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- Yeast-like filamentous fungi: Molecular identification and in vitro susceptibility study. [Journal Article]
- MMMed Mycol 2018 Dec 06
- Yeast-like filamentous fungi, collected in Italy from 1985 to 2018, were submitted to molecular identification and antifungal susceptibility testings. Clinical isolates were identified as Magnusiomyc...
Yeast-like filamentous fungi, collected in Italy from 1985 to 2018, were submitted to molecular identification and antifungal susceptibility testings. Clinical isolates were identified as Magnusiomyces capitatus (28), M. clavatus (18), and Geotrichum candidum (2). M. clavatus was prevalent among blood isolates (18/24), M. capitatus among isolates from other biological materials. The intrinsic echinocandin resistance was confirmed. Both species had low minimum inhibitory concentrations (MICs) of itraconazole, posaconazole, and voriconazole, while M. clavatus had lower MIC of flucytosine and higher MIC of isavuconazole than M. capitatus. The intrinsic resistance of these species to echinocandins could be the reason of the recent increase of M. clavatus bloodstream infections.
- Emerging concepts in HIV-associated cryptococcal meningitis. [Journal Article]
- COCurr Opin Infect Dis 2018 Nov 30
- CONCLUSIONS: Recently completed and ongoing clinical trials are increasing our understanding of how to optimize induction therapy for cryptococcal meningitis. Advocacy efforts are needed to broaden access to amphotericin formulations and flucytosine.
- EQUAL Cryptococcus Score 2018: A European Confederation of Medical Mycology Score Derived From Current Guidelines to Measure QUALity of Clinical Cryptococcosis Management. [Review]
- OFOpen Forum Infect Dis 2018; 5(11):ofy299
- Cryptococcocis is an opportunistic fungal infection with high morbidity and mortality. Guidelines to aid clinicians regarding diagnosis, management, and treatment can be extensive and challenging to ...
Cryptococcocis is an opportunistic fungal infection with high morbidity and mortality. Guidelines to aid clinicians regarding diagnosis, management, and treatment can be extensive and challenging to comply with. There is no tool to measure guideline adherence. To create such a tool, we reviewed current guidelines from the Infectious Diseases Society of America, the World Health Organization, the American Society of Transplantation, and recent significant publications to select the strongest recommendations as vital components of our scoring tool. Items included diagnostic tests (blood, tissue, and cerebrospinal fluid cultures, Cryptococcus antigen, India ink, histopathology with special fungal stains, central nervous system imaging), pharmacological (amphotericin B, flucytosine, azoles) and nonpharmacological treatments (intracranial pressure management, immunomodulation, infectious disease consultation), and follow-up of central nervous system complications. The EQUAL Cryptococcus Score 2018 weighs and aggregates the recommendations for the optimal management of cryptococcosis. Providing a tool that could measure guideline adherence or facilitate clinical decision-making.
- High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B-Based Therapy Under Routine Care Conditions in Africa. [Journal Article]
- OFOpen Forum Infect Dis 2018; 5(11):ofy267
- CONCLUSIONS: Mortality rates following HIV-associated CM treated with AmB-d and fluconazole in a routine health care setting in Botswana were very high. The findings highlight the inadequacies of current antifungal treatments for HIV-associated CM and underscore the difficulties of administering and monitoring intravenous amphotericin B deoxycholate therapy in resource-poor settings.
- Synergistic Antifungal Activity of Isoquercitrin: Apoptosis and Membrane Permeabilization Related to Reactive Oxygen Species in Candida albicans. [Journal Article]
- ILIUBMB Life 2018 Nov 27
- Isoquercitrin (ISO), one of phytochemical isolated from aerial parts of Aster yomena, has been reported to have antifungal activity. However, the synergistic effect and the mechanism of ISO in combin...
Isoquercitrin (ISO), one of phytochemical isolated from aerial parts of Aster yomena, has been reported to have antifungal activity. However, the synergistic effect and the mechanism of ISO in combination with conventional antifungal agents are poorly understood. Therefore, synergistic antifungal effect between ISO and conventional antifungal agents was investigated. ISO at non-antifungal concentration interacts synergistically with amphotericin B (AMB) and fluconazole (FLC), but the combination with flucytosine (5-FC) showed no interaction. ISO disrupted an antioxidant system by inhibiting the activity of superoxide dismutase. This redox imbalance was shown to induce intracellular reactive oxygen species (ROS) accumulation and oxidative stress. ISO combined with FLC caused metacaspase activation and DNA condensation, markers of apoptosis, higher than the combination with ISO/AMB. In contrast, ISO with AMB synergistically stimulated membrane permeabilization compared to ISO/FLC. Scavenging ROS consequently reduced the synergy-induced apoptosis and membrane permeabilization, indicating combinations induced ROS were associated with the synergy effect of ISO. In conclusion, AMB and FLC enhanced the antifungal potency of ISO through oxidative stress when used in synergy. © 2018 IUBMB Life, 9999(9999):1-10, 2018.
- AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial. [Journal Article]
- TTrials 2018 Nov 23; 19(1):649
- CONCLUSIONS: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment.
- Probing the evolutionary robustness of two repurposed drugs targeting iron uptake in Pseudomonas aeruginosa. [Journal Article]
- EMEvol Med Public Health 2018; 2018(1):246-259
- CONCLUSIONS: Our work highlights that antivirulence treatments are not evolutionarily robust per se. Instead, evolutionary robustness is a relative measure, with specific treatments occupying different positions on a continuous scale.
- Pharmacological inhibition of pigmentation in Cryptococcus. [Journal Article]
- FYFEMS Yeast Res 2019 Jan 01; 19(1)
- Melanin formation is a promising target for antifungal development. We screened a collection of 727 compounds that were previously approved for clinical use in humans for inhibition of pigmentation i...
Melanin formation is a promising target for antifungal development. We screened a collection of 727 compounds that were previously approved for clinical use in humans for inhibition of pigmentation in Cryptococcus gattii, a lethal fungal pathogen that causes damage to both immunocompetent and immunocompromised hosts. The pyrimidine analogues flucytosine (5-fluorocytosine [5-FC]), 5-fluorouracil (5-FU) and carmofur were identified as efficient inhibitors of pigmentation in the C. gattii model. Since melanin synthesis is enzymatically catalyzed by laccase in Cryptococcus, we investigated whether inhibition of pigmentation by the pyrimidine analogues was laccase-mediated. Enzyme activity and expression of LAC genes were not involved in the effects of the pyrimidine analogues, suggesting alternative cellular targets for inhibition of pigmentation. To address this hypothesis, we screened a collection of approximately 8000 mutants of C. gattii that were produced by insertional mutation after incubation with Agrobacterium tumefaciens and identified a gene product required for the anti-pigmentation activity of 5-FC as a beta-DNA polymerase. Reduced expression of this gene affected capsule formation and urease activity, suggesting essential roles in the cryptococcal physiology. These results demonstrate a previously unknown antifungal activity of 5-FC and reveal a promising target for the development of novel antifungals.
- Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010-16. [Journal Article]
- JAJ Antimicrob Chemother 2018 Oct 30
- CONCLUSIONS: Provision of specialist input to optimize antifungal prescribing resulted in significant cost savings without compromising on microbiological or clinical outcomes. Our model is readily implementable by hospitals with high numbers of at-risk patients and antifungal expenditure.
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- Leave no one behind: response to new evidence and guidelines for the management of cryptococcal meningitis in low-income and middle-income countries. [Review]
- LILancet Infect Dis 2018 Oct 18
- In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-relat...
In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.