Curr Fungal Infect Rep
· 2017 · PMID 29213345
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PURPOSE OF REVIEW: Chronic pulmonary aspergillosis (CPA) is a serious long-term fungal disease of the lung with a worldwide prevalence. Treatment of CPA is not straightforward given the often-multiple associated co-morbi...PURPOSE OF REVIEW: Chronic pulmonary aspergillosis (CPA) is a serious long-term fungal disease of the lung with a worldwide prevalence. Treatment of CPA is not straightforward given the often-multiple associated co-morbidities, complex clinical picture, drug interactions, toxicities and intolerances. RECENT FINDINGS: First line treatment is oral itraconazole or voriconazole. In the event of intolerance or toxicity, patients may be swapped from itraconazole to voriconazole or vice versa. In the event of resistance or further intolerance, third line treatment with posaconazole could be initiated. In those with pan-azole resistance, short-term courses of intravenous liposomal amphotericin B or micafungin are fourth line therapy, keeping in mind the nephrotoxic effects of amphotericin B. SUMMARY: The available evidence for current treatments in CPA is limited and based mostly on retrospective cohort studies. There is a real need to raise awareness of this devastating disease to enable early treatment as well as prospective drug trials and studies to identify potential patient factors that correlate with progression, severity and overall outcomes in order to target future therapies.
Curr Fungal Infect Rep
· 2017 · PMID 28904649
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PURPOSE OF REVIEW: Comparative genome sequencing studies of human fungal pathogens enable identification of genes and variants associated with virulence and drug resistance. This review describes current approaches, reso...PURPOSE OF REVIEW: Comparative genome sequencing studies of human fungal pathogens enable identification of genes and variants associated with virulence and drug resistance. This review describes current approaches, resources, and advances in applying whole genome sequencing to study clinically important fungal pathogens. RECENT FINDINGS: Genomes for some important fungal pathogens were only recently assembled, revealing gene family expansions in many species and extreme gene loss in one obligate species. The scale and scope of species sequenced is rapidly expanding, leveraging technological advances to assemble and annotate genomes with higher precision. By using iteratively improved reference assemblies or those generated de novo for new species, recent studies have compared the sequence of isolates representing populations or clinical cohorts. Whole genome approaches provide the resolution necessary for comparison of closely related isolates, for example, in the analysis of outbreaks or sampled across time within a single host. SUMMARY: Genomic analysis of fungal pathogens has enabled both basic research and diagnostic studies. The increased scale of sequencing can be applied across populations, and new metagenomic methods allow direct analysis of complex samples.
Curr Fungal Infect Rep
· 2017 · PMID 28680526
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PURPOSE OF REVIEW: Diagnosis during early stages of invasive aspergillosis (IA) and targeted antifungal treatment has the potential to improve survival significantly. Despite advances in the diagnostic arsenal, invasive...PURPOSE OF REVIEW: Diagnosis during early stages of invasive aspergillosis (IA) and targeted antifungal treatment has the potential to improve survival significantly. Despite advances in the diagnostic arsenal, invasive mold infections remain difficult to diagnose-especially at early stages before typical radiological signs develop. Varying availability and time-to-results are important limitations of current approved biomarkers and molecular assays for diagnosis of IA. Here, we will give an update on the -specific lateral-flow device (LFD) test. We further review promising findings on feasibility of point-of-care (POC) detection of urinary excreted fungal galactomannan-like antigens. RECENT FINDINGS: POC LFD assays for detection of antigens are currently in development. The -specific LFD test, which is based on the JF5 antibody (Ab), detects an extracellular glycoprotein antigen secreted during active growth of spp. The test has shown promising results in various studies. In addition, a monoclonal Ab476-based LFD for POC detection of urinary excreted fungal galactomannan-like antigens has been developed but needs further validation. SUMMARY: Important advances have been made in the development of LFD assays for IA. Most promising is the -specific LFD test; commercial availability is still pending, however. The search for reliable POC tests for other molds, including mucorales, continues.
Curr Fungal Infect Rep
· 2017 · PMID 28680525
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PURPOSE OF REVIEW: This review summarizes the fungal diagnostic measures currently available for use in paediatric patients at high risk for developing invasive fungal disease (IFD) and those suspected of having an IFD....PURPOSE OF REVIEW: This review summarizes the fungal diagnostic measures currently available for use in paediatric patients at high risk for developing invasive fungal disease (IFD) and those suspected of having an IFD. The clinical utility of each test is described based on reported performances of individual tests in specific paediatric populations. RECENT FINDINGS: Available studies in the paediatric population are scarce and are characterized by a huge heterogeneity in underlying diseases (e.g. different risk for IFD), different study objectives and management strategies (screening versus diagnostic) used. SUMMARY: A final valuation of paediatric studies on fungal diagnostic tools is limited. While the galactomannan and fungal PCR assays are useful to exclude the presence of IFD, it is unclear if mannan, mannan antibodies and β-D-glucan are of benefit due to a lack of studies or validation of the cut-off, respectively. Well-designed multicentre paediatric studies are urgently needed to improve the outcome of IFD.
Curr Fungal Infect Rep
· 2016 · PMID 28035247
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For a long time, the microbiology of cystic fibrosis has been focussed on and associated Gram-negative pathogens. An increasing body of evidence has been compiled demonstrating an important role for moulds and yeasts wi...For a long time, the microbiology of cystic fibrosis has been focussed on and associated Gram-negative pathogens. An increasing body of evidence has been compiled demonstrating an important role for moulds and yeasts within this complex patient group. Whether or not fungi are active participants, spectators or transient passersby remain to be elucidated. However, functionally, they do appear to play a contributory role in pathogenesis, albeit we do not know if this is a direct or indirect effect. The following review examines some of the key evidence for the role of fungi in CF pathogenesis.
Dekkers BGJ, Bakker M, van der Elst KCM
… +4 more, Sturkenboom MGG, Veringa A, Span LFR, Alffenaar JC
Curr Fungal Infect Rep
· 2016 · PMID 27358662
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Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic prope...Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole.
Curr Fungal Infect Rep
· 2016 · PMID 27358661
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Diagnostic tools for invasive fungal infections have continuously improved within the last decades. Nowadays, cultural methods, antigen testing, and molecular tests, such as polymerase chain reaction, are widely used. Th...Diagnostic tools for invasive fungal infections have continuously improved within the last decades. Nowadays, cultural methods, antigen testing, and molecular tests, such as polymerase chain reaction, are widely used. These methods, however, are accompanied with different limitations as various availability, various turnaround time or high costs. A new generation of point-of-care test has shown promising results in various studies and may overcome some of these limitations. We therefore reviewed the literature for the most promising new point-of-care tests for invasive aspergillosis (-specific lateral-flow device test, proximity ligation antigen assay), cryptococcosis (cryptococcal lateral-flow assay), and for histoplasmosis (loop-mediated isothermal amplification assay).
Zoll J, Snelders E, Verweij PE
… +1 more, Melchers WJ
Curr Fungal Infect Rep
· 2016 · PMID 27358660
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New state-of-the-art techniques in sequencing offer valuable tools in both detection of mycobiota and in understanding of the molecular mechanisms of resistance against antifungal compounds and virulence. Introduction of...New state-of-the-art techniques in sequencing offer valuable tools in both detection of mycobiota and in understanding of the molecular mechanisms of resistance against antifungal compounds and virulence. Introduction of new sequencing platform with enhanced capacity and a reduction in costs for sequence analysis provides a potential powerful tool in mycological diagnosis and research. In this review, we summarize the applications of next-generation sequencing techniques in mycology.
Curr Fungal Infect Rep
· 2016 Jun · PMID 27158322
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Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and micros...Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turn-around-times are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge.
Warris A, European Paediatric Mycology Network (EPMyN)*
Curr Fungal Infect Rep
· 2016 · PMID 27127543
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The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specifi...The European Paediatric Mycology Network (EPMyN) was launched in 2014 to create a European platform for research and education in the field of paediatric mycology. The EPMyN aims to address the lack of paediatric specific evidence and knowledge needed to (1) improve the management and outcome of invasive fungal infections in children and neonates and to (2) enhance and develop paediatric antifungal stewardship programmes.
Moriyama B, Kadri S, Henning SA
… +3 more, Danner RL, Walsh TJ, Penzak SR
Curr Fungal Infect Rep
· 2015 Jun · PMID 26918067
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Voriconazole is an antifungal triazole that is the first line agent for treatment of invasive aspergillosis. It is metabolized by CYP2C19, CYP2C9, and CYP3A4 and demonstrates wide interpatient variability in serum concen...Voriconazole is an antifungal triazole that is the first line agent for treatment of invasive aspergillosis. It is metabolized by CYP2C19, CYP2C9, and CYP3A4 and demonstrates wide interpatient variability in serum concentrations. Polymorphisms in CYP2C19 contribute to variability in voriconazole pharmacokinetics. Here, evidence is examined for the use of voriconazole therapeutic drug monitoring (TDM) and the role of CYP2C19 genotyping in voriconazole dosing. The majority of studies exploring the impact of voriconazole TDM on efficacy and safety have found TDM to be beneficial. However, most of these studies are observational, with only one being a randomized controlled trial. High-volume multicenter randomized controlled trials of TDM are currently not available to support definitive guidelines. There is a significant relationship in healthy volunteers between CYP2C19 genotype and voriconazole pharmacokinetics, but this association is markedly less visible in actual patients. While CYP2C19 genotype data may explain variability of voriconazole serum levels, they alone are not sufficient to guide initial dosing. The timeliness of availability of CYP2C19 genotype data in treatment of individual patients also remains challenging. Additional studies are needed before implementation of CYP2C19 genotyping for voriconazole dosing into routine clinical care.
Curr Fungal Infect Rep
· 2015 Dec · PMID 26779297
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species are the leading cause of invasive fungal infections in premature infants. Associated with substantial morbidity and mortality, these infections represent serious and sometimes catastrophic complications in the co...species are the leading cause of invasive fungal infections in premature infants. Associated with substantial morbidity and mortality, these infections represent serious and sometimes catastrophic complications in the course of hospitalization of a preterm infant in the neonatal intensive care unit. Although virulence factors of and the host defense mechanisms that are important in protection from candidiasis have been the subject of intensive study, considerably less is known about the features of this disease that are specific to premature neonates. As animal models for neonatal candidiasis have been developed, efforts to understand the similarities and differences of candidiasis in the neonatal host relative to other immunocompromised patients have begun to provide insights to these questions.
van Diepeningen AD, Brankovics B, Iltes J
… +2 more, van der Lee TA, Waalwijk C
Curr Fungal Infect Rep
· 2015 · PMID 26301000
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Infections caused by the genus have emerged over the past decades and range from onychomycosis and keratitis in healthy individuals to deep and disseminated infections with high mortality rates in immune-compromised pat...Infections caused by the genus have emerged over the past decades and range from onychomycosis and keratitis in healthy individuals to deep and disseminated infections with high mortality rates in immune-compromised patients. As antifungal susceptibility can differ between the different species, identification at species level is recommended. Several clinical observations as hyaline hyphae in tissue, necrotic lesions in the skin and positive blood tests with fungal growth or presence of fungal cell wall components may be the first hints for fusariosis. Many laboratories rely on morphological identification, but especially multi-locus sequencing proves better to discriminate among members of the species complexes involved in human infection. DNA-based diagnostic tools have best discriminatory power when based on translation elongation factor 1-α or the RNA polymerase II second largest subunit. However, assays based on the detection of other fusarial cell compounds such as peptides and cell wall components may also be used for identification. The purpose of this review is to provide an overview and a comparison of the different tools currently available for the diagnosis of fusariosis.
Curr Fungal Infect Rep
· 2015 · PMID 26029319
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Therapeutic drug monitoring (TDM) involves the measurement of plasma or serum drug concentration to adapt dosages to achieve predefined target concentrations that are associated with optimal clinical response while minim...Therapeutic drug monitoring (TDM) involves the measurement of plasma or serum drug concentration to adapt dosages to achieve predefined target concentrations that are associated with optimal clinical response while minimizing the chance of encountering toxicity. Many papers in the field of antifungal drugs have focused on the evidence that supports the use of TDM thereby emphasizing the breakpoints or target concentrations in general literature. This review focuses on the process of TDM to inform health care workers on the fundaments and prerequisites that safeguard the good application of TDM. Knowledge on the complete process of TDM including pharmacokinetics (and relevant covariates), pharmacodynamic aspects, trials that are necessary to provide us with evidence, translation of knowledge to other populations and pathogens, and implications for the pre-analytical, analytical, and post-analytical phases (the process of TDM) are discussed in relevant detail. For each individual step, recommendations are made for the readers. We believe this will be a valuable resource and to be of added value to the many papers that focus on relations between exposure and efficacy or toxicity. It will help to achieve greater benefit of TDM.
Curr Fungal Infect Rep
· 2014 Jun · PMID 25685251
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Pathogenic fungi encounter many different host environments to which they must adapt rapidly to ensure growth and survival. They also must be able to cope with alterations in established niches during long-term persisten...Pathogenic fungi encounter many different host environments to which they must adapt rapidly to ensure growth and survival. They also must be able to cope with alterations in established niches during long-term persistence in the host. Many eukaryotic pathogens have evolved a highly plastic genome, and large-scale chromosomal changes including aneuploidy, and loss of heterozygosity (LOH) can arise under various in vitro and in vivo stresses. Both aneuploidy and LOH can arise quickly during a single cell cycle, and it is hypothesized that they provide a rapid, albeit imprecise, solution to adaptation to stress until better and more refined solutions can be acquired by the organism. While LOH, with the extreme case of haploidization in , can purge the genome from recessive lethal alleles and/or generate recombinant progeny with increased fitness, aneuploidy, in the absence or rarity of meiosis, can serve as a non-Mendelian mechanism for generating genomic variation.
Curr Fungal Infect Rep
· 2015 · PMID 32218881
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The onset of a pulmonary infiltrate in a solid organ transplant (SOT) recipient is both a challenging diagnostic and therapeutic challenge. We outline the potential aetiologies of a pulmonary infiltrate in a SOT recipien...The onset of a pulmonary infiltrate in a solid organ transplant (SOT) recipient is both a challenging diagnostic and therapeutic challenge. We outline the potential aetiologies of a pulmonary infiltrate in a SOT recipient, with particular attention paid to fungal pathogens. A diagnostic and empirical therapy approach to a pulmonary infiltrate, especially invasive fungal disease (IFD) in SOT recipients, is provided.
Curr Fungal Infect Rep
· 2014 Dec · PMID 25530825
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Combat-related invasive fungal (mold) wound infections (IFIs) have emerged as an important and morbid complication following explosive blast injuries among military personnel. Similar to trauma-associated IFI cases among...Combat-related invasive fungal (mold) wound infections (IFIs) have emerged as an important and morbid complication following explosive blast injuries among military personnel. Similar to trauma-associated IFI cases among civilian populations, as in agricultural accidents and natural disasters, these infections occur in the setting of penetrating wounds contaminated by environmental debris. Specific risk factors for combat-related IFI include dismounted (patrolling on foot) blast injuries occurring mostly in southern Afghanistan, resulting in above knee amputations requiring resuscitation with large-volume blood transfusions. Diagnosis of IFI is based upon early identification of a recurrently necrotic wound following serial debridement and tissue-based histopathology examination with special stains to detect invasive disease. Fungal culture of affected tissue also provides supportive information. Aggressive surgical debridement of affected tissue is the primary therapy. Empiric antifungal therapy should be considered when there is a strong suspicion for IFI. Both liposomal amphotericin B and voriconazole should be considered initially for treatment since many of the cases involve not only Mucorales species but also or spp., with narrowing of regimen based upon clinical mycology findings.
Curr Fungal Infect Rep
· 2014 Dec · PMID 29780439
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Echinocandins are the newest antifungal agents approved for use in treating infections in the US. They act by interfering with 1,3-β-D-glucan synthase and therefore disrupt cell wall production and lead to cell death....Echinocandins are the newest antifungal agents approved for use in treating infections in the US. They act by interfering with 1,3-β-D-glucan synthase and therefore disrupt cell wall production and lead to cell death. There is no intrinsic resistance to echinocandins among species, and isolates from historic collections archived before the release of the echinocandins show no resistance. Resistance to the echinocandins remains low among most species and ranges overall from 0-1%. Among isolates of , the proportion of resistant isolates is higher and has been reported to be as high as 13.5% in at least one hospital. Antifungal resistance is due to specific amino acid mutations in the Fksp subunit(s) of the 1,3-β-D-glucan synthase protein which are localized to one of two hotspots. These mutations are being recognized in isolates from patients who have failed echinocandin therapy, and often lead to a poor outcome. While the future looks bright for the echinocandins against most species, remains a species of concern and resistance rates of to the echinocandins should be monitored closely.
Curr Fungal Infect Rep
· 2014 Jun · PMID 24839528
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The fungus is a frequent commensal colonizer of the human gastrointestinal (GI) tract, but is also an opportunistic pathogen. This review explores features that distinguish the colonizing and pathogenic forms of in a b...The fungus is a frequent commensal colonizer of the human gastrointestinal (GI) tract, but is also an opportunistic pathogen. This review explores features that distinguish the colonizing and pathogenic forms of in a biofilm is used as an example of a pathogenic form of the organism, because biofilms are a common feature of device-associated infections. Biofilms (complex, sessile communities of cells) have been the subject of several large-scale gene expression studies. Biofilms and commensal colonizing the murine GI tract show a variety of differentially expressed genes. Cell surface proteins encoded by these differentially expressed genes are especially attractive as targets for new clinical prevention, diagnosis, or treatment tools that are specific for in its pathogenic biofilm state.
Curr Fungal Infect Rep
· 2014 Mar · PMID 24660045
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species are fungal pathogens that are a leading cause of mortality. Initial inoculation is through the pulmonary route and, if disseminated, results in severe invasive infection including meningoencephalitis. Macrophages...species are fungal pathogens that are a leading cause of mortality. Initial inoculation is through the pulmonary route and, if disseminated, results in severe invasive infection including meningoencephalitis. Macrophages are the dominant phagocytic cell that interacts with . Emerging theories suggest that microevolution in macrophages is linked to survival and virulence within the host. In addition, elaborates virulence factors as well as usurps host machinery to establish macrophage activation states that are permissive to intracellular survival and replication. In this review, we provide an update of the recent findings pertaining to macrophage interaction with and focus on new avenues for biomedical research.