invasive fungal infection. Fifteen (20%) had candidemia (non-albicans in 60%), and 60 (80%) had a mold infection (non-Aspergillus in 55%). Crude mortality was 21.7%. The most common underlying diseases were myeloid leukemia (n = 26, 34.7%) and acute lymphoblastic leukemia (n = 24, 32%). Compared to other malignancies, acute myeloid leukemia was significantly associated with the development of invasive fungal infections. Profound neutropenia and high treatment intensity were present in 89% and 73% of patients with IFI respectively. The current mortality rates of invasive fungal infection in children with cancer are lower than previously reported in children and adults. However, the proportion of non-albicans candidemia is increasing, and non-Aspergillus molds are emerging as important pathogens, which may have important implications for prophylaxis and empiric therapy. Improved prevention, early detection, and advanced treatment strategies are needed to improve the outcome.

Invasive infections caused by non-Aspergillus moulds identified by sequencing analysis at a tertiary care hospital in Taiwan, 2000–2008

The clinical and microbiological characteristics of 103 patients with cultures positive for non-Aspergillus moulds in the period 2000 to 2008 were described. Among these patients, 27 had proven or probable invasive infections caused by Fusarium (n = 12), Paecilomyces (n = 7), Zygomycetes (n = 5) and Scedopsorium species (n = 3). The incidence of invasive infections caused by these moulds has not increased during the study period. Lung was the most common infection site and disseminated disease was observed in three leukaemic patients. The overall mortality rate was 40.7%, and was highest in cases zygomycosis. Antifungal susceptibility varied considerably among species. Amphotericin B and posaconazole demonstrated greatest activity against these moulds.

Characteristics of pathogenic fungi and antifungal therapy in cystic fibrosis

A defective mucociliary clearance facilitates colonization with bacteria and fungal spores in cystic fibrosis patients. Yeasts and molds are cultured from the cystic fibrosis respiratory tract and often their clinical relevance is unknown. Candida spp. are the most commonly isolated yeasts, whereas Aspergillus spp., Scedosporium apiospermum, as well as Exophiala dermatitidis in some countries, are the most frequent molds recovered from respiratory specimens. Molecular biotyping studies have revealed that some fungal genotypes are capable of chronically colonizing the airways. Persistent Aspergillus fumigatus infection is associated with an increased risk of pulmonary exacerbations requiring hospitalization. The prevalence of non-Aspergillus molds may be underestimated due to overgrowth of Pseudomonas and Aspergillus spp. on routine media. Allergic bronchopulmonary aspergillosis is usually treated by oral steroids and an antifungal azole drug. Interactions with the co-medication have to be considered. A small number of antifungal pharmacokinetic studies indicate a high inter-subject variability for itraconazole, voriconazole and posaconazole, and therefore therapeutic drug monitoring is recommended.

Mucormycosis, Pseudallescheriasis, and Other Uncommon Mold Infections

Serious infections due to non-Aspergillus molds are being encountered with increasing frequency. Factors likely responsible for the rise of these infections include aging populations in countries with advanced medical technologies, the resultant increase in incidence of many cancers, increasingly intensive myeloablative therapies for these cancers, increasingly intensive care for critically ill patients, and increases in the frequency of solid organ and hematopoietic stem cell transplantation. Although diagnostic and therapeutic modalities have improved, mortality rates for invasive mold infections remain high. In this review, we summarize current knowledge about non-Aspergillus mold infections of the chest, with a focus on risk factors, clinical features, diagnosis, and treatment.

Disseminated Scopulariopsis brevicaulis infection in an allogeneic stem cell recipient: case report and review of the literature

AbstractA fatal case of disseminated Scopulariopsis brevicaulis infection in an allogeneic stem cell transplant recipient is described. The patient was initially thought to have pulmonary aspergillosis, on the basis of clinical signs and antigenaemia, but Aspergillus was not isolated by culture. Scopulariopsis brevicaulis was subsequently isolated from skin and then from sputum and stool. Further investigation revealed that the infection had spread from a primary pulmonary site to the skin. A review of the literature underscores the difficulty of diagnosing infections caused by such emerging fungal pathogens and the poor outcome of immunocompromised patients with non-Aspergillus mould infections.

Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant‐Associated Infection Surveillance Network (TRANSNET)

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among organ transplant recipients. Multicenter prospective surveillance data to determine disease burden and secular trends are lacking. The Transplant-Associated Infection Surveillance Network (TRANSNET) is a consortium of 23 US transplant centers, including 15 that contributed to the organ transplant recipient dataset. We prospectively identified IFIs among organ transplant recipients from March, 2001 through March, 2006 at these sites. To explore trends, we calculated the 12-month cumulative incidence among 9 sequential cohorts. During the surveillance period, 1208 IFIs were identified among 1063 organ transplant recipients. The most common IFIs were invasive candidiasis (53%), invasive aspergillosis (19%), cryptococcosis (8%), non-Aspergillus molds (8%), endemic fungi (5%), and zygomycosis (2%). Median time to onset of candidiasis, aspergillosis, and cryptococcosis was 103, 184, and 575 days, respectively. Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006, a total of 729 IFIs were reported among 633 persons. One-year cumulative incidences of the first IFI were 11.6%, 8.6%, 4.7%, 4.0%, 3.4%, and 1.3% for small bowel, lung, liver, heart, pancreas, and kidney transplant recipients, respectively. One-year incidence was highest for invasive candidiasis (1.95%) and aspergillosis (0.65%). Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005. We detected a slight increase in IFIs during the surveillance period. These data provide important insights into the timing and incidence of IFIs among organ transplant recipients, which can help to focus effective prevention and treatment strategies.

Diagnostic challenges and recent advances in the early management of invasive fungal infections

During the past 20 yr, the population of immunocompromized patients at risk of developing invasive fungal infections (IFIs) has increased, and there has been a shift in fungal epidemiology, with more infections caused by non-Aspergillus molds and yeasts, which are often resistant to one or more antifungal drugs. Traditional diagnostic methods, such as culture and the histopathology of infected tissue, often fail to detect IFIs until the later stages. Furthermore, invasive diagnostic methods to obtain tissue may be contraindicated in severely ill patients; even when tissue is available, the morphology of several filamentous fungi is identical, or the cultures may fail to grow the pathogen. Recently developed non-invasive diagnostic techniques, such as tests for serum markers and polymerase chain reaction assays, may allow for earlier and more accurate diagnoses - crucial in the effort to reduce morbidity and the risk of mortality. This article reviews current approaches to diagnosis and treatment, focusing on how an early and accurate diagnosis can guide treatment and improve outcomes. Strategies for improving the management of IFIs also are discussed.

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

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.

Invasive mould infections in the setting of hematopoietic cell transplantation: current trends and new challenges

Invasive mould infections remain major causes of infection-related mortality following hematopoietic stem cell transplantation (HSCT). In this review, we summarize the recent advances in the diagnosis, prevention, and management of invasive mould infections in HSCT recipients. The evolving epidemiologic characteristics of post-HSCT invasive mould infections, specifically the rising incidence of Aspergillus and non-Aspergillus mould infections in the postengraftment period, necessitate the development of preventive strategies. The efficacy of prophylactic broad-spectrum triazoles against invasive mould infections in HSCT recipients has now been demonstrated in two large prospective studies. However, concerns over drug absorption, interactions, and costs may shift attention from universal prophylaxis to risk stratification and preemptive strategies. In this regard, recent studies have highlighted the potential of genetic polymorphism analysis to identify HSCT recipients at risk for invasive aspergillosis, and efforts are underway to improve the predictive values of antigen and nucleic acid detection assays. Emerging data on risk factors for invasive aspergillosis relapse after HSCT, antifungal drug monitoring, and the use of galactomannan testing to monitor treatment response may help inform therapeutic decisions for HSCT recipients. Evidence-driven management of invasive mould infections in HSCT recipients is becoming increasingly individualized, integrating host factors and pharmacologic and epidemiologic considerations. However, the optimal approach to invasive mould infection prevention in HSCT recipients remains to be resolved by prospective clinical studies.

DisseminatedScopulariopsis brevicaulisinfection in an allogeneic stem cell recipient: case report and review of the literature

A fatal case of disseminated Scopulariopsis brevicaulis infection in an allogeneic stem cell transplant recipient is described. The patient was initially thought to have pulmonary aspergillosis, on the basis of clinical signs and antigenaemia, but Aspergillus was not isolated by culture. Scopulariopsis brevicaulis was subsequently isolated from skin and then from sputum and stool. Further investigation revealed that the infection had spread from a primary pulmonary site to the skin. A review of the literature underscores the difficulty of diagnosing infections caused by such emerging fungal pathogens and the poor outcome of immunocompromised patients with non-Aspergillus mould infections.

Fungal infections after lung transplantation

Lung transplant's Achilles heel is chronic rejection. This is the reason why high immunosuppression is used, which leads to the development of infections. Fungal infections are a great obstacle in lung transplant patients' progress, not only because of their impact on patient survival, but also because fungal infections indirectly have an influence on the graft's progress. This review highlights the changing spectrum of invasive fungal infections as well as the most recent developments in diagnosis, prophylaxis, treatment and monitoring of lung transplantation. Fungal infections have a bimodal presentation: early onset, in relation to difficult postsurgeries and prior colonizations, and late onset, primarily in relation to chronic rejection and terminal renal insufficiency. The clinical impact of non-Aspergillus moulds is still unknown. Recent efforts have focused on nonculture-based methods to establish a rapid diagnosis. However, multicentre studies are needed to establish the diagnostic value of galactomannan antigen assay in invasive aspergillosis in lung transplantation. In addition, studies of the sensitivity and specificity of PCR assays are required to establish their diagnostic value. Unfortunately, only some advances in the diagnosis of aspergillosis have been achieved. Prophylaxis should be tailored according to the different individual patient's risk status. Combined treatments, including surgical therapy, may be useful in some patients.

Successful therapy with ABLC, surgery and posaconazole for Rhizopus microsporus var. rhizopodiformis liver eumycetoma in a child with acute leukaemia

Invasive fungal infection negatively influences the morbidity and mortality in heavily immuno-incompetent patients. Diagnosis of non-Aspergillus mould infections remains challenging despite application of a wide spectrum of non-culture-based microbiological techniques. Invasive diagnostic procedures are often essential. In this article, we present the case of a 15-month-old boy diagnosed with Rhizopus microsporus var. rhizopodiformis liver mycetoma during induction chemotherapy for acute promyelocytic leukaemia. Following surgery, he was effectively treated with a combination of ABLC and posaconazole during ongoing intensive chemotherapy. Posaconazole was also used as long-term secondary prophylaxis.

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.

271: The Clinical Impact of Non-Aspergillus Mold Colonization in Lung Transplant Recipients (LuTx)

Invasive mold infections in LuTx recipients by aspergillus species have a high impact on post-transplant morbidity and mortality. Non-aspergillus colonizations frequently occur but the clinical impact of positive cultures after LuTx is not well studied.

Scedosporium prolificans: an emerging pathogen in France?

For the last ten years, non-Aspergillus mold species have been increasingly involved in human invasive infections, probably as a consequence of more intense immunosuppression and prolonged patient survival, and of selective pressure since antifungal agents are currently used for prophylaxis or therapy. Scedosporium prolificans, one of these emerging fungi, has been isolated in a broad spectrum of clinical presentations in humans, including respiratory-tract colonization, superficial or locally invasive infections, and disseminated infections in immunocompromised patients. Here, we report the recent emergence of invasive infections due to S. prolificans in France, and describe four new cases diagnosed during the last six years. Only one disseminated scedosporiosis has been reported before this in France, in 1994. Three out of our four cases were breakthrough infections in immunocompromised patients receiving posaconazole or voriconazole therapy. The aims of the present review were thus to gain a better understanding of scedosporiosis epidemiology and clinical features, and to review recent advances in multimodal management of these infections, including surgery, recovery and/or enhancement of immunity, and antifungal combinations, especially voriconazole plus terbinafine.

In vitro Activities of Antifungal Drugs Against Yeasts Isolated from Blood Cultures and Moulds Isolated from Various Clinically Significant Sites in Singapore

Fungaemia carries with it high mortality rates and appropriate as well as timely antifungal therapy has been shown to be life saving. We studied the invitro activities of antifungal agents using the Etest method, against 100 Candida isolates from blood cultures, 10 Cryptococcus isolates from blood or cerebrospinal fluid and 50 mould isolates from various clinically significant sites of patients in Singapore General Hospital, from June 2004 to December 2006. Overall, the yeasts appeared to have low minimum inhibitory concentrations (MICs) for all the 5 antifungal drugs tested except for fluconazole. The overall high MIC90 values of the moulds against the azoles were largely attributed to the non-Aspergillus moulds. Posaconazole, itraconazole, voriconazole and caspofungin appear effective against local strains of Aspergillus species, although there are no interpretive breakpoints. The results show that the local fungal strains studied appear to be susceptible to the usual antifungal drugs recommended in the literature.

Post-transplant Colonization With Non- Aspergillus Molds and Risk of Development of Invasive Fungal Disease in Lung Transplant Recipients

The clinical significance and risk of progression to invasive disease of the non-Aspergillus molds from the bronchoalveolar lavage (BAL) of lung transplant (LTx) recipients are not known. We reviewed the medical records from March 1996 to March 2006 of all LTx recipients whose BAL culture grew non-Aspergillus mold. The clinical characteristics, administration of prophylaxis, and outcomes were recorded. Eighty-five non-Aspergillus molds were isolated from the BAL of 75 patients. Of these LTx recipients, 14.5% had a BAL with non-Aspergillus mold. Emphysema was the most common underlying diagnosis for transplantation (41.3%) and the most common isolate was Cladosporium. Isolation of a non-Aspergillus mold occurred at a median of 415 days after LTx. Prophylaxis with an anti-mold agent was noted in 44.7% (38 of 85) of the isolates. Median follow-up was 765 days. There were no cases of proven invasive fungal infection up to 1 year after isolation of the mold; and only 1 case of probable zygomycosis. Isolation of non-Aspergillus molds in the BAL of LTx recipients may not be associated with the development of invasive disease, irrespective of anti-fungal prophylaxis. These results suggest that initiation of targeted anti-fungal prophylaxis after isolation of non-Aspergillus molds from BAL may not be warranted.

Stage-specific innate immune recognition ofAspergillus fumigatusand modulation by echinocandin drugs

The pulmonary innate immune system clears inhaled Aspergillus fumigatus conidia (spores) from terminal airways. Failure to control conidial germination in immune compromised hosts can result in hyphal tissue invasion and fatal disease. Insight into the molecular recognition of A. fumigatus by host leukocytes indicates that the innate immune system exploits obligate changes in fungal cell wall composition that occur at the first stage of germination, conidial swelling. Germinating spores activate at least two host signal transduction pathways. Surface exposure of fungal beta-(1,3) glucan, a polysaccharide constituent of the fungal cell wall, triggers dectin-1 signaling by host phagocytes. Spore germination leads to the induction of Toll-like receptor (TLR) signaling as well. This stage-specific recognition mechanism focuses host antifungal responses on cells with the potential for tissue invasion and may serve to limit potentially deleterious effects of inflammation in space and time. Fungal beta-(1,3) glucan not only activates host innate immune responses but also represents the target of echinocandin drugs. The activity of echinocandin drugs has largely been understood on the basis of pharmacologic growth inhibition of yeast and moulds, resulting in lysis of yeast cells and stunting of dysmorphic hyphae. The recognition that fungal beta-1,3 glucan activates dectin-1 signaling suggests that echinocandin drugs may exert immune modulatory effects by altering innate immune responses to drug-treated fungal cells, a view supported by recent data from studies on C. albicans, A. fumigatus, and non-Aspergillus moulds.