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Janeczko M, Masłyk M, Demchuk OM, Kurowska-Okoń A, Kwaśnik M, Górka K, Martyna A, Foll-Josselin B, Ruchaud S, Bach S, Woliński P, Jasiński R, Mirosław B, Sadczuk M, Kubiński K. Development of a novel family of antifungal agents based on a quinone methide oxime framework. Sci Rep 2025; 15:13458. [PMID: 40251320 PMCID: PMC12008262 DOI: 10.1038/s41598-025-98609-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 04/14/2025] [Indexed: 04/20/2025] Open
Abstract
Given the widespread occurrence of fungal infections, the phenomenon of fungal drug resistance, and the limited number of systemic antimycotic therapies, novel chemicals should be developed to control pathogenic fungi. We propose using quinone methide oximes as a novel framework for developing a novel class of antifungal agents. Compound 2 was destroyed mature biofilms at the concentration of 0.5 µg/mL (MIC/4) and prevented hyphal growth of Candida albicans at 0.125 µg/mL (MIC/16). The chemical applied at the concentration of 16-128 µg/mL inhibited the growth of the majority of the clinical isolates of Candida used, including those exhibiting resistance towards systemic drugs. Our safety studies performed with the use of normal human cells revealed that compound 2 was not toxic at the antifungal concentrations tested. Surprisingly, compound 2 showed low inhibitory activity against a set of protein kinases in comparison with its parental compound 1.
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Affiliation(s)
- Monika Janeczko
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Maciej Masłyk
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Oleg M Demchuk
- Department of Chemistry, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Antonina Kurowska-Okoń
- Department of Chemistry, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Mateusz Kwaśnik
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Kamila Górka
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Aleksandra Martyna
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland
| | - Béatrice Foll-Josselin
- Sorbonne Université, USR3151 CNRS/UPMC, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique, Place Georges Teissier, Roscoff, F-29688, France
| | - Sandrine Ruchaud
- Sorbonne Université, USR3151 CNRS/UPMC, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique, Place Georges Teissier, Roscoff, F-29688, France
| | - Stéphane Bach
- Sorbonne Université, USR3151 CNRS/UPMC, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique, Place Georges Teissier, Roscoff, F-29688, France
| | - Przemysław Woliński
- Department of Organic Chemistry and Technology, Cracow University of Technology, Warszawska 24, Cracow, 31-155, Poland
| | - Radomir Jasiński
- Department of Organic Chemistry and Technology, Cracow University of Technology, Warszawska 24, Cracow, 31-155, Poland
| | - Barbara Mirosław
- Department of General and Coordination Chemistry and Crystallography, Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie- Sklodowska University in Lublin, Maria Curie-Sklodowska sq. 2, Lublin, 20-031, Poland
| | - Małgorzata Sadczuk
- Chair and Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, 4A Chodzki Street, Lublin, 20-093, Poland
| | - Konrad Kubiński
- Department of Molecular Biology, The John Paul II Catholic University of Lublin, ul. Konstantynów 1i, Lublin, 20-708, Poland.
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2
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Chou CH, Chao QT, Lu YS, Lee TF, Hsueh PR, Huang YT, Liao CH. Comparison of the BluePoint MoldID oligonucleotide array and Bruker Biotyper MALDI-TOF MS for the identification of filamentous fungi. J Clin Microbiol 2025; 63:e0104824. [PMID: 39636116 PMCID: PMC11784249 DOI: 10.1128/jcm.01048-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024] Open
Abstract
BluePoint MoldID can identify 43 fungal species through nucleic acid array hybridization and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) can identify 247 filamentous fungi through mass spectrometry. First, 43 standard isolates from the Bioresource Collection and Research Center, Taiwan, and the College of American Pathologists and 41 clinical Aspergillus species isolates confirmed by rDNA-ITS sequencing were analyzed using BluePoint MoldID and Bruker MALDI-TOF MS. BluePoint MoldID accurately identified 79% (34/43) of the standard isolates to the species level but failed to recognize nine isolates absent from its database; additionally, 87.8% (36/41) of the clinical isolates were identified at the species level, with 80.5% (33/41) accuracy. MALDI-TOF MS identified 86% (37/43) of the standard isolates, with 81.4% (35/43) accurately identified at the species level and two at the genus level, and identified all the clinical isolates, with 92.6% (38/41) accurately identified at the species level. Next, we analyzed 93 clinical Aspergillus species and compared the results by rDNA-ITS sequencing. BluePoint MoldID identified 87.1% (81/93) of the isolates at the species level, with 80.6% (75/93) accuracy. MALDI-TOF MS identified 97.8% (91/93) of the isolates, including some uncommon species, with 90.3% (84/93) accuracy at the species level. BluePoint MoldID and MALDI-TOF MS had turnaround times of 8 and 2 h, respectively, significantly reducing the time needed to identify filamentous fungi. IMPORTANCE The BluePoint MoldID kit is an oligonucleotide array used for the identification of filamentous fungi, and it has not yet been mentioned in recent studies. We used a BluePoint MoldID kit to identify standard and clinical filamentous fungal isolates and compared its performance with that of Bruker MALDI-TOF MS. The former accurately identified 80.2% of the isolates (142/177), and the latter identified 92.6% of the isolates (164/177). The performance of the BluePoint MoldID kit was slightly inferior to that of Bruker MALDI-TOF MS because of the smaller database. However, the BluePoint MoldID kit can cover most clinically common opportunistic fungal infections; thus, it offers an alternative method for laboratories that lack MALDI-TOF MS equipment, as the device is less expensive.
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Affiliation(s)
- Chia-Hua Chou
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Qiao-Ting Chao
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yun-Shan Lu
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Tai-Fen Lee
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Po-Ren Hsueh
- Division of Infectious Diseases, Department of Internal Medicine, China Medical University, School of Medicine, Taichung, Taiwan
- Department of Laboratory Medicine, China Medical University, School of Medicine, Taichung, Taiwan
| | - Yu-Tsung Huang
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Hsing Liao
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Infectious Diseases, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan
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Velkova L, Abrashev R, Miteva-Staleva J, Dishliyska V, Dolashki A, Spasova B, Dolashka P, Angelova M, Krumova E. The Role of Oxidative Stress in the Antifungal Activity of Two Mollusk Fractions on Resistant Fungal Strains. Int J Mol Sci 2025; 26:985. [PMID: 39940751 PMCID: PMC11817555 DOI: 10.3390/ijms26030985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
Fungal infections are a significant global public health challenge because of their widespread occurrence, morbidity, and profound social and economic consequences. Antifungal resistance is also an increasing concern, posing a substantial risk to public health. There is a growing interest in searching for new antifungal drugs isolated from natural sources. This study aimed to evaluate the antifungal activity of novel mollusk fractions against fungal strains resistant to nystatin and amphotericin B. In addition, the role of oxidative stress in the mechanism of damage was determined. The mucus from the garden snail Cornu aspersum (MCa/1-20) and the hemolymph fraction from the marine snail Rapana venosa (HLRv/3-100) were obtained and characterized via 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometric -analyses. The results demonstrate that the spores and biomass of both mollusk fractions have a significant fungicidal effect against Penicillium griseofulvum, and Aspergillus niger. Compared to the control group, the release of intracellular proteins and reducing sugars was significantly increased in the treated groups. The data showed increased levels of oxidative stress biomarkers (lipid peroxidation and oxidatively damaged proteins) and a downregulated antioxidant enzyme defense, corresponding to increased antifungal activity. To our knowledge, this is the first study evaluating oxidative stress as a factor in mollusk fractions' antifungal activity.
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Affiliation(s)
- Lyudmila Velkova
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Academician G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (L.V.); (A.D.); or (P.D.)
| | - Radoslav Abrashev
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
| | - Jeny Miteva-Staleva
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
| | - Vladislava Dishliyska
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
| | - Aleksandar Dolashki
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Academician G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (L.V.); (A.D.); or (P.D.)
| | - Boryana Spasova
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
| | - Pavlina Dolashka
- Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Academician G. Bonchev Str., bl. 9, 1113 Sofia, Bulgaria; (L.V.); (A.D.); or (P.D.)
- Centre of Competence “Clean Technologies for Sustainable Environment—Waters, Waste, Energy for a Circular Economy”, 1000 Sofia, Bulgaria
| | - Maria Angelova
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
| | - Ekaterina Krumova
- Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Academician G. Bonchev 26, 1113 Sofia, Bulgaria; (R.A.); (J.M.-S.); (V.D.); (B.S.); (M.A.)
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4
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Cohen DG, Heidenreich TM, Schorey JW, Ross JN, Hammers DE, Vu HM, Moran TE, Winski CJ, Stuckey PV, Ross RL, Yee EA, Santiago-Tirado FH, Lee SW. Minimal domain peptides derived from enterocins exhibit potent antifungal activity. FRONTIERS IN FUNGAL BIOLOGY 2024; 5:1506315. [PMID: 39749139 PMCID: PMC11693670 DOI: 10.3389/ffunb.2024.1506315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Accepted: 11/21/2024] [Indexed: 01/04/2025]
Abstract
The antimicrobial peptide (AMP) circularized bacteriocin enterocin AS-48 produced by Enterococcus sp. exhibits broad-spectrum antibacterial activity via dimer insertion into the plasma membrane to form membrane pore structures, compromising membrane integrity and leading to bactericidal activity. A specific alpha-helical region of enterocin AS-48 has been shown to be responsible for the membrane-penetrating activity of the peptide. The canon syn-enterocin peptide library, generated using rational design techniques to have ninety-five synthetic peptide variants from the truncated, linearized, membrane-interacting domain of enterocin AS-48, was screened against three clinically relevant fungal strains: Cryptococcus neoformans, Candida albicans, and Candida auris for potential antifungal activity. Twelve peptides exhibited antifungal activity against C. neoformans, and two peptides exhibited activity against C. albicans. The fourteen active antifungal peptides were minimally cytotoxic to an immortalized human keratinocyte cell line (HaCats). Four select peptides were identified with minimum inhibitory concentrations (MICs) below 8 µM against C. neoformans. In 36-hour cell growth tests with these fungicidal peptides, fungicidal peptide no. 32 displayed inhibitory properties comparable to the leading antifungal medication fluconazole against C. neoformans. Screening of peptide no. 32 against a deletion library of C. neoformans mutants revealed that the mechanism of action of peptide no. 32 may relate to multivesicular bodies (MVBs) or polysaccharide capsule targeting. These findings importantly demonstrate that naturally derived AMPs produced by bacteria can be sourced, engineered, and modified to exhibit potent antifungal activity. Our results will contribute to the development of broad treatment alternatives to fungal infections and lend themselves to direct implications for possible treatment options for C. neoformans infections.
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Affiliation(s)
- Dorrian G. Cohen
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Theresa M. Heidenreich
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | | | - Jessica N. Ross
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Daniel E. Hammers
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Henry M. Vu
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Thomas E. Moran
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Christopher J. Winski
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Peter V. Stuckey
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | - Robbi L. Ross
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
| | | | - Felipe H. Santiago-Tirado
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
- Eck Institute for Global Health, Notre Dame, IN, United States
| | - Shaun W. Lee
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, United States
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5
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Windyaswari AS, Nugraha MFI, Hartati R, Elfahmi. Isolation and antimicrobial activity of secondary metabolites of pothos tener wall. Nat Prod Res 2024:1-9. [PMID: 39102533 DOI: 10.1080/14786419.2024.2384081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 07/08/2024] [Accepted: 07/18/2024] [Indexed: 08/07/2024]
Abstract
The Pothos genus is extensively utilised in traditional medicine in China and India. An underexplored species of Pothos tener Wall was identified in Sulawesi, Indonesia. Antimicrobial activity was assessed using microdilutions and streak plates against Staphylococcus aureus, Eschericia coli, Aeromonas hydrophila, Aspergillus niger, and Candida albicans. Significant effectiveness was observed in the methanol extract, as indicated by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values for three different extracts (methanol, ethyl acetate, and n-hexane) of P. tener. The isolates obtained were structurally analysed using Ultraviolet (UV)-spectroscopy, Fourier-transform Infra Red-Spectroscopy (FT-IR), Mass Spectroscopy (MS), Nuclear Magnetic Resonance (NMR), and antimicrobial testing after undergoing fractionation and subfractionation. The isolate obtained was stigmasterol with moderate antimicrobial activity against A. niger and A. hydrophila, with MIC equivalent to MBC of 500 µg/ml. The first report of stigmasterol from P. tener has potent antimicrobial properties, bolstering empirical data in this field.
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Affiliation(s)
- Ari Sri Windyaswari
- Department of Pharmaceutical Biology, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
- Department of Biology Pharmacy, Faculty of Pharmacy, University of Jenderal Achmad Yani, Cimahi, Indonesia
| | - Media Fitri Isma Nugraha
- Research Centre for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency, Cibinong, Indonesia
| | - Rika Hartati
- Department of Pharmaceutical Biology, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
| | - Elfahmi
- Department of Pharmaceutical Biology, School of Pharmacy, Bandung Institute of Technology, Bandung, Indonesia
- University Centre of Excellence for Nutraceuticals, Bioscience and Biotechnology Research Centre, Bandung Institute of Technology, Bandung, Indonesia
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Mezochow AK, Schaubel DE, Peyster EG, Lewis JD, Goldberg DS, Bittermann T. Hospitalizations for opportunistic infections following transplantation and associated risk factors: A national cohort study of Medicare beneficiaries. Transpl Infect Dis 2024; 26:e14317. [PMID: 38852064 PMCID: PMC11315637 DOI: 10.1111/tid.14317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 05/25/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND Opportunistic infections (OIs) are a significant cause of morbidity and mortality after organ transplantation, though data in the liver transplant (LT) population are limited. METHODS We performed a retrospective cohort study of LT recipients between January 1, 2007 and Deceber 31, 2016 using Medicare claims data linked to the Organ Procurement and Transplantation Network database. Multivariable Cox regression models evaluated factors independently associated with hospitalizations for early (≤1 year post transplant) and late (>1 year) OIs, with a particular focus on immunosuppression. RESULTS There were 11 320 LT recipients included in the study, of which 13.2% had at least one OI hospitalization during follow-up. Of the 2638 OI hospitalizations, 61.9% were early post-LT. Cytomegalovirus was the most common OI (45.4% overall), although relative frequency decreased after the first year (25.3%). Neither induction or maintenance immunosuppression were associated with early OI hospitalization (all p > .05). The highest risk of early OI was seen with primary sclerosing cholangitis (aHR 1.74; p = .003 overall). Steroid-based and mechanistic target of rapamycin inhibitor-based immunosuppression at 1 year post LT were independently associated with increased late OI (p < .001 overall). CONCLUSION This study found OI hospitalizations to be relatively common among LT recipients and frequently occur later than previously reported. Immunosuppression regimen may be an important modifiable risk factor for late OIs.
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Affiliation(s)
- Alyssa K Mezochow
- Department of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Douglas E Schaubel
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Eliot G Peyster
- Advanced Heart Failure and Transplant Medicine, Division of Cardiovascular Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James D Lewis
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David S Goldberg
- Division of Digestive Health & Liver Diseases, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Therese Bittermann
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Gastroenterology & Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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7
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Wu YP, Li FC, Ma HY, Yang XY, Zuo J, Tian YX, Lv L, Wang K, Fan YC. Characteristics and risk factors for invasive fungal infection in hospitalized patients with acute-on-chronic hepatitis B liver failure: a retrospective cohort study from 2010 to 2023. Front Microbiol 2024; 15:1391814. [PMID: 38601929 PMCID: PMC11004317 DOI: 10.3389/fmicb.2024.1391814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 03/12/2024] [Indexed: 04/12/2024] Open
Abstract
BACKGROUND AND AIM The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients. METHODS A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method. RESULTS There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990). CONCLUSION IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.
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Affiliation(s)
- Yin-Ping Wu
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Feng-Cai Li
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Hang-Yu Ma
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Xue-Yan Yang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Jing Zuo
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Yu-Xin Tian
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
| | - Li Lv
- Clinical Follow-up Center, Qilu Hospital of Shandong University, Jinan, China
| | - Kai Wang
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Hepatology Institute of Shandong University, Jinan, China
| | - Yu-Chen Fan
- Department of Hepatology, Qilu Hospital of Shandong University, Jinan, China
- Hepatology Institute of Shandong University, Jinan, China
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8
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Brakel A, Grochow T, Fritsche S, Knappe D, Krizsan A, Fietz SA, Alber G, Hoffmann R, Müller U. Evaluation of proline-rich antimicrobial peptides as potential lead structures for novel antimycotics against Cryptococcus neoformans. Front Microbiol 2024; 14:1328890. [PMID: 38260890 PMCID: PMC10800876 DOI: 10.3389/fmicb.2023.1328890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/18/2023] [Indexed: 01/24/2024] Open
Abstract
Background Cryptococcosis and cryptococcal meningitis, caused by Cryptococcus neoformans infections, lead to approximately 180,000 deaths per year, primarily in developing countries. Individuals with compromised immune systems, e.g., due to HIV infection (AIDS) or chemotherapy, are particularly vulnerable. Conventional treatment options are often limited and can cause severe side effects. Therefore, this study aimed to investigate the antifungal effect of insect-derived proline-rich antimicrobial peptides (PrAMPs) against C. neoformans. These peptides are known for their low toxicity and their high efficacy in murine infection models, making them a promising alternative for treatment. Results A preliminary screening of the minimal inhibitory concentrations (MICs) of 20 AMPs, including the well-known PrAMPs Onc112, Api137, and Chex1Arg20 as well as the cathelicidin CRAMP against the C. neoformans strains 1841, H99, and KN99α revealed promising results, with MICs as low as 1.6 μmol/L. Subsequent investigations of selected peptides, determining their influence on fungal colony-forming units, confirmed their strong activity. The antifungal activity was affected by factors such as peptide net charge and sequence, with stronger effects at higher net charges probably due to better intracellular uptake confirmed by confocal laser scanning microscopy. Inactive scrambled peptides suggest a specific intracellular target, although scanning electron microscopy showed that PrAMPs also damaged the cell exterior for a low proportion of the cells. Possible pore formation could facilitate entry into the cytosol.
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Affiliation(s)
- Alexandra Brakel
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
| | - Thomas Grochow
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Stefanie Fritsche
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
- Institute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Daniel Knappe
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
| | - Andor Krizsan
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
| | - Simone A. Fietz
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Gottfried Alber
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
- Institute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Ralf Hoffmann
- Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Bioanalytical Chemistry, Leipzig University, Leipzig, Germany
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
| | - Uwe Müller
- Center for Biotechnology and Biomedicine, Leipzig University, Leipzig, Germany
- Institute of Immunology/Molecular Pathogenesis, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
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9
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Singh S, Patil VM, Paliwal SK, Masand N. Nanotechnology-based Drug Delivery of Topical Antifungal Agents. Pharm Nanotechnol 2024; 12:185-196. [PMID: 37594096 DOI: 10.2174/2211738511666230818125031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/03/2023] [Accepted: 07/13/2023] [Indexed: 08/19/2023]
Abstract
Among the various prominent fungal infections, superficial ones are widespread. A large number of antifungal agents and their formulations for topical use are commercially available. They have some pharmacokinetic limitations which cannot be retracted by conventional delivery systems. While nanoformulations composed of lipidic and polymeric nanoparticles have the potential to overcome the limitations of conventional systems. The broad spectrum category of antifungals i.e. azoles (ketoconazole, voriconazole, econazole, miconazole, etc.) nanoparticles have been designed, prepared and their pharmacokinetic and pharmacodynamic profile was established. This review briefly elaborates on the types of nano-based topical drug delivery systems and portrays their advantages for researchers in the related field to benefit the available antifungal therapeutics.
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Affiliation(s)
- Sumita Singh
- Department of Pharmacy, Banasthali Vidyapith, Tonk, Rajasthan, India
- Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India
| | - Vaishali M Patil
- Charak School of Pharmacy, Chaudhary Charan Singh (CCS) University, Meerut, Uttar Pradesh, India
| | | | - Neeraj Masand
- Department of Pharmacy, Lala Lajpat Rai Memorial Medical College, Meerut, Uttar Pradesh, India
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10
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Szymankiewicz MT, Szczepanska A, Stefaniuk E. Evaluation of the BioFire® FilmArray® Pneumonia plus Panel for Detecting Bacterial Etiological Agents of Lower Respiratory Tract Infections in an Oncologic Hospital. Comparison with Conventional Culture Method. Pol J Microbiol 2023; 72:391-398. [PMID: 37815433 PMCID: PMC10725156 DOI: 10.33073/pjm-2023-035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 08/20/2023] [Indexed: 10/11/2023] Open
Abstract
Conventional methods used to determine pneumonia pathogens are characterized by low sensitivity and long turnaround times. Introducing new tests with better parameters in patients at higher risk of infections is highly anticipated. The results of the conventional quantitative culture method (CM) in determining the bacterial etiology of pneumonia were compared with the results of the Pneumonia plus Panel test (PNP; BioFire® Diagnostics, USA) in 79 samples of bronchoalveolar lavage (BAL). Materials were collected from 79 patients with suspected pneumonia treated in an oncologic hospital due to solid tumors. Only 16/79 BAL samples (20.3%) were true positive (TP) for bacterial etiology in CM vs. 27/79 samples (34.2%) true positive in the PNP test. The total agreement between methods of interpreting the result (positive or negative) was 84.8%. The most prevalent pathogens in both methods were Staphylococcus aureus, followed by Escherichia coli, Pseudomonas aeruginosa, and Haemophilus influenzae. The PNP test identified several respiratory pathogens that were not grown in culture. The semiquantitative value reported by the PNP test was higher than that reported by culture. The PNP test vs. combined test (PNP test and CM methods) demonstrated positive predictive value (PPV) and negative predictive value (NPV) values of 100.0% and 98.1%, and the sensitivity and specificity were 96.4% and 100.0%. The PNP test is a good tool for determining the etiology of bacterial pneumonia and may support the care of an oncologic patient. However, further large-sample studies are needed to research in strictly defined groups of oncologic patients.
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Affiliation(s)
| | - Anna Szczepanska
- Department of Microbiology, Prof. F. Łukaszczyk Oncology Centre, Bydgoszcz, Poland
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11
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Zhao Z, Liu C, Yang J, Ren G, Zhang L, Wang T. Pulmonary cryptococcosis closely mimicking lung cancer in a membranous nephropathy patient taking calcineurin inhibitor. IDCases 2023; 34:e01916. [PMID: 37867565 PMCID: PMC10585382 DOI: 10.1016/j.idcr.2023.e01916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 10/24/2023] Open
Abstract
In patients with membranous nephropathy (MN), malignancy may be either the underlying disease or results of immunosuppressive therapy which may also lead to opportunistic infections including the pulmonary cryptococcosis. On CT scan, nodule is the most common feature in pulmonary cryptococcosis and it can mimic lung cancer both clinically and radiologically. Therefore, pulmonary nodular lesions caused by cryptococcosis may be easily misdiagnosed and require unnecessary surgical treatment. As such, we herein presented an isolated subpleural solitary nodule with satellite lesion that closely mimicked lung cancer on both contrast-enhanced computed tomography (CT) scan and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT in an MN patient under long-term tacrolimus regimen. Cryptococcosis was ascertained by the finding of oval thick-walled yeast on histopathology of the lung biopsy specimen taken during the Argon-Helium cryotherapy. Further, the pulmonary lesions progressively dissipated after antifungal treatment. Arguably, our experience may help clinicians in general and nephrologists in particular with a better understanding of the cryptococcal infection manifesting as pulmonary nodule(s) in the MN patients and contribute to more efficacious differential diagnosis against the lung cancer.
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Affiliation(s)
- ZhiPeng Zhao
- Graduate School of HeBei Medical University, Shijiazhuang 050011, China
| | - Chong Liu
- Department of Medical Imaging, the First Hospital of HeBei Medical University, ShiJiaZhuang 050030, China
| | - JianZhu Yang
- Department of Pathology, the First Hospital of HeBei Medical University, ShiJiaZhuang 050030, China
| | - GuangWei Ren
- Department of Nephrology, the First Hospital of HeBei Medical University, ShiJiaZhuang 050030, China
| | - LiHong Zhang
- Department of Nephrology, the First Hospital of HeBei Medical University, ShiJiaZhuang 050030, China
| | - Tao Wang
- Department of Nephrology, the First Hospital of HeBei Medical University, ShiJiaZhuang 050030, China
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Arafa SH, Elbanna K, Osman GEH, Abulreesh HH. Candida diagnostic techniques: a review. JOURNAL OF UMM AL-QURA UNIVERSITY FOR APPLIED SCIENCES 2023; 9:360-377. [DOI: 10.1007/s43994-023-00049-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/27/2023] [Indexed: 01/03/2025]
Abstract
AbstractFungal infections (mycoses) represent a major health issue in humans. They have emerged as a global concern for medical professionals by causing high morbidity and mortality. Fungal infections approximately impact one billion individuals per annum and account for 1.6 million deaths. The diagnosis of Candida infections is a challenging task. Laboratory-based Candida species identification techniques (molecular, commercial, and conventional) have been reviewed and summarized. This review aims to discuss the mycoses history, taxonomy, pathogenicity, and virulence characteristics.
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de Oliveira Kocerginsky P, Dos Santos Soares PH, Lyra HFS, Cadena PG, de Lima-Neto RG, Pontes-Filho NT, Lima-Filho JVM, Costa-Júnior SD, Neves RP, Cavalcanti IMF, Santos-Magalhães NS. Efficacy and non-toxicity of ciclopirox olamine-loaded liposomes against Cryptococcus neoformans clinical isolates. Braz J Microbiol 2023; 54:1513-1521. [PMID: 37540461 PMCID: PMC10484888 DOI: 10.1007/s42770-023-01071-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 07/03/2023] [Indexed: 08/05/2023] Open
Abstract
The aim of this study was to evaluate the efficacy and non-toxicity of ciclopirox olamine-loaded liposomes against Cryptococcus neoformans clinical isolates. Initially, 24-1 fractional experimental design was carried out to obtain an optimized formulation of liposomes containing CPO (CPO-LipoC), which were then used to prepare stealth liposomes (CPO-LipoS). Liposomal formulations were characterized by their mean size diameter, polydispersity index (PDI), and drug encapsulation efficiency (EE%). Immunosuppressed mice were exposed to CPO-LipoS at 0.5 mg/kg/day for 14 days to verify possible histopathological alterations in the liver and kidneys. Immunosuppressed mice infected with C. neoformans were treated with CPO-LipoS at 0.5 mg/kg/day for 14 days to quantify the fungal burden in spleen, liver, lungs, and brain. CPO-LipoS presented a mean size diameter, PDI, and EE% of 101.4 ± 0.7 nm, 0.307, and 96.4 ± 0.9%, respectively. CPO-LipoS was non-toxic for the liver and kidneys of immunosuppressed mice. At the survival curve, all infected animals submitted to treatment with CPO-LipoS survived until the end of the experiment. Treatment with CPO-LipoS reduced C. neoformans cells in the spleen (59.3 ± 3.4%), liver (75.0 ± 3.6%), lungs (75.7 ± 6.7%), and brain (54.2 ± 3.2%). CPO-LipoS exhibit antifungal activity against C. neoformans, and the encapsulation of CPO into stealth liposomes allows its use as a systemic drug for treating cryptococcosis.
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Affiliation(s)
- Patrícia de Oliveira Kocerginsky
- Biosciences Center, Laboratory of Medical Mycology, Federal University of Pernambuco (UFPE), Av Reitor Joaquim Amazonas, S/N, Cidade Universitária, Recife, PE, 50740-570, Brazil
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Pedro Henrique Dos Santos Soares
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Hannah Ferreira Soares Lyra
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Pabyton Gonçalves Cadena
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
- Department of Animal Morphology and Physiology, Federal Rural University of Pernambuco (UFRPE), Rua Dom Manoel de Medeiros, S/N, Dois Irmãos, Recife, PE, 52171-900, Brazil
| | - Reginaldo Gonçalves de Lima-Neto
- Biosciences Center, Laboratory of Medical Mycology, Federal University of Pernambuco (UFPE), Av Reitor Joaquim Amazonas, S/N, Cidade Universitária, Recife, PE, 50740-570, Brazil
- Health Sciences Center, Department of Tropical Medicine, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Nicodemos Teles Pontes-Filho
- Center for Health Sciences, Department of Pathology, Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - José Vitor Moreira Lima-Filho
- Department of Biology, Federal Rural University of Pernambuco (UFRPE), Rua Dom Manoel de Medeiros, 401, Dois Irmãos, Recife, PE, 52171-900, Brazil
| | - Sérgio Dias Costa-Júnior
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil
| | - Rejane Pereira Neves
- Biosciences Center, Laboratory of Medical Mycology, Federal University of Pernambuco (UFPE), Av Reitor Joaquim Amazonas, S/N, Cidade Universitária, Recife, PE, 50740-570, Brazil
| | - Isabella Macário Ferro Cavalcanti
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.
- Academic Center of Vitória (CAV), Laboratory of Microbiology and Immunology, Vitória de Santo Antão, Federal University of Pernambuco (UFPE), Rua Alto Do Reservatório, S/N, Vitória de Santo Antão, PE, Brazil.
| | - Nereide Stela Santos-Magalhães
- Keizo Asami Institute (iLIKA), Federal University of Pernambuco (UFPE), Av. Prof. Moraes Rego, 1235, Cidade Universitária, Recife, PE, 50670-901, Brazil.
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Khateb AM, Alofi FS, Almutairi AZ. Increased prevalence of fungemia in Medina, Saudi Arabia. FRONTIERS IN EPIDEMIOLOGY 2023; 3:1180331. [PMID: 38455891 PMCID: PMC10910952 DOI: 10.3389/fepid.2023.1180331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/18/2023] [Indexed: 03/09/2024]
Abstract
Background The prevalence of fungal infection is increasing globally due to an increase in the immunocompromised and aging population. We investigated epidemiological changes in fungemia in one of the major centers in Medina over seven years period with 87,447 admissions. Methods Retrospective search of records for causative agents of fungemia in inpatients at King Fahad Hospital (KFH) in 2013-2019. Fungal-positive blood cultures, demographic, and treatment data were extracted. Results A total of 331 fungemia episodes proven by blood culture were identified in 46 patients. The annual prevalence of fungemia increased from 0.072 in 2013 to 1.546 patients per 1,000 in 2019. The mean age of fungemia episodes was 56 years, and 62% of episodes occurred in females. Samples from central blood incubated aerobically yielded the highest fungemia rate, accounting for 55% (n = 182). Among yeast species, Candida parapsilosis was responsible for the highest number of episodes 37% (n = 122), followed by Candida glabrata (32%; n = 107), Candid albicans (29%; n = 94), and Cryptococcus neoformans (1%; n = 4). Among molds, Lichtheimia (Absidia) species was the most common (1%; n = 3). Yeast-like fungi Trichosporion mucoides accounted for (0.003% n = 1). The use of antifungal treatment has increased (96%) over the years (2013-2019). An increase in resistance rate of 2% was found in C. albicans and C. glabrata. The most prevalent comorbidity was renal disease (24.2%). Conclusions C. parapsilosis was the leading cause of fungemia. The association of renal disease with increased candidemia was alarming. This study is a fundamental resource to establish management policies for fungal infection in the region.
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Affiliation(s)
- Aiah M. Khateb
- Department of Medical Laboratory Technology, Collage of Applied Medical Science, Taibah University, Medina, Saudi Arabia
| | - Fadwa S. Alofi
- Infectious Diseases Department, King Fahad Hospital, Medina, Saudi Arabia
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15
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Khan A, Moni SS, Ali M, Mohan S, Jan H, Rasool S, Kamal MA, Alshahrani S, Halawi M, Alhazmi HA. Antifungal Activity of Plant Secondary Metabolites on Candida albicans: An Updated Review. Curr Mol Pharmacol 2023; 16:15-42. [PMID: 35249516 DOI: 10.2174/1874467215666220304143332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 11/24/2021] [Accepted: 12/06/2021] [Indexed: 11/22/2022]
Abstract
Fungal infections have been increasing continuously worldwide, especially in immunocompromised individuals. Fungi, regarded as eukaryotic pathogens, have many similarities to the host cells, which inhibit anti-fungal drug development progress. Various fungal model systems have been studied, and it was concluded that Candida spp. is the most common disease-causing fungus. Candida species are well known to cause infections not only in our mouth, skin, and vagina, but they are also a frequent cause of life-threatening hospital bloodstream infections. The morphological and developmental pathways of Candida have been studied extensively, providing insight into the fungus development. Candida albicans is known to be the most pathogenic species responsible for a variety of infections in humans. Conventional anti-fungal drugs, mainly azoles drugs available in the market, have been used for years developing resistance in C. albicans. Hence, the production of new anti-fungal drugs, which require detailed molecular knowledge of fungal pathogenesis, needs to be encouraged. Therefore, this review targets the new approach of "Green Medicines" or the phytochemicals and their secondary metabolites as a source of novel anti-fungal agents to overcome the drug resistance of C. albicans, their mechanism of action, and their combined effects with the available anti-fungal drugs.
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Affiliation(s)
- Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | | | - M Ali
- Department of Pharmacognosy, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | - Syam Mohan
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan, 45142, Saudi Arabia
- School of Health Sciences, University of Petroleum and Energy Studies, Dehradun, Uttarakhand, India
| | - Huma Jan
- Department of Clinical Biochemistry, University of Kashmir, Hazratbal, Srinagar -190006, J&K, India
| | - Saiema Rasool
- Department of School Education, Govt. of Jammu & Kashmir, Srinagar, 190001 J&K, India
| | - Mohammad A Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589. Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
- Enzymoics, 7 Peterlee place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, Australia
| | - Saeed Alshahrani
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | - Maryam Halawi
- Department of Clinical Pharmacy, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
| | - Hassan A Alhazmi
- Substance Abuse and Toxicology Research Center, Jazan University, Jazan, 45142, Saudi Arabia
- Department of Pharmaceutical Chemistry, College of Pharmacy, Jazan University, Jazan, 45142, Saudi Arabia
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Malhotra S, Ranjan V, Suman C, Patil S, Malhotra A, Bhatia NK. Advanced Microbiological Diagnostic Techniques in Fungal Infections of the Central Nervous System. VIRAL AND FUNGAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM: A MICROBIOLOGICAL PERSPECTIVE 2023:419-463. [DOI: 10.1007/978-981-99-6445-1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ouyang J, Yan J, Zhou X, Isnard S, Harypursat V, Cui H, Routy JP, Chen Y. Relevance of biomarkers indicating gut damage and microbial translocation in people living with HIV. Front Immunol 2023; 14:1173956. [PMID: 37153621 PMCID: PMC10160480 DOI: 10.3389/fimmu.2023.1173956] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Accepted: 04/10/2023] [Indexed: 05/10/2023] Open
Abstract
The intestinal barrier has the daunting task of allowing nutrient absorption while limiting the entry of microbial products into the systemic circulation. HIV infection disrupts the intestinal barrier and increases intestinal permeability, leading to microbial product translocation. Convergent evidence has shown that gut damage and an enhanced level of microbial translocation contribute to the enhanced immune activation, the risk of non-AIDS comorbidity, and mortality in people living with HIV (PLWH). Gut biopsy procedures are invasive, and are not appropriate or feasible in large populations, even though they are the gold standard for intestinal barrier investigation. Thus, validated biomarkers that measure the degree of intestinal barrier damage and microbial translocation are needed in PLWH. Hematological biomarkers represent an objective indication of specific medical conditions and/or their severity, and should be able to be measured accurately and reproducibly via easily available and standardized blood tests. Several plasma biomarkers of intestinal damage, i.e., intestinal fatty acid-binding protein (I-FABP), zonulin, and regenerating islet-derived protein-3α (REG3α), and biomarkers of microbial translocation, such as lipopolysaccharide (LPS) and (1,3)-β-D-Glucan (BDG) have been used as markers of risk for developing non-AIDS comorbidities in cross sectional analyses and clinical trials, including those aiming at repair of gut damage. In this review, we critically discuss the value of different biomarkers for the estimation of gut permeability levels, paving the way towards developing validated diagnostic and therapeutic strategies to repair gut epithelial damage and to improve overall disease outcomes in PLWH.
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Affiliation(s)
- Jing Ouyang
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Jiangyu Yan
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Xin Zhou
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Canadian HIV Trials Network, Canadian Institutes for Health Research, Vancouver, BC, Canada
| | - Vijay Harypursat
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- Clinical Research Center, Chongqing Public Health Medical Center, Chongqing, China
| | - Hongjuan Cui
- Cancer Center, Medical Research Institute, Southwest University, Chongqing, China
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montréal, QC, Canada
- Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC, Canada
- Division of Hematology, McGill University Health Centre, Montréal, QC, Canada
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
| | - Yaokai Chen
- Department of Infectious Diseases, Chongqing Public Health Medical Center, Chongqing, China
- *Correspondence: Jean-Pierre Routy, ; Yaokai Chen,
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Carvajal SK, Vargas-Casanova Y, Pineda-Castañeda HM, García-Castañeda JE, Rivera-Monroy ZJ, Parra-Giraldo CM. In Vitro Antifungal Activity of Chimeric Peptides Derived from Bovine Lactoferricin and Buforin II against Cryptococcus neoformans var. grubii. Antibiotics (Basel) 2022; 11:antibiotics11121819. [PMID: 36551475 PMCID: PMC9774238 DOI: 10.3390/antibiotics11121819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/09/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Cryptococcosis is associated with high rates of morbidity and mortality. The limited number of antifungal agents, their toxicity, and the difficulty of these molecules in crossing the blood-brain barrier have made the exploration of new therapeutic candidates against Cryptococcus neoformans a priority task. To optimize the antimicrobial functionality and improve the physicochemical properties of AMPs, chemical strategies include combinations of peptide fragments into one. This study aimed to evaluate the binding of the minimum activity motif of bovine lactoferricin (LfcinB) and buforin II (BFII) against C. neoformans var. grubii. The antifungal activity against these chimeras was evaluated against (i) the reference strain H99, (ii) three Colombian clinical strains, and (iii) eleven mutant strains, with the aim of evaluating the possible antifungal target. We found high activity against these strains, with a MIC between 6.25 and 12.5 µg/mL. Studies were carried out to evaluate the effect of the combination of fluconazole treatments, finding a synergistic effect. Finally, when fibroblast cells were treated with 12.5 µg/mL of the chimeras, a viability of more than 65% was found. The results obtained in this study identify these chimeras as potential antifungal molecules for future therapeutic applications against cryptococcosis.
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Affiliation(s)
- Silvia Katherine Carvajal
- Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia
| | - Yerly Vargas-Casanova
- Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia
| | - Héctor Manuel Pineda-Castañeda
- Chemistry Department, Universidad Nacional de Colombia, Carrera 45 No. 26–85, Building 451, Office 409, Bogotá D.C. 111321, Colombia
| | - Javier Eduardo García-Castañeda
- Pharmacy Department, Universidad Nacional de Colombia, Bogotá Carrera 45 No. 26–85, Building 450, Bogotá D.C. 111321, Colombia
| | - Zuly Jenny Rivera-Monroy
- Chemistry Department, Universidad Nacional de Colombia, Carrera 45 No. 26–85, Building 451, Office 409, Bogotá D.C. 111321, Colombia
| | - Claudia Marcela Parra-Giraldo
- Unidad de Proteómica y Micosis Humanas, Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia
- Correspondence: ; Tel.: +57-1-3208320 (ext. 4305)
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Wang Y, Zhao X, Zhou Y, Lu J, Yu H, Li S. Establishment and application of loop-mediated isothermal amplification coupled with nanoparticle-based lateral flow biosensor (LAMP-LFB) for visual and rapid diagnosis of Candida albicans in clinical samples. Front Bioeng Biotechnol 2022; 10:1025083. [PMID: 36420441 PMCID: PMC9676452 DOI: 10.3389/fbioe.2022.1025083] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/24/2022] [Indexed: 10/29/2023] Open
Abstract
Candida albicans is an opportunistic pathogenic yeast that predominantly causes invasive candidiasis. Conventional methods for detecting Candida species are costly, take 3-5 days, and require skilled technicians. Rapid pathogen identification is important in managing invasive candidiasis infection. Here, a novel molecular diagnostic assay termed loop-mediated isothermal amplification combined with nanoparticles-based lateral flow biosensor (LAMP-LFB) was developed for C. albicans rapid detection. A set of six primers was designed based on the C. albicans species-specific internal transcribed spacer 2 (ITS2) gene. The C. albicans-LAMP results were visually reported by LFB within 2 min. Various fungal strains representing Candida species, as well as several Gram-negative and Gram-positive bacterial species, were used to determine the analytical sensitivity and specificity of the assay. The optimal LAMP conditions were 64 °C for 40 min, with a sensitivity of 1 fg of genomic DNA template from C. albicans pure cultures. No cross-reactions were obtained with non-albicans strains. Thus, the analytical specificity of the LAMP-LFB assay was 100%. The entire procedure could be completed within 85 min, including specimen processing (40 min), isothermal reaction (40 min), and result reporting (within 2 min). In 330 clinical samples (including 30 whole blood, 100 middle segment urine, and 200 sputum samples), all C. albicans-positive (62/330) samples were identified by LAMP-LFB assay, and the diagnostic accuracy was 100% when compared to the traditional clinical cultural-based methods. Thus, this assay can be used as a diagnostic tool for the rapid, accurate, sensitive, low-cost and specific detection of C. albicans strains, especially in resource-limited settings.
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Affiliation(s)
- Yu Wang
- Department of Clinical Laboratory, The First People’s Hospital of Guiyang, Guiyang, China
| | - Xue Zhao
- Department of Clinical Laboratory, The First People’s Hospital of Guiyang, Guiyang, China
| | - Yuhong Zhou
- School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China
| | - Jingrun Lu
- Department of Clinical Laboratory, The First People’s Hospital of Guiyang, Guiyang, China
| | - Honglan Yu
- Department of Clinical Laboratory, The First People’s Hospital of Guiyang, Guiyang, China
| | - Shijun Li
- Laboratory of Bacterial Infectious Disease of Experimental Center, Guizhou Provincial Centre for Disease Control and Prevention, Guiyang, China
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20
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Wang Y, Xu F, Nichols CB, Shi Y, Hellinga HW, Alspaugh JA, Distefano MD, Beese LS. Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase. J Med Chem 2022; 65:13753-13770. [PMID: 36218371 PMCID: PMC10755971 DOI: 10.1021/acs.jmedchem.2c00902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Infections by fungal pathogens are difficult to treat due to a paucity of antifungals and emerging resistances. Next-generation antifungals therefore are needed urgently. We have developed compounds that prevent farnesylation of Cryptoccoccus neoformans Ras protein by inhibiting protein farnesyltransferase with 3-4 nanomolar affinities. Farnesylation directs Ras to the cell membrane and is required for infectivity of this lethal pathogenic fungus. Our high-affinity compounds inhibit fungal growth with 3-6 micromolar minimum inhibitory concentrations (MICs), 4- to 8-fold better than Fluconazole, an antifungal commonly used in the clinic. Compounds bound with distinct inhibition mechanisms at two alternative, partially overlapping binding sites, accessed via different inhibitor conformations. We showed that antifungal potency depends critically on the selected inhibition mechanism because this determines the efficacy of an inhibitor at low in vivo levels of enzyme and farnesyl substrate. We elucidated how chemical modifications of the antifungals encode desired inhibitor conformation and concomitant inhibitory mechanism.
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Affiliation(s)
- You Wang
- Department of Biochemistry, Duke University School
of Medicine, Durham, North Carolina, USA 27710
| | - Feng Xu
- Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota, USA 55455
| | - Connie B. Nichols
- Department of Medicine, Duke University School of
Medicine, Durham, North Carolina, USA 27710
- Department of Molecular Genetics and Microbiology,
Duke University School of Medicine, Durham, North Carolina, USA 27710
| | - Yuqian Shi
- Department of Biochemistry, Duke University School
of Medicine, Durham, North Carolina, USA 27710
| | - Homme W. Hellinga
- Department of Biochemistry, Duke University School
of Medicine, Durham, North Carolina, USA 27710
| | - J. Andrew Alspaugh
- Department of Medicine, Duke University School of
Medicine, Durham, North Carolina, USA 27710
- Department of Molecular Genetics and Microbiology,
Duke University School of Medicine, Durham, North Carolina, USA 27710
| | - Mark D. Distefano
- Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota, USA 55455
| | - Lorena S. Beese
- Department of Biochemistry, Duke University School
of Medicine, Durham, North Carolina, USA 27710
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21
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Liu W, Li M, Xu Y, Wang F, Wang J, Wang H, Xu X, Wang Y, Sun H. Evaluation of the Performance of a Multiplex Real-Time PCR Assay for the Identification of Aspergillus, Cryptococcus neoformans, and Pneumocystis jirovecii Simultaneously from Sputum in Multicenter. Infect Drug Resist 2022; 15:6009-6017. [PMID: 36267265 PMCID: PMC9576602 DOI: 10.2147/idr.s379043] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 09/28/2022] [Indexed: 11/23/2022] Open
Abstract
PURPOSE To evaluate the performance of a multiplex real-time polymerase chain reaction (PCR) assay for the simultaneous identification of Aspergillus, Cryptococcus neoformans, and Pneumocystis jirovecii from sputum. PATIENTS AND METHODS Sputum samples (n=537) from patients with suspected invasive fungal infection (IFI) were collected from four centers; they were tested by both multiplex real-time PCR assay and DNA sequencing. DNA sequencing was considered as the reference method, and the performance of the multiplex real-time assay was evaluated by determining the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The interference experiment, repeatability, reproducibility, and stability of the multiplex real-time PCR assay were also evaluated. RESULTS The detection performance of the multiplex real-time assay, compared with that of DNA sequencing, for the three pathogens was as follows: sensitivity, specificity, PPV, and NPV for Aspergillus, Cryptococcus neoformans, and Pneumocystis jirovecii were 99.40%, 98.64%, 97.09%, and 99.73%; 100%, 99.59%, 96.36%, and 100.00%; and 99.28%, 98.50%, 95.80%, and 99.75%, respectively. The consistency of the two methods was almost perfect: the kappa value was between 0.97 and 0.98. The minimum detection limit of the multiplex real-time assay for each of the three pathogens was 1250 copies/mL. Interference experiment showed that blood and normally used antifungal drugs had no effect on the results. No cross-reactivity was detected for any bacteria or fungi. In 40 patients, mixed infections by Aspergillus and/or Cryptococcus neoformans and/or Pneumocystis jirovecii were detected by the multiplex real-time assay. Among these patients, those with acquired immune deficiency syndrome (AIDS) ranked first, with Aspergillus and Pneumocystis mixed infection accounting for 75%. CONCLUSION The multiplex real-time PCR assay is fast, sensitive, and specific and has good clinical application prospects.
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Affiliation(s)
- Wenjing Liu
- Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, 100730, People’s Republic of China
| | - Min Li
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
| | - Yingchun Xu
- Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, 100730, People’s Republic of China
| | - Fengchao Wang
- The First Affiliated Hospital of Bengbu Medical College, Anhui, 233004, People’s Republic of China
| | - Jing Wang
- Chongqing Public Health Medical Center, Chongqing, 400036, People’s Republic of China
| | - Huizhu Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
| | - Xinmin Xu
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
| | - Yajie Wang
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, People’s Republic of China
| | - Hongli Sun
- Department of Laboratory Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, 100730, People’s Republic of China
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22
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Yang Q, Xie J, Cai Y, Wang N, Wang Y, Zhang L, Li Y, Yu J, Li Y, Wang H, Zhang K. Efficacy and Safety of Combination Antifungals as Empirical, Preemptive, and Targeted Therapies for Invasive Fungal Infections in Intensive-Care Units. Infect Drug Resist 2022; 15:5331-5344. [PMID: 36110125 PMCID: PMC9470118 DOI: 10.2147/idr.s381851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose To determine whether combinations of antifungal drugs are effective and safe for patients in intensive-care units. Methods This study compared the efficacy and safety of caspofungin (CAS), voriconazole (VOR), amphotericin B liposome (L-AmB), CAS+VOR, and CAS+L-AmB as empirical, preemptive, and targeted therapies for invasive fungal infection (IFI). Results Comparing the CAS, VOR, and CAS+VOR groups revealed that there were no differences in response rates between all therapy types, IFI-associated death within 90 days was less common in the CAS+VOR group (1.8%) than the VOR group (14.3%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For empirical or preemptive therapy, the CAS group had a better response rate (80.0%) than the CAS+VOR group (47.1%), and there were more adverse events in the VOR group than in the CAS group (P < 0.05). For targeted therapy, no differences were found for efficacy and safety. There were no differences among the CAS, L-AmB, and CAS+L-AmB groups in efficacy and safety. Conclusion Patients who received CAS monotherapy as an empirical or preemptive therapy could achieve good outcomes. Patients who received CAS+VOR or CAS+L-AmB achieved almost the same outcomes when compared with those who received CAS, VOR, and L-AmB monotherapy as targeted therapies, but those who received CAS+VOR had a lower IFI mortality rate than did those who received VOR monotherapy.
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Affiliation(s)
- Qianting Yang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Jiao Xie
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Yan Cai
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Na Wang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Yan Wang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Li Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Youjia Li
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Jingjie Yu
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Ya Li
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Haitao Wang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
| | - Kanghuai Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
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23
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Perez-Rodriguez A, Eraso E, Quindós G, Mateo E. Antimicrobial Peptides with Anti-Candida Activity. Int J Mol Sci 2022; 23:ijms23169264. [PMID: 36012523 PMCID: PMC9409312 DOI: 10.3390/ijms23169264] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/10/2022] [Accepted: 08/13/2022] [Indexed: 02/06/2023] Open
Abstract
Mycoses are accountable for millions of infections yearly worldwide. Invasive candidiasis is the most usual, presenting a high morbidity and mortality. Candida albicans remains the prevalent etiologic agent, but the incidence of other species such as Candida parapsilosis, Candida glabrata and Candida auris keeps increasing. These pathogens frequently show a reduced susceptibility to commonly used antifungal drugs, including polyenes, triazoles and echinocandins, and the incidence of emerging multi-drug-resistant strains of these species continues to increase. Therefore, the need to search for new molecules that target these pathogenic species in a different manner is now more urgent than ever. Nature is an almost endless source of interesting new molecules that could meet this need. Among these molecules, antimicrobial peptides, present in different sources in nature, possess some advantages over conventional antifungal agents, even with their own drawbacks, and are considered as a promising pharmacological option against a wide range of microbial infections. In this review, we describe 20 antimicrobial peptides from different origins that possess an activity against Candida.
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24
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D’Auria FD, Casciaro B, De Angelis M, Marcocci ME, Palamara AT, Nencioni L, Mangoni ML. Antifungal Activity of the Frog Skin Peptide Temporin G and Its Effect on Candida albicans Virulence Factors. Int J Mol Sci 2022; 23:ijms23116345. [PMID: 35683025 PMCID: PMC9181532 DOI: 10.3390/ijms23116345] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 01/26/2023] Open
Abstract
The increasing resistance to conventional antifungal drugs is a widespread concern, and a search for new compounds, active against different species of fungi, is demanded. Antimicrobial peptides (AMPs) hold promises in this context. Here we investigated the activity of the frog skin AMP Temporin G (TG) against a panel of fungal strains, by following the Clinical and Laboratory Standards Institute protocols. TG resulted to be active against (i) Candida species and Cryptococcus neoformans, with MIC50 between 4 µM and 64 µM after 24 h of incubation; (ii) dermatophytes with MIC80 ranging from 4 to 32 µM, and (iii) Aspergillus strains with MIC80 of 128 µM. In addition, our tests revealed that TG reduced the metabolic activity of Candida albicans cells, with moderate membrane perturbation, as proven by XTT and Sytox Green assays, respectively. Furthermore, TG was found to be effective against some C. albicans virulence factors; indeed, at 64 µM it was able to inhibit ~90% of yeast-mycelial switching, strongly prevented biofilm formation, and led to a 50% reduction of metabolic activity in mature biofilm cells, and ~30-35% eradication of mature biofilm biomass. Even though further studies are needed to deepen our knowledge of the mechanisms of TG antifungal activity, our results suggest this AMP as an attractive lead compound for treatment of fungal diseases.
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Affiliation(s)
- Felicia Diodata D’Auria
- Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy; (F.D.D.); (M.D.A.); (M.E.M.); (A.T.P.)
| | - Bruno Casciaro
- Department of Biochemical Sciences, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy;
| | - Marta De Angelis
- Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy; (F.D.D.); (M.D.A.); (M.E.M.); (A.T.P.)
| | - Maria Elena Marcocci
- Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy; (F.D.D.); (M.D.A.); (M.E.M.); (A.T.P.)
| | - Anna Teresa Palamara
- Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy; (F.D.D.); (M.D.A.); (M.E.M.); (A.T.P.)
- Department of Infectious Diseases, Istituto Superiore di Sanità, 00161 Rome, Italy
| | - Lucia Nencioni
- Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy; (F.D.D.); (M.D.A.); (M.E.M.); (A.T.P.)
- Correspondence: (L.N.); (M.L.M.); Tel.: +39-0649914608 (L.N.); +39-0649910838 (M.L.M.)
| | - Maria Luisa Mangoni
- Department of Biochemical Sciences, Laboratory Affiliated to Istituto Pasteur Italia Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, Italy;
- Correspondence: (L.N.); (M.L.M.); Tel.: +39-0649914608 (L.N.); +39-0649910838 (M.L.M.)
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25
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Guo YL, Lu X, Zhu L, Du DF, Liu B, Chen ZHK, Chen S, Zhang WJ, Chen ZS, Chang S. Infective Artery Rupture of Renal Allografts: A Single-Center Retrospective Study in China. Curr Med Sci 2022; 42:847-855. [PMID: 35511412 DOI: 10.1007/s11596-022-2557-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 08/18/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVE This study investigated the composition of pathogenic microorganisms, clinical features, and therapeutic strategies of infective artery rupture of renal allografts in recipients receiving deceased donor (DD) kidneys. METHODS We retrospectively studied the clinical data of the DD kidney transplant recipients with donor-associated infection at Tongji Hospital, Wuhan, China from January 1, 2015 to December 31, 2018, related recipients and corresponding donors. We collected the entire results of pathogenic microorganisms cultured from these related ruptured kidneys and then analyzed their distribution and differences. RESULTS A total of 1440 kidney transplants from DD were performed in our center. The total incidence of infective artery rupture in kidney transplants was about 0.76% (11/1440), and the annual incidence ranged from 0.25% to 1.03%. The microbial culture results revealed that 11 recipients suffered from infective artery rupture and 3 recipients who accepted the kidney from same donor had the donor-associated pathogens, including 9 fungal strains (28.1%) and 23 bacterial strains (71.9%). There were 4 recipients infected with multi-drug-resistant Staphylococcus and Klebsiella pneumoniae from the above 11 recipients, of which, 10 recipients underwent graft loss, and one died of septic shock. The microbial cultures of the remaining 3 recipients who received appropriate anti-infective regimens turned negative eventually, and the patients were discharged successfully without significant complications. CONCLUSION Renal recipients with infections derived from DDs were at high risk of artery rupture, graft loss, or even death. Appropriate anti-infective treatment is essential to reduce the incidence of artery rupture and mortality.
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Affiliation(s)
- Yu-Liang Guo
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Xia Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Dun-Feng Du
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Bin Liu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Zhong-Hua Klaus Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Wei-Jie Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Zhi-Shui Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China.,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China.,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Sheng Chang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. .,Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, 430030, China. .,NHC Key Laboratory of Organ Transplantation, Wuhan, 430030, China. .,Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China.
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26
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Xu S, Zhang G, Wang M, Lin T, Liu W, Wang Y. Phage nanoparticle as a carrier for controlling fungal infection. Appl Microbiol Biotechnol 2022; 106:3397-3403. [PMID: 35501488 DOI: 10.1007/s00253-022-11932-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 04/19/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022]
Abstract
A mass of nanocarriers have been exploited and utilized for prevention of fungi, including organic nanomaterials, inorganic nanoparticles, polypeptides, and viruses. Due to biological safety and flexible genetic engineering property, bacteriophages, as bionanoparticles, are widely used in the diagnosis and treatment of microorganisms, which can be easily loaded with proteins and drugs. In particular, random DNAs can be inserted into the genome of phage by phage display technology, and it is possible to obtain the peptide/antibody targeting fungi from phage library. Meanwhile, phages displaying specific peptides are able to conjugate with other nanoparticles, which have both characteristics of peptides and nanomaterials, and have been used for precise detection of fungi. Additionally, phage nanomaterials as carriers can reduce the toxicity of drugs, increase the time of drug circulation, stimulate the immune response, and have an anti-fungal effect by itself. In this review, we summarize the recent applications of bacteriophages on the study of fungi. The improvement of our understanding of bacteriophage will supply new tools for controlling fungal infections. These phage libraries were used to pan the specific peptides for diagnosis, prevention, and treatment of fungi. KEY POINTS: • System fungal infection has no significant clinical symptoms; it is important to develop vaccine, diagnosis, and therapeutic agents to reduce mortality; phage is an ideal carrier for vaccine and drug to stimulate immune response and improve the efficiency of drug, and also can improve the sensitivity of detection • This review summarized recent studies on phage-based fungal vaccine and threw light on the developing therapeutic phage in the treatment of fungal infection.
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Affiliation(s)
- Songbai Xu
- Department Neurosurg, First Hospital Jilin University, Changchun, People's Republic of China
| | - Guangxin Zhang
- Jilin Provincial Key Laboratory On Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Meng Wang
- Department of Respiratory Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People's Republic of China
| | - Tie Lin
- Department of Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Wei Liu
- Jilin Provincial Key Laboratory On Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, People's Republic of China
| | - Yicun Wang
- Jilin Provincial Key Laboratory On Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, People's Republic of China.
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27
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Su Q, Pan J, Zhang L, Xia L, Gao Y, Li J. Observation of Voriconazole in the Treatment of Liver Failure Complicated With Invasive Pulmonary Fungal Infection Induced by Chinese Patent Medicine in Teenagers: 2 Case Reports. Front Pharmacol 2022; 13:862222. [PMID: 35517824 PMCID: PMC9065283 DOI: 10.3389/fphar.2022.862222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/16/2022] [Indexed: 12/05/2022] Open
Abstract
Background: Drug-induced liver injury (DILI) caused by Chinese patent medicines is increasing in China. The incidence of invasive fungal infections (IFIs) is increasing due to the suppression of the immune function in greater numbers of patients. Invasive procedures such as deep vein catheterization and the use of glucocorticoids are also predisposing factors to IFIs. The clinical presentation of IFI in teenagers is often atypical, challenging to diagnose, difficult to treat, and associated with a high fatality rate. Case presentation: Herein, we report 2 teenagers with liver failure after receiving oral Chinese patent medicines. Case 1 was a 14-year-old boy who presented with subacute liver failure who had been administered a Chinese patent medicine that included acetaminophen. Administration of glucocorticoids and non-bioartificial liver treatment improved his condition. Subsequently, invasive pulmonary Aspergillus (IPA) was diagnosed and was successfully treated with voriconazole for 85 days. Case 2 was a 17-year-old girl who presented with acute liver failure after taking the Chinese patent medicine QubaiBabuqi tablets for vitiligo. Chest computed tomography (CT) revealed multiple pulmonary nodules with an intermittent low-grade fever, and she was diagnosed with IPA. She was initially treated with caspofungin (23 days) and then voriconazole (406 days) for 429 days. Her liver function returned to normal, and lung lesions were absorbed in 2 patients. At the same time, two to three histopathological examinations of the liver biopsy showed that the drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy. Conclusion: To the best of our knowledge, this is the first report of the successful treatment of 2 cases of liver failure (Child-Pugh class C) caused by Chinese patent medicines complicated with IPA in teenagers. Drug-induced autoimmune-like phenomena could be improved by glucocorticoid therapy.
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Affiliation(s)
| | | | | | | | | | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, China
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28
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Antifungal Strategy in Patients with Invasive Fungal Disease Associated with Hematological Malignancies Based on Risk Stratification. THE CANADIAN JOURNAL OF INFECTIOUS DISEASES & MEDICAL MICROBIOLOGY = JOURNAL CANADIEN DES MALADIES INFECTIEUSES ET DE LA MICROBIOLOGIE MEDICALE 2022; 2022:1743596. [PMID: 35432663 PMCID: PMC9010196 DOI: 10.1155/2022/1743596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 03/05/2022] [Accepted: 03/22/2022] [Indexed: 01/11/2023]
Abstract
Patients with hematological malignancies (HM) often develop the invasive fungal disease (IFD), causing important morbidity/mortality. While treatment guidelines are available, risk stratification models for optimizing antifungal therapy strategies are few. Clinical records from 458 HM patients with IFD were retrospectively analyzed. Following Chinese treatment guidelines, patients received empirical (n = 239) or diagnostic-driven therapy (n = 219). The effectiveness rate was 87.9% for the empirical and 81.7% for the diagnostic-driven therapy groups (P ≥ 0.05). The incidence of adverse reactions was 18.4% and 16.9%, respectively (P ≥ 0.05). All risk factors of IFD in HM patients were estimated in the univariate analyses and multivariate analyses by the chi-square test and logistic regression model. Duration ≥14 days (OR = 18.340, P=0.011), relapsed/refractory disease (OR = 11.670, P=0.005), IFD history (OR = 5.270, P=0.021), and diabetes (OR = 3.120, P=0.035) were significantly associated with IFD in the multivariate analysis. Patients with more than 3 of these factors have a significant difference in effective rates between the empirical (85.7%) and diagnostic-driven (41.6%) therapy (P=0.008). Empirical and diagnostic-driven therapy effective rates were 80.6% and 70.9% in the patients with two risk factors (P > 0.05) and 85.1% and 85.4% in the patients with one risk factor (P > 0.05). Thus, there was no significant difference in effectiveness in patients with one or two risk factors. The abovementioned risk stratification can guide clinical antifungal therapy. The patients with 3 or more risk factors benefit from empirical therapy.
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Rafiq M, Rivieccio F, Zimmermann AK, Visser C, Bruch A, Krüger T, González Rojas K, Kniemeyer O, Blango MG, Brakhage AA. PLB-985 Neutrophil-Like Cells as a Model To Study Aspergillus fumigatus Pathogenesis. mSphere 2022; 7:e0094021. [PMID: 34986319 PMCID: PMC8730815 DOI: 10.1128/msphere.00940-21] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 12/13/2021] [Indexed: 11/20/2022] Open
Abstract
Fungal infections remain a major global concern. Emerging fungal pathogens and increasing rates of resistance mean that additional research efforts and resources must be allocated to advancing our understanding of fungal pathogenesis and developing new therapeutic interventions. Neutrophilic granulocytes are a major cell type involved in protection against the important fungal pathogen Aspergillus fumigatus, where they employ numerous defense mechanisms, including production of antimicrobial extracellular vesicles. A major drawback to work with neutrophils is the lack of a suitable cell line system for the study of fungal pathogenesis. To address this problem, we assessed the feasibility of using differentiated PLB-985 neutrophil-like cells as an in vitro model to study A. fumigatus infection. We find that dimethylformamide-differentiated PLB-985 cells provide a useful recapitulation of many aspects of A. fumigatus interactions with primary human polymorphonuclear leukocytes. We show that differentiated PLB-985 cells phagocytose fungal conidia and acidify conidia-containing phagolysosomes similar to primary neutrophils, release neutrophil extracellular traps, and also produce antifungal extracellular vesicles in response to infection. In addition, we provide an improved method for the isolation of extracellular vesicles produced during infection by employing a size exclusion chromatography-based approach. Advanced liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics revealed an enrichment of extracellular vesicle marker proteins and a decrease of cytoplasmic proteins in extracellular vesicles isolated using this improved method. Ultimately, we find that differentiated PLB-985 cells can serve as a genetically tractable model to study many aspects of A. fumigatus pathogenesis. IMPORTANCE Polymorphonuclear leukocytes are an important defense against human fungal pathogens, yet our model systems to study this group of cells remain very limited in scope. In this study, we established that differentiated PLB-985 cells can serve as a model to recapitulate several important aspects of human polymorphonuclear leukocyte interactions with the important human fungal pathogen Aspergillus fumigatus. The proposed addition of a cultured neutrophil-like cell line to the experimental toolbox to study fungal pathogenesis will allow for a more mechanistic description of neutrophil antifungal biology. In addition, the easier handling of the cell line compared to primary human neutrophils allowed us to use PLB-985 cells to provide an improved method for isolation of neutrophil-derived extracellular vesicles using size exclusion chromatography. Together, these results provide significant tools and a baseline knowledge for the future study of neutrophil-derived extracellular vesicles in the laboratory.
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Affiliation(s)
- Muhammad Rafiq
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Flora Rivieccio
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Ann-Kathrin Zimmermann
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Corissa Visser
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Alexander Bruch
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Thomas Krüger
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Katherine González Rojas
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Olaf Kniemeyer
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Matthew G. Blango
- Junior Research Group RNA Biology of Fungal Infections, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
| | - Axel A. Brakhage
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (Leibniz-HKI), Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Friedrich Schiller University, Jena, Germany
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Busca A, Cinatti N, Gill J, Passera R, Dellacasa CM, Giaccone L, Dogliotti I, Manetta S, Corcione S, De Rosa FG. Management of Invasive Fungal Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: The Turin Experience. Front Cell Infect Microbiol 2022; 11:805514. [PMID: 35071052 PMCID: PMC8782257 DOI: 10.3389/fcimb.2021.805514] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Accepted: 12/13/2021] [Indexed: 02/03/2023] Open
Abstract
Background Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are exposed to an increased risk of invasive fungal infections (IFIs) due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GvHD) and incomplete immune reconstitution. Although clinical benefit from antifungal prophylaxis has been demonstrated, IFIs remain a leading cause of morbidity and mortality in these patients. In the last decades, attention has also been focused on potential risk factors for IFI to tailor an antifungal prevention strategy based on risk stratification. Aim of the Study This retrospective single-center study aimed to assess the epidemiology and the prognostic factors of IFI in a large cohort of allo-HSCT patients. Methods Between January 2004 and December 2020, 563 patients with hematological malignancies received an allo-HSCT at the Stem Cell Transplant Unit in Turin: 191 patients (34%) received grafts from a matched sibling donor, 284 (50.5%) from a matched unrelated donor, and 87 (15.5%) from an haploidentical family member. The graft source was peripheral blood in 81.5% of the patients. Our policy for antifungal prophylaxis included fluconazole in matched related and unrelated donors, while micafungin was administered in patients receiving haploidentical transplant. According to this practice, fluconazole was administered in 441 patients (79.6%) and micafungin in 62 (11.2%), while only 9 patients received mold-active prophylaxis. Galactomannan testing was routinely performed twice a week; patients with persisting fever unresponsive to broad spectrum antibiotics were evaluated with lung high-resolution computed tomography (HRCT) scan. In case of imaging suggestive of IFI, bronchoalveolar lavage (BAL) was performed whenever feasible. Statistical Analysis Only probable/proven IFI (PP-IFI) occurring during the first 12 months after transplant have been evaluated. IFIs were classified as probable or proven according to the new revised European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) consensus criteria. Multivariate competing risk regression, binary logistic, and proportional hazard models were performed to identify risk factors for PP-IFI. Results A total of 58 PP-IFIs (n = 47 probable; n = 11 proven) occurred in our patients resulting in a cumulative incidence of 4.1%, 8.1%, and 9.6% at 30, 180, and 365 days, respectively. Molds were the predominant agents (n = 50 Aspergillus; n = 1 Mucor), followed by invasive candidemia (n = 5 non-albicans Candida; n = 1 Candida albicans; n = 1 Trichosporon). Lung was the most frequent site involved in patients with mold infections (47/51, 92.2%). Median time from HSCT to IFI was 98.44 days (0–365 days). Only 34.5% of patients with IFI were neutropenic at the time of infection. The presence of IFI had a significant impact on overall survival at 1 year (IFI, 32.8% vs. non-IFI, 54.6%; p < 0.001). IFI-related mortality rate was 20.7% in the overall population, 17% in patients with probable IFI, and 36% in patients with proven IFI. Multivariate competing risk regression revealed that donor type was the factor significantly associated to the risk of IFI [subdistribution hazard ratio (SDHR), 1.91, IC 1.13–3.20; p = 0.015]. BAL was informative in a consistent number of cases (36/57, 63.2%) leading to the identification of fungal (21), bacterial (4), viral (3), and polymicrobial (8) infections. Overall, 79 patients (14%) received a diagnostic-driven treatment, and 63 patients (11.2%) received a fever-driven treatment. Liposomal amphoteric B was the drug used in the majority of patients receiving diagnostic-driven therapy (30/79, 38%), while caspofungin was administered more frequently in patients who received a fever-driven strategy (27/63, 42.9%). Conclusion According to our experience, a non-mold active prophylaxis in patients undergoing allo-HSCT is feasible when combined with an intensive diagnostic work-up including CT scan and BAL. BAL performed at the onset of the disease may provide informative results in most patients. A diagnostic-driven treatment strategy may contribute to limit the use of costly antifungal therapies.
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Affiliation(s)
- Alessandro Busca
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Natascia Cinatti
- Department of Medical Sciences, Division of Internal Medicine, University of Turin, Turin, Italy
| | - Jessica Gill
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy.,Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy
| | - Roberto Passera
- Department of Medical Sciences, Division of Nuclear Medicine, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Chiara Maria Dellacasa
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Luisa Giaccone
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy.,Department of Molecular Biotechnology and Health Sciences, Division of Hematology, University of Turin, Turin, Italy
| | - Irene Dogliotti
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Sara Manetta
- Department of Oncology, SSD Trapianto Allogenico di Cellule Staminali, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, Turin, Italy
| | - Silvia Corcione
- Department of Medical Sciences, Division of Infectious Diseases, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Francesco Giuseppe De Rosa
- Department of Medical Sciences, Division of Infectious Diseases, Azienda Ospedaliera Universitaria (A.O.U.) Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
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Salehi M, Ghaderkhani S, Sharifian RA, Dehghan Manshadi SA, Samiee Fard E, Khodavaisy S, Pourahmad R, Foroushani AR, Rodini K, Kamali Sarvestani H. The Value of Nasal and Oral Clinical Examination in Febrile Neutropenic Patients for Initiating Antifungal Therapy as a Preemptive Method. Front Med (Lausanne) 2022; 8:803600. [PMID: 35155481 PMCID: PMC8835583 DOI: 10.3389/fmed.2021.803600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/23/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Invasive fungal infections (IFIs) are complications that lead to mortality and morbidity in hematologic malignancies. The time of starting antifungal therapy is vital. Preemptive antifungal therapy has appeared recently as a new policy for the management of IFIs based on noninvasive ways in neutropenic patients. METHODS We enrolled leukemia patients with neutropenia after chemotherapy in Imam Khomeini Hospital Complex, Tehran, Iran. Patients who entered the neutropenic phase were divided into two categories (empirical and preemptive) for receiving antifungal agents. The patients were clinically examined in the preemptive group every day to find IFIs. As soon as clinical evidence of IFIs was observed, antifungal was prescribed. The empirical group patients received antifungals based on the ward protocol. Based on the data in each group, the diagnostic and therapeutic results of cases are followed-up to 3 months. To compare percentages between the two groups, the chi-squared test was used. And to compare two means between the two groups, the independent t-test was used. All the statistical analyses were done in the Statistical Package for the Social Sciences (SPSS) version 24 software (IBM Corporation, Armonk, New York, USA). RESULTS We assessed 132 leukemic patients with inclusion and exclusion criteria. Eventually, 80 patients were enrolled. The mean age was 35.52 years. Demographics data and distribution of leukemia type show no significant differences between the two groups. Despite a higher percentage of IFIs discovered in the preemptive group than the empirical group (25 vs. 18.75%, respectively), but data show no significant differences. The average days of IFIs diagnosis since the beginning of neutropenia in the empirical group were 9.5 days while in the preemptive group, the average days were 5.4 days (p < 0.05). Totally, there were 15 patients with a proven IFI in each group (40% in the empirical group and 60% in the preemptive group). Results significantly show an increase in surgical sinus debridement in the empirical groups (83.3%) vs. the preemptive groups (55.5%), (p < 0.05). The mortality rate differed significantly among the two groups; it was 7.5% in the preemptive group and 25% in the empirical group (p < 0.05). CONCLUSION Daily oral and nasal cavities examination to find the symptoms of IFIs and then start preemptive antifungal agents may be able to lead to accurate diagnosis, earlier treatment, and decreasing sinus surgery debridement in leukemia patients with neutropenia.
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Affiliation(s)
- Mohammadreza Salehi
- Department of Infectious Disease, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Sara Ghaderkhani
- Department of Infectious Disease, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramezan Ali Sharifian
- Department of Internal Medicine, Imam Khomeini Hospital Complex, Hematology and Oncology Ward, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Ali Dehghan Manshadi
- Department of Infectious Disease, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Elahe Samiee Fard
- Department of Infectious Disease, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Sadegh Khodavaisy
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramtin Pourahmad
- Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Abbas Rahimi Foroushani
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Kamran Rodini
- Department of Internal Medicine, Imam Khomeini Hospital Complex, Hematology and Oncology Ward, Tehran University of Medical Sciences, Tehran, Iran
| | - Hasti Kamali Sarvestani
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Amir A, Levin-Khalifa M, Dvash T. Water-Soluble Nystatin and Derivative. ACS Med Chem Lett 2022; 13:182-187. [PMID: 35178173 PMCID: PMC8842097 DOI: 10.1021/acsmedchemlett.1c00538] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/13/2022] [Indexed: 11/28/2022] Open
Abstract
Fungal infections are increasingly causing more morbidity and mortality, especially for immunocompromised people. In recent years, there is growing evidence that new medicine-resistant fungal strains are posing added challenges in the clinic. Nystatin is a known antifungal from the polyene family. Due to Nystatin limited solubility and high toxicity, it is used mainly to treat oral and dermal fungal infections. In search for new Nystatin derivatives and formulations, we obtained amide derivatives and a deoxycholate formulation that were not described previously for this compound. Furthermore, we tested the potency of the derivatives and formulation by the USP(81) method and minimum inhibitory concentration of Candida albicans and Aspergillus niger. Additionally, the in vitro toxicity and stability were tested, and it was found that the ethanol amide derivative of Nystatin was fully water-soluble (up to 100 mg/mL) with the same potency of Nystatin but with 13.5 times lower toxicity. The ethanol amide derivative of Nystatin is a promising candidate for future drug development.
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Gao Y, Qu M, Song C, Yin L, Zhang M. Cerebral vasculitis caused by Talaromyces marneffei and Aspergillus niger in a HIV-positive patient: a case report and literature review. J Neurovirol 2022; 28:274-280. [PMID: 34981436 PMCID: PMC9187570 DOI: 10.1007/s13365-021-01032-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 10/27/2021] [Accepted: 11/27/2021] [Indexed: 11/29/2022]
Abstract
Cerebral vasculitis is a long-standing but flourishing and fadeless research topic. Infections are a frequent cause of cerebral vasculitis, vital to diagnose due to involvement of specific anti-infection treatments. A 65-year-old man visited the hospital for his neurological symptoms without obvious inducements. After admission, radiological examination and comprehensive conventional microbiological tests (CMTs) revealed suspected intracranial infectious vasculitis. Metagenomic next-generation sequencing (mNGS) and reverse transcription-polymerase chain reaction further confirmed that his cerebral vasculitis was caused by Talaromyces marneffei (T. marneffei) and Aspergillus niger (A. niger) co-infection. The patient’s final diagnosis changed from initial herpetic encephalitis, due to the past history of cephalosome and facial herpes and non-significant antiviral therapeutic effects, to fungal cerebral vasculitis. The patient was discharged after use of targeted antifungal therapies on day 18 of his admission, and his associated symptoms disappeared completely at follow-up 3 weeks later. We first illustrated the presence of uncommon cerebral vasculitis caused by T. marneffei and A. niger in a human immunodeficiency virus-positive patient. In clinically suspected patients with infectious cerebral vasculitis, mNGS should be performed to detect potential pathogens if CMTs may not provide useful pathogenic clues, highlighting the importance of mNGS in the diagnosis and treatment of infectious diseases.
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Affiliation(s)
- Yidong Gao
- Department of Encephalopathy, The Third People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fujian, 350122, Fuzhou, China
| | - Man Qu
- The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co. Ltd., Nanjing, 210042, China
| | - Chao Song
- The State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co. Ltd., Nanjing, 210042, China
| | - Lufeng Yin
- Department of Encephalopathy, The Third People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fujian, 350122, Fuzhou, China
| | - Min Zhang
- Department of Encephalopathy, The Third People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine, Fujian, 350122, Fuzhou, China.
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Luberto L, Neroni B, Gandini O, Fiscarelli EV, Salvatori G, Roscilli G, Marra E. Genetic Vaccination as a Flexible Tool to Overcome the Immunological Complexity of Invasive Fungal Infections. Front Microbiol 2021; 12:789774. [PMID: 34975811 PMCID: PMC8715041 DOI: 10.3389/fmicb.2021.789774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/25/2021] [Indexed: 11/13/2022] Open
Abstract
The COVID-19 pandemic has highlighted genetic vaccination as a powerful and cost-effective tool to counteract infectious diseases. Invasive fungal infections (IFI) remain a major challenge among immune compromised patients, particularly those undergoing allogeneic hematopoietic bone marrow transplantation (HSCT) or solid organ transplant (SOT) both presenting high morbidity and mortality rates. Candidiasis and Aspergillosis are the major fungal infections among these patients and the failure of current antifungal therapies call for new therapeutic aids. Vaccination represents a valid alternative, and proof of concept of the efficacy of this approach has been provided at clinical level. This review will analyze current understanding of antifungal immunology, with a particular focus on genetic vaccination as a suitable strategy to counteract these diseases.
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Affiliation(s)
- Laura Luberto
- Takis s.r.l., Rome, Italy
- *Correspondence: Laura Luberto,
| | - Bruna Neroni
- Cystic Fibrosis Diagnostic Section, U.O. Microbiology and Immunology Diagnostic, Department of Immunology and Laboratory Medicine, Children’s Hospital Bambino Gesù Organization IRCCS, Rome, Italy
| | - Orietta Gandini
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Ersilia Vita Fiscarelli
- Cystic Fibrosis Diagnostic Section, U.O. Microbiology and Immunology Diagnostic, Department of Immunology and Laboratory Medicine, Children’s Hospital Bambino Gesù Organization IRCCS, Rome, Italy
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Su CF, Lai CC, Li TH, Chang YF, Lin YT, Chen WS, Tsao YP, Wang WH, Chang YS, Tsai CY. Epidemiology and risk of invasive fungal infections in systemic lupus erythematosus: a nationwide population-based cohort study. Ther Adv Musculoskelet Dis 2021; 13:1759720X211058502. [PMID: 34840609 PMCID: PMC8613894 DOI: 10.1177/1759720x211058502] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 10/14/2021] [Indexed: 12/14/2022] Open
Abstract
Introduction Infections are a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Among various infections, invasive fungal infections (IFIs) have a particularly high mortality rate; however, studies examining IFIs in patients with SLE are limited. Methods Patients diagnosed as having SLE between 1997 and 2012 were enrolled from Taiwan's National Health Insurance Research Database along with age- and sex-matched non-SLE controls at a ratio of 1:10. IFIs were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and validated by the prescriptions of systemic antifungal agents. The incidence rate (IR), incidence rate ratio (IRR), and all-cause mortality rate of IFIs and its subtypes were analyzed. A Cox multivariate regression model with time-dependent covariates was applied to analyze independent risk factors for IFIs. Results A total of 24,541 patients with SLE and 245,410 non-SLE controls were included. We observed 445 IFI episodes in the SLE cohort, with an all-cause mortality rate of 26.7%. Candida spp. (52.8%) was the most common pathogen, followed by Cryptococcus spp. (18.2%) and Aspergillus spp. (18.2%). The IR of IFIs in the SLE cohort was 20.83 per 10,000 person-years, with an IRR of 11.1 [95% confidence interval (CI): 9.8-12.6] relative to the non-SLE controls. Juvenile patients with SLE aged ⩽18 years had the highest IRR of 47.2 (95% CI: 26.9-86.8). Intravenous steroid therapy administered within 60 days (hazard ratio: 29.11, 95% CI: 23.30-36.37) was the most critical risk factor for overall IFIs and each of the three major fungal pathogens. Distinct risk factors were found among different IFI subtypes. Conclusion Patients with SLE had a higher risk of IFIs, especially juvenile patients. Intravenous steroid therapy is the most critical risk factor for IFIs. This study provides crucial information for the risk stratification of IFIs in SLE. Plain Language Summaries Patients with systemic lupus erythematosus and physicians treating this patient group should be aware of the risk of invasive fungal infections.Invasive fungal infections (IFIs) are a severe complication with a high mortality rate among patients with systemic lupus erythematosus (SLE); however, studies on this topic are scant. We performed a nationwide population-based study in Taiwan to estimate the incidence and mortality of and risk factors for IFIs. We found an incidence rate of 20.83 per 10,000 person-years for IFIs, with a mortality rate of 26.7%. Juvenile patients aged ⩽18 years had the highest relative risk of IFIs. Although candidiasis was the most common IFI, cryptococcosis and aspergillosis should be concerned in juvenile patients as well. Intravenous steroid therapy was the most critical risk factor for all IFIs, and different immunosuppressive agents posed different risks in patients for acquiring certain fungal pathogens.Our findings provide pivotal epidemiological information and indicate risk factors for IFIs in patients with SLE. Age and exposure to specific immunosuppressants and steroids might help predict the risk of IFIs. Because the manifestation of these infections is sometimes indistinguishable from a lupus flare, physicians should be aware of this fatal complication, especially when patients are not responsive to immunosuppressive therapy. Early recognition, implication of diagnostic tools, and empirical antimicrobial agents can be the key to treating patients with IFIs. Additional studies are required to develop a risk management program for patients with SLE.
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Affiliation(s)
- Chin-Fang Su
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei
| | - Chien-Chih Lai
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei
| | - Yu-Fan Chang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei
| | - Yi-Tsung Lin
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei
| | - Wei-Sheng Chen
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei
| | - Yen-Po Tsao
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei
| | - Wen-Hsiu Wang
- Department of Medicine, Mackay Medical College, New Taipei City
| | - Yu-Sheng Chang
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, No. 291, Zhongzheng Road, Zhonghe District, New Taipei City 23561
| | - Chang-Youh Tsai
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei
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Preparation and Antimicrobial Activity of Chitosan and Its Derivatives: A Concise Review. Molecules 2021; 26:molecules26123694. [PMID: 34204251 PMCID: PMC8233993 DOI: 10.3390/molecules26123694] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 12/12/2022] Open
Abstract
Despite the advantages presented by synthetic polymers such as strength and durability, the lack of biodegradability associated with the persistence in the environment for a long time turned the attention of researchers to natural polymers. Being biodegradable, biopolymers proved to be extremely beneficial to the environment. At present, they represent an important class of materials with applications in all economic sectors, but also in medicine. They find applications as absorbers, cosmetics, controlled drug delivery, tissue engineering, etc. Chitosan is one of the natural polymers which raised a strong interest for researchers due to some exceptional properties such as biodegradability, biocompatibility, nontoxicity, non-antigenicity, low-cost and numerous pharmacological properties as antimicrobial, antitumor, antioxidant, antidiabetic, immunoenhancing. In addition to this, the free amino and hydroxyl groups make it susceptible to a series of structural modulations, obtaining some derivatives with different biomedical applications. This review approaches the physico-chemical and pharmacological properties of chitosan and its derivatives, focusing on the antimicrobial potential including mechanism of action, factors that influence the antimicrobial activity and the activity against resistant strains, topics of great interest in the context of the concern raised by the available therapeutic options for infections, especially with resistant strains.
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Karavalakis G, Yannaki E, Papadopoulou A. Reinforcing the Immunocompromised Host Defense against Fungi: Progress beyond the Current State of the Art. J Fungi (Basel) 2021; 7:jof7060451. [PMID: 34204025 PMCID: PMC8228486 DOI: 10.3390/jof7060451] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 12/11/2022] Open
Abstract
Despite the availability of a variety of antifungal drugs, opportunistic fungal infections still remain life-threatening for immunocompromised patients, such as those undergoing allogeneic hematopoietic cell transplantation or solid organ transplantation. Suboptimal efficacy, toxicity, development of resistant variants and recurrent episodes are limitations associated with current antifungal drug therapy. Adjunctive immunotherapies reinforcing the host defense against fungi and aiding in clearance of opportunistic pathogens are continuously gaining ground in this battle. Here, we review alternative approaches for the management of fungal infections going beyond the state of the art and placing an emphasis on fungus-specific T cell immunotherapy. Harnessing the power of T cells in the form of adoptive immunotherapy represents the strenuous protagonist of the current immunotherapeutic approaches towards combating invasive fungal infections. The progress that has been made over the last years in this field and remaining challenges as well, will be discussed.
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Affiliation(s)
- Georgios Karavalakis
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
| | - Evangelia Yannaki
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Anastasia Papadopoulou
- Hematology Department-Hematopoietic Cell Transplantation Unit, Gene and Cell Therapy Center, “George Papanikolaou” Hospital, 57010 Thessaloniki, Greece; (G.K.); (E.Y.)
- Correspondence: ; Tel.: +30-2313-307-693; Fax: +30-2313-307-521
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Renzi DF, de Almeida Campos L, Miranda EH, Mainardes RM, Abraham WR, Grigoletto DF, Khalil NM. Nanoparticles as a Tool for Broadening Antifungal Activities. Curr Med Chem 2021; 28:1841-1873. [PMID: 32223729 DOI: 10.2174/0929867327666200330143338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/28/2020] [Accepted: 03/09/2020] [Indexed: 11/22/2022]
Abstract
Fungal infections are diseases that are considered neglected although their infection rates have increased worldwide in the last decades. Thus, since the antifungal arsenal is restricted and many strains have shown resistance, new therapeutic alternatives are necessary. Nanoparticles are considered important alternatives to promote drug delivery. In this sense, the objective of the present study was to evaluate the contributions of newly developed nanoparticles to the treatment of fungal infections. Studies have shown that nanoparticles generally improve the biopharmaceutical and pharmacokinetic characteristics of antifungals, which is reflected in a greater pharmacodynamic potential and lower toxicity, as well as the possibility of prolonged action. It also offers the proposition of new routes of administration. Nanotechnology is known to contribute to a new drug delivery system, not only for the control of infectious diseases but for various other diseases as well. In recent years, several studies have emphasized its application in infectious diseases, presenting better alternatives for the treatment of fungal infections.
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Affiliation(s)
- Daniele Fernanda Renzi
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
| | - Laís de Almeida Campos
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
| | - Eduardo Hösel Miranda
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
| | - Rubiana Mara Mainardes
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
| | - Wolf-Rainer Abraham
- Helmholtz Center for Infection Research, Chemical Microbiology, Inhoffenstraße 7, 38124 Braunschweig, Germany
| | - Diana Fortkamp Grigoletto
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
| | - Najeh Maissar Khalil
- Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda Élio Antonio Dalla Vecchia, 838 - CEP 85040-167, Guarapuava-PR, Brazil
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Dunne MR, Wagener J, Loeffler J, Doherty DG, Rogers TR. Unconventional T cells - New players in antifungal immunity. Clin Immunol 2021; 227:108734. [PMID: 33895356 DOI: 10.1016/j.clim.2021.108734] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 04/06/2021] [Accepted: 04/20/2021] [Indexed: 12/29/2022]
Abstract
Life-threatening invasive fungal diseases (IFD) are increasing in incidence, especially in immunocompromised patients and successful resolution of IFD requires a variety of different immune cells. With the limited repertoire of available antifungal drugs there is a need for more effective therapeutic strategies. This review interrogates the evidence on the human immune response to the main pathogens driving IFD, with a focus on the role of unconventional lymphocytes e.g. natural killer (NK) cells, gamma/delta (γδ) T cells, mucosal associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILC). Recent discoveries and new insights into the roles of these novel lymphocyte groups in antifungal immunity will be discussed, and we will explore how an improved understanding of antifungal action by lymphocytes can inform efforts to improve antifungal treatment options.
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Affiliation(s)
- Margaret R Dunne
- Department of Clinical Microbiology, Trinity College Dublin, Sir Patrick Dun Research Laboratory, St James's Hospital, Dublin 8, Ireland; Department of Immunology, School of Medicine, Trinity College Dublin, Dublin 8, Ireland.
| | - Johannes Wagener
- Department of Clinical Microbiology, Trinity College Dublin, Sir Patrick Dun Research Laboratory, St James's Hospital, Dublin 8, Ireland
| | - Juergen Loeffler
- Department of Internal Medicine II, WÜ4i, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Derek G Doherty
- Department of Immunology, School of Medicine, Trinity College Dublin, Dublin 8, Ireland
| | - Thomas R Rogers
- Department of Clinical Microbiology, Trinity College Dublin, Sir Patrick Dun Research Laboratory, St James's Hospital, Dublin 8, Ireland
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Sá NPD, Barros PPD, Junqueira JC, Valério AD, Lino CI, Oliveira RBD, Rosa CA, Johann S. Antivirulence activity and in vivo efficacy of a thiazole derivative against candidiasis. J Mycol Med 2021; 31:101134. [PMID: 33862540 DOI: 10.1016/j.mycmed.2021.101134] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022]
Abstract
Candida albicans is a pathogen equipped with a variety of commensal and virulence traits that help it colonize the microbiota and invade host tissue during infection. In this study, we investigated the potential anticandidal activity of 3-[2-(4-(4-methoxyphenyl)thiazol-2-yl)hydrazino)]butan-1-ol (MT), a thiazolylhydrazone compound synthesized by our group, and identified it as a promising antifungal agent. The activity of MT was evaluated in vitro and in vivo against C. albicans as well as its ability to inhibit virulence factors. For this, the ability of MT to inhibit the adhesion of C. albicans to human buccal epithelial cells and biofilm formation and filamentation was tested. In addition, the potential in vivo activity of MT was evaluated in murine models of oral candidiasis. Our results confirmed the antifungal activity of MT, with a minimal inhibitory concentration range of 0.5-2 µg/mL. Indeed, MT treatment in vitro decreased the expression of C. albicans genes involved in biofilm formation and morphogenesis and encoding hydrolytic enzymes, which was also confirmed through phenotypic observations. In addition, MT promoted a decrease in the colony forming units recovered from the tongues of mice with oral candidiasis. In this work, we present a potent antivirulence compound that shows potential for candidiasis therapy, especially for topical use.
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Affiliation(s)
- Nívea Pereira de Sá
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, PO Box 486, 31270-901 Belo Horizonte, Minas Gerais, Brazil; Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, United States
| | - Patrícia Pimentel de Barros
- Departamento de Biociências e Diagnóstico Bucal, Instituto de Ciência e Tecnologia, Universidade Estadual Paulista "Júlio de Mesquita Filho", São José dos Campos, São Paulo, Brazil; Postgraduate Program in Nursing, University of Guarulhos, São Paulo, Brazil
| | - Juliana Campos Junqueira
- Departamento de Biociências e Diagnóstico Bucal, Instituto de Ciência e Tecnologia, Universidade Estadual Paulista "Júlio de Mesquita Filho", São José dos Campos, São Paulo, Brazil
| | - Aline Dias Valério
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, PO Box 486, 31270-901 Belo Horizonte, Minas Gerais, Brazil
| | - Cleudiomar Inácio Lino
- Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Renata Barbosa de Oliveira
- Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Carlos Augusto Rosa
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, PO Box 486, 31270-901 Belo Horizonte, Minas Gerais, Brazil
| | - Susana Johann
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, PO Box 486, 31270-901 Belo Horizonte, Minas Gerais, Brazil.
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Recent Advances in Genome Editing Tools in Medical Mycology Research. J Fungi (Basel) 2021; 7:jof7040257. [PMID: 33808382 PMCID: PMC8067129 DOI: 10.3390/jof7040257] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022] Open
Abstract
Manipulating fungal genomes is an important tool to understand the function of target genes, pathobiology of fungal infections, virulence potential, and pathogenicity of medically important fungi, and to develop novel diagnostics and therapeutic targets. Here, we provide an overview of recent advances in genetic manipulation techniques used in the field of medical mycology. Fungi use several strategies to cope with stress and adapt themselves against environmental effectors. For instance, mutations in the 14 alpha-demethylase gene may result in azole resistance in Aspergillusfumigatus strains and shield them against fungicide's effects. Over the past few decades, several genome editing methods have been introduced for genetic manipulations in pathogenic fungi. Application of restriction enzymes to target and cut a double-stranded DNA in a pre-defined sequence was the first technique used for cloning in Aspergillus and Candida. Genome editing technologies, including zinc-finger nucleases (ZFNs) and transcriptional activator-like effector nucleases (TALENs), have been also used to engineer a double-stranded DNA molecule. As a result, TALENs were considered more practical to identify single nucleotide polymorphisms. Recently, Class 2 type II Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 technology has emerged as a more useful tool for genome manipulation in fungal research.
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Dell'Olmo E, Gaglione R, Cesaro A, Cafaro V, Teertstra WR, de Cock H, Notomista E, Haagsman HP, Veldhuizen EJA, Arciello A. Host defence peptides identified in human apolipoprotein B as promising antifungal agents. Appl Microbiol Biotechnol 2021; 105:1953-1964. [PMID: 33576886 PMCID: PMC7907042 DOI: 10.1007/s00253-021-11114-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/04/2020] [Accepted: 01/13/2021] [Indexed: 01/08/2023]
Abstract
Abstract Therapeutic options to treat invasive fungal infections are still limited. This makes the development of novel antifungal agents highly desirable. Naturally occurring antifungal peptides represent valid candidates, since they are not harmful for human cells and are endowed with a wide range of activities and their mechanism of action is different from that of conventional antifungal drugs. Here, we characterized for the first time the antifungal properties of novel peptides identified in human apolipoprotein B. ApoB-derived peptides, here named r(P)ApoBLPro, r(P)ApoBLAla and r(P)ApoBSPro, were found to have significant fungicidal activity towards Candida albicans (C. albicans) cells. Peptides were also found to be able to slow down metabolic activity of Aspergillus niger (A. niger) spores. In addition, experiments were carried out to clarify the mechanism of fungicidal activity of ApoB-derived peptides. Peptides immediately interacted with C. albicans cell surfaces, as indicated by fluorescence live cell imaging analyses, and induced severe membrane damage, as indicated by propidium iodide uptake induced upon treatment of C. albicans cells with ApoB-derived peptides. ApoB-derived peptides were also tested on A. niger swollen spores, initial hyphae and branched mycelium. The effects of peptides were found to be more severe on swollen spores and initial hyphae compared to mycelium. Fluorescence live cell imaging analyses confirmed peptide internalization into swollen spores with a consequent accumulation into hyphae. Altogether, these findings open interesting perspectives to the application of ApoB-derived peptides as effective antifungal agents. Key points
Human cryptides identified in ApoB are effective antifungal agents. ApoB-derived cryptides exert fungicidal effects towards C. albicans cells. ApoB-derived cryptides affect different stages of growth of A. niger. Graphical abstract![]() Supplementary Information The online version contains supplementary material available at 10.1007/s00253-021-11114-3.
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Affiliation(s)
- Eliana Dell'Olmo
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy
- Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Section Molecular Host Defence, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Rosa Gaglione
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy
- Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy
| | - Angela Cesaro
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy
| | - Valeria Cafaro
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Wieke R Teertstra
- Molecular Microbiology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Hans de Cock
- Molecular Microbiology, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Eugenio Notomista
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Henk P Haagsman
- Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Section Molecular Host Defence, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Edwin J A Veldhuizen
- Department of Biomolecular Health Sciences, Division of Infectious Diseases and Immunology, Section Molecular Host Defence, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
| | - Angela Arciello
- Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy.
- Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
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L Kandaurava S, S Baslyk K, A Migas A, V Hill A, I Bydanov O, A Mishkova V, V Aleinikova O. Comparative study of prophylaxis with high and low doses of voriconazole in children with malignancy. Curr Med Mycol 2021; 6:27-34. [PMID: 34195457 PMCID: PMC8226053 DOI: 10.18502/cmm.6.4.5331] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background and Purpose: Children with acute myeloid leukemia and relapses of leukemia are at high risk of developing fungal infections and need antifungal prophylaxis. This study aimed to compare the efficacy and toxicity of two different dosage regimens of voriconazole (VRC) during prophylactic administration in children with malignancy and neutropenia. Materials and Methods: This prospective study was conducted at the Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology from May 2017 to December 2019.
The present study included 21 Caucasian patients with malignant hematological diseases (20 patients with acute myeloid leukemia and relapses of leukemia
and 1 patient with Non-Hodgkin's lymphoma) aged 2-18 years. All patients were randomly divided into two groups that received different dosage regimens
of VRCZ prophylaxis. Patients in the “high-dose” group received VRCZ at a dose of 9 mg/kg twice a day PO, or 8 mg/kg twice a day IV without a loading dose
(children of 2-11 and adolescents and of 12-14 years old with <50 kg weight body), or a dose of 4 mg/kg twice a day PO or IV (adolescents
of 12-14 years old with ≥50 kg body weight and all adolescents over 14 years old). Patients in the “low-dose” group received VRCZ at a dose of
4 mg/kg twice a day, PO or IV, without a loading dose (children of 2-11 and adolescents of 12-14 years old with <50 kg body weight),
or at a dose of 3 mg/kg twice a day, PO or IV (adolescents of 12-14 years old with ≥ 50 kg body weight and all adolescents over 14 years old).
When neutropenia recurred (after the next chemotherapy block), the patients were re-randomized and prophylaxis was resumed in the absence
of fungal infection. Therefore, some patients (n=12, 57%) entered the study several times (maximum four times, after each chemotherapy block).
In total, 21 patients experienced 40 episodes of VRCZ prophylaxis. Results: In the high-dose group (n=20 episodes of prophylaxis), invasive fungal infections (IFI) signs were recorded in one (5%) case.
In the low-dose group (n=20 episodes), IFI signs were observed in six (30%) cases (P=0.0375). The residual serum concentration was significantly
higher in patients who received high doses of VRCZ (P<0.0001). Most patients with IFI (n=6, 86%) had a mean value (i.e., <0.74 μg/ml)
of the residual serum concentration of the medication. Median of the first signs of fungal infection was 22 days from the start of prophylaxis.
The dosage was the only highly significant factor that affected the metabolism of VRCZ. Conclusion: The likelihood of IFI was significantly lower in children who prophylactically received VRCZ in high doses (P=0.0375) and had ≥
0.74 μg/ml residual serum concentration of the medication (P=0.0258). Residual serum concentration of VRCZ reached a plateau by day sixth
of the treatment. In children, the dosage was the only highly significant factor affecting the metabolism of VRCZ.
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Affiliation(s)
- Sviatlana L Kandaurava
- Infection Control Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Kseniya S Baslyk
- Laboratory of Genetic Biotechnology, Scientific Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Alexandr A Migas
- Laboratory of Genetic Biotechnology, Scientific Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Anna V Hill
- Group of Molecular Biology and Transplant Processing, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Oleg I Bydanov
- Automated Control Systems Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Volha A Mishkova
- Laboratory of Molecular and Genetic Research, Scientific Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
| | - Olga V Aleinikova
- Laboratory of Cellular Biotechnology and Cytotherapy, Scientific Department, Belarusian Research Center for Pediatric Oncology, Hematology, and Immunology, Minsk, Belarus
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The Future of Antifungal Drug Therapy: Novel Compounds and Targets. Antimicrob Agents Chemother 2021; 65:AAC.01719-20. [PMID: 33229427 DOI: 10.1128/aac.01719-20] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Fungal infections are a universal problem and are routinely associated with high morbidity and mortality rates in immunocompromised patients. Existing therapies comprise five different classes of antifungal agents, four of which target the synthesis of ergosterol and cell wall glucans. However, the currently available antifungals have many limitations, including poor oral bioavailability, narrow therapeutic indices, and emerging drug resistance resulting from their use, thus making it essential to investigate the development of novel drugs which can overcome these limitations and add to the antifungal armamentarium. Advances have been made in antifungal drug discovery research and development over the past few years as evidenced by the presence of several new compounds currently in various stages of development. In the following minireview, we provide a comprehensive summary of compounds aimed at one or more novel molecular targets. We also briefly describe potential pathways relevant for fungal pathogenesis that can be considered for drug development in the near future.
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Nguyen S, Truong JQ, Bruning JB. Targeting Unconventional Pathways in Pursuit of Novel Antifungals. Front Mol Biosci 2021; 7:621366. [PMID: 33511160 PMCID: PMC7835888 DOI: 10.3389/fmolb.2020.621366] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/11/2020] [Indexed: 01/31/2023] Open
Abstract
The impact of invasive fungal infections on human health is a serious, but largely overlooked, public health issue. Commonly affecting the immunocompromised community, fungal infections are predominantly caused by species of Candida, Cryptococcus, and Aspergillus. Treatments are reliant on the aggressive use of pre-existing antifungal drug classes that target the fungal cell wall and membrane. Despite their frequent use, these drugs are subject to unfavorable drug-drug interactions, can cause undesirable side-effects and have compromised efficacy due to the emergence of antifungal resistance. Hence, there is a clear need to develop novel classes of antifungal drugs. A promising approach involves exploiting the metabolic needs of fungi by targeted interruption of essential metabolic pathways. This review highlights potential antifungal targets including enolase, a component of the enolase-plasminogen complex, and enzymes from the mannitol biosynthesis and purine nucleotide biosynthesis pathways. There has been increased interest in the enzymes that comprise these particular pathways and further investigation into their merits as antifungal targets and roles in fungal survival and virulence are warranted. Disruption of these vital processes by targeting unconventional pathways with small molecules or antibodies may serve as a promising approach to discovering novel classes of antifungals.
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Affiliation(s)
- Stephanie Nguyen
- Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Jia Q Truong
- School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - John B Bruning
- Institute of Photonics and Advanced Sensing (IPAS), School of Biological Sciences, The University of Adelaide, Adelaide, SA, Australia
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Huseynov RM, Javadov SS, Osmanov A, Khasiyev S, Valiyeva SR, Almammadova E, Denning DW. The burden of serious fungal infections in Azerbaijan. Ther Adv Infect Dis 2021; 8:20499361211043969. [PMID: 34497715 PMCID: PMC8419541 DOI: 10.1177/20499361211043969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 08/17/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Azerbaijan is an upper middle-income country in South Caucasus with an area of 86,600 km2 and a total population of 10 million people and gross domestic product of US $4480 per capita. The aim of this research is to estimate fungal infection burden and highlight the problem at national and international levels. METHODS Fungal infection burden was estimated using data from epidemiological papers and population at risk and LIFE (Leading International Fungal Education) modelling. RESULTS The number of people living with human immunodeficiency virus (PLHIV) in 2018 was 6193, 29% of them not receiving antiretroviral therapy. Based on 90% and 20% rates of oral and oesophageal candidiasis in patients with CD4 cell count <200 µl-1 we estimate 808 and 579 patients with oral and oesophageal candidiasis, respectively. The annual incidences of cryptococcal meningitis and Pneumocystis pneumonia are 5 and 55 cases, respectively. We estimated 2307 cases of chronic pulmonary aspergillosis (CPA), 4927 patients with allergic bronchopulmonary aspergillosis (ABPA), and 6504 with severe asthma with fungal sensitization (SAFS). Using data on chronic obstructive pulmonary diseases (COPD), lung cancer, acute myeloid leukaemia rates, and number of transplantations, we estimated 693 cases of invasive aspergillosis following these conditions. Using a low-European rate for invasive candidiasis, we estimated 499 and 75 patients with candidemia and intra-abdominal candidiasis respectively. The number of adult women (15-55 years) in Azerbaijan is ~2,658,000, so it was estimated that 159,490 women suffer from recurrent vulvovaginal candidiasis (rVVC). DISCUSSION In total, the estimated number of people suffering from fungal diseases in Azerbaijan is 225,974 (2.3% of the population). However, the fungal rate is underestimated due to lack of epidemiological data. The most imminent need is improvement in diagnostic capabilities. This aim should be achieved via establishing a reference laboratory and equipping major clinical centers with essential diagnostics assays.
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Affiliation(s)
- Ravil M. Huseynov
- The Department of Medical Microbiology and Immunology, Azerbaijan Medical University, Mardanov Qardashlari 98, Baku, Azerbaijan
| | - Samir S. Javadov
- The Department of Medical Microbiology and Immunology, Azerbaijan Medical University, Baku, Azerbaijan
| | - Ali Osmanov
- Global Action Fund for Fungal Infections, Geneva, Switzerland
| | - Shahin Khasiyev
- The Department of Informatics and Statistics, Ministry of Health of Azerbaijan Republic, Baku, Azerbaijan
| | - Samira R. Valiyeva
- Republican Centre for Combating AIDS, Ministry of Health of Azerbaijan Republic, Baku, Azerbaijan
| | - Esmira Almammadova
- Republican Centre for Combating AIDS, Ministry of Health of Azerbaijan Republic, Baku, Azerbaijan
| | - David W. Denning
- Global Action Fund for Fungal Infections, Geneva, Switzerland
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
- National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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47
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El Zein S, Hindy JR, Kanj SS. Invasive Saprochaete Infections: An Emerging Threat to Immunocompromised Patients. Pathogens 2020; 9:pathogens9110922. [PMID: 33171713 PMCID: PMC7694990 DOI: 10.3390/pathogens9110922] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/16/2022] Open
Abstract
Saprochaete clavata and Saprochaete capitata are emerging fungal pathogens that are responsible for life threatening infections in immunocompromised patients, particularly in the setting of profound neutropenia. They have been associated with multiple hospital outbreaks mainly in Europe. In this article, we present a comprehensive review of the epidemiology, clinical presentation, diagnosis, antifungal susceptibility and treatment of these organisms. The diagnosis of invasive Saprochaete disease is challenging and relies primarily on the isolation of the fungi from blood or tissue samples. Both species are frequently misidentified as they are identical macroscopically and microscopically. Internal transcribed spacer sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry are useful tools for the differentiation of these fungi to a species level. Saprochaete spp. are intrinsically resistant to echinocandins and highly resistant to fluconazole. Current literature suggests the use of an amphotericin B formulation with or without flucytosine for the initial treatment of these infections. Treatment with extended spectrum azoles might be promising based on in vitro minimum inhibitory concentration values and results from case reports and case series. Source control and recovery of the immune system are crucial for successful therapy.
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Affiliation(s)
- Said El Zein
- Internal Medicine Department, Wayne State University/Detroit Medical Center, Detroit, MI 48201, USA;
| | - Joya-Rita Hindy
- Division of Infectious Diseases, Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon;
| | - Souha S. Kanj
- Division of Infectious Diseases, Internal Medicine Department, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon;
- Correspondence:
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48
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Martos-Benítez FD, Soler-Morejón CDD, Lara-Ponce KX, Orama-Requejo V, Burgos-Aragüez D, Larrondo-Muguercia H, Lespoir RW. Critically ill patients with cancer: A clinical perspective. World J Clin Oncol 2020; 11:809-835. [PMID: 33200075 PMCID: PMC7643188 DOI: 10.5306/wjco.v11.i10.809] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/09/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer patients account for 15% of all admissions to intensive care unit (ICU) and 5% will experience a critical illness resulting in ICU admission. Mortality rates have decreased during the last decades because of new anticancer therapies and advanced organ support methods. Since early critical care and organ support is associated with improved survival, timely identification of the onset of clinical signs indicating critical illness is crucial to avoid delaying. This article focused on relevant and current information on epidemiology, diagnosis, and treatment of the main clinical disorders experienced by critically ill cancer patients.
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Affiliation(s)
| | | | | | | | | | | | - Rahim W Lespoir
- Intensive Care Unit 8B, Hermanos Ameijeiras Hospital, Havana 10300, Cuba
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49
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Firacative C. Invasive fungal disease in humans: are we aware of the real impact? Mem Inst Oswaldo Cruz 2020; 115:e200430. [PMID: 33053052 PMCID: PMC7546207 DOI: 10.1590/0074-02760200430] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 09/24/2020] [Indexed: 01/08/2023] Open
Abstract
Despite the medical advances and interventions to improve the quality of life of those in intensive care, people with cancer or severely immunocompromised or other susceptible hosts, invasive fungal diseases (IFD) remain severe and underappreciated causes of illness and death worldwide. Therefore, IFD continue to be a public health threat and a major hindrance to the success of otherwise life-saving treatments and procedures. Globally, hundreds of thousands of people are affected every year with Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Pneumocystis jirovecii, endemic dimorphic fungi and Mucormycetes, the most common fungal species causing invasive diseases in humans. These infections result in morbidity and mortality rates that are unacceptable and represent a considerable socioeconomic burden. Raising the general awareness of the significance and impact of IFD in human health, in both the hospital and the community, is hence critical to understand the scale of the problem and to raise interest to help fighting these devastating diseases.
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Affiliation(s)
- Carolina Firacative
- Universidad del Rosario, School of Medicine and Health Sciences, Studies in Translational Microbiology and Emerging Diseases (MICROS) Research Group, Bogota, Colombia
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50
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Enhancing the differentiation of pulmonary lymphoma and fungal pneumonia in hematological patients using texture analysis in 3-T MRI. Eur Radiol 2020; 31:695-705. [PMID: 32822054 PMCID: PMC7813714 DOI: 10.1007/s00330-020-07137-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 06/08/2020] [Accepted: 08/03/2020] [Indexed: 11/15/2022]
Abstract
Objectives To evaluate texture analysis in nonenhanced 3-T MRI for differentiating pulmonary fungal infiltrates and lymphoma manifestations in hematological patients and to compare the diagnostic performance with that of signal intensity quotients (“nonenhanced imaging characterization quotients,” NICQs). Methods MR scans were performed using a speed-optimized imaging protocol without an intravenous contrast medium including axial T2-weighted (T2w) single-shot fast spin-echo and T1-weighted (T1w) gradient-echo sequences. ROIs were drawn within the lesions to extract first-order statistics from original images using HeterogeneityCAD and PyRadiomics. NICQs were calculated using signal intensities of the lesions, muscle, and fat. The standard of reference was histology or clinical diagnosis in follow-up. Statistical testing included ROC analysis, clustered ROC analysis, and DeLong test. Intra- and interrater reliability was tested using intraclass correlation coefficients (ICC). Results Thirty-three fungal infiltrates in 16 patients and 38 pulmonary lymphoma manifestations in 19 patients were included. Considering the leading lesion in each patient, diagnostic performance was excellent for T1w entropy (AUC 80.2%; p < 0.005) and slightly inferior for T2w energy (79.9%; p < 0.005), T1w uniformity (79.6%; p < 0.005), and T1w energy (77.0%; p < 0.01); the best AUC for NICQs was 72.0% for T2NICQmean (p < 0.05). Intra- and interrater reliability was good to excellent (ICC > 0.81) for these parameters except for moderate intrarater reliability of T1w energy (ICC = 0.64). Conclusions T1w entropy, uniformity, and energy and T2w energy showed the best performances for differentiating pulmonary lymphoma and fungal pneumonia and outperformed NICQs. Results of the texture analysis should be checked for their intrinsic consistency to identify possible incongruities of single parameters. Key Points • Texture analysis in nonenhanced pulmonary MRI improves the differentiation of pulmonary lymphoma and fungal pneumonia compared with signal intensity quotients. • T1w entropy, uniformity, and energy along with T2w energy show the best performances for differentiating pulmonary lymphoma from fungal pneumonia. • The results of the texture analysis should be checked for their intrinsic consistency to identify possible incongruities of single parameters.
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