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1.
Sci Adv ; 9(29): eadh8839, 2023 07 21.
Article En | MEDLINE | ID: mdl-37478175

Using a citizen science approach, we identify a country-wide exposure to aerosolized spores of a human fungal pathogen, Aspergillus fumigatus, that has acquired resistance to the agricultural fungicide tebuconazole and first-line azole clinical antifungal drugs. Genomic analysis shows no distinction between resistant genotypes found in the environment and in patients, indicating that at least 40% of azole-resistant A. fumigatus infections are acquired from environmental exposures. Hotspots and coldspots of aerosolized azole-resistant spores were not stable between seasonal sampling periods. This suggests a high degree of atmospheric mixing resulting in an estimated per capita cumulative annual exposure of 21 days (±2.6). Because of the ubiquity of this measured exposure, it is imperative that we determine sources of azole-resistant A. fumigatus to reduce treatment failure in patients with aspergillosis.


Aspergillosis , Citizen Science , Humans , Aspergillus fumigatus/genetics , Drug Resistance, Fungal/genetics , Aspergillosis/drug therapy , Aspergillosis/microbiology , Antifungal Agents/pharmacology , Azoles/pharmacology
2.
JMIR Med Inform ; 11: e43567, 2023 Feb 06.
Article En | MEDLINE | ID: mdl-36745495

BACKGROUND: Electronic patient portals are online applications that allow patients access to their own health information, a form of asynchronous virtual care. The long-term impact of portals on the use of traditional primary care services is unclear, but it is an important question at this juncture, when portals are being incorporated into many primary care practices. OBJECTIVE: We sought to investigate how an electronic patient portal affected the use of traditional, synchronous primary care services over a much longer time period than any existing studies and to assess the impact of portal messaging on clinicians' workload. METHODS: We conducted a propensity-score-matched, open-cohort, interrupted time-series evaluation of a primary care portal from its implementation in 2010. We extracted information from the electronic medical record regarding age, sex, education, income, family health team enrollment, diagnoses at index date, and number of medications prescribed in the previous year. We also extracted the annual number of encounters for up to 8 years before and after the index date and provider time spent on secure messaging through the portal. RESULTS: A total of 7247 eligible portal patients and 7647 eligible potential controls were identified, with 3696 patients matched one to one. We found that portal registration was associated with an increase in the number of certain traditional encounters over the time period surrounding portal registration. Following the index year, there was a significant jump in annual number of visits to physicians in the portal arm (0.42 more visits/year vs control, P<.001) but not for visits to nurse practitioners and physician assistants. The annual number of calls to the practice triage nurses also showed a greater increase in the portal arm compared to the control arm after the index year (an additional 0.10 calls, P=.006). The average provider time spent on portal-related work was 5.7 minutes per patient per year. CONCLUSIONS: We found that portal registration was associated with a subsequent increase in the number of some traditional encounters and an increase in clerical workload for providers. Portals have enormous potential to truly engage patients as partners in their own health care, but their impact on use of traditional health care services and clerical burden must also be considered when they are incorporated into primary care.

3.
J Community Psychol ; 51(2): 539-559, 2023 03.
Article En | MEDLINE | ID: mdl-35390183

Using a school-based intervention, Let's Be Friends (LBF), designed to promote the social information-processing (SIP) skills of third-grade children in rural China, the specific aim of this study was to assess the moderating effects of school characteristics on program outcomes. We systematically tested the moderating effects of six school-resource variables (i.e., student-teacher ratio, school size, number of library books per student, number of computers per 100 students, percentage of teachers with middle- and high-level titles, and percentage of teachers with high-level title or "backbone" recognition) on outcomes in a controlled trial of LBF program. School resources (i.e., small school size, low student-teacher ratio, and more teachers with high-level title or backbone) were associated with SIP skill acquisition, reduced aggressive behavior, and higher cognitive concentration. School contextual characteristics condition the impact of social-emotional education programs in Chinese rural primary schools.


Schools , Social Skills , Child , Humans , Students/psychology , Emotions , Cognition
4.
Methods Mol Biol ; 2517: 21-32, 2022.
Article En | MEDLINE | ID: mdl-35674942

MALDI-ToF MS has become the standard method for routine identification of most medically important yeasts in clinical and public health laboratories and has largely replaced phenotypic identification methods as a first-line identification tool. Fungal identification is based on extensive and well-curated mass spectra libraries usually provided by the manufacturer of the MALDI-ToF MS platform; however, many centers do create specialized or in-house database collections to aid analysis. Most MALDI-ToF MS systems offer simple and standardized workflows for the identification of clinically relevant yeasts to species level with a high throughput, high accuracy, and a low overall cost per test. This makes MALDI-ToF MS an ideal platform for use in routine clinical, diagnostic, and research microbiology laboratories which may lack experience or expertise in the identification of pathogenic fungi.In this chapter we review three standard protocols for the proteomic-based identification of Candida auris isolated from cultures of clinical or environmental surveillance samples in diagnostic and research laboratories.


Candida auris , Microbiological Techniques , Microbiological Techniques/methods , Proteomics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Yeasts
5.
J Fungi (Basel) ; 8(4)2022 Mar 25.
Article En | MEDLINE | ID: mdl-35448574

Subcutaneous fungal infections, which typically result from traumatic introduction (implantation) of fungal elements into the skin or underlying tissues, can present as a range of different clinical entities including phaeohyphomycosis, chromoblastomycosis, subcutaneous nodules or masses, and genuine eumycetoma. Here, we mined our laboratory information management system for such infections in humans and domestic animals for the period 2016-2022, including (i) fungal isolates referred for identification and/or susceptibility testing; (ii) infections diagnosed at our laboratory using panfungal PCR approaches on infected tissue; and (iii) organisms cultured in our laboratory from biopsies. In total, 106 cases were retrieved, involving 39 fungal species comprising 26 distinct genera. Subcutaneous infections with Alternaria species were the most frequent (36 cases), which possibly reflects the ubiquitous nature of this common plant pathogen. A substantial proportion of Alternaria spp. isolates exhibited reduced in vitro susceptibility to voriconazole. Notably, a significant number of subcutaneous infections were diagnosed in renal and other solid organ transplant recipients post transplantation, suggesting that humans may harbour "inert" subcutaneous fungal elements from historical minor injuries that present as clinical infections upon later immunosuppression. The current study underscores the diversity of fungi that can cause subcutaneous infections. While most organisms catalogued here were responsible for occasional infections, several genera (Alternaria, Exophiala, Phaeoacremonuim, Scedosporium) were more frequently recovered in our searches, suggesting that they possess virulence factors that facilitate subcutaneous infections and/or inhabit natural niches that make them more likely to be traumatically inoculated.

6.
Cereb Cortex ; 32(13): 2705-2716, 2022 06 16.
Article En | MEDLINE | ID: mdl-34671805

The objectives of this study were to investigate the long-term associations between changes in physical activity levels and hippocampal volumes over time, while considering the influence of age, sex, and APOE-ε4 genotype. We investigated the effects of change in physical activity on hippocampal volumes in 411 middle age (mean age = 47.2 years) and 375 older age (mean age = 63.1 years) adults followed up to 12 years. An annual volume decrease was observed in the left (middle age: 0.46%; older age: 0.51%) but not in the right hippocampus. Each additional 10 metabolic equivalents (METs, ~2 h of moderate exercise) increase in weekly physical activity was associated with 0.33% larger hippocampal volume in middle age (equivalent to ~1 year of typical aging). In older age, each additional MET was associated with 0.05% larger hippocampal volume; however, the effects declined with time by 0.005% per year. For older age APOE-ε4 carriers, each additional MET was associated with a 0.10% increase in hippocampal volume. No sex effects of physical activity change were found. Increasing physical activity has long-term positive effects on hippocampal volumes and appears especially beneficial for older APOE-ε4 carriers. To optimize healthy brain aging, physical activity programs should focus on creating long-term exercise habits.


Exercise , Hippocampus , Aged , Aging/genetics , Apolipoprotein E4/genetics , Apolipoproteins E/genetics , Genotype , Hippocampus/diagnostic imaging , Humans , Magnetic Resonance Imaging , Middle Aged
8.
Med Mycol ; 59(11): 1068-1075, 2021 Nov 03.
Article En | MEDLINE | ID: mdl-34259872

Starting late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a devastating global pandemic of coronavirus-19 disease (COVID-19) with ∼179 million cases and ∼3.9 million deaths to date. COVID-19 ranges from asymptomatic infection to severe illness with acute respiratory distress requiring critical care in up to 40% of hospitalized patients. Numerous reports have identified COVID-19-associated pulmonary aspergillosis (CAPA) as an important infective complication of COVID-19. In the UK, the pandemic has had unprecedented impacts on the National Health Service (NHS'): each wave of infections required hospitals to reconfigure for large surges in patients requiring intensive care, to the detriment of most aspects of non-COVID care including planned operations, outpatient appointments, general practitioner consultations and referrals. The UK National Mycology Reference Laboratory (MRL) offers a comprehensive service for the diagnosis and management of fungal disease nationwide, with a test portfolio that includes: diagnosis of allergies to fungal and other respiratory allergens; diagnosis of superficial and invasive/systemic fungal infections using traditional mycological, serological and molecular approaches; identification and susceptibility testing of the causative fungi; therapeutic drug monitoring of patients receiving antifungal therapy. Here, we describe the impact of the first 14 months of the COVID-19 pandemic on MRL activities. Changes to MRL workload closely mirrored many of the NHS-wide challenges, with marked reductions in 'elective' mycological activities unrelated to the pandemic and dramatic surges in tests that contributed to the diagnosis and management of COVID-19-related secondary fungal infections, in particular CAPA and candidemia in COVID-19 patients in intensive care. LAY SUMMARY: The COVID-19 pandemic has had an unprecedented impact on the UK National Health Service, with hospitals forced to repeatedly reconfigure to prepare for large surges in COVID-19 patients. Here we describe the impact of the first 14 months of the UK pandemic on the workload of the National Mycology Reference Laboratory.


COVID-19 , Laboratories/statistics & numerical data , Mycology , Workload , Humans , Pandemics , State Medicine , United Kingdom
9.
J Fungi (Basel) ; 7(4)2021 Apr 02.
Article En | MEDLINE | ID: mdl-33918216

Mucoromycoses (infections caused by members of the order Mucorales, phylum Mucoromycota [ex-Zygomycota]) are highly destructive, rapidly progressive infections, with dire prognoses especially when they occur in immunocompromised hosts. Current treatment guidelines recommend liposomal formulations of amphotericin B with adjunctive surgery as first line therapy, with the newer triazoles posaconazole or isavuconazole as alternative treatments, or as salvage therapy. Among the many organisms belonging to this order, a limited number of species in the genera Rhizopus, Mucor, Lichtheimia and Rhizomucor are responsible for most cases of human infection. Here, we present the minimum inhibitory concentration data (MICs) for amphotericin B, posaconazole, isavuconazole, itraconazole and voriconazole with a panel of over 300 isolates of the five most common agents of human infection (Lichtheimia corymbifera, Rhizopus arrhizus, R. microsporus, Rhizomucor pusillus and Mucor spp.) determined using the CLSI broth microdilution method. In agreement with previous studies, the most active antifungal drug for all Mucorales was amphotericin B, with MICs within the range that would predict susceptibility with Aspergillus fumigatus. Conversely, MICs for voriconazole against all species tested were high, and above the range associated with clinical efficacy with A. fumigatus. Interestingly, whilst isavuconazole and posaconazole MIC distributions indicated in vitro activity against some members of the Mucorales, activity was species-dependent for both agents. These data underscore the importance of accurate identification of the causative agents of mucoromycosis, coupled with antifungal susceptibility testing of individual isolates, in determining the optimal treatment of infections caused by these aggressive opportunistic human fungal pathogens.

10.
Jt Comm J Qual Patient Saf ; 47(4): 228-233, 2021 04.
Article En | MEDLINE | ID: mdl-33451896

BACKGROUND: Specialty palliative care is a limited resource. The surprise question ("Would you be surprised if this patient died within the next 12 months?") is a screening tool for clinicians to identify people nearing the end of life. The researchers used a modified surprise question (MSQ) to improve primary palliative care in a neurocritical care unit. METHODS: A palliative care physician attended interdisciplinary rounds up to three days a week and asked the primary neurocritical care team, for each patient admitted in the previous 24 hours, the MSQ: "Would you be surprised if this patient died during this hospital stay?" If the response was "No," the unit social worker identified the patient's surrogate decision maker (SDM), and the primary team was encouraged to conduct a goals of care (GOC) conversation. The frequency of SDM documentation, occurrence and timing of GOC conversations, and palliative care and hospice consultations were measured for the baseline six months before the intervention, and six months after. RESULTS: Among 350 patients admitted to the neurocritical care unit during the study, the age, gender, prehospitalization presence of advance directives, and mortality were comparable between the baseline (n = 173) and intervention (n = 177) periods. Compared to the baseline period, there was a higher frequency during the intervention period of documentation of SDM (31.8% vs. 54.2%, p = 0.00002), all GOC conversations (35.3% vs. 53.1%, p = 0.008), GOC conversations conducted by the primary team (27.2% vs. 47.5%, p = 0.00009), palliative care consultations (11.6% vs. 23.2%, p = 0.004), and hospice consultations (2.3% vs. 9.6%, p = 0.004). CONCLUSION: The MSQ can be used as a tool to identify the risk of mortality, facilitate palliative care delivered by the primary team, and improve end-of-life care.


Hospice Care , Terminal Care , Advance Directives , Humans , Palliative Care , Patient Care Planning
11.
Med Mycol ; 59(3): 253-258, 2021 Mar 04.
Article En | MEDLINE | ID: mdl-32525988

Candida auris is a serious nosocomial health risk, with widespread outbreaks in hospitals worldwide. Successful management of such outbreaks has depended upon intensive screening of patients to identify those that are colonized and the subsequent isolation or cohorting of affected patients to prevent onward transmission. Here we describe the evaluation of a novel chromogenic agar, CHROMagarTM Candida Plus, for the specific identification of Candida auris isolates from patient samples. Candida auris colonies on CHROMagarTM Candida Plus are pale cream with a distinctive blue halo that diffuses into the surrounding agar. Of over 50 different species of Candida and related genera that were cultured in parallel, only the vanishingly rare species Candida diddensiae gave a similar appearance. Moreover, both the rate of growth and number of colonies of C. auris recovered from swabs of pure and mixed Candida species were substantially increased on CHROMagarTM Candida Plus agar when compared with growth on the traditional mycological isolation medium, Sabouraud dextrose agar. Taken together, the present data suggest that CHROMagarTM Candida Plus agar is an excellent alternative to current conventional mycological media for the screening of patients who are potentially colonized/infected with Candida auris, can be reliably used to identify this emerging fungal pathogen, and should be tested in a clinical setting. LAY ABSTRACT: Candida auris is a novel pathogenic yeast that has been associated with large hospital outbreaks across several continents. Affected patients become colonized, predominantly on the skin, with large quantities of C. auris which they then shed into the hospital environment. Identification of C. auris is challenging using routine laboratory methods, and time consuming when patients are colonized with a mixture of different Candida species. Here we demonstrate that a novel chromogenic agar, CHROMagarTM Candida Plus, permits the rapid differentiation of C. auris from a wide range of other yeast species and is potentially ideally suited to screening of patients that are suspected of being colonized or infected with this medically important yeast.


Agar/chemistry , Candida/growth & development , Candida/isolation & purification , Culture Media/chemistry , Agar/standards , Candidiasis/microbiology , Humans , Microbiological Techniques , Saccharomycetales/growth & development , Saccharomycetales/isolation & purification
12.
Front Cell Infect Microbiol ; 11: 761596, 2021.
Article En | MEDLINE | ID: mdl-35024355

Scedosporium spp. are the second most prevalent filamentous fungi after Aspergillus spp. recovered from cystic fibrosis (CF) patients in various regions of the world. Although invasive infection is uncommon prior to lung transplantation, fungal colonization may be a risk factor for invasive disease with attendant high mortality post-transplantation. Abundant in the environment, Scedosporium aurantiacum has emerged as an important fungal pathogen in a range of clinical settings. To investigate the population genetic structure of S. aurantiacum, a MultiLocus Sequence Typing (MLST) scheme was developed, screening 24 genetic loci for polymorphisms on a tester strain set. The six most polymorphic loci were selected to form the S. aurantiacum MLST scheme: actin (ACT), calmodulin (CAL), elongation factor-1α (EF1α), RNA polymerase subunit II (RPB2), manganese superoxide dismutase (SOD2), and ß-tubulin (TUB). Among 188 global clinical, veterinary, and environmental strains, 5 to 18 variable sites per locus were revealed, resulting in 8 to 23 alleles per locus. MLST analysis observed a markedly high genetic diversity, reflected by 159 unique sequence types. Network analysis revealed a separation between Australian and non-Australian strains. Phylogenetic analysis showed two major clusters, indicating correlation with geographic origin. Linkage disequilibrium analysis revealed evidence of recombination. There was no clustering according to the source of the strains: clinical, veterinary, or environmental. The high diversity, especially amongst the Australian strains, suggests that S. aurantiacum may have originated within the Australian continent and was subsequently dispersed to other regions, as shown by the close phylogenetic relationships between some of the Australian sequence types and those found in other parts of the world. The MLST data are accessible at http://mlst.mycologylab.org. This is a joined publication of the ISHAM/ECMM working groups on "Scedosporium/Pseudallescheria Infections" and "Fungal Respiratory Infections in Cystic Fibrosis".


Scedosporium , Australia/epidemiology , Genetic Variation , Humans , Multilocus Sequence Typing , Phylogeny , Polymorphism, Genetic , Scedosporium/genetics
13.
Neurobiol Aging ; 97: 97-105, 2021 01.
Article En | MEDLINE | ID: mdl-33190123

Understanding heterogeneity in brain aging trajectories is important to estimate the extent to which aging outcomes can be optimized. Although brain changes in late life are well-characterized, brain changes in middle age are not well understood. In this study, we investigated hippocampal change in a generally healthy community-living population of middle (n = 421, mean age 47.2 years) and older age (n = 411, mean age 63.0 years) individuals, over a follow-up of up to 12 years. Manually traced hippocampal volumes were analyzed using multilevel models and latent class analysis to investigate longitudinal aging trajectories and laterality and sex effects, and to identify subgroups that follow different aging trajectories. Hippocampal volumes decreased on average by 0.18%/year in middle age and 0.3%/year in older age. Men tended to experience steeper declines than women in middle age only. Three subgroups of individuals following different trajectories were identified in middle age and 2 in older age. Contrary to expectations, the subgroup containing two-thirds of older age participants maintained stable hippocampal volumes across the follow-up.


Aging/pathology , Hippocampus/pathology , Independent Living , Age Factors , Female , Follow-Up Studies , Humans , Male , Middle Aged , Organ Size
14.
Materials (Basel) ; 13(22)2020 Nov 17.
Article En | MEDLINE | ID: mdl-33212783

Under some circumstances, composites with a corrugated reinforcement geometry show larger necking strains compared to traditional straight reinforced composites. In this work, finite element modeling studies were performed for linearly hardening materials, examining the effect of material parameters on the stress-strain response of both corrugation and straight-reinforced composites. These studies showed that improvements in necking strain depend on the ability of the corrugation to unbend and to provide a boost in work hardening at the right time. It was found that there is a range of matrix yield strengths and hardening rates for which a corrugated geometry will improve the necking strain and also a lower threshold of reinforcement yield strength below which no improvement in necking strain is possible. In addition, benefit maps and surfaces were generated that show which regions of property space benefit through corrugation and the corresponding improvement in necking strain that can be achieved.

15.
J Clin Microbiol ; 59(1)2020 12 17.
Article En | MEDLINE | ID: mdl-33087440

COVID-19-associated pulmonary aspergillosis (CAPA) was recently reported as a potential infective complication affecting critically ill patients with acute respiratory distress syndrome following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with incidence rates varying from 8 to 33% depending on the study. However, definitive diagnosis of CAPA is challenging. Standardized diagnostic algorithms and definitions are lacking, clinicians are reticent to perform aerosol-generating bronchoalveolar lavages for galactomannan testing and microscopic and cultural examination, and questions surround the diagnostic sensitivity of different serum biomarkers. Between 11 March and 14 July 2020, the UK National Mycology Reference Laboratory received 1,267 serum and respiratory samples from 719 critically ill UK patients with COVID-19 and suspected pulmonary aspergillosis. The laboratory also received 46 isolates of Aspergillus fumigatus from COVID-19 patients (including three that exhibited environmental triazole resistance). Diagnostic tests performed included 1,000 (1-3)-ß-d-glucan and 516 galactomannan tests on serum samples. The results of this extensive testing are presented here. For a subset of 61 patients, respiratory specimens (bronchoalveolar lavage specimens, tracheal aspirates, and sputum samples) in addition to serum samples were submitted and subjected to galactomannan testing, Aspergillus-specific PCR, and microscopy and culture. The incidence of probable/proven and possible CAPA in this subset of patients was approximately 5% and 15%, respectively. Overall, our results highlight the challenges in biomarker-driven diagnosis of CAPA, especially when only limited clinical samples are available for testing, and the importance of a multimodal diagnostic approach involving regular and repeat testing of both serum and respiratory samples.


Antigens, Fungal/blood , Aspergillus fumigatus/isolation & purification , Invasive Pulmonary Aspergillosis/diagnosis , Invasive Pulmonary Aspergillosis/epidemiology , Adult , Aged , Aged, 80 and over , Aspergillus fumigatus/drug effects , Bronchoalveolar Lavage Fluid/microbiology , COVID-19/etiology , Critical Illness , Female , Galactose/analogs & derivatives , Humans , Invasive Pulmonary Aspergillosis/complications , Invasive Pulmonary Aspergillosis/drug therapy , Male , Mannans/blood , Middle Aged , Proteoglycans , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , United Kingdom , beta-Glucans/blood
16.
Med Mycol Case Rep ; 29: 43-45, 2020 Sep.
Article En | MEDLINE | ID: mdl-32817812

Exophiala is a ubiquitous genus encompassing more than forty species, a number of which have been associated with superficial or systemic infections in humans, and other hot- or cold-blooded animals. Here we report a human case of subcutaneous mycotic cyst caused by Exophiala campbellii. To our knowledge, this is only the third reported human infection caused by E. campbellii, all three of which involved subcutaneous nodules in patients who had resided in the United Kingdom.

17.
Neuroimage ; 221: 117150, 2020 11 01.
Article En | MEDLINE | ID: mdl-32668298

BACKGROUND: Epidemiological studies suggest physical activity (PA) can slow or prevent both cognitive decline and age-related atrophy in frontal and hippocampal gray matter volumes. However, much of this evidence is based on self-reported measures of PA. METHODS: PA was measured objectively with a SenseWear™ Armband to examine the cross-sectional associations between the duration of light, moderate and vigorous intensity PA with gray matter volume in the dorsolateral prefrontal cortex (DLPFC) and hippocampus in 167 (female: 43%) cognitively healthy older adults aged 73 to 78. RESULTS: The duration of objective moderate to vigorous intensity physical activity (MVPA) was associated with a greater volume of the right DLPFC (ߠ​= â€‹0.16; p â€‹= â€‹0.04). In addition, objective moderate-intensity PA alone was also associated with greater volume of the left (ߠ​= â€‹0.17; p â€‹= â€‹0.03) and right (ߠ​= â€‹0.19; p â€‹= â€‹0.01) DLPFC after controlling for covariates and adjustment for multiple comparisons. In contrast, there were no significant associations between light- or vigorous-intensity PA and gray matter volumes (all p â€‹> â€‹0.05). No associations between PA and cognitive performance were detected, and self-reported PA was not associated with any of the outcomes investigated. CONCLUSIONS: These findings suggest that an intensity-dependent relationship may exist, whereby a greater duration of MVPA, perhaps driven by moderate-intensity PA, is associated with preserved gray matter volume in frontal regions of the brain. Future research should investigate the mechanisms of this dose-effect and determine whether greater brain volumes associated with objective PA convey protective effects against cognitive decline.


Aging/physiology , Executive Function/physiology , Exercise/physiology , Gray Matter/anatomy & histology , Hippocampus/anatomy & histology , Prefrontal Cortex/anatomy & histology , Psychomotor Performance/physiology , Actigraphy , Aged , Cohort Studies , Female , Humans , Magnetic Resonance Imaging , Male , Wearable Electronic Devices
18.
Med Mycol ; 58(7): 996-999, 2020 Oct 01.
Article En | MEDLINE | ID: mdl-32396168

We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks.


Antifungal Agents/therapeutic use , Drug Monitoring , Drug-Related Side Effects and Adverse Reactions , Mycoses/drug therapy , Nitriles/blood , Nitriles/therapeutic use , Pyridines/blood , Pyridines/therapeutic use , Serum/chemistry , Triazoles/blood , Triazoles/therapeutic use , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Sex Factors , United Kingdom , Young Adult
19.
J Antimicrob Chemother ; 75(5): 1194-1205, 2020 05 01.
Article En | MEDLINE | ID: mdl-32025716

BACKGROUND: Epidemiological cut-off values and clinical interpretive breakpoints have been developed for a number of antifungal agents with the most common Candida species that account for the majority of infections due to pathogenic yeasts species. However, less-common species, for which susceptibility data are limited, are increasingly reported in high-risk patients and breakthrough infections. METHODS: The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical yeast isolates submitted from across the UK. Between 2002 and 2016, >32 000 isolates representing 94 different yeast species were referred to the laboratory. Here we present antifungal susceptibility profiles generated over this period for amphotericin B, fluconazole, voriconazole, itraconazole, anidulafungin and flucytosine against 35 species of uncommon yeast using CLSI methodologies. MIC data were interpreted against epidemiological cut-off values and clinical breakpoints developed with Candida albicans, in order to identify species with unusually skewed MIC distributions that potentially indicate resistance. RESULTS: Potential resistance to at least one antifungal agent (>10% of isolates with MICs greater than the epidemiological cut-off or clinical breakpoint) was evidenced for 29/35 species examined here. Four species exhibited elevated MICs with all of the triazole antifungal drugs against which they were tested, and 21 species exhibited antifungal resistance to agents from at least two different classes of antifungal agent. CONCLUSIONS: This study highlights a number of yeast species with unusual MIC distributions and provides data to aid clinicians in deciding which antifungal regimens may be appropriate when confronted with infections with rarer yeasts.


Amphotericin B , Fluconazole , Amphotericin B/pharmacology , Anidulafungin , Antifungal Agents/pharmacology , Flucytosine/pharmacology , Humans , Itraconazole , Microbial Sensitivity Tests , Phylogeny , United Kingdom , Voriconazole/pharmacology
20.
Med Mycol ; 58(2): 219-226, 2020 Feb 01.
Article En | MEDLINE | ID: mdl-31111912

Candidemia is widely reported as the fourth most common form of bloodstream infection worldwide. Reports of breakthrough cases of candidemia are increasing, especially in the context of a move away from azole antifungals as prophylactic or first line treatment toward the use of echinocandin agents. The global evaluation of echinocandin antifungal susceptibility since 2003 has included switches in testing methodologies and the move to a sentinel echinocandin approach for classification reporting. This study compiles previously unpublished data from echinocandin susceptibility testing of UK clinical isolates of C. glabrata received at the Public Health England Mycology Reference Laboratory from 2003 to 2016 and reevaluates the prevalence of resistance in light of currently accepted testing protocols. From 2015 onward, FKS gene mutation detection using a novel Pyrosequencing® assay was assessed as a predictor of echinocandin resistance alongside conventional susceptibility testing. Overall, our data show that echinocandin resistance in UK isolates of C. glabrata is a rare phenomenon and prevalence has not appreciably increased in the last 14 years. The pyrosequencing assay was able to successfully detect hot spot mutations in FKS1 and FKS2, although not all isolates that exhibited phenotypic resistance demonstrated detectable hot spot mutations. We propose that a rapid genomic based detection method for FKS mutations, as part of a multifactorial approach to susceptibility testing, could help provide accurate and timely management decisions especially in regions where echinocandin resistance has been reported to be emerging in this important pathogen.


Antifungal Agents/pharmacology , Candida glabrata/drug effects , Candidiasis/microbiology , Drug Resistance, Multiple, Fungal/genetics , Echinocandins/pharmacology , Fungal Proteins/genetics , Antifungal Agents/therapeutic use , Candida glabrata/genetics , Candidiasis/drug therapy , Echinocandins/therapeutic use , High-Throughput Nucleotide Sequencing , Humans , Microbial Sensitivity Tests , Mutation , Prevalence , United Kingdom
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