142 results on '"Annette W. Fothergill"'
Search Results
2. Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
- Author
-
Visesato Mor, Antonella Rella, Amir M. Farnoud, Ashutosh Singh, Mansa Munshi, Arielle Bryan, Shamoon Naseem, James B. Konopka, Iwao Ojima, Erika Bullesbach, Alan Ashbaugh, Michael J. Linke, Melanie Cushion, Margaret Collins, Hari Krishna Ananthula, Larry Sallans, Pankaj B. Desai, Nathan P. Wiederhold, Annette W. Fothergill, William R. Kirkpatrick, Thomas Patterson, Lai Hong Wong, Sunita Sinha, Guri Giaever, Corey Nislow, Patrick Flaherty, Xuewen Pan, Gabriele Vargas Cesar, Patricia de Melo Tavares, Susana Frases, Kildare Miranda, Marcio L. Rodrigues, Chiara Luberto, Leonardo Nimrichter, and Maurizio Del Poeta
- Subjects
Microbiology ,QR1-502 - Abstract
ABSTRACT Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2015
- Full Text
- View/download PDF
3. The Celecoxib Derivative AR-12 Has Broad-Spectrum Antifungal Activity In Vitro and Improves the Activity of Fluconazole in a Murine Model of Cryptococcosis
- Author
-
Melanie T. Cushion, Justin P. Halterman, Kristy Koselny, Thomas F. Patterson, Nathan P. Wiederhold, Annette W. Fothergill, Damian J. Krysan, Chad Rappelye, Louis DiDone, Melanie Wellington, and Julianne Green
- Subjects
Male ,0301 basic medicine ,Antifungal Agents ,030106 microbiology ,Drug Evaluation, Preclinical ,Mice, Inbred Strains ,Microbial Sensitivity Tests ,Saccharomyces cerevisiae ,Pharmacology ,Echinocandins ,Lipopeptides ,03 medical and health sciences ,chemistry.chemical_compound ,Caspofungin ,Drug Resistance, Fungal ,In vivo ,Gene Expression Regulation, Fungal ,Histoplasma ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,Candida albicans ,Fluconazole ,Candida ,Cryptococcus neoformans ,chemistry.chemical_classification ,Sulfonamides ,biology ,Pneumocystis ,Drug Synergism ,Cryptococcosis ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Infectious Diseases ,chemistry ,Celecoxib ,Pyrazoles ,Azole ,medicine.drug - Abstract
Only one new class of antifungal drugs has been introduced into clinical practice in the last 30 years, and thus the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib derivative which has been tested in a phase I clinical trial as an anticancer agent. AR-12 inhibits fungal acetyl coenzyme A (acetyl-CoA) synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity, including activity against yeasts (e.g., Candida albicans , non- albicans Candida spp., Cryptococcus neoformans ), molds (e.g., Fusarium , Mucor ), and dimorphic fungi ( Blastomyces , Histoplasma , and Coccidioides ) with MICs of 2 to 4 μg/ml. AR-12 is also active against azole- and echinocandin-resistant Candida isolates, and subinhibitory AR-12 concentrations increase the susceptibility of fluconazole- and echinocandin-resistant Candida isolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad-spectrum antifungal activity.
- Published
- 2016
4. The Investigational Fungal Cyp51 Inhibitor VT-1129 Demonstrates Potent In Vitro Activity against Cryptococcus neoformans and Cryptococcus gattii
- Author
-
Shawn R. Lockhart, William J. Hoekstra, Annette W. Fothergill, Thomas F. Patterson, Carol B. Bolden, Naureen Iqbal, Nathan P. Wiederhold, Robert J. Schotzinger, Nina T. Grossman, Stephen Brand, Edward P. Garvey, and Elizabeth A. Ottinger
- Subjects
0301 basic medicine ,Antifungal Agents ,Genotype ,Pyridines ,030106 microbiology ,Gene Expression ,Tetrazoles ,Microbial Sensitivity Tests ,Drug resistance ,Microbiology ,Fungal Proteins ,Sterol 14-Demethylase ,03 medical and health sciences ,Drug Resistance, Fungal ,medicine ,Pharmacology (medical) ,Fluconazole ,Cryptococcus gattii ,Pharmacology ,Cryptococcus neoformans ,Fungal protein ,biology ,Fungal genetics ,Drugs, Investigational ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,030104 developmental biology ,Infectious Diseases ,Susceptibility ,14-alpha Demethylase Inhibitors ,medicine.drug - Abstract
The in vitro activities of the novel fungal Cyp51 inhibitor VT-1129 were evaluated against a large panel of Cryptococcus neoformans and Cryptococcus gattii isolates. VT-1129 demonstrated potent activities against both Cryptococcus species as demonstrated by low MIC 50 and MIC 90 values. For C. gattii , the in vitro potency was maintained against all genotypes. In addition, significantly lower geometric mean MICs were observed for VT-1129 than for fluconazole against C. neoformans , including isolates with reduced fluconazole susceptibility.
- Published
- 2016
5. Update from the Laboratory
- Author
-
Deanna A. Sutton, Annette W. Fothergill, Mohammad T. Albataineh, and Nathan P. Wiederhold
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Susceptibility testing ,Resistance (ecology) ,medicine.drug_class ,business.industry ,030106 microbiology ,Immunocompromised patient ,Bioinformatics ,Microbiology ,03 medical and health sciences ,Infectious Diseases ,Invasive Mycoses ,medicine ,Identification (biology) ,business - Abstract
Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed.
- Published
- 2016
6. Multilaboratory Evaluation of In Vitro Antifungal Susceptibility Testing of Dermatophytes for ME1111
- Author
-
Robert Rennie, Mahmoud A. Ghannoum, Luis Ostrosky-Zeichner, Daniel J. Diekema, Nathan P. Wiederhold, Vishnu Chaturvedi, Thomas J. Walsh, Nancy L. Wengenack, and Annette W. Fothergill
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Susceptibility testing ,Antifungal Agents ,medicine.drug_class ,Epidermophyton floccosum ,030106 microbiology ,Mycology ,Microbial Sensitivity Tests ,Trichophyton rubrum ,Microbiology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Phenols ,medicine ,Dermatomycoses ,Humans ,Trichophyton ,Reproducibility ,biology ,Arthrodermataceae ,Reproducibility of Results ,biology.organism_classification ,In vitro ,Pyrazoles - Abstract
ME1111 is a novel small molecule antifungal agent under development for the topical treatment of onychomycosis. Standardization of the susceptibility testing method for this candidate antifungal is needed. Toward this end, 8 independent laboratories determined the interlaboratory reproducibility of ME1111 susceptibility testing. In addition, we subsequently identified 2 strains as quality control (QC) isolates for the method. In the reproducibility study, 5 blinded clinical strains each of Trichophyton rubrum , Trichophyton mentagrophytes , and Epidermophyton floccosum were tested, while the QC study tested 6 blinded T. rubrum or T. mentagrophytes ATCC strains. Testing was performed in frozen microtiter panels according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 methodology. In the reproducibility study, 9 of 15 clinical strains showed interlaboratory agreement of >90% at the 80% inhibition endpoint, with a range of agreement of 76.2% to 100%. In the QC study, 4 of the 6 ATCC strains showed interlaboratory agreement of >90%. ME1111 demonstrated excellent interlaboratory agreement when tested against dermatophytes. Based on this data, the CLSI Subcommittee on Antifungal Susceptibility Tests approved the susceptibility testing of ME1111 against dermatophytes according to M38-A2 methodology, which stipulates RPMI 1640 as the test medium, an inoculum size of 1 to 3 × 10 3 CFU/ml, and an incubation time and temperature of 96 h at 35°C. The MIC endpoint should be 80% inhibition compared with the growth control. T. rubrum ATCC MYA-4438 and T. mentagrophytes ATCC 28185 were selected as QC isolates, with an acceptable range of 0.12 to 1 μg/ml for the two strains.
- Published
- 2016
7. Erratum for Mor et al., 'Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids'
- Author
-
Amir M. Farnoud, Hari Krishna Ananthula, Lai Hong Wong, Ashutosh Singh, Visesato Mor, Michael J. Linke, Margaret S. Collins, Susana Frases, Chiara Luberto, Gabriele Vargas Cesar, Xuewen Pan, Corey Nislow, Erika E. Büllesbach, William R. Kirkpatrick, Annette W. Fothergill, Larry Sallans, Alan Ashbaugh, Iwao Ojima, James B. Konopka, Melanie T. Cushion, Marcio L. Rodrigues, Thomas F. Patterson, Leonardo Nimrichter, Arielle M. Bryan, Maurizio Del Poeta, Shamoon Naseem, Patricia de Melo Tavares, Kildare Miranda, Antonella Rella, Sunita Sinha, Nathan P. Wiederhold, Patrick Flaherty, Pankaj B. Desai, Guri Giaever, and Mansa Munshi
- Subjects
0301 basic medicine ,Antifungal Agents ,Drug-Related Side Effects and Adverse Reactions ,Cell Survival ,030106 microbiology ,Colony Count, Microbial ,Drug Evaluation, Preclinical ,Microbial Sensitivity Tests ,Computational biology ,Biology ,Microbiology ,Cell Line ,Mice ,03 medical and health sciences ,Microscopy, Electron, Transmission ,Virology ,Benzyl Compounds ,Animals ,Sphingolipids ,Microbial Viability ,Molecular Structure ,Macrophages ,Candidiasis ,Fungi ,Drug Synergism ,Sphingolipid ,QR1-502 ,Biosynthetic Pathways ,Disease Models, Animal ,Treatment Outcome ,Identification (biology) ,Erratum ,Research Article - Abstract
Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM., IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2018
8. VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection
- Author
-
Thomas F. Patterson, William J. Hoekstra, Edward P. Garvey, Robert J. Schotzinger, Scott G. Filler, Ashraf S. Ibrahim, Teclegiorgis Gebremariam, Annette W. Fothergill, and Nathan P. Wiederhold
- Subjects
Male ,Antifungal Agents ,Pyridines ,Rhizopus arrhizus var. arrhizus ,Tetrazoles ,Microbial Sensitivity Tests ,Biology ,Microbiology ,Drug levels ,Immunocompromised Host ,Mice ,Species Specificity ,Rhizopus ,Amphotericin B ,medicine ,Animals ,Mucormycosis ,Experimental Therapeutics ,Pharmacology (medical) ,Rhizopus arrhizus ,Pharmacology ,Mice, Inbred ICR ,medicine.disease ,biology.organism_classification ,Survival Analysis ,In vitro ,Infectious Diseases ,Liposomal amphotericin ,medicine.drug - Abstract
We studied the efficacy of the investigational drug VT-1161 against mucormycosis. VT-1161 had more potent in vitro activity against Rhizopus arrhizus var. arrhizus than against R. arrhizus var. delemar . VT-1161 treatment demonstrated dose-dependent plasma drug levels with prolonged survival time and lowered tissue fungal burden in immunosuppressed mice infected with R. arrhizus var. arrhizus and was as effective as high-dose liposomal amphotericin B treatment. These results support further development of VT-1161 against mucormycosis.
- Published
- 2015
9. Phylogeny of the Clinically Relevant Species of the Emerging Fungus Trichoderma and Their Antifungal Susceptibilities
- Author
-
Josep Guarro, Deanna A. Sutton, Annette W. Fothergill, José F. Cano-Lira, Marcelo Sandoval-Denis, Josepa Gené, and Nathan P. Wiederhold
- Subjects
Microbiology (medical) ,Antifungal Agents ,Trichoderma longibrachiatum ,Molecular Sequence Data ,macromolecular substances ,Mycology ,Microbial Sensitivity Tests ,Fungus ,Communicable Diseases, Emerging ,Microbiology ,Peptide Elongation Factor 1 ,Hypocrea ,DNA, Ribosomal Spacer ,Animals ,Cluster Analysis ,Humans ,Internal transcribed spacer ,DNA, Fungal ,Ribosomal DNA ,Phylogeny ,Trichoderma ,biology ,Chitinases ,food and beverages ,Trichoderma harzianum ,biology.organism_classification ,Actins ,Mycoses ,Multilocus sequence typing ,Multilocus Sequence Typing - Abstract
A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha ( Tef1 ), endochitinase CHI18-5 ( Chi18-5 ), and actin 1 ( Act1 ) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins.
- Published
- 2014
10. Osteomyelitis caused by Aspergillus species: a review of 310 reported cases
- Author
-
Elena Orsetti, Deanna A. Sutton, E. Marchionni, Francesco Barchiesi, Rosaria Gesuita, E. Gabrielli, Annette W. Fothergill, Lucia Brescini, Pamela Castelli, and Silvia Staffolani
- Subjects
Microbiology (medical) ,medicine.medical_specialty ,Antifungal Agents ,Itraconazole ,Antifungal drug ,Comorbidity ,Aspergillosis ,Gastroenterology ,Aspergillus fumigatus ,Amphotericin B ,Internal medicine ,medicine ,Humans ,aspergillosis ,Demography ,Voriconazole ,Antifungals ,biology ,Osteomyelitis ,osteomyelitis ,General Medicine ,medicine.disease ,biology.organism_classification ,Combined Modality Therapy ,Survival Analysis ,Surgery ,Transplantation ,Aspergillus ,Infectious Diseases ,Debridement ,immunosuppressed patients ,spondylodiscitis ,medicine.drug - Abstract
Aspergillus osteomyelitis is a rare infection. We reviewed 310 individual cases reported in the literature from 1936 to 2013. The median age of patients was 43 years (range, 0–86 years), and 59% were males. Comorbidities associated with this infection included chronic granulomatous disease (19%), haematological malignancies (11%), transplantation (11%), diabetes (6%), pulmonary disease (4%), steroid therapy (4%), and human immunodeficiency virus infection (4%). Sites of infection included the spine (49%), base of the skull, paranasal sinuses and jaw (18%), ribs (9%), long bones (9%), sternum (5%), and chest wall (4%). The most common infecting species were Aspergillus fumigatus (55%), Aspergillus flavus (12%), and Aspergillus nidulans (7%). Sixty-two percent of the individual cases were treated with a combination of an antifungal regimen and surgery. Amphotericin B was the antifungal drug most commonly used, followed by itraconazole and voriconazole. Several combination or sequential therapies were also used experimentally. The overall crude mortality rate was 25%.
- Published
- 2014
11. Impact of New Antifungal Breakpoints on Antifungal Resistance in Candida Species
- Author
-
Deanna A. Sutton, Nathan P. Wiederhold, Dora I. McCarthy, and Annette W. Fothergill
- Subjects
Microbiology (medical) ,Voriconazole ,Antifungal ,Antifungal Agents ,biology ,Candida glabrata ,medicine.drug_class ,business.industry ,Candidiasis ,Micafungin ,Microbial Sensitivity Tests ,Mycology ,bacterial infections and mycoses ,biology.organism_classification ,Microbiology ,Drug Resistance, Fungal ,medicine ,Humans ,Anidulafungin ,Candida albicans ,business ,Fluconazole ,Candida ,medicine.drug - Abstract
We reviewed our antifungal susceptibility data for micafungin, anidulafungin, fluconazole, and voriconazole against Candida species and compared resistance rates determined by the previous and recently revised CLSI antifungal breakpoints. With the new breakpoints, resistance was significantly increased for micafungin (from 0.8% to 7.6%), anidulafungin (from 0.9% to 7.3%), and voriconazole (from 6.1% to 18.4%) against Candida glabrata . Resistance was also increased for fluconazole against Candida albicans (from 2.1% to 5.7%).
- Published
- 2014
12. In vitro pharmacodynamics and in vivo efficacy of fluconazole, amphotericin B and caspofungin in a murine infection by Candida lusitaniae
- Author
-
Josep Guarro, Marcelo Sandoval-Denis, Deanna A. Sutton, F. Javier Pastor, Javier Capilla, and Annette W. Fothergill
- Subjects
Male ,Microbiology (medical) ,Antifungal Agents ,Colony Count, Microbial ,Microbial Sensitivity Tests ,Pharmacology ,Kidney ,Microbiology ,Echinocandins ,Lipopeptides ,Mice ,chemistry.chemical_compound ,Caspofungin ,In vivo ,Amphotericin B ,hemic and lymphatic diseases ,parasitic diseases ,medicine ,Animals ,Pharmacology (medical) ,Fluconazole ,Candida ,biology ,Candida lusitaniae ,fungi ,Candidiasis ,General Medicine ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,chemistry ,Murine model ,Pharmacodynamics ,medicine.drug - Abstract
The in vitro activities of fluconazole (FLC), amphotericin B (AmB) and caspofungin (CSP) were evaluated against three isolates of Candida lusitaniae using time–kill curves. AmB showed in vitro fungicidal activity, whilst FLC and CSP exerted mainly strain-dependent fungistatic activity. The in vivo efficacies of the three drugs were evaluated in a murine model of disseminated infection. The doses administered were FLC 50 mg/kg/day, AmB 0.8 mg/kg/day and CSP 5 mg/kg/day. All three drugs were able to reduce the fungal burden in the kidneys of infected mice, with AmB showing the highest efficacy, followed by CSP. At least in this model, FLC, AmB and CSP are good candidates for treating invasive infections by C. lusitaniae.
- Published
- 2014
13. The Novel Arylamidine T-2307 Maintains In Vitro and In Vivo Activity against Echinocandin-Resistant Candida albicans
- Author
-
Thomas F. Patterson, Annette W. Fothergill, Laura K. Najvar, Marcos Olivo, Nathan P. Wiederhold, Dora I. McCarthy, Junichi Mitsuyama, Rosie Bocanegra, Yoshiko Fukuda, and William R. Kirkpatrick
- Subjects
Male ,Antifungal Agents ,Echinocandin ,Amidines ,Improved survival ,Microbial Sensitivity Tests ,Pharmacology ,Placebo ,Microbiology ,Echinocandins ,Mice ,chemistry.chemical_compound ,Drug Resistance, Fungal ,In vivo ,Candida albicans ,polycyclic compounds ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,Mice, Inbred ICR ,biology ,Candidiasis ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,Corpus albicans ,Infectious Diseases ,chemistry ,Caspofungin ,medicine.drug - Abstract
We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans . T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections.
- Published
- 2015
14. Evaluation of the correlation of caspofungin MICs and treatment outcome in murine infections by wild type strains of Candida parapsilosis
- Author
-
Valentina Salas, Josep Guarro, Annette W. Fothergill, Michael G. Rinaldi, Emilio Mayayo, Javier Capilla, Deanna A. Sutton, and F. Javier Pastor
- Subjects
Male ,Microbiology (medical) ,beta-Glucans ,Serial dilution ,Treatment outcome ,Colony Count, Microbial ,Microbial Sensitivity Tests ,Biology ,Candida parapsilosis ,Microbiology ,Echinocandins ,Lipopeptides ,Mice ,chemistry.chemical_compound ,Caspofungin ,Animals ,Sensu stricto ,Candida ,Broth microdilution ,Candidiasis ,Wild type ,General Medicine ,bacterial infections and mycoses ,biology.organism_classification ,In vitro ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,chemistry ,Proteoglycans - Abstract
We have evaluated the in vitro activity of caspofungin against 36 wild-type strains of Candida parapsilosis sensu stricto using 3 techniques: broth microdilution, disk diffusion, and the determination of minimal fungicidal concentration (MFC). The first 2 methods showed a good in vitro activity of caspofungin, but the MFCs were ≥2 dilutions above their corresponding MICs. In a murine model of disseminated infection, we evaluated the efficacy of caspofungin at 5 mg/kg against 8 strains of C. parapsilosis representing different degrees of in vitro susceptibility (0.12–1 μg/mL). All the isolates responded to treatment and (1→3)-β-D-glucan levels were reduced in all the cases; however, the study revealed differences among isolates, since caspofungin reduced the tissue burden of mice infected with isolates with MICs ≤0.5 μg/mL but was less effective against those with MICs of 1 μg/mL.
- Published
- 2013
15. Repurposing auranofin as an antifungal: In vitro activity against a variety of medically important fungi
- Author
-
Nathan P. Wiederhold, Annette W. Fothergill, Anand Srinivasan, Ashok K. Chaturvedi, Thomas F. Patterson, Jose L. Lopez-Ribot, Floyd L. Wormley, and Anand K. Ramasubramanian
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal ,Auranofin ,Antifungal Agents ,medicine.drug_class ,030106 microbiology ,Immunology ,Microbial Sensitivity Tests ,Pharmacology ,Biology ,Microbiology ,03 medical and health sciences ,Candida albicans ,medicine ,Humans ,Repurposing ,Aspergillus fumigatus ,Brief Report ,Candidiasis ,Drug Repositioning ,Fungi ,medicine.disease ,biology.organism_classification ,In vitro ,Antirheumatic Agents ,Drug repositioning ,030104 developmental biology ,Infectious Diseases ,Rheumatoid arthritis ,Parasitology ,medicine.drug - Abstract
Repositioning old drugs can significantly decrease the time and effort that it takes to develop novel antifungal therapeutics, which represents a pressing and unmet clinical need due to the devastating nature of fungal infections. We have previously described the activity of auranofin, a gold thiol compound used to treat rheumatoid arthritis, against Candida albicans biofilms. Here we evaluate its antifungal spectrum of action and describe its activity against a variety of medically important fungi.
- Published
- 2016
16. Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species
- Author
-
Annette W. Fothergill, Mohammad T. Albataineh, Nathan P. Wiederhold, Carmita Sanders, M. L. McElmeel, and Dora I. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,Mycology ,Microbial Sensitivity Tests ,Biology ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Echinocandins ,Lipopeptides ,Caspofungin ,polycyclic compounds ,Humans ,Etest ,Candida ,Broth microdilution ,Reproducibility of Results ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,In vitro ,Corpus albicans ,chemistry ,Polystyrenes - Abstract
Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of ≥0.5 μg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others.
- Published
- 2016
17. Update from the Laboratory: Clinical Identification and Susceptibility Testing of Fungi and Trends in Antifungal Resistance
- Author
-
Mohammad T, Albataineh, Deanna A, Sutton, Annette W, Fothergill, and Nathan P, Wiederhold
- Subjects
Antifungal Agents ,Mycoses ,Drug Resistance, Fungal ,Fungi ,Humans ,Microbial Sensitivity Tests ,Laboratories - Abstract
Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed.
- Published
- 2016
18. Voriconazole minimum inhibitory concentrations are predictive of treatment outcome in experimental murine infections by Candida glabrata
- Author
-
Deanna A. Sutton, Marta Sanchis, Josep Guarro, Annette W. Fothergill, Javier Capilla, Adela Martin-Vicente, Nathan P. Wiederhold, Mariana Castanheira, Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, and Universitat Rovira i Virgili
- Subjects
Male ,0301 basic medicine ,Microbiology (medical) ,Antifungal Agents ,030106 microbiology ,Treatment outcome ,Colony Count, Microbial ,Candida glabrata ,Microbial Sensitivity Tests ,Pharmacology ,0924-8579 ,Kidney ,Inhibitory postsynaptic potential ,Mice ,03 medical and health sciences ,In vivo ,medicine ,voriconazole ,Animals ,Pharmacology (medical) ,Voriconazole ,Ciències de la salut ,biology ,fungal infection ,Candidiasis ,Health sciences ,General Medicine ,biology.organism_classification ,Ciencias de la salud ,Treatment efficacy ,In vitro ,Disease Models, Animal ,Treatment Outcome ,Infectious Diseases ,Càndida glabrata ,Murine model ,Micosi ,Immunology ,Voriconazol ,medicine.drug - Abstract
DOI: 10.1016/j.ijantimicag.2015.12.020 In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from ¿0.03 ¿g/mL to 8 ¿g/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 ¿g/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus.
- Published
- 2016
- Full Text
- View/download PDF
19. Rare Arthroconidial Fungi in Clinical Samples: Scytalidium cuboideum and Arthropsis hispanica
- Author
-
Josepa Gené, Annette W. Fothergill, Deanna A. Sutton, Josep Guarro, Josep Cano, and Alejandra Giraldo
- Subjects
Antifungal ,medicine.medical_specialty ,Antifungal Agents ,medicine.drug_class ,Veterinary (miscellaneous) ,Antifungal drugs ,Molecular Sequence Data ,Microbial Sensitivity Tests ,Biology ,DNA, Ribosomal ,Applied Microbiology and Biotechnology ,Microbiology ,Medical microbiology ,Ascomycota ,Microbial ecology ,DNA, Ribosomal Spacer ,Botany ,medicine ,Humans ,DNA, Fungal ,Scytalidium cuboideum ,Genes, rRNA ,RNA, Fungal ,Sequence Analysis, DNA ,United States ,Mycoses ,RNA, Ribosomal ,Agronomy and Crop Science ,Arthropsis hispanica - Abstract
We report the presence of the two arthroconidial anamorphic fungi, Scytalidium cuboideum and Arthropsis hispanica, in clinical samples from the USA. Both fungi were morphologically and molecularly identified. The antifungal susceptibility of four isolates of A. hispanica and five of S. cuboideum to eight antifungal drugs is provided.
- Published
- 2012
20. Resistant Fusarium Keratitis Progressing to Endophthalmitis
- Author
-
Sean L. Edelstein, Levent Akduman, Annette W. Fothergill, Benjamin H. Durham, and Hugo Y. Hsu
- Subjects
Fusariosis ,Fusarium ,Susceptibility testing ,Antifungal Agents ,Drug resistance ,Eye Enucleation ,Keratitis ,Microbiology ,Endophthalmitis ,Coumarins ,Drug Resistance, Multiple, Fungal ,medicine ,Humans ,biology ,business.industry ,Disease progression ,Middle Aged ,Eye infection ,medicine.disease ,biology.organism_classification ,Ophthalmology ,Treatment Outcome ,Disease Progression ,business ,Eye Infections, Fungal - Abstract
To report a case of multidrug-resistant Fusarium sp keratitis that progressed to endophthalmitis and that eventually required enucleation.Case report and literature review. Isolate identification and susceptibility testing were performed by the Fungus Testing Laboratory at San Antonio, TX.A 52-year-old soft contact lens wearer had a corneal abrasion and developed a corneal infiltrate. Examination of corneal scrapings revealed filamentous hyphae with septation and conidia. Despite aggressive antifungal therapy with topical natamycin, amphotericin B, and systemic fluconazole, the keratitis progressed, and a penetrating keratoplasty was performed. Histopathologic analysis of the corneal button showed disruption of Descemet's membrane with periodic acid-Schiff-positive fungal hyphae on both sides. Recurrent infection of the graft and progression to endophthalmitis was treated with repeated intravitreal amphotericin B injections, repeat penetrating keratoplasties, and pars plana vitrectomies. Even after systemic use of itraconazole, voriconazole, and posaconazole and topical use of voriconazole, the infection progressed and an enucleation was required. Isolate identification and susceptibility testing found a multidrug-resistant Fusarium solani species complex, partially sensitive to natamycin only.Multidrug-resistant Fusarium sp is rare and may have devastating consequences in patients with advanced keratitis progressing to endophthalmitis. Such an extensive multidrug resistance is surprising in that resistance to antifungal treatment is supposedly rare. Empirical antifungal therapy is usually instituted using one or more antifungal agents, without checking antifungal sensitivities. In light of the growing concern for increased emergence of resistant strains, we propose a lower threshold to check for sensitivities in the face of unresponsive fungal infections.
- Published
- 2012
21. First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States
- Author
-
Jonathan Lindner, Carmita Sanders, Annette W. Fothergill, Felipe Gutierrez, Veronica Garcia Gil, Mohammad T. Albataineh, Nathan P. Wiederhold, Hongxin Fan, Deanna A. Sutton, and Dora I. McCarthy
- Subjects
0301 basic medicine ,Microbiology (medical) ,Azoles ,Antifungal Agents ,030106 microbiology ,Mutation, Missense ,Azole resistance ,Mycology ,Microbial Sensitivity Tests ,Aspergillosis ,Aspergillus fumigatus ,Microbiology ,03 medical and health sciences ,Sterol 14-Demethylase ,Drug Resistance, Fungal ,medicine ,Humans ,In patient ,chemistry.chemical_classification ,biology ,biology.organism_classification ,medicine.disease ,United States ,chemistry ,Azole - Abstract
Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.
- Published
- 2015
22. The novel arylamidine T-2307 demonstrates in vitro and in vivo activity against echinocandin-resistant Candida glabrata
- Author
-
Annette W. Fothergill, Laura K. Najvar, Rosie Bocanegra, Thomas F. Patterson, Nathan P. Wiederhold, Dora I. McCarthy, Junichi Mitsuyama, Yoshiko Fukuda, and Marcos Olivo
- Subjects
0301 basic medicine ,Microbiology (medical) ,Male ,Antifungal Agents ,Echinocandin ,030106 microbiology ,Amidines ,Colony Count, Microbial ,Candida glabrata ,Microbial Sensitivity Tests ,Biology ,Neutropenia ,Kidney ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,In vivo ,polycyclic compounds ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Original Research ,Pharmacology ,Mice, Inbred ICR ,Candidiasis ,bacterial infections and mycoses ,medicine.disease ,Caspofungin Acetate ,biology.organism_classification ,In vitro ,Disease Models, Animal ,Infectious Diseases ,Treatment Outcome ,chemistry ,Immunocompetence ,Caspofungin ,medicine.drug - Abstract
OBJECTIVES Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata. METHODS In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu. RESULTS T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin. CONCLUSIONS T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida.
- Published
- 2015
23. Two new species ofMucorfrom clinicalsamples
- Author
-
Michael G. Rinaldi, Alberto M. Stchigel, Eduardo Alvarez, Valentina Salas, Deanna A. Sutton, Josep Guarro, Annette W. Fothergill, and Josep Cano
- Subjects
Mucorales ,Antifungal Agents ,Molecular Sequence Data ,Mucor velutinosus ,Microbial Sensitivity Tests ,Mucor ellipsoideus ,DNA, Ribosomal ,Microbiology ,Phylogenetics ,Amphotericin B ,DNA, Ribosomal Spacer ,Botany ,medicine ,Humans ,Mucormycosis ,DNA, Fungal ,Mycological Typing Techniques ,Phylogeny ,Mucor ,biology ,Sporangium ,Temperature ,Fungal genetics ,Sequence Analysis, DNA ,General Medicine ,Triazoles ,Ribosomal RNA ,biology.organism_classification ,United States ,medicine.drug_formulation_ingredient ,Infectious Diseases ,Itraconazole - Abstract
Two new species in the order Mucorales, Mucor velutinosus and Mucor ellipsoideus, isolated from human clinical specimens in the USA, are described and illustrated. The former species is similar to Mucor ramosissimus, from which it can be differentiated by its ability to grow at 37°C and produce verrucose sporangiospores. Mucor ellipsoideus is also able to grow and sporulate at 37°C like M. indicus, the nearest phylogenetic species in this study, however, the former has narrow ellipsoidal sporangiospores in contrast to the subglobose to ellipsoidal sporangiospores of M. indicus. Analysis of the sequences of the ITS and the D1-D2 regions of the rRNA genes confirmed the novelty of these species. The in vitro antifungal susceptibility of the new species showed that amphotericin B was active against all isolates and posaconazole and itraconazole showed low activity.
- Published
- 2011
24. Screening for drug-resistantCandidayeasts with chromogenic agar
- Author
-
Erin Brockway, Spencer W. Redding, Dora I. McCarthy, Michael J. Broker, Thomas F. Patterson, Annette W. Fothergill, Fadi P. Haikal, William R. Kirkpatrick, and Joseph D. Zimmerman
- Subjects
Posaconazole ,Antifungal Agents ,food.ingredient ,Echinocandin ,Microbial Sensitivity Tests ,Biology ,Article ,Microbiology ,Agar dilution ,chemistry.chemical_compound ,food ,medicine ,Humans ,Agar ,Candida ,Voriconazole ,Candidiasis ,Micafungin ,General Medicine ,bacterial infections and mycoses ,Culture Media ,Infectious Diseases ,chemistry ,Anidulafungin ,Caspofungin ,medicine.drug - Abstract
We examined the utility of agar dilution to screen yeasts for reduced susceptibility to several newer antifungal drugs including echinocandins and azoles. We compared agar dilution susceptibility screening with the Clinical and Laboratory Standards Institute (CLSI) method for Candida isolates. We added echinocandins and azoles to CHROMagar Candida medium prior to its solidifi cation. Assessment of resistance was based on growth characteristics, wherein decreased colony size in the presence of antifungal drugs was used as an indicator of susceptibility. Clinical Candida isolates of C. albicans , C. glabrata , C. parapsilosis , C. tropicalis , C. guilliermondii , C. lusitaniae , C. rugosa and C. dubliniensis were screened for drug susceptibility. Overall, antifungal susceptibility of the yeasts to anidulafungin, caspofungin, micafungin, posaconazole and voriconazole, determined using CHROMagar agar dilution, were shown to be 96, 80, 94, 90 and 97% as accurate, respectively, as those determined by the CLSI method, i.e., within one tube dilution of CLSI MICs. Categorical errors by percentage had a broader range. Major errors noted with anidulafungin, caspofungin and micafungin were 3, 6 and 0%, respectively, while very major errors were 15, 55 and 38%, respectively. Major errors with posaconazole and voriconazole were 12 and 0%, respectively, while very major errors were 0 and 22%, respectively, compared to CLSI standards. Most of the assessment errors were found with C. glabrata and C. parapsilosis . Agar dilution screening for drug susceptibility with the current panel of antifungal drugs is rapid, accurate and effective. However, the determination of resistance or non-susceptibility in yeasts may be more problematic, and may be species dependent.
- Published
- 2010
25. Trichosporon mycotoxinivorans , a Novel Respiratory Pathogen in Patients with Cystic Fibrosis
- Author
-
Annette W. Fothergill, Michael G. Rinaldi, Howard J. Schmidt, Patrick W. Hickey, Deanna A. Sutton, Brian L. Wickes, and Thomas J. Walsh
- Subjects
Microbiology (medical) ,Pathology ,medicine.medical_specialty ,Antifungal Agents ,Pancreatic disease ,Cystic Fibrosis ,Molecular Sequence Data ,Microbial Sensitivity Tests ,Mycology ,Biology ,Cystic fibrosis ,Microbiology ,Echinocandins ,Fatal Outcome ,Trichosporon ,Amphotericin B ,medicine ,Humans ,Trichosporon mycotoxinivorans ,Lung ,Pathogen ,Retrospective Studies ,Molecular Epidemiology ,Lung Diseases, Fungal ,Triazoles ,medicine.disease ,biology.organism_classification ,Pneumonia ,Mycoses ,Sputum ,Radiography, Thoracic ,medicine.symptom ,medicine.drug - Abstract
This report describes the molecular epidemiology, in vitro susceptibility, colonial and microscopic morphologies, and biochemical features of Trichosporon mycotoxinivorans , a newly recognized pathogen that appears to have a propensity for patients with cystic fibrosis. The index patient died with histologically documented Trichosporon pneumonia complicating cystic fibrosis. This is also the first report of disease caused by a Trichosporon species in a nontransplant patient with cystic fibrosis. As T. mycotoxinivorans has not previously been recognized as a respiratory pathogen, the significance of its recovery from sputum samples was not initially appreciated. Genetic analysis of archived clinical samples found three additional cases of T. mycotoxinivorans infection which had previously been identified as other members of the genus. An additional isolate of T. mycotoxinivorans was identified from a clinical sample on initial testing. Three of these four cases were also patients with cystic fibrosis. All isolates had MICs at 48 h of amphotericin B of ≥1 μg/ml and of echinocandins of ≥16 μg/ml, but they displayed various susceptibilities to the triazoles. In summary, Trichosporon mycotoxinivorans is a newly recognized human pathogen that is associated with cystic fibrosis.
- Published
- 2009
26. Studies on peptidyl nucleoside antibiotics: synthesis and antifungal evaluation of pyranosyl nucleoside analogs of nikkomycin
- Author
-
Michael G. Rinaldi, Annette W. Fothergill, Christina S. Stauffer, and Apurba Dutta
- Subjects
Pharmacology ,Antifungal ,Antifungal Agents ,Nucleoside analogue ,Stereochemistry ,medicine.drug_class ,Antibiotics ,Drug Evaluation, Preclinical ,Nucleosides ,Microbial Sensitivity Tests ,Biology ,Streptomyces ,Anti-Bacterial Agents ,Structure-Activity Relationship ,Aminoglycosides ,Biochemistry ,Drug Discovery ,medicine ,Molecular Medicine ,Structure–activity relationship ,Peptides ,Nucleoside ,medicine.drug ,Biological evaluation - Abstract
Background: The Streptomyces-derived nikkomycins are a unique class of peptidyl nucleoside natural products, with potent antifungal activity against a variety of pathogenic fungi. Results: In continuation of our structure–activity relationship studies on the nikkomycins, this paper describes the strategic design, synthesis and biological evaluation of a ‘doubly modified’ generation of nikkomycin analogs. The structural modifications included a ring-expanded carbohydrate core and a simplified peptidyl side chain. Biological screening of these novel analogs against clinical isolates of various human pathogenic fungi indicated that the described modifications of the structural features of nikkomycin could be a potentially beneficial strategy towards optimizing the antifungal potency of this class of peptidyl nucleoside antibiotics. Conclusion: Continued investigation of the pyranosyl nikkomycin analogs is warranted to fully explore and optimize the structural features of this novel lead for the desired development of a new class of therapeutically useful antifungal drugs.
- Published
- 2009
27. The Epidemiology of Candida Colonization and Invasive Candidiasis in a Surgical Intensive Care Unit Where Fluconazole Prophylaxis is Utilized
- Author
-
Sandra M. Swoboda, Elizabeth Colantuoni, Shelley S. Magill, Craig W. Hendrix, Pamela A. Lipsett, William G. Merz, Annette W. Fothergill, and Christine E. Shields
- Subjects
Male ,Antifungal Agents ,Colony Count, Microbial ,Candida glabrata ,Severity of Illness Index ,law.invention ,Randomized controlled trial ,law ,Odds Ratio ,Medicine ,Prospective Studies ,Prospective cohort study ,Fluconazole ,Fungemia ,Aged, 80 and over ,Academic Medical Centers ,Cross Infection ,biology ,Incidence ,Candidiasis ,Middle Aged ,Intensive care unit ,Survival Rate ,Intensive Care Units ,Treatment Outcome ,Surgical Procedures, Operative ,Cohort ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Critical Illness ,Risk Assessment ,Statistics, Nonparametric ,Young Adult ,Internal medicine ,Preoperative Care ,Humans ,Aged ,business.industry ,medicine.disease ,biology.organism_classification ,Surgery ,Clinical trial ,Logistic Models ,Multivariate Analysis ,business ,Follow-Up Studies - Abstract
Objective To determine whether Candida glabrata colonization and invasive candidiasis (IC) increased among critically ill surgical patients 3 years after the introduction of fluconazole prophylaxis to a surgical intensive care unit (SICU). Summary background data Fluconazole prophylaxis has been shown in randomized clinical trials to reduce the occurrence of candidiasis in some patient populations, including high-risk SICU patients. One such trial was performed in The Johns Hopkins Hospital SICU in 1998. Whether the epidemiology of Candida colonization and IC has changed in SICUs where fluconazole prophylaxis is routinely utilized has not been adequately studied. Methods We conducted a prospective, observational study of subjects admitted for > or = 3 days to the SICU of a large, urban, academic medical center, where fluconazole prophylaxis had been utilized for approximately 3 years. Surveillance fungal cultures of rectal/fecal swabs, urine, and endotracheal aspirates were performed on admission to the SICU, once weekly, and upon discharge from the SICU. Demographic and clinical data were collected. C. glabrata colonization and IC prevalence among patients in the prospective cohort were compared with the prevalence among SICU patients enrolled in the 1998 clinical trial of fluconazole for the prevention of candidiasis that was performed at the same institution. Results C. glabrata colonization was not significantly more common among patients in the 2003 cohort as compared with patients in the 1998 trial (adjusted odds ratio [OR]: 0.90, 95% confidence interval [CI]: 0.57-1.41). Patients with IC in the 2003 cohort were not more likely than those in the 1998 trial to have IC due to C. glabrata (adjusted OR: 1.93, 95% CI: 0.20-18.98), while patients with IC in the 2003 cohort were less likely than patients in the 1998 trial to have acquired IC in the ICU (adjusted OR: 0.08, 95% CI: 0.009-0.82). Conclusions There was no increase in C. glabrata colonization or in the proportion of IC due to C. glabrata after a 3-year period of routine fluconazole prophylaxis for selected SICU patients.
- Published
- 2009
28. Assessment of Aspergillus fumigatus Burden in Pulmonary Tissue of Guinea Pigs by Quantitative PCR, Galactomannan Enzyme Immunoassay, and Quantitative Culture
- Author
-
Brian L. Wickes, Rosie Bocanegra, Thomas F. Patterson, Marsha C. Kinney, Laura K. Najvar, John R. Graybill, Annette W. Fothergill, Monica L. Herrera, Ana C. Vallor, and William R. Kirkpatrick
- Subjects
Male ,Antifungal Agents ,Guinea Pigs ,Colony Count, Microbial ,Antifungal drug ,Mycology ,Aspergillosis ,Polymerase Chain Reaction ,Microbiology ,Aspergillus fumigatus ,Immunoenzyme Techniques ,Mannans ,Galactomannan ,chemistry.chemical_compound ,medicine ,Animals ,Humans ,Experimental Therapeutics ,Pharmacology (medical) ,DNA, Fungal ,Lung ,DNA Primers ,Pharmacology ,Voriconazole ,Base Sequence ,Lung Diseases, Fungal ,biology ,medicine.diagnostic_test ,Galactose ,Triazoles ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Pyrimidines ,Infectious Diseases ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,chemistry ,Immunoassay ,Immunology ,medicine.drug - Abstract
Early diagnosis of invasive pulmonary aspergillosis is problematic in some patient groups due to the lack of rapid, sensitive, specific, and reliable diagnostic tests. Fungal burden and therapeutic efficacy were assessed by survival, quantitative culture (CFU counts), galactomannan enzyme immunoassay (GM-EIA), and quantitative PCR (qPCR) in a new guinea pig model of invasive pulmonary aspergillosis using an aerosol challenge. At 1 day postinfection, qPCR determined that the pulmonary fungal burden was 2 log 10 higher than that determined by CFU counting and increased significantly ( P < 0.03) over time. In contrast, the tissue burden assessed by CFU counting did not rise over the course of the study. Therapy with the antifungal drug voriconazole produced statistically significant decreases in pulmonary fungal burden, as detected by CFU counting ( P < 0.02), qPCR, and GM-EIA (both P < 0.0002). Daily assessment of the progression of fungal infection in serum was performed by qPCR and GM-EIA. GM-EIA demonstrated a statistically significant reduction in the fungal load on days 6 and 7 in voriconazole-treated animals compared to time-matched controls ( P < 0.02). Confirmation of fungal tissue burden by two or more methods should provide a more precise account of the burden, allowing improved assessment of diagnostic and therapeutic strategies in invasive pulmonary aspergillosis.
- Published
- 2008
29. In Vitro Antifungal Susceptibility and Molecular Characterization of Clinical Isolates of Fusarium verticillioides ( F. moniliforme ) and Fusarium thapsinum
- Author
-
Josep Guarro, Michael G. Rinaldi, Deanna A. Sutton, Mónica Azor, Annette W. Fothergill, Josepa Gené, and Josep Cano
- Subjects
Fusarium ,Antifungal ,Posaconazole ,Antifungal Agents ,medicine.drug_class ,Molecular Sequence Data ,Microbial Sensitivity Tests ,Naphthalenes ,Microbiology ,Drug Resistance, Fungal ,Tubulin ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Terbinafine ,Pharmacology ,biology ,Phylogenetic tree ,Fusarium thapsinum ,food and beverages ,Sequence Analysis, DNA ,Fungi imperfecti ,Triazoles ,biology.organism_classification ,In vitro ,Infectious Diseases ,Mycoses ,Susceptibility ,medicine.drug - Abstract
A microdilution method was used to test 11 antifungal drugs against clinical isolates of Fusarium thapsinum and three different phylogenetic clades of Fusarium verticillioides that were characterized by sequencing a region of the β-tubulin gene. Terbinafine was the most-active drug against both species, followed by posaconazole against F. verticillioides .
- Published
- 2008
30. Persistent pulmonary infection with an azole-resistantCoccidioidesspecies
- Author
-
John D. Kriesel, Michael G. Rinaldi, Deanna A. Sutton, Annette W. Fothergill, and Susan Schulman
- Subjects
Azoles ,Lung Diseases ,Male ,Antifungal Agents ,Drug resistance ,Biology ,Drug Resistance, Fungal ,Recurrence ,Amphotericin B ,medicine ,Humans ,Coccidioides ,chemistry.chemical_classification ,Coccidioidomycosis ,Antibody titer ,General Medicine ,Middle Aged ,Complement fixation test ,biology.organism_classification ,medicine.disease ,Meningitis, Fungal ,Infectious Diseases ,chemistry ,Immunology ,Azole ,Meningitis ,Fluconazole ,medicine.drug - Abstract
We report a case of a life-threatening, recurrent, and azole-resistant pulmonary coccidioidomycosis in a patient receiving long-term fluconazole therapy for a history of coccidioidal meningitis. Since this diagnosis, the patient has received weekly amphotericin B for more than four years and remains in remission with a stable serum Coccidioides complement fixation antibody titer.
- Published
- 2008
31. Multicenter Evaluation of a New Disk Agar Diffusion Method for Susceptibility Testing of Filamentous Fungi with Voriconazole, Posaconazole, Itraconazole, Amphotericin B, and Caspofungin
- Author
-
David Ellis, Annette W. Fothergill, Shawn A. Messer, Ana Espinel-Ingroff, M. A. Pfaller, Beth A. Arthington-Skaggs, A. Wang, D. L. Gibbs, Naureen Iqbal, and M. Rinaldi
- Subjects
Microbiology (medical) ,Posaconazole ,Antifungal Agents ,food.ingredient ,Microbial Sensitivity Tests ,Mycology ,Peptides, Cyclic ,Disk Diffusion Antimicrobial Tests ,Aspergillus fumigatus ,Microbiology ,Echinocandins ,Lipopeptides ,chemistry.chemical_compound ,food ,Caspofungin ,Amphotericin B ,medicine ,Agar ,Agar diffusion test ,Voriconazole ,biology ,Fungi ,Reproducibility of Results ,Triazoles ,biology.organism_classification ,Culture Media ,Pyrimidines ,chemistry ,Itraconazole ,medicine.drug - Abstract
The purpose of this study was to correlate inhibition zone diameters, in millimeters (agar diffusion disk method), with the broth dilution MICs or minimum effective concentrations (MECs) (CLSI M38-A method) of five antifungal agents to identify optimal testing guidelines for disk mold testing. The following disk diffusion testing parameters were evaluated for 555 isolates of the molds Absidia corymbifera , Aspergillus sp. (five species), Alternaria sp., Bipolaris spicifera , Fusarium sp. (three species), Mucor sp. (two species), Paecilomyces lilacinus , Rhizopus sp. (two species), and Scedosporium sp. (two species): (i) two media (supplemented Mueller-Hinton agar [2% dextrose and 0.5 μg/ml methylene blue] and plain Mueller-Hinton [MH] agar), (ii) three incubation times (16 to 24, 48, and 72 h), and (iii) seven disks (amphotericin B and itraconazole 10-μg disks, voriconazole 1- and 10-μg disks, two sources of caspofungin 5-μg disks [BBL and Oxoid], and posaconazole 5-μg disks). MH agar supported better growth of all of the species tested (24 to 48 h). The reproducibility of zone diameters and their correlation with either MICs or MECs (caspofungin) were superior on MH agar (91 to 100% versus 82 to 100%; R , 0.71 to 0.93 versus 0.53 to 0.96 for four of the five agents). Based on these results, the optimal testing conditions for mold disk diffusion testing were (i) plain MH agar; (ii) incubation times of 16 to 24 h (zygomycetes), 24 h ( Aspergillus fumigatus , A. flavus , and A. niger ), and 48 h (other species); and (iii) the posaconazole 5-μg disk, voriconazole 1-μg disk, itraconazole 10-μg disk (for all except zygomycetes), BBL caspofungin 5-μg disk, and amphotericin B 10-μg (zygomycetes only).
- Published
- 2007
32. Multicenter Evaluation of the New VITEK 2 Advanced Colorimetric Yeast Identification Card
- Author
-
D. Jane Hata, Annette W. Fothergill, Leslie Hall, Davise H. Larone, and Nancy L. Wengenack
- Subjects
Quality Control ,Microbiology (medical) ,Time Factors ,Reproducibility of Results ,Mycology ,Reference Standards ,Biology ,bacterial infections and mycoses ,equipment and supplies ,Sensitivity and Specificity ,Yeast ,Microbiology ,Clinical microbiology ,Mycoses ,Multicenter study ,Yeasts ,Humans ,Species identification ,Colorimetry ,Mycological Typing Techniques ,Reference standards - Abstract
The performance of the new VITEK 2 Advanced Colorimetry yeast identification (YST) card for use with the VITEK 2 system (bioMérieux, Inc., Hazelwood, MO) was compared to that of the API 20C AUX (API) system (bioMérieux SA, Marcy-l'Etoile, France) in a multicenter evaluation. A total of 12 quality control, 64 challenge, and 623 clinical yeast isolates were used in the study. Comparisons of species identification, platform reliability, and substrate reproducibility were made between YST and API, with API considered the reference standard. Quality control testing to assess system and substrate reproducibility matched expected results ≥95% of the time. The YST card correctly identified 100% of the challenge strains, which covered the species range of the manufacturer's performance claims. Using clinical isolates, the YST card correctly identified 98.5%, with 1.0% of isolates incorrectly identified and 0.5% unidentified. Among clinical isolates, the YST card generated fewer low-discrimination results (18.9%) than did API (30.0%). The time to identification with YST was 18 h, compared to 48 to 72 h with API. The colorimetric YST card used with the VITEK 2 provides a highly automated, objective yeast identification method with excellent performance and reproducibility. We found this system useful for timely and accurate identification of significant yeast species in the clinical microbiology laboratory.
- Published
- 2007
33. Absence of an Active Metabolite for the Triazole Antifungal Pramiconazole
- Author
-
Jannie Ausma, Gennethel Pennick, Hilde Bohets, Annette W. Fothergill, V. Van de Velde, and Marcel Borgers
- Subjects
Antifungal Agents ,business.industry ,Pramiconazole ,Metabolite ,Imidazoles ,Triazole ,Dermatology ,General Medicine ,Metabolism ,Triazoles ,Pharmacology ,medicine.disease_cause ,Yeast ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Tandem Mass Spectrometry ,Dermatophyte ,Humans ,Medicine ,Bioassay ,business ,Active metabolite ,medicine.drug - Abstract
Pramiconazole is an antifungal with high potential for the treatment of dermatophyte and yeast infections of the skin. It is currently not known whether pramiconazole is active alone as the parent agent or assisted by active metabolites. The in vitro metabolism as well as the metabolic stability of pramiconazole was investigated in subcellular liver fractions and isolated hepatocytes of several species. Results indicate that the metabolism of pramiconazole was slow, since the enzyme-mediated disappearance of pramiconazole was rather slow. To investigate whether pramiconazole was converted into an active metabolite in humans, serum samples from healthy volunteers receiving a daily dose of 100 or 200 mg pramiconazole for one week were assayed with an agar diffusion bioassay and liquid chromatography-tandem mass spectrometry. It was concluded that there was no active metabolite present in serum samples from healthy volunteers after oral dosing of pramiconazole.
- Published
- 2007
34. Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
- Author
-
Sunita Sinha, Larry Sallans, Ashutosh Singh, Amir M. Farnoud, Shamoon Naseem, Pankaj B. Desai, Antonella Rella, Kildare Miranda, James B. Konopka, Guri Giaever, Iwao Ojima, Thomas F. Patterson, Margaret S. Collins, Nathan P. Wiederhold, Gabriele Vargas Cesar, Erika E. Büllesbach, Alan Ashbaugh, Hari Krishna Ananthula, Lai Hong Wong, Marcio L. Rodrigues, Arielle M. Bryan, Visesato Mor, William R. Kirkpatrick, Patricia de Melo Tavares, Michael J. Linke, Mansa Munshi, Maurizio Del Poeta, Xuewen Pan, Corey Nislow, Annette W. Fothergill, Susana Frases, Patrick Flaherty, Leonardo Nimrichter, Chiara Luberto, and Melanie T. Cushion
- Subjects
Virulence ,Drug resistance ,Pharmacology ,Biology ,medicine.disease ,Cell morphology ,Microbiology ,Sphingolipid ,QR1-502 ,In vitro ,3. Good health ,In vivo ,Cell culture ,Virology ,Cryptococcosis ,medicine - Abstract
Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [ N ′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo- N ′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5 , COS111 , MKK1 , and STE2 , which are involved in vesicular transport and cell cycle progression, are targeted by BHBM. IMPORTANCE Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
- Published
- 2015
35. Detection of triazole resistance among Candida species by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS)
- Author
-
Nathan P. Wiederhold, Deanna A. Sutton, Annette W. Fothergill, and Mehmet Ali Saraçli
- Subjects
Voriconazole ,Posaconazole ,Reproducibility ,Antifungal Agents ,Triazole ,Reproducibility of Results ,General Medicine ,Microbial Sensitivity Tests ,Triazoles ,Corpus albicans ,Microbiology ,Matrix-assisted laser desorption/ionization ,chemistry.chemical_compound ,Infectious Diseases ,Antibiotic resistance ,chemistry ,Drug Resistance, Fungal ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,medicine ,Humans ,Fluconazole ,medicine.drug ,Candida - Abstract
MALDI-TOF MS can rapidly identify microorganisms to the species level and may be able to detect antimicrobial resistance. We evaluated the ability of this technology to detect triazole resistance in Candida species.35 C. albicans, 35 C. glabrata, and 37 C. tropicalis strains were exposed to fluconazole, voriconazole, or posaconazole at two different concentrations plus a drug-free control: a midrange concentration (CLSI clinical breakpoint or epidemiologic cut-off value), and a high concentration (fluconazole 64 μg/ml, voriconazole & posaconazole 16 μg/ml). The MALDI-TOF MS spectra at these concentrations were used to create the individual composite correlation index (CCI) matrices for each isolate. When the CCI of the midrange/highest concentration was lower than that of the midrange/null concentration, the strain was classified as resistant. These results were then compared to the classifications for susceptible or resistant obtained by measuring the MICs according to the CLSI M27-A3 antifungal susceptibility testing (AFST) method.The MALDI-TOF MS assay was able to classify triazole susceptibility against all strains. Overall, essential agreement between MALDI-TOF MS and AFST varied between 54% and 97%, and was highest for posaconazole against C. glabrata. The reproducibility of the MALDI-TOF MS assay varied between 54.3 and 82.9% and was best for fluconazole against C. albicans and posaconazole against C. glabrata. Reproducibility was also higher for C. glabrata isolates compared to C. albicans and C. tropicalis.These results demonstrate that MALDI-TOF MS may be used to simultaneously determine the Candida species and classification as susceptible or resistant to triazole antifungals. Further studies are needed to refine the methodology and improve the reproducibility of this assay.
- Published
- 2015
36. Evaluation of VT-1161 for Treatment of Coccidioidomycosis in Murine Infection Models
- Author
-
John N. Galgiani, Robert J. Schotzinger, Hien T. Trinh, Edward P. Garvey, William J. Hoekstra, Eric R. G. Lewis, Maria L. Lewis, Annette W. Fothergill, Bridget M. Barker, Adina Doyle, Lisa F. Shubitz, and Nathan P. Wiederhold
- Subjects
Antifungal Agents ,Pyridines ,Tetrazoles ,Microbial Sensitivity Tests ,Pharmacology ,Biology ,Placebo ,Fungal Proteins ,Mice ,Sterol 14-Demethylase ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Coccidioides ,Experimental Therapeutics ,Fluconazole ,Fungemia ,Fungal protein ,Coccidioidomycosis ,medicine.disease ,biology.organism_classification ,Survival Analysis ,Valley fever ,Disease Models, Animal ,Infectious Diseases ,Treatment Outcome ,14-alpha Demethylase Inhibitors ,Female ,medicine.drug ,Half-Life - Abstract
Coccidioidomycosis, or valley fever, is a growing health concern endemic to the southwestern United States. Safer, more effective, and more easily administered drugs are needed especially for severe, chronic, or unresponsive infections. The novel fungal CYP51 inhibitor VT-1161 demonstrated in vitro antifungal activity, with MIC 50 and MIC 90 values of 1 and 2 μg/ml, respectively, against 52 Coccidioides clinical isolates. In the initial animal study, oral doses of 10 and 50 mg/kg VT-1161 significantly reduced fungal burdens and increased survival time in a lethal respiratory model in comparison with treatment with a placebo ( P < 0.001). Oral doses of 25 and 50 mg/kg VT-1161 were similarly efficacious in the murine central nervous system (CNS) model compared to placebo treatment ( P < 0.001). All comparisons with the positive-control drug, fluconazole at 50 mg/kg per day, demonstrated either statistical equivalence or superiority of VT-1161. VT-1161 treatment also prevented dissemination of infection from the original inoculation site to a greater extent than fluconazole. Many of these in vivo results can be explained by the long half-life of VT-1161 leading to sustained high plasma levels. Thus, the efficacy and pharmacokinetics of VT-1161 are attractive characteristics for long-term treatment of this serious fungal infection.
- Published
- 2015
37. Antifungal Susceptibility Testing
- Author
-
Annette W. Fothergill, Michael G. Rinaldi, and Deanna A. Sutton
- Subjects
Microbiology (medical) ,Antifungal ,Susceptibility testing ,medicine.medical_specialty ,Antifungal Agents ,business.industry ,medicine.drug_class ,Fungi ,Microbial Sensitivity Tests ,Patient care ,Infectious Diseases ,Drug Resistance, Fungal ,Humans ,Medicine ,Treatment decision making ,medicine.symptom ,Laboratories ,business ,Intensive care medicine ,Confusion - Abstract
Antifungal susceptibility testing has been in routine use now for more than 15 years and has become a useful tool for clinicians who are faced with difficult treatment decision. Although most clinicians order susceptibility testing, much confusion still exists regarding the use of the results. Sufficient data have been generated to determine susceptibility trends for specific fungi against specific agents, but correlation data are minimal. Despite the lack of correlation data, antifungal susceptibility testing continues to provide useful information to assist with patient care.
- Published
- 2006
38. Miconazole: a historical perspective
- Author
-
Annette W. Fothergill
- Subjects
Microbiology (medical) ,chemistry.chemical_classification ,Antifungal Agents ,Miconazole ,Nonprescription Drugs ,Biology ,Pharmacology ,Microbiology ,Infectious Diseases ,Mycoses ,chemistry ,Ergosterol synthesis ,Virology ,Yeast fungi ,Vaginal candidiasis ,medicine ,Animals ,Humans ,Azole ,medicine.drug - Abstract
Miconazole is an imidazole that has been successfully used for over 30 years for the treatment of superficial and cutaneous disease. This agent is distinguished from other azoles by possessing two mechanisms of action. The first mechanism is shared with other azoles and involves the inhibition of ergosterol synthesis. Another mechanism involves inhibition of peroxidases, which results in the accumulation of peroxide within the cell resulting in cell death. Susceptibility patterns for miconazole demonstrate that yeast fungi remain largely susceptible even in light of repeated exposures. Despite the release of newer azoles and other classes of antifungals, miconazole remains a highly prescribed treatment for vaginal candidiasis.
- Published
- 2006
39. Mistaken Identity: Neosartorya pseudofischeri and Its Anamorph Masquerading as Aspergillus fumigatus
- Author
-
Jennifer L. Gribskov, James I. Ito, S. Arunmozhi Balajee, Kieren A. Marr, Mary E. Brandt, and Annette W. Fothergill
- Subjects
Microbiology (medical) ,Antifungal Agents ,Microbial Sensitivity Tests ,Mycology ,Eurotiales ,Peritonitis ,Aspergillosis ,Aspergillus fumigatus ,Microbiology ,medicine ,Humans ,Diagnostic Errors ,DNA, Fungal ,Mycological Typing Techniques ,Voriconazole ,Endocarditis ,Lung Diseases, Fungal ,biology ,Neosartorya pseudofischeri ,Fungi imperfecti ,biology.organism_classification ,medicine.disease ,medicine.drug_formulation_ingredient ,Phenotype ,Mycoses ,Neosartorya ,Aspergillus lentulus ,medicine.drug - Abstract
Invasive fungal infections caused by Neosartorya pseudofischeri S. W. Peterson [anamorph Aspergillus thermomutatus (Paden) S. W. Peterson] are extremely rare. Phenotypically, the anamorphic state of N. pseudofischeri resembles Aspergillus fumigatus , the predominant agent of invasive aspergillosis in immunocompromised hosts. We report the recovery of three clinical isolates of N. pseudofischeri , all initially misidentified by morphological characteristics as A. fumigatus . All three isolates were correctly identified by sequencing portions of the β-tubulin and the rodlet A genes. Only one of the three isolates produced the confirmatory fruiting bodies and was thus classified as N. pseudofischeri ; the other isolates did not produce asci and were therefore identified as A. thermomutatus . All three isolates had higher MICs to voriconazole in vitro compared to A. fumigatus Af293. This report emphasizes that phenotypic identification of filamentous fungi may not identify morphologically similar, but genetically distinct, members of the genus Aspergillus section Fumigati . Accurate identification of these organisms may be clinically meaningful, given their potential differences in antifungal susceptibilities.
- Published
- 2005
40. In Vitro Efficacy of Lufenuron against Filamentous Fungi and Blood Concentrations after PO Administration in Horses
- Author
-
Nicole C. Scotty, Tim J. Evans, Elizabeth Giuliano, Philip J. Johnson, George E. Rottinghaus, Annette W. Fothergill, and Tim J. Cutler
- Subjects
General Veterinary - Published
- 2005
41. Quality Control and Reference Guidelines for CLSI Broth Microdilution Susceptibility Method (M38-A Document) for Amphotericin B, Itraconazole, Posaconazole, and Voriconazole
- Author
-
Wiley A. Schell, Michael G. Rinaldi, Elias K. Manavathu, M. A. Pfaller, Mahmoud A. Ghannoum, Annette W. Fothergill, Ana Espinel-Ingroff, Luis Ostrosky-Zeichner, and Thomas J. Walsh
- Subjects
Quality Control ,Microbiology (medical) ,Posaconazole ,Antifungal Agents ,Itraconazole ,Microbial Sensitivity Tests ,Mycology ,Aspergillus fumigatus ,Microbiology ,Drug Resistance, Fungal ,Amphotericin B ,medicine ,Humans ,Voriconazole ,biology ,Broth microdilution ,Fungi ,Triazoles ,biology.organism_classification ,Paecilomyces variotii ,Pyrimidines ,Paecilomyces ,medicine.drug - Abstract
Although standard conditions are available for testing the susceptibilities of filamentous fungi to antifungal agents by the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards) broth microdilution assay, quality control (QC) MIC limits have not been established for any mold-agent combination. This multicenter (eight-center) study documented the reproducibility of tests for one isolate of Paecilomyces variotii ATCC MYA-3630 and 11 other mold isolates (three isolates of Aspergillus fumigatus ; two isolates of A. terreus ; one isolate each of A. flavus , A. nidulans , Fusarium moniliforme , and F. solani ; and two isolates of Scedosporium apiospermum ) by the CLSI reference broth microdilution method (M38-A document). Control limits (amphotericin B, 1 to 4 μg/ml; itraconazole, 0.06 to 0.5 μg/ml; posaconazole, 0.03 to 0.25 μg/ml; voriconazole, 0.015 to 0.12 μg/ml) for the selected QC P. variotii ATCC MYA-3630 were established by the analysis of replicate MIC results. Reference isolates and corresponding MIC ranges were also established for 6 of the 12 molds evaluated. MIC limits were not proposed for the other five molds tested due to low testing reproducibility for these isolates.
- Published
- 2005
42. Caspofungin in Combination with Amphotericin B against Candida glabrata
- Author
-
Elisabetta Spreghini, Francesco Barchiesi, Michael G. Rinaldi, D. Arzeni, Daniele Giannini, Gianfranco Greganti, Giorgio Scalise, and Annette W. Fothergill
- Subjects
Male ,Antifungal Agents ,medicine.drug_class ,Antibiotics ,Amfotericina B ,Colony Count, Microbial ,Candida glabrata ,Microbial Sensitivity Tests ,Pharmacology ,Biology ,Peptides, Cyclic ,Microbiology ,Echinocandins ,Lipopeptides ,Mice ,chemistry.chemical_compound ,Caspofungin ,Amphotericin B ,medicine ,Animals ,Experimental Therapeutics ,Pharmacology (medical) ,Fungemia ,Candidiasis ,biochemical phenomena, metabolism, and nutrition ,equipment and supplies ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,Amphotéricine B ,Regimen ,Treatment Outcome ,Infectious Diseases ,chemistry ,Drug Therapy, Combination ,medicine.drug - Abstract
The effects of caspofungin combined with amphotericin B were investigated with Candida glabrata . Although in vitro experiments showed an indifferent interaction, the combination regimen was the only therapeutic approach yielding organ sterilization in a murine candidemia model.
- Published
- 2005
43. Scedosporium apiospermum Soft Tissue Infection Successfully Treated with Voriconazole: Potential Pitfalls in the Transition from Intravenous to Oral Therapy
- Author
-
Daniel B. DiGiulio, Nancy M. McClenny, Michael G. Rinaldi, Annette W. Fothergill, Jose G. Montoya, Joanna Schaenman, Laurence F. Mirels, and Gerald J. Berry
- Subjects
Microbiology (medical) ,Oral dose ,Voriconazole ,medicine.medical_specialty ,Surgical debridement ,Soft tissue ,Scedosporium apiospermum ,Biology ,Surgery ,Scedosporium ,medicine ,Soft tissue infection ,Oral therapy ,medicine.drug - Abstract
An immunocompromised patient with an invasive soft tissue infection due to Scedosporium apiospermum was successfully treated with voriconazole and surgical debridement. After transition from intravenous to oral therapy, successive adjustments of the oral dose were required to achieve complete resolution. For soft tissue infections due to molds characterized by thin, septate hyphae branching at acute angles, voriconazole should be considered a first-line antifungal agent. The potential usefulness of plasma voriconazole levels for guiding optimal therapy should be investigated.
- Published
- 2005
44. In vitroactivities of new and established triazoles against opportunistic filamentous and dimorphic fungi
- Author
-
Gloria M. González, Michael G. Rinaldi, Annette W. Fothergill, Deanna A. Sutton, and David Loebenberg
- Subjects
Antifungal Agents ,biology ,Blastomyces dermatitidis ,Coccidioides immitis ,Fungi ,Microbial Sensitivity Tests ,General Medicine ,Triazoles ,bacterial infections and mycoses ,Ravuconazole ,biology.organism_classification ,Microbiology ,Pseudallescheria boydii ,Fonsecaea pedrosoi ,Thiazoles ,Pyrimidines ,Infectious Diseases ,Mycoses ,Species Specificity ,Humans ,Sporothrix schenckii ,Voriconazole ,Paecilomyces ,skin and connective tissue diseases ,Dimorphic fungus - Abstract
The in vitro activities of three new triazoles were determined and compared to those of itraconazole and fluconazole against 306 clinical isolates of Blastomyces dermatitidis, Cladophialophora carrionii, Coccidioides immitis, Fonsecaea pedrosoi, Fusarium spp., Histoplasma capsulatum, Paecilomyces lilacinus, Pseudallescheria boydii and Sporothrix schenckii. Minimum inhibitory concentrations (MIC) were determined by a broth macrodilution method of the National Committee for Clinical Laboratory Standards M38-A procedure. Itraconazole (geometric mean MIC, 0.16-0.65 microg/ml), voriconazole (geometric mean MIC, 0.18-1.44 microg/ml), ravuconazole (geometric mean MIC, 0.18-1.09 microg/ml), and posaconazole (geometric mean MIC, 0.18-1.38 microg/ml), had relatively uniform values showing potent in vitro inhibitory activity against B. dermatitidis, C. carrionii, C. immitis, F. pedrosoi, H. capsulatum, and S. schenckii. The in vitro activity was variable with strains of P. boydii, P. lilacinus and Fusarium spp.
- Published
- 2005
45. Comparison of MICs of Fluconazole and Flucytosine When Dissolved in Dimethyl Sulfoxide or Water
- Author
-
Annette W. Fothergill, Nathan P. Wiederhold, and Carmita Sanders
- Subjects
Microbiology (medical) ,Antifungal ,Antifungal Agents ,medicine.drug_class ,Flucytosine ,Microbial Sensitivity Tests ,Mycology ,Biology ,Pharmacology ,chemistry.chemical_compound ,medicine ,Humans ,Potency ,Dimethyl Sulfoxide ,Fluconazole ,Candida ,Chromatography ,Dimethyl sulfoxide ,Water ,Solvent ,chemistry ,Mic values ,Solvents ,medicine.drug - Abstract
A total of 145 clinical strains of Candida species were tested by the Clinical and Laboratory Standards Institute M27-A3 methodology to determine if replacing water with dimethyl sulfoxide as the solvent for fluconazole and flucytosine impacted the in vitro potency. No significant differences in MIC values were observed with either antifungal between the two solvents against any Candida species, and the essential agreement for each agent between the two solvents was greater than 99%.
- Published
- 2013
46. MIC Values of Voriconazole Are Predictive of Treatment Results in Murine Infections by Aspergillus terreus Species Complex
- Author
-
Valentina Salas, Josep Guarro, Michael G. Rinaldi, Enrique Calvo, Annette W. Fothergill, F. Javier Pastor, Deanna A. Sutton, and Emilio Mayayo
- Subjects
Male ,Drug ,Antifungal Agents ,media_common.quotation_subject ,Microbial Sensitivity Tests ,Treatment results ,Biology ,Microbiology ,Mannans ,Mice ,Galactomannan ,chemistry.chemical_compound ,Drug Resistance, Fungal ,Amphotericin B ,medicine ,Animals ,Aspergillosis ,Experimental Therapeutics ,Pharmacology (medical) ,Aspergillus terreus ,skin and connective tissue diseases ,media_common ,Pharmacology ,Voriconazole ,Galactose ,Triazoles ,bacterial infections and mycoses ,Prognosis ,biology.organism_classification ,Survival Analysis ,Aspergillus ,Pyrimidines ,Infectious Diseases ,chemistry ,Murine model ,Mic values ,medicine.drug - Abstract
We evaluated the efficacy of voriconazole against nine strains of Aspergillus terreus with different MICs (0.12 to 4 μg/ml) by using a murine model. Markers of efficacy included survival, tissue burden, galactomannan antigenemia, and drug serum levels. Voriconazole was especially effective in prolonging survival and reducing the fungal load in infections by strains that showed MICs that were less than or equal to the epidemiological cutoff value (1 μg/ml). In vitro data might be useful for predicting the outcome of A. terreus infections.
- Published
- 2013
47. Voriconazole minimum inhibitory concentrations are predictive of treatment outcome in experimental murine infections by Candida glabrata
- Author
-
Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, Universitat Rovira i Virgili, Javier Luque; Marta Sanchis; Mariana Castanheira; Adela Martin-Vicente; Deanna A. Sutton; Annette W. Fothergill; Nathan P. Wiederhold; Josep Guarro, Unitat de Micologia i Microbiologia Ambiental, Ciències Mèdiques Bàsiques, Universitat Rovira i Virgili, and Javier Luque; Marta Sanchis; Mariana Castanheira; Adela Martin-Vicente; Deanna A. Sutton; Annette W. Fothergill; Nathan P. Wiederhold; Josep Guarro
- Abstract
DOI: 10.1016/j.ijantimicag.2015.12.020, In this study, 27 clinical isolates of Candida glabrata with voriconazole (VRC) minimum inhibitory concentrations (MICs) ranging from ¿0.03 ¿g/mL to 8 ¿g/mL were tested to determine whether in vitro data are predictive of in vivo efficacy. The efficacy of VRC administered at 40 mg/kg was assayed in a neutropenic murine model of disseminated infection by C. glabrata. The reduction in fungal tissue burden in the kidneys was used as a marker of treatment efficacy. VRC reduced the fungal tissue burden in mice infected with strains that had MICs below the epidemiological cut-off value (ECV) of 0.25 ¿g/mL. Variable efficacy of VRC was obtained when the MIC equalled the ECV, and VRC was ineffective when the MIC exceeded the ECV. These results suggest that the use of in vitro data could be useful to predict the outcome for infections by this fungus.
- Published
- 2016
48. In Vitro Activities of Voriconazole in Combination with Three Other Antifungal Agents against Candida glabrata
- Author
-
Elisabetta Spreghini, Monia Maracci, Annette W. Fothergill, Michael G. Rinaldi, Giorgio Scalise, Francesco Barchiesi, and Isabella Baldassarri
- Subjects
Antifungal Agents ,genetic structures ,Flucytosine ,Candida glabrata ,Microbial Sensitivity Tests ,Naphthalenes ,Biology ,Pharmacology ,Microbiology ,chemistry.chemical_compound ,In vivo ,Amphotericin B ,medicine ,Pharmacology (medical) ,Terbinafine ,Voriconazole ,Ergosterol ,Broth microdilution ,Drug Synergism ,Triazoles ,biology.organism_classification ,Drug Combinations ,Kinetics ,Pyrimidines ,Infectious Diseases ,chemistry ,Susceptibility ,medicine.drug - Abstract
Candida glabrata has recently emerged as a significant pathogen involved in both superficial and deep-seated infections. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of voriconazole (VOR) in combination with terbinafine (TRB), amphotericin B (AMB), and flucytosine (5FC) against 20 clinical isolates of C. glabrata . Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤0.50, was observed in 75% of VOR-TRB, 10% of VOR-AMB, and 5% of VOR-5FC interactions. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. In particular, the MICs were reduced to ≤1.0 μg/ml as a result of the combination for all isolates for which the AMB MIC at the baseline was ≥2.0 μg/ml. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were greater that those produced by each drug alone. Finally, killing curves showed that VOR-AMB exhibited synergistic interactions, while VOR-5FC sustained fungicidal activities against C. glabrata . These studies demonstrate that the in vitro activity of VOR against this important yeast pathogen can be enhanced upon combination with other drugs that have different modes of action or that target a different step in the ergosterol pathway. Further studies are warranted to elucidate the potential beneficial effects of such combination regimens in vivo.
- Published
- 2004
49. Candida glabrata is an emerging cause of oropharyngeal candidiasis in patients receiving radiation for head and neck cancer
- Author
-
Spencer W. Redding, Brent J. Coco, Annette W. Fothergill, Marta Caceres Dahiya, Thomas F. Patterson, Michael G. Rinaldi, William R. Kirkpatrick, and Charles R. Thomas
- Subjects
Adult ,Male ,medicine.medical_specialty ,Antifungal Agents ,medicine.medical_treatment ,Oropharynx ,Candida glabrata ,Opportunistic Infections ,Gastroenterology ,Oropharyngeal Candidiasis ,Immunocompromised Host ,Candidiasis, Oral ,Drug Resistance, Fungal ,Internal medicine ,medicine ,Humans ,Candida albicans ,Fluconazole ,General Dentistry ,Mycosis ,Aged ,biology ,Head and neck cancer ,Pharyngeal Diseases ,Middle Aged ,medicine.disease ,biology.organism_classification ,Surgery ,Radiation therapy ,stomatognathic diseases ,Otorhinolaryngology ,Chemotherapy, Adjuvant ,Concomitant ,Carcinoma, Squamous Cell ,Mouth Neoplasms ,Oral Surgery ,medicine.drug - Abstract
Oropharyngeal candidiasis (OPC) is relatively common in patients receiving radiation for head and neck cancer occurring in approximately 25% of patients. Candida albicans has been described as the primary infecting organism. Recently, other organisms, particularly Candida glabrata, have emerged as causative agents of OPC among immunocompromised patients. This study describes the characteristics of 6 patients with head and neck cancer treated with radiotherapy at our institution, who were found to have Candida glabrata-associated OPC and their responses to oral fluconazole. All 6 patients were successfully treated with oral fluconazole. However, most did not respond to the usual dose of 100 mg/day necessitating doses ranging from 200 to 800 mg/day to achieve clinical cure. All 3 patients receiving radiation only were successfully treated with up to 200 mg/day; 2 of 3 patients receiving concomitant chemoradiation required doses ranging from 400 to 800 mg/day. As with systemic infection, previous fluconazole use appears to be a risk factor for this infection, but not with all patients.
- Published
- 2004
50. Multiple Patterns of Resistance to Fluconazole in Candida glabrata Isolates from a Patient with Oropharyngeal Candidiasis Receiving Head and Neck Radiation
- Author
-
Thomas F. Patterson, Michael G. Rinaldi, Spencer W. Redding, Annette W. Fothergill, William White, Brent J. Coco, Tony Y. Eng, Jose L. Lopez-Ribot, Stephen P. Saville, and William R. Kirkpatrick
- Subjects
Male ,Microbiology (medical) ,Antifungal Agents ,medicine.medical_treatment ,Candida glabrata ,Mycology ,Biology ,Abnormalities, Radiation-Induced ,Oropharyngeal Candidiasis ,Drug Resistance, Fungal ,medicine ,Humans ,Fluconazole ,Mycosis ,Head and neck cancer ,Candidiasis ,Pharyngitis ,Fungi imperfecti ,Middle Aged ,medicine.disease ,biology.organism_classification ,Radiation therapy ,Immunology ,medicine.symptom ,Head ,Neck ,medicine.drug - Abstract
Candida glabrata has emerged in recent years as a significant cause of systemic fungal infection. We have previously reported on the first three patients receiving radiation for head and neck cancer to develop oropharyngeal candidiasis due to C. glabrata . The goal of this study was to track the development of increased fluconazole resistance in C. glabrata isolates and to evaluate previously described genetic mechanisms associated with this resistance from one of these three patients. The patient was a 52-year-old man with squamous cell carcinoma treated with radiation. At week 7 of his radiation, he developed oropharyngeal candidiasis, which was treated with 200 mg of fluconazole daily for 2 weeks. Serial cultures from this and three subsequent time points yielded C. glabrata . Isolates from these cultures were subjected to antifungal susceptibility testing, DNA karyotyping, and evaluation of the expression of genes previously associated with C. glabrata resistance to fluconazole, CgCDR1 , CgCDR2 , and CgERG11 . Two strains (A and B) of C. glabrata were identified and found to display different patterns of resistance development and gene expression. Strain A developed resistance over a 2-week period and showed no overexpression of these genes. In contrast, strain B first showed resistance 6 weeks after fluconazole therapy was discontinued but showed overexpression of all three genes. In conclusion, development of resistance to fluconazole by C. glabrata is a highly varied process involving multiple molecular mechanisms.
- Published
- 2003
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.