Isothermal microcalorimetry for antifungal susceptibility testing of Mucorales, Fusarium spp., and Scedosporium spp.

PubMed

Furustrand Tafin, Ulrika; Meis, Jacques F; Trampuz, Andrej

2012-08-01

We evaluated isothermal microcalorimetry for real-time susceptibility testing of non-Aspergillus molds. MIC and minimal effective concentration (MEC) values of Mucorales (n = 4), Fusarium spp. (n = 4), and Scedosporium spp. (n = 4) were determined by microbroth dilution according to the Clinical Laboratory Standard Institute M38-A2 guidelines. Heat production of molds was measured at 37 °C in Sabouraud dextrose broth inoculated with 2.5 × 10(4) spores/mL in the presence of amphotericin B, voriconazole, posaconazole, caspofungin, and anidulafungin. As determined by microcalorimetry, amphotericin B was the most active agent against Mucorales (MHIC 0.06-0.125 μg/mL) and Fusarium spp. (MHIC 1-4 μg/mL), whereas voriconazole was the most active agent against Scedosporium spp. (MHIC 0.25 to 8 μg/mL). The percentage of agreement (within one 2-fold dilution) between the MHIC and MIC (or MEC) was 67%, 92%, 75%, and 83% for amphotericin B, voriconazole, posaconazole, and caspofungin, respectively. Microcalorimetry provides additional information on timing of antifungal activity, enabling further investigation of drug-mold and drug-drug interaction, and optimization of antifungal treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

A multicenter phase 2 study of empirical low-dose liposomal amphotericin B in patients with refractory febrile neutropenia.

PubMed

Miyao, Kotaro; Sawa, Masashi; Kurata, Mio; Suzuki, Ritsuro; Sakemura, Reona; Sakai, Toshiyasu; Kato, Tomonori; Sahashi, Satomi; Tsushita, Natsuko; Ozawa, Yukiyasu; Tsuzuki, Motohiro; Kohno, Akio; Adachi, Tatsuya; Watanabe, Keisuke; Ohbayashi, Kaneyuki; Inagaki, Yuichiro; Atsuta, Yoshiko; Emi, Nobuhiko

2017-01-01

Invasive fungal infection (IFI) is a major life-threatening problem encountered by patients with hematological malignancies receiving intensive chemotherapy. Empirical antifungal agents are therefore important. Despite the availability of antifungal agents for such situations, the optimal agents and administration methods remain unclear. We conducted a prospective phase 2 study of empirical 1 mg/kg/day liposomal amphotericin B (L-AMB) in 80 patients receiving intensive chemotherapy for hematological malignancies. All enrolled patients were high-risk and had recurrent prolonged febrile neutropenia despite having received broad-spectrum antibacterial therapy for at least 72 hours. Fifty-three patients (66.3 %) achieved the primary endpoint of successful treatment, thus exceeding the predefined threshold success rate. No patients developed IFI. The treatment completion rate was 73.8 %, and only two cases ceased treatment because of adverse events. The most frequent events were reversible electrolyte abnormalities. We consider low-dose L-AMB to provide comparable efficacy and improved safety and cost-effectiveness when compared with other empirical antifungal therapies. Additional large-scale randomized studies are needed to determine the clinical usefulness of L-AMB relative to other empirical antifungal therapies.

Antimicrobial Susceptibility of Tinea Capitis in Children from Egypt

PubMed Central

Doss, Reham William; El-Rifaie, Abdel-Aziz; Radi, Nagla; El-Sherif, Aya Yehia

2018-01-01

Background: Dermatophytic fungi of genera Trichophyton and Microsporum are the most important fungal species causing tinea capitis. Choice of treatment for tinea capitis is determined by the species of fungus. Aim: The aim of the study was to investigate the most prevalent fungal species causing tinea capitis in children from Egypt and the most useful antifungal agent for treatment. Patients and Methods: A total of 100 patients diagnosed clinically with tinea capitis were included in the study. Samples were collected and sent to the microbiology and immunology laboratory for sample processing and fungal identification by routine laboratory techniques. A study of antifungal susceptibility to chosen antifungal medications (fluconazole, ketoconazole, clotrimazole, miconazole, amphotericin, caspofungin, itraconazole, terbinafine, and griseofulvin) was done by minimum inhibitory concentration technique. Results: Our analysis revealed that Microsporum canis is the most commonly isolated strain. Amphotericin was the most effective antifungal agent followed by terbinafine. The most sensitive strain to fluconazole and griseofulvin is Microsporum gypseum, while Microsporum audouinii was mostly responsive to terbinafine. Conclusion: Identification and evaluation of the antifungal susceptibility of the pathogenic species in a certain geographic region is important to achieve a good clinical response. PMID:29692458

Risk of Fungemia Due to Rhodotorula and Antifungal Susceptibility Testing of Rhodotorula Isolates

PubMed Central

Zaas, Aimee K.; Boyce, Molly; Schell, Wiley; Lodge, Barbara Alexander; Miller, Jackie L.; Perfect, John R.

2003-01-01

Rhodotorula infections occur among patients with immunosuppression and/or central venous catheters. Using standardized methods (NCCLS M27-A), we determined the antifungal susceptibilities of 10 Rhodotorula bloodstream infection isolates. Patient information was collected for clinical correlation. The MICs of amphotericin B and posaconazole were the lowest, and the MICs of triazoles and echinocandins were higher than those of other antifungal agents. PMID:14605170

Evaluation of Candida species and antifungal susceptibilities among children with invasive candidiasis

PubMed Central

Sütçü, Murat; Acar, Manolya; Genç, Gonca Erköse; Kökçü, İlknur; Aktürk, Hacer; Atay, Gürkan; Törun, Selda Hançerli; Salman, Nuran; Erturan, Zayre; Somer, Ayper

2017-01-01

Aim Non-albicans Candida species and resistant microorganisms have been more commonly isolated in invasive candidiasis in recent years. The aim of this study was to evaluate the distrubution of Candida spp and antifungal resistance in our clinic. Material and Methods Fifty-four Candida isolates and antifungal susceptibility results obtained from patients diagnosed as having invasive candidiasis between December 2012 and June 2016 were included. Clinical and laboratory data were retrospectively analyzed. E-test method was used in order to determine antifungal susceptibilities of Candida spp for amphotericin B, fluconazole, voriconazole, ketoconazole, itraconazole, anidulafungin, caspofungin, and flucytosine. Results The clinical diagnoses of the patients were candidemia (n=27, 50%), catheter-related blood stream infection (n=1, 1.8%), urinary tract infection (n=13, 24%), surgical site infection (n=4, 7.4%), intraabdominal infection (n=3, 5.5%), empyema (n=2, 3.7%), and pneumonia (n=4, 7.4%). The most common isolated agent was C. albicans (n=27, 50%) and the others were C. parapsilosis (n=13, 24%), C. tropicalis (n=6, 11.1%), C. glabrata (n=3, 5.6%), C. lusitaniae (n=2, 3.7%), and unspecified Candida spp. (n=3, 5.6%). Fluconazole resistance was 7.4% among all isolates. Resistance against itraconazole, ketoconazole, anidulafungin, voriconazole and caspofungin were 33.3%, 12.5%, 11.1%, 5%, and 2.5%, respectively. Isolates presented intermediate resistance against itraconazole (41.7%), voriconazole (5.6%), and amphotericin B (3.7%) to varying extents. All of the isolates were susceptible to flucytosine. Conclusions In our clinic, C. albicans and non-albicans Candida species were equally distributed and antifungal susceptibilities against major antifungal agents such as fluconazole, amphotericin B, and caspofungin were found considerably high. PMID:29062248

Isobolographic Analysis of Pharmacodynamic Interactions between Antifungal Agents and Ciprofloxacin against Candida albicans and Aspergillus fumigatus▿

PubMed Central

Stergiopoulou, Theodouli; Meletiadis, Joseph; Sein, Tin; Papaioannidou, Paraskevi; Tsiouris, Ioannis; Roilides, Emmanuel; Walsh, Thomas J.

2008-01-01

Patients suffering from invasive mycoses often receive concomitant antifungal therapy and antibacterial agents. Assessment of pharmacodynamic interactions between antifungal and antibacterial agents is complicated by the absence of a common antifungal end point for both agents. Ciprofloxacin has no intrinsic antifungal activity but may interact with antifungal agents, since it inhibits DNA gyrase (topoisomerase II), which is abundant in fungi. We therefore employed isobolographic analysis adapted to incorporate a nonactive agent in order to analyze the potential in vitro interaction between the fluoroquinolone ciprofloxacin and several representative antifungal agents against Candida albicans and Aspergillus fumigatus strains by using a microdilution checkerboard technique. In agreement with earlier in vitro studies, conventional fractional inhibitory concentration index analysis was unable to detect interactions between ciprofloxacin and antifungal agents. However, isobolographic analysis revealed significant pharmacodynamic interactions between antifungal agents and ciprofloxacin against C. albicans and A. fumigatus strains. Amphotericin B demonstrated concentration-dependent interactions for both species, with synergy (interaction indices, 0.14 to 0.81) observed at ciprofloxacin concentrations of <10.64 μg/ml. Synergy (interaction indices, 0.10 to 0.86) was also found for voriconazole and caspofungin against A. fumigatus. Isobolographic analysis may help to elucidate the pharmacodynamic interactions between antifungal and non-antifungal agents and to develop better management strategies against invasive candidiasis and aspergillosis. PMID:18299413

In Vitro Interactions between Non-Steroidal Anti-Inflammatory Drugs and Antifungal Agents against Planktonic and Biofilm Forms of Trichosporon asahii

PubMed Central

Cong, Lin; Lu, Xuelian

2016-01-01

Increasing drug resistance has brought enormous challenges to the management of Trichosporon spp. infections. The in vitro antifungal activities of non-steroidal anti-inflammatory drugs (NSAIDs) against Candida spp. and Cryptococcus spp. were recently discovered. In the present study, the in vitro interactions between three NSAIDs (aspirin, ibuprofen and diclofenac sodium) and commonly used antifungal agents (fluconazole, itraconazole, voriconazole, caspofungin and amphotericin B) against planktonic and biofilm cells of T. asahii were evaluated using the checkerboard microdilution method. The spectrophotometric method and the XTT reduction assay were used to generate data on biofilm cells. The fractional inhibitory concentration index (FICI) and the ΔE model were compared to interpret drug interactions. Using the FICI, the highest percentages of synergistic effects against planktonic cells (86.67%) and biofilm cells (73.33%) were found for amphotericin B/ibuprofen, and caspofungin/ibuprofen showed appreciable percentages (73.33% for planktonic form and 60.00% for biofilm) as well. We did not observe antagonism. The ΔE model gave consistent results with FICI (86.67%). Our findings suggest that amphotericin B/ibuprofen and caspofungin/ibuprofen combinations have potential effects against T. asahii. Further in vivo and animal studies to investigate associated mechanisms need to be conducted. PMID:27275608

Continuous infusion of amphotericin B deoxycholate: an innovative, low-cost strategy in antifungal treatment.

PubMed

Falci, Diego R; dos Santos, Rodrigo P; Wirth, Fernanda; Goldani, Luciano Z

2011-03-01

The combination of amphotericin B and sodium deoxycholate is the formulation most used in clinical practice. The development of new agents such as amphotericin with lipid formulations, caspofungin, voriconazole and other azolic derivatives, promoted alternatives to amphotericin B deoxycholate. However, because of the high cost of these new drugs, their use is difficult in a scenario of limited resources. A few strategies have been devised to make the use of amphotericin B deoxycholate less toxic. In this review, we seek to describe the accumulated knowledge about this molecule, with focus on its use in continuous infusion, which appears to be an alternative to reduce toxicity, while maintaining its clinical efficacy. © 2009 Blackwell Verlag GmbH.

Antifungal activities of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Fusarium spp.

PubMed

Venturini, Tarcieli Pozzebon; Chassot, Francieli; Loreto, Érico Silva; Keller, Jéssica Tairine; Azevedo, Maria Izabel; Zeni, Gilson; Santurio, Janio Morais; Alves, Sydney Hartz

2016-07-01

Herein, we describe the in vitro activity of a combination of the organoselenium compounds diphenyl diselenide and ebselen alone and in combination with amphotericin B, caspofungin, itraconazole, and voriconazole against 25 clinical isolates of Fusarium spp. For this analysis, we used the broth microdilution method based on the M38-A2 technique and checkerboard microdilution method. Diphenyl diselenide (MIC range = 4-32 μg/ml) and ebselen (MIC range = 2-8 μg/ml) showed in vitro activity against the isolates tested. The most effective combinations were (synergism rates): ebselen + amphotericin B (88%), ebselen + voriconazole (80%), diphenyl diselenide + amphotericin B (72%), and diphenyl diselenide + voriconazole (64%). Combination with caspofungin resulted in low rates of synergism: ebselen + caspofungin, 36%, and diphenyl diselenide + caspofungin, 28%; combination with itraconazole demonstrated indifferent interactions. Antagonistic effects were not observed for any of the combinations tested. Our findings suggest that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation in in vivo experimental models, especially in combination with amphotericin B and voriconazole. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

In vitro antifungal activity and mechanism of essential oil from fennel (Foeniculum vulgare L.) on dermatophyte species.

PubMed

Zeng, Hong; Chen, Xinping; Liang, Jingnan

2015-01-01

Fennel seed essential oil (FSEO) is a plant-derived natural therapeutic against dermatophytes. In this study, the antifungal effects of FSEO were investigated from varied aspects, such as MIC and minimum fungicidal concentration, mycelia growth, spore germination and biomass. The results indicated that FSEO had potent antifungal activities on Trichophyton rubrum ATCC 40051, Trichophyton tonsurans 10-0400, Microsporum gypseum 44693-1 and Trichophyton mentagrophytes 10-0060, which is better than the commonly used antifungal agents fluconazole and amphotericin B. Flow cytometry and transmission electron microscopy experiments suggested that the antifungal mechanism of FSEO was to damage the plasma membrane and intracellular organelles. Further study revealed that it could also inhibit the mitochondrial enzyme activities, such as succinate dehydrogenase, malate dehydrogenase and ATPase. With better antifungal activity than the commonly used antifungal agents and less possibility of inducing drug resistance, FSEO could be used as a potential antidermatophytic agent. © 2015 The Authors.

Multicentre Etest evaluation of in vitro activity of conventional antifungal drugs against European bovine mastitis Prototheca spp. isolates.

PubMed

Jagielski, Tomasz; Buzzini, Pietro; Lassa, Henryka; Malinowski, Edward; Branda, Eva; Turchetti, Benedetta; Polleichtner, Angela; Roesler, Uwe; Lagneau, Paul-Emile; Marques, Sara; Silva, Eliane; Thompson, Gertrude; Stachowiak, Radosław; Bielecki, Jacek

2012-08-01

Bovine mammary protothecosis is a serious pathology that entails high economic losses in the dairy industry. The disease, the frequency of which has recently been increasing worldwide, is caused by unicellular, achlorophyllous, yeast-like algae of two species: Prototheca zopfii and Prototheca blaschkeae. The objective of this study was to investigate the in vitro activity of a panel of conventional antifungal drugs against Prototheca spp. isolates. A total of 144 P. zopfii genotype 2 and P. blaschkeae strains isolated from milk of mastitic cows were subjected to drug susceptibility testing by Etest methodology. Five out of ten antifungal drugs tested exhibited no activity against Prototheca spp. isolates. The best activity against Prototheca spp. was demonstrated by amphotericin B (MIC₉₀ of 1.5 mg/L). The MICs differed significantly (P < 0.01) between P. zopfii genotype 2 and P. blaschkeae, with the latter species being more susceptible to amphotericin B and azoles. Marked differences (P < 0.05) in azole and amphotericin B activities were noted among Prototheca spp. isolates originating from different European countries. Based on the correlation coefficients, a considerable cross-interaction was found among MICs of azoles and between MICs of azoles and amphotericin B for Prototheca spp. (P < 0.03). This study represents the largest, cross-European evaluation of antifungal activity against Prototheca spp. to date. The activity of amphotericin B against Prototheca spp. validates its potential use as a therapeutic agent against bovine protothecosis. For laboratory testing of drug activity against Prototheca spp., the Etest method is encouraged, due to its technical simplicity, rapidity and high intra- and inter-laboratory reproducibility.

Management of Aspergillus osteomyelitis: report of failure of liposomal amphotericin B and response to voriconazole in an immunocompetent host and literature review.

PubMed

Stratov, I; Korman, T M; Johnson, P D R

2003-05-01

Presented here is a case of Aspergillus osteomyelitis in an immunocompetent patient that progressed despite surgery and prolonged treatment with liposomal amphotericin B; the report is followed by a review of the literature. The review of this case and 41 similar cases found an overall cure rate of 69%. The importance of surgery when amphotericin B is used as first-line therapy is indicated by a 14% cure rate when amphotericin B is used alone compared to 75% when combined with surgery. When therapy is failing or surgery is contraindicated, dose escalation using a lipid formulation was not effective. On review, the addition of another agent, in particular 5-fluorocytosine, appears to be more beneficial. The patient reported here responded rapidly to voriconazole, a promising new antifungal agent for Aspergillus infections.

In Vitro Antifungal Susceptibility of Neoscytalidium dimidiatum Clinical Isolates from Malaysia.

PubMed

James, Jasper Elvin; Santhanam, Jacinta; Lee, Mei Chen; Wong, Choon Xian; Sabaratnam, Parameswari; Yusoff, Hamidah; Tzar, Mohd Nizam; Razak, Mohd Fuat Abdul

2017-04-01

Neoscytalidium dimidiatum is an opportunistic fungus causing cutaneous infections mostly, which are difficult to treat due to antifungal resistance. In Malaysia, N. dimidiatum is associated with skin and nail infections, especially in the elderly. These infections may be mistaken for dermatophyte infections due to similar clinical appearance. In this study, Neoscytalidium isolates from cutaneous specimens, identified using morphological and molecular methods (28 Neoscytalidium dimidiatum and 1 Neoscytalidium sp.), were evaluated for susceptibility towards antifungal agents using the CLSI broth microdilution (M38-A2) and Etest methods. Amphotericin B, voriconazole, miconazole and clotrimazole showed high in vitro activity against all isolates with MIC ranging from 0.0313 to 1 µg/mL. Susceptibility towards fluconazole and itraconazole was noted in up to 10% of isolates, while ketoconazole was inactive against all isolates. Clinical breakpoints for antifungal drugs are not yet available for most filamentous fungi, including Neoscytalidium species. However, the results indicate that clinical isolates of N. dimidiatum in Malaysia were sensitive towards miconazole, clotrimazole, voriconazole and amphotericin B, in vitro.

Activities of E1210 and comparator agents tested by CLSI and EUCAST broth microdilution methods against Fusarium and Scedosporium species identified using molecular methods.

PubMed

Castanheira, Mariana; Duncanson, Frederick P; Diekema, Daniel J; Guarro, Josep; Jones, Ronald N; Pfaller, Michael A

2012-01-01

Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC(90) values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC(90) was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC(50) for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC(90) for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

Activities of E1210 and Comparator Agents Tested by CLSI and EUCAST Broth Microdilution Methods against Fusarium and Scedosporium Species Identified Using Molecular Methods

PubMed Central

Duncanson, Frederick P.; Diekema, Daniel J.; Guarro, Josep; Jones, Ronald N.; Pfaller, Michael A.

2012-01-01

Fusarium (n = 67) and Scedosporium (n = 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC90 values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC90 was 0.12 μg/ml for S. apiospermum, but 1 to >8 μg/ml for other tested agents. Against S. aurantiacum, the MEC50 for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. Against S. prolificans, the MEC90 for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results. PMID:22083469

Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses.

PubMed

Öz, Yasemin; Özdemir, Havva Gül; Gökbolat, Egemen; Kiraz, Nuri; Ilkit, Macit; Seyedmousavi, Seyedmojtaba

2016-04-01

Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (E max) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5-1.0, 1.0, 0.5-1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0-4.0, 0.5, 1.0 for A. flavus, and 0.12-0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0-16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03-0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (E(max) = 0.63 h(-1), r(2) = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (E(max) = 0.39 h(-1), r(2) = 0.87), voriconazole (E(max) = 0.35 h(-1), r(2) = 0.098), and itraconazole (E(max) = 0.01 h(-1), r(2) = 0.98). Overall, the antifungal susceptibility of the non-fumigatus Aspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates.

Activity of Posaconazole and Other Antifungal Agents against Mucorales Strains Identified by Sequencing of Internal Transcribed Spacers▿

PubMed Central

Alastruey-Izquierdo, Ana; Castelli, Maria Victoria; Cuesta, Isabel; Monzon, Araceli; Cuenca-Estrella, Manuel; Rodriguez-Tudela, Juan Luis

2009-01-01

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates. PMID:19171801

Activity of posaconazole and other antifungal agents against Mucorales strains identified by sequencing of internal transcribed spacers.

PubMed

Alastruey-Izquierdo, Ana; Castelli, Maria Victoria; Cuesta, Isabel; Monzon, Araceli; Cuenca-Estrella, Manuel; Rodriguez-Tudela, Juan Luis

2009-04-01

The antifungal susceptibility profiles of 77 clinical strains of Mucorales species, identified by internal transcribed spacer sequencing, were analyzed. MICs obtained at 24 and 48 h were compared. Amphotericin B was the most active agent against all isolates, except for Cunninghamella and Apophysomyces isolates. Posaconazole also showed good activity for all species but Cunninghamella bertholletiae. Voriconazole had no activity against any of the fungi tested. Terbinafine showed good activity, except for Rhizopus oryzae, Mucor circinelloides, and Rhizomucor variabilis isolates.

Effect of 2-Phenylethanol as Antifungal Agent and Common Antifungals (Amphotericin B, Fluconazole, and Itraconazole) on Candida Species Isolated from Chronic and Recurrent Cases of Candidal Vulvovaginitis.

PubMed

Majdabadi, Niloufar; Falahati, Mehraban; Heidarie-Kohan, Fariba; Farahyar, Shirin; Rahimi-Moghaddam, Parvaneh; Ashrafi-Khozani, Mahtab; Razavi, Tandis; Mohammadnejad, Sina

2018-04-01

The antifungal effects of 2-phenylethanol are clearly visible through its intervention in Candida morphogenesis. Chronic and recurrent vulvovaginitis, however, does not respond to this standard experimental therapy; therefore, the study presented in this article investigated the effect of common antifungal drugs (amphotericin B [AMB], fluconazole [FLU], and itraconazole [ITC]), in combination with 2-phenylethanol, on the Candida species isolated from cases of chronic and recurrent vulvovaginitis, thereby allowing the recommendation of a more appropriate treatment option. Forty isolates from patients with chronic and recurrent vaginal candidiasis were investigated in this experimental study. The specimens were examined by direct microscopy, culturing, and PCR to identify the species. The antifungal effects of 2-phenylethanol and conventional drugs, both alone and in combination, were determined in duplicate. Finally, the findings were analyzed. In this study, 40 strains of Candida species were identified, whose agents were Candida albicans (95%) and Candida africana (5%). After 48 h, the minimum inhibitory concentration (MIC) range of the 2-phenylethanol was 800-3,200 μg/mL. Also, in the final study on the MIC levels of common antifungal drugs, AMB (0.42 μg/mL) had the lowest MIC, FLU (40.51 μg/mL) had the highest MIC, and the combination of ITC and 2-phenylethanol had the lowest fractional inhibitory concentration index (FICI) of any of the combinations (FICI range, 0.26-1.03). Combining FLU and ITC with 2-phenylethanol can effectively increase their antifungal effect.

Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives.

PubMed

Lino, Cleudiomar Inácio; Gonçalves de Souza, Igor; Borelli, Beatriz Martins; Silvério Matos, Thelma Tirone; Santos Teixeira, Iasmin Natália; Ramos, Jonas Pereira; Maria de Souza Fagundes, Elaine; de Oliveira Fernandes, Philipe; Maltarollo, Vinícius Gonçalves; Johann, Susana; de Oliveira, Renata Barbosa

2018-05-10

In the search for new antifungal agents, a novel series of fifteen hydrazine-thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 μM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Antifungal resistance in mucorales.

PubMed

Dannaoui, E

2017-11-01

The order Mucorales, which includes the agents of mucormycosis, comprises a large number of species. These fungi are characterised by high-level resistance to most currently available antifungal drugs. Standardised antifungal susceptibility testing methods are now available, allowing a better understanding of the in vitro activity of antifungal drugs against members of Mucorales. Such tests have made apparent that antifungal susceptibility within this group may be species-specific. Experimental animal models of mucormycosis have also been developed and are of great importance in bridging the gap between in vitro results and clinical trials. Amphotericin B, posaconazole and isavuconazole are currently the most active agents against Mucorales; however, their activity remains suboptimal and new therapeutic strategies are needed. Combination therapy could be a promising approach to overcome resistance, but further studies are required to confirm its benefits and safety for patients. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

[Adequacy of new systemic antifungal agents prescriptions in a teaching hospital].

PubMed

Pavese, P; Ouachi, Z; Vittoz, J-P; Lebeau, B; Foroni, L; Allenet, B; Stahl, J-P; François, P

2007-12-01

The aim of this study was to evaluate the adequacy and the conformity of prescriptions of new systemic antifungal drugs to guidelines and scientific data. Each prescription of liposomal amphotericin B (lip Amb), voriconazole, and caspofungin made between May 2003 and May 2004 in a teaching hospital were reviewed by an infectious diseases specialist. He used criteria based on marketing authorization, national recommendations, and scientific data. One hundred and fifteen files were studied during the 12-month period and 203 prescriptions analyzed. Most patients were immunodepressed. The indication of the treatment was appropriate for 127 prescriptions (62.6%). Dose and drug interactions were compliant with prescription rules for 158 prescriptions (77.8%). Among the causes of misuse, 16.3% concerned combinations of antifungals. Prescriptions of liposomal amphotericin B, voriconazole and caspofungin complied with guidelines respectively in 69.7, 60.6 and 36.8% of the cases. Among the 127 appropriate prescriptions, the use of cheaper molecules with an equivalent clinical effectiveness would have allowed saving 13.6% of the total cost of these prescriptions. This study will lead us to implement policies for new antifungal prescription.

Antifungal activity of caspofungin in experimental infective endocarditis caused by Candida albicans.

PubMed

Victorio, Gerardo Becerra; Bourdon, Lorena Michele Brennan; Benavides, Leonel García; Huerta-Olvera, Selene G; Plascencia, Arturo; Villanueva, José; Martinez-Lopez, Erika; Hernández-Cañaveral, Iván Isidro

2017-05-01

Infective endocarditis is a disease characterised by heart valve lesions, which exhibit extracellular matrix proteins that act as a physical barrier to prevent the passage of antimicrobial agents. The genus Candida has acquired clinical importance given that it is increasingly being isolated from cases of nosocomial infections. To evaluate the activity of caspofungin compared to that of liposomal amphotericin B against Candida albicans in experimental infective endocarditis. Wistar rats underwent surgical intervention and infection with strains of C. albicans to develop infective endocarditis. Three groups were formed: the first group was treated with caspofungin, the second with liposomal amphotericin B, and the third received a placebo. In vitro sensitivity was first determined to further evaluate the effect of these treatments on a rat experimental model of endocarditis by semiquantitative culture of fibrinous vegetations and histological analysis. Our semiquantitative culture of growing vegetation showed massive C. albicans colonisation in rats without treatment, whereas rats treated with caspofungin showed significantly reduced colonisation, which was similar to the results obtained with liposomal amphotericin B. The antifungal activity of caspofungin is similar to that of liposomal amphotericin B in an experimental model of infective endocarditis caused by C. albicans.

Keratitis-associated fungi form biofilms with reduced antifungal drug susceptibility.

PubMed

Zhang, Xiaoyan; Sun, Xuguang; Wang, Zhiqun; Zhang, Yang; Hou, Wenbo

2012-11-21

To investigate the biofilm-forming capacity of Fusarium solani, Cladosporium sphaerospermum, and Acremonium implicatum, and the activities of antifungal agents against the three keratitis-associated fungi. The architecture of biofilms was analyzed using scanning electron microscopy and confocal scanning laser microscopy (CSLM). Susceptibility against six antifungal drugs was measured using the CLSI M38-A method and XTT reduction assay. Time course analyses of CSLM revealed that biofilm formation occurred in an organized fashion through four distinct developmental phases: adhesion, germling formation, microcolony formation, and biofilm maturation. Scanning electron microscopy revealed that mature biofilms displayed a complex three-dimensional structure, consisting of coordinated network of hyphal structures glued by the extracellular matrix (ECM). The antifungal susceptibility testing demonstrated a time-dependent decrease in efficacy for all six antifungal agents as the complexity of fungal hyphal structures developed. Natamycin (NAT), amphotericin B (AMB), and NAT were the most effective against F. solani, C. sphaerospermum, and A. implicatum biofilm, respectively. Corneal isolates of F. solani, C. sphaerospermum, and A. implicatum could produce biofilms that were resistant to antifungal agents in vitro.

Relationship between the Antifungal Susceptibility Profile and the Production of Virulence-Related Hydrolytic Enzymes in Brazilian Clinical Strains of Candida glabrata

PubMed Central

de Oliveira, Jean Carlos Almeida

2017-01-01

Candida glabrata is a facultative intracellular opportunistic fungal pathogen in human infections. Several virulence-associated attributes are involved in its pathogenesis, host-pathogen interactions, modulation of host immune defenses, and regulation of antifungal drug resistance. This study evaluated the in vitro antifungal susceptibility profile to five antifungal agents, the production of seven hydrolytic enzymes related to virulence, and the relationship between these phenotypes in 91 clinical strains of C. glabrata. All C. glabrata strains were susceptible to flucytosine. However, some of these strains showed resistance to amphotericin B (9.9%), fluconazole (15.4%), itraconazole (5.5%), or micafungin (15.4%). Overall, C. glabrata strains were good producers of catalase, aspartic protease, esterase, phytase, and hemolysin. However, caseinase and phospholipase in vitro activities were not detected. Statistically significant correlations were identified between micafungin minimum inhibitory concentration (MIC) and esterase production, between fluconazole and micafungin MIC and hemolytic activity, and between amphotericin B MIC and phytase production. These results contribute to clarify some of the C. glabrata mechanisms of pathogenicity. Moreover, the association between some virulence attributes and the regulation of antifungal resistance encourage the development of new therapeutic strategies involving virulence mechanisms as potential targets for effective antifungal drug development for the treatment of C. glabrata infections. PMID:28814823

Use of systemic antifungals in daily clinical practice in the haematology and oncology setting: results of a prospective observational analysis.

PubMed

Metzke, Barbara; Neubauer, Werner Christian; Hieke, Stefanie; Jung, Manfred; Wäsch, Ralph; Engelhardt, Monika

2012-09-01

To assess the role of systemic antifungal drugs as well as the frequency of potential drug interactions and adverse drug events of commonly used antifungals in an unselected haematology/oncology patient cohort. A prospective analysis was performed in our haematology/oncology department between October 2006 and September 2009. Data were obtained from 250 consecutive patients who received treatment and/or prophylaxis with fluconazole (n = 191), liposomal amphotericin B (n = 105), voriconazole (n = 62), caspofungin (n = 27) and/or posaconazole (n = 22). We performed detailed reviews of patient charts and laboratory values in close cooperation with treating physicians and nursing staff and participated regularly in ward and chart rounds. Potential drug interactions were assessed using the electronic database Micromedex® 1.0 (Healthcare Series). In terms of adverse drug events, caspofungin (56%) and voriconazole (58%) revealed a slightly more favourable safety profile than liposomal amphotericin B (66%) and posaconazole (64%). We confirmed frequent nephrotoxic effects with the use of liposomal amphotericin B (20%). Regarding potential drug interactions, 97 (66%) of 147 evaluated patients were exposed to at least 1 of 22 different potentially interacting drug combinations involving systemic antifungal agents. Cyclosporine was the most prevalent potentially interacting drug in our cohort. Systemic antifungal drugs are widely used in the haematology/oncology setting and exhibit numerous potential drug interactions and adverse events in cancer patients. Our results highlight the challenges related to antifungal drugs and should valuably contribute to a safe and efficient application of this increasingly important class of drugs. Copyright © 2012 John Wiley & Sons, Ltd.

Evaluation of Amphotericin B and Chloramphenicol as Alternative Drugs for Treatment of Chytridiomycosis and Their Impacts on Innate Skin Defenses

PubMed Central

Holden, Whitney M.; Ebert, Alexander R.; Canning, Peter F.

2014-01-01

Chytridiomycosis, an amphibian skin disease caused by the emerging fungal pathogen Batrachochytrium dendrobatidis, has been implicated in catastrophic global amphibian declines. The result is an alarming decrease in amphibian diversity that is a great concern for the scientific community. Clinical trials testing potential antifungal drugs are needed to identify alternative treatments for amphibians infected with this pathogen. In this study, we quantified the MICs of chloramphenicol (800 μg/ml), amphotericin B (0.8 to 1.6 μg/ml), and itraconazole (Sporanox) (20 ng/ml) against B. dendrobatidis. Both chloramphenicol and amphotericin B significantly reduced B. dendrobatidis infection in naturally infected southern leopard frogs (Rana [Lithobates] sphenocephala), although neither drug was capable of complete fungal clearance. Long-term exposure of R. sphenocephala to these drugs did not inhibit antimicrobial peptide (AMP) synthesis, indicating that neither drug is detrimental to this important innate skin defense. However, we observed that chloramphenicol, but not amphotericin B or itraconazole, inhibited the growth of multiple R. sphenocephala skin bacterial isolates in vitro at concentrations below the MIC against B. dendrobatidis. These results indicate that treatment with chloramphenicol might dramatically alter the protective natural skin microbiome when used as an antifungal agent. This study represents the first examination of the effects of alternative antifungal drug treatments on amphibian innate skin defenses, a crucial step to validating these treatments for practical applications. PMID:24771024

Colorimetric susceptibility testing for Aspergillus fumigatus: comparison of menadione-augmented 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and Alamar blue tests.

PubMed Central

Jahn, B; Stüben, A; Bhakdi, S

1996-01-01

Two colorimetric methods that use Alamar Blue or 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for assaying the in vitro activities of antifungal agents have been described. We report that both tests performed similarly when the antifungal activity of amphotericin B against Candida albicans was determined. However, only the MTT test generated interpretable data when Aspergillus fumigatus was used. PMID:8818910

In Vitro Activities of Five Antifungal Drugs Against Opportunistic Agents of Aspergillus Nigri Complex.

PubMed

Badali, Hamid; Fakhim, Hamed; Zarei, Fereshteh; Nabili, Mojtaba; Vaezi, Afsane; Poorzad, Nafiseh; Dolatabadi, Somayeh; Mirhendi, Hossein

2016-04-01

Black aspergilli, particularly Aspergillus niger and A. tubingensis, are the most common etiological agents of otomycosis followed by onychomycosis, pulmonary aspergillosis and aspergilloma. However, so far there is no systematic study on their antifungal susceptibility profiles. A collection of 124 clinical and environmental species of black aspergilli consisted of A. niger, A. tubingensis, A. uvarum. A. acidus and A. sydowii were verified by DNA sequencing of the partial β-tubulin gene. MICs of amphotericin B, itraconazole, voriconazole, posaconazole, and MECs of caspofungin were performed based on CLSI M38-A2. Posaconazole and caspofungin had the lowest MIC range (0.016-0.125 µg/ml and 0.008-0.031 µg/ml, respectively), followed by amphotericin B (0.25-4 µg/ml), voriconazole (0.125-16 µg/ml) and itraconazole (0.25 to >16) in an increasing order. Some strains of A. niger showed high MIC value for itraconazole and voriconazole (>16 µg/ml), in contrast only environmental isolates of A. tubingensis had high itraconazole MICs (>16 µg/ml). These results confirm that posaconazole and caspofungin are potential drugs for treatment of aspergillosis due to opportunistic agents of Aspergillus Nigri complex. However, in vivo efficacy remains to be determined.

Treatment of murine invasive candidiasis with amphotericin B and cilofungin: evidence for enhanced activity with combination therapy.

PubMed Central

Sugar, A M; Goldani, L Z; Picard, M

1991-01-01

The in vivo interactions of cilofungin, an echinocandin antifungal agent, and amphotericin B, a polyene derivative, in a murine model of disseminated candidiasis have been investigated. While single therapy with either drug alone prolonged survival of infected mice, kidney colony counts were not appreciably reduced. In contrast, combination therapy, especially at higher doses of both drugs, resulted in significant prolongation of survival and suppression of growth of yeast cells in the kidneys. Combination therapy of experimental candidiasis with cilofungin and amphotericin B did not result in antagonism; rather, additive or synergistic effects were seen. Future preclinical work with other echinocandin and polyene derivatives should include studies evaluating the in vivo interactions of both classes of compounds. PMID:1759836

The patterns of colonization and antifungal susceptibility of Candida, isolated from preterm neonates in Khorramabad, South West of Iran.

PubMed

Kooshki, P; Rezaei-Matehkolaei, A; Mahmoudabadi, A Z

2018-06-01

Usually, 7-20% of preterm neonates colonized by Candida species present invasive candidiasis. Candida albicans, and several non-albicans species cause invasive infection with C. albicans being the most dominant agent. In the last two decades, infection due to non-albicans have been increased dramatically due to their low sensitivity to antifungal drugs such as fluconazole. The aim of present study was to evaluate Candida colonization pattern and antifungal susceptibility among preterm neonates from Khorramabad, South west of Iran. Samples were collected from 80 preterm neonates, cultured on CHROMagar Candida and incubated at 37°C. All recovered isolates were primarily screened based on classical methods and identified by PCR-RFLP targeting the ITS-rDNA regions. Antifungal susceptibility testing of all isolates was performed according to the CLSI method against amphotericin B, caspofungin, itraconazole, fluconazole and voriconazole. Totally 23 isolates of Candida species were recovered from 20 patients (female: male, 50:50) including, C. albicans (18), C. parapsilosis (2) and C. glabrata (1). Furthermore, the blood cultures from two patients were yielded C. albicans and C. parapsilosis so that patient with C. albicans died after five days. Generally, in this study, 9 (39.1%) isolates were resistant to amphotericin B including; 7 (30.4%) C. albicans and 2 (8.7%) C. parapsilosis. In addition, 2 (8.7%) and 4 (17.4%) isolates were also resistant to itraconazole and caspofungin, respectively. In conclusion, Candida colonization among preterm neonates is still an important issue in hospitals. In addition, in spite of a significant amphotericin B resistant Candida, voriconazole, fluconazole, and itraconazole are valuable antifungals, due to fully sensitivity to Candida. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Proanthocyanidins polymeric tannin from Stryphnodendron adstringens are active against Candida albicans biofilms.

PubMed

Luiz, Raul Leal Faria; Vila, Taissa Vieira Machado; de Mello, João Carlos Palazzo; Nakamura, Celso Vataru; Rozental, Sonia; Ishida, Kelly

2015-03-19

Biofilm formation is important in Candida albicans pathogenesis and constitutes a mechanism of antifungal resistance. Thus, we evaluated the effect of proanthocyanidins polymer-rich fractions from Stryphnodendron adstringens (fraction F2 and subfraction F2.4) against C. albicans biofilms. Firstly, the antifungal activity of F2 and F2.4 against planktonic cells of Candida albicans (ATCC 10231) was determined using broth microdilution method. Anti-biofilm effect of F2 and F2.4 was evaluated during biofilm formation or on mature biofilm of C. albicans and compared with standard antifungals amphotericin B and fluconazole. Metabolic activity of sessile and dispersion cells from biofilms after antifungal treatments were measured using a tetrazolium reduction assay and the biofilm total biomass was quantified by crystal violet-based assay. Morphological alterations after treatments were observed using scanning electron microscopy. The anti-biofilm effect of F2 and F2.4 were comparable to standard antifungals (amphotericin B and fluconazole). F2 and F2.4 treatments reduced biofilm metabolic activity (in sessile and in dispersion cells) during biofilm formation, and in mature biofilms, unlike fluconazole, which only prevents the biofilm formation. Treatments with F2, F2.4 or fluconazole reduced biofilm biomass during biofilm formation, but not in mature biofilm. Amphotericin B presented higher inhibitory effect on biofilm formation and on mature biofilm of C. albicans. F2 and F2.4 treatments led to the appearance of dumbbell-shaped blastoconidia and of blastoconidia clusters in biofilms. Proanthocyanidins polymer-rich fractions from S. adstringens successfully inhibited C. albicans planktonic growth and biofilm development, and they represent a potential new agent for the treatment of biofilm-associated candidiasis.

Antifungal Activity of Amphotericin B Conjugated to Nanosized Magnetite in the Treatment of Paracoccidioidomycosis

PubMed Central

Saldanha, Camila Arruda; Garcia, Mônica Pereira; Iocca, Diego Cesar; Rebelo, Luciana Guilherme; Souza, Ana Camila Oliveira; Bocca, Anamélia Lorenzetti; Almeida Santos, Maria de Fátima Menezes; Morais, Paulo Cesar; Azevedo, Ricardo Bentes

2016-01-01

This study reports on in vitro and in vivo tests that sought to assess the antifungal activity of a newly developed magnetic carrier system comprising amphotericin B loaded onto the surface of pre-coated (with a double-layer of lauric acid) magnetite nanoparticles. The in vitro tests compared two drugs; i.e., this newly developed form and free amphotericin B. We found that this nanocomplex exhibited antifungal activity without cytotoxicity to human urinary cells and with low cytotoxicity to peritoneal macrophages. We also evaluated the efficacy of the nanocomplex in experimental paracoccidioidomycosis. BALB/c mice were intratracheally infected with Paracoccidioides brasiliensis and treated with the compound for 30 or 60 days beginning the day after infection. The newly developed amphotericin B coupled with magnetic nanoparticles was effective against experimental paracoccidioidomycosis, and it did not induce clinical, biochemical or histopathological alterations. The nanocomplex also did not induce genotoxic effects in bone marrow cells. Therefore, it is reasonable to believe that amphotericin B coupled to magnetic nanoparticles and stabilized with bilayer lauric acid is a promising nanotool for the treatment of the experimental paracoccidioidomycosis because it exhibited antifungal activity that was similar to that of free amphotericin B, did not induce adverse effects in therapeutic doses and allowed for a reduction in the number of applications. PMID:27303789

Fluconazole-, amphotericin-B-, caspofungin-, and anidulafungin-resistant Candida ciferrii: an unknown cause of systemic mycosis in a child.

PubMed

Agın, Hasan; Ayhan, Yüce; Devrim, Ilker; Gülfidan, Gamze; Tulumoglu, Sener; Kayserili, Ertan

2011-09-01

Candida ciferrii, which is known as an agent of superficial yeast infection and onychomycosis, has rarely been isolated as an agent of candidemia. Limited reports have suggested different patterns of antifungal sensitivity. We report a rare candidemia case caused by c.ciferrii in an 8-year-old child in which isolated candida species were resistant to amphotericin-B (MIC > 1 μg/ml), fluconazole, (MIC ≥ 64 μg/ml), caspofungin (MIC ≥ 32 μg/ml), and anidulafungin (MIC ≥ 32 μg/ml) but sensitive to voriconazole (MIC ≤ 0.12 μg/ml). As far as we aware, this was the first recorded C. ciferrii candidemia case in children.

Synergistic Activity of the Tyrocidines, Antimicrobial Cyclodecapeptides from Bacillus aneurinolyticus, with Amphotericin B and Caspofungin against Candida albicans Biofilms

PubMed Central

Troskie, Anscha Mari; Rautenbach, Marina; Delattin, Nicolas; Vosloo, Johan Arnold; Dathe, Margitta; Thevissen, Karin

2014-01-01

Tyrocidines are cationic cyclodecapeptides from Bacillus aneurinolyticus that are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonic Candida albicans in the low-micromolar range. These tyrocidines also prevented C. albicans biofilm formation in vitro. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of mature C. albicans biofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using a Caenorhabditis elegans infection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment. PMID:24752256

Non Candida albicans fungal peritonitis in continuous ambulatory peritoneal dialysis patients.

PubMed

Kleinpeter, M A; Butt, A A

2001-01-01

We report four episodes of non Candida albicans peritonitis (NCAP) in 3 patients on continuous ambulatory peritoneal dialysis (CAPD). Risk factors for NCAP included diabetes mellitus and prior antibiotic use in half of the cases. The antibiotic treatment was prescribed for exit-site infection (ESI) or peritonitis in the patient. Treatment for NCAP included antifungal therapy with oral fluconazole or intravenous amphotericin B. The NCAP resulted in catheter loss in 100% of the patients over time. Initial catheter salvage in one patient was followed 6 months later by catheter loss following treatment of a bacterial peritonitis that was complicated by the development of Candida (Torulopsis) glabrata peritonitis unresponsive to treatment with intravenous amphotericin B. Although the literature suggests that Candida peritonitis responds to oral fluconazole with and without catheter removal, this series suggests that the treatment of NCAP includes removal of the peritoneal dialysis catheter with appropriate antifungal agents.

Yeast Colonization and Drug Susceptibility Pattern in the Pediatric Patients With Neutropenia

PubMed Central

Haddadi, Pedram; Zareifar, Soheila; Badiee, Parisa; Alborzi, Abdolvahab; Mokhtari, Maral; Zomorodian, Kamiar; Pakshir, Keyvan; Jafarian, Hadis

2014-01-01

Background: Pediatric patients with neutropenia are vulnerable to invasive Candida infections. Candida is the primary cause of fungal infections, particularly in immunosuppressed patients. Candida albicans has been the most common etiologic agent of these infections, affecting 48% of patients Objectives: The aim of this study was to identify Candida spp. isolated from children with neutropenia and determine the antifungal susceptibility pattern of the isolated yeasts. Patients and Methods: In this study 188 children with neutropenia were recruited, fungal surveillance cultures were carried out on nose, oropharynx, stool, and urine samples. Identification of Candida strains was performed using germ tube and chlamydospore production tests on an API 20 C AUX system. Susceptibility testing on seven antifungal agents was performed using the agar-based E-test method. Results: A total of 229 yeasts were isolated. Among those, C. albicans was the most common species followed by C. krusei, C. parapsilosis, C. glabrata, C. tropicalis, C. famata, C. dubliniensis, C. kefyr, and other Candida species. C. glabrata was the most resistant isolated yeasts, which was 70% resistant to fluconazole and 50% to itraconazole, 7.5% to amphotericin B and 14% to ketoconazole. All the tested species were mostly sensitive to caspofungin. Conclusions: Knowledge about the susceptibility patterns of colonized Candida spp. can be helpful for clinicians to manage pediatric patients with neutropenia. In this study, caspofungin was the most effective antifungal agent against the colonized Candida spp. followed by conventional amphotericin B. PMID:25485060

Study of strains of Candida spp. Isolated from catheters in UHC of Oran (Algeria): Identification and antifungal susceptibility.

PubMed

Bendjelloul, M; Boucherit-Otmani, Z; Boucherit, K

2016-09-01

The increasing incidence of Candida spp., and the vital prognosis often compromise for patients with Candida species make urgent the exact knowledge of their distribution worldwide and exhaust action antifungals currently used in clinical. That why we carry out an epidemiological study of Candida species and testing their susceptibility against two antifungals: amphotericin B and caspofungin. Samplings of peripheral venous catheters (PVC) were carried out from during 8months on the services of Internal medicine, Surgery A and Neonatology of Oran's University Hospital Center (UHC). The study of the susceptibility of Candida species to antifungal agents was performed according to the Clinical Laboratory Standards Institute (CLSI 2008). From 300 samples, 25 yeasts were isolated. The rate of colonization PVC was 8.33% by Candida spp. The most isolated strains were Candida parapsilosis with 64% of cases, followed by Candida albicans (12%) then 8% for Candida glabrata and Candida krusei. However, only 4% of isolates were Candida famata or Candida lusitaniae. Furthermore all isolated strains were susceptible to amphotericin B with Minimum Inhibitory Concentrations (MIC) ranging from 0.25 to 1μg/mL. MIC obtained with caspofungin vary from 0.0625 to 2μg/mL for all strains. Moreover, one strain of C. krusei is resistant to caspofungin with a MIC superior to 8μg/mL. All though caspofungin is at least as effective as amphotericin B, it is better tolerated for the treatment of invasive fungal infections. Copyright © 2016. Published by Elsevier Masson SAS.

Microscopic Evaluation, Molecular Identification, Antifungal Susceptibility, and Clinical Outcomes in Fusarium, Aspergillus and, Dematiaceous Keratitis

PubMed Central

Gajjar, Devarshi U.; Pal, Anuradha K.; Ghodadra, Bharat K.; Vasavada, Abhay R.

2013-01-01

Purpose. Fusarium, Aspergillus, and Dematiaceous are the most common fungal species causing keratitis in tropical countries. Herein we report a prospective study on fungal keratitis caused by these three fungal species. Methodology. A prospective investigation was undertaken to evaluate eyes with presumed fungal keratitis. All the fungal isolates (n = 73) obtained from keratitis infections were identified using morphological and microscopic characters. Molecular identification using sequencing of the ITS region and antifungal susceptibility tests using microdilution method were done. The final clinical outcome was evaluated in terms of the time taken for resolution of keratitis and the final visual outcome. The results were analyzed after segregating the cases into three groups, namely, Fusarium, Aspergillus, and Dematiaceous keratitis. Results. Diagnosis of fungal keratitis was established in 73 (35.9%) cases out of 208 cases. The spectra of fungi isolated were Fusarium spp. (26.6%), Aspergillus spp. (21.6%), and Dematiaceous fungi (11.6%). The sequence of the ITS region could identify the Fusarium and Aspergillus species at the species complex level, and the Dematiaceous isolates were accurately identified. Using antifungal agents such as fluconazole, natamycin, amphotericin B, and itraconazole, the minimum inhibitory concentrations (MICs) for Fusarium spp. were >32 μg/mL, 4–8 μg/mL, 0.5–1 μg/mL, and >32 μg/mL, respectively. Antifungal susceptibility data showed that Curvularia spp. was highly resistant to all the antifungal agents. Overall, natamycin and amphotericin B were found to be the most effective antifungal agents. The comparative clinical outcomes in all cases showed that the healing response in terms of visual acuity of the Dematiaceous group was significantly good when compared with the Fusarium and Aspergillus groups (P < 0.05). The time required for healing in the Fusarium group was statistically significantly less when compared with the Aspergillus and Dematiaceous groups. Conclusion. This study demonstrates important differences in microscopic features of scraping material and antifungal susceptibility between the three groups. Early and accurate identification coupled with the MIC data, and thereby appropriate treatment is crucial for complete recovery. PMID:24260740

[Invasive mould disease in haematological patients].

PubMed

Ruiz-Camps, Isabel; Jarque, Isidro

2014-01-01

Invasive mould infections (IMI) are a persistent problem with high morbidity and mortality rates among patients receiving chemotherapy for hematological malignancies and hematopoietic stem cell transplant recipients. Management of IMI in this setting has become increasingly complex with the advent of new antifungal agents and diagnostic tests, which have resulted in different therapeutic strategies (prophylactic, empirical, pre-emptive, and directed). A proper assessment of the individual risk for IMI appears to be critical in order to use the best prophylactic and therapeutic approach and increase the survival rates. Among the available antifungal drugs, the most frequently used in the hematologic patient are fluconazole, mould-active azoles (itraconazole, posaconazole and voriconazole), candins (anidulafungin, caspofungin and micafungin), and lipid formulations of amphotericin B. Specific recommendations for their use, and criteria for selecting the antifungal agents are discussed in this paper. Copyright © 2014. Published by Elsevier Espana.

A Cationic Polymer That Shows High Antifungal Activity against Diverse Human Pathogens.

PubMed

Rank, Leslie A; Walsh, Naomi M; Liu, Runhui; Lim, Fang Yun; Bok, Jin Woo; Huang, Mingwei; Keller, Nancy P; Gellman, Samuel H; Hull, Christina M

2017-10-01

Invasive fungal diseases are generally difficult to treat and often fatal. The therapeutic agents available to treat fungi are limited, and there is a critical need for new agents to combat these deadly infections. Antifungal compound development has been hindered by the challenge of creating agents that are highly active against fungal pathogens but not toxic to the host. Host defense peptides (HDPs) are produced by eukaryotes as a component of the innate immune response to pathogens and have served as inspiration for the development of many new antibacterial compounds. HDP mimics, however, have largely failed to exhibit potent and selective antifungal activity. Here, we present an HDP-like nylon-3 copolymer that is effective against diverse fungi while displaying only mild to moderate toxicity toward mammalian cells. This polymer is active on its own and in synergy with existing antifungal drugs against multiple species of Candida and Cryptococcus , reaching levels of efficacy comparable to those of the clinical agents amphotericin B and fluconazole in some cases. In addition, the polymer acts synergistically with azoles against different species of Aspergillus , including some azole-resistant strains. These findings indicate that nylon-3 polymers are a promising lead for development of new antifungal therapeutic strategies. Copyright © 2017 American Society for Microbiology.

Análisis de Costo Efectividad de Estrategias de Tratamiento Antimicótico en Pacientes con Neutropenia Febril Persistente y Tratamiento Antibiótico de Amplio Espectro.

PubMed

Gamboa Garay, Oscar Andrés; Fuentes Pachón, Juan Camilo; Cuervo Maldonado, Sonia Isabel; Gómez Rincón, Julio Cesar; Castillo Londoño, Juan Sebastian

2012-12-01

To assess cost-effectiveness of antifungal treatment on patients with persistent fever neutropenia: empiric antifungal therapy (EAT) vs. anticipated antifungal therapy (AAT). A decision model was performed to evaluate the cost-effectiveness of antifungal treatment strategies in patients with febrile neutropenia not responding to a broad spectrum antibiotic treatment. The strategies included were: 1) EAT with amphotericin B deoxycholate; 2) EAT with liposomal amphotericin B; 3) EAT with caspofungin; and 4) AAT with voriconazole and amphotericin B deoxycholate or liposomal amphotericin B or caspofungin in patients who initiate treatment despite having negative CT scan and galactomannan or fail to voriconazole. Effectiveness was measured as the number of deaths averted. Cost-effectiveness and incremental cost-effectiveness ratios were calculated. Deterministic and probabilistic sensitivity analyzes were performed. EAT with Amphotericin B deoxycholate was the least expensive and least effective strategy. The EAT with caspofungin was the most effective. The cost per death averted for caspofungin when compared with amphotericin B deoxycholate was $17,011,073.83, which would indicate that this strategy would be cost-effective for the country if the willingness to pay per death averted is equal to or greater than this value. EAT with liposomal amphotericin B and AAT with voriconazole were dominated by AET with caspofungin, which is less costly and more effective. EAT with caspofungin would be cost-effective for Colombia if the threshold per death averted is greater to $18.000.000. If the threshold is lesser the EAT with amphotericin B deoxycholate would be the election. Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Antifungal Susceptibility and Phylogeny of Opportunistic Members of the Order Mucorales

PubMed Central

Vitale, Roxana G.; de Hoog, G. Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W. J.; Dolatabadi, Somayeh; Meis, Jacques F.

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended. PMID:22075600

Antifungal susceptibility and phylogeny of opportunistic members of the order mucorales.

PubMed

Vitale, Roxana G; de Hoog, G Sybren; Schwarz, Patrick; Dannaoui, Eric; Deng, Shuwen; Machouart, Marie; Voigt, Kerstin; van de Sande, Wendy W J; Dolatabadi, Somayeh; Meis, Jacques F; Walther, Grit

2012-01-01

The in vitro susceptibilities of 66 molecularly identified strains of the Mucorales to eight antifungals (amphotericin B, terbinafine, itraconazole, posaconazole, voriconazole, caspofungin, micafungin, and 5-fluorocytosine) were tested. Molecular phylogeny was reconstructed based on the nuclear ribosomal large subunit to reveal taxon-specific susceptibility profiles. The impressive phylogenetic diversity of the Mucorales was reflected in susceptibilities differing at family, genus, and species levels. Amphotericin B was the most active drug, though somewhat less against Rhizopus and Cunninghamella species. Posaconazole was the second most effective antifungal agent but showed reduced activity in Mucor and Cunninghamella strains, while voriconazole lacked in vitro activity for most strains. Genera attributed to the Mucoraceae exhibited a wide range of MICs for posaconazole, itraconazole, and terbinafine and included resistant strains. Cunninghamella also comprised strains resistant to all azoles tested but was fully susceptible to terbinafine. In contrast, the Lichtheimiaceae completely lacked strains with reduced susceptibility for these antifungals. Syncephalastrum species exhibited susceptibility profiles similar to those of the Lichtheimiaceae. Mucor species were more resistant to azoles than Rhizopus species. Species-specific responses were obtained for terbinafine where only Rhizopus arrhizus and Mucor circinelloides were resistant. Complete or vast resistance was observed for 5-fluorocytosine, caspofungin, and micafungin. Intraspecific variability of in vitro susceptibility was found in all genera tested but was especially high in Mucor and Rhizopus for azoles and terbinafine. Accurate molecular identification of etiologic agents is compulsory to predict therapy outcome. For species of critical genera such as Mucor and Rhizopus, exhibiting high intraspecific variation, susceptibility testing before the onset of therapy is recommended.

The inhibition of Candida species by selected essential oils and their synergism with amphotericin B.

PubMed

Rosato, Antonio; Vitali, Cesare; Gallo, Daniela; Balenzano, Luca; Mallamaci, Rosanna

2008-08-01

In this work we highlight a possible synergistic anti-Candida effect between Melaleuca alternifolia, Origanum vulgare and Pelargonium graveolens essential oils and the antifungal compound Amphotericin B. The antifungal activity was assessed using the agar dilution method in eleven Candida strains. The results obtained indicate the occurrence of a synergistic interaction between the essential oils under study and Amphotericin B. P. graveolens essential oil appeared to be the most effective, inhibiting all the Candida species evaluated by this study.

Multicenter, International Study of MIC/MEC Distributions for Definition of Epidemiological Cutoff Values for Sporothrix Species Identified by Molecular Methods

PubMed Central

Abreu, D. P. B.; Almeida-Paes, R.; Brilhante, R. S. N.; Chakrabarti, A.; Córdoba, S.; Gonzalez, G. M.; Guarro, J.; Johnson, E. M.; Kidd, S. E.; Pereira, S. A.; Rozental, S.; Szeszs, M. W.; Ballesté Alaniz, R.; Bonifaz, A.; Bonfietti, L. X.; Borba-Santos, L. P.; Capilla, J.; Colombo, A. L.; Dolande, M.; Isla, M. G.; Melhem, M. S. C.; Mesa-Arango, A. C.; Oliveira, M. M. E.; Panizo, M. M.; Pires de Camargo, Z.; Zancope-Oliveira, R. M.; Turnidge, J.

2017-01-01

ABSTRACT Clinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenic Sporothrix species to antifungal agents are based on a collaborative study that evaluated five clinically relevant isolates of Sporothrix schenckii sensu lato and some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents and Sporothrix species and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for the species. We collected available CLSI MICs/minimal effective concentrations (MECs) of amphotericin B, five triazoles, terbinafine, flucytosine, and caspofungin for 301 Sporothrix schenckii sensu stricto, 486 S. brasiliensis, 75 S. globosa, and 13 S. mexicana molecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, and South and North America) using conidial inoculum suspensions and 48 to 72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs for S. schenckii and S. brasiliensis, respectively: amphotericin B, 4 and 4 μg/ml; itraconazole, 2 and 2 μg/ml; posaconazole, 2 and 2 μg/ml; and voriconazole, 64 and 32 μg/ml. Ketoconazole and terbinafine ECVs for S. brasiliensis were 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine (or any other antifungal agent) ECVs for S. schenckii, as well as ECVs for S. globosa and S. mexicana. These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy. PMID:28739796

Breaking the Mold: A Review of Mucormycosis and Current Pharmacological Treatment Options.

PubMed

Riley, Treavor T; Muzny, Christina A; Swiatlo, Edwin; Legendre, Davey P

2016-09-01

To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options. An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations. Studies written in the English language from January 1960 to March 2016 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently. Mucormycosis is a rare invasive fungal infection with an exceedingly high mortality and few therapeutic options. It has a distinct predilection for invasion of endothelial cells in the vascular system, which is likely important in dissemination of disease from a primary focus of infection. Six distinct clinical syndromes can occur in susceptible hosts, including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, widely disseminated, and miscellaneous infection. Diagnosis of mucormycosis is typically difficult to make based on imaging studies, sputum culture, bronchoalveolar lavage culture, or needle aspirate. Surgical debridement prior to dissemination of infection improves clinical outcomes. Surgery combined with early, high-dose systemic antifungal therapy yields greater than a 1.5-fold increase in survival rates. The Mucorales are inherently resistant to most widely used antifungal agents. Amphotericin B is appropriate for empirical therapy, whereas posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B. © The Author(s) 2016.

Antifungal activity against Candida albicans of starch Pickering emulsion with thymol or amphotericin B in suspension and calcium alginate films.

PubMed

Cossu, Andrea; Wang, Min S; Chaudhari, Amol; Nitin, Nitin

2015-09-30

Conventional antifungal treatments against Candida albicans in the oral cavity often result in increased cytotoxicity. The goal of this study was to determine the potential of starch Pickering emulsion as a delivery vehicle for an antifungal natural phenolic compound such as thymol in simulated saliva fluid (SSF) compared to amphotericin B. An oil-in-water (o/w) emulsion was stabilized using starch particles. Physical stability of the emulsion and disruption induced by α-amylase activity in SSF was evaluated. Encapsulated thymol in o/w emulsion was compared to encapsulated amphotericin B for antifungal activity against C. albicans in suspension using emulsions or zone inhibition assay on agar plates using emulsions dispersed in alginate films. Results showed that the emulsions were stable for at least three weeks. Digestion of the emulsion by α-amylase led to coalescence of emulsion droplets. The antifungal activity of thymol and amphotericin B in emulsion formulation was enhanced upon incubation with α-amylase. Results from the zone inhibition assay demonstrated efficacy of the emulsions dispersed in alginate films. Interestingly, addition of α-amylase to the alginate films resulted in a decreased inhibitory effect. Overall, this study showed that starch Pickering emulsions have a potential to deliver hydrophobic antifungal compounds to treat oral candidiasis. Copyright © 2015 Elsevier B.V. All rights reserved.

In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates.

PubMed

Homa, Mónika; Galgóczy, László; Tóth, Eszter; Tóth, Liliána; Papp, Tamás; Chandrasekaran, Muthusamy; Kadaikunnan, Shine; Alharbi, Naiyf S; Vágvölgyi, Csaba

2015-11-01

In the present study, in vitro antifungal activities of five antipsychotic drugs (i.e., chlorpromazine hydrochloride, CPZ; trifluoperazine hydrochloride, TPZ; amantadine hydrochloride; R-(-)-deprenyl hydrochloride, and valproic acid sodium salt) and five conventional antifungal drugs (i.e., amphotericin B, AMB; caspofungin, CSP; itraconazole; terbinafine, TRB and voriconazole, VRC) were investigated in broth microdilution tests against four clinical and five environmental Scedosporium and Pseudallescheria isolates. When used alone, phenothiazines CPZ and TPZ exerted remarkable antifungal effects. Thus, their in vitro combinations with AMB, CSP, VRC, and TRB were also examined against the clinical isolates. In combination with antifungal agents, CPZ was able to act synergistically with AMB and TRB in cases of one and two isolates, respectively. In all other cases, indifferent interactions were revealed. Antagonism was not observed between the tested agents. These combinations may establish a more effective and less toxic therapy after further in vitro and in vivo studies for Scedosporium and Pseudallescheria infections. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Phosphomannose isomerase and phosphomannomutase gene disruptions in Streptomyces nodosus: impact on amphotericin biosynthesis and implications for glycosylation engineering.

PubMed

Nic Lochlainn, Laura; Caffrey, Patrick

2009-01-01

Streptomycetes synthesise several bioactive natural products that are modified with sugar residues derived from GDP-mannose. These include the antifungal polyenes, the antibacterial antibiotics hygromycin A and mannopeptimycins, and the anticancer agent bleomycin. Three enzymes function in biosynthesis of GDP-mannose from the glycolytic intermediate fructose 6-phosphate: phosphomannose isomerase (PMI), phosphomannomutase (PMM) and GDP-mannose pyrophosphorylase (GMPP). Synthesis of GDP-mannose from exogenous mannose requires hexokinase or phosphotransferase enzymes together with PMM and GMPP. In this study, a region containing genes for PMI, PMM and GMPP was cloned from Streptomyces nodosus, producer of the polyenes amphotericins A and B. Inactivation of the manA gene for PMI resulted in production of amphotericins and their aglycones, 8-deoxyamphoteronolides. A double mutant lacking the PMI and PMM genes produced 8-deoxyamphoteronolides in good yields along with trace levels of glycosylated amphotericins. With further genetic engineering these mutants may activate alternative hexoses as GDP-sugars for transfer to aglycones in vivo.

Aspergillus vertebral osteomyelitis after simultaneous kidney-pancreas transplantation.

PubMed

Salvalaggio, P R O; Bassetti, M; Lorber, M I; Micheletto, G C; Friedman, A L; Andriole, V T; Basadonna, G P

2003-12-01

Aspergillus osteomyelitis is a rare complication of invasive aspergillosis after organ transplantation. This is the report of a 46-year-old man who underwent a simultaneous pancreas and kidney transplantation, complicated by an Aspergillus osteomyelitis and diskitis of the lumbar spine. Prompt diagnosis with needle biopsy, followed by antifungal therapy using caspofungin, a new antifungal agent recommended for the treatment of refractory aspergillosis, in combination with amphotericin B and an early surgical intervention led to clinical resolution of the infection. Reported cases of spinal aspergillosis after transplantation are reviewed in terms of clinical presentation, risk factors, therapeutic options, and outcome.

Synergistic activity of the tyrocidines, antimicrobial cyclodecapeptides from Bacillus aneurinolyticus, with amphotericin B and caspofungin against Candida albicans biofilms.

PubMed

Troskie, Anscha Mari; Rautenbach, Marina; Delattin, Nicolas; Vosloo, Johan Arnold; Dathe, Margitta; Cammue, Bruno P A; Thevissen, Karin

2014-07-01

Tyrocidines are cationic cyclodecapeptides from Bacillus aneurinolyticus that are characterized by potent antibacterial and antimalarial activities. In this study, we show that various tyrocidines have significant activity against planktonic Candida albicans in the low-micromolar range. These tyrocidines also prevented C. albicans biofilm formation in vitro. Studies with the membrane-impermeable dye propidium iodide showed that the tyrocidines disrupt the membrane integrity of mature C. albicans biofilm cells. This membrane activity correlated with the permeabilization and rapid lysis of model fungal membranes containing phosphatidylcholine and ergosterol (70:30 ratio) induced by the tyrocidines. The tyrocidines exhibited pronounced synergistic biofilm-eradicating activity in combination with two key antifungal drugs, amphotericin B and caspofungin. Using a Caenorhabditis elegans infection model, we found that tyrocidine A potentiated the activity of caspofungin. Therefore, tyrocidines are promising candidates for further research as antifungal drugs and as agents for combinatorial treatment. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Risk assessment for the spread of Candida sp. in dental chair unit waterlines using molecular techniques.

PubMed

Mazari, Wissame; Boucherit-Otmani, Zahia; El Haci, Imad Abdelhamid; Ilahi, Amine; Boucherit, Kebir

2018-05-04

The aim of this study was to evaluate the presence of yeasts in dental chair unit waterlines (DCUWLs) and to test their ability to form biofilms. Eighteen dental waterlines were analysed by culture in liquid Sabouraud in order to allow the quantification and the purification of isolated yeasts from their internal surfaces. All isolates were identified by standard laboratory procedures, including CHROMagar Candida medium for orientation, commercial yeast identification system Api Candida, MALDI-TOF MS and DNA sequencing. To evaluate their kinetics of antifungal susceptibility during different phases of biofilm formation, these yeasts were subjected to three antifungal agents. From the 18 DCUWLs studied, 10 were altered (55.56%). Eleven strains of Candida sp. [Candida albicans (2), Candida guilliermondii (5) and Candida glabrata (4)] and two species of non-Candida; Rhodotorula spp. (1) and Trichosporon spp. (2) were identified. The majority of yeasts in planktonic form were susceptible to amphotericin B, caspofungin and voriconazole, except C. albicans was resistant to voriconazole. In the biofilm form, caspofungin was the most effective antifungal agent for all isolated strains. For the other antifungal agents, sessile cells were resistant. Several types of yeasts were identified; the most frequently isolated genus was Candida. The majority of these yeasts had the ability to form biofilms and resisted antifungal agents used in this study. © 2018 FDI World Dental Federation.

Activities of Fluconazole, Caspofungin, Anidulafungin, and Amphotericin B on Planktonic and Biofilm Candida Species Determined by Microcalorimetry

PubMed Central

Maiolo, Elena Maryka; Furustrand Tafin, Ulrika; Borens, Olivier

2014-01-01

We investigated the activities of fluconazole, caspofungin, anidulafungin, and amphotericin B against Candida species in planktonic form and biofilms using a highly sensitive assay measuring growth-related heat production (microcalorimetry). C. albicans, C. glabrata, C. krusei, and C. parapsilosis were tested, and MICs were determined by the broth microdilution method. The antifungal activities were determined by isothermal microcalorimetry at 37°C in RPMI 1640. For planktonic Candida, heat flow was measured in the presence of antifungal dilutions for 24 h. Candida biofilm was formed on porous glass beads for 24 h and exposed to serial dilutions of antifungals for 24 h, and heat flow was measured for 48 h. The minimum heat inhibitory concentration (MHIC) was defined as the lowest antifungal concentration reducing the heat flow peak by ≥50% (≥90% for amphotericin B) at 24 h for planktonic Candida and at 48 h for Candida biofilms (measured also at 24 h). Fluconazole (planktonic MHICs, 0.25 to >512 μg/ml) and amphotericin B (planktonic MHICs, 0.25 to 1 μg/ml) showed higher MHICs than anidulafungin (planktonic MHICs, 0.015 to 0.5 μg/ml) and caspofungin (planktonic MHICs, 0.125 to 0.5 μg/ml). Against Candida species in biofilms, fluconazole's activity was reduced by >1,000-fold compared to its activity against the planktonic counterparts, whereas echinocandins and amphotericin B mainly preserved their activities. Fluconazole induced growth of planktonic C. krusei at sub-MICs. At high concentrations of caspofungin (>4 μg/ml), paradoxical growth of planktonic C. albicans and C. glabrata was observed. Microcalorimetry enabled real-time evaluation of antifungal activities against planktonic and biofilm Candida organisms. It can be used in the future to evaluate new antifungals and antifungal combinations and to study resistant strains. PMID:24566186

Synergy and antagonism between iron chelators and antifungal drugs in Cryptococcus.

PubMed

Lai, Yu-Wen; Campbell, Leona T; Wilkins, Marc R; Pang, Chi Nam Ignatius; Chen, Sharon; Carter, Dee A

2016-10-01

Fungal infections remain very difficult to treat, and developing new antifungal drugs is difficult and expensive. Recent approaches therefore seek to augment existing antifungals with synergistic agents that can lower the therapeutic dose, increase efficacy and prevent resistance from developing. Iron limitation can inhibit microbial growth, and iron chelators have been employed to treat fungal infections. In this study, chequerboard testing was used to explore combinations of iron chelators with antifungal agents against pathogenic Cryptococcus spp. with the aim of determining how disruption to iron homeostasis affects antifungal susceptibility. The iron chelators ethylenediaminetetraacetic acid (EDTA), deferoxamine (DFO), deferiprone (DFP), deferasirox (DSX), ciclopirox olamine and lactoferrin (LF) were paired with the antifungal agents amphotericin B (AmB), fluconazole, itraconazole, voriconazole and caspofungin. All chelators except for DFO increased the efficacy of AmB, and significant synergy was seen between AmB and LF for all Cryptococcus strains. Addition of exogenous iron rescued cells from the antifungal effect of LF alone but could not prevent inhibition by AmB + LF, indicating that synergy was not due primarily to iron chelation but to other properties of LF that were potentiated in the presence of AmB. Significant synergy was not seen consistently for other antifungal-chelator combinations, and EDTA, DSX and DFP antagonised the activity of azole drugs in strains of Cryptococcus neoformans var. grubii. This study highlights the range of interactions that can be induced by chelators and indicates that most antifungal drugs are not enhanced by iron limitation in Cryptococcus. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Advances in the treatment of invasive neonatal candidiasis

PubMed Central

Botero-Calderon, Lorena; Benjamin, Daniel K.; Cohen-Wolkowiez, Michael

2015-01-01

Introduction Invasive candidiasis is responsible for approximately 10% of nosocomial sepsis in very-low-birth-weight (VLBW) infants and is associated with substantial morbidity and mortality. Over the last 2 decades, the antifungal armamentarium against Candida spp. has increased; however, efficacy and safety studies in this population are lacking. Areas covered We reviewed the medical literature and extracted information on clinical and observational studies evaluating the use of antifungal agents in neonates with invasive candidiasis. Expert opinion Efficacy and safety data for antifungals in neonates are lacking, and the majority of studies conducted to date have concentrated on pharmacokinetic/pharmacodynamic evaluations. Unlike other anti-infective agents, efficacy data in the setting of neonatal candidiasis cannot be extrapolated from adult studies due to differences in the pathophysiology of the disease in this population relative to older children and adults. Data collected thus far or data submitted to regulatory agencies for amphotericin B deoxycholate, fluconazole, and micafungin suggest that these are the current agents of choice for this disease in neonates until data for newer antifungal agents become available. For prophylaxis, data from fluconazole randomized controlled trials will be submitted to the regulatory agencies for labeling. Ultimately, the field of therapeutics for neonatal candidiasis will require multidisciplinary collaboration given the numerous challenges associated with conducting clinical trials in neonates. PMID:25842986

Effects of the Hematoregulatory Peptide SK&F 107647 Alone and in Combination with Amphotericin B against Disseminated Candidiasis in Persistently Neutropenic Rabbits

PubMed Central

Lyman, Caron A.; Gonzalez, Corina; Schneider, Mark; Lee, James; Walsh, Thomas J.

1999-01-01

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia. PMID:10471559

Synergistic activity of lysozyme and antifungal agents against Candida albicans biofilms on denture acrylic surfaces.

PubMed

Samaranayake, Y H; Cheung, B P K; Parahitiyawa, N; Seneviratne, C J; Yau, J Y Y; Yeung, K W S; Samaranayake, L P

2009-02-01

Denture related oral candidiasis is a recalcitrant fungal infection not easily resolved by topical antifungals. The antimycotic protein lysozyme, in saliva is an important host defense mechanism although its activity against Candida biofilms on denture acrylic has not been evaluated. (i) To establish a clinically relevant denture acrylic assay model to develop standardized Candida albicans biofilms, and (ii) assess the inhibitory effects of lysozyme alone and, the latter combined with antifungals (nystatin, amphotericin B, ketoconazole and 5-fluorocytosine) on sessile Candida cells and, finally (iii) to visualize the accompanying ultrastructural changes. The rotating-disc biofilm reactor was used to develop standardized 48 h Candida biofilms on acrylic discs in YNB/100 mM glucose medium and the biofilm metabolic activity was monitored using a tetrazolium reduction assay. The biofilm metabolic activity was similar in 18 identical denture acrylic discs (p<0.05) thus validating the rotating-disc biofilm model. Very low concentrations of lysozyme (6.25 microg/ml) significantly (p<0.01) inhibited Candida biofilm formation indicating that lysozyme may likely regulate intra-oral Candida biofilm development. Although 100 microg/ml lysozyme killed 45% of sessile Candida cells, further increasing its concentration (up to 240 microg/ml) had no such effect. Nystatin, amphotericin B, and ketoconazole in association with 100 microg/ml lysozyme exhibited effective synergistic killing of biofilm Candida in comparison to drug-free controls. Scanning electron and confocal scanning laser microscopy analysis confirmed the latter trends. Our results indicate that agents found in biological fluids such as lysozyme could be a safe adjunct to antifungals in future treatment strategies for recalcitrant candidal infections.

Liposomal Amphotericin B (AmBisome®): A review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions

PubMed Central

Stone, Neil RH; Bicanic, Tihana; Salim, Rahuman; Hope, William

2016-01-01

Liposomal amphotericin B (AmBisome®; LAmB) is a unique lipid formulation of amphotericin B. LAmB is a standard of care for a wide range of medically important opportunistic fungal pathogens. LAmB has a significantly improved toxicity profile compared with conventional amphotericin B deoxycholate (DAmB). Despite nearly 20 years of clinical use, the pharmacokinetics and pharmacodynamics of this agent, which differ considerably from DAmB, remain relatively poorly understood and underutilized in the clinical setting. The molecular pharmacology, preclinical and clinical pharmacokinetics, and clinical experience with LAmB for the most commonly encountered fungal pathogens are reviewed. In vitro, experimental animal models and human clinical trial data are summarized, and novel routes of administration and dosing schedules are discussed. LAmB is a formulation that results in reduced toxicity as compared with DAmB while retaining the antifungal effect of the active agent. Its long terminal half-life and retention in tissues suggest that single or intermittent dosing regimens are feasible, and these should be actively investigated in both preclinical models and in clinical trials. Significant gaps remain in knowledge of pharmacokinetics and pharmacodynamics in special populations such as neonates and children, pregnant women and obese patients. PMID:26818726

Pharmacodynamics of Amphotericin B Deoxycholate, Amphotericin B Lipid Complex, and Liposomal Amphotericin B against Aspergillus fumigatus

PubMed Central

Al-Nakeeb, Zaid; Petraitis, Vidmantas; Goodwin, Joanne; Petraitiene, Ruta; Walsh, Thomas J.

2015-01-01

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1→3)-β-d-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the “average” patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1→3)-β-d-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1→3)-β-d-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1→3)-β-d-glucan levels in the majority of patients. PMID:25712363

A UBI 31-38 Peptide-coumarin Conjugate: Photophysical Features, Imaging Tracking and Synergism with Amphotericin B Against Cryptococcus.

PubMed

Ferreira, Soraya M Z M D; Carneiro, Hellem C; Alves, Rosemeire B; Batista, Ana Carolina S; da Silva Junior, Eufranio N; Dias, Gleiston G; Resende, Jarbas M; Santos, Daniel A; Oliveira, Debora L; Rodrigues, Marcio L; Freitas, Rossimiriam P

2018-01-01

Cryptococcosis is a fungal disease of global significance for which new effective treatments are needed. The conjugation of the synthetic antimicrobial peptide fragment UBI 31-38 to a coumarin derivative showed to be an effective approach for the design of a novel anticryptococcal agent. In addition to antifungal activity, the conjugate exhibited intense fluorescence, which could be valuable for mechanistic investigations of this molecule. In this work, we studied the photophysical properties of the conjugate and confocal scanning laser microscopy was used to inspect the distribution of the peptide-coumarin conjugate in Cryptococcus cell. The synergism of this compound with amphotericin B or fluconazole against C. gattii and C. neoformans strains was also investigated. The results indicated that the fluorescent conjugate alone as well as its combination with amphotericin B are promising tools against cryptococcosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Colonization and antifungals susceptibility patterns of Candida species isolated from hospitalized patients in ICUs and NICUs.

PubMed

Zarei Mahmoudabadi, Ali; Rezaei-Matehkolaei, Ali; Navid, Mojgan; Torabizadeh, Mehdi; Mazdarani, Shahnam

2015-07-01

Several studies have shown that there are an increasing in invasive candidiasis during 2-3 last decades. Although, Candida albicans is considered as the most common candidiasis agents, other non-albicans such as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis were raised as infectious agents. Resistance to fluconazole among non-albicans species is an important problem for clinicians during therapy and prophylaxis. The aim of current study was to detect the Candida species from hospitalized neonatal and children in intensive care units (ICUs) and neonatal intensive care units (NICUs). In addition, the susceptibility of isolated agents were also evaluated against three antifungals. In the present study 298 samples including 98 blood samples, 100 urines and 100 swabs from oral cavity were inoculated on CHROMagar Candida. Initial detection was done according to the coloration colonies on CHROMagar Candida . Morphology on cornmeal agar, germ tube formation and growth at 45°C were confirmed isolates. Amphotericin B, fluconazole and terbinafine (Lamisil) were used for the susceptibility tests using microdilution method. In the present study 21% and 34% of urines and swabs from oral cavity were positive for Candida species, respectively. The most common species was C. albicans (62.5%) followed by C. tropicalis (15.6%), C. glabrata (6.3%) and Candida species (15.6%). Our study indicated that the most tested species of Candida, 70.3% were sensitive to fluconazole at the concentration of ≤8 μg/mL. Whereas 9 (14.1%) of isolates were resistant to amphotericine B at ≥8 μg/mL. This study demonstrates the importance of species identification and antifungals susceptibility testing for hospitalized patients in ICUs and NICUs wards.

Colonization and antifungals susceptibility patterns of Candida species isolated from hospitalized patients in ICUs and NICUs

PubMed Central

Zarei Mahmoudabadi, Ali; Rezaei-Matehkolaei, Ali; Navid, Mojgan; Torabizadeh, Mehdi; Mazdarani, Shahnam

2015-01-01

Background: Several studies have shown that there are an increasing in invasive candidiasis during 2-3 last decades. Although, Candida albicans is considered as the most common candidiasis agents, other non-albicans such as C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis were raised as infectious agents. Resistance to fluconazole among non-albicans species is an important problem for clinicians during therapy and prophylaxis. Objectives: The aim of current study was to detect the Candida species from hospitalized neonatal and children in intensive care units (ICUs) and neonatal intensive care units (NICUs). In addition, the susceptibility of isolated agents were also evaluated against three antifungals. Materials and Methods: In the present study 298 samples including 98 blood samples, 100 urines and 100 swabs from oral cavity were inoculated on CHROMagar Candida. Initial detection was done according to the coloration colonies on CHROMagar Candida . Morphology on cornmeal agar, germ tube formation and growth at 45°C were confirmed isolates. Amphotericin B, fluconazole and terbinafine (Lamisil) were used for the susceptibility tests using microdilution method. Results: In the present study 21% and 34% of urines and swabs from oral cavity were positive for Candida species, respectively. The most common species was C. albicans (62.5%) followed by C. tropicalis (15.6%), C. glabrata (6.3%) and Candida species (15.6%). Our study indicated that the most tested species of Candida, 70.3% were sensitive to fluconazole at the concentration of ≤8 μg/mL. Whereas 9 (14.1%) of isolates were resistant to amphotericine B at ≥8 μg/mL. Conclusions: This study demonstrates the importance of species identification and antifungals susceptibility testing for hospitalized patients in ICUs and NICUs wards. PMID:26312235

[Fungal infectivities of implanted catheters due to Candida sp. Biofilms formation and resistance].

PubMed

Seddiki, S M L; Boucherit-Otmani, Z; Boucherit, K; Kunkel, D

2015-06-01

Candidemia are the most common fungal infections in hospitals. However, the catheters are subject to be altered by Candida biofilms which increase the risk of invasive nosocomial infections due to the high resistance to antifungal agents. Therefore, the minimum inhibitory concentrations of planktonic (MIC) and sessile cells (CIMS) were evaluated. To review the in vivo biofilms structures of Candida sp. formed on the inner and/or external surfaces of collected catheters, we used scanning electron microscopy (SEM). The level of biofilm resistance was assessed against two conventional antifungal agents: amphotericin B (AmB), which belongs to the class of polyenes, and fluconazole (FLZ) which is an azole. The SEM observation of biofilms of Candida sp. reveals complex structures. Compared to MICs, the calculation of CIMS showed an increase of 32 times with AmB and of 128 times with FLZ. Catheters offer an ideal surface to Candida sp. to form biofilms. This complex structure induces the increase of the resistance of sessile cells against two antifungal agents, AmB and FLZ. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Host immune reactivity determines the efficacy of combination immunotherapy and antifungal chemotherapy in candidiasis.

PubMed

Mencacci, A; Cenci, E; Bacci, A; Bistoni, F; Romani, L

2000-02-01

In immunocompetent mice with candidiasis, successful therapy with amphotericin B and fluconazole relies on the induction of protective, T helper (Th) type 1 responses, an effect potentiated by concomitant interleukin (IL)-4 neutralization. To assess the therapeutic efficacy of combined treatments with antifungals and immunomodulators in conditions of immunosuppression, leukopenic or neutropenic mice with disseminated candidiasis were treated with amphotericin B or fluconazole alone or in combination with soluble IL-4 receptor (sIL-4R) or recombinant (r) IL-12 or IL-10 neutralizing monoclonal antibodies. We found that (1) the synergistic effect of sIL-4R and antifungals is retained in immunocompromised mice; (2) synergism with amphotericin B was superior to that with fluconazole, particularly in leukopenic mice; (3) rIL-12 synergized with fluconazole in neutropenic mice; and (4) IL-10 neutralization was always of limited efficacy. This study indicates that the therapeutic efficacy of antifungals is differentially potentiated by cytokines or cytokine antagonists and is influenced by host immune reactivity.

Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias.

PubMed

Schaffner, A; Schaffner, M

1995-10-01

Fungal infections are a major problem in patients with hematologic malignancy. Attempts to reduce their frequency with antifungal agents have not been successful. A double-blind, controlled, single-center trial was conducted with 96 consecutive patients undergoing 154 episodes of chemotherapy. Patients received 400 mg of fluconazole or placebo until bone marrow recovery or initiation of intravenous amphotericin B infusions. End points were amphotericin B use, fungal infection, stable neutrophil count > 0.5 x 10(9)/L, toxicity precluding further fluconazole use, and death. By Kaplan-Meier estimation, the time to initiation of amphotericin B therapy was shorter in 76 patients treated with placebo than in 75 treated with fluconazole (P = .003). Also, fluconazole reduced the number of febrile days by 20% (P = .002) and prevented oropharyngeal candidiasis (1/75 vs. 9/76, P = .018). The frequency of deep mycoses (8/76 vs. 8/75) and outcome were unaffected. Fluconazole did not have a favorable effect on infection-related health care costs and was associated with prolonged severe neutropenia (P = .01).

Biofilm-forming capacity of blood-borne Candida albicans strains and effects of antifungal agents.

PubMed

Turan, Hanni; Demirbilek, Müge

Infections related to Candida albicans biofilms and subsequent antifungal resistance have become more common with the increased use of indwelling medical devices. Regimens for preventing fungal biofilm formation are needed, particularly in high-risk patients. In this study, we investigated the biofilm formation rate of multiple strains of Candida albicans (n=162 clinical isolates), their antifungal susceptibility patterns, and the efficacy of certain antifungals for preventing biofilm formation. Biofilm formation was graded using a modified Christensen's 96-well plate method. We further analyzed 30 randomly chosen intense biofilm-forming isolates using the XTT method. Minimum biofilm inhibition concentrations (MBIC) of caspofungin, micafungin, anidulafungin, fluconazole, voriconazole, posaconazole, itraconazole, and amphotericin B were determined using the modified Calgary biofilm method. In addition, the inhibitory effects of antifungal agents on biofilm formation were investigated. Our study showed weak, moderate, and extensive biofilm formation in 29% (n=47), 38% (n=61), and 23% (n=37) of the isolates, respectively. We found that echinocandins had the lowest MBIC values and that itraconazole inhibited biofilm formation in more isolates (26/32; 81.3%) than other tested agents. In conclusion, echinocandins were most effective against formed biofilms, while itraconazole was most effective for preventing biofilm formation. Standardized methods are needed for biofilm antifungal sensitivity tests when determining the treatment and prophylaxis of C. albicans infections. Copyright © 2017 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus

PubMed Central

Shekhova, Elena

2017-01-01

ABSTRACT Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of Aspergillus fumigatus with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds. PMID:28848005

Molecular Characterization, Structural Modeling, and Evaluation of Antimicrobial Activity of Basrai Thaumatin-Like Protein against Fungal Infection.

PubMed

Yasmin, Nusrat; Saleem, Mahjabeen; Naz, Mamoona; Gul, Roquyya; Rehman, Hafiz Muzzammel

2017-01-01

A thaumatin-like protein gene from Basrai banana was cloned and expressed in Escherichia coli . Amplified gene product was cloned into pTZ57R/T vector and subcloned into expression vector pET22b(+) and resulting pET22b-basrai TLP construct was introduced into E. coli BL21. Maximum protein expression was obtained at 0.7 mM IPTG concentration after 6 hours at 37°C. Western blot analysis showed the presence of approximately 20 kDa protein in induced cells. Basrai antifungal TLP was tried as pharmacological agent against fungal disease. Independently Basrai antifungal protein and amphotericin B exhibited their antifungal activity against A. fumigatus ; however combined effect of both agents maximized activity against the pathogen. Docking studies were performed to evaluate the antimicrobial potential of TLP against A. fumigatus by probing binding pattern of antifungal protein with plasma membrane ergosterol of targeted fungal strain. Ice crystallization primarily damages frozen food items; however addition of antifreeze proteins limits the growth of ice crystal in frozen foods. The potential of Basrai TLP protein, as an antifreezing agent, in controlling the ice crystal formation in frozen yogurt was also studied. The scope of this study ranges from cost effective production of pharmaceutics to antifreezing and food preserving agent as well as other real life applications.

Molecular Characterization, Structural Modeling, and Evaluation of Antimicrobial Activity of Basrai Thaumatin-Like Protein against Fungal Infection

PubMed Central

Yasmin, Nusrat; Naz, Mamoona; Gul, Roquyya; Rehman, Hafiz Muzzammel

2017-01-01

A thaumatin-like protein gene from Basrai banana was cloned and expressed in Escherichia coli. Amplified gene product was cloned into pTZ57R/T vector and subcloned into expression vector pET22b(+) and resulting pET22b-basrai TLP construct was introduced into E. coli BL21. Maximum protein expression was obtained at 0.7 mM IPTG concentration after 6 hours at 37°C. Western blot analysis showed the presence of approximately 20 kDa protein in induced cells. Basrai antifungal TLP was tried as pharmacological agent against fungal disease. Independently Basrai antifungal protein and amphotericin B exhibited their antifungal activity against A. fumigatus; however combined effect of both agents maximized activity against the pathogen. Docking studies were performed to evaluate the antimicrobial potential of TLP against A. fumigatus by probing binding pattern of antifungal protein with plasma membrane ergosterol of targeted fungal strain. Ice crystallization primarily damages frozen food items; however addition of antifreeze proteins limits the growth of ice crystal in frozen foods. The potential of Basrai TLP protein, as an antifreezing agent, in controlling the ice crystal formation in frozen yogurt was also studied. The scope of this study ranges from cost effective production of pharmaceutics to antifreezing and food preserving agent as well as other real life applications. PMID:28875151

Comparison of two antifungal susceptibility testing of Candida sp. isolates using agar diffusion method: Neo-sensitabs® tablets and Bio-rad® disks.

PubMed

Uwingabiye, J; Iken, M; Zohoun, A G; Boumhil, L; Lemkhente, Z; Naoui, H; Bouchrik, M; Lmimouni, B

2016-03-01

The aim of our study was to evaluate the concordance between the two antifungal susceptibility testing of Candida sp. isolates using agar diffusion method: Neo-Sensitabs(®) tablets and Bio-Rad(®) disks. This is a prospective study conducted in the Laboratory of Parasitology and Mycology of the Mohammed V military teaching hospital from February to August 2012. Upon receiving blood cultures and peripheral sites samples, the identification of Candida isolates performed using routine phenotypic standard tests and the realization of the antifungal susceptibility was carried out on Neo-sensitabs(®) tablets and Bio-Rad(®) disks. A total of 38 Candida strains were isolated: 15 C. albicans (39%), 13 C. glabrata (34%), 5 C. tropicalis (13%), 4 C. krusei (11%) and 1 C. dubliniensis (3%). There were no significant difference (P>0.05) in susceptibility rate between both methods for all antifungal agents tested except for 5-fluorocytosine. The concordance percentage between two methods was 100% for amphotericin B, 97.4% for fluconazole, 94.7% for voriconazole and 73% for 5-fluorocytosine. Both methods are easy to perform, rapid and cost effective. Our results showed the best agreement between the two methods for testing the susceptibility of Candida isolates to amphotericin B, fluconazole and voriconazole while for the 5-fluorocytosine, the concordance rate was low. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Unexplored antifungal activity of linear battacin lipopeptides against planktonic and mature biofilms of C. albicans.

PubMed

De Zoysa, Gayan Heruka; Glossop, Hugh Douglas; Sarojini, Vijayalekshmi

2018-02-25

Novel antifungal agents are required against pathogenic fungi such as Candida albicans. We report the anticandidal activity of battacin lipopeptide antibiotics with previously unexplored antifungal activity. From amongst sixteen battacin lipopeptides tested against C. alibicans (SC5314) the 4-methyl hexanoyl conjugated trimeric lipopeptide 13 emerged as the lead candidate with a MIC of 6.25 μM and negligible haemolysis of mouse red blood cells. The potency of this lipopeptide was maintained under acidic conditions. Additionally, antifungal activity was further enhanced with amphotericin B at its non-haemolytic concentrations. Herein we have demonstrated for the first time that battacin lipopeptides prevent C. albicans biofilm colonisation as well as inhibit pre-formed biofilms of this fungal pathogen. XTT biofilm assays revealed that 13 prevented colonisation of C. albicans biofilms at its MIC (6.25 μM) and, at a higher concentration, eradicated 24 h (25 μM) and 48 h (62.5 μM) old preformed biofilms. In comparison, we found that amphotericin at much lower concentrations prevented biofilm colonisation (0.78 μM) and inhibited 24 h old preformed biofilms (6.25 μM), however was completely inactive against 48 h old preformed biofilms. Thus, lipopeptide 13 is more effective than amphotericin at eradicating more mature C. albicans biofilms. The membrane lytic mechanism of action of compound 13 was validated by a colorimetric assay using lipid vesicles mimicking fungal membranes in which compound 13 effected an immediate dark purple to red colour transition of suspended vesicles upon peptide interaction. In addition, TEM images of C. albicans cells exposed to 13 showed clearly disrupted cellular membranes. Interestingly, compound 13 increased the endogenous generation of reactive oxygen species (ROS) in a concentration dependent manner. In the presence of an antioxidant, ascorbic acid, ROS production was diminished yet antifungal activity persisted, possibly indicating that ROS production is a secondary effect from membrane lysis caused by lipopeptide 13. The lipopeptide was non-haemolytic against mouse red blood cells at the highest tested concentration (1 mM). Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Activity and in vivo tracking of Amphotericin B loaded PLGA nanoparticles.

PubMed

Souza, A C O; Nascimento, A L; de Vasconcelos, N M; Jerônimo, M S; Siqueira, I M; R-Santos, L; Cintra, D O S; Fuscaldi, L L; Pires Júnior, O R; Titze-de-Almeida, R; Borin, M F; Báo, S N; Martins, O P; Cardoso, V N; Fernandes, S O; Mortari, M R; Tedesco, A C; Amaral, A C; Felipe, M S S; Bocca, A L

2015-05-05

The development of biocompatible polymeric nanoparticles has become an important strategy for optimizing the therapeutic efficacy of many classical drugs, as it may expand their activities, reduce their toxicity, increase their bioactivity and improve biodistribution. In this study, nanoparticles of Amphotericin B entrapped within poly (lactic-co-glycolic) acid and incorporated with dimercaptosuccinic acid (NANO-D-AMB) as a target molecule were evaluated for their physic-chemical characteristics, pharmacokinetics, biocompatibility and antifungal activity. We found high plasma concentrations of Amphotericin B upon treatment with NANO-D-AMB and a high uptake of nanoparticles in the lungs, liver and spleen. NANO-D-AMB exhibited antifungal efficacy against Paracoccidioides brasiliensis and induced much lower cytotoxicity levels compared to D-AMB formulation in vivo and in vitro. Together, these results confirm that NANO-D-AMB improves Amphotericin B delivery and suggest this delivery system as a potential alternative to the use of Amphotericin B sodium deoxycholate. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Molecular organization, localization and orientation of antifungal antibiotic amphotericin B in a single lipid bilayer

PubMed Central

Grudzinski, Wojciech; Sagan, Joanna; Welc, Renata; Luchowski, Rafal; Gruszecki, Wieslaw I.

2016-01-01

Amphotericin B is a popular antifungal antibiotic, a gold standard in treatment of systemic mycotic infections, due to its high effectiveness. On the other hand, applicability of the drug is limited by its considerable toxicity to patients. Biomembranes are a primary target of physiological activity of amphotericin B and both the pharmacologically desired and toxic side effects of the drug relay on its molecular organization in the lipid phase. In the present work, molecular organization, localization and orientation of amphotericin B, in a single lipid bilayer system, was analysed simultaneously, thanks to application of a confocal fluorescence lifetime imaging microscopy of giant unilamellar vesicles. The results show that the presence of sterols, in the lipid phase, promotes formation of supramolecular structures of amphotericin B and their penetration into the membrane hydrophobic core. The fact that such an effect is substantially less pronounced in the case of cholesterol than ergosterol, the sterol of fungal membranes, provides molecular insight into the selectivity of the drug. PMID:27620838

Activities of Available and Investigational Antifungal Agents against Rhodotorula Species

PubMed Central

Diekema, D. J.; Petroelje, B.; Messer, S. A.; Hollis, R. J.; Pfaller, M. A

2005-01-01

Rhodotorula species are emerging pathogens in immunocompromised patients. We report the in vitro activities of eight antifungals against 64 Rhodotorula isolates collected in surveillance programs between 1987 and 2003. Rhodotorula strains are resistant in vitro to fluconazole (MIC at which 50% of the isolates tested are inhibited [MIC50], >128 μg/ml) and caspofungin (MIC50, >8 μg/ml). Amphotericin B (MIC50,1 μg/ml) and flucytosine (MIC50, 0.12 μg/ml) are both active in vitro, and the new and investigational triazoles all have some in vitro activity, with ravuconazole being the most active (MIC50, 0.25 μg/ml). PMID:15635020

Development and characterization of oral liposomes of vegetal ceramide based amphotericin B having enhanced dry solubility and solubility.

PubMed

Skiba-Lahiani, Malika; Hallouard, François; Mehenni, Lyes; Fessi, Hatem; Skiba, Mohamed

2015-03-01

Despite the development of new antifungal, amphotericin B remains one of the most effective agents in the treatment of systemic fungal infections. Many patients exhibit nevertheless intolerance to amphotericin B at higher dosages and parenteral formulations present unlike per os ones, associated risks and high care cost. Free amphotericin B per os showed however an apparently poor absorption. In this study, we evaluate the potential of amphotericin B liposomes formulated with vegetal ceramides for oral administration. Ceramides, one of the constituents of cellular cytoplasmic membranes, constitute an important element in the construction and stability of their lipid bilayer. To fulfill this objective, vegetal ceramides, composed essentially of glucosylceramides, were firstly incorporated in various liposome preparations, entrapping or not amphotericin B, in comparison with phosphatidylcholine liposomes. Then, these preparations were introduced in an "Artificial-Stomach-Duodenum" model to improve their stability for oral administration. The formulation of amphotericin B liposomes containing ceramides presented a mean hydrodynamic size of about 200nm. We showed also that cholesterol and phospholipids are required to prevent drug leakage and to obtain lamellar structure respectively. In "Artificial-Stomach-Duodenum" model, ceramides conferred to liposomes better membrane stability. In addition, ceramides did not alter their drug encapsulation yield being by 75%. This could be explained by the fact that ceramides as we proved, limited the detergent effect of bile salts on liposome membranes. Copyright © 2014 Elsevier B.V. All rights reserved.

Induction of Mitochondrial Reactive Oxygen Species Production by Itraconazole, Terbinafine, and Amphotericin B as a Mode of Action against Aspergillus fumigatus.

PubMed

Shekhova, Elena; Kniemeyer, Olaf; Brakhage, Axel A

2017-11-01

Drug resistance in fungal pathogens is of incredible importance to global health, yet the mechanisms of drug action remain only loosely defined. Antifungal compounds have been shown to trigger the intracellular accumulation of reactive oxygen species (ROS) in human-pathogenic yeasts, but the source of those ROS remained unknown. In the present study, we examined the role of endogenous ROS for the antifungal activity of the three different antifungal substances itraconazole, terbinafine, and amphotericin B, which all target the fungal cell membrane. All three antifungals had an impact on fungal redox homeostasis by causing increased intracellular ROS production. Interestingly, the elevated ROS levels induced by antifungals were abolished by inhibition of the mitochondrial respiratory complex I with rotenone. Further, evaluation of lipid peroxidation using the thiobarbituric acid assay revealed that rotenone pretreatment decreased ROS-induced lipid peroxidation during incubation of Aspergillus fumigatus with itraconazole and terbinafine. By applying the mitochondrion-specific lipid peroxidation probe MitoPerOx, we also confirmed that ROS are induced in mitochondria and subsequently cause significant oxidation of mitochondrial membrane in the presence of terbinafine and amphotericin B. To summarize, our study suggests that the induction of ROS production contributes to the ability of antifungal compounds to inhibit fungal growth. Moreover, mitochondrial complex I is the main source of deleterious ROS production in A. fumigatus challenged with antifungal compounds. Copyright © 2017 American Society for Microbiology.

[In vitro antifungal activity of azoles and amphotericin B against Malassezia furfur by the CLSI M27-A3 microdilution and Etest® methods].

PubMed

Galvis-Marín, Juan Camilo; Rodríguez-Bocanegra, María Ximena; Pulido-Villamarín, Adriana Del Pilar; Castañeda-Salazar, Rubiela; Celis-Ramírez, Adriana Marcela; Linares-Linares, Melva Yomary

Malassezia furfur is a human skin commensal yeast that can cause skin and opportunistic systemic infections. Given its lipid dependant status, the reference methods established by the Clinical and Laboratory Standards Institute (CLSI) to evaluate antifungal susceptibility in yeasts are not applicable. To evaluate the in vitro susceptibility of M. furfur isolates from infections in humans to antifungals of clinical use. The susceptibility profile to amphotericin B, itraconazole, ketoconazole and voriconazole of 20 isolates of M. furfur, using the broth microdilution method (CLSI M27-A3) and Etest ® , was evaluated. Itraconazole and voriconazole had the highest antifungal activity against the isolates tested. The essential agreement between the two methods for azoles antifungal activity was in the region of 60-85% and the categorical agreement was around 70-80%, while the essential and categorical agreement for amphotericin B was 10%. The azoles were the compounds that showed the highest antifungal activity against M. furfur, as determined by the two techniques used; however more studies need to be performed to support that Etest ® is a reliable method before its implementation as a routine clinical laboratory test. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Investigation of the mechanism of action of 3-(4-bromophenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-one against Candida albicans by flow cytometry.

PubMed

Vale-Silva, Luís A; Buchta, Vladimír; Vokurková, Doris; Pour, Milan

2006-05-01

The mechanism of action of the antifungal agent 3-(4-bromophenyl)-5-acyloxymethyl-2,5-dihydrofuran-2-one against Candida albicans was investigated by flow cytometry, using propidium iodide, DiBAC4(3), and FUN-1 as the fluorescent dyes. A related but less active agent, together with amphotericin B and fluconazole, was tested in parallel for comparison of the results. The incrustoporine derivative was found to have a potent fungicidal activity on C. albicans, resulting in damage of cell membrane.

[Fungi isolated from the vagina and their susceptibility to antifungals].

PubMed

Macura, Anna B; Skóra, Magdalena

2012-06-01

Because of the presence of various fungi and changes in their spectrum in the mycosis of vagina it is necessary to perform periodic overviews including testing their susceptibility to antifungal agents. The objective of the study was to evaluate susceptibility of the fungi isolated from vaginas to antifungal drugs and to analyse the fungi responsible for vaginal mycosis in patients referred during a 7-year study The study was carried out in a group of patients suspected of vaginal mycosis between January 1, 2005 and December 31, 2011. An analysis of the fungi isolated from their vaginas was performed. The susceptibility of the fungi to six antifungals (5-fluorocytosine, amphotericin B, miconazole, ketoconazole, itraconazole and fluconazole) was evaluated using a semiquantitative Fungitest. A total of 4775 mycological test results were evaluated. Fungi were present in 30.6% of the material. C. albicans was the most frequently isolated fungal species (80.2%), followed by C. glabrata (5.8%), and S. cerevisiae (5.5%). Itraconazole turned out to be the least effective drug. C. krusei. was the species most resistant to antifungals, including fluconazole. 1. C. albicans is the species most frequently isolated from a vagina. It is highly susceptible to azoles, the antimycotics generally used in the treatment of vaginal mycosis. 2. Out of the azoles under study ketoconazole was the most active against fungi in vitro while itraconazole was the least active. 3. The Candida non-albicans species, and particularly C. krusei, are less susceptible to antimycotics. 4. Amphotericin B and 5-fluorocytosine are most effective against Candida strains and S. cerevisiae, however they are not used in the treatment of vaginal mycosis because of their high toxicity

Postantifungal effect of the combination of caspofungin with voriconazole and amphotericin B against clinical Candida krusei isolates.

PubMed

Oz, Yasemin; Kiremitci, Abdurrahman; Dag, Ilknur; Metintas, Selma; Kiraz, Nuri

2013-01-01

We evaluated the postantifungal effects (PAFEs) of caspofungin (CAS), voriconazole (VOR), amphotericin B (AmB), and the combinations of CAS + VOR and CAS + AmB against 30 clinical Candida krusei isolates at 0.25, 1 and 4 times the MIC of each individually and in the indicated combinations. Antifungals were removed after 1 hour and colony counts were performed at 0, 2, 6, 24, and 48 h. VOR did not display any measurable PAFE regardless of antifungal concentrations, while AmB and CAS exhibited dose-dependent PAFE. The most effective agent producing a prolonged PAFE in this study was CAS. Although the combination of CAS with VOR generated longer PAFEs at 0.25 and 1 times their respective MICs in comparison with CAS alone, this combination was indifferent rather than synergistic. However, the combination of CAS with AmB at 4 times their MICs exhibited the best performance, reducing the colony counts during the 48 h after removal of drugs and resulted in synergic interaction in respect to 20 (67%) isolates. Consequently, CAS has a prolonged PAFE in vitro against C. krusei isolates, and the combination of AmB + CAS may increase significantly the efficacy of CAS. Our data may be useful in optimizing dosing regimens for these agents and their combinations, although further studies are needed to explore the clinical usefulness of our results.

Use of external ventriculostomy and intrathecal anti-fungal treatment in cerebral mucormycotic abscess.

PubMed

Grannan, Benjamin L; Yanamadala, Vijay; Venteicher, Andrew S; Walcott, Brian P; Barr, John C

2014-10-01

Mucormycosis is an invasive fungal infection associated with a high mortality. Cerebral mucor abscesses can result secondary to rhinocerebral or hematogenous spread. Amphotericin B, posaconazole, and aggressive surgical resection are the hallmarks of treatment. While amphotericin is typically administered intravenously, less is known about the use of intrathecal amphotericin B. We describe a 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses. Copyright © 2014. Published by Elsevier Ltd.

Potato Dextrose Agar Antifungal Susceptibility Testing for Yeasts and Molds: Evaluation of Phosphate Effect on Antifungal Activity of CMT-3

PubMed Central

Liu, Yu; Tortora, George; Ryan, Maria E.; Lee, Hsi-Ming; Golub, Lorne M.

2002-01-01

The broth macrodilution method (BMM) for antifungal susceptibility testing, approved by the National Committee for Clinical Laboratory Standards (NCCLS), was found to have deficiencies in testing of the antifungal activity of a new type of antifungal agent, a nonantibacterial chemically modified tetracycline (CMT-3). The high content of phosphate in the medium was found to greatly increase the MICs of CMT-3. To avoid the interference of phosphate in the test, a new method using potato dextrose agar (PDA) as a culture medium was developed. Eight strains of fungi, including five American Type Culture Collection strains and three clinical isolates, were used to determine the MICs of amphotericin B and itraconazole with both the BMM and the PDA methods. The MICs of the two antifungal agents determined with the PDA method showed 99% agreement with those determined with the BMM method within 1 log2 dilution. Similarly, the overall reproducibility of the MICs with the PDA method was above 97%. Three other antifungal agents, fluconazole, ketoconazole, and CMT-3, were also tested in parallel against yeasts and molds with both the BMM and the PDA methods. The MICs of fluconazole and ketoconazole determined with the PDA method showed 100% agreement within 1 log2 dilution of those obtained with the BMM method. However, the MICs of CMT-3 determined with the BMM method were as high as 128 times those determined with the PDA method. The effect of phosphate on the antifungal activity of CMT-3 was evaluated by adding Na2HPO4 to PDA in the new method. It was found that the MIC of CMT-3 against a Penicillium sp. increased from 0.5 μg/ml (control) to 2.0 μg/ml when the added phosphate was used at a concentration of 0.8 mg/ml, indicating a strong interference of Na2HPO4 with the antifungal activity of CMT-3. Except for fluconazole, all the other antifungal agents demonstrated clear end points among the yeasts and molds tested. Nevertheless, with its high reproducibility, good agreement with NCCLS proposed MIC ranges, and lack of interference of phosphate, the PDA method shows promise as a useful assay for antifungal susceptibility testing and screening for new antifungal agents, especially for drugs that may be affected by high (supraphysiologic) phosphate concentrations. PMID:11959582

Endogenous Aspergillus endophthalmitis. Clinical features and treatment outcomes.

PubMed

Weishaar, P D; Flynn, H W; Murray, T G; Davis, J L; Barr, C C; Gross, J G; Mein, C E; McLean, W C; Killian, J H

1998-01-01

This study evaluated the clinical features and treatment outcomes in patients with endogenous Aspergillus endophthalmitis. The study design was a multicenter retrospective chart review. Ten patients (12 eyes) with culture-proven endogenous Aspergillus endophthalmitis treated by 1 of the authors were studied. Intravitreous amphotericin B injection, pars plana vitrectomy, systemic amphotericin B therapy, and oral anti-fungal therapy were performed. Elimination of endogenous Aspergillus endophthalmitis and Snellen visual acuity, best corrected, were measured. All patients had a 1- to 3-day history of pain and marked loss of visual acuity in the involved eyes. Varying degrees of vitritis was present in all 12 eyes. In 8 of 12 eyes, a central macular chorioretinal inflammatory lesion was present. Four patients (six eyes) had associated pulmonary diseases and were receiving concurrent steroid therapy. One of these patients with chronic asthma also was abusing intravenous drugs. Overall, six patients (six eyes) had a history of intravenous drug abuse, whereas a seventh patient (one eye) was suspected of abusing intravenous drugs. Blood cultures and echocardiograms were negative for systemic aspergillosis. Management consisted of a pars plana vitrectomy in 10 of 12 eyes. Intravitreous amphotericin B was administered in 11 of 12 eyes. Systemic amphotericin B therapy was used in eight patients. One patient was treated with oral antifungal agents. In three eyes without central macular involvement, final visual acuities were 20/25 to 20/200. In eight eyes with initial central macular involvement, final visual acuities were 20/400 in three eyes and 5/200 or less in four eyes. Two painful eyes with marked inflammation, hypotony, and retinal detachment were enucleated. Endogenous Aspergillus endophthalmitis usually has an acute onset of intraocular inflammation and often has a characteristic chorioretinal lesion located in the macula. Although treatment with pars plana vitrectomy and intravitreous amphotericin B is capable of eliminating the ocular infection, the visual outcome generally is poor, especially when there is direct macular involvement.

Quinoline derivatives bearing pyrazole moiety: Synthesis and biological evaluation as possible antibacterial and antifungal agents.

PubMed

El Shehry, Mohamed F; Ghorab, Mostafa M; Abbas, Samir Y; Fayed, Eman A; Shedid, Said A; Ammar, Yousry A

2018-01-01

In an attempt for development of new antimicrobial agents, three series of quinoline derivatives bearing pyrazole moiety have been synthesized. The first series was synthesized through the synthesis of 4-(quinolin-2-yloxy)benzaldehyde and 4-(quinolin-2-yloxy)acetophenone and then treatment with ketone or aldehyde derivatives to afford the corresponding chalcones. Cyclization of the latter chalcones with hydrazine derivatives led to the formation of new pyrazoline derivatives. The second series was synthesized via the synthesis of 2-hydrazinylquinoline and then treatment with formylpyrazoles to afford the corresponding hydrazonyl pyrazole derivatives. The third series was synthesized through the treatment of 2-hydrazinylquinoline with ethoxyethylidene, dithioacetal and arylidene derivatives to afford the corresponding pyrazole derivatives. The synthesized compounds were evaluated for their expected antibacterial and antifungal activities; where, the majority of these compounds showed potent antibacterial and antifungal activities against the tested strains of bacteria and fungi. Pyrazole derivative 13b showed better results when compared with the reference drugs as revealed from their MIC values (0.12-0.98 μg/mL). The pyrazole derivative 13b showed fourfold potency of gentamycin in inhibiting the growth of S. flexneri (MIC 0.12 μg/mL). Also, compound 13b showed fourfold potency of amphotericin B in inhibiting the growth of A. clavatus (MIC 0.49 μg/mL) and C. albicans (MIC 0.12 μg/mL), respectively. The same compound showed twofold potency of gentamycin in inhibiting the growth of P. vulgaris (MIC 0.98 μg/mL), equipotent to the ampicillin and amphotericin B in inhibiting the growth of S. epidermidis (MIC 0.49 μg/mL), A. fumigatus (MIC 0.98 μg/mL), respectively. Thus, these studies suggest that quinoline derivatives bearing pyrazole moiety are interesting scaffolds for the development of novel antibacterial and antifungal agents. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Comparison of In Vitro Activity of Liposomal Nystatin against Aspergillus Species with Those of Nystatin, Amphotericin B (AB) Deoxycholate, AB Colloidal Dispersion, Liposomal AB, AB Lipid Complex, and Itraconazole

PubMed Central

Oakley, Karen L.; Moore, Caroline B.; Denning, David W.

1999-01-01

We compared the in vitro activity of liposomal nystatin (Nyotran) with those of other antifungal agents against 60 Aspergillus isolates. Twelve isolates were itraconazole resistant. For all isolates, geometric mean (GM) MICs (micrograms per milliliter) were 2.30 for liposomal nystatin, 0.58 for itraconazole, 0.86 for amphotericin B (AB) deoxycholate, 9.51 for nystatin, 2.07 for liposomal AB, 2.57 for AB lipid complex, and 0.86 for AB colloidal dispersion. Aspergillus terreus (GM, 8.72 μg/ml; range, 8 to 16 μg/ml) was significantly less susceptible to all of the polyene drugs than all other species (P = 0.0001). PMID:10223948

Effects of ascorbic acid and α-tocopherol on the therapeutic index of amphotericin B.

PubMed

Belhachemi, M H; Boucherit, K; Boucherit-Otmani, Z; Belmir, S; Benbekhti, Z

2014-12-01

Amphotericin B (AmB) remains the antifungal polyene of choice in deep fungal infections, but its high toxicity to mammalian cells limits its use. This toxicity is partly due to lipid peroxidation exerted by amphotericin B in cell membranes. The work we have undertaken focused on the one part the evaluation of the efficacy of amphotericin B in the presence of some antioxidants vitamins (vitamin C "ascorbic acid" and vitamin E "α-tocopherol") against the yeast Candida albicans ATCC 10231. Secondly, we have tested the cytotoxicity of these formulations on human red blood cells. The results showed a significant improvement in the efficiency of our formulations tested from 7% to 12% compared with amphotericin B alone at therapeutic concentrations. Furthermore, the addition of vitamin C and vitamin E protects human red blood cells against the cytotoxicity induced by amphotericin B with 17%. This is due may be to the antioxidant power of vitamins which confer protection against the autoxidation of the molecule of amphotericin B. On the other hand, it is noticed that the yeast regrows after 24h whatever in complex with vitamin C or vitamin E of the stock solution. On completion of this study, the incorporation of antioxidant vitamins that we propose to the reaction medium of antifungal improved the therapeutic index of amphotericin B. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Isolation of potentially pathogenic fungi from selected pigeons' feeding sites in Karachi: A new dimension to health hazard.

PubMed

Naz, Sehar Afshan; Yaseen, Muhammad; Jabeen, Nusrat; Shafique, Maryam

2017-06-01

To determine the presence of pathogenic fungal strains in areas where pigeons are present in a large number. This study was conducted at the Federal Urdu University of Arts, Science and Technology, Karachi, from February 2015 to March2016, and comprised samples of soil contaminated with pigeons' excreta. The samples were collected from 20 different pigeon-feeding places in the city. These samples were processed for the isolation and identification of fungi by using standard conventional methods. The fungal strains isolated were also tested for their susceptibility to commonly used antifungal agents by disc diffusion technique. There were 105 samples. A wide variety of fungal strains belonging to different genera of Aspergillus, Rhizopus, Penicillium, Fusarium and Candida were isolated and identified by using conventional methods. The antifungal resistance pattern of these strains also depicts emergence of resistance against commonly used antifungal agents such as amphotericin B and fluconazole. The soil and air of places densely populated with pigeons were found to be loaded with fungal spores and many of them were potential pathogens.

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae

PubMed Central

Ioannou, Petros; Andrianaki, Aggeliki; Akoumianaki, Tonia; Kyrmizi, Irene; Albert, Nathaniel; Perlin, David; Samonis, George

2015-01-01

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae. PMID:26643329

In vitro inhibitory effects of farnesol and interactions between farnesol and antifungals against biofilms of Candida albicans resistant strains.

PubMed

Xia, Jinping; Qian, Fang; Xu, Wenqian; Zhang, Zhenzhen; Wei, Xin

2017-04-01

Antifungal resistance is a serious problem in clinical infections. Farnesol, which is a potential antifungal agent against biofilms formed by Candida albicans resistant strains (a fluconazole-resistant isolate derived from SC5314 and two clinical Candida resistant isolates), was investigated in this study. The inhibitory effects of farnesol on biofilms were examined by XTT assay. The morphological changes and biofilm thicknesses were analyzed by scanning electron microscopy and confocal laser scanning microscopy, respectively. Additionally, the checkerboard microdilution method was used to investigate the interactions between farnesol and antifungals (fluconazole, amphotericin B, caspofungin, itraconazole, terbinafine and 5-flurocytosine) against biofilms. The results showed decreased SMICs of farnesol and thinner biofilms in the farnesol-treated groups, indicating that farnesol inhibited the development of biofilms formed by the resistant strain. Furthermore, there were synergistic effects between farnesol and fluconazole/5-flurocytosine, while there were antagonistic effects between farnesol and terbinafine/itraconazole, respectively, on the biofilms formed by the resistant strains.

Candida infective endocarditis: an observational cohort study with a focus on therapy.

PubMed

Arnold, Christopher J; Johnson, Melissa; Bayer, Arnold S; Bradley, Suzanne; Giannitsioti, Efthymia; Miró, José M; Tornos, Pilar; Tattevin, Pierre; Strahilevitz, Jacob; Spelman, Denis; Athan, Eugene; Nacinovich, Francisco; Fortes, Claudio Q; Lamas, Cristiane; Barsic, Bruno; Fernández-Hidalgo, Nuria; Muñoz, Patricia; Chu, Vivian H

2015-04-01

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Candida Infective Endocarditis: an Observational Cohort Study with a Focus on Therapy

PubMed Central

Johnson, Melissa; Bayer, Arnold S.; Bradley, Suzanne; Giannitsioti, Efthymia; Miró, José M.; Tornos, Pilar; Tattevin, Pierre; Strahilevitz, Jacob; Spelman, Denis; Athan, Eugene; Nacinovich, Francisco; Fortes, Claudio Q.; Lamas, Cristiane; Barsic, Bruno; Fernández-Hidalgo, Nuria; Muñoz, Patricia; Chu, Vivian H.

2015-01-01

Candida infective endocarditis is a rare disease with a high mortality rate. Our understanding of this infection is derived from case series, case reports, and small prospective cohorts. The purpose of this study was to evaluate the clinical features and use of different antifungal treatment regimens for Candida infective endocarditis. This prospective cohort study was based on 70 cases of Candida infective endocarditis from the International Collaboration on Endocarditis (ICE)-Prospective Cohort Study and ICE-Plus databases collected between 2000 and 2010. The majority of infections were acquired nosocomially (67%). Congestive heart failure (24%), prosthetic heart valve (46%), and previous infective endocarditis (26%) were common comorbidities. Overall mortality was high, with 36% mortality in the hospital and 59% at 1 year. On univariate analysis, older age, heart failure at baseline, persistent candidemia, nosocomial acquisition, heart failure as a complication, and intracardiac abscess were associated with higher mortality. Mortality was not affected by use of surgical therapy or choice of antifungal agent. A subgroup analysis was performed on 33 patients for whom specific antifungal therapy information was available. In this subgroup, 11 patients received amphotericin B-based therapy and 14 received echinocandin-based therapy. Despite a higher percentage of older patients and nosocomial infection in the echinocandin group, mortality rates were similar between the two groups. In conclusion, Candida infective endocarditis is associated with a high mortality rate that was not impacted by choice of antifungal therapy or by adjunctive surgical intervention. Additionally, echinocandin therapy was as effective as amphotericin B-based therapy in the small subgroup analysis. PMID:25645855

[In vitro susceptibility of isolates of Paracoccidioides spp complex to systemic antifungals using the microdilution method].

PubMed

Cermehol, Julman R; Alvarado, Primavera; Mendoza, Mireya; Herndndez, Isabel; Cuestal, De

2015-09-01

Broth microdilution, the reference method recommended by the Clinical Laboratory Standards Institute (CLSI), is not available for use with dimorphic fungi, such as those of the Paracoccidioides genus. In this work, in vitro susceptibility of the Paracoccidioides complex (n=19) to systemic antifungals: amphotericin B, 5-flucytosine, ketoconazole, itraconazole, fluconazole, voriconazole and caspofungin, was evaluated using the microdilution method (Document M27-A3, M27-S3), with some modifications such as: culture time in Sabouraud dextrose agar (7-10 days), RPMI 1640 medium supplemented with 2% glucose and the incubation time (7, 8 and 18 days). The sensitivity in vitro was variable; the majority of Paracoccidioides isolates was susceptible to ketoconazol (73.7%), followed by voriconazole (68.4%), itraconazole (63.1%), amphotericin B (52.6%), fluconazole (47.4%), 5-flucytosine (42.1%) and caspofungin (5%). The overall resistance was mainly to caspofungin (94.7%), followed by 5-flucytosine (52.6%) and amphotericin B (47.4%). Fifty-three percent of the isolates were susceptible-dose dependent to fluconazole followed by itraconazole (15.7%) and 5-fluorocytosine (5.3%). Amphotericin B, itraconazole and voriconazole were the most potent antifungal drugs against Paracoccidioides spp (CMI: 0.03-1 microg/mL). Based on these results, we tentatively propose a microdilution assay protocol for susceptibility testing of Paracoccidioides spp to antifungal drugs. This method may be clinically useful to predict resistance, even though further studies are needed.

Disseminated Geosmithia argillacea infection in a German shepherd dog.

PubMed

Grant, David C; Sutton, Deanna A; Sandberg, Christina A; Tyler, Ronald D; Thompson, Elizabeth H; Romanelli, Anna M; Wickes, Brian L

2009-03-01

We report a systemic mycosis in a German Shepherd dog caused by Geosmithia argillacea. Although this etiologic agent microscopically resembles a Penicillium species, and is histopathologically compatible with members of the genus Aspergillus, morphologic features and molecular characterization clearly separate it from these genera. This appears to be the first report of disseminated disease by this species in humans or animals. In vitro antifungal susceptibility testing suggests resistance to amphotericin B and voriconazole and susceptibility to caspofungin, itraconazole, and posaconazole.

Dynamics of Mixed- Candida Species Biofilms in Response to Antifungals.

PubMed

Vipulanandan, G; Herrera, M; Wiederhold, N P; Li, X; Mintz, J; Wickes, B L; Kadosh, D

2018-01-01

Oral infections caused by Candida species, the most commonly isolated human fungal pathogen, are frequently associated with biofilms. Although Candida albicans is the predominant organism found in patients with oral thrush, a biofilm infection, there is an increasing incidence of oral colonization and infections caused by non- albicans Candida species, including C. glabrata, C. dubliniensis, and C. tropicalis, which are frequently more resistant to antifungal treatment. While single-species Candida biofilms have been well studied, considerably less is known about the dynamics of mixed- Candida species biofilms and how these dynamics are altered by antifungal treatment. To address these questions, we developed a quantitative polymerase chain reaction-based approach to determine the precise species composition of mixed- Candida species biofilms formed by clinical isolates and laboratory strains in the presence and absence of clinically relevant concentrations of 3 commonly used antifungals: fluconazole, caspofungin, and amphotericin B. In monospecies biofilms, fluconazole exposure favored growth of C. glabrata and C. tropicalis, while caspofungin generally favored significant growth of all species to a varying degree. Fluconazole was not effective against preformed mixed- Candida species biofilms while amphotericin B was potent. As a general trend, in mixed- Candida species biofilms, C. albicans lost dominance in the presence of antifungals. Interestingly, presence in mixed versus monospecies biofilms reduced susceptibility to amphotericin B for C. tropicalis and C. glabrata. Overall, our data suggest that antifungal treatment favors the growth of specific non- albicans Candida species in mixed- Candida species biofilms.

Significance of Algal Polymer in Designing Amphotericin B Nanoparticles

PubMed Central

Bhatia, Saurabh; Kumar, Vikash; Sharma, Kiran; Nagpal, Kalpana; Bera, Tanmoy

2014-01-01

Development of oral amphotericin B (AmB) loaded nanoparticles (NPs) demands a novel technique which reduces its toxicity and other associated problems. Packing of AmB in between two oppositely charged ions by polyelectrolyte complexation technique proved to be a successful strategy. We have developed a novel carrier system in form of polyelectrolyte complex of AmB by using chitosan (CS) and porphyran (POR) as two oppositely charged polymers with TPP as a crosslinking agent. Initially POR was isolated from Porphyra vietnamensis followed by the fact that its alkali induced safe reduction in molecular weight was achieved. Formulation was optimized using three-factor three-level (33) central composite design. High concentration of POR in NPs was confirmed by sulfated polysaccharide (SP) assay. Degradation and dissolution studies suggested the stability of NPs over wide pH range. Hemolytic toxicity data suggested the safety of prepared formulation. In vivo and in vitro antifungal activity demonstrated the high antifungal potential of optimized formulation when compared with standard drug and marketed formulations. Throughout the study TPP addition did not cause any significant changes. Therefore, these experimental oral NPs may represent an interesting carrier system for the delivery of AmB. PMID:25478596

Addition of DNase Improves the In Vitro Activity of Antifungal Drugs against Candida albicans Biofilms

PubMed Central

Martins, Margarida; Henriques, Mariana; Lopez-Ribot, José L.; Oliveira, Rosário

2011-01-01

SUMMARY Background Cells within Candida albicans biofilms display decreased susceptibility to most clinically used antifungal agents. We recently demonstrated that extracellular DNA (eDNA) plays an important role in biofilm integrity, as a component of the biofilm matrix. Objective To gain insight into the contributions of eDNA to C. albicans biofilms antifungal susceptibility by the investigation of the impact of the combined use of deoxyribonuclease I (DNase) and antifungals to treat biofilms. Methods C. albicans biofilms were formed using a simple and reproducible 96-well plate-based method. The activity of the combined use of 0.13 mg l−1 DNase and antifungals was estimated by the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) reduction assay, and total viable counts. Results and Conclusions Here we report the improved efficacy of amphotericin B when in combination with DNase against C. albicans biofilms, as assessed by XTT readings and viable counts. Furthermore, although DNase increased the efficacy of caspofungin in the reduction of mitochondrial activity, no changes were observed in terms of culturable cells. DNase did not affect biofilm cells susceptibility to fluconazole. This work suggests that agents that target processes affecting the biofilm structural integrity may have potential use as adjuvants of a catheter–lock therapy. PMID:21668524

Managing cryptococcosis in the immunocompromised host.

PubMed

Jarvis, Joseph N; Dromer, Francoise; Harrison, Thomas S; Lortholary, Olivier

2008-12-01

Expanding access to antiretroviral treatment has dramatically improved the long-term prognosis of patients with HIV-associated cryptococcal disease who survive the acute infection. However, the incidence and acute mortality of HIV-associated cryptococcal meningitis remain high. In this context, this review summarizes urgently needed recent work aimed at improving the acute management of cryptococcal infection in immunocompromised hosts. Studies have started to optimize antifungal regimens and address the complications of raised cerebrospinal fluid pressure and cryptococcal immune reconstitution syndrome. Amphotericin B at 1 mg/kg per day has been shown to be more rapidly fungicidal than the standard dose of 0.7 mg/kg per day, and new data support the importance of combination therapy with flucytosine. Amphotericin B and fluconazole at 800 mg is an alternative combination that appears superior to amphotericin B alone. At a dosage of 400 mg per day, fluconazole alone is much less rapidly fungicidal than amphotericin B and is associated with the development of secondary resistance. Recent findings support the use of rapidly fungicidal initial antifungal therapy with amphotericin B-based combination treatment. Where amphotericin B treatment is not yet feasible, studies are needed to optimize oral regimens. Based on accumulating data on rate of clearance of infection, the most promising new regimens in terms of fungicidal activity and safety could be selected for clinical endpoint trials.

Clinical Appearance of Oral Candida Infection and Therapeutic Strategies

PubMed Central

Patil, Shankargouda; Rao, Roopa S.; Majumdar, Barnali; Anil, Sukumaran

2015-01-01

Candida species present both as commensals and opportunistic pathogens of the oral cavity. For decades, it has enthralled the clinicians to investigate its pathogenicity and to improvise newer therapeutic regimens based on the updated molecular research. Candida is readily isolated from the oral cavity, but simple carriage does not predictably result in development of an infection. Whether it remains as a commensal, or transmutes into a pathogen, is usually determined by pre-existing or associated variations in the host immune system. The candida infections may range from non-life threatening superficial mucocutaneous disorders to invasive disseminated disease involving multiple organs. In fact, with the increase in number of AIDS cases, there is a resurgence of less common forms of oral candida infections. The treatment after confirmation of the diagnosis should include recognizing and eliminating the underlying causes such as ill-fitting oral appliances, history of medications (antibiotics, corticosteroids, etc.), immunological and endocrine disorders, nutritional deficiency states and prolonged hospitalization. Treatment with appropriate topical antifungal agents such as amphotericin, nystatin, or miconazole usually resolves the symptoms of superficial infection. Occasionally, administration of systemic antifungal agents may be necessary in immunocompromised patients, the selection of which should be based upon history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data. PMID:26733948

Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B*

PubMed Central

Zeng, Guisheng; Qingsong, Lin; Kwang, Lim Teck; Tong, Cao; Chan, Fong Yee; Wang, Yue; Seneviratne, Chaminda Jayampath

2016-01-01

Candida albicans is a major fungal pathogen causing lethal infections in immunocompromised patients. C. albicans forms antifungal tolerant biofilms contributing significantly to therapeutic failure. The recently established haploid C. albicans biofilm model provides a new toolbox to uncover the mechanism governing the higher antifungal tolerance of biofilms. Here, we comprehensively examined the proteomics and antifungal susceptibility of standard diploid (SC5314 and BWP17) and stable haploid (GZY792 and GZY803) strains of C. albicans biofilms. Subsequent downstream analyses identified alkyl hydroperoxide reductase 1 (AHP1) as a critical determinant of C. albicans biofilm's tolerance of amphotericin B. At 32 μg/ml of amphotericin B, GZY803 haploid biofilms showed 0.1% of persister population as compared with 1% of the diploid biofilms. AHP1 expression was found to be lower in GZY803 biofilms, and AHP1 overexpression in GZY803 restored the percentage of persister population. Consistently, deleting AHP1 in the diploid strain BWP17 caused a similar increase in amphotericin B susceptibility. AHP1 expression was also positively correlated with the antioxidant potential. Furthermore, C. albicans ira2Δ/Δ biofilms were susceptible to amphotericin B and had a diminished antioxidant capacity. Interestingly, AHP1 overexpression in the ira2Δ/Δ strain restored the antioxidant potential and enhanced the persister population against amphotericin B, and shutting down the AHP1 expression in ira2Δ/Δ biofilms reversed the effect. In conclusion, we provide evidence that the AHP1 gene critically determines the amphotericin B tolerance of C. albicans biofilms possibly by maintaining the persisters' antioxidant capacity. This finding will open up new avenues for developing therapies targeting the persister population of C. albicans biofilms. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD004274. PMID:27644984

Comparative Ploidy Proteomics of Candida albicans Biofilms Unraveled the Role of the AHP1 Gene in the Biofilm Persistence Against Amphotericin B.

PubMed

Truong, Thuyen; Zeng, Guisheng; Qingsong, Lin; Kwang, Lim Teck; Tong, Cao; Chan, Fong Yee; Wang, Yue; Seneviratne, Chaminda Jayampath

2016-11-01

Candida albicans is a major fungal pathogen causing lethal infections in immunocompromised patients. C. albicans forms antifungal tolerant biofilms contributing significantly to therapeutic failure. The recently established haploid C. albicans biofilm model provides a new toolbox to uncover the mechanism governing the higher antifungal tolerance of biofilms. Here, we comprehensively examined the proteomics and antifungal susceptibility of standard diploid (SC5314 and BWP17) and stable haploid (GZY792 and GZY803) strains of C. albicans biofilms. Subsequent downstream analyses identified alkyl hydroperoxide reductase 1 (AHP1) as a critical determinant of C. albicans biofilm's tolerance of amphotericin B. At 32 μg/ml of amphotericin B, GZY803 haploid biofilms showed 0.1% of persister population as compared with 1% of the diploid biofilms. AHP1 expression was found to be lower in GZY803 biofilms, and AHP1 overexpression in GZY803 restored the percentage of persister population. Consistently, deleting AHP1 in the diploid strain BWP17 caused a similar increase in amphotericin B susceptibility. AHP1 expression was also positively correlated with the antioxidant potential. Furthermore, C. albicans ira2Δ/Δ biofilms were susceptible to amphotericin B and had a diminished antioxidant capacity. Interestingly, AHP1 overexpression in the ira2Δ/Δ strain restored the antioxidant potential and enhanced the persister population against amphotericin B, and shutting down the AHP1 expression in ira2Δ/Δ biofilms reversed the effect. In conclusion, we provide evidence that the AHP1 gene critically determines the amphotericin B tolerance of C. albicans biofilms possibly by maintaining the persisters' antioxidant capacity. This finding will open up new avenues for developing therapies targeting the persister population of C. albicans biofilms. The mass spectrometry proteomics data are available via ProteomeXchange with identifier PXD004274. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Antifungal activity of Zuccagnia punctata Cav.: evidence for the mechanism of action.

PubMed

Svetaz, Laura; Agüero, María Belén; Alvarez, Sandra; Luna, Lorena; Feresin, Gabriela; Derita, Marcos; Tapia, Alejandro; Zacchino, Susana

2007-08-01

Petroleum ether and dichloromethane extracts of fruits, aerial parts and exudate of Zuccagnia punctata Cav. (Fabaceae) showed moderate antifungal activities against the yeasts C. albicans, S. cerevisiae and C. neoformans (MICs: 62.5 - 250 microg/mL) and very strong antifungal activities against the dermatophytes M. gypseum, T. rubrum and T. mentagrophytes (MICs: 8 - 16 microg/mL) thus supporting the ethnopharmacological use of this plant. Antifungal activity-directed fractionation of active extracts by using bioautography led to the isolation of 2',4'-dihydroxy-3'-methoxychalcone (1) and 2',4'-dihydroxychalcone (2) as the compounds responsible for the antifungal activity. Second-order studies included MIC (80), MIC (50) and MFC of both chalcones in an extended panel of clinical isolates of the most sensitive fungi, and also comprised a series of targeted assays. They showed that the most active chalcone 2 is fungicidal rather than fungistatic, does not disrupt the fungal membranes up to 4 x MFC and does not act by inhibiting the fungal cell wall. So, 2',4'-dihydroxychalcone would act by a different mechanism of action than the antifungal drugs in current clinical use, such as amphotericin B, azoles or echinocandins, and thus appears to be very promising as a novel antifungal agent.

In vitro antifungal susceptibility testing of Scopulariopsis brevicaulis strains using agar diffusion method.

PubMed

Skóra, Magdalena; Macura, Anna B

2011-01-01

The genus Scopulariopsis is a common soil saprotroph and has been isolated from air, organic waste and also from plant, animal and human tissues. Scopulariopsis has mainly been associated in humans with superficial mycoses, but it has also been described as the cause of subcutaneous and invasive infections. The most common aetiological agent of infections in humans is Scopulariopsis brevicaulis. This species has been reported to be resistant in vitro to broad-spectrum antifungal agents available today. The aim of the study was to establish in vitro antifungal susceptibility of 35 S. brevicaulis strains against amphotericin B (AMB), flucytosine (FC), caspofungin (CAS), terbinafine (TER), ciclopirox (CIC), voriconazole (VOR), clotrimazole (CTR), miconazole (MCZ), econazole (ECO), ketoconazole (KET), itraconazole (ITR), and fluconazole (FLU). Antifungal susceptibility tests were evaluated by an agar diffusion method (Neo-Sensitabs, Rosco, Denmark). AMB, FC, CAS, ITR and FLU showed no antifungal activity against S. brevicaulis. TER, CIC, CTR, KET, VOR, ECO, and MCZ revealed inhibitory activity for S. brevicaulis, but it varied for each of the drugs. The best antifungal effect was observed for TER and CIC. All isolates had large inhibition zones for TER and CIC. CTR was also inhibitory for all tested S. brevicaulis isolates, but the diameters of inhibition zones were smaller than for TER and CIC. Nearly 89% isolates showed inhibition zones for KET and the mean diameter of the inhibition zone was comparable to CTR. The least antifungal activity exhibited VQR, ECO and MCZ. Because of the multiresistance of S. brevicaulis, infections due to this species may not respond to particular antifungal treatment and other therapeutic approaches should be considered, e.g., combined therapy and/or surgery.

Saccharomyces cerevisiae biofilm tolerance towards systemic antifungals depends on growth phase.

PubMed

Bojsen, Rasmus; Regenberg, Birgitte; Folkesson, Anders

2014-12-04

Biofilm-forming Candida species cause infections that can be difficult to eradicate, possibly because of antifungal drug tolerance mechanisms specific to biofilms. In spite of decades of research, the connection between biofilm and drug tolerance is not fully understood. We used Saccharomyces cerevisiae as a model for drug susceptibility of yeast biofilms. Confocal laser scanning microscopy showed that S. cerevisiae and C. glabrata form similarly structured biofilms and that the viable cell numbers were significantly reduced by treatment of mature biofilms with amphotericin B but not voriconazole, flucytosine, or caspofungin. We showed that metabolic activity in yeast biofilm cells decreased with time, as visualized by FUN-1 staining, and mature, 48-hour biofilms contained cells with slow metabolism and limited growth. Time-kill studies showed that in exponentially growing planktonic cells, voriconazole had limited antifungal activity, flucytosine was fungistatic, caspofungin and amphotericin B were fungicidal. In growth-arrested cells, only amphotericin B had antifungal activity. Confocal microscopy and colony count viability assays revealed that the response of growing biofilms to antifungal drugs was similar to the response of exponentially growing planktonic cells. The response in mature biofilm was similar to that of non-growing planktonic cells. These results confirmed the importance of growth phase on drug efficacy. We showed that in vitro susceptibility to antifungal drugs was independent of biofilm or planktonic growth mode. Instead, drug tolerance was a consequence of growth arrest achievable by both planktonic and biofilm populations. Our results suggest that efficient strategies for treatment of yeast biofilm might be developed by targeting of non-dividing cells.

Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species

PubMed Central

Nagayoshi, Yohsuke; Shimamura, Shintaro; Nakayama, Hironobu; Minematsu, Asuka; Yamauchi, Shunsuke; Takazono, Takahiro; Nakamura, Shigeki; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi; Izumikawa, Koichi

2017-01-01

The pathogenic fungus Candida glabrata is often resistant to azole antifungal agents. Drug efflux through azole transporters, such as Cdr1 and Cdr2, is a key mechanism of azole resistance and these genes are under the control of the transcription factor Pdr1. Recently, the monoamine oxidase A (MAO-A) inhibitor clorgyline was shown to inhibit the azole efflux pumps, leading to increased azole susceptibility in C. glabrata. In the present study, we have evaluated the effects of clorgyline on susceptibility of C. glabrata to not only azoles, but also to micafungin and amphotericin B, using wild-type and several mutant strains. The addition of clorgyline to the culture media increased fluconazole susceptibility of a C. glabrata wild-type strain, whereas micafungin and amphotericin B susceptibilities were markedly decreased. These phenomena were also observed in other medically important Candida species, including Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida krusei. Expression levels of CDR1, CDR2 and PDR1 mRNAs and an amount of Cdr1 protein in the C. glabrata wild-type strain were highly increased in response to the treatment with clorgyline. However, loss of Cdr1, Cdr2, Pdr1, and a putative clorgyline target (Fms1), which is an ortholog of human MAO-A, or overexpression of CDR1 did not affect the decreased susceptibility to micafungin and amphotericin B in the presence of clorgyline. The presence of other azole efflux pump inhibitors including milbemycin A4 oxime and carbonyl cyanide 3-chlorophenylhydrazone also decreased micafungin susceptibility in C. glabrata wild-type, Δcdr1, Δcdr2, and Δpdr1 strains. These findings suggest that azole efflux pump inhibitors increase azole susceptibility but concurrently induce decreased susceptibility to other classes of antifungals independent of azole transporter functions. PMID:28700656

Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species.

PubMed

Nagayoshi, Yohsuke; Miyazaki, Taiga; Shimamura, Shintaro; Nakayama, Hironobu; Minematsu, Asuka; Yamauchi, Shunsuke; Takazono, Takahiro; Nakamura, Shigeki; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi; Izumikawa, Koichi

2017-01-01

The pathogenic fungus Candida glabrata is often resistant to azole antifungal agents. Drug efflux through azole transporters, such as Cdr1 and Cdr2, is a key mechanism of azole resistance and these genes are under the control of the transcription factor Pdr1. Recently, the monoamine oxidase A (MAO-A) inhibitor clorgyline was shown to inhibit the azole efflux pumps, leading to increased azole susceptibility in C. glabrata. In the present study, we have evaluated the effects of clorgyline on susceptibility of C. glabrata to not only azoles, but also to micafungin and amphotericin B, using wild-type and several mutant strains. The addition of clorgyline to the culture media increased fluconazole susceptibility of a C. glabrata wild-type strain, whereas micafungin and amphotericin B susceptibilities were markedly decreased. These phenomena were also observed in other medically important Candida species, including Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida krusei. Expression levels of CDR1, CDR2 and PDR1 mRNAs and an amount of Cdr1 protein in the C. glabrata wild-type strain were highly increased in response to the treatment with clorgyline. However, loss of Cdr1, Cdr2, Pdr1, and a putative clorgyline target (Fms1), which is an ortholog of human MAO-A, or overexpression of CDR1 did not affect the decreased susceptibility to micafungin and amphotericin B in the presence of clorgyline. The presence of other azole efflux pump inhibitors including milbemycin A4 oxime and carbonyl cyanide 3-chlorophenylhydrazone also decreased micafungin susceptibility in C. glabrata wild-type, Δcdr1, Δcdr2, and Δpdr1 strains. These findings suggest that azole efflux pump inhibitors increase azole susceptibility but concurrently induce decreased susceptibility to other classes of antifungals independent of azole transporter functions.

Ebselen exerts antifungal activity by regulating glutathione (GSH) and reactive oxygen species (ROS) production in fungal cells.

PubMed

Thangamani, Shankar; Eldesouky, Hassan E; Mohammad, Haroon; Pascuzzi, Pete E; Avramova, Larisa; Hazbun, Tony R; Seleem, Mohamed N

2017-01-01

Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear. The antifungal effect of ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of ebselen. Ebselen's antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model. Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp., at concentrations ranging from 0.5 to 2μg/ml. Ebselen rapidly eradicates a high fungal inoculum within 2h of treatment. Investigation of the drug's antifungal mechanism of action indicates that ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of ebselen's in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load. Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of ebselen supports further investigation for repurposing it for use as an antifungal agent. The present study shows that ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development. Copyright © 2016 Elsevier B.V. All rights reserved.

[Economic evaluation of voriconazole versus amphotericin B in the treatment of invasive aspergilosis].

PubMed

Grau Cerrato, S; Mateu-de Antonio, J; Soto Alvarez, J; Muñoz Jareño, M A; Salas Sánchez, E; Marín-Casino, M; Rubio Terrés, C

2005-01-01

Invasive aspergillosis is an infection with high incidence and mortality. Voriconazole is a new antifungal agent that presents a high efficacy against Aspergillus. The aim of this evaluation was to carry out a pharmacoeconomic analysis of the use of voriconazole versus amphotericin B deoxycholate in the treatment of invasive aspergillosis in Spain. A cost-effectiveness analysis has been performed by building a decision analytical model. Effectiveness data, probabilities of the different branches of the decision tree and consumption of healthcare resources were obtained from a clinical trial that compared voriconazole versus amphotericin B in the treatment of invasive aspergillosis and from a local expert panel in order to incorporate the model in the daily medical practice in our country. Only direct medical costs were included in the model (drug acquisition, length of hospital stay, analytical tests and treatment of therapeutic failures). The perspective chosen for this analysis was hospital assistance and the time horizon selected was 12 weeks, the maximum time that patients were followed up in the referenced clinical trial. Therapeutic success was reached in 52.8% of patients treated with voriconazole and in 31.6% of the group treated with amphotericin B. The cost of treating a patient with voriconazole or amphotericin B was of 56,296 and 56,382 Euros respectively, while the cost/effectiveness ratio was of 106,621 and 178,424 Euros. The incremental analysis performed shows how the use of voriconazole versus amphotericin B produces a healthcare resources saving of 406 Euros per patient. Voriconazole is more efficient than amphotericin B deoxycholate in the treatment of invasive aspergillosis, (thus) resulting in healthcare resources saving due to better clinical results with lower associated costs.

Albumin Enhances Caspofungin Activity against Aspergillus Species by Facilitating Drug Delivery to Germinating Hyphae.

PubMed

Ioannou, Petros; Andrianaki, Aggeliki; Akoumianaki, Tonia; Kyrmizi, Irene; Albert, Nathaniel; Perlin, David; Samonis, George; Kontoyiannis, Dimitrios P; Chamilos, Georgios

2015-12-07

The modest in vitro activity of echinocandins against Aspergillus implies that host-related factors augment the action of these antifungal agents in vivo. We found that, in contrast to the other antifungal agents (voriconazole, amphotericin B) tested, caspofungin exhibited a profound increase in activity against various Aspergillus species under conditions of cell culture growth, as evidenced by a ≥4-fold decrease in minimum effective concentrations (MECs) (P = 0. 0005). Importantly, the enhanced activity of caspofungin against Aspergillus spp. under cell culture conditions was strictly dependent on serum albumin and was not observed with the other two echinocandins, micafungin and anidulafungin. Of interest, fluorescently labeled albumin bound preferentially on the surface of germinating Aspergillus hyphae, and this interaction was further enhanced upon treatment with caspofungin. In addition, supplementation of cell culture medium with albumin resulted in a significant, 5-fold increase in association of fluorescently labeled caspofungin with Aspergillus hyphae (P < 0.0001). Collectively, we found a novel synergistic interaction between albumin and caspofungin, with albumin acting as a potential carrier molecule to facilitate antifungal drug delivery to Aspergillus hyphae. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Antifungal activity of Brazilian medicinal plants involved in popular treatment of mycoses.

PubMed

Cruz, M C S; Santos, P O; Barbosa, A M; de Mélo, D L F M; Alviano, C S; Antoniolli, A R; Alviano, D S; Trindade, R C

2007-05-04

A survey of medicinal plants used to treat common mycoses was done in the Curituba district, Sergipe State, Brazil. One hundred inhabitants were interviewed by health agents and traditional healers. Four different plants were the most cited (more than 50% of the citations): Ziziphus joazeiro, Caesalpinia pyramidalis, Bumelia sartorum and Hymenea courbaril. The aqueous extracts obtained following traditional methods and using different parts of these plants, were submitted to drop agar diffusion tests for primary antimicrobial screening. Only the water infusion extract of Ziziphus joazeiro and Caesalpinea pyramidalis presented a significant antifungal activity against Trichophyton rubrum, Candida guilliermondii, Candida albicans, Cryptococcus neoformans and Fonsecaea pedrosoi, when compared to the antifungal agent amphotericin B. The minimal inhibitory concentration (MIC) of the bioactive extracts was evaluated by the microdilution method. Best activity with a MIC of 6.5 microg/ml for both extracts was observed against Trichophyton rubrum and Candida guilliermondii. Ziziphus joazeiro and Caesalpinea pyramidalis extracts presented also low acute toxicity in murine models. The present study validates the folk use of these plant extracts and indicates that they can be effective potential candidates for the development of new strategies to treat fungal infections.

Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

PubMed Central

Baltazar, Ludmila Matos; Werneck, Silvia Maria Cordeiro; Soares, Betânia Maria; Ferreira, Marcus Vinicius L.; Souza, Danielle G.; Pinotti, Marcos; Santos, Daniel Assis

2015-01-01

Paracoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced by Paracoccidioides spp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production by Paracoccidioides yeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI. PMID:25896704

Antifungal susceptibility testing of Malassezia yeast: comparison of two different methodologies.

PubMed

Rojas, Florencia D; Córdoba, Susana B; de Los Ángeles Sosa, María; Zalazar, Laura C; Fernández, Mariana S; Cattana, María E; Alegre, Liliana R; Carrillo-Muñoz, Alfonso J; Giusiano, Gustavo E

2017-02-01

All Malassezia species are lipophilic; thus, modifications are required in susceptibility testing methods to ensure their growth. Antifungal susceptibility of Malassezia species using agar and broth dilution methods has been studied. Currently, few tests using disc diffusion methods are being performed. The aim was to evaluate the in vitro susceptibility of Malassezia yeast against antifungal agents using broth microdilution and disc diffusion methods, then to compare both methodologies. Fifty Malassezia isolates were studied. Microdilution method was performed as described in reference document and agar diffusion test was performed using antifungal tablets and discs. To support growth, culture media were supplemented. To correlate methods, linear regression analysis and categorical agreement was determined. The strongest linear association was observed for fluconazole and miconazole. The highest agreement between both methods was observed for itraconazole and voriconazole and the lowest for amphotericin B and fluconazole. Although modifications made to disc diffusion method allowed to obtain susceptibility data for Malassezia yeast, variables cannot be associated through a linear correlation model, indicating that inhibition zone values cannot predict MIC value. According to the results, disc diffusion assay may not represent an alternative to determine antifungal susceptibility of Malassezia yeast. © 2016 Blackwell Verlag GmbH.

In vitro susceptibility and multilocus sequence typing of Fusarium isolates causing keratitis.

PubMed

Dallé da Rosa, P; Nunes, A; Borges, R; Batista, B; Meneghello Fuentefria, A; Goldani, L Z

2018-05-17

Fungal keratitis is recognized as a significant cause of ocular morbidity and blindness especially in developing countries. In this study, we aimed to present the molecular identification and susceptibility of Fusarium isolates causing fungal keratitis in a university hospital in southern Brazil. The samples were identified using the second largest subunit of the RNA polymerase gene (RPB2) and the translation elongation factor 1-alpha (TEF1), while the antifungal susceptibility was tested by the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) methodology. The majority of the isolates belonged to the Fusarium solani species complex (F. solani, F. keratoplasticum and F. falciforme) and Fusarium oxysporum species complex. Antifungal susceptibility has shown that amphotericin B and natamycin were the most effective antifungals across all isolates, followed by voriconazole. Variation among Fusarium complexes in their antifungal sensitivities was observed in our study. The identification of Fusarium species from human samples is important not only from an epidemiological viewpoint, but also for choosing the appropriate antifungal agent for difficult-to-treat Fusarium infections such as keratitis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

In Vitro Antifungal Susceptibility of Oral Candida Isolates from Patients Suffering from Caries and Chronic Periodontitis.

PubMed

De-la-Torre, Janire; Ortiz-Samperio, María Esther; Marcos-Arias, Cristina; Marichalar-Mendia, Xabier; Eraso, Elena; Echebarria-Goicouria, María Ángeles; Aguirre-Urizar, José Manuel; Quindós, Guillermo

2017-06-01

Caries and chronic periodontitis are common oral diseases where a higher Candida colonization is reported. Antifungal agents could be adjuvant drugs for the therapy of both clinical conditions. The aim of the current study has been to evaluate the in vitro activities of conventional and new antifungal drugs against oral Candida isolates from patients suffering from caries and/or chronic periodontitis. In vitro activities of amphotericin B, fluconazole, itraconazole, miconazole, nystatin, posaconazole and voriconazole against 126 oral Candida isolates (75 Candida albicans, 18 Candida parapsilosis, 11 Candida dubliniensis, six Candida guilliermondii, five Candida lipolytica, five Candida glabrata, four Candida tropicalis and two Candida krusei) from 61 patients were tested by the CLSI M27-A3 method. Most antifungal drugs were highly active, and resistance was observed in less than 5% of tested isolates. Miconazole was the most active antifungal drug, being more than 98% of isolates susceptible. Fluconazole, itraconazole, and the new triazoles, posaconazole and voriconazole, were also very active. Miconazole, fluconazole and voriconazole have excellent in vitro activities against all Candida isolates and could represent suitable treatment for a hypothetically adjunctive therapy of caries and chronic periodontitis.

Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

PubMed Central

Voltan, Aline Raquel; Quindós, Guillermo; Alarcón, Kaila P Medina; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares; Chorilli, Marlus

2016-01-01

Invasive mycoses are a major problem for immunocompromised individuals and patients in intensive care units. Morbidity and mortality rates of these infections are high because of late diagnosis and delayed treatment. Moreover, the number of available antifungal agents is low, and there are problems with toxicity and resistance. Alternatives for treating invasive fungal infections are necessary. Nanostructured systems could be excellent carriers for antifungal drugs, reducing toxicity and targeting their action. The use of nanostructured systems for antifungal therapy began in the 1990s, with the appearance of lipid formulations of amphotericin B. This review encompasses different antifungal drug delivery systems, such as liposomes, carriers based on solid lipids and nanostructure lipids, polymeric nanoparticles, dendrimers, and others. All these delivery systems have advantages and disadvantages. Main advantages are the improvement in the antifungal properties, such as bioavailability, reduction in toxicity, and target tissue, which facilitates innovative therapeutic techniques. Conversely, a major disadvantage is the high cost of production. In the near future, the use of nanosystems for drug delivery strategies can be used for delivering peptides, including mucoadhesive systems for the treatment of oral and vaginal candidiasis. PMID:27540288

Betamethasone augments the antifungal effect of menadione--towards a novel anti-Candida albicans combination therapy.

PubMed

Jakab, Ágnes; Emri, Tamás; Sipos, Lilla; Kiss, Ágnes; Kovács, Renátó; Dombrádi, Viktor; Kemény-Beke, Ádám; Balla, József; Majoros, László; Pócsi, István

2015-08-01

The fluorinated glucocorticoid betamethasone stimulated both the extracellular phospholipase production and hypha formation of the opportunistic human pathogen Candida albicans and also decreased the efficiency of the polyene antimycotics amphotericin B and nystatin against C. albicans in a dose-dependent manner. Importantly, betamethasone increased synergistically the anti-Candida activity of the oxidative stress generating agent menadione, which may be exploited in future combination therapies to prevent or cure C. albicans infections, in the field of dermatology. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multicenter surveillance of species distribution and antifungal susceptibilities of Candida bloodstream isolates in South Korea.

PubMed

Jung, Sook-In; Shin, Jong Hee; Song, Jae-Hoon; Peck, Kyong Ran; Lee, Kyungwon; Kim, Mi-Na; Chang, Hyun Ha; Moon, Chi Sook

2010-06-01

Multicenter data on in vitro susceptibility of Candida bloodstream isolates to echinocandin antifungal agents is still lacking in South Korea. We performed a prospective multicenter study to determine the species distribution of Candida bloodstream isolates and their susceptibility to five antifungal agents, including caspofungin and micafungin. A total of 639 isolates were collected from 20 tertiary hospitals between September 2006 and August 2007. Antifungal susceptibilities were determined through the use of the CLSI broth microdilution method M27-A3. The overall species distribution was as follows; Candida albicans (38%), Candida parapsilosis (26%), Candia tropicalis (20%), Candida glabrata (11%), and miscellaneous Candida species (5%). Although C. parapsilosis and miscellaneous Candida species were less susceptible to both echinocandins, all 639 isolates were susceptible to both caspofungin and micafungin (MIC,

Use of decimal assay for additivity to demonstrate synergy in pair combinations of econazole, nikkomycin Z, and ibuprofen against Candida albicans in vitro.

PubMed Central

Tariq, V N; Scott, E M; McCain, N E

1995-01-01

Interactions between six compounds (econazole, miconazole, amphotericin B, nystatin, nikkomycin Z, and ibuprofen) were investigated for their antifungal activities against Candida albicans by using pair combinations in an in vitro decimal assay for additivity based on disk diffusion. Additive interactions were observed between miconazole and econazole, amphotericin B and nystatin, and amphotericin B and ibuprofen, while an antagonistic interaction was observed between econazole and amphotericin B. Synergistic interactions were recorded for the combinations of econazole and ibuprofen, econazole and nikkomycin Z, and ibuprofen and nikkomycin Z. PMID:8592989

Comparison of the EUCAST and CLSI Broth Microdilution Methods for Testing Isavuconazole, Posaconazole, and Amphotericin B against Molecularly Identified Mucorales Species

PubMed Central

Singh, Pradeep Kumar; Kathuria, Shallu

2015-01-01

We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical Mucorales isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for Mucorales AFST are warranted. PMID:26438489

Synergistic Fungistatic Effects of Lactoferrin in Combination with Antifungal Drugs against Clinical Candida Isolates

PubMed Central

Kuipers, M. E.; de Vries, H. G.; Eikelboom, M. C.; Meijer, D. K. F.; Swart, P. J.

1999-01-01

Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of Candida species. Distinct antifungal activities of lactoferrin were observed against clinical isolates of Candida. The MICs generally were determined to be in the range of 0.5 to 100 mg · ml−1. Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of Candida by using lactoferrin and the three antifungals tested. Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml). Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several Candida species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with Candida is an attractive therapeutic option. Since fluconazole-resistant Candida species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated. PMID:10543740

Synergistic fungistatic effects of lactoferrin in combination with antifungal drugs against clinical Candida isolates.

PubMed

Kuipers, M E; de Vries, H G; Eikelboom, M C; Meijer, D K; Swart, P J

1999-11-01

Because of the rising incidence of failures in the treatment of oropharyngeal candidosis in the case of severely immunosuppressed patients (mostly human immunodeficiency virus [HIV]-infected patients), there is need for the development of new, more effective agents and/or compounds that support the activity of the common antifungal agents. Since lactoferrin is one of the nonspecific host defense factors present in saliva that exhibit antifungal activity, we studied the antifungal effects of human, bovine, and iron-depleted lactoferrin in combination with fluconazole, amphotericin B, and 5-fluorocytosine in vitro against clinical isolates of Candida species. Distinct antifungal activities of lactoferrin were observed against clinical isolates of Candida. The MICs generally were determined to be in the range of 0.5 to 100 mg. ml(-1). Interestingly, in the combination experiments we observed pronounced cooperative activity against the growth of Candida by using lactoferrin and the three antifungals tested. Only in a limited concentration range was minor antagonism detected. The use of lactoferrin and fluconazole appeared to be the most successful combination. Significant reductions in the minimal effective concentrations of fluconazole were found when it was combined with a relatively low lactoferrin concentration (1 mg/ml). Such combinations still resulted in complete growth inhibition, while synergy of up to 50% against several Candida species was observed. It is concluded that the combined use of lactoferrin and antifungals against severe infections with Candida is an attractive therapeutic option. Since fluconazole-resistant Candida species have frequently been reported, especially in HIV-infected patients, the addition of lactoferrin to the existing fluconazole therapy could postpone the occurrence of species resistance against fluconazole. Clinical studies to further elucidate the potential utility of this combination therapy have been initiated.

[Susceptibility to antifungal agents of Candida sp. and biofilm formation].

PubMed

Ciok-Pater, Emilia; Białucha, Agata; Gospodarek, Eugenia; Ostafin, Agnieszka

2011-01-01

In recent years the increase in frequency of fungal infections with Candida sp. was noticed. These infections are connected with ability of Candida sp. to form biofilm on surfaces of biomaterials used in medicine. Furthermore fungal infections make serious therapeutic problems because ofbiofilm resistance to antifungal agents actually. The aim of the study was to evaluate the susceptibility to antifungal agents of Candida sp. and their ability to form biofilm on different biomaterials. 50 strains of Candida sp. isolated from patients of University Hospital No. 1 of dr A. Jurasz in Bydgoszcz were examined. API Candida (bioMérieux) tests were used to identify Candida sp. strains. The susceptibility of the yeast strains to antifungal agents was evaluated by ATB FUNGUS 2 INT (bioMérieux) tests. The susceptibility of examined strains to voriconazole, posaconazole, caspofungin and anidulafungin was assessed by means ofEtests (AB BIODISK) method employing drug concentrations from 0,002 to 32 microg/ml. All analysed strains were susceptible to amphotericin B and caspofungin. Biofilm formation on different biomaterials (silicon, latex, polychloride vinyl, polypropylene, nylon) was measured after 72 hour incubation at 37 degrees C. All examined yeasts formed biofilm on all analysed biomaterials. The highest number of strains formed biofilm on surface of polychloride vinyl: 23 (92,0%) by C. albicans strains and 24 (96,0%) Candida non-albicans strains. The lowest number of the strains formed biofilm on the surface of nylon: 12 (48,0%) of C. albicans strains and 9 (36,0%) of Candida non-albicans strains. The studied strains resistant to azoles and anidulafungin display stronger ability to form biofilm on surfaces of all analysed biomaterials.

Detection of Candida species in pregnant Chinese women with a molecular beacon method.

PubMed

Zhai, Yanhong; Liu, Jing; Zhou, Li; Ji, Tongzhen; Meng, Lingxin; Gao, Yang; Liu, Ran; Wang, Xiao; Li, Lin; Lu, Binghuai; Cao, Zheng

2018-04-20

Candida pathogens are commonly found in women and can cause vulvovaginal candidiasis (VVC), whose infection rate is further increased during pregnancy. We aimed to study the Candida prevalence and strain distribution in pregnant Chinese women with a molecular beacon assay. From March 2016 to February 2017, a total of 993 pregnant women attending routine antenatal visits at the Beijing Obstetrics and Gynecology Hospital were enrolled. For Candida detection and identification, a unique molecular beacon assay was presented and compared with a traditional phenotypic method. Antifungal susceptibility was tested with the following agents: 5-flucytosine, amphotericin B, fluconazole, itraconazole and voriconazole. The prevalence of Candida was found to be 21.8 % when using the molecular method and 15.0 % when using the phenotypic method. The distribution of the Candida spp. was listed in order of decreasing prevalence: Candida albicans (79.8 %), Candida glabrata (13.5 %), Candida parapsilosis (3.7 %), Candida krusei (2.2 %) and Candida tropicalis (1.1 %). We found that 90.7 % of the Candida detection results were consistent between the molecular and the phenotypic methods. In the cases where the sequencing analyses for the Candida isolates resulted in inconsistent identification, the molecular method showed higher sensitivity than the phenotypic method (96.0 vs 64.6 %). C. albicans, C. glabrata and C. parapsilosis were essentially susceptible to all five antifungal agents tested, whereas C. tropicalis and C. krusei were susceptible to voriconazole and amphotericin B. By exhibiting good sensitivity and specificity, the molecular assay may offer a fast and accurate Candida screening platform for pregnant women.

Fungal peritonitis by Thermoascus crustaceus in a peritoneal dialysis patient from Chile.

PubMed

Alvarez, Eduardo; Castillo, Alvaro; Iturrieta, Isabel

Fungal peritonitis is a relatively uncommon infection in peritoneal dialysis patients. However, it can be associated with significant morbimortality. In recent reports, Candida species and other filamentous fungi have been reported as being aetiological agents. Thermoascus species are ubiquitous, thermophilic fungi, with an anamorph in the Paecilomyces genus. Here we present the first report of fungal peritonitis by Thermoascus crustaceus from Chile. We present the case of an 83-year-old female patient, with a history of cholecystectomy, hernia repair, severe arterial hypertension, hip and knee osteoarthritis and several episodes of peritoneal dialysis with a cloudy exudate. Bacterial cultures were negative. In addition, a history of two months with intermittent fever peaks mainly in the evening was reported. Blood culture bottles inoculated with peritoneal fluid revealed the presence of fungal growth. Morphological and molecular studies allowed us to identify the aetiological agent as Thermoascus crustaceus. An antifungal susceptibility test was performed using the M38-A2 method, developed by the Clinical and Laboratory Standards Institute (CLSI). The MIC values to amphotericin B, itraconazole, voriconazole and echinochandins were 0.5, 0.25, 0.25 and 0.125μg/ml, respectively. Antifungal treatment with amphotericin B was prescribed, with good patient progress. Fungal peritonitis is a very rare entity. Moreover, the spectrum of fungal pathogens continues to expand, a reason for which morphological and molecular studies are necessary for a rapid diagnosis. Copyright © 2017 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Candida albicans gastrointestinal colonization and invasion in the mouse: effect of antibacterial dosing, antifungal therapy and immunosuppression.

PubMed

Kinsman, O S; Pitblado, K

1989-12-01

Infant mice infected with Candida albicans by the oral-intragastric route became colonized in the gut and were persistently colonized into adulthood. Faecal levels of Candida were correlated with total gastrointestinal Candida and provided a useful means of detecting yeast overgrowth or elimination. Antibacterial agents promoting Candida overgrowth when given by the oral or parenteral route included ceftriaxone, augmentin and cefoperazone. Ceftizoxime had less effect. Ceftazidime and latamoxef produced raised levels only by the oral route. Gentamicin, vancomycin and metronidazole did not affect the Candida levels. Dosing with some antibacterials promoted an increase in gastrointestinal Candida and invasion to a greater extent than immunosuppression. Antifungal therapy to reduce gastrointestinal colonization was investigated using amphotericin B, nystatin, ketoconazole, intraconazole and fluconazole. Fluconazole was most effective at reducing faecal Candida.

The polyene antifungals, amphotericin B and nystatin, cause cell death in Saccharomyces cerevisiae by a distinct mechanism to amphibian-derived antimicrobial peptides.

PubMed

Serhan, George; Stack, Colin M; Perrone, Gabriel G; Morton, Charles Oliver

2014-05-12

There is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying specific mechanisms of action of membrane-interacting antimicrobial drugs on the model fungus Saccharomyces cerevisiae is one avenue towards addressing this issue. The S. cerevisiae deletion mutants Δizh2, Δizh3, Δaif1 and Δstm1 were demonstrated to be resistant to amphibian-derived antimicrobial peptides (AMPs). The purpose of this study was to examine whether AMPs and polyene antifungals have a similar mode of action; this was done by comparing the relative tolerance of the mutants listed above to both classes of antifungal. In support of previous findings on solid media it was shown that Δizh2 and Δizh3 mutants had increased resistance to both amphotericin B (1-2 μg ml-1) and nystatin (2.5 - 5 μg ml-1) in liquid culture, after acute exposure. However, Δaif1 and Δstm1 had wild-type levels of susceptibility to these polyenes. The generation of reactive oxygen species (ROS) after exposure to amphotericin B was also reduced in Δizh2 and Δizh3. These data indicated that polyene antifungal and AMPs may act via distinct mechanisms of inducing cell death in S. cerevisiae. Further understanding of the mechanism(s) involved in causing cell death and the roles of IZH2 and IZH3 in drug susceptibility may help to inform improved drug design and treatment of fungal pathogens.

Comparison of the EUCAST and CLSI Broth Microdilution Methods for Testing Isavuconazole, Posaconazole, and Amphotericin B against Molecularly Identified Mucorales Species.

PubMed

Chowdhary, Anuradha; Singh, Pradeep Kumar; Kathuria, Shallu; Hagen, Ferry; Meis, Jacques F

2015-12-01

We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical Mucorales isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for Mucorales AFST are warranted. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients

PubMed Central

Britz, Erika; Zulu, Thokozile G.; Mpembe, Ruth S.; Naicker, Serisha D.; Schwartz, Ilan S.

2017-01-01

ABSTRACT Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomyces africanus, a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent. PMID:28356416

Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs

PubMed Central

Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M. A.; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E.; Casadevall, Arturo

2015-01-01

The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. PMID:26711773

Fonsecaea Pedrosoi: A Rare Etiology in Fungal Keratitis

PubMed Central

Sangwan, Jyoti; Lathwal, Sumit; Juyal, Deepak; Sharma, Neelam

2013-01-01

Fungal corneal ulcer is common in India due to tropical climate and a large agrarian population that is at risk. Fonsecaea pedrosoi is the most common agent of chromoblastomycosis, a chronic localized fungal infection of the skin and subcutaneous tissues mainly involving lower extremities. We report a rare case of corneal chromoblastomycosis caused by F.pedrosoi, which was successfully treated with topical Amphotericin B followed by a long course of oral antifungal therapy. To the best of our knowledge, this is the first case of mycotic keratitis caused by F.pedrosoi, from the foothills of Himalayas. PMID:24298496

Antifungal activity of Cymbopogon winterianus jowitt ex bor against Candida albicans

PubMed Central

de Oliveira, Wylly Araújo; de Oliveira Pereira, Fillipe; de Luna, Giliara Carol Diniz Gomes; Lima, Igara Oliveira; Wanderley, Paulo Alves; de Lima, Rita Baltazar; de Oliveira Lima, Edeltrudes

2011-01-01

Candida albicans is an opportunistic yeast and a member of the normal human flora that commonly causes infections in patients with any type of deficiency of the immune system. The essential oils have been tested for antimycotic activity and pose much potential as antifungal agents. This work investigated the activity of the essential oil of Cymbopogon winterianus against C. albicans by MIC, MFC and time-kill methods. The essential oil (EO) was obtained by hydrodistillation using a Clevenger-type apparatus. It was tested fifteen strains of C. albicans. The MIC was determined by the microdilution method and the MFC was determined when an aliquot of the broth microdilution was cultivated in SDA medium. The phytochemical analysis of EO showed presence of citronellal (23,59%), geraniol (18,81%) and citronellol (11,74%). The EO showed antifungal activity, and the concentrations 625 µg/mL and 1250 µg/mL inhibited the growth of all strains tested and it was fungicidal, respectively. The antimicrobial activity of various concentrations of EO was analyzed over time, it was found concentration-dependent antifungal activity, whose behavior was similar to amphotericin B and nystatin. PMID:24031651

Candida tropicalis from veterinary and human sources shows similar in vitro hemolytic activity, antifungal biofilm susceptibility and pathogenesis against Caenorhabditis elegans.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Oliveira, Jonathas Sales de; Evangelista, Antônio José de Jesus; Serpa, Rosana; Silva, Aline Lobão da; Aguiar, Felipe Rodrigues Magalhães de; Pereira, Vandbergue Santos; Castelo-Branco, Débora de Souza Collares Maia; Pereira-Neto, Waldemiro Aquino; Cordeiro, Rossana de Aguiar; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha

2016-08-30

The aim of this study was to evaluate the in vitro hemolytic activity and biofilm antifungal susceptibility of veterinary and human Candida tropicalis strains, as well as their pathogenesis against Caenorhabditis elegans. Twenty veterinary isolates and 20 human clinical isolates of C. tropicalis were used. The strains were evaluated for their hemolytic activity and biofilm production. Biofilm susceptibility to itraconazole, fluconazole, voriconazole, amphotericin B and caspofungin was assessed using broth microdilution assay. The in vivo evaluation of strain pathogenicity was investigated using the nematode C. elegans. Hemolytic factor was observed in 95% of the strains and 97.5% of the isolates showed ability to form biofilm. Caspofungin and amphotericin B showed better results than azole antifungals against mature biofilms. Paradoxical effect on mature biofilm metabolic activity was observed at elevated concentrations of caspofungin (8-64μg/mL). Azole antifungals were not able to inhibit mature C. tropicalis biofilms, even at the higher tested concentrations. High mortality rates of C. elegans were observed when the worms were exposed to with C. tropicalis strains, reaching up to 96%, 96h after exposure of the worms to C. tropicalis strains. These results reinforce the high pathogenicity of C. tropicalis from veterinary and human sources and show the effectiveness of caspofungin and amphotericin B against mature biofilms of this species. Copyright © 2016 Elsevier B.V. All rights reserved.

Virulence and antifungal therapy of murine disseminated infection by Rhodotorula mucilaginosa.

PubMed

Thomson, Pamela; López-Fernández, Loida; Guarro, Josep; Capilla, Javier

2017-09-01

Rhodotorula infections have emerged in recent years causing mainly fungemia associated to high mortality. We have evaluated the in vitro activity of nine antifungal drugs against four clinical strains of Rhodotorula mucilaginosa, being amphotericin B, voriconazole and posaconazole the most active compounds. The experimental virulence of this fungus and the efficacy of the three mentioned drugs were evaluated in disseminated infections in neutropenic mice. Infection resulted in a high fungal load in all the organs studied without evident particular tropism. All treated animals showed reduced burden respect to the control in a strain dependent manner being voriconazole slightly superior to posaconazole and amphotericin B. Copyright © 2017 Elsevier Inc. All rights reserved.

In Vitro Activities of Amphotericin B, Terbinafine, and Azole Drugs against Clinical and Environmental Isolates of Aspergillus terreus Sensu Stricto

PubMed Central

Fernández, Mariana S.; Rojas, Florencia D.; Cattana, María E.; Sosa, María de los Ángeles; Iovannitti, Cristina A.; Giusiano, Gustavo E.

2015-01-01

The antifungal susceptibilities of 40 clinical and environmental isolates of A. terreus sensu stricto to amphotericin B, terbinafine, itraconazole, and voriconazole were determined in accordance with CLSI document M38-A2. All isolates had itraconazole and voriconazole MICs lower than epidemiologic cutoff values, and 5% of the isolates had amphotericin B MICs higher than epidemiologic cutoff values. Terbinafine showed the lowest MICs. No significant differences were found when MICs of clinical and environmental isolates were compared. PMID:25824228

Refractory sporotrichosis due to Sporothrix brasiliensis in humans appears to be unrelated to in vivo resistance.

PubMed

Almeida-Paes, Rodrigo; Oliveira, Manoel Marques Evangelista; Freitas, Dayvison Francis Saraiva; Valle, Antônio Carlos Francesconi do; Gutierrez-Galhardo, Maria Clara; Zancopé-Oliveira, Rosely Maria

2017-07-01

Sporotrichosis is a subacute to chronic infection caused by members of the Sporothrix schenckii complex. Itraconazole is the first choice antifungal drug for treating this infection, with terbinafine and potassium iodide as alternatives and amphotericin B used in cases of severe infections. Correlation of antifungal susceptibility data with the clinical outcome of the patients is scarce. The aim of this study was to correlate clinical and mycological data in patients with refractory sporotrichosis. In this work, antifungal susceptibilities, determined according to the reference M38-A2 CLSI protocol, of 25 Sporothrix strains, isolated from seven human cases of sporotrichosis with adversities in the treatment, are presented. Tested drugs included itraconazole, ketoconazole, posaconazole, voriconazole, terbinafine, and amphotericin B. Fungi were identified using the T3B PCR fingerprinting. This method identified all strains as Sporothrix brasiliensis and also demonstrated a high degree of similarity between the strains. In general, voriconazole was ineffective against all strains, and elevated minimal inhibitory concentrations (MICs) were observed for amphotericin B. High itraconazole and terbinafine MICs were not observed in S. brasiliensis isolates from patients of this study. Moreover, a significant increase in itraconazole and terbinafine MIC values from strains isolated from the same patient in different periods was not observed. The results suggest that the antifungal susceptibility to terbinafine and itraconazole determined by the reference method does not play an important role in therapeutic failure of sporotrichosis and that acquisition of resistance during prolonged antifungal treatment is not likely to occur in S. brasiliensis. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Short communication: Cold atmospheric plasma inactivation of Prototheca zopfii isolated from bovine milk.

PubMed

Tyczkowska-Sieron, E; Markiewicz, J; Grzesiak, B; Krukowski, H; Glowacka, A; Tyczkowski, J

2018-01-01

Mastitis is a serious bovine diseases that can be caused by Prototheca zopfii, yeast-like algae belonging to the family Chlorellaceae. The substantial economic losses and health damage associated with bovine mastitis emphasize the need to develop effective strategies aimed at control of the infection. Unfortunately, P. zopfii is highly resistant to most common antibacterial and antifungal agents, as well as to heat treatment. We report here the first attempt to use cold atmospheric plasma to inactivate this pathogen. We studied 20 strains of P. zopfii isolated from milk samples taken from cows with clinical or subclinical mastitis. The studies confirmed the high level of resistance of P. zopfii to typical antifungal agents, such as voriconazole, fluconazole, amphotericin B, caspofungin, anidulafungin, and micafungin. In contrast, each of the strains revealed high susceptibility to cold atmospheric plasma, >2-fold higher compared with a reference strain of Candida albicans. The obtained results are promising and open up a new approach in the fight against P. zopfii. Copyright © 2018 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Enzymatic Activity and Susceptibility to Antifungal Agents of Brazilian Environmental Isolates of Hortaea werneckii.

PubMed

Formoso, Andrea; Heidrich, Daiane; Felix, Ciro Ramón; Tenório, Anne Carolyne; Leite, Belize R; Pagani, Danielle M; Ortiz-Monsalve, Santiago; Ramírez-Castrillón, Mauricio; Landell, Melissa Fontes; Scroferneker, Maria L; Valente, Patricia

2015-12-01

Four strains of Hortaea werneckii were isolated from different substrates in Brazil (a salt marsh macrophyte, a bromeliad and a marine zoanthid) and had their identification confirmed by sequencing of the 26S rDNA D1/D2 domain or ITS region. Most of the strains were able to express amylase, lipase, esterase, pectinase and/or cellulase, enzymes that recognize components of plant cells as substrates, but did not express albuminase, keratinase, phospholipase and DNAse, whose substrates are animal-related. Urease production was positive for all isolates, while caseinase, gelatinase and laccase production were variable among the strains. All the strains grew in media containing up to 30% NaCl. We propose that the primary substrate associated with H. werneckii is plant-related, in special in saline environments, where the fungus may live as a saprophyte and decomposer. Infection of animal-associated substrates would be secondary, with the fungus acting as an opportunistic animal pathogen. All strains were resistant to fluconazole and presented high MIC for amphotericin B, while they were susceptible to all the other antifungal agents tested.

Genetic diversity and antifungal susceptibility of Fusarium isolates in onychomycosis.

PubMed

Rosa, Priscila D; Heidrich, Daiane; Corrêa, Carolina; Scroferneker, Maria Lúcia; Vettorato, Gerson; Fuentefria, Alexandre M; Goldani, Luciano Z

2017-09-01

Fusarium species have emerged as an important human pathogen in skin disease, onychomycosis, keratitis and invasive disease. Onychomycosis caused by Fusarium spp. The infection has been increasingly described in the immunocompetent and immunosuppressed hosts. Considering onychomycosis is a difficult to treat infection, and little is known about the genetic variability and susceptibility pattern of Fusarium spp., further studies are necessary to understand the pathogenesis and better to define the appropriate antifungal treatment for this infection. Accordingly, the objective of this study was to describe the in vitro susceptibility to different antifungal agents and the genetic diversity of 35 Fusarium isolated from patients with onychomycosis. Fusarium spp. were isolated predominantly from female Caucasians, and the most frequent anatomical location was the nail of the hallux. Results revealed that 25 (71.4%) of isolates belonged to the Fusarium solani species complex, followed by 10 (28.5%) isolates from the Fusarium oxysporum species complex. Noteworthy, the authors report the first case of Neocosmospora rubicola isolated from a patient with onychomycosis. Amphotericin B was the most effective antifungal agent against the majority of isolates (60%, MIC ≤4 μg/mL), followed by voriconazole (34.2%, MIC ≤4 μg/mL). In general, Fusarium species presented MIC values >64 μg/mL for fluconazole, itraconazole and terbinafine. Accurate pathogen identification, characterisation and susceptibility testing provide a better understanding of pathogenesis of Fusarium in onychomycosis. © 2017 Blackwell Verlag GmbH.

Vertebral osteomyelitis due to Aspergillus fumigatus in a patient with chronic granulomatous disease successfully treated with antifungal agents and interferon-gamma.

PubMed

Al-Tawfiq, Jaffar A; Al-Abdely, Hail M

2010-05-01

We report a case of invasive aspergillosis due to Aspergillus fumigatus involving the cervical and thoracic vertebrae and upper mediastinum of a 17 year-old Saudi male with chronic granulomatous disease (CGD). The patient did not respond to a long course of liposomal amphotericin B but did to surgical drainage and a combination of caspofungin and itraconazole with subsequent suppression with oral voriconazole. Fourteen months after the start of therapy, the patient had anterior dislocation of T2 thoracic vertebra with cord transection and quadriplegia. He was then treated intravenously with liquid itraconazole and interferon-gamma. The patient made a remarkable recovery over a 2-year period and was eventually able to walk independently. Thus, a combination of antifungals and interferon-gamma may have resulted in the positive outcome in this case.

A Case Report of Penile Infection Caused by Fluconazole- and Terbinafine-Resistant Candida albicans.

PubMed

Hu, Yongxuan; Hu, Yanqing; Lu, Yan; Huang, Shiyun; Liu, Kangxing; Han, Xue; Mao, Zuhao; Wu, Zhong; Zhou, Xianyi

2017-04-01

Candida albicans is the most common pathogen that causes balanoposthitis. It often causes recurrence of symptoms probably due to its antifungal resistance. A significant number of balanitis Candida albicans isolates are resistant to azole and terbinafine antifungal agents in vitro. However, balanoposthitis caused by fluconazole- and terbinafine-resistant Candida albicans has rarely been reported. Here, we describe a case of a recurrent penile infection caused by fluconazole- and terbinafine-resistant Candida albicans, as well as the treatments administered to this patient. The isolate from the patient was tested for drug susceptibility in vitro. It was sensitive to itraconazole, voriconazole, clotrimazole and amphotericin B, but not to terbinafine and fluconazole. Thus, oral itraconazole was administrated to this patient with resistant Candida albicans penile infection. The symptoms were improved, and mycological examination result was negative. Follow-up treatment of this patient for 3 months showed no recurrence.

[Susceptibility to azoles and amphotericin B of isolates of Candida spp. Experience of a university health network, between 2004 and 2010].

PubMed

Porte, Lorena; León, Pilar; Gárate, Cynthia; Guzmán, Ana María; Labarca, Jaime; García, Patricia

2012-04-01

To describe antifungal susceptibility testing surveillance (December 2004-September 2010) in Candida spp., for amphotericin B, fluconazole and voriconazole, at the Laboratorio de Microbiología, Pontificia Universidad Católica de Chile. The study was performed utilizing E test and included yeasts from invasive origin and isolates in which antifungal susceptibility testing was asked for by the patient's physician. The yeasts were mainly recovered from urine samples (n: 64), blood cultures (n: 51) and secretions (n: 24). Two hundred ninety three isolates were studied: C. albicans (38%), C. glabrata (30%), C. tropicalis (11%), C. parapsilosis (10%), C. krusei (4%) and others (7%). All Candida species were 100% susceptible to amphotericin B, except C. krusei (1/12). Fluconazole's global susceptibility in C. albicans was 91.8%, but 100% in isolates from blood cultures versus 76% in isolates from urine. C. tropicalis was 93.9% susceptible to fluconazole, C. parapsilosis, 90% and C. glabrata 30.3%. C. krusei had no susceptible isolates to fluconazole. Voriconazole resistance was mainly present in C. glabrata (11.5%). We recommend the study of antifungal susceptibility in isolates from invasive origin, selected urine strains and C. glabrata. Fluconazole remains effective in C. albicans from blood.

Integrated therapy for HIV and cryptococcosis.

PubMed

Srichatrapimuk, Sirawat; Sungkanuparph, Somnuek

2016-11-29

Cryptococcosis has been one of the most common opportunistic infections and causes of mortality among HIV-infected patients, especially in resource-limited countries. Cryptococcal meningitis is the most common form of cryptococcosis. Laboratory diagnosis of cryptococcosis includes direct microscopic examination, isolation of Cryptococcus from a clinical specimen, and detection of cryptococcal antigen. Without appropriate treatment, cryptococcosis is fatal. Early diagnosis and treatment is the key to treatment success. Treatment of cryptococcosis consists of three main aspects: antifungal therapy, intracranial pressure management for cryptococcal meningitis, and restoration of immune function with antiretroviral therapy (ART). Optimal integration of these three aspects is crucial to achieving successful treatment and reducing the mortality. Antifungal therapy consists of three phases: induction, consolidation, and maintenance. A combination of two drugs, i.e. amphotericin B plus flucytosine or fluconazole, is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases. In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality. Aggressive control of intracranial pressure should be done. Management options include therapeutic lumbar puncture, lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt. Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used. ART has proven to have a great impact on survival rates among HIV-infected patients with cryptococcosis. The time to start ART in HIV-infected patients with cryptococcosis has to be deferred until 5 weeks after the start of antifungal therapy. In general, any effective ART regimen is acceptable. Potential drug interactions between antiretroviral agents and amphotericin B, flucytosine, and fluconazole are minimal. Of most potential clinical relevance is the concomitant use of fluconazole and nevirapine. Concomitant use of these two drugs should be cautious, and patients should be monitored closely for nevirapine-associated adverse events, including hepatotoxicity. Overlapping toxicities of antifungal and antiretroviral drugs and immune reconstitution inflammatory syndrome are not uncommon. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with cryptococcosis.

Antifungal susceptibility profile of diferent yeasts isolates from wild animals, cow's milk with subclinical mastitis and hospital environment.

PubMed

Mendes, J F; Gonçalves, C L; Ferreira, G F; Esteves, I A; Freitas, C H; Villarreal, J P V; Mello, J R B; Meireles, M C A; Nascente, P S

2018-02-01

Yeast infections have acquired great importance due to increasing frequency in immunocompromised patients or patients undergoing invasive diagnostic and therapeutic techniques, and also because of its high morbidity and mortality. At the same time, it has been seen an increase in the emergence of new pathogenic species difficult to diagnose and treat. The aim of this study was to determine the in vitro susceptibility of 89 yeasts from different sources against the antifungals amphotericin B, voriconazole, fluconazole and flucytosine, using the VITEK® 2 Compact system. The antifungal susceptibility was performed automatically by the Vitek® 2 Compact system. The origin of the yeasts was: Group 1 - microbiota of wild animals (W) (26/89), 2 - cow's milk with subclinical mastitis (M) (27/89) and 3 - hospital enviorment (H) (36/89). Of the 89 yeasts submitted to the Vitek® 2 test, 25 (20.9%) were resistant to fluconazole, 11 (12.36%) to amphotericin B, 3 (3.37%) to voriconazole, and no sample was resistant to flucytosine. Regarding the minimum inhibitory concentration (MIC), fluconazole showed an MIC between 1 and 64 mg/mL for the three groups, voriconazole had an MIC between 0.12 and 8 mg/mL, amphotericin B had an MIC between 0.25 and 4 mg/mL for group H and group W respectively, between 0.25 and 16 mg/mL for group M and flucytosine had an MIC equal to 1μg/mL for all groups. The yeasts isolated from the H group showed the highest resistance to fluconazole 12/89 (13.49%), followed by group W (7.87%) and group M (5.62%). The more resistant group to voriconazole was followed by the M and H groups, the W group showed no resistance to this antifungal. Group H was the least resistant (2.25%) to amphotericin.

Invasive pulmonary Aspergillosis in organ transplants--Focus on lung transplants.

PubMed

Geltner, Christian; Lass-Flörl, Cornelia

2016-03-01

Infections with filamentous fungi are common in transplant recipients. The risk for aspergillosis and other invasive pulmonary mycosis (IPM) is high in patients undergoing stem cell and lung transplantations. The mortality rates range from 20% to 60% and depend on a number of risk factors. The typical manifestations of IPM are lung infiltrates, consolidations, and fungal tracheobronchitis. The most common infectious agent is Aspergillus fumigatus. Infections caused by non-Aspergillus molds are more frequent for various reasons. The species distribution of non-Aspergillus molds varies in different locations. Furthermore, infections caused by Mucor and Penicillium are increasing, as are infections caused by species resistant to azoles and amphotericin B. Most centers use antifungal prophylaxis with inhaled amphotericin B or oral azoles. Early diagnosis and therapy is crucial. Reliable information on the local microbiological spectrum is a prerequisite for the effective treatment of molds with primary or secondary resistance to antimycotic drugs. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

In Vitro Antifungal Activities of a Series of Dication-Substituted Carbazoles, Furans, and Benzimidazoles

PubMed Central

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan K.; Tidwell, Richard R.; Kumar, Arvind; Boykin, David W.; Perfect, John R.

1998-01-01

Aromatic dicationic compounds possess antimicrobial activity against a wide range of eucaryotic pathogens, and in the present study an examination of the structures-functions of a series of compounds against fungi was performed. Sixty-seven dicationic molecules were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. The MICs of a large number of compounds were comparable to those of the standard antifungal drugs amphotericin B and fluconazole. Unlike fluconazole, potent inhibitory compounds in this series were found to have excellent fungicidal activities. The MIC of one of the most potent compounds against C. albicans was 0.39 μg/ml, and it was the most potent compound against C. neoformans (MIC, ≤0.09 μg/ml). Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. Since some of these compounds have been safely given to animals, these classes of molecules have the potential to be developed as antifungal agents. PMID:9756748

Successful management of chronic disseminated candidiasis in hematologic patients treated with high-dose liposomal amphotericin B: a retrospective study of the SEIFEM registry.

PubMed

Della Pepa, Roberta; Picardi, M; Sorà, F; Stamouli, M; Busca, A; Candoni, A; Delia, M; Fanci, R; Perriello, V; Zancanella, M; Nosari, A; Salutari, P; Marchesi, F; Pane, F; Pagano, L

2016-09-01

Chronic disseminated candidiasis (CDC) is a complication of Candida infection in immunocompromised patients, involving the liver and spleen, and rarely other organs. The aim of the study is to identify the best antifungal drug for hematologic immunocompromised patients with CDC. In this multicentric retrospective study, the charts of 20 patients with CDC following cytotoxic agent protocols for hematological malignancies, diagnosed from 2003 to 2013, were analyzed. The response to systemic antifungal therapy within 90 days from CDC diagnosis and the possible delay in chemotherapy plan, due to the infection, were evaluated. Six patients were treated with high-dose (HD; 5 mg/kg/daily) liposomal amphotericin B (L-AmB), whereas three received standard-dose (SD) L-AmB (3 mg/kg/daily). Azoles were given to six patients; the remaining five were treated with echinocandins. All patients treated with HD L-AmB (6/6-100 %) achieved complete resolution of CDC; one of them had to interrupt the chemotherapy program for the infection. In the SD L-AmB group, treatment failed in the 100 % of cases and one patient had to delay chemotherapy for the infection. Of the six patients who received azoles, two achieved complete resolution of the infection, four experienced treatment failure, and only three performed chemotherapy as planned. Echinocandins treatment resulted in complete resolution of the infection in 2/5 cases, partial response in 2/5 cases, and failure in one case. In this group, 3/5 patients completed chemotherapy as planned. This study shows that HD L-AmB was particularly effective against CDC in hematologic patients, allowing most patients to continue cytotoxic agent program.

An in vitro study of antifungal drug susceptibility of Candida species isolated from human immunodeficiency virus seropositive and human immunodeficiency virus seronegative individuals in Lucknow population Uttar Pradesh.

PubMed

Dar, Mohammad Shafi; Sreedar, Gadiputi; Shukla, Abhilasha; Gupta, Prashant; Rehan, Ahmad Danish; George, Jiji

2015-01-01

Candidiasis is the most common opportunistic infection in human immunodeficiency virus (HIV) seropositive patients, starting from asymptomatic colonization to pathogenic forms and gradual colonization of non-albicans in patients with advanced immunosuppression leads to resistance for azole group of antifungal drugs with high rate of morbidity and mortality. To isolate the Candida species and determine of antifungal drug susceptibility against fluconazole, itraconazole, nystatin, amphotericin B, and clotrimazolein HIV seropositive and control individuals, with or without clinical oropharyngeal candidiasis (OPC). Includes samples from faucial region of 70 subjects with and without clinical candidiasis in HIV seropositive and controls were aseptically inoculated onto Sabaraud's Dextrose Agar media and yeasts were identified for the specific species by Corn Meal Agar, sugar fermentation and heat tolerance tests. Antifungal drug susceptibility of the isolated species was done against above-mentioned drugs by E-test and disc diffusion method. The commonly isolated species in HIV seropositive and controls were Candida albicans, Candida glabrata and Candida tropicalis Candida guilliermondii and Candida dubliniensis isolated only in HIV seropositive patients. Susceptibility against selected antifungal drugs was observed more in HIV-negative individuals whereas susceptible dose-dependent and resistance were predominant in HIV-positive patients. Resistance is the major problem in the therapy of OPC, especially in HIV seropositive patients due to aggressive and prolonged use of antifungal agents, therefore, our study emphasizes the need for antifungal drug susceptibility testing whenever antifungal treatment is desired, especially in HIV-infected subjects.

Susceptibility of 100 filamentous fungi: comparison of two diffusion methods, Neo-Sensitabs and E-test, for amphotericin B, caspofungin, itraconazole, voriconazole and posaconazole.

PubMed

Colosi, Ioana A; Faure, Odile; Dessaigne, Bérangére; Bourdon, Cécile; Lebeau, Bernadette; Colosi, Horaţiu A; Pelloux, Hervé

2012-05-01

We compared the E-test method to that of the Neo-Sensitabs tablet diffusion assay for evaluating the in vitro susceptibility of 100 clinical isolates of filamentous fungi (Aspergillus spp., Fusarium spp., Scedosporium spp., zygomycetes and other molds) to amphotericin B, itraconazole, voriconazole, caspofungin, and posaconazole. We determined the categorical agreement level between E-test minimum inhibitory concentrations (MIC) and tablet end-points, as opposed to the following disagreement parameters: very major error - resistant parameter (R) in E-test and susceptible (S) in tablet; major error - S by E-test and R by tablet; minor error - shifts between S and susceptible dose-dependent (S-DD) or S-DD and R. We also performed linear regression analyses and computed Pearson's correlation coefficients (R values) between the log transforms of MICs and the inhibition zone diameters of the five studied antifungal agents. For itraconazole we obtained 97% categorical agreement and R = -0.727. Categorical agreement for caspofungin and voriconazole was 96% and R =-0.821 and R = -0.789, respectively. For posaconazole the categorical agreement was 94% and R =-0.743. Amphotericin B exhibited a lower degree of agreement (76%, R = -0.672), especially in studies of Aspergillus spp. Our results suggest a potential value of the Neo-Sensitabs assay for in vitro susceptibility testing of molds to itraconazole, voriconazole, caspofungin and posaconazole, while amphotericin B exhibited an overall lower degree of agreement.

Local administration of amphotericin B against aspergilloma in the prepontine cistern--case report.

PubMed

Nabika, Shinya; Kiya, Katsuzo; Satoh, Hideki; Mizoue, Tatsuya; Araki, Hayato; Oshita, Jumpei

2007-02-01

A 21-year-old man presented with aspergilloma in the prepontine cistern that developed after treatment for cerebellar hematoma following rupture of an arteriovenous malformation. He became bedridden with neurological signs of tetraparesis, disturbed ocular movement, and bulbar palsy, despite alert consciousness. Repeat magnetic resonance imaging 1 year later revealed a space-occupying lesion in the prepontine cistern along the clivus. This multilobular enhanced mass lesion gradually enlarged towards the brainstem over the following 4 years, resulting in loss of spontaneous breathing and dependence on a mechanical respirator. Surgical treatment via a lateral suboccipital approach was selected to reduce the size of the mass lesion and confirm the diagnosis. Histological examination revealed the presence of Aspergillus fumigatus. Treatment with amphotericin B (1 mg/kg/day) and fluconazole (100 mg/kg/day) injected into the peripheral veins was initiated, but was stopped due to the appearance of renal dysfunction. An Ommaya tube was then inserted into the prepontine cistern via a transsylvian approach to provide high concentrations of amphotericin B around the granulomatous lesion. He gradually improved, corresponding to the decreased size of the aspergilloma just after surgery. Surgical reduction of granuloma combined with local administration of antifungal agent is a good treatment option in patients with aspergilloma refractory to systemic administration.

Alginate Oligosaccharides Inhibit Fungal Cell Growth and Potentiate the Activity of Antifungals against Candida and Aspergillus spp

PubMed Central

Tøndervik, Anne; Sletta, Håvard; Klinkenberg, Geir; Emanuel, Charlotte; Powell, Lydia C.; Pritchard, Manon F.; Khan, Saira; Craine, Kieron M.; Onsøyen, Edvar; Rye, Phil D.; Wright, Chris; Thomas, David W.; Hill, Katja E.

2014-01-01

The oligosaccharide OligoG, an alginate derived from seaweed, has been shown to have anti-bacterial and anti-biofilm properties and potentiates the activity of selected antibiotics against multi-drug resistant bacteria. The ability of OligoG to perturb fungal growth and potentiate conventional antifungal agents was evaluated using a range of pathogenic fungal strains. Candida (n = 11) and Aspergillus (n = 3) spp. were tested using germ tube assays, LIVE/DEAD staining, scanning electron microscopy (SEM), atomic force microscopy (AFM) and high-throughput minimum inhibition concentration assays (MICs). In general, the strains tested showed a significant dose-dependent reduction in cell growth at ≥6% OligoG as measured by optical density (OD600; P<0.05). OligoG (>0.5%) also showed a significant inhibitory effect on hyphal growth in germ tube assays, although strain-dependent variations in efficacy were observed (P<0.05). SEM and AFM both showed that OligoG (≥2%) markedly disrupted fungal biofilm formation, both alone, and in combination with fluconazole. Cell surface roughness was also significantly increased by the combination treatment (P<0.001). High-throughput robotic MIC screening demonstrated the potentiating effects of OligoG (2, 6, 10%) with nystatin, amphotericin B, fluconazole, miconazole, voriconazole or terbinafine with the test strains. Potentiating effects were observed for the Aspergillus strains with all six antifungal agents, with an up to 16-fold (nystatin) reduction in MIC. Similarly, all the Candida spp. showed potentiation with nystatin (up to 16-fold) and fluconazole (up to 8-fold). These findings demonstrate the antifungal properties of OligoG and suggest a potential role in the management of fungal infections and possible reduction of antifungal toxicity. PMID:25409186

Anti-Rhodotorula activity of mycophenolic acid enhanced in the presence of polyene antibiotic nystatin.

PubMed

Kinoshita, H; Wongsuntornpoj, S; Ihara, F; Nihira, T

2017-02-01

Rhodotorula species are opportunistic pathogens, which cause not only systemic fungaemia but also other localized infections. Despite serious side effects such as nephrotoxicity and hypokalemia, amphotericin B (a polyene antifungal) has been commonly prescribed for Rhodotorula infection because Rhodotorula species are resistant against a candin family of antifungal agents. In this study, novel active compounds against Rhodotorula species were screened from the extracts of entomopathogenic fungi based on the synergistic effect of polyene nystatin (NYS), which causes efficient targeting of compounds due to increased permeability through the fungal cell membrane. Around 37% of culture extracts from 31 entomopathogenic fungal strains showed anti-Rhodotorula activity in the synergistic bioassay system, suggesting that the coexistence assay with NYS enhanced the discovery of anti-Rhodotorula compounds. Judging from various physicochemical data, the active component from strain HF763 was identified as an immunosuppressant drug, mycophenolic acid (MPA). The minimum inhibitory concentration of MPA against three pathogenic Rhodotorula strains was determined, focusing on the synergistic effect with NYS. The results revealed that the values decreased by at least 87% in the presence of NYS, indicating that MPA showed a synergistic effect with NYS. This study aimed to screen active compounds against Rhodotorula species that are resistant to a candin family of antifungal agents, from entomopathogenic fungi. Assuming that most of the latent antifungal compounds do not exert their activity due to their inability to penetrate the membrane, we took advantage of polyene nystatin in the screening to increase permeability through the fungal cell membrane. The result of the screening revealed hidden antifungal activity of mycophenolic acid, demonstrating that the method applied in this study unlocks the potentials of bioresources, and proposes a new remedy for mycosis. © 2016 The Society for Applied Microbiology.

Identification of Candida parapsilosis Sensu Lato in Pediatric Patients and Antifungal Susceptibility Testing

PubMed Central

Dudiuk, Catiana; Fernández, Mariana; Rojas, Florencia; Alegre, Liliana; Córdoba, Susana; Garcia-Effron, Guillermo; Giusiano, Gustavo

2017-01-01

ABSTRACT A total of 59 Candida parapsilosis sensu stricto and 1 Candida orthopsilosis recovered from catheters and blood cultures of pediatric patients from the northeastern region of Argentina were studied. Susceptibility to azoles, amphotericin B, and echinocandins was tested by the broth microdilution method. According to CLSI clinical breakpoints, >91% of the strains were azole susceptible, whereas 15% showed high amphotericin B MICs. PMID:28483957

Biofilm Production and Antibiofilm Activity of Echinocandins and Liposomal Amphotericin B in Echinocandin-Resistant Yeast Species

PubMed Central

Marcos-Zambrano, Laura Judith; Gómez-Perosanz, Marta; Escribano, Pilar; Zaragoza, Oscar; Bouza, Emilio

2016-01-01

The echinocandins and liposomal amphotericin B are active against biofilm produced by echinocandin-susceptible Candida strains. However, few data have been reported on the production of biofilm by echinocandin-resistant isolates and their antifungal susceptibility. We studied the production of biofilm by fks mutant Candida strains and intrinsically echinocandin-resistant non-Candida isolates and the susceptibility of both entities to liposomal amphotericin B and echinocandins. We analyzed the production of biofilm by isolates from patients with fungemia (fks mutant Candida, n = 5; intrinsically echinocandin-resistant non-Candida, n = 12; and Candida wild type, n = 10). Biofilm formation was measured to classify strains according to biomass (crystal violet assay) and metabolic activity (XTT reduction assay). Preformed biofilms were tested against liposomal amphotericin B, caspofungin, micafungin, and anidulafungin. The sessile MIC was defined as the antifungal concentration yielding a 50% or 80% reduction in the metabolic activity of the biofilm compared to that of the growth control (SMIC50 and SMIC80, respectively). fks mutant Candida isolates formed biofilms in a fashion similar to that of Candida wild-type strains. The echinocandins had the highest activity against biofilms formed by wild-type Candida isolates, followed by fks mutant Candida isolates and non-Candida isolates. Liposomal amphotericin B had the highest activity against fks mutant Candida biofilms. The formation of biofilm by echinocandin-resistant strains was similar to that of wild-type strains, although resistance to echinocandins remained high. PMID:27021323

Multilocus Phylogeny and Antifungal Susceptibility of Aspergillus Section Circumdati from Clinical Samples and Description of A. pseudosclerotiorum sp. nov.

PubMed Central

Siqueira, J. P. Z.; Sutton, D. A.; García, D.; Wiederhold, N.; Peterson, S. W.; Guarro, J.

2017-01-01

ABSTRACT A multilocus phylogenetic study was carried out to assess species identity of a set of 34 clinical isolates from Aspergillus section Circumdati from the United States and to determine their in vitro antifungal susceptibility against eight antifungal drugs. The genetic markers used were the internal transcribed spacer (ITS) region, and fragments of the beta-tubulin (BenA), calmodulin (CaM), and RNA polymerase II second largest subunit (RPB2) genes. The drugs tested were amphotericin B, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and terbinafine. The most common species sampled was A. westerdijkiae (29.4%), followed by a novel species, which was described here as A. pseudosclerotiorum (23.5%). Other species identified were A. sclerotiorum (17.6%), A. ochraceus (8.8%), A. subramanianii (8.8%), and A. insulicola and A. ochraceopetaliformis, with two isolates (5.9%) of each. The drugs that showed the most potent activity were caspofungin, micafungin, and terbinafine, while amphotericin B showed the least activity. PMID:28053212

Multilocus Phylogeny and Antifungal Susceptibility of Aspergillus Section Circumdati from Clinical Samples and Description of A. pseudosclerotiorum sp. nov.

PubMed

Siqueira, J P Z; Sutton, D A; Gené, J; García, D; Wiederhold, N; Peterson, S W; Guarro, J

2017-03-01

A multilocus phylogenetic study was carried out to assess species identity of a set of 34 clinical isolates from Aspergillus section Circumdati from the United States and to determine their in vitro antifungal susceptibility against eight antifungal drugs. The genetic markers used were the internal transcribed spacer (ITS) region, and fragments of the beta-tubulin ( BenA ), calmodulin ( CaM ), and RNA polymerase II second largest subunit ( RPB2 ) genes. The drugs tested were amphotericin B, itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin, micafungin, and terbinafine. The most common species sampled was A. westerdijkiae (29.4%), followed by a novel species, which was described here as A. pseudosclerotiorum (23.5%). Other species identified were A. sclerotiorum (17.6%), A. ochraceus (8.8%), A. subramanianii (8.8%), and A. insulicola and A. ochraceopetaliformis , with two isolates (5.9%) of each. The drugs that showed the most potent activity were caspofungin, micafungin, and terbinafine, while amphotericin B showed the least activity. Copyright © 2017 American Society for Microbiology.

Scedosporium prolificans Osteomyelitis in an Immunocompetent Child Treated with Voriconazole and Caspofungin, as Well as Locally Applied Polyhexamethylene Biguanide

PubMed Central

Steinbach, William J.; Schell, Wiley A.; Miller, Jackie L.; Perfect, John R.

2003-01-01

Scedosporium species are increasingly isolated from immunocompromised and immunocompetent patients. Unfortunately, Scedosporium infections are generally resistant to amphotericin B, and Scedosporium prolificans strains are particularly resistant to the antifungal agents now in use. We report here on an immunocompetent child with S. prolificans-associated osteomyelitis successfully treated with debridement, local irrigation with polyhexamethylene biguanide, and the systemic administration of voriconazole and caspofungin despite poor in vitro activity of voriconazole alone against the isolate. We also review the treatments and outcomes of 28 reported cases of osteomyelitis or septic arthritis caused by Scedosporium species in immunocompetent patients. PMID:12904435

Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs.

PubMed

Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M A; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E; Casadevall, Arturo; Gonçalves, Teresa

2015-12-28

The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Amphotericin B Colloidal Dispersion Combined with Flucytosine with or without Fluconazole for Treatment of Murine Cryptococcal Meningitis

PubMed Central

Diamond, DeAnn M.; Bauer, Madeline; Daniel, Barbra E.; Leal, Mary Ann E.; Johnson, Debra; Williams, Byron K.; Thomas, Ann M.; Ding, James C.; Najvar, Laura; Graybill, J. Richard; Larsen, Robert A.

1998-01-01

Studies with animals and in vitro studies have demonstrated that flucytosine plus amphotericin B or fluconazole has significantly improved mycologic activity against meningitis caused by Cryptococcus neoformans compared to the activity of amphotericin B or fluconazole used alone. However, few doses have been tested in combination. This study evaluated the antifungal efficacy of amphotericin B colloidal dispersion (ABCD) combined with flucytosine with and without fluconazole in a murine model of cryptococcal meningitis. The following dosages were tested: ABCD at 0 to 12.5 mg/kg of body weight given intravenously 3 days/week, flucytosine at 0 to 110 mg/kg/day, and fluconazole at 0 to 50 mg/kg/day. Meningitis was established in male BALB/c mice by intracerebral injection of C. neoformans. Treatment with flucytosine with or without fluconazole dissolved in the sole source of drinking water was started on day 2; animals were sacrificed at 16 days, and the numbers of fungal colonies in the brain were quantified. A survival rate of 100% was achieved with ABCD plus flucytosine without fluconazole; however, the addition of fluconazole was required to prevent weight loss (P < 0.00001) and to achieve the maximum antifungal effect (P < 0.00001). The only region of dose combinations for which the 99% confidence intervals were less than 100 CFU/g of brain was defined by ABCD at 5.0 to 7.5 mg/kg combined with flucytosine at 20 to 60 mg/kg/day and fluconazole at 30 to 40 mg/kg/day. The triple combination of ABCD plus flucytosine and fluconazole was necessary to achieve the greatest antifungal activity. PMID:9517927

Multicenter Evaluation of MIC Distributions for Epidemiologic Cutoff Value Definition To Detect Amphotericin B, Posaconazole, and Itraconazole Resistance among the Most Clinically Relevant Species of Mucorales

PubMed Central

Chakrabarti, A.; Chowdhary, A.; Cordoba, S.; Dannaoui, E.; Dufresne, P.; Fothergill, A.; Ghannoum, M.; Gonzalez, G. M.; Guarro, J.; Kidd, S.; Lass-Flörl, C.; Meis, J. F.; Pelaez, T.; Tortorano, A. M.; Turnidge, J.

2015-01-01

Clinical breakpoints (CBPs) have not been established for the Mucorales and any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole, and itraconazole and four Mucorales species. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10 Apophysomyces variabilis, 32 Cunninghamella bertholletiae, 136 Lichtheimia corymbifera, 10 Mucor indicus, 123 M. circinelloides, 19 M. ramosissimus, 349 Rhizopus arrhizus, 146 R. microsporus, 33 Rhizomucor pusillus, and 36 Syncephalastrum racemosum isolates. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs for L. corymbifera were 1 and 2 μg/ml, those for M. circinelloides were 1 and 2 μg/ml, those for R. arrhizus were 2 and 4 μg/ml, and those for R. microsporus were 2 and 2 μg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, those for M. circinelloides were 4 and 4, those for R. arrhizus were 1 and 2, and those for R. microsporus were 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 μg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated. PMID:25583714

Multicenter evaluation of MIC distributions for epidemiologic cutoff value definition to detect amphotericin B, posaconazole, and itraconazole resistance among the most clinically relevant species of Mucorales.

PubMed

Espinel-Ingroff, A; Chakrabarti, A; Chowdhary, A; Cordoba, S; Dannaoui, E; Dufresne, P; Fothergill, A; Ghannoum, M; Gonzalez, G M; Guarro, J; Kidd, S; Lass-Flörl, C; Meis, J F; Pelaez, T; Tortorano, A M; Turnidge, J

2015-03-01

Clinical breakpoints (CBPs) have not been established for the Mucorales and any antifungal agent. In lieu of CBPs, epidemiologic cutoff values (ECVs) are proposed for amphotericin B, posaconazole, and itraconazole and four Mucorales species. Wild-type (WT) MIC distributions (organisms in a species-drug combination with no detectable acquired resistance mechanisms) were defined with available pooled CLSI MICs from 14 laboratories (Argentina, Australia, Canada, Europe, India, Mexico, and the United States) as follows: 10 Apophysomyces variabilis, 32 Cunninghamella bertholletiae, 136 Lichtheimia corymbifera, 10 Mucor indicus, 123 M. circinelloides, 19 M. ramosissimus, 349 Rhizopus arrhizus, 146 R. microsporus, 33 Rhizomucor pusillus, and 36 Syncephalastrum racemosum isolates. CLSI broth microdilution MICs were aggregated for the analyses. ECVs comprising ≥95% and ≥97.5% of the modeled populations were as follows: amphotericin B ECVs for L. corymbifera were 1 and 2 μg/ml, those for M. circinelloides were 1 and 2 μg/ml, those for R. arrhizus were 2 and 4 μg/ml, and those for R. microsporus were 2 and 2 μg/ml, respectively; posaconazole ECVs for L. corymbifera were 1 and 2, those for M. circinelloides were 4 and 4, those for R. arrhizus were 1 and 2, and those for R. microsporus were 1 and 2, respectively; both itraconazole ECVs for R. arrhizus were 2 μg/ml. ECVs may aid in detecting emerging resistance or isolates with reduced susceptibility (non-WT MICs) to the agents evaluated. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Species spectrum and antifungal susceptibility profile of vaginal isolates of Candida in Kuwait.

PubMed

Alfouzan, W; Dhar, R; Ashkanani, H; Gupta, M; Rachel, C; Khan, Z U

2015-03-01

The study was undertaken to determine the prevalence of vulvovaginal candidiasis (VVC) among patients with vaginitis, frequency of different Candida species, and their susceptibility profile. Over six months period, high vaginal swabs were cultured on Sabouraud's dextrose agar and isolates were identified by culture on CHROMagar Candida and Vitek2 yeast identification system or/and API 20C (BioMerieux, France). Antifungal susceptibility of the Candida isolates was determined by E-test against amphotericin B, flucytosine, fluconazole, voriconazole, posaconazole and caspofungin. One thousand seven hundred and fifty-two women with vaginitis were screened for the prevalence of Candida spp. Vaginal swab cultures of 231 (13.2%) women yielded Candida spp. The isolation rates of different species were as follows: Candida albicans (73.9%), Candida glabrata (19.8%), Candida kefir (1.94%), Candida tropicalis (0.96%), Candida parapsilosis (0.96%), Candida krusei (0.96%), Candida guilliermondii (0.96%), and Saccharomyces cerevisiae (0.52%). All strains of C. albicans and non-C. albicans were susceptible to most of the antifungal agents tested. The high frequency with which C. albicans was recovered and its azole susceptibility support the continued use of azole agents for empirical therapy of uncomplicated VVC. However, a larger controlled study is required to determine the role of non-C. albicans in recurrent VVC. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

In Vitro Activity of E1210, a Novel Antifungal, against Clinically Important Yeasts and Molds▿

PubMed Central

Miyazaki, Mamiko; Horii, Takaaki; Hata, Katsura; Watanabe, Nao-aki; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

2011-01-01

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC90 of ≤0.008 to 0.06 μg/ml), except for Candida krusei (MICs of 2 to >32 μg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC90 of 0.13 μg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 μg/ml), Scedosporium prolificans (MIC of 0.03 μg/ml), and Paecilomyces lilacinus (MICs of 0.06 μg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections. PMID:21825291

In Vitro Activities of Four Novel Triazoles against Scedosporium spp.

PubMed Central

Carrillo, A. J.; Guarro, J.

2001-01-01

In order to develop new approaches to the treatment of the severe and usually fatal infections caused by Scedosporium spp., the in vitro antifungal activities of four novel triazoles (posaconazole, ravuconazole, voriconazole, and UR-9825) and some current antifungals (amphotericin B, ketoconazole, itraconazole, and nystatin) were determined. The latter group was clearly ineffective against the two species tested. The four new antifungals showed activity against Scedosporium apiospermum, and UR-9825 and voriconazole were active against S. prolificans. PMID:11408242

Epidemiology and treatment approaches in management of invasive fungal infections

PubMed Central

Kriengkauykiat, Jane; Ito, James I; Dadwal, Sanjeet S

2011-01-01

Over the past 20 years, the number of invasive fungal infections has continued to persist, due primarily to the increased numbers of patients subjected to severe immunosuppression. Despite the development of more active, less toxic antifungal agents and the standard use of antifungal prophylaxis, invasive fungal infections (especially invasive mold infections) continue to be a significant factor in hematopoietic cell and solid organ transplantation outcomes, resulting in high mortality rates. Since the use of fluconazole as standard prophylaxis in the hematopoietic cell transplantation setting, invasive candidiasis has come under control, but no mold-active antifungal agent (except for posaconazole in the setting of acute myelogenous leukemia and myelodysplastic syndrome) has been shown to improve the survival rate over fluconazole. With the advent of new azole and echinocandin agents, we have seen the emergence of more azole-resistant and echinocandin-resistant fungi. The recent increase in zygomycosis seen in the hematopoietic cell transplantation setting may be due to the increased use of voriconazole. This has implications for the empiric approach to pulmonary invasive mold infections when zygomycosis cannot be ruled out. It is imperative that an amphotericin B product, an antifungal that has never developed resistance in over 50 years, be initiated. The clinical presentations of invasive mold infections and invasive candidiasis can be nonspecific and the diagnostic tests insensitive, so a high index of suspicion and immediate initiation of empiric therapy is required. Unfortunately, our currently available serologic tests do not predict infection ahead of disease, and, therefore cannot be used to initiate “preemptive” therapy. Also, the Aspergillus galactomannan test gives a false negative result in patients receiving antimold prophylaxis, ie, virtually all of our patients with hematologic malignancy and hematopoietic cell transplant recipients. We may eventually be able to select patients at highest risk for invasive fungal infections for prophylaxis by genetic testing. However, with our current armamentarium of antifungal agents and widespread use of prophylaxis in high-risk groups (hematologic malignancy, hematopoietic cell transplantation), we continue to see high incidence and mortality rates, and our future hope lies in reversing the immunosuppression or augmenting the immune system of these severely immunocompromised hosts by developing and utilizing immunotherapy, immunoprophylaxis, and vaccines. PMID:21750627

Antifungal susceptibility of clinical and environmental isolates of Cryptococcus neoformans to four antifungal drugs determined by two techniques.

PubMed

Moraes, E M P; Prímola, N S; Hamdan, Júnia Soares

2003-06-01

A total of 64 Cryptococcus neoformans strains, including clinical and environmental Brazilian isolates var. neoformans and var. gattii, were tested for susceptibility to amphotericin B, 5-flucytosine, fluconazole and itraconazole. The tests were performed according to the recommendations of National Committee of Clinical Laboratory Standards and the method of macrodilution in liquid medium of Shadomy et al. [Manual de Microbiologia Clínica, 4th ed. Buenos Aires: Editorial Medica Panamericana, 1987: 1229-38]. For most drugs there was a significant difference between the readings taken at 24 and 48 h with both methods. When the minimum inhibitory concentrations obtained by the two techniques were compared, significant differences were observed for amphotericin B and fluconazole. Overall, differences in drug susceptibility with respect to the origin of the isolates or the variety of the fungus were not observed. As an exception, the gattii variety exhibited a high resistance rate to amphotericin B when the technique of Shadomy et al. was applied, a fact possibly related to the greater difficulty for treatment of the disease caused by this fungal variety.

Identification of Candida parapsilosis Sensu Lato in Pediatric Patients and Antifungal Susceptibility Testing.

PubMed

Cattana, Maria Emilia; Dudiuk, Catiana; Fernández, Mariana; Rojas, Florencia; Alegre, Liliana; Córdoba, Susana; Garcia-Effron, Guillermo; Giusiano, Gustavo

2017-07-01

A total of 59 Candida parapsilosis sensu stricto and 1 Candida orthopsilosis recovered from catheters and blood cultures of pediatric patients from the northeastern region of Argentina were studied. Susceptibility to azoles, amphotericin B, and echinocandins was tested by the broth microdilution method. According to CLSI clinical breakpoints, >91% of the strains were azole susceptible, whereas 15% showed high amphotericin B MICs. Copyright © 2017 American Society for Microbiology.

Reporting an outbreak of Candida pelliculosa fungemia in a neonatal intensive care unit.

PubMed

Lin, Hsiao-Chuan; Lin, Hsiang-Yu; Su, Bai-Hong; Ho, Mao-Wang; Ho, Cheng-Mao; Lee, Ching-Yi; Lin, Ming-Hsia; Hsieh, Hsin-Yang; Lin, Hung-Chih; Li, Tsai-Chung; Hwang, Kao-Pin; Lu, Jang-Jih

2013-12-01

Fungemia in preterm infants is associated with high mortality and morbidity. This study reports an outbreak of unusual fungemia in a tertiary neonatal intensive care unit (NICU). Ten Candida pelliculosa bloodstream isolates were identified from six infants hospitalized in the NICU from February to March 2009. Environmental study was performed, and genetic relatedness among the 10 clinical isolates of C pelliculosa and six control C pelliculosa strains was characterized by randomly amplified polymorphic DNA assay. In vitro susceptibility of isolates to six antifungal agents was analyzed by broth microdilution method. Amphotericin B was given to infected infants and prophylactic fluconazole was prescribed to the other noninfected extremely low birth weight infants during the outbreak. Thrombocytopenia (platelet counts <100×10(9)/L) was the early laboratory finding in four infants. One of six patients died, making overall mortality 17%. Fluconazole, voriconazole, amphotericin B, and micafungin provided good antifungal activity. Cultures from the environment and hands of caregivers were all negative. Molecular studies indicated the outbreak as caused by a single strain. The outbreak was controlled by strict hand washing, cohort infected patients, confined physicians and nurses to take care of patients, prophylactic fluconazole to uninfected neonates, and proper management of human milk. The study demonstrated the clinical importance of emerged non-albicans Candida species in NICU. For unusual pathogen isolated from immunocompromised hosts, more attention should be paid to monitor the possibility of an outbreak. Copyright © 2012. Published by Elsevier B.V.

Cost-effectiveness evaluation of voriconazole versus liposomal amphotericin B as empirical therapy for febrile neutropenia in Australia.

PubMed

Al-Badriyeh, Daoud; Liew, Danny; Stewart, Kay; Kong, David C M

2009-01-01

A major randomized clinical trial, evaluating voriconazole versus liposomal amphotericin B (LAMB) as empirical therapy in febrile neutropenia, recommended voriconazole as a suitable alternative to LAMB. The current study sought to investigate the health economic impact of using voriconazole and LAMB for febrile neutropenia in Australia. A decision analytic model was constructed to capture downstream consequences of empirical antifungal therapy with each agent. The main outcomes were: success, breakthrough fungal infection, persistent baseline fungal infection, persistent fever, premature discontinuation and death. Underlying transition probabilities and treatment patterns were derived directly from trial data. Resource use was estimated using an expert panel. Cost inputs were obtained from the latest Australian representative published sources. The perspective adopted was that of the Australian hospital. Uncertainty and sensitivity analyses were undertaken via the Monte Carlo simulation. Compared with voriconazole, LAMB was associated with a net cost saving of AU$1422 (2.9%) per patient. A similar trend was observed with the cost per death prevented and successful treatment. LAMB dominated voriconazole as it resulted in higher efficacy and lower costs when compared with voriconazole. The results were most sensitive to the duration of therapy and the alternative therapy used post discontinuations. In uncertainty analysis, LAMB had 99.8% chance of costing less than voriconazole. In this study, which used the current standard five component endpoint to assess the impact of empirical antifungal therapy, LAMB was associated with cost savings relative to voriconazole.

Molecular Identification and Antifungal Susceptibility Pattern of Non-albicans Candida Species Isolated from Vulvovaginal Candidiasis

PubMed Central

Nejat, Ziba Abbasi; Farahyar, Shirin; Falahati, Mehraban; Khozani, Mahtab Ashrafi; Hosseini, Aga Fateme; Faiazy, Azamsadat; Ekhtiari, Masoome; Hashemi-Hafshenjani, Saeideh

2018-01-01

Background: Vulvovaginal candidiasis (VVC) is an important health problem caused by Candida spp. The aim of this study was molecular identification, phylogenetic analysis, and evaluation of antifungal susceptibility of non-albicans Candida isolates from VVC. Methods: Vaginal secretion samples were collected from 550 vaginitis patients at Sayyad Shirazi Medical and Educational Center of Gorgan (Golestan Province, Iran) from May to October 2015. Samples were analyzed using conventional mycological and molecular approaches. Clinical isolates were analyzed with specific PCR using CGL primers, and the internal transcribed spacer region and the D1-D2 domain of the large-subunit rRNA gene were amplified and sequenced. Susceptibility to amphotericin B, fluconazole, itraconazole, and clotrimazole was determined by the guidelines of the Clinical and Laboratory Standard Institute. Results: In total, 35 non-albicans Candida isolates were identified from VVC patients. The isolates included 27 strains of Candida glabrata (77.1%), 5 Candida krusei (Pichia kudriavzevii; 14.3%), 2 Candida kefyr (Kluyveromyces marxianus; 5.7%), and 1 Candida lusitaniae (Clavispora lusitaniae; 2.9%). The fungicides itraconazole and amphotericin B were effective against all species. One isolate of C. glabrata showed resistance to fluconazole and clotrimazole, and 26 isolates of C. glabrata indicated dose-dependent susceptibility to fluconazole. C. lusitaniae was susceptible in a dose-dependent manner to fluconazole and resistant to clotrimazole. Conclusions: Non-albicans Candida spp. are common agents of vulvovaginitis, and C. glabrata is the most common species in the tested patients. PMID:28688376

Antifungal susceptibility of 175 Aspergillus isolates from various clinical and environmental sources.

PubMed

Sabino, Raquel; Carolino, Elisabete; Veríssimo, Cristina; Martinez, Marife; Clemons, Karl V; Stevens, David A

2016-10-01

Some environmental Aspergillus spp. isolates have been described as resistant to antifungals, potentially causing an emerging medical problem. In the present work, the antifungal susceptibility profile of 41 clinical and 134 environmental isolates of Aspergillus was determined using the CLSI microdilution method. The aim of this study was to compare environmental and clinical isolates with respect to their susceptibility, and assess the potential implications for therapy of isolates encountered in different environments. To our knowledge, this is the first report comparing antifungal susceptibility profiles of Aspergillus collected from different environmental sources (poultries, swineries, beach sand, and hospital environment). Significant differences were found in the distribution of the different species sections for the different sources. Significant differences were also found in the susceptibility profile of the different Aspergillus sections recovered from the various sources. Clear differences were found between the susceptibility of clinical and environmental isolates for caspofungin, amphotericin B and posaconazole, with clinical isolates showing overall greater susceptibility, except for caspofungin. In comparison to clinical isolates, hospital environmental isolates showed significantly less susceptibility to amphotericin B and posaconazole. These data indicate that species section identity and the site from which the isolate was recovered influence the antifungal susceptibility profile, which may affect initial antifungal choices. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Antifungal susceptibilities of Candida species isolated from urine culture.

PubMed

Toka Özer, Türkan; Durmaz, Süleyman; Yula, Erkan

2016-09-01

Candida spp. are the most common opportunistic mycosis worldwide. Although Candida albicans is the most common cause of urinary tract infections, the frequency of non-albicans Candida species is increasing with common use of antifungal in the prophylaxis and treatment. This may lead to difficulties in treatment. Antifungal tests should be applied with identification of species for effective treatment. In this study, identification of Candida species isolated from urine culture and investigation of susceptibility of these strains to amphotericin B, flucytosine, fluconazole, voriconazole was aimed. In this study, 58 Candida strains isolated from urine cultures at Osmaniye State Hospital between January 2012 and April 2013 were included. Urine culture and antifungal susceptibility tests were applied. Incidence rate of Candida spp. was determined as C. albicans (56.9%), Candida glabrata (20.6%), Candida tropicalis (10.3%), Candida parapsilosis (7%), Candida krusei (3.4%), Candida kefyr (1.8%). Most of the isolates were susceptible to amphotericin B, flucytosine, fluconazole, voriconazole. Twenty three (39.7%) Candida strains were isolated from internal medical branches and Intensive Care Unit and 12 (20.6%) from the Surgical Medical Branches. C. albicans and C. glabrata species were isolated most frequently as a candiduria factor in this hospital between January 2012 and April 2013. The analysis of antifungal susceptibility profile shows no significant resistance to antifungals. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Antifungal activity of eicosanoic acids isolated from the endophytic fungus Mycosphaerella sp. against Cryptococcus neoformans and C. gattii.

PubMed

Pereira, Cristiane Bigatti; Pereira de Sá, Nívea; Borelli, Beatriz Martins; Rosa, Carlos Augusto; Barbeira, Paulo Jorge Sanches; Cota, Betania Barros; Johann, Susana

2016-11-01

The antifungal effects of two eicosanoic acids, 2-amino-3,4-dihydroxy-2-25-(hydroxymethyl)-14-oxo-6,12-eicosenoic acid (compound 1) and myriocin (compound 2), isolated from Mycosphaerella sp. were evaluated against Cryptococcus neoformans and C. gattii. The compounds displayed antifungal activities against several isolates of C. neoformans and C. gattii, with minimal inhibitory concentration (MIC) values ranging from 0.49 to 7.82 μM for compound 1 and 0.48-1.95 μM for compound 2. In the checkerboard microtiter test, both compounds exhibited synergistic activity with amphotericin B against C. gattii. Ultrastructural analysis revealed several signs of damage in C. gattii and C. neoformans cells treated with compounds 1 and 2, including deformities in cell shape, depressions on the surface, and withered cells. The cells of C. gattii treated with compounds 1 and 2 showed less loss of cellular material in comparison to those treated with amphotericin B. The difference in cellular material loss increased in a test compound concentration-dependent manner. Consistent with this observation, compounds 1 and 2 were able to internalize propidium iodide (PI) in C. gattii cells. In addition, compound 2 induced the formation of several pseudohyphae, suggesting that it could reduce virulence in C. gattii cells. The study results show that these natural products led to membrane damage; however, this may not be the main target of action. These compounds have potential antifungal activity and could be useful in further studies for developing more effective combination therapies with amphotericin B and reducing side effects in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antifungal susceptibility testing of Candida species isolated from the immunocompromised patients admitted to ten university hospitals in Iran: comparison of colonizing and infecting isolates.

PubMed

Badiee, Parisa; Badali, Hamid; Boekhout, Teun; Diba, Kambiz; Moghadam, Abdolkarim Ghadimi; Hossaini Nasab, Ali; Jafarian, Hadis; Mohammadi, Rasoul; Mirhendi, Hossein; Najafzadeh, Mohammad Javad; Shamsizadeh, Ahmad; Soltani, Jafar

2017-11-21

Antifungal susceptibility testing is a subject of interest in the field of medical mycology. The aim of the present study were the distributions and antifungal susceptibility patterns of various Candida species isolated from colonized and infected immunocompromised patients admitted to ten university hospitals in Iran. In totally, 846 Candida species were isolated from more than 4000 clinical samples and identified by the API 20 C AUX system. Antifungal susceptibility testing was performed by broth microdilution method according to CLSI. The most frequent Candida species isolated from all patients was Candida albicans (510/846). The epidemiological cutoff value and percentage of wild-type species for amphotericin B and fluconazole in Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei were 0.5 μg/ml (95%) and 4 μg/ml (96%); 1 μg/ml (95%) and 8 μg/ml (95%); 0.5 μg/ml (99%) and 19 μg/ml (98%); and 4 μg/ml (95%) and 64 μg/ml (95%), respectively. The MIC90 and epidemiological cutoff values to posaconazole in Candida krusei were 0.5 μg/ml. There were significant differences between infecting and colonizing isolates of Candida tropicalis in MIC 90 values of amphotericin B, and isolates of Candida glabrata in values of amphotericin B, caspofungin, and voriconazole (P < 0.05). Our findings suggest that the susceptibility patterns of Candida species (colonizing and infecting isolates) in immunocompromised patients are not the same and acquired resistance was seen in some species.

Identification, antifungal susceptibility and scanning electron microscopy of a keratinolytic strain of Rhodotorula mucilaginosa: a primary causative agent of onychomycosis.

PubMed

da Cunha, Marcel M L; dos Santos, Luana P B; Dornelas-Ribeiro, Marcos; Vermelho, Alane B; Rozental, Sonia

2009-04-01

Onychomycosis is a dermatological problem of high prevalence that mainly affects the hallux toenail. Onychomycosis caused by the yeast Rhodotorula mucilaginosa was identified using colony morphology, light microscopy, urease and carbohydrate metabolism in a 57-year-old immunocompetent patient from Rio de Janeiro, Brazil. High-resolution scanning electron microscopy of nail fragments, processed by a noncoating method, led to the observation with fine detail of the structures of both nail and fungus involved in the infection. Yeasts were mainly found inside grooves in the nail. Budding yeasts presented a spiral pattern of growth and blastoconidia were found in the nail groove region. Keratinase assays and keratin enzymography revealed that this isolate was highly capable of degrading keratin. Antifungal susceptibility tests showed that the fungus was susceptible to low concentrations of amphotericin B and 5-flucytosine and resistant to high concentrations of fluconazole, itraconazole, voriconazole and terbinafine. These findings showed data for the first time concerning the interaction of R. mucilaginosa in toenail infection and suggest that this emerging yeast should also be considered an opportunistic primary causative agent of onychomycosis.

Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility.

PubMed Central

Geber, A; Hitchcock, C A; Swartz, J E; Pullen, F S; Marsden, K E; Kwon-Chung, K J; Bennett, J E

1995-01-01

We have cloned and sequenced the structural genes encoding the delta 5,6 sterol desaturase (ERG3 gene) and the 14 alpha-methyl sterol demethylase (ERG11 gene) from Candida glabrata L5 (leu2). Single and double mutants of these genes were created by gene deletion. The phenotypes of these mutants, including sterol profiles, aerobic viabilities, antifungal susceptibilities, and generation times, were studied. Strain L5D (erg3 delta::LEU2) accumulated mainly ergosta-7,22-dien-3 beta-ol, was aerobically viable, and remained susceptible to antifungal agents but had a slower generation time than its parent strain. L5LUD (LEU2 erg11 delta::URA3) strains required medium supplemented with ergosterol and an anaerobic environment for growth. A spontaneous aerobically viable mutant, L5LUD40R (LEU erg11 delta::URA3), obtained from L5LUD (LEU2 erg11 delta::URA3), was found to accumulate lanosterol and obtusifoliol, was resistant to azole antifungal agents, demonstrated some increase in resistance to amphotericin B, and exhibited a 1.86-fold increase in generation time in comparison with L5 (leu2). The double-deletion mutant L5DUD61 (erg3 delta::LEU2 erg11 delta::URA3) was aerobically viable, produced mainly 14 alpha-methyl fecosterol, and had the same antifungal susceptibility pattern as L5LUD40R (LEU2 erg11 delta::URA3), and its generation time was threefold greater than that of L5 (leu2). Northern (RNA) analysis revealed that the single-deletion mutants had a marked increase in message for the undeleted ERG3 and ERG11 genes. These results indicate that differences in antifungal susceptibilities and the restoration of aerobic viability exist between the C. glabrata ergosterol mutants created in this study and those sterol mutants with similar genetic lesions previously reported for Saccharomyces cerevisiae. PMID:8593007

In Vitro Antifungal Susceptibility of Yeast and Mold Phases of Isolates of Dimorphic Fungal Pathogen Emergomyces africanus (Formerly Emmonsia sp.) from HIV-Infected South African Patients.

PubMed

Maphanga, Tsidiso G; Britz, Erika; Zulu, Thokozile G; Mpembe, Ruth S; Naicker, Serisha D; Schwartz, Ilan S; Govender, Nelesh P

2017-06-01

Disseminated emmonsiosis is an important AIDS-related mycosis in South Africa that is caused by Emergomyces africanus , a newly described and renamed dimorphic fungal pathogen. In vitro antifungal susceptibility data can guide management. Identification of invasive clinical isolates was confirmed phenotypically and by sequencing of the internal transcribed spacer region. Yeast and mold phase MICs of fluconazole, voriconazole, itraconazole, posaconazole, caspofungin, anidulafungin, micafungin, and flucytosine were determined with custom-made frozen broth microdilution (BMD) panels in accordance with Clinical and Laboratory Standards Institute recommendations. MICs of amphotericin B, itraconazole, posaconazole, and voriconazole were determined by Etest. Fifty unique E. africanus isolates were tested. The yeast and mold phase geometric mean (GM) BMD and Etest MICs of itraconazole were 0.01 mg/liter. The voriconazole and posaconazole GM BMD MICs were 0.01 mg/liter for both phases, while the GM Etest MICs were 0.001 and 0.002 mg/liter, respectively. The fluconazole GM BMD MICs were 0.18 mg/liter for both phases. The GM Etest MICs of amphotericin B, for the yeast and mold phases were 0.03 and 0.01 mg/liter. The echinocandins and flucytosine had very limited in vitro activity. Treatment and outcome data were available for 37 patients; in a multivariable model including MIC data, only isolation from blood (odds ratio [OR], 8.6; 95% confidence interval [CI], 1.3 to 54.4; P = 0.02) or bone marrow (OR, 12.1; 95% CI, 1.2 to 120.2; P = 0.03) (versus skin biopsy) was associated with death. In vitro susceptibility data support the management of disseminated emmonsiosis with amphotericin B, followed by itraconazole, voriconazole, or posaconazole. Fluconazole was a relatively less potent agent. Copyright © 2017 American Society for Microbiology.

Clinical and microbiological characteristics of Rhodotorula mucilaginosa infections in a tertiary-care facility.

PubMed

Capoor, M R; Aggarwal, S; Raghvan, C; Gupta, D K; Jain, A K; Chaudhary, R

2014-01-01

Rhodotorula spp. are an emergent opportunistic pathogen, particularly in immunocompromised individuals. The aim of the study was to review reported cases of Rhodotorula infection over a period of 9 years to determine epidemiology, risk factors, treatment and outcome. The Rhodotorula spp. were isolated from cerebrospinal fluid (9) and blood (5). The most common pre-disposing factors were prolonged hospital stay (>1 month) and prolonged usage of broad-spectrum antibiotics (>1 month). All the isolates were identified as R. mucilaginosa by conventional methods. Amphotericin B demonstrated lowest minimum inhibitory concentration (MIC) as compared with other anti-fungal agents (fluconazole, itraconazole and voriconazole). The recognition of unusual yeasts as an agent of life-threatening infection and their intrinsic resistance increases the burden on the mycology laboratory for complete species identification and to determine minimum inhibitory concentration.

Small-molecule suppressors of Candida albicans biofilm formation synergistically enhance the antifungal activity of amphotericin B against clinical Candida isolates

PubMed Central

You, Jianlan; Du, Lin; King, Jarrod B.; Hall, Brian E.; Cichewicz, Robert H.

2013-01-01

A new class of fungal biofilm inhibitors represented by shearinines D (3) and E (4) were obtained from a Penicillium sp. isolate. The inhibitory activities of 3 and 4 were characterized using a new imaging flow-cytometer technique, which enabled the rapid phenotypic analysis of Candida albicans cell types (budding yeast cells, germ tube cells, pseudohyphae, and hyphae) in biofilms populations. The results were confirmed by experimental data obtained from three-dimensional confocal laser scanning microscopy and 2,3- bis-(2-methoxy-4- nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) assays. These data indicate that 3 and 4 inhibited C. albicans biofilm formation by blocking the outgrowth of hyphae at a relatively late stage of biofilm development (IC50 = 8.5 μM and 7.6 μM, respectively). However, 3 and 4 demonstrated comparatively weak activity at disrupting existing biofilms. Compounds 3 and 4 also exhibited synergistic activities with amphotericin B against C. albicans and others clinical Candida isolates by enhancing the potency of amphotericin B up to eight-fold against cells in both developing and established biofilms. These data suggest that the Candida biofilm disruption and amphotericin B potentiating effects of 3 and 4 could be mediated through multiple biological targets. The shearinines are good tools for testing the potential advantages of using adjunctive therapies in combination with antifungals. PMID:23387427

[Infective fungal endocarditis in patients with no previous cardiac disease].

PubMed

Marcano Sanz, L; Naranjo Ugalde, A; González Guillén, A; Bermúdez Gutiérrez, G; Frías Griskho, F

2013-02-01

Infective endocarditis is a serious and uncommon condition affecting the endocardium. Less than 10% of these cases are of fungal origin. A growing number of individuals are at high risk, due to insertion of central venous catheters, total parenteral nutrition and prolonged exposure to broad-spectrum antibiotics, even without previous heart diseases. We retrospectively analysed the records of six children with Candida endocarditis, reviewing the comorbidities, clinical outcome, and treatment. The antifungal agents used were amphotericin B, 5-fluorocytosine and fluconazole. Patients underwent surgical excision of vegetation, five tricuspid valve repairs and one mitral valve replacement. There were no hospital deaths, and one child needed a new valvuloplasty one year later. The mean follow up was five years, and all have good valvular function without recurrent endocarditis. A combination of synergistic long-term antifungal treatment and early surgical intervention is recommended. Copyright © 2011 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Rhodotorula fungemia: Report of two cases in Sfax (Tunisia).

PubMed

Guidara, R; Trabelsi, H; Neji, S; Cheikhrouhou, F; Sellami, H; Makni, F; Ayadi, A

2016-06-01

Rhodotorula is emerging as an important cause of nosocomial and opportunistic infections. We present two cases of Rhodotorula mucilaginosa fungemia diagnosed at our hospital during the last decade. The first case was of a term neonate who presented congenital heart disease (interventricular communication) and body dysmorphic disorder. He was admitted for respiratory failure and sepsis. The second case involved in a 33-year-old woman that had Hodgkinien lymphoma associated to tuberculosis. Identification was performed using commercial systems and confirmed by PCR sequencing of internal transcribed spacer, ITS1 and ITS2 regions of rDNA. Antifungal susceptibility tested by sensititre yeast revealed susceptibility to amphotericin B and resistance to fluconazole for the two strains. These cases emphasize the emerging importance of Rhodotorula sp. as a pathogen and it must be considered a potential pathogen in patients with immunosupression and with central venous catheters. Correct identification is mandatory for appropriate management, as Rhodotorula spp. are resistant to antifungal agents, such as fluconazole. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Variability in the clinical distributions of Candida species and the emergence of azole-resistant non-Candida albicans species in public hospitals in the Midwest region of Brazil.

PubMed

Mattos, Karine; Rodrigues, Luana Carbonera; Oliveira, Kelly Mari Pires de; Diniz, Pedro Fernando; Marques, Luiza Inahê; Araujo, Adriana Almeida; Chang, Marilene Rodrigues

2017-01-01

Incidence and antifungal susceptibility of Candida spp. from two teaching public hospitals are described. The minimum inhibitory concentrations of fluconazole, voriconazole, itraconazole, and amphotericin B were determined using Clinical Laboratory Standard Institute broth microdilution and genomic differentiation using PCR. Of 221 Candida isolates, 50.2% were obtained from intensive care unit patients; 71.5% were recovered from urine and 9.1% from bloodstream samples. Candida parapsilosis sensu stricto was the most common candidemia agent. We observed variations in Candida species distribution in hospitals in the same geographic region and documented the emergence of non-C. albicans species resistant to azoles.

Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis.

PubMed

de Melo, Nadja Rodrigues; Abdrahman, Ahmed; Greig, Carolyn; Mukherjee, Krishnendu; Thornton, Catherine; Ratcliffe, Norman A; Vilcinskas, Andreas; Butt, Tariq M

2013-01-01

Candida albicans is a major human pathogen whose treatment is challenging due to antifungal drug toxicity, drug resistance and paucity of antifungal agents available. Myrocin (MYR) inhibits sphingosine synthesis, a precursor of sphingolipids, an important cell membrane and signaling molecule component. MYR also has dual immune suppressive and antifungal properties, potentially modulating mammalian immunity and simultaneously reducing fungal infection risk. Wax moth (Galleria mellonella) larvae, alternatives to mice, were used to establish if MYR suppressed insect immunity and increased survival of C. albicans-infected insects. MYR effects were studied in vivo and in vitro, and compared alone and combined with those of approved antifungal drugs, fluconazole (FLC) and amphotericin B (AMPH). Insect immune defenses failed to inhibit C. albicans with high mortalities. In insects pretreated with the drug followed by C. albicans inoculation, MYR+C. albicans significantly increased mortality to 93% from 67% with C. albicans alone 48 h post-infection whilst AMPH+C. albicans and FLC+C. albicans only showed 26% and 0% mortalities, respectively. MYR combinations with other antifungal drugs in vivo also enhanced larval mortalities, contrasting the synergistic antifungal effect of the MYR+AMPH combination in vitro. MYR treatment influenced immunity and stress management gene expression during C. albicans pathogenesis, modulating transcripts putatively associated with signal transduction/regulation of cytokines, I-kappaB kinase/NF-kappaB cascade, G-protein coupled receptor and inflammation. In contrast, all stress management gene expression was down-regulated in FLC and AMPH pretreated C. albicans-infected insects. Results are discussed with their implications for clinical use of MYR to treat sphingolipid-associated disorders.

Genotyping and In Vitro Antifungal Susceptibility Testing of Fusarium Isolates from Onychomycosis in India.

PubMed

Gupta, Chhavi; Jongman, Marit; Das, Shukla; Snehaa, K; Bhattacharya, S N; Seyedmousavi, S; van Diepeningen, Anne D

2016-08-01

Onychomycosis refers to fungal infection of the nail and is commonly caused by dermatophytes, while yeasts and non-dermatophytic molds (NDM) are increasingly recognized as pathogens in nail infections. The present study was done to delineate molecular epidemiology of Fusarium onychomycosis in India. Five hundred nail samples of Indian patients clinically suspected of onychomycosis were subjected to direct microscopy and fungal culture. Representative Fusarium isolates were further identified to species level by multi-locus sequencing for internal transcribed spacer, translation elongation factor 1 alpha (tef1-α) and RNA polymerase II subunit (rpb2) regions (primer pairs: ITS1/ITS4, EF1/EF2, 5f2/7cr, respectively). These representative strains were also tested for in vitro antifungal susceptibility by the broth microdilution method. Members of the genus Fusarium proved to be the most common NDM responsible for onychomycosis. The Fusarium spp. responsible for onychomycosis belonged to the Fusarium solani species complex (F. keratoplasticum and F. falciforme) and Fusarium fujikuroi species complex (F. proliferatum, F. acutatum and F. sacchari). Antifungal susceptibility results indicated that amphotericin B was the most effective antifungal across all isolates (MIC ranging 0.5-2 mg/L), followed by voriconazole (MIC ranging 1-8 µg/ml). However, a large variation was shown in susceptibility to posaconazole (MIC ranging 0.5 to >16 µg/ml). To conclude, we identified different Fusarium spp. responsible for onychomycosis in India with variation within species in susceptibility to antifungal agents, showing that fusariosis requires correct and prompt diagnosis as well as antifungal susceptibility testing.

In vitro antifungal susceptibility of Trichophyton violaceum isolated from tinea capitis patients.

PubMed

Deng, S; de Hoog, G S; Verweij, P E; Zoll, J; Ilkit, M; Morsali, F; Abliz, P; Wang, X; Zhan, P; Yang, L; Hasimu, H; Liao, W; Pan, W; Seyedmousavi, S

2015-04-01

Trichophyton violaceum is an anthropophilic dermatophyte that is endemic to parts of Africa and Asia and is sporadic in Europe. T. violaceum mainly causes tinea capitis in both children and adolescents. Although the infections caused by T. violaceum are of considerable medical importance, its antifungal susceptibility profile remains poorly examined. In this study, we tested the in vitro antifungal susceptibility of a set of clinical T. violaceum isolates obtained from tinea capitis patients, using the CLSI broth microdilution method. We tested eight antifungals and used isolates collected from Western China (21), Eastern China (12), the Middle East (1), Europe (20), South Africa (7) and Canada (1). The geometric means of the MICs of the antifungals for all isolates were as follows (in increasing order): posaconazole, 0.021 mg/L; terbinafine, 0.023 mg/L; voriconazole, 0.062 mg/L; amphotericin B, 0.20 mg/L; itraconazole, 0.34 mg/L; caspofungin, 0.56 mg/L; fluconazole, 4.23 mg/L; and flucytosine, 8.46 mg/L. No statistically significant differences in the susceptibility profiles of T. violaceum were detected within the geographical regions tested. Posaconazole, terbinafine and voriconazole were shown to be the most potent antifungal agents against T. violaceum isolates obtained from tinea capitis patients worldwide. These results might help clinicians in developing appropriate therapies that have a high probability of successfully treating tinea capitis due to T. violaceum. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Evaluation of antifungal combination against Cryptococcus spp.

PubMed

Reichert-Lima, Franqueline; Busso-Lopes, Ariane F; Lyra, Luzia; Peron, Isabela Haddad; Taguchi, Hideaki; Mikami, Yuzuru; Kamei, Katsuiko; Moretti, Maria Luiza; Schreiber, Angelica Z

2016-09-01

The second cause of death among systemic mycoses, cryptococcosis treatment represents a challenge since that 5-flucytosine is not currently available in Brazil. Looking for alternatives, this study evaluated antifungal agents, alone and combined, correlating susceptibility to genotypes. Eighty Cryptococcus clinical isolates were genotyped by URA5 gene restriction fragment length polymorphism. Antifungal susceptibility was assessed following CLSI-M27A3 for amphotericin (AMB), 5-flucytosine (5FC), fluconazole (FCZ), voriconazole (VRZ), itraconazole (ITZ) and terbinafine (TRB). Drug interaction chequerboard assay evaluated: AMB + 5FC, AMB + FCZ, AMB + TRB and FCZ + TRB. Molecular typing divided isolates into 14 C. deuterogattii (VGII) and C. neoformans isolates were found to belong to genotype VNI (n = 62) and VNII (n = 4). C. neoformans VNII was significantly less susceptible than VNI (P = 0.0407) to AMB; C. deuterogattii was significantly less susceptible than VNI and VNII to VRZ (P < 0.0001). C. deuterogattii was less susceptible than C. neoformans VNI for FCZ (P = 0.0170), ITZ (P < 0.0001) and TRB (P = 0.0090). The combination FCZ + TRB showed 95.16% of synergistic effect against C. neoformans genotype VNI isolates and all combinations showed 100% of synergism against genotype VNII isolates, suggesting the relevance of cryptococcal genotyping as it is widely known that the various genotypes (now species) have significant impact in antifungal susceptibilities and clinical outcome. In difficult-to-treat cryptococcosis, terbinafine and different antifungal combinations might be alternatives to 5FC. © 2016 Blackwell Verlag GmbH.

Candida profiles and antifungal resistance evolution over a decade in Lebanon.

PubMed

Araj, George Farah; Asmar, Rima George; Avedissian, Aline Zakaria

2015-09-27

Infection with and antifungal resistance of Candida species have been on the rise globally. Relevant data on these pathogens are relatively few in our region, including Lebanon, thus warranting this study. This retrospective study of Candida spp. profiles and their in vitro antifungal susceptibility was based on analysis requests for 186 Candida non-albicans and 61 C. albicans during three periods (2005-2007, 2009-2011, and 2012-2014) over the span of the last 10 years at the American University of Beirut Medical Center (AUBMC), a major tertiary care center in Lebanon. Identification of Candida was done using the API 20C AUX system, and the E-test was used to determine the minimum inhibitory concentrations (MICs) of antifungal agents. Among the 1,300-1,500 Candida isolates recovered yearly, C. albicans rates decreased from 86% in 2005 to around 60% in 2014. Simultaneously, the non-albicans rates increased from 14% in 2005 to around 40% in 2014, revealing 11 species, the most frequent of which were C. tropicalis, C. glabrata, and C. parapsilosis. All these demonstrated high resistance (35%-79%) against itraconazole, but remained uniformly susceptible (100%) to amphotericin B. Though C. albicans and the other species maintained high susceptibility against fluconazole and voriconazole, their MIC90 showed an elevated trend over time, and C. glabrata had the highest resistance rates. The observed rise in resistance among Candida spp. in Lebanon mandates the need for close surveillance and monitoring of antifungal drug resistance for both epidemiologic and treatment purposes.

Fungemia Due to Fusarium sacchari in an Immunosuppressed Patient

PubMed Central

Guarro, Josep; Nucci, Marcio; Akiti, Tiyomi; Gené, Josepa; Barreiro, M. Da Gloria C.; Gonçalves, Renato T.

2000-01-01

The fungus Fusarium sacchari was isolated repeatedly from the blood of an immunosuppressed host. The infection was treated successfully with a small dose of amphotericin B. The strain was resistant to this antifungal in vitro. MICs and minimum fungicidal concentrations of six antifungals for the clinical isolate are provided. To our knowledge, this is the first report involving this fungus in a case of fungemia. PMID:10618130

Etest Cannot Be Recommended for In Vitro Susceptibility Testing of Mucorales

PubMed Central

Caramalho, Rita; Maurer, Elisabeth; Binder, Ulrike; Araújo, Ricardo; Dolatabadi, Somayeh; Lass-Flörl, Cornelia

2015-01-01

Amphotericin B and posaconazole susceptibility patterns were determined for the most prevalent Mucorales, following EUCAST (European Committee on Antimicrobial Susceptibility Testing) broth microdilution guidelines. In parallel, Etest was performed and evaluated against EUCAST. The overall agreement of MICs gained with Etest and EUCAST was 75.1%; therefore, Etest cannot be recommended for antifungal susceptibility testing of Mucorales. Amphotericin B was the most active drug against Mucorales species in vitro, while the activities of posaconazole were more restricted. PMID:25845881

Determination of antifungal activities in serum samples from mice treated with different antifungal drugs allows detection of an active metabolite of itraconazole.

PubMed

Maki, Katsuyuki; Watabe, Etsuko; Iguchi, Yumi; Nakamura, Hideko; Tomishima, Masaki; Ohki, Hidenori; Yamada, Akira; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

2006-01-01

To establish an in vitro method of predicting in vivo efficacy of antifungal drugs against Candida albicans and Aspergillus fumigatus, the antifungal activities of fluconazole, itraconazole, and amphotericin B were determined in mouse serum. The minimum inhibitory concentration (MIC) of each drug was measured using mouse serum as a diluent. For C. albicans, the assay endpoint of azoles was defined as inhibition of mycelial extension (mMIC) and for A. fumigatus, as no growth (MIC). The MICs of amphotericin B for both pathogens were defined as the MIC at which no mycelial growth occurred. Serum MIC or mMIC determinations were then used to estimate the concentration of the drugs in serum of mice treated with antifungal drugs by multiplying the antifungal titer of the serum samples by the serum (m)MIC. The serum drug concentrations were also determined by HPLC. The serum concentrations estimated microbiologically showed good agreement with those determined by HPLC, except for itraconazole. Analysis of the serum samples from itraconazole-treated mice by a sensitive bioautography revealed the presence of additional spots, not seen in control samples of itraconazole. The bioautography assay demonstrated that the additional material detected in serum from mice treated with itraconazole was an active metabolite of itraconazole. The data showed that the apparent reduction in the itraconazole serum concentration as determined by HPLC was the result of the formation of an active metabolite, and that the use of a microbiological method to measure serum concentrations of drugs can provide a method for prediction of in vivo efficacy of antifungal drugs.

Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis

PubMed Central

2014-01-01

Background Sporotrichosis is a chronic subcutaneous mycosis of humans and animals, which is typically acquired by traumatic inoculation of plant material contaminated with Sporothrix propagules, or via animals, mainly felines. Sporothrix infections notably occur in outbreaks, with large epidemics currently taking place in southeastern Brazil and northeastern China. Pathogenic species include Sporothrix brasiliensis, Sporothrix schenckii s. str., Sporothrix globosa, and Sporothrix luriei, which exhibit differing geographical distribution, virulence, and resistance to antifungals. The phylogenetically remote species Sporothrix mexicana also shows a mild pathogenic potential. Methods We assessed a genetically diverse panel of 68 strains. Susceptibility profiles of medically important Sporothrix species were evaluated by measuring the MICs and MFCs for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), posaconazole (PCZ), flucytosine (5FC), and caspofungin (CAS). Haplotype networks were constructed to reveal interspecific divergences within clinical Sporothrix species to evaluate genetically deviant isolates. Results ITC and PCZ were moderately effective against S. brasiliensis (MIC90 = 2 and 2 μg/mL, respectively) and S. schenckii (MIC90 = 4 and 2 μg/mL, respectively). PCZ also showed low MICs against the rare species S. mexicana. 5FC, CAS, and FLC showed no antifungal activity against any Sporothrix species. The minimum fungicidal concentration ranged from 2 to >16 μg/mL for AMB against S. brasiliensis and S. schenckii, while the MFC90 was >16 μg/mL for ITC, VRC, and PCZ. Conclusion Sporothrix species in general showed high degrees of resistance against antifungals. Evaluating a genetically diverse panel of strains revealed evidence of multidrug resistant phenotypes, underlining the need for molecular identification of etiologic agents to predict therapeutic outcome. PMID:24755107

Oral Candida in Patients with Fixed Orthodontic Appliance: In Vitro Combination Therapy.

PubMed

Alhamadi, Wisam; Al-Saigh, Rafal J; Al-Dabagh, Nebras N; Al-Humadi, Hussam W

2017-01-01

Fixed orthodontic appliance (FOA) increases the cariogenic microorganisms of mouth including candida. The aim was to evaluate the pharmacodynamic effects of some antibacterial drugs in combination with most applicable antifungal agents on candida isolated from patients with FOA. Three antifungal agents (amphotericin B (AMB), ketoconazole (KET), and itraconazole (ITZ)) and three antibacterial drugs (ciprofloxacin (CIP), doxycycline (DOX), and metronidazole (MET)) with serial concentrations have been used and microdilution broth method has been done for single and combination therapy, then fungal growth was assessed spectrophotometrically, and the combinations were evaluated by bliss independent analysis. According to bliss independent interaction, the synergistic interactions depended on Δ E values that showed the best for CIP was with AMB (Δ E = 55.14) followed with KET (Δ E = 41.23) and lastly ITR (Δ E = 39.67) at CIP = 150 mg/L. DOX was optimal with KET (Δ E = 42.11) followed with AMB (Δ E = 40.77) and the lowest with ITR (Δ E = 9.12) at DOX = 75 mg/L. MET is the best with AMB (Δ E = 40.95) and then with ITR (Δ E = 35.45) and finally KET (Δ E = 15.15) at MET 200 mg/L. Moreover, usage of higher concentrations of antibacterial agents revealed inhibitory effects. This study uncovers the optimum antibiotic combination therapy against cariogenic candida with FOA by usage of low therapeutic concentrations.

Combination Antifungal Therapy for Cryptococcal Meningitis

PubMed Central

Day, Jeremy N.; Chau, Tran T.H.; Wolbers, Marcel; Mai, Pham P.; Dung, Nguyen T.; Mai, Nguyen H.; Phu, Nguyen H.; Nghia, Ho D.; Phong, Nguyen D.; Thai, Cao Q.; Thai, Le H.; Chuong, Ly V.; Sinh, Dinh X.; Duong, Van A.; Hoang, Thu N.; Diep, Pham T.; Campbell, James I.; Sieu, Tran P.M.; Baker, Stephen G.; Chau, Nguyen V.V.; Hien, Tran T.

2014-01-01

BACKGROUND Combination antifungal therapy (amphotericin B deoxycholate and flucytosine) is the recommended treatment for cryptococcal meningitis but has not been shown to reduce mortality, as compared with amphotericin B alone. We performed a randomized, controlled trial to determine whether combining flucytosine or high-dose fluconazole with high-dose amphotericin B improved survival at 14 and 70 days. METHODS We conducted a randomized, three-group, open-label trial of induction therapy for cryptococcal meningitis in patients with human immunodeficiency virus infection. All patients received amphotericin B at a dose of 1 mg per kilogram of body weight per day; patients in group 1 were treated for 4 weeks, and those in groups 2 and 3 for 2 weeks. Patients in group 2 concurrently received flucytosine at a dose of 100 mg per kilogram per day for 2 weeks, and those in group 3 concurrently received fluconazole at a dose of 400 mg twice daily for 2 weeks. RESULTS A total of 299 patients were enrolled. Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P = 0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P<0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy. CONCLUSIONS Amphotericin B plus flucytosine, as compared with amphotericin B alone, is associated with improved survival among patients with cryptococcal meningitis. A survival benefit of amphotericin B plus fluconazole was not found. (Funded by the Wellcome Trust and the British Infection Society; Controlled-Trials.com number, ISRCTN95123928.) PMID:23550668

[A case of chronic mucocutaneous candidasis cured with micafungin].

PubMed

Suzuki, Tomokazu; Imamura, Akifumi

2005-02-01

Chronic mucocutaneous candidasis (CMC) is a chronic intractable infection of skin, nails, and mucous membrane with Candida. Until very recently, the main stay of therapy had been the use of transfer factor or antifungal azole derivatives. Although they show definite benefits, the effects are temporal and recurrences are inevitable. Furthermore, the prolonged use of antifungals will sometimes induce resistant strains, making the treatment more difficult. Recently we experienced a case of CMC caused by resistant Candida spp. and treated it successfully with a new antifungal agent, micafungin (MCFG). The patient is a 37-year-old woman. She was eight month, her tongue was covered with a white coat. Two months later, intractable cutaneous eruptions appeared on the head and back and the diagnosis of CMC was made. Since then she has been treated on multiple occasions with transfer factor, recombinant IL-2, ketoconazole or clotrimazole. She was referred to us because of esophageal candidiasis. On admission, oral and esophageal mucous membranes were thickly coated with white pseudomembranes. The titer of Candida antigen test was less than twice ; plasma beta-D-gulcan was 20.14 pg/mL ; and CD4 was 376/microL. A few Candida albicans and (1+) Candida glabrata were cultured from oral swab. Both species were resistant to itraconazole but sensitive to MCFG and amphotericin B (MIC: < 0.03microg/ml for both). A drip infusion of MCFG (75mg/day) was started and three days later the oral lesions disappeared. At the end of a 2-week course of i. v. MCFG, the interior of the esophagus was clear. No recurrence was noted in one month. Less toxic than amphotericin B, MCFG will be a drug of choice in patients infected with azole-resistant fungi. To avoid the abuse of MCFG and the development of the resistant strains, the susceptibility test is recommended in every case of systemic candidiasis.

Frequent detection of ‘azole’ resistant Candida species among late presenting AIDS patients in northwest Ethiopia

PubMed Central

2013-01-01

Background The chronic use of antifungal agents in the treatment of fungal infection in general and oropharyngeal candidiasis mainly in AIDS patient’s leads to the selection of strain resistant to these therapies and a shift in the spectrum of Candida species. This study determines the species diversity and in vitro susceptibility of Candida isolates from late presenting AIDS patients in northwest Ethiopia. Methods Two hundred and twenty one HIV/AIDS patients were assessed with a standardized evaluation form at enrolment. Oral rinses were cultured on CHROMagar plates at 37°C for 48 hours and Candida species identification were made following standard microbiological techniques. In vitro drug susceptibility tests were made using broth microdilution method. Results The colonization rate of Candida species was found to be 82.3% (177/215). C. albicans was the predominant species isolated from 139 (81%) patients but there was a diversity of other species. C. glabrata was the most frequent non-albicans species isolated in 22.5% (40/177) of the patients followed by C. tropicalis 14.1% (27/177), C. krusei 5.6% (10) and other unidentifiable Candida species 4% (7/177). Recurrent episodes of oropharyngeal candidiasis and previous exposure to antifungal drugs were found to be predisposing factors for colonization by non-albicans species. Irrespective of the Candida species identified 12.2% (11/90), 7.7% (7/90) and 4.7% (4) of the isolates were resistant to fluconazole, ketoconazole and itraconazole, respectively. In contrast, resistance to micafungin, amphotericin B and 5-Fluorocytosine was infrequent. Conclusion HIV/AIDS patients are orally colonized by single or multiple albicans and non- albicans Candida species that are frequently resistant to azoles and occasionally to amphotericin B, 5-Fluorocytosine and micafungin. These highlight the need for national surveillance for examining Candida epidemiology and resistance to antifungal drugs. PMID:23398783

[Treatment approach for fungal infections in critically ill patients admitted to intensive care units: results of a multicenter survey].

PubMed

Alvarez-Lerma, Francisco; Nolla, Joan; Palomar, Mercedes; León, María A

2003-02-01

Two consensus conferences taking place in the United States and Spain were organized to optimize diagnosis and treatment of Candida spp. infections. Among other results, clinical scenarios in which early prescription of antifungal agents is indicated were identified. To determine the criteria followed by physicians for prescribing antifungal agents in critically ill patients in our country and to investigate adherence to the guidelines proposed by the consensus conferences. A questionnaire was designed and directed to 4th- and 5th-year residents in intensive care medicine and to specialists in intensive care with training in infectious diseases or other medical areas. Four case reports for which expert consensus indicates early antifungal treatment were included in the questionnaire; 1) recurrent peritonitis secondary to perforation of the digestive tract, with mixed flora including fungi; 2) persistent febrile syndrome in a patient with multiple mucosal fungal colonizations treated with broad-spectrum antibiotics; 3) candiduria and pyuria in a febrile patient; and 4) candidemia. A total of 135 questionnaires from 45 different ICUs were returned (60% response rate). In the candidemia and fungal peritonitis examples, early treatment with antifungal agents was indicated in 100% and 85.9% of responses, respectively, whereas for sepsis with multifocal candidiasis and candiduria associated with pyuria and fever, early treatment was prescribed in only 41.5% and 55.6% of responses, respectively. There were no significant differences in response with regard to degree of training of the physicians surveyed. Fluconazole prescription predominated, mainly at doses of 400 mg/day, in mixed peritonitis, disseminated candidiasis and candiduria, whereas amphotericin B lipid formulations were preferentially indicated in cases of candidemia. Antifungal treatment (early or late) was prescribed in all responses for candidemia, in 95.5% for mixed peritonitis (fungi and bacteria), in 79.5% for multifocal candidiasis in patients with persistent sepsis, and in 77.9% for candiduria with fever and pyuria. Adherence to recommendations from the consensus conferences was high among intensive medicine specialists, with no differences according to level of training in infectious diseases.

Role of humoral mediators in, and influence of a liposomal formulation on, acute amphotericin B nephrotoxicity.

PubMed

Sabra, R; Zeinoun, N; Sharaf, L H; Ghali, R; Beshara, G; Serhal, H

2001-04-01

The mechanisms responsible for amphotericin B nephrotoxicity remain incompletely understood, but clearly involve reduction in renal blood flow and glomerular filtration rate. Both direct effects of amphotericin B on contractile vascular cells, and indirect effects, due to humoural mediators, have been proposed. This study examines the role of nitric oxide, endothelin and angiotensin II in the acute nephrotoxic effects of amphotericin B in rats, and compares the anti-fungal and nephrotoxic effects of liposomal amphotericin B and amphotericin B-deoxycholate. Anaesthetized rats were given infusions of amphotericin B-deoxycholate in the presence or absence of N-nitro-L-arginine, PD 145065, a non-specific endothelin receptor antagonist, and L-158809, an angiotensin II type I receptor antagonist, or increasing doses of liposomal amphotericin B. Amphotericin B-deoxycholate (0.03 mg/kg/min intravenously) caused a significant 44% reduction in glomerular filtration rate and 65% maximal fall in renal blood flow. N-Nitro-L-arginine-treated rats had a lower renal blood flow and glomerular filtration rate at baseline, but sustained similar reduction of 53% and 75% in these parameters, respectively. PD145065 and L-158809 did not modify these effects either. Increasing doses of liposomal amphotericin B (from 0.01 up to 0.50 mg/kg/min.) induced no change in either glomerular filtration rate or renal blood flow. In vitro susceptibility tests revealed similar potency for liposomal amphotericin B and amphotericin B-deoxycholate in their fungistatic effects and slightly higher potency for amphotericin B-deoxycholate in their fungicidal effect. These results suggest that endogenous endothelin, angiotensin II or nitric oxide systems are not involved in the nephrotoxic effects of amphotericin B. The liposomal amphotericin B results suggest that amphotericin B nephrotoxicity is due to a direct interaction of amphotericin B with renal cells that is prevented by its encapsulation in liposomes.

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation

PubMed Central

Alvarez, Celeste; Andes, David R.; Kang, Jeong Yeon; Krug, Carmen; Kwon, Glen S.

2017-01-01

Purpose Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination’s activity against Candida albicans. Methods We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 hours. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. Results The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. Conclusions Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy. PMID:28205003

Antifungal Efficacy of an Intravenous Formulation Containing Monomeric Amphotericin B, 5-Fluorocytosine, and Saline for Sodium Supplementation.

PubMed

Alvarez, Celeste; Andes, David R; Kang, Jeong Yeon; Krug, Carmen; Kwon, Glen S

2017-05-01

Amphotericin B (AmB) and 5-fluorocytosine (5-FC) exhibit additive to synergistic activity against systemic mycoses. Incompatibility of prescribed formulations precludes concomitant IV administration, a route with distinct advantages. Previously, we used PEG-DSPE micelles to produce a reformulation of Fungizone (AmB-SD), AmB solubilized by sodium deoxycholate, called mAmB-90. Herein, we describe a second reformulation that facilitates co-delivery of mAmB-90 and 5-FC, and evaluate the effect of PEG-DSPE micelles on the combination's activity against Candida albicans. We assessed the effect of 5-FC addition on the stability, in vitro toxicity, and antifungal efficacy of mAmB-90. The aggregation state and particle size of mAmB-90 combined with 5-FC (FmAmB-90) was evaluated over 48 h. Hemolytic activity was measured in vitro. Antifungal activity was determined in vitro against C. albicans. The efficacy of monotherapy and combination treatment was evaluated in a neutropenic mouse model of disseminated candidiasis. The aggregation state, particle size, and hemolytic activity of mAmB-90 were unaffected by 5-FC. While antifungal activity was similar in vitro, mAmB-90 alone and combined with 5-FC was more potent than AmB-SD in vivo. Short-term stability and in vivo efficacy of our formulation suggest potential to simultaneously deliver AmB and 5-FC for potent antifungal efficacy.

Silver nanoparticles from Pilimelia columellifera subsp. pallida SL19 strain demonstrated antifungal activity against fungi causing superficial mycoses.

PubMed

Wypij, Magdalena; Czarnecka, Joanna; Dahm, Hanna; Rai, Mahendra; Golinska, Patrycja

2017-09-01

In this study, we present the in vitro antifungal activity of silver nanoparticles (AgNPs) synthesized from acidophilic actinobacterium Pilimelia columellifera subsp. pallida SL19 strain, alone and in combination with antibiotics viz., amphotericin B, fluconazole, and ketoconazole against pathogenic fungi, namely Candida albicans, Malassezia furfur, and Trichophyton erinacei. The minimum inhibitory concentration (MIC) and minimum biocidal concentration (MBC) of AgNPs against test fungi were evaluated. The fractional inhibitory concentration (FIC) index was determined to estimate antifungal activity of AgNPs combined with antibiotics. Antifungal activity of AgNPs varied among the tested fungal strains. M. furfur was found to be most sensitive to biogenic silver nanoparticles, followed by C. albicans and T. erinacei. The lowest MIC of AgNPs was noticed against M. furfur (16 μg ml -1 ). Synergistic effect was observed on C. albicans when AgNP were combined with amphotericin B and ketoconazole and on M. furfur with fluconazole and ketoconazole (FIC index of 0.5). Cytotoxic effect of AgNPs on HeLa and 3T3 cell lines was evaluated. The IC 50 values were found to be 55 and 25 μg ml -1 , respectively. The present study indicates that silver nanoparticles from P. columellifera subsp. pallida SL19 strain have antifungal activity, both alone and in combination with antibiotics, and offer a valuable contribution to nanomedicine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Asarones from Acorus calamus in combination with azoles and amphotericin B: a novel synergistic combination to compete against human pathogenic Candida species in vitro.

PubMed

Kumar, S Nishanth; Aravind, S R; Sreelekha, T T; Jacob, Jubi; Kumar, B S Dileep

2015-04-01

The increase in drug resistance to current antifungal drugs brings enormous challenges to the management of Candida infection. Therefore, there is a continuous need for the discovery of new antimicrobial agents that are effective against Candida infections especially from natural source especially from medical plants. The present investigation describes the synergistic anticandidal activity of two asarones (∞ and β) purified from Acorus calamus in combination with three clinically used antifungal drugs (fluconazole, clotrimazole, and amphotericin B). The synergistic anticandidal activities of asarones and drugs were assessed using the checkerboard microdilution and time-kill assays. The results of the present study showed that the combined effects of asarones and drugs principally recorded substantial synergistic activity (fractional inhibitory concentration index (FICI) <0.5). Time-kill study by combination of the minimal inhibitory concentration (MIC) of asarones and drugs (1:1) recorded that the growth of the Candida species was significantly arrested between 0 and 2 h and almost completely attenuated between 2 and 6 h of treatment. These findings have potential implications in adjourning the development of resistance as the anticandidal activity is achieved with lower concentrations of asarones and drugs. The combination of asarones and drugs also significantly inhibit the biofilm formation by Candida species, and this would also help to fight against drug resistance because biofilms formed by Candida species are ubiquitous in nature and are characterized by their recalcitrance toward antimicrobial treatment. The in vitro synergistic activity of asarones and drugs against pathogenic Candida species is reported here for the first time.

[Activity of amphotericin B and anidulafungin, alone and combined, against Candida tropicalis biofilms developed on Teflon® and titanium].

PubMed

Fernández-Rivero, Marcelo Ernesto; Del Pozo, José L; Valentín, Amparo; Fornes, Victoria; Molina de Diego, Araceli; Pemán, Javier; Cantón, Emilia

Current therapeutic strategies have a limited efficacy against Candida biofilms that form on the surfaces of biomedical devices. Few studies have evaluated the activity of antifungal agents against Candida tropicalis biofilms. To evaluate the activity of amphotericin B (AMB) and anidulafungin (AND), alone and in combination, against C. tropicalis biofilms developed on polytetrafluoroethylene (teflon -PTFE) and titanium surfaces using time-kill assays. Assays were performed using the CDC Biofilm Reactor equipped with PTFE and titanium disks with C. tropicalis biofilms after 24h of maturation. The concentrations assayed were 40mg/l for AMB and 8mg/l for AND, both alone and combined. After 24, 48 and 72h of exposure to the antifungals, the cfu/cm 2 was determined by a vortexing-sonication procedure. AMB reduced biofilm viable cells attached to PTFE and titanium by ≥99% and AND by 89.3% on PTFE and 96.8% on titanium. The AMB+AND combination was less active than AMB alone, both on PTFE (decrease of cfu/cm 2 3.09 Log 10 vs. 1.08 when combined) and titanium (4.51 vs. 1.53 when combined), being the interaction irrelevant on both surfaces. AMB is more active than AND against C. tropicalis biofilms. Yeast killing rates are higher on titanium than on PTFE surfaces. The combination of AMB plus AND is less effective than AMB alone on both surfaces. Copyright © 2017 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Amphotericin B releasing topical nanoemulsion for the treatment of candidiasis and aspergillosis.

PubMed

Sosa, Lilian; Clares, Beatriz; Alvarado, Helen L; Bozal, Nuria; Domenech, Oscar; Calpena, Ana C

2017-10-01

The present study was designed to develop a nanoemulsion formulation of Amphotericin B (AmB) for the treatment of skin candidiasis and aspergillosis. Several ingredients were selected on the basis of AmB solubility and compatibility with skin. The formulation that exhibited the best properties was selected from the pseudo-ternary phase diagram. After physicochemical characterization its stability was assessed. Drug release and skin permeation studies were also accomplished. The antifungal efficacy and skin tolerability of developed AmB nanoemulsion was demonstrated. Finally, our results showed that the developed AmB formulation could provide an effective local antifungal effect without theoretical systemic absorption, based on its skin retention capacity, which might avoid related side effect. These results suggested that the nanoemulsion may be an optimal therapeutic alternative for the treatment of skin fungal infections with AmB. Copyright © 2017 Elsevier Inc. All rights reserved.

[INVESTIGATION ON ANTIFUNGAL SUSCEPTIBILITY OF CANDIDA YEASTS IN PREGNANT PATIENTS WITH CONFIRMED VULVOVAGINAL CANDIDIASIS AND THEIR NEWBORNS.

PubMed

Chokoeva, A; Kouzmanov, A; Ivanova, Z; Zisova, L; Amalie, G; Petleshkova, P; Miteva-Katrandzhieva, Ts; Krasteva, M; Uchikova, E

Background Vulvovaginal candidiasis (VVU) is considered as a special risk factor during pregnancy, with important influence on the reproductive function of the patients and on the morbidity in the newborns from mothers with VVC. Maternal VVC is a major risk factor for the development of candida-colonization of the infant, which in turn is the first step towards the development of mucocutaneous or systemic candidiasis and Candida-septicemia in the newborn. In pregnant patients, the possible applicable local and systemic medications are limited, while the therapeutic resistance in chronic recurrent forms of VVC increases, facts that require precision of the diagnosic approach to optimize the therapeutic recommendations in pregnant patients, considered as a high risk group. The aim of this study was to investigate in vitro antifungal susceptibility of Candida yeasts to current antifungal agents in pregnant patients with confirmed VVC before the act of birth. Material and Methods Vaginal secretions of 23 healthy pregnant women with proven Candida vaginitis were taken within 48 hours before birth and the presence of yeasls of Candida was confirmed by culture examination. Between 47-72 hours after birth, samples were taken for Candida colonization of the oralmucosa and feces of their newborns. Samples were plated on Sabouraud agar and cultured in an incubator for 2 to 3 days at a temperature of 25° C. Species identification of the isolated yeasts were performed by commercial API Candida test - API 20C AUX (BioMerieux, Marcy-l'Etoile, France). Part of the isolates was identified by commercial whale AUXACOLOR (BioRad, Mames la Coquette, France). Antifungal sensitivity of isolated strains was examined by applying commercial solicitation ready kit and methods of disc diffusion and E-test, as the aim of the authors was to assess their potential for use in the diagnosis, and the correlation between them. Results Candida albicans was the prevalent etiological agent in pregnant patients with VVC immediately before birth (n = 22, 91.67 +/- 0.06%). Positive Candida colonization was detected in 14 (58.33%) of their newborns (n = 24), as no statistically significant difference was established, depending on the mode of delivery. The investigated antifungal susceptibility with test Fungifast (ELITech Microbiology Reagents), found 100% sensitivity of Candida albicans to Amphotericin B, Flucytosin and Voriconazole. Intermediate susceptibility to Itraconazole was found in 6 of 23 (26%) maternal isolates, and 5 of 23 (22%) isolates were moderately sensitive to Fluconazole. Candida krusei showed complete resistance to Fluconazole and Itraconazole. Within the group of antifungals for topical application (Econazole, Ketoconazole, Miconazole, Nystatin), the results established that 100% of the studied fungi were sensitive to Nystatin, while within the groups of azoles for vaginal and topical use - C.krusei was 100% resistant, as the sensitivity of C. albicans varied between 60-80%. Conclusion Our recommendation, based on the esablished results is that in pregnant with uncomplicated VVC as a first-line therapy should be considered the group of vaginal azoles and Nystatin, while the systemic therapy should be considered carefully and only after the firSt trimester. In cases of oral and intestinal candidiasis in neonatology, we recommend a therapy with minimal absorbable antifungals as Nystatin and miconazole (amphotericin B is available in our country), while systemic antifungal should be initiated only as a second choice. The exact etiological diagnosis is especially important because in our country there is a tendency for increased incidence of non-albicans fungus resistant to therapy, and that changes the therapeutic behavior.

Amphotericin B Injection

MedlinePlus

... antifungals. It works by slowing the growth of fungi that cause infection. ... may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

[Activity of butenafine against ocular pathogenic filamentous fungi in vitro].

PubMed

Xu, Yan; Pang, Guang-ren; Zhao, Dong-qing; Gao, Chuan-wen; Zhou, Lu-tan; Sun, Sheng-tao; Wang, Bing-liang; Chen, Zu-ji

2010-01-01

To investigate antifungal activity of butenafine in comparison with that of natamycin, amphotericin B and fluconazole against ocular pathogenic filamentous fungi in vitro. It was an experimental study. Susceptibility tests were performed against 260 isolates of ocular pathogenic filamentous fungi by broth dilution antifungal susceptibility test of filamentous fungi approved by the Clinical and Laboratory Standards Institute (CLSI) M38-A document. The isolates included Fusarium spp. (136), Aspergillus spp. (98), Alternaria alternata (9), Curvularia lunata (3), and unusual ocular pathogens (14). Final concentration ranged from 0.008 to 16.000 mg/L for butenafine, from 0.031 to 16.000 mg/L for amphotericin B and natamycin, and from 0.5 to 256.0 mg/L for fluconazole. Following incubation at 35 degrees C for 48 h, minimal inhibitory concentration (MIC) was determined according to the CLSI M38-A document. For amphotericin B and natamycin, the MIC was defined as the lowest drug concentration that prevented any discernible growth. For butenafine and fluconazole, the MIC was defined as the lowest concentration in which an approximately 75% reduction compared to the growth of the control was observed. Candida parapsilosis ATCC22019 was used as quality control strains to validated the results. Mean MIC and MIC range, the MIC at which 50% of the isolates tested were inhibited (MIC(50)) and the MIC at which 90% of the isolates tested were inhibited (MIC(90)), were provided for all the isolates tested by using descriptive statistical analysis with the statistical SPSS package (version 13.0). MIC(90) of butenafine, natamycin, amphotericin B and fluconazole were 4, 8, 2 and 512 mg/L for Fusarium spp., respectively; 0.063, 32.000, 2.000 and 256.000 mg/L for Aspergillus spp., respectively; 0.5, 8.0, 2.0 and 128.0 mg/L for Alternaria alternate, respectively; 0.125, 2.000, 0.500 and 4.000 mg/L for Curvularia lunata, respectively; and 1, 4, 1 and 256 mg/L for unusual ocular pathogens, respectively. Butenafine exhibits potent antifungal activity against a wide variety of ocular pathogenic fungi, especially for Aspergillus spp., Alternaria alternata, Curvularia lunata, and some unusual ocular pathogens and may have a role in future studies of antifungal eye drops and treating fungal keratitis.

Coccidioidomycosis.

PubMed Central

Galgiani, J N

1993-01-01

Coccidioidomycosis is a systemic fungal infection endemic to the southwestern United States and other parts of the western hemisphere. Although producing a wide range of disorders in healthy persons, immunosuppression predisposes to especially severe disease. Thus, a knowledge of the pathogenesis of coccidioidal infections and its relation to the normal immune responses is useful to understand the diversity of problems that Coccidioides immitis may cause. Diagnosis usually requires laboratory studies such as fungal culture or specific serologic testing. Fortunately, many patients do not need to be treated for the infection to resolve. Therapy for the more severe forms of coccidioidal infection was once limited to amphotericin B but now includes azole antifungal agents. These expanded alternatives now require physicians to weigh many factors in determining the best management for specific patients. Images PMID:8212681

Targeting nanodisks via a single chain variable antibody--apolipoprotein chimera.

PubMed

Iovannisci, David M; Beckstead, Jennifer A; Ryan, Robert O

2009-02-06

Nanodisks (ND) are nanometer scale complexes of phospholipid and apolipoprotein that have been shown to function as drug delivery vehicles. ND harboring significant quantities of the antifungal agent, amphotericin B, or the bioactive isoprenoid, all trans retinoic acid, have been generated and characterized. As currently formulated, ND possess limited targeting capability. In this study, we constructed a single chain variable antibody (scFv).apolipoprotein chimera and assessed the ability of this fusion protein to form ND and recognize the antigen to which the scFv is directed. Data obtained revealed that alpha-vimentin scFv.apolipoprotein A-I is functional in ND formation and antigen recognition, opening the door to the use of such chimeras in targeting drug-enriched ND to specific tissues.

Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy.

PubMed

Mattiuzzi, Gloria N; Kantarjian, Hagop; Faderl, Stefan; Lim, JoAnn; Kontoyiannis, Dimitrios; Thomas, Deborah; Wierda, William; Raad, Isaam; Garcia-Manero, Guillermo; Zhou, Xian; Ferrajoli, Alexandra; Bekele, Nebiyou; Estey, Elihu

2004-02-01

The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population. Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.5 mg/kg intravenously 3 times weekly. This treatment group was compared with a historical control group that had similar baseline characteristics and received prophylactic liposomal amphotericin B (L-AmB) 3 mg/kg 3 times weekly. The primary endpoint was the incidence of documented or suspected fungal infections during and up to 4 weeks after cessation of prophylaxis. Reported adverse events were used to assess tolerability. The overall efficacy of antifungal prophylaxis was similar in patients who received ABLC and patients who received L-AmB (P=0.95). Among 131 ABLC-treated patients and 70 L-AmB-treated patients who were assessed for efficacy and safety, 49% of patients in each group completed therapy without developing a documented or suspected fungal infection. Documented fungal infections occurred in 5% of ABLC-treated patients and in 4% of L-AmB-treated patients. Alternative antifungal strategies were required because of persistent fever or pneumonia of unknown pathogen in 28% and 32% of ABLC-treated and L-AmB-treated patients, respectively. Grade 3 and 4 adverse events, therapy discontinuations due to adverse events, and survival rates also were similar between treatment groups. ABLC and L-AmB appeared to have similar efficacy and were tolerated well as antifungal prophylaxis in patients with AML and high-risk MDS who were undergoing induction chemotherapy. Copyright 2003 American Cancer Society.

Etest cannot be recommended for in vitro susceptibility testing of mucorales.

PubMed

Caramalho, Rita; Maurer, Elisabeth; Binder, Ulrike; Araújo, Ricardo; Dolatabadi, Somayeh; Lass-Flörl, Cornelia; Lackner, Michaela

2015-01-01

Amphotericin B and posaconazole susceptibility patterns were determined for the most prevalent Mucorales, following EUCAST (European Committee on Antimicrobial Susceptibility Testing) broth microdilution guidelines. In parallel, Etest was performed and evaluated against EUCAST. The overall agreement of MICs gained with Etest and EUCAST was 75.1%; therefore, Etest cannot be recommended for antifungal susceptibility testing of Mucorales. Amphotericin B was the most active drug against Mucorales species in vitro, while the activities of posaconazole were more restricted. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

In Vitro Antifungal Activities of the New Triazole UR-9825 against Clinically Important Filamentous Fungi

PubMed Central

Capilla, Javier; Ortoneda, Montserrat; Pastor, Francisco Javier; Guarro, Josep

2001-01-01

We used a modified reference microdilution method (the M-38P method) to evaluate the in vitro activities of the new triazole UR-9825 in comparison with those of amphotericin B against 77 strains of opportunistic filamentous fungi. UR-9825 was clearly more active than amphotericin B against all fungi except Fusarium solani and Scytalidium spp. Notably, UR-9825 had low MICs for Aspergillus fumigatus and Paecilomyces lilacinus (MICs at which 90% of isolates are inhibited, 0.125 μg/ml for both species). PMID:11502542

Amphotericin B-conjugated polypeptide hydrogels as a novel innovative strategy for fungal infections

NASA Astrophysics Data System (ADS)

Shu, Chang; Li, Tengfei; Yang, Wen; Li, Duo; Ji, Shunli; Ding, Li

2018-03-01

The present work is focused on the design and development of novel amphotericin B (AmB)-conjugated biocompatible and biodegradable polypeptide hydrogels to improve the antifungal activity. Using three kinds of promoting self-assembly groups (2-naphthalene acetic acid (Nap), naproxen (Npx) and dexamethasone (Dex)) and polypeptide sequence (Phe-Phe-Asp-Lys-Tyr, FFDKY), we successfully synthesized the Nap-FFDK(AmB)Y gels, Npx-FFDK(AmB)Y gels and Dex-FFDK(AmB)Y gels. The AmB-conjugated hydrogelators are highly soluble in different aqueous solutions. The cryo-transmission electron microscopy and scanning electron microscopy micrographs of hydrogels afford nanofibres with a width of 20-50 nm. Powder X-ray diffraction analyses demonstrate that the crystalline structures of the AmB and Dex are changed into amorphous structures after the formation of hydrogels. Circular dichroism spectra of the solution of blank carriers and the corresponding drug deliveries further help elucidate the molecular arrangement in gel phase, indicating the existence of turn features. The in vitro drug releases suggest that the AmB-conjugated hydrogels are suitable as drug-controlled release vehicles for hydrophobic drugs. The antifungal effect of AmB-conjugated hydrogels significantly exhibits the antifungal activity against Candida albicans. The results of the present study indicated that the AmB-conjugated hydrogels are suitable carriers for poorly water soluble drugs and for enhancement of therapeutic efficacy of antifungal drugs.

Invasive Aspergillosis in Hematological Patients.

PubMed

Kimura, Shun-Ichi

2016-01-01

Invasive aspergillosis (IA) is still one of the leading causes of morbidity and mortality in hematological patients, although its outcome has been improving. Prolonged and profound neutropenia in patients receiving intensive chemotherapy for acute leukemia and stem cell transplantation is a major risk factor for IA. Allogeneic stem cell transplant recipients with graft-versus-host disease and corticosteroid use are also at high risk. Management in a protective environment with high efficiency particular air (HEPA) filter is generally recommended to prevent aspergillosis in patients with prolonged and profound neutropenia. Antifungal prophylaxis against Aspergillus species should be considered in patients with past history of aspergillosis or colonization of Aspergillus species, at facilities with high incidence of IA and those without a protective environment. Early diagnosis and prompt antifungal treatment is important to improve outcome. Imaging studies such as computed tomography and biomarkers such as galactomannan antigen and β-D-glucan are useful for early diagnosis. Empirical antifungal treatment based on persistent or recurrent fever during neutropenia despite broad-spectrum antibiotic therapy is generally recommended in high-risk patients. Alternatively, a preemptive treatment strategy has recently been proposed in the context of progress in the early diagnosis of IA based on the results of imaging studies and biomarkers. Voriconazole is recommended for initial therapy for IA. Liposomal amphotericin B is considered as alternative initial therapy. Combination antifungal therapy of echinocandin with voriconazole or liposomal amphotericin B could be a choice for refractory cases.

Prevalence and Treatment Management of Oropharyngeal Candidiasis in Cancer Patients: Results of the French Candidoscope Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gligorov, Joseph; Bastit, Laurent; Gervais, Honorine

2011-06-01

Purpose: The aim of this pharmaco-epidemiological study was to evaluate the prevalence of oropharyngeal candidiasis (OPC) in cancer patients treated with chemotherapy and/or radiotherapy. Methods and Materials: Signs and symptoms of OPC were noted for all patients. Antifungal therapeutic management was recorded in OPC patients. Patients receiving local antifungal treatments were monitored until the end of treatment. Results: Enrolled in the study were 2,042 patients with solid tumor and/or lymphoma treated with chemotherapy and/or another systemic cancer treatment and/or radiotherapy. The overall prevalence of OPC was 9.6% (95% confidence interval, 8.4%-11.0%]in this population. It was most frequent in patients treatedmore » with combined chemoradiotherapy (22.0%) or with more than two cytotoxic agents (16.9%). Local antifungal treatments were prescribed in 75.0% of OPC patients as recommended by guidelines. The compliance to treatment was higher in patients receiving once-daily miconazole mucoadhesive buccal tablet (MBT; 88.2%) than in those treated with several daily mouthwashes of amphotericin B (40%) or nystatin (18.8%). Conclusion: OPC prevalence in treated cancer patients was high. Local treatments were usually prescribed as per guidelines. Compliance to local treatments was better with once-daily drugs.« less

[In vitro antifungal resistance in Candida albicans from HIV-infected patients with and without oral candidosis.].

PubMed

Ceballos Salobreña, A; Gaitán Cepeda, L A; Orihuela Cañada, F; Olea Barrionuevo, D; Ceballos García, L; Quindós, G

1999-12-01

The main purpose of this study has been to determine the in vitro antifungal susceptibility of clinical isolates from HIV-infected or AIDS patients, depending on the presence of oral candidosis. The oral cavity of 307 HIV-infected or AIDS patients was examined and an oral swab was cultured on Sabouraud glucose agar and studied by conventional mycological methods. In vitro antifungal susceptibility to amphotericin B, nystatin, fluconazole, itraconazole and ketoconazole was tested by disk diffusion with Neo-Sensitabs tablets (Rosco Diagnostica, Dinamarca). One hundred and thirty five Candida albicans isolates (91 serotype A, 38 serotype B, three C. albicans variety stellatoidea and three untyped isolates), three Candida krusei and two Candida glabrata were obtained. All the isolates were susceptible to nystatin and amphotericin B. However, 7.9% isolates were resistant to fluconazole and 2.9% isolates were resistant to ketoconazole or itraconazole. Nearly all C. krusei and C. glabrata isolates, 31% patients with candidosis and 20% Candida-colonized patients showed decreased susceptibility to azoles. This study shows that polyenes had a great in vitro efficacy against clinical isolates from HIV-infected patients and that in vitro resistance to azoles is not as high as observed in other countries.

Anticryptococcal effect of amphotericin B is mediated through macrophage production of nitric oxide.

PubMed Central

Tohyama, M; Kawakami, K; Saito, A

1996-01-01

Amphotericin B (AmB) is a classical antifungal drug and one of the most effective antifungal drugs for the treatment of systemic fungal infection. It is also known to have various immunomodulating activities other than its direct antifungal effect. In the present study, we demonstrated that AmB augmented gamma interferon (IFN-gamma)-induced killing potentials of murine peritoneal macrophages against Cryptococcus neoformans in a dose-dependent manner. This effect was strongly blocked by NG-monomethyl-L-arginine, a competitive inhibitor of nitric oxide (NO) synthesis. In addition, AmB markedly augmented macrophage NO production induced by IFN-gamma with a dose-response curve similar to that seen with its effect on the anticryptococcal activity. These effects were partially mediated by either tumor necrosis factor alpha or interleukin-1, because AmB enhanced IFN-gamma-induced production of these cytokines by macrophages and their specific antibodies partially inhibited the AmB-induced enhancement of NO generation when they were used separately. Our results indicate that AmB induces the production of tumor necrosis factor alpha and IL-1 by macrophages and augments their anticryptococcal activity through triggering the NO-dependent pathway. PMID:8843304

Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species.

PubMed

Lackner, Michaela; de Hoog, G Sybren; Verweij, Paul E; Najafzadeh, Mohammad J; Curfs-Breuker, Ilse; Klaassen, Corné H; Meis, Jacques F

2012-05-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC(90) of ≤ 2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains.

Species-Specific Antifungal Susceptibility Patterns of Scedosporium and Pseudallescheria Species

PubMed Central

Lackner, Michaela; de Hoog, G. Sybren; Verweij, Paul E.; Najafzadeh, Mohammad J.; Curfs-Breuker, Ilse; Klaassen, Corné H.

2012-01-01

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC90 of ≤2 μg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains. PMID:22290955

Direct comparison of the pharmacodynamics of four antifungal drugs in a mouse model of disseminated candidiasis using microbiological assays of serum drug concentrations.

PubMed

Maki, Katsuyuki; Holmes, Ann R; Watabe, Etsuko; Iguchi, Yumi; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

2007-01-01

The aim of this study was to compare the pharmacodynamics of the azole antifungal drugs fluconazole, itraconazole and ketoconazole, and the polyene antifungal amphotericin B, in a mouse model of disseminated Candida albicans infection. In order to directly compare effective serum concentrations of these antifungals, drug concentrations were assayed microbiologically by measuring inhibition of C. albicans mycelial growth (mMIC) in a mouse serum-based assay (serum antifungal titer). Efficacy in the mouse infection model was determined using an organ-based (kidney burden) endpoint. For all four drugs, the serum antifungal titers, 8 hr after administration of single doses of drugs at a range of drug concentrations, correlated closely with C. albicans kidney fungal burden in the mouse model. The results showed that determining serum antifungal titer may be used to accurately represent kidney fungal burden in a mouse model of disseminated candidiasis and allowed direct comparison of the pharmacodynamics of differing classes of antifungal drugs.

Rare fungal infectious agents: a lurking enemy

PubMed Central

Skiada, Anna; Pavleas, Ioannis; Drogari-Apiranthitou, Maria

2017-01-01

In the expanding population of immunocompromised patients and those treated in intensive care units, rare fungal infectious agents have emerged as important pathogens, causing invasive infections associated with high morbidity and mortality. These infections may present either as de novo or as breakthrough invasive infections in high-risk patients with hematologic malignancies receiving prophylactic or empirical antifungal therapy or in patients with central venous catheters. Diagnosis and treatment are challenging. Physicians should have a high index of suspicion because early diagnosis is of paramount importance. Conventional diagnostic methods such as cultures and histopathology are still essential, but rapid and more specific molecular techniques for both detection and identification of the infecting pathogens are being developed and hopefully will lead to early targeted treatment. The management of invasive fungal infections is multimodal. Reversal of risk factors, if feasible, should be attempted. Surgical debridement is recommended in localized mold infections. The efficacy of various antifungal drugs is not uniform. Amphotericin B is active against most yeasts, except Trichosporon, as well as against Mucorales, Fusarium, and some species of Paecilomyces and dimorphic fungi. The use of voriconazole is suggested for the treatment of trichosporonosis and scedosporiosis. Combination treatment, though recommended as salvage therapy in some infections, is controversial in most cases. Despite the use of available antifungals, mortality remains high. The optimization of molecular-based techniques, with expansion of reference libraries and the possibility for direct detection of resistance mechanisms, is awaited with great interest in the near future. Further research is necessary, however, in order to find the best ways to confront and destroy these lurking enemies. PMID:29152230

Changing Epidemiology of Mucoralean Fungi: Chronic Cutaneous Infection Caused by Mucor irregularis.

PubMed

Chander, Jagdish; Kaur, Mandeep; Bhalla, Mala; Punia, Rajpal Singh; Singla, Nidhi; Bhola, Kalyani; Alastruey-Izquierdo, Ana; Stchigel, Alberto M; Guarro, Josep

2015-10-01

The fungi pertaining to order Mucorales usually cause an acute form of clinical disease called mucormycosis. A primary chronic presentation in an immunocompetent patient is a rare form of mucormycosis. Mucor irregularis is known for causing chronic cutaneous infections geographically confined to Asia, mainly in China. We describe a case of primary chronic cutaneous mucormycosis caused by M. irregularis from a new geographical niche in India, highlighting changing aspects of its epidemiology. The patient was a farmer with a history of skin lesions over the lower limb for the past 6 years. The biopsy taken from the lesions showed pauci-septate hyphae with right-angle branching on KOH wet mount as well as special fungal stains. On fungal culture, greyish-white cottony mycelial growth of Mucormycetes was obtained. The strain was finally identified as M. irregularis on macro- and microscopic features on 2 % MEA and DNA sequencing. The antifungal susceptibility was done using EUCAST broth microdilution method and was found to be susceptible to commonly used antifungal agents. The patient was started on oral itraconazole and saturated solution of potassium iodide (SSKI). While undergoing treatment for 2 months, he was lost to follow-up, however, after a year when he recently visited the hospital; the disease got completely healed with no new crops of skin lesions. Mucoralean fungi should also be suspected in cases with chronic presentation, in immunocompetent host, as there is emergence of such fungi in new endemic areas, particularly located in Asia. The role of other antifungal agents apart from amphotericin B for the treatment of chronic mucormycosis needs to be explored.

Anti-fungal activity of Morinda citrifolia (noni) extracts against Candida albicans: an in vitro study.

PubMed

Barani, K; Manipal, Sunayana; Prabu, D; Ahmed, Adil; Adusumilli, Preethi; Jeevika, C

2014-01-01

The aim of this study was to investigate the anti-fungal activity of Morinda citrifolia fruit extract on Candida albicans. Juice extract from M. citrifolia fruit was lyophilized and used in anti-fungal testing. Anti-fungal activity of M. citrifolia fruit extract against C. albicans was tested in vitro at various concentrations. The inhibitory effect of M. citrifolia extract on C. albicans was determined by agar culture and applied broth dilution test. M. citrifolia extract at 1000 μg/ml concentration effectively inhibited the growth of C. albicans (16.6 ± 0.3) compared with the positive control - amphotericin B (20.6 ± 0.6). It was found to be a dose-dependent reaction. M. citrifolia fruit extract had an anti-fungal effect on C. albicans and the inhibitory effect varied with concentration.

Miltefosine inhibits Candida albicans and non-albicans Candida spp. biofilms and impairs the dispersion of infectious cells.

PubMed

Vila, Taissa; Ishida, Kelly; Seabra, Sergio Henrique; Rozental, Sonia

2016-11-01

Candida spp. can adhere to and form biofilms over different surfaces, becoming less susceptible to antifungal treatment. Resistance of biofilms to antifungal agents is multifactorial and the extracellular matrix (ECM) appears to play an important role. Among the few available antifungals for treatment of candidaemia, only the lipid formulations of amphotericin B (AmB) and the echinocandins are effective against biofilms. Our group has previously demonstrated that miltefosine has an important effect against Candida albicans biofilms. Thus, the aim of this work was to expand the analyses of the in vitro antibiofilm activity of miltefosine to non-albicans Candida spp. Miltefosine had significant antifungal activity against planktonic cells and the development of biofilms of C. albicans, Candida parapsilosis, Candida tropicalis and Candida glabrata. The activity profile in biofilms was superior to fluconazole and was similar to that of AmB and caspofungin. Biofilm-derived cells with their ECM extracted became as susceptible to miltefosine as planktonic cells, confirming the importance of the ECM in the biofilm resistant behaviour. Miltefosine also inhibited biofilm dispersion of cells at the same concentration needed to inhibit planktonic cell growth. The data obtained in this work reinforce the potent inhibitory activity of miltefosine on biofilms of the four most pathogenic Candida spp. and encourage further studies for the utilisation of this drug and/or structural analogues on biofilm-related infections. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Anti-cryptococcal activity of ethanol crude extract and hexane fraction from Ocimum basilicum var. Maria bonita: mechanisms of action and synergism with amphotericin B and Ocimum basilicum essential oil.

PubMed

Cardoso, Nathalia N R; Alviano, Celuta S; Blank, Arie F; Arrigoni-Blank, Maria de Fátima; Romanos, Maria Teresa V; Cunha, Marcel M L; da Silva, Antonio Jorge R; Alviano, Daniela S

2017-12-01

Ocimum basilicum L. (Lamiaceae) has been used in folk medicine to treat headaches, kidney disorders, and intestinal worms. This study evaluates the anti-cryptococcal activity of ethanol crude extract and hexane fraction obtained from O. basilicum var. Maria Bonita leaves. The MIC values for Cryptococcus sp. were obtained according to Clinical and Laboratory Standards Institute in a range of 0.3-2500 μg/mL. The checkerboard assay evaluated the association of the substances tested (in a range of 0.099-2500 μg/mL) with amphotericin B and O. basilicum essential oil for 48 h. The ethanol extract, hexane fraction and associations in a range of 0.3-2500 μg/mL were tested for pigmentation inhibition after 7 days of treatment. The inhibition of ergosterol synthesis and reduction of capsule size were evaluated after the treatment with ethanol extract (312 μg/mL), hexane fraction (78 μg/mL) and the combinations of essential oil + ethanol extract (78 μg/mL + 19.5 μg/mL, respectively) and essential oil + hexane fraction (39.36 μg/mL + 10 μg/mL, respectively) for 24 and 48 h, respectively. The hexane fraction presented better results than the ethanol extract, with a low MIC (156 μg/mL against C. neoformans T 444 and 312 μg/mL against C. neoformans H99 serotype A and C. gattii WM779 serotype C). The combination of the ethanol extract and hexane fraction with amphotericin B and essential oil enhanced their antifungal activity, reducing the concentration of each substance needed to kill 100% of the inoculum. The substances tested were able to reduce the pigmentation, capsule size and ergosterol synthesis, which suggest they have important mechanisms of action. These results provide further support for the use of ethanol extracts of O. basilicum as a potential source of antifungal agents.

Amphotericin B formulations: a comparative review of efficacy and toxicity.

PubMed

Hamill, Richard J

2013-06-01

Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3-6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV-infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile.

Characterization of the inhibitory effect of voriconazole on the fungicidal activity of amphotericin B against Candida albicans in an in vitro kinetic model.

PubMed

Lignell, Anders; Löwdin, Elisabeth; Cars, Otto; Sjölin, Jan

2008-07-01

The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. Voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.

Ocular blastomycosis in dogs: 73 cases, 108 eyes (1985-1993).

PubMed

Bloom, J D; Hamor, R E; Gerding, P A

1996-10-01

To evaluate clinical signs of ocular blastomycosis in dogs, to determine response of blastomycosis-infected eyes to treatment with systemically administered amphotericin B and ketoconazole, and to identify prognostic indicators of successful antifungal treatment. Retrospective study. 73 dogs. Medical records were reviewed for all dogs with confirmed blastomycosis and ocular disease seen at our hospital between 1985 and 1993. 6 eyes had anterior segment disease, 24 had posterior segment disease, and 78 had endophthalmitis. 40 eyes were treated with a combination of amphotericin B and ketoconazole, and 16 of the 40 responded favorably. However, 16 of the 24 eyes that were not severely affected responded favorably, but none of the 16 eyes that were severely affected did. Dogs with blastomycosis had posterior segment disease, without complete retinal separation, had a good prognosis for retaining vision. Results of histologic examination suggested that secondary glaucoma was a manifestation of endophthalmitis and was indicative of a grave prognosis for response to antifungal and antiglaucoma treatment.

[Pharmacology of the antifungals used in the treatment of aspergillosis].

PubMed

Azanza, José Ramón; Sádaba, Belén; Gómez-Guíu, Almudena

2014-01-01

The treatment of invasive aspergillosis requires the use of drugs that characteristically have complex pharmacokinetic properties, the knowledge of which is essential to achieve maximum efficacy with minimal risk to the patient. The lipid-based amphotericin B formulations vary significantly in their pharmacokinetic behaviour, with very high plasma concentrations of the liposomal form, probably related to the presence of cholesterol in their structure. Azoles have a variable absorption profile, particularly in the case of itraconazole and posaconazole, with the latter very dependent on multiple factors. This may also lead to variations in voriconazole, which requires considering the possibility of monitoring plasma concentrations. The aim of this article is to review some of the most relevant aspects of the pharmacology of the antifungals used in the prophylaxis and treatment of the Aspergillus infection. For this reason, it includes the most relevant features of some of the azoles normally prescribed in this infection (itraconazole, posaconazole and voriconazole) and the amphotericin B formulations. Copyright © 2014. Published by Elsevier Espana.

Synthesis and Anti-microbial Activity of Novel Phosphatidylethanolamine-N-amino Acid Derivatives.

PubMed

Vijeetha, Tadla; Balakrishna, Marrapu; Karuna, Mallampalli Sri Lakshmi; Surya Koppeswara Rao, Bhamidipati Venkata; Prasad, Rachapudi Badari Narayana; Kumar, Koochana Pranay; Surya Narayana Murthy, Upadyaula

2015-01-01

The study involved synthesis of five novel amino acid derivatives of phosphatidylethanolamine isolated from egg yolk lecithin employing a three step procedure i) N-protection of L-amino acids with BOC anhydride in alkaline medium ii) condensation of - CO2H group of N-protected amino acid with free -NH2 of PE by a peptide linkage and iii) deprotection of N-protected group of amino acids to obtain phosphatidylethanolamine-N-amino acid derivatives in 60-75% yield. The five L-amino acids used were L glycine, L-valine, L-leucine, L-isoleucine and L-phenylalanine. The amino acid derivatives were screened for anti-baterial activity against B. subtilis, S. aureus, P. aeroginosa and E. coli taking Streptomycin as reference compound and anti-fungal activity against C. albicans, S. cervisiae, A. niger taking AmphotericinB as reference compound. All the amino acid derivatives exhibited extraordinary anti-bacterial activities about 3 folds or comparable to Streptomycin and moderate or no anti-fungal activity against Amphotericin-B.

Evaluation of virulence factors and antifungal susceptibility patterns of different Candida species isolated from the female camel (Camelus dromedarius) genital tract.

PubMed

Sharifzadeh, Aghil; Soltani, Minoo; Shokri, Hojjatollah

2015-08-01

The purposes of this study were to investigate the enzymatic activity of different Candida species and their antifungal susceptibility patterns. The study involved a total of 83 isolates of Candida from the genital tract of the female Camelus dromedarius. After species identification, the isolates were analysed for the production/activity of phospholipase, proteinase and haemolysin. In addition, the agar disc diffusion method was performed on the basis of CLSI guidelines M44-A2 protocol for antifungal susceptibility testing. All the isolates were able to produce phospholipase, proteinase and haemolysin. A total of 35.48%, 87.09% and 64.51% of C. albicans isolates exhibited very high phospholipase, proteinase and haemolytic activities, respectively, whereas very high phospholipase, proteinase and haemolytic activities were determined in 5.76%, 23.07% and 45.16% of non-C. albicans isolates respectively. Overall, 61 (73.5%) of Candida isolates were susceptible to fluconazole, 70 (84.3%) susceptible to clotrimazole, 82 (98.8%) susceptible to voriconazole, 76 (91.6%) susceptible to itraconazole, 75 (90.4%) susceptible to ketoconazole, 83 (100%) susceptible to amphotericin B, 81 (97.6%) susceptible to nystatin and 36 (43.4%) susceptible to flucytosine. Candida isolates showed higher haemolytic activity than that of other secreted hydrolases among vaginal Candida species. In addition, amphotericin B was the most in vitro effective antifungal drug and flucytosine had the poorest activity under such conditions. © 2015 Blackwell Verlag GmbH.

Rhodotorula minuta as onychomycosis agent in a Chinese patient: first report and literature review.

PubMed

Zhou, Jie; Chen, Min; Chen, Hongduo; Pan, Weihua; Liao, Wanqing

2014-03-01

Onychomycosis is a common superficial fungal infection, which usually caused by dermatophytes, yeast and non-dermatophytic moulds. Recently, we isolated a Rhodotorula minuta isolate from a 15-year-old immunocompetent girl student in Hangzhou (China) that was identified using microscopy, culture morphology, histological diagnosis, API 20C AUX Yeast Identification Kit and sequencing of the Internal Transcribed Spacer region. In vitro, antifungal susceptibility tests showed that this yeast isolate was susceptible to low concentrations of amphotericin B, itraconazole, voriconazole and 5-flvoriconaz but that it appeared to be dose-dependent susceptible to fluconazole(MIC = 16 μg/ml). Furthermore, the effective result of therapy with itraconazole against R. minuta was consistent with that of susceptibility tests. © 2013 Blackwell Verlag GmbH.

Susceptibility profile and epidemiological cut-off values of Cryptococcus neoformans species complex from Argentina.

PubMed

Córdoba, Susana; Isla, Maria G; Szusz, Wanda; Vivot, Walter; Altamirano, Rodrigo; Davel, Graciela

2016-06-01

Epidemiological cut-off values (ECVs) based on minimal inhibitory concentration (MIC) distribution have been recently proposed for some antifungal drug/Cryptococcus neoformans combinations. However, these ECVs vary according to the species studied, being serotypes and the geographical origin of strains, variables to be considered. The aims were to define the wild-type (WT) population of the C. neoformans species complex (C. neoformans) isolated from patients living in Argentina, and to propose ECVs for six antifungal drugs. A total of 707 unique C. neoformans isolates obtained from HIV patients suffering cryptococcal meningitis were studied. The MIC of amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole and posaconazole was determined according to the EDef 7.2 (EUCAST) reference document. The MIC distribution, MIC50 , MIC90 and ECV for each of these drugs were calculated. The highest ECV, which included ≥95% of the WT population modelled, was observed for flucytosine and fluconazole (32 μg ml(-1) each). For amphotericin B, itraconazole, voriconazole and posaconazole, the ECVs were: 0.5, 0.5, 0.5 and 0.06 μg ml(-1) respectively. The ECVs determined in this study may aid in identifying the C. neoformans strains circulating in Argentina with decreased susceptibility to the antifungal drugs tested. © 2016 Blackwell Verlag GmbH.

Antifungal susceptibilities of Cryptococcus neoformans.

PubMed

Archibald, Lennox K; Tuohy, Marion J; Wilson, Deborah A; Nwanyanwu, Okey; Kazembe, Peter N; Tansuphasawadikul, Somsit; Eampokalap, Boonchuay; Chaovavanich, Achara; Reller, L Barth; Jarvis, William R; Hall, Gerri S; Procop, Gary W

2004-01-01

Susceptibility profiles of medically important fungi in less-developed countries remain uncharacterized. We measured the MICs of amphotericin B, 5-flucytosine, fluconazole, itraconazole, and ketoconazole for Cryptococcus neoformans clinical isolates from Thailand, Malawi, and the United States and found no evidence of resistance or MIC profile differences among the countries.

The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation.

PubMed

Larkin, Emily; Hager, Christopher; Chandra, Jyotsna; Mukherjee, Pranab K; Retuerto, Mauricio; Salem, Iman; Long, Lisa; Isham, Nancy; Kovanda, Laura; Borroto-Esoda, Katyna; Wring, Steve; Angulo, David; Ghannoum, Mahmoud

2017-05-01

Candida auris , a new multidrug-resistant Candida spp. which is associated with invasive infection and high rates of mortality, has recently emerged. Here, we determined the virulence factors (germination, adherence, biofilm formation, phospholipase and proteinase production) of 16 C. auris isolates and their susceptibilities to 11 drugs belonging to different antifungal classes, including a novel orally bioavailable 1,3-β-d-glucan synthesis inhibitor (SCY-078). We also examined the effect of SCY-078 on the growth, ultrastructure, and biofilm-forming abilities of C. auris Our data showed that while the tested strains did not germinate, they did produce phospholipase and proteinase in a strain-dependent manner and had a significantly reduced ability to adhere and form biofilms compared to that of Candida albicans ( P = 0.01). C. auris isolates demonstrated reduced susceptibility to fluconazole and amphotericin B, while, in general, they were susceptible to the remaining drugs tested. SCY-078 had an MIC 90 of 1 mg/liter against C. auris and caused complete inhibition of the growth of C. auris and C. albicans Scanning electron microscopy analysis showed that SCY-078 interrupted C. auris cell division, with the organism forming abnormal fused fungal cells. Additionally, SCY-078 possessed potent antibiofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control ( P < 0.05 for both comparisons). Our study shows that C. auris expresses several virulence determinants (albeit to a lesser extent than C. albicans ) and is resistant to fluconazole and amphotericin B. SCY-078, the new orally bioavailable antifungal, had potent antifungal/antibiofilm activity against C. auris , indicating that further evaluation of this antifungal is warranted. Copyright © 2017 Larkin et al.

Molecular typing and in vitro antifungal susceptibility of Cryptococcus spp from patients in Midwest Brazil.

PubMed

Favalessa, Olivia Cometti; de Paula, Daphine Ariadne Jesus; Dutra, Valeria; Nakazato, Luciano; Tadano, Tomoko; Lazera, Marcia dos Santos; Wanke, Bodo; Trilles, Luciana; Walderez Szeszs, Maria; Silva, Dayane; Hahn, Rosane Christine

2014-08-13

Cryptococcosis is a systemic fungal infection that affects humans and animals, mainly due to Cryptococcus neoformans and Cryptococcus gattii. Following the epidemic of acquired immunodeficiency syndrome (AIDS), fungal infections by C. neoformans have become more common among immunocompromised patients. Cryptococcus gattii has primarily been isolated as a primary pathogen in healthy hosts and occurs endemically in northern and northeastern Brazil. We to perform genotypic characterization and determine the in vitro susceptibility profile to antifungal drugs of the Cryptococcus species complex isolated from HIV-positive and HIV-negative patients attended at university hospitals in Cuiabá, MT, in the Midwestern region of Brazil. Micromorphological features, chemotyping with canavanine-glycine-bromothymol blue (CGB) agar and genotyping by URA5-RFLP were used to identify the species. The antifungal drugs tested were amphotericin B, fluconazole, flucytosine, itraconazole and voriconazole. Minimum inhibitory concentrations (MICs) were determined according to the CLSI methodology M27-A3. Analysis of samples yelded C. neoformans AFLP1/VNI (17/27, 63.0%) and C. gattii AFLP6/VGII (10/27, 37.0%). The MICs ranges for the antifungal drugs were: amphotericin B (0.5-1 mg/L), fluconazole (1-16 mg/L), flucytosine (1-16 mg/L), itraconazole (0.25-0.12 mg/L) and voriconazole (0.06-0.5 mg/L). Isolates of C. neoformans AFLP1/VNI were predominant in patients with HIV/AIDS, and C. gattii VGII in HIV-negative patients. The genotypes identified were susceptible to the antifungal drugs tested. It is worth emphasizing that AFLP6/VGII is a predominant genotype affecting HIV-negative individuals in Cuiabá. These findings serve as a guide concerning the molecular epidemiology of C. neoformans and C. gattii in the State of Mato Grosso.

Species Identification and In Vitro Antifungal Susceptibility of Aspergillus terreus Species Complex Clinical Isolates from a French Multicenter Study.

PubMed

Imbert, S; Normand, A C; Ranque, S; Costa, J M; Guitard, J; Accoceberry, I; Bonnal, C; Fekkar, A; Bourgeois, N; Houzé, S; Hennequin, C; Piarroux, R; Dannaoui, E; Botterel, F

2018-05-01

Aspergillus section Terrei is a species complex currently comprised of 14 cryptic species whose prevalence in clinical samples as well as antifungal susceptibility are poorly known. The aims of this study were to investigate A. Terrei clinical isolates at the species level and to perform antifungal susceptibility analyses by reference and commercial methods. Eighty-two clinical A. Terrei isolates were collected from 8 French university hospitals. Molecular identification was performed by sequencing parts of beta-tubulin and calmodulin genes. MICs or minimum effective concentrations (MECs) were determined for 8 antifungal drugs using both EUCAST broth microdilution (BMD) methods and concentration gradient strips (CGS). Among the 79 A. Terrei isolates, A. terreus stricto sensu ( n = 61), A. citrinoterreus ( n = 13), A. hortai ( n = 3), and A. alabamensis ( n = 2) were identified. All strains had MICs of ≥1 mg/liter for amphotericin B, except for two isolates (both A. hortai ) that had MICs of 0.25 mg/liter. Four A. terreus isolates were resistant to at least one azole drug, including one with pan-azole resistance, yet no mutation in the CYP51A gene was found. All strains had low MECs for the three echinocandins. The essential agreements (EAs) between BMD and CGS were >90%, except for those of amphotericin B (79.7%) and itraconazole (73.4%). Isolates belonging to the A section Terrei identified in clinical samples show wider species diversity beyond the known A. terreus sensu stricto Azole resistance inside the section Terrei is uncommon and is not related to CYP51A mutations here. Finally, CGS is an interesting alternative for routine antifungal susceptibility testing. Copyright © 2018 American Society for Microbiology.

Multidrug-resistant Fusarium in keratitis: a clinico-mycological study of keratitis infections in Chennai, India.

PubMed

Tupaki-Sreepurna, Ananya; Al-Hatmi, Abdullah M S; Kindo, Anupma J; Sundaram, Murugan; de Hoog, G Sybren

2017-04-01

In this study, we aimed to present the first molecular epidemiological data from Chennai, India, analyse keratitis cases that have been monitored in a university hospital during 2 years, identify the responsible Fusarium species and determine antifungal susceptibilities. A total of 10 cases of keratitis were included in the study. Fusarium isolates were identified using the second largest subunit of the RNA polymerase gene (RPB2) and the translation elongation factor 1 alpha (TEF1). Antifungal susceptibility was tested by the broth microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) methodology. The aetiological agents belonged to Fusarium solani species complex (FSSC) (n = 9) and Fusarium sambucinum species complex (FSAMSC) (n = 1), and the identified species were Fusarium keratoplasticum (n = 7), Fusarium falciforme (n = 2) and Fusarium sporotrichioides (n = 1). All strains showed multidrug resistance to azoles and caspofungin but exhibited lower minimum inhibitory concentration (MIC) to natamycin and amphotericin B. Fusarium keratoplasticum and Fusarium falciforme belonging to the Fusarium solani species complex were the major aetiological agents of Fusarium keratitis in this study. Early presentation and 5% topical natamycin was associated with better patient outcome. Preventative measures and monitoring of local epidemiological data play an important role in clinical practice. © 2016 Blackwell Verlag GmbH.

A Case of Onychomycosis Caused by Rhodotorula glutinis.

PubMed

Uludag Altun, Hatice; Meral, Tuba; Turk Aribas, Emel; Gorpelioglu, Canan; Karabicak, Nilgun

2014-01-01

Rhodotorula spp. have emerged as opportunistic pathogens, particularly in immunocompromised patients. The current study reports a case of onychomycosis caused by Rhodotorula glutinis in a 74-year-old immunocompetent female. The causative agent was identified as R. glutinis based on the pinkish-orange color; mucoid-appearing yeast colonies on Sabouraud Dextrose Agar at 25°C; morphological evaluation in the Corn Meal-Tween 80 agar; observed oval/round budding yeast at 25°C for 72 hours; no observed pseudohyphae; positive urease activity at 25°C for 4 days; and assimilation features detected by API ID 32C kit and automated Vitek Yeast Biochemical Card 2 system. Antifungal susceptibility test results were as follows: amphotericin B (MIC = 0.5 µg/mL), fluconazole (MIC = 128 µg/mL), itraconazole (MIC = 0.125 µg/mL), voriconazole (MIC = 1 µg/mL), posaconazole (MIC = 0.5 µg/mL), anidulafungin (MIC = 0.5 µg/mL), and caspofungin (MIC = 16 µg/mL). Antifungal therapy was initiated with oral itraconazole at a dose of 400 mg/day; seven-day pulse therapy was planned at intervals of three weeks. Clinical recovery was observed in the clinical evaluation of the patient before the start of the third cure. Although R. glutinis has rarely been reported as the causative agent of onychomycosis, it should be considered.

[Invasive candidiasis in non-neutropenic adults : Guideline-based management in the intensive care unit].

PubMed

Glöckner, A; Cornely, O A

2013-12-01

Invasive Candida infections represent a diagnostic and therapeutic challenge for clinicians particularly in the intensive care unit (ICU). Despite substantial advances in antifungal agents and treatment strategies, invasive candidiasis remains associated with a high mortality. Recent guideline recommendations on the management of invasive candidiasis by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) from 2012, the German Speaking Mycological Society and the Paul Ehrlich Society for Chemotherapy (DMykG/PEG) from 2011 and the Infectious Diseases Society of America (IDSA) from 2009 provide valuable guidance for diagnostic procedures and treatment of these infections but need to be interpreted in the light of the individual situation of the patient and the local epidemiology of fungal pathogens. The following recommendations for management of candidemia are common to all three guidelines. Any positive blood culture for Candida indicates disseminated infection or deep organ infection and requires antifungal therapy. Treatment should be initiated as soon as possible. Removal or changing of central venous catheters or other foreign material in the bloodstream is recommended whenever possible. Ophthalmological examination for exclusion of endophthalmitis and follow-up blood cultures during therapy are also recommended. Duration of therapy should be 14 days after clearance of blood cultures and resolution of symptoms. Consideration of surgical options and a prolonged antifungal treatment (weeks to months) are required when there is organ involvement. During the last decade several new antifungal agents were introduced into clinical practice. These innovative drugs showed convincing efficacy and favorable safety in randomized clinical trials. Consequently, they were integrated in recent therapeutic guidelines, often replacing former standard drugs as first-line options. Echinocandins have emerged as the generally preferred primary treatment in candidemia. The expert panel of ESCMID views fluconazole only as a marginally recommended therapy for this indication. The use of amphotericin B deoxycholate should be generally avoided because of toxicity.

In vitro pyrogen test for toxic or immunomodulatory drugs.

PubMed

Daneshian, Mardas; Guenther, Armin; Wendel, Albrecht; Hartung, Thomas; von Aulock, Sonja

2006-06-30

Pyrogenic contaminations of some classes of injectable drugs, e.g. toxic or immunomodulatory as well as false-positive drugs, represent a major risk which cannot yet be excluded due to the limitations of current tests. Here we describe a modification of the In vitro Pyrogen Test termed AWIPT (Adsorb, Wash, In vitro Pyrogen Test), which addresses this problem by introducing a pre-incubation step in which pyrogenic contaminations in the test sample are adsorbed to albumin-coated beads. After rinsing, the beads are incubated with human whole blood and the release of the endogenous pyrogen interleukin-1beta is measured as a marker of pyrogenic activity. Intentional contaminations with lipopolysaccharide were retrieved from the chemotherapeutic agents paclitaxel, cisplatin and liposomal daunorubicin, the antibiotic gentamicin, the antifungal agent liposomal amphotericin B, and the corticosteroid prednisolone at lower dilutions than in the standard in vitro pyrogen test. This represents a promising new approach for the detection of pyrogenic contamination in drugs or in drugs containing interfering additives and should lead to improved safety levels.

Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species.

PubMed

Chitty, Jessica L; Butler, Mark S; Suboh, Azzah; Edwards, David J; Cooper, Matthew A; Fraser, James A; Robertson, Avril A B

2018-02-01

Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 μg/ml. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates of C. neoformans var. gattii had an MIC of 0.78 to 12.5 μg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents. Copyright © 2018 Chitty et al.

Antimicrobial Octapeptin C4 Analogues Active against Cryptococcus Species

PubMed Central

Chitty, Jessica L.; Butler, Mark S.; Suboh, Azzah; Edwards, David J.; Cooper, Matthew A.; Fraser, James A.

2017-01-01

ABSTRACT Resistance to antimicrobials is a growing problem in both developed and developing countries. In nations where AIDS is most prevalent, the human fungal pathogen Cryptococcus neoformans is a significant contributor to mortality, and its growing resistance to current antifungals is an ever-expanding threat. We investigated octapeptin C4, from the cationic cyclic lipopeptide class of antimicrobials, as a potential new antifungal. Octapeptin C4 was a potent, selective inhibitor of this fungal pathogen with an MIC of 1.56 μg/ml. Further testing of octapeptin C4 against 40 clinical isolates of C. neoformans var. grubii or neoformans showed an MIC of 1.56 to 3.13 μg/ml, while 20 clinical isolates of C. neoformans var. gattii had an MIC of 0.78 to 12.5 μg/ml. In each case, the MIC values for octapeptin C4 were equivalent to, or better than, current antifungal drugs fluconazole and amphotericin B. The negatively charged polysaccharide capsule of C. neoformans influences the pathogen's sensitivity to octapeptin C4, whereas the degree of melanization had little effect. Testing synthetic octapeptin C4 derivatives provided insight into the structure activity relationships, revealing that the lipophilic amino acid moieties are more important to the activity than the cationic diaminobutyric acid groups. Octapeptins have promising potential for development as anticryptococcal therapeutic agents. PMID:29158283

Rapid susceptibility testing of fungi by flow cytometry using vital staining.

PubMed Central

Wenisch, C; Linnau, K F; Parschalk, B; Zedtwitz-Liebenstein, K; Georgopoulos, A

1997-01-01

A 1-h assay for antifungal susceptibility testing measuring the impairment of fungal metabolic activity was developed. Yeast viability was analyzed by flow cytometry with a novel fluorescent probe, FUN-1, which emits a red fluorescence when the yeast is metabolically active. For nine Candida albicans strains tested, this method yielded results comparable to those obtained by the standard M27 procedure for amphotericin B, flucytosine, fluconazole, and ketoconazole. Whether the flow cytometry antifungal susceptibility test results correlate with the in vivo activities of the drugs remains to determined. PMID:8968873

A disseminated infection with the antifungal-multiresistant teleomorphic fungus Neocosmospora vasinfecta in a patient with acute B-lymphoblastic leukemia.

PubMed

Gabriel, Frédéric; D'Almeida, Mahussi; Albert, Olivier; Fitton-Ouhabi, Valérie; Noël, Thierry; Accoceberry, Isabelle

2013-02-09

We report on a fatal invasive infection due to the ascomycetous fungus Neocosmospora vasinfecta, in a 20-year-old European patient suffering from an acute lymphoblastic leukemia. The infection could not be controlled by a bitherapy combining liposomal amphotericin B and voriconazole. This is the second case of disseminated infection reported with this unusual fungus, which develops under its teleomorphic state, is fully resistant to all systemic antifungals, and which is known to live in tropical countries.

A disseminated infection with the antifungal-multiresistant teleomorphic fungus Neocosmospora vasinfecta in a patient with acute B-lymphoblastic leukemia

PubMed Central

Gabriel, Frédéric; D’Almeida, Mahussi; Albert, Olivier; Fitton-Ouhabi, Valérie; Noël, Thierry; Accoceberry, Isabelle

2013-01-01

We report on a fatal invasive infection due to the ascomycetous fungus Neocosmospora vasinfecta, in a 20-year-old European patient suffering from an acute lymphoblastic leukemia. The infection could not be controlled by a bitherapy combining liposomal amphotericin B and voriconazole. This is the second case of disseminated infection reported with this unusual fungus, which develops under its teleomorphic state, is fully resistant to all systemic antifungals, and which is known to live in tropical countries. PMID:24432214

In Vitro Activities of Eight Antifungal Drugs against 106 Waterborne and Cutaneous Exophiala Species

PubMed Central

Najafzadeh, M. J.; Saradeghi Keisari, M.; Vicente, V. A.; Feng, P.; Shamsian, S. A. A.; Rezaei-Matehkolaei, A.; de Hoog, G. S.; Curfs-Breuker, I.

2013-01-01

The in vitro activities of eight antifungal drugs against 106 clinical and environmental isolates of waterborne and cutaneous Exophiala species were tested. The MICs and minimum effective concentrations for 90% of the strains tested (n = 106) were, in increasing order, as follows: posaconazole, 0.063 μg/ml; itraconazole, 0.25 μg/ml; micafungin, 1 μg/ml; voriconazole, 2 μg/ml; isavuconazole, 4 μg/ml; caspofungin, 8 μg/ml; amphotericin B, 16 μg/ml; fluconazole, 64 μg/ml. PMID:24100491

Effects of disrupting the polyketide synthase gene WdPKS1 in Wangiella [Exophiala] dermatitidis on melanin production and resistance to killing by antifungal compounds, enzymatic degradation, and extremes in temperature

PubMed Central

Paolo, William F; Dadachova, Ekaterina; Mandal, Piyali; Casadevall, Arturo; Szaniszlo, Paul J; Nosanchuk, Joshua D

2006-01-01

Background Wangiella dermatitidis is a human pathogenic fungus that is an etiologic agent of phaeohyphomycosis. W. dermatitidis produces a black pigment that has been identified as a dihydroxynaphthalene melanin and the production of this pigment is associated with its virulence. Cell wall pigmentation in W. dermatitidis depends on the WdPKS1 gene, which encodes a polyketide synthase required for generating the key precursor for dihydroxynaphthalene melanin biosynthesis. Results We analyzed the effects of disrupting WdPKS1 on dihydroxynaphthalene melanin production and resistance to antifungal compounds. Transmission electron microscopy revealed that wdpks1Δ-1 yeast had thinner cell walls that lacked an electron-opaque layer compared to wild-type cells. However, digestion of the wdpks1Δ-1 yeast revealed small black particles that were consistent with a melanin-like compound, because they were acid-resistant, reacted with melanin-binding antibody, and demonstrated a free radical signature by electron spin resonance analysis. Despite lacking the WdPKS1 gene, the mutant yeast were capable of catalyzing the formation of melanin from L-3,4-dihyroxyphenylalanine. The wdpks1Δ-1 cells were significantly more susceptible to killing by voriconazole, amphotericin B, NP-1 [a microbicidal peptide], heat and cold, and lysing enzymes than the heavily melanized parental or complemented strains. Conclusion In summary, W. dermatitidis makes WdPKS-dependent and -independent melanins, and the WdPKS1-dependent deposition of melanin in the cell wall confers protection against antifungal agents and environmental stresses. The biological role of the WdPKS-independent melanin remains unclear. PMID:16784529

In vitro susceptibility of Candida albicans clinical isolates to eight antifungal agents in Ouagadougou (Burkina Faso).

PubMed

Zida, A; Yacouba, A; Bamba, S; Sangare, I; Sawadogo, M; Guiguemde, T; Kone, S; Traore, L K; Ouedraogo-Traore, R; Guiguemde, R T

2017-12-01

In recent years, the infection Candida albicans infection worldwide has risen, and the incidence of resistance to traditional antifungal therapies is also increasing. The aim of this study was to evaluate in vitro susceptibility of C. albicans clinical isolates to eight antifungal agents in Ouagadougou. A cross-sectional study was conducted from January 2013 to December 2015 at Yalgado Ouédraogo University Teaching Hospital. Two hundred seven strains have been isolated from 347 symptomatic patients received in different clinical services. Samples were cultured on Sabouraud Dextrose Agar supplemented with Cloramphenicol. Isolates were diagnosed as C. albicans using germ tube test, chlamydospore formation on Corn Meal Agar, and Api-Candida test (Biomérieux). Antifungal susceptibility testing was performed by disk diffusion method and isolates classified as susceptible, susceptible dose-dependent and resistant. Three hundred forty-seven (347) patients are included in this study. Two hundred and six (206) out of 347 collected samples (59.36%) were found positive for C. albicans. The strains were mostly isolated from vulvovaginal (49%) and oral infections (40.3%). The highest resistance rates of azoles were obtained with fluconazole (66.5%), itraconazole (52.3%) and ketoconazole (22.9%) when all clinical isolates were included. The resistance rates of fluconazole, itraconazole and ketoconazole remain highest for vulvovaginal and oral isolates. The rate of resistance to the polyene amphotericin B was 32.0% for all clinical isolates and was 56.4% for vulvovaginal strains. Resistance rate to nystatin was 6.3% for all clinical isolates. Cross-resistance analysis with data of all clinical strains revealed that the incidence of resistance to ketoconazole and itraconazole in fluconazole-resistant isolates was significantly higher than recorded for fluconazole-susceptible isolates. In vitro C. albicans antifungal susceptibility test in this study showed relatively high resistance to commonly and widely used azoles (fluconazole, ketoconazole). Most C. albicans clinical isolates were susceptible to nystatin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Antifungal Susceptibilities of Cryptococcus neoformans

PubMed Central

Tuohy, Marion J.; Wilson, Deborah A.; Nwanyanwu, Okey; Kazembe, Peter N.; Tansuphasawadikul, Somsit; Eampokalap, Boonchuay; Chaovavanich, Achara; Reller, L.Barth; Jarvis, William R.; Hall, Gerri S.; Procop, Gary W.

2004-01-01

Susceptibility profiles of medically important fungi in less-developed countries remain uncharacterized. We measured the MICs of amphotericin B, 5-flucytosine, fluconazole, itraconazole, and ketoconazole for Cryptococcus neoformans clinical isolates from Thailand, Malawi, and the United States and found no evidence of resistance or MIC profile differences among the countries. PMID:15078612

Targeted Disruption of Melanin Biosynthesis Genes in the Human Pathogenic Fungus Lomentospora prolificans and Its Consequences for Pathogen Survival

PubMed Central

Al-Laaeiby, Ayat; Kershaw, Michael J.; Penn, Tina J.; Thornton, Christopher R.

2016-01-01

The dematiaceous (melanised) fungus Lomentospora (Scedosporium) prolificans is a life-threatening opportunistic pathogen of immunocompromised humans, resistant to anti-fungal drugs. Melanin has been shown to protect human pathogenic fungi against antifungal drugs, oxidative killing and environmental stresses. To determine the protective role of melanin in L. prolificans to oxidative killing (H2O2), UV radiation and the polyene anti-fungal drug amphotericin B, targeted gene disruption was used to generate mutants of the pathogen lacking the dihydroxynaphthalene (DHN)-melanin biosynthetic enzymes polyketide synthase (PKS1), tetrahydroxynapthalene reductase (4HNR) and scytalone dehydratase (SCD1). Infectious propagules (spores) of the wild-type strain 3.1 were black/brown, whereas spores of the PKS-deficient mutant ΔLppks1::hph were white. Complementation of the albino mutant ΔLppks1::hph restored the black-brown spore pigmentation, while the 4HNR-deficient mutant ΔLp4hnr::hph and SCD-deficient mutant ΔLpscd1::hph both produced orange-yellow spores. The mutants ΔLppks1::hph and ΔLp4hnr::hph showed significant reductions in spore survival following H2O2 treatment, while spores of ΔLpscd1::hph and the ΔLppks1::hph complemented strain ΔLppks1::hph:PKS showed spore survivals similar to strain 3.1. Spores of the mutants ΔLp4hnr::hph and ΔLpscd1::hph and complemented strain ΔLppks1::hph:PKS showed spore survivals similar to 3.1 following exposure to UV radiation, but survival of ΔLppks1::hph spores was significantly reduced compared to the wild-type strain. Strain 3.1 and mutants ΔLp4hnr::hph and ΔLppks1::hph:PKS were resistant to amphotericin B while, paradoxically, the PKS1- and SCD1-deficient mutants showed significant increases in growth in the presence of the antifungal drug. Taken together, these results show that while melanin plays a protective role in the survival of the pathogen to oxidative killing and UV radiation, melanin does not contribute to its resistance to amphotericin B. PMID:27023523

Targeted Disruption of Melanin Biosynthesis Genes in the Human Pathogenic Fungus Lomentospora prolificans and Its Consequences for Pathogen Survival.

PubMed

Al-Laaeiby, Ayat; Kershaw, Michael J; Penn, Tina J; Thornton, Christopher R

2016-03-24

The dematiaceous (melanised) fungus Lomentospora (Scedosporium) prolificans is a life-threatening opportunistic pathogen of immunocompromised humans, resistant to anti-fungal drugs. Melanin has been shown to protect human pathogenic fungi against antifungal drugs, oxidative killing and environmental stresses. To determine the protective role of melanin in L. prolificans to oxidative killing (H₂O₂), UV radiation and the polyene anti-fungal drug amphotericin B, targeted gene disruption was used to generate mutants of the pathogen lacking the dihydroxynaphthalene (DHN)-melanin biosynthetic enzymes polyketide synthase (PKS1), tetrahydroxynapthalene reductase (4HNR) and scytalone dehydratase (SCD1). Infectious propagules (spores) of the wild-type strain 3.1 were black/brown, whereas spores of the PKS-deficient mutant ΔLppks1::hph were white. Complementation of the albino mutant ΔLppks1::hph restored the black-brown spore pigmentation, while the 4HNR-deficient mutant ΔLp4hnr::hph and SCD-deficient mutant ΔLpscd1::hph both produced orange-yellow spores. The mutants ΔLppks1::hph and ΔLp4hnr::hph showed significant reductions in spore survival following H₂O₂ treatment, while spores of ΔLpscd1::hph and the ΔLppks1::hph complemented strain ΔLppks1::hph:PKS showed spore survivals similar to strain 3.1. Spores of the mutants ΔLp4hnr::hph and ΔLpscd1::hph and complemented strain ΔLppks1::hph:PKS showed spore survivals similar to 3.1 following exposure to UV radiation, but survival of ΔLppks1::hph spores was significantly reduced compared to the wild-type strain. Strain 3.1 and mutants ΔLp4hnr::hph and ΔLppks1::hph:PKS were resistant to amphotericin B while, paradoxically, the PKS1- and SCD1-deficient mutants showed significant increases in growth in the presence of the antifungal drug. Taken together, these results show that while melanin plays a protective role in the survival of the pathogen to oxidative killing and UV radiation, melanin does not contribute to its resistance to amphotericin B.

Epidemiological and mycological characteristics of candidemia in patients with hematological malignancies attending a tertiary-care center in India.

PubMed

Dewan, Eshani; Biswas, Debasis; Kakati, Barnali; Verma, S K; Kotwal, Aarti; Oberoi, Aroma

2015-09-01

We undertook the present study to ascertain the contributing risk factors and explore the epidemiological and mycological characteristics of opportunistic candidemia among patients with hematological malignancies. Observational cross-sectional study in a tertiary care center. Consecutive patients with hematological malignancies reporting to the collaborating medical and pediatric units with a febrile episode were recruited and screened for candidemia by blood culture. Recovered Candida isolates were speciated and antifungal susceptibility testing was performed as per Clinical and Laboratory Standards Institute guideline (CLSI) guidelines M44-A. Further analysis was done for potential risk factors and compared between culture positive and negative patients. Of 150 patients recruited, the majority (n=27) were between 51 and 60 years and the male to female ratio was 1.63:1. Fifteen patients (10%) were culture positive. The culture positivity was significantly higher in acute lymphocytic leukemia (ALL) than in non-ALL patients (p=0.03). There was significant association of candidaemia with leucopenia, chemotherapeutic drugs, corticosteroids and presence of indwelling devices. Duration of disease (p=0.032) and duration of hospitalization (p=0.003) were significantly prolonged in culture positive patients. C. tropicalis was the commonest isolate (46.67%), with non- Candida albicans outnumbering C. albicans in all categories of hematological malignancies (2.75:1). All isolates of C. albicans were uniformly sensitive to all the azoles, but only 50% were sensitive to amphotericin B and none to nystatin and flucytosine. This observational study identifies ALL and chronic lymphocytic leukemia (CLL) as the forms of hematological malignancy predominantly associated with candidemia; specifies risk factors and chemotherapeutic agents predisposing patients towards its occurrence; reports a preponderance of C. tropicalis among the causative agents and finds voriconazole to be the most effective antifungal agent against the recovered isolates. This information could assist in tailoring prophylactic and therapeutic antifungal practices for this infection, according to local epidemiological and mycological characteristics. Copyright © 2015. Published by Elsevier B.V.

Development of a high-throughput Candida albicans biofilm chip.

PubMed

Srinivasan, Anand; Uppuluri, Priya; Lopez-Ribot, Jose; Ramasubramanian, Anand K

2011-04-22

We have developed a high-density microarray platform consisting of nano-biofilms of Candida albicans. A robotic microarrayer was used to print yeast cells of C. albicans encapsulated in a collagen matrix at a volume as low as 50 nL onto surface-modified microscope slides. Upon incubation, the cells grow into fully formed "nano-biofilms". The morphological and architectural complexity of these biofilms were evaluated by scanning electron and confocal scanning laser microscopy. The extent of biofilm formation was determined using a microarray scanner from changes in fluorescence intensities due to FUN 1 metabolic processing. This staining technique was also adapted for antifungal susceptibility testing, which demonstrated that, similar to regular biofilms, cells within the on-chip biofilms displayed elevated levels of resistance against antifungal agents (fluconazole and amphotericin B). Thus, results from structural analyses and antifungal susceptibility testing indicated that despite miniaturization, these biofilms display the typical phenotypic properties associated with the biofilm mode of growth. In its final format, the C. albicans biofilm chip (CaBChip) is composed of 768 equivalent and spatially distinct nano-biofilms on a single slide; multiple chips can be printed and processed simultaneously. Compared to current methods for the formation of microbial biofilms, namely the 96-well microtiter plate model, this fungal biofilm chip has advantages in terms of miniaturization and automation, which combine to cut reagent use and analysis time, minimize labor intensive steps, and dramatically reduce assay costs. Such a chip should accelerate the antifungal drug discovery process by enabling rapid, convenient and inexpensive screening of hundreds-to-thousands of compounds simultaneously.

Susceptibility and molecular characterization of Candida species from patients with vulvovaginitis.

PubMed

Fornari, Gheniffer; Vicente, Vania Aparecida; Gomes, Renata Rodrigues; Muro, Marisol Dominguez; Pinheiro, Rosangela Lameira; Ferrari, Carolina; Herkert, Patricia Fernanda; Takimura, Marcos; Carvalho, Newton Sérgio de; Queiroz-Telles, Flavio

2016-01-01

Vulvovaginal candidiasis affects women of reproductive age, which represents approximately 15-25% of vaginitis cases. The present study aimed to isolate and characterize yeast from the patients irrespective of the presentation of clinical symptoms. The isolates were subjected to in vitro susceptibility profile and characterization by molecular markers, which intended to assess the distribution of species. A total of 40 isolates were obtained and identified through the CHROMagar, API20aux and by ITS and D1/D2 regions sequencing of DNAr gene. Candida albicans strains were genotyped by the ABC system and the isolates were divided into two genotypic groups. The identity of the C. albicans, C. glabrata, C. guilliermondii, C. kefyr and Saccharomyces cerevisiae isolates was confirmed by the multilocus analysis. The strains of Candida, isolated from patients with complications, were found to be resistant to nystatin but sensitive to fluconazole, amphotericin B and ketoconazole, as observed by in vitro sensitivity profile. The isolates from asymptomatic patients, i.e., the colonized group, showed a dose-dependent sensitivity to the anti-fungal agents, fluconazole and amphotericin B. However, the isolates of C. albicans that belong to distinct genotypic groups showed the same in vitro susceptibility profile. Copyright © 2016. Published by Elsevier Editora Ltda.

Synthesis, in-vitro antibacterial, antifungal, and molecular modeling of potent anti-microbial agents with a combined pyrazole and thiophene pharmacophore.

PubMed

Mabkhot, Yahia Nasser; Kaal, Nahed Ahmed; Alterary, Seham; Al-Showiman, Salim S; Barakat, Assem; Ghabbour, Hazem A; Frey, Wolfgang

2015-05-14

Ethyl 5-acetyl-4-methyl-2-(phenylamino)thiophene-3-carboxylate (2) and there derivatives 3a-c, 4, 6a-c and 9a-f were synthesized. The structure of compound 2 was deduced by 1H-NMR, 13C-NMR, FT-IR, MS, microanalysis, and single-crystal X-ray crystallography. The compound crystallized in the monoclinic system, with space group P21/c and cell coordinates a = 8.5752(16) Å, b = 21.046(4) Å, c = 8.2941(12) Å, β = 101.131(6)°, V = 1468.7(4) Å3, and Z = 4. Compounds 2, 3a-c, 4, 5a-c and 9a-f were subjected into in vitro antimicrobial activity tests. Compounds 3a and 3c were more potent than standard drug amphotericin B, showing MIC values of 23.8 ± 0.42 and 24.3 ± 0.68, respectively, against Aspergillus fumigatus while the standard drug MIC was 23.7 ± 0.1. Compound 3c was also more potent (MIC 24.8 ± 0.64) than the standard drug amphotericin B (MIC 19.7 ± 0.2) against Syncephalastrum racemosum. Compounds 4 and 9f also showed promising anti-microbial activity. Molecular modeling was performed for the most active compounds.

Susceptibility of Candida albicans biofilms to azithromycin, tigecycline and vancomycin and the interaction between tigecycline and antifungals.

PubMed

Ku, Tsun Sheng N; Palanisamy, Suresh K A; Lee, Samuel A

2010-11-01

Despite growing data on antimicrobial lock therapy (ALT) in treating bacterial catheter-related bloodstream infections (CR-BSIs), ALT has not been established as a treatment option for CR-BSI caused by Candida albicans. Based on our finding that high-dose doxycycline exhibited antifungal activity against mature C. albicans biofilms, we evaluated additional antibacterial agents with Gram-positive activity [azithromycin, tigecycline (TIG) and vancomycin]. After screening these antibiotics, it was found that TIG had substantial antifungal activity against mature C. albicans biofilms. Therefore, TIG was assayed alone and in combination with fluconazole (FLC), amphotericin B (AmB) or caspofungin (CAS). TIG at 2048 μg/mL resulted in a >50% reduction in the growth of planktonic C. albicans cells. TIG inhibited the formation of biofilms from 128 μg/mL. Against mature biofilms, 2048 μg/mL TIG reduced metabolic activity by 84.2%. Furthermore, addition of 512 μg/mL TIG to FLC at all concentrations tested provided additional reduction in the metabolic activity of mature biofilms. However, this was not superior to 512 μg/mL TIG alone. TIG at 512 μg/mL increased the antifungal effect of lower concentrations of AmB (0.03125-0.25 μg/mL), but at 0.03125 μg/mL and 0.0625 μg/mL this effect was not superior to 512 μg/mL TIG alone. TIG inhibited the antifungal effect of higher concentrations of AmB (≥ 2 μg/mL). TIG at 512 μg/mL inhibited the antifungal activity of CAS at lower concentrations (0.25-8 μg/mL). These data indicate that high-dose TIG is highly active in vitro against planktonic cells, forming biofilms and mature biofilms of C. albicans. Published by Elsevier B.V.

Purification and characterization of antifungal phenazines from a fluorescent Pseudomonas strain FPO4 against medically important fungi.

PubMed

Gorantla, J N; Kumar, S Nishanth; Nisha, G V; Sumandu, A S; Dileep, C; Sudaresan, A; Kumar, M M Sree; Lankalapalli, R S; Kumar, B S Dileep

2014-09-01

The strain FPO4 was isolated from the rhizoplane of rice plant root and identified as a fluorescent Pseudomonas aeruginosa on the basis of 16S rDNA sequences and BLAST analysis. The extracellular metabolites produced by this strain were purified by silica gel column chromatography and isolated four pure compounds. Based on the spectral data the four compounds were identified as phenazin-1-ol, phenazine-1-carboxylic acid (PCA), 2-heptyl-3-hydroxyl-4(1H)-quinolone (PQS), and phenazine-1-carboxamide (PCN), respectively. Phenazin-1-ol and PCA were active against all the eight fungi tested. The highest activity of 4 μg/mL by PCA was recorded against Trichophyton rubrum, a human pathogen responsible for causing athlete's foot, jock itch, ringworm and fingernail fungus infections, followed by Candida albicans and Candida tropicalis. The activity of phenazin-1-ol, PCA against Candida spp. was found to be better than the standard antifungal agent amphotericin B. Furthermore, the present study reports the antimicrobial activity of the purified phenazines on major human pathogen, T. rubrum for the first time. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Fungal prosthetic valve endocarditis with mycotic aneurysm: Case report.

PubMed

Brandão, Mariana; Almeida, Jorge; Ferraz, Rita; Santos, Lurdes; Pinho, Paulo; Casanova, Jorge

2016-09-01

Fungal prosthetic valve endocarditis is an extremely severe form of infective endocarditis, with poor prognosis and high mortality despite treatment. Candida albicans is the most common etiological agent for this rare but increasingly frequent condition. We present a case of fungal prosthetic valve endocarditis due to C. albicans following aortic and pulmonary valve replacement in a 38-year-old woman with a history of surgically corrected tetralogy of Fallot, prior infective endocarditis and acute renal failure with need for catheter-based hemodialysis. Antifungal therapy with liposomal amphotericin B was initiated prior to cardiac surgery, in which the bioprostheses were replaced by homografts, providing greater resistance to recurrent infection. During hospitalization, a mycotic aneurysm was diagnosed following an episode of acute arterial ischemia, requiring two vascular surgical interventions. Despite the complications, the patient's outcome was good and she was discharged on suppressive antifungal therapy with oral fluconazole for at least a year. The reported case illustrates multiple risk factors for fungal endocarditis, as well as complications and predictors of poor prognosis, demonstrating its complexity. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of Amphotericin B antibiotic on the properties of model lipid membrane

NASA Astrophysics Data System (ADS)

Kiryakova, S.; Dencheva-Zarkova, M.; Genova, J.

2014-12-01

Model membranes formed from natural and synthetic lipids are an interesting object for scientific investigations due to their similarity to biological cell membrane and their simple structure with controlled composition and properties. Amphotericin B is an important polyene antifungal antibiotic, used for treatment of systemic fungal infections. It is known from the literature that the studied antibiotic has a substantial effect on the transmembrane ionic channel structures. When applied to the lipid membranes it has the tendency to create pores and in this way to affect the structure and the properties of the membrane lipid bilayer. In this work the thermally induced shape fluctuations of giant quasi-spherical liposomes have been used to study the influence of polyene antibiotic amphotericin B on the elastic properties of model lipid membranes. It have been shown experimentally that the presence of 3 mol % of AmB in the lipid membrane reduces the bending elasticity of the lipid membrane for both studied cases: pure SOPC membrane and mixed SOPC-Cholesterol membrane. Interaction of the amphotericin B with bilayer lipid membranes containing channels have been studied in this work. Model membranes were self-assembled using the patch-clamp and tip-dip patch clamp technique. We have found that amphotericin B is an ionophore and reduces the resistance of the lipid bilayer.

Stimulation of monocytes, macrophages, and microglia by amphotericin B and macrophage colony-stimulating factor promotes remyelination.

PubMed

Döring, Axinia; Sloka, Scott; Lau, Lorraine; Mishra, Manoj; van Minnen, Jan; Zhang, Xu; Kinniburgh, David; Rivest, Serge; Yong, V Wee

2015-01-21

Approaches to stimulate remyelination may lead to recovery from demyelinating injuries and protect axons. One such strategy is the activation of immune cells with clinically used medications, since a properly directed inflammatory response can have healing properties through mechanisms such as the provision of growth factors and the removal of cellular debris. We previously reported that the antifungal medication amphotericin B is an activator of circulating monocytes, and their tissue-infiltrated counterparts and macrophages, and of microglia within the CNS. Here, we describe that amphotericin B activates these cells through engaging MyD88/TRIF signaling. When mice were subjected to lysolecithin-induced demyelination of the spinal cord, systemic injections of nontoxic doses of amphotericin B and another activator, macrophage colony-stimulating factor (MCSF), further elevated the representation of microglia/macrophages at the site of injury. Treatment with amphotericin B, particularly in combination with MCSF, increased the number of oligodendrocyte precursor cells and promoted remyelination within lesions; these pro-regenerative effects were mitigated in mice treated with clodronate liposomes to reduce circulating monocytes and tissue-infiltrated macrophages. Our results have identified candidates among currently used medications as potential therapies for the repair of myelin. Copyright © 2015 the authors 0270-6474/15/351136-13$15.00/0.

Experimental treatment of Curvularia infection.

PubMed

Paredes, Katihuska; Capilla, Javier; Sutton, Deanna A; Mayayo, Emilio; Fothergill, Annette W; Guarro, Josep

2014-08-01

We have evaluated the efficacy of amphotericin B, posaconazole, and voriconazole in immunosuppressed murine models of disseminated infection by Curvularia spicifera and Curvularia hawaiiensis. The 3 antifungals improved survival of mice in comparison to controls; however, only the 2 azoles were able to reduce significantly the fungal load. Copyright © 2014 Elsevier Inc. All rights reserved.

[Use of flour from sunflower oil cake in the biosynthesis of antigungal antibiotics].

PubMed

Sukharevich, V M; Shvetsova, N N; Prodan, S I; Malkov, M A

1977-04-01

The possibility of replacing soybean meal and corn-steep liquor by food wastes of the oilpress industry and the meal of the sunflower oil cake in particular is discussed as applied to the fermentation media for production of antifungal antibiotics, such as levorin, mycoheptin, amphotericin. The studies showed that replacement of soybean meal by sunflower oil cake meal with simultaneous increasing of the amount of carbohydrates in the medium increased the levorin levels by 60--70 per cent as compared to the media used at present. When soybean meal and corn-steep liquor were simultaneously replaced by sunflower oil cake meal in amounts of 3--4 per cent the levels of mycoheptin in the fermentation broth increased by 30--65 per cent respectively. Replacement of soybean meal and corn-steep liquor by 3 per cent of sunflow oil cake meal in the medium used presently increased the amphotericin levels by 27 percent as compared to the control. Therefore, sunflower oil cake meal is a substitute of full value for soybean meal and corn-steep liquor in the fermentation media for production of antifungal antibiotics.

[Isolation of Scedosporium apiospermum (teleomorph: Pseudallescheria apiosperma) from an acute myeloid leukemia patient].

PubMed

Ergin, Cağrı; Kutlu, Murat; Arıkan Akdağlı, Sevtap; Sarıbaş, Zeynep; Aydeniz Ozansoy, Fatma; Sarı, Ismail; Dursunoğlu, Neşe

2013-04-01

Scedosporium apiospermum is an emerging opportunistic pathogen that may lead to life-threatening infections especially in immunosuppressive individuals. In this report, S.apiospermum infection in a 62 year old male patient with acute myeloid leukemia was presented. During remission-induction chemotherapy, piperacillin-tazobactam therapy was started for febrile neutropenia. Since fever had continued, treatment was switched to imipenem and also amphotericin B deoxycholate was added to the treatment protocol. Because of allergic reaction to amphotericin B, caspofungin was started at the fifth day of neutropenic fever. Following imaging studies with high resolution computerized thorasic tomography, antifungal therapy was changed to voriconazole due to findings suggestive of invasive aspergillosis. Since galactomannan antigen was found negative at the first day of voriconazole therapy, bronchoalveolar lavage material from apical segment of the left lower lobe was cultured onto various microbiologic media. S.apiospermum (Teleomorph: Pseudallescheria apiosperma) was isolated on the fourth day of cultivation. According to CLSI M38-A2 microdilution procedure, minimum inhibitory concentrations (MIC) of voriconazole, caspofungin, amphotericin B and posaconazole were found as 0.06, 2, 8 and 4 µg/ml, respectively. Since neutropenia was resolved, the patient was discharged with continued voriconazole therapy. It was concluded that antifungal susceptibility tests should be performed for Scedosporium species and the results should be compared to the clinical response. The determination of MIC breakpoints may provide useful information for the recommendation and use of optimal choices for the treatment of Scedosporium infections.

Aspergillus spondylodiscitis after multivisceral transplantation.

PubMed

Gerlach, Undine A; Kohler, Sven; Sauer, Igor M; Joerres, Dinah; Kandziora, Frank; Neuhaus, Peter; Pratschke, Johann; Pascher, Andreas

2009-01-01

Although spondylodiscitis is rare, it is increasingly described in patients with compromised immunity due to malignancy, chemotherapy or immunosuppression. Typical pathogens are staphylococcus aureus and enterobacteria; fungal spondylodiscitis is uncommon. We present a case of aspergillus spondylodiscitis following pulmonary aspergillosis in a patient with multivisceral and kidney transplantation. Due to irreversible disc destruction, surgical restoration by autologous iliac crest graft was required in addition to intravenous antifungal therapy, which consisted of voriconazole, caspofungin and liposomal amphotericin B. Aspergillus spondylodiscitis is a diagnostic and therapeutic challenge, a combination of surgical debridement and antifungal therapy is inevitable to prevent rapid progression of invasive aspergillosis and neurological damage.

Antifungal catheter lock therapy for the management of a persistent Candida albicans bloodstream infection in an adult receiving hemodialysis.

PubMed

Paul DiMondi, V; Townsend, Mary L; Johnson, Melissa; Durkin, Michael

2014-07-01

Antifungal catheter lock therapy (AfLT) with liposomal amphotericin B has been used in the treatment of pediatric central line infections caused by Candida species; however, reports describing the use of liposomal amphotericin B lock therapy in the adult hemodialysis patient population are lacking. Management of central line-associated candidemia with systemic therapy alone is often challenging due to the propensity of Candida species to form biofilms on foreign bodies. We describe a 64-year-old woman who was receiving hemodialysis 3 times/week and was hospitalized with persistent fungemia. Despite receiving intravenous micafungin, she had multiple positive blood cultures for Candida albicans, which finally cleared after 7 days. Her double-lumen catheter was considered the most likely nidus of infection. Although catheter removal would have been preferred, this was not possible given her vasculopathy, history of multiple bloodstream infections, and lack of other available sites for vascular access. Catheter exchange was performed, and liposomal amphotericin B AfLT was administered in combination with intravenous micafungin for a total of 6 days. During this time, the patient experienced no discernible adverse effects secondary to AfLT. At discharge, AfLT was discontinued, and intravenous micafungin was changed to oral fluconazole. After 6 months of treatment, the patient remained culture negative and maintained her dialysis access. To our knowledge, this is the first case report of liposomal amphotericin B catheter lock therapy used to manage a persistent C. albicans bloodstream infection in an adult receiving hemodialysis. AfLT is a novel concept for treating catheter-associated fungal infections. Liposomal amphotericin B was chosen based on its favorable in vitro activity against Candida species biofilms in catheter lock environments. We identified several barriers to implementing AfLT, and these issues may prohibit the use of AfLT. This case report illustrates the benefits and challenges of managing catheter-associated fungal infections with AfLT. Further study is required to examine the efficacy, safety, and feasibility of this approach. © 2014 Pharmacotherapy Publications, Inc.

Targeting the Oxidative Stress Response System of Fungi with Redox-Potent Chemosensitizing Agents

PubMed Central

Kim, Jong H.; Chan, Kathleen L.; Faria, Natália C. G.; Martins, M. de L.; Campbell, Bruce C.

2012-01-01

The cellular antioxidant system is a target in the antifungal action of amphotericin B (AMB) and itraconazole (ITZ), in filamentous fungi. The sakAΔ mutant of Aspergillus fumigatus, a mitogen-activated protein kinase (MAPK) gene deletion mutant in the antioxidant system, was found to be more sensitive to AMB or ITZ than other A. fumigatus strains, a wild type and a mpkCΔ mutant (a MAPK gene deletion mutant in the polyalcohol sugar utilization system). Complete fungal kill (≥99.9%) by ITZ or AMB was also achieved by much lower dosages for the sakAΔ mutant than for the other strains. It appears msnA, an Aspergillus ortholog to Saccharomyces cerevisiae MSN2 (encoding a stress-responsive C2H2-type zinc-finger regulator) and sakA and/or mpkC (upstream MAPKs) are in the same stress response network under tert-butyl hydroperoxide (t-BuOOH)-, hydrogen peroxide (H2O2)- or AMB-triggered toxicity. Of note is that ITZ-sensitive yeast pathogens were also sensitive to t-BuOOH, showing a connection between ITZ sensitivity and antioxidant capacity of fungi. Enhanced antifungal activity of AMB or ITZ was achieved when these drugs were co-applied with redox-potent natural compounds, 2,3-dihydroxybenzaldehyde, thymol or salicylaldehyde, as chemosensitizing agents. We concluded that redox-potent compounds, which target the antioxidant system in fungi, possess a chemosensitizing capacity to enhance efficacy of conventional drugs. PMID:22438852

Flaws in design, analysis and interpretation of Pfizer's antifungal trials of voriconazole and uncritical subsequent quotations.

PubMed

Jørgensen, Karsten J; Johansen, Helle Krogh; Gøtzsche, Peter C

2006-01-19

We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.

In vitro susceptibility of Sporothrix schenckii to six antifungal agents determined using three different methods.

PubMed

Alvarado-Ramírez, Eidi; Torres-Rodríguez, Josep M

2007-07-01

The in vitro susceptibility of Sporothrix schenckii to antifungal drugs has been determined with three different methods. Nineteen Peruvian clinical isolates of S. schenckii were tested against amphotericin B (AB), flucytosine (FC), fluconazole (FZ), itraconazole (IZ), voriconazole (VZ), and ketoconazole (KZ). Modified NCCLS M38-A, Sensititre YeastOne (SYO), and ATB Fungus 2 (ATBF2) methods were used to determine the MICs. ATCC isolates of Candida parapsilosis, Candida krusei, and Aspergillus flavus were used for quality control. Sporothrix inocula were prepared with the mycelial form growing on potato dextrose agar at 28 +/- 2 degrees C. MICs of AB, FC, FZ, and IZ were determined with all three methods, VZ with M38-A and SYO, and KZ with only SYO. The three methods showed high MICs of FZ and FC (MIC(90) of 0.5 microg/ml), being homogeneously lower than those of IZ and KZ. The M38-A method showed a variable MIC range of VZ (4.0 to 16 microg/ml); the geometric mean (GM) was 9.3 mug/ml. The MIC range of AB was wide (0.06 to 16 microg/ml), but the GM was 1.2 microg/ml, suggesting that the MIC is strain dependent. Agreement (two log(2) dilutions) between commercial techniques and the modified M38-A method was very high with FZ, IZ, and FC. In AB and VZ, the agreement was lower, being related to the antifungal concentrations of each method. The highest activity against S. schenckii was found with IZ and KZ. Lack of activity was observed with FZ, VZ, and FC. When AB is indicated for sporotrichosis, the susceptibility of the strain must be analyzed. Commercial quantitative antifungal methods have a limited usefulness in S. schenckii.

Current Antimicrobial Usage for the Management of Neutropenic Fever in Korea: A Nationwide Survey

PubMed Central

Choi, Su-Mi; Park, Sun Hee; Lee, Dong-Gun; Choi, Jung-Hyun; Yoo, Jin-Hong

2008-01-01

A nationwide questionnaire-based survey was performed to evaluate the current clinical practices for the management of neutropenic fever in hematology units and hematopoietic stem cell transplantation (HSCT) centers throughout Korea. A 86.9% response rate was obtained from a total of 46 doctors and practical policies of the 33 sites were analysed. Approximately 42.4% and 84.8% of the sites responded that they used oral fluoroquinolone as prophylaxis for neutropenic patients receiving chemotherapy and HSCT, respectively. Additionally, 42.4% of the sites responded that they used antifungal prophylaxis in the chemotherapy groups whereas 90.9% of the sites responded that they used antifungal prophylaxis in HSCT recipients. Approximately half of the responding sites prescribed combination regimen with 3rd or 4th cephalosporin plus aminoglycoside as a first-line therapy. Most of the sites considered persistent fever for 2-4 days or aggravated clinical symptoms for 1-2 days as failure of the first-line regimen, and they changed antibiotics to second-line regimens that varied widely among the sites. Twenty-seven sites (84.4%) responded that they considered adding an antifungal agent when fever persisted for 5-7 days despite antibacterial therapy. Amphotericin B deoxycholate was preferred as a first-line antifungal, which was probably due to the limitations of the national health insurance system. The role of oral antibiotics in the management of neutropenic fever still accounted for a small portion. To the best of our knowledge, this survey is the first report to examine the practical policies currently in place for the management of neutropenic fever in Korea and the results of this survey may help to establish a Korean guideline in the future. PMID:19119433

Dihydroorotate dehydrogenase inhibitor F901318 has potent in vitro activity against Scedosporium species and Lomentospora prolificans.

PubMed

Wiederhold, Nathan P; Law, Derek; Birch, Michael

2017-07-01

Scedosporium species and Lomentospora prolificans are increasing causes of invasive infections in immunocompromised hosts and many isolates are resistant to available antifungals. Our objective was to assess the in vitro potency of F901318, a member of the orotomide class of antifungals, against Scedosporium species and L. prolificans . The in vitro potency of F901318 was evaluated against 66 Scedosporium and 7 L. prolificans clinical isolates using the CLSI M38-A2 reference standard. Scedosporium species included Scedosporium apiospermum ( n  =   43), Scedosporium aurantiacum ( n  =   6), Scedosporium dehoogii ( n  =   2) and Scedosporium boydii ( n  =   15). Positive comparators included amphotericin B, caspofungin, posaconazole and voriconazole. Against S. apiospermum and S. boydii F901318 geometric mean MICs/MECs (0.079 and 0.046 mg/L, respectively) were significantly lower than those observed with amphotericin (3.404 and 5.595 mg/L), posaconazole (1.937 and 1.823 mg/L), voriconazole (0.784 and 0.630 mg/L) and caspofungin (5.703 and 7.639 mg/L) ( P  <   0.001). Against S. aurantiacum and S. dehoogii the F901318 MIC range (0.12-0.5 mg/L) was also lower than those for the other antifungals (0.5 to >8 mg/L). F901318 also maintained activity against L. prolificans isolates (range 0.12-0.25 mg/L) in contrast to other antifungals, of which none demonstrated in vitro activity. F901318 demonstrated potent in vitro activity against Scedosporium species and L. prolificans . This activity was maintained against isolates that had significantly reduced susceptibility to the other antifungals. Further studies are warranted to evaluate the in vivo efficacy of F901318 against Scedosporium species and L. prolificans . © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

In vitro interactions between amphotericin B and hydrocortisone: potential implications for intrathecal therapy.

PubMed

Hodge, Greg; Cohen, Stuart H; Thompson, George R

2015-09-01

Fungal meningitis remains a severe and often lethal infection requiring aggressive antifungal therapy and in refractory cases the use of intrathecal amphotericin B (AmB). Administration of amphotericin B by this method may result in clinically apparent adverse reactions such as paresthesias, radiculitis, or myelopathy. Coadministration of hydrocortisone is therefore often given in an attempt to avoid these effects; however, the potential consequences of this approach on fungal growth or on drug synergy/antagonism had not previously been assessed. We used the checkerboard titration broth microdilution method to analyze interactions by fractional inhibitory concentration indices (FICIs). The combination of amphotericin B and hydrocortisone resulted in synergy or indifference against all isolates (Candida, Cryptococcus, and Coccidioides) during in vitro testing at low concentrations. Antagonism was observed using higher hydrocortisone concentrations (those not observed in vivo) suggesting possible steric hindrance or binding to AmB may occur at doses unlikely to be present during clinical care. Concurrent hydrocortisone and AmB administration should not be avoided due to in vitro antagonism concerns. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cyclic dipeptides from rhabditid entomopathogenic nematode-associated Bacillus cereus have antimicrobial activities.

PubMed

Nishanth Kumar, S; Nath, Vishnu Sukumari; Pratap Chandran, R; Nambisan, Bala

2014-02-01

The cell free culture filtrate of Bacillus cereus associated with an entomopathogenic nematode, Rhabditis (Oscheius) sp. exhibited strong antimicrobial activity. The ethyl acetate extract of the bacterial culture filtrate was purified by silica gel column chromatography to obtain four bioactive compounds. The structure and absolute stereochemistry of these compounds were determined based on extensive spectroscopic analyses (FABMS, (1)H NMR, (13)C NMR, (1)H-(1)H COSY, (1)H-(13)C HMBC) and Marfey's method. The compounds were identified as cyclic dipeptides (CDPs): cyclo(L-Pro-L-Trp), cyclo(L-Leu-L-Val), cyclo(D-Pro-D-Met), and cyclo(D-Pro-D-Phe), respectively. Compounds recorded significant antibacterial activity against all the test bacteria (Staphylococcus epidermidis, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant S. aureus) except cyclo(L-Leu-L-Val). Cyclo(L-Leu-L-Val) recorded activity only against Gram positive bacteria. Best antibacterial activity was recorded by cyclo(L-Pro-L-Trp) against S. aureus (4 μg/ml). The four compounds were active against all the five fungi tested (Trichophyton rubrum, Aspergillus flavus, Candida albicans, Candida tropicalis and Cryptococcus neoformans) and the activity was compared with amphotericin B, the standard fungicide. The highest activity of 1 μg/ml by cyclo(L-Pro-L-Trp) was recorded against T. rubrum, a human pathogen responsible for causing athlete's foot, jock itch, and ringworm. The activity of cyclo(L-Pro-L-Trp) against T. rubrum, C. neoformans and C. albicans were better than amphotericin B, the standard antifungal agent. To our knowledge, this is the first report of antifungal activity of CDPs against the human pathogenic fungi T. rubrum and C. neoformans. The four CDPs are nontoxic to healthy human cell line up to 200 μg/ml. We conclude that the bacterium associated with entomopathogenic nematode is promising sources of natural antimicrobial secondary metabolites, which may receive greater benefit as potential sources of new drugs in the pharmaceutical industry.

Rhodotorula fungemia of an intensive care unit patient and review of published cases.

PubMed

Spiliopoulou, Anastasia; Anastassiou, Evangelos D; Christofidou, Myrto

2012-10-01

Rhodotorula species are commensal yeasts that have emerged as a cause of life-threatening fungemia in severely immunocompromised patients. A case of Rhodotorula mucilaginosa fungemia in a 48-year-old woman that had undergone consecutive abdominal surgeries due to ovarian cancer and bowel necrosis while she was receiving fluconazole prophylaxis is presented. Several risk factors were identified such as presence of central venous catheters, solid organ neoplasm, abdominal surgery and administration of antibiotics. Identification was performed using commercial systems. The yeast was resistant to fluconazole, posaconazole and voriconazole and to echinocandins, whereas MIC to amphotericin B was 1.5 mg/L. Furthermore, published cases of Rhodotorula spp fungemia during the last decade are reviewed. In conclusion, Rhodotorula spp must be considered a potential pathogen in patients with immunosupression and central venous catheters. Correct identification is mandatory for appropriate management, as Rhodotorula spp are resistant to antifungal agents, such as fluconazole and echinocandins.

Water-soluble polymer–drug conjugates for combination chemotherapy against visceral leishmaniasis

PubMed Central

Nicoletti, Salvatore; Seifert, Karin; Gilbert, Ian H.

2010-01-01

There is a need for new safe, effective and short-course treatments for leishmaniasis; one strategy is to use combination chemotherapy. Polymer–drug conjugates have shown promise for the delivery of anti-leishmanial agents such as amphotericin B. In this paper, we report on the preparation and biological evaluation of polymer–drug conjugates of N-(2-hydroxypropyl)methacrylamide (HPMA), amphotericin B and alendronic acid. The combinatorial polymer–drug conjugates were effective anti-leishmanial agents in vitro and in vivo, but offered no advantage over the single poly(HPMA)–amphotericin B conjugates. PMID:20338769

Amphotericin-B entrapped lecithin/chitosan nanoparticles for prolonged ocular application.

PubMed

Chhonker, Yashpal S; Prasad, Yarra Durga; Chandasana, Hardik; Vishvkarma, Akhilesh; Mitra, Kalyan; Shukla, Praveen K; Bhatta, Rabi S

2015-01-01

Fungal keratitis is the major cause of vision loss worldwide. Amphotericin-B is considered as the drug of choice for fungal infections. However, its use in ophthalmic drug delivery is limited by the low precorneal residence at ocular surface as a result of blinking reflex, tear turnover and nasopharyngeal drainage. We report Amphotericin-B loaded lecithin/chitosan nanoparticles for prolonged ocular application. The prepared nanoparticles were in the size range of 161.9-230.5 nm, entrapment efficiency of 70-75%, theoretical drug loading of 5.71% with positive zeta potential of 26.6-38.3 mV. As demonstrated by antifungal susceptibility against Candida albicans and Aspergillus fumigatus, nanoparticles were more effective than marketed formulation. They exhibited pronounced mucoadhesive properties. In-vivo pharmacokinetic studies in New Zealand albino rabbit eyes indicated improved bioavailablity (∼ 2.04 fold) and precorneal residence time (∼ 3.36 fold) by nanoparticles prepared from low molecular weight chitosan as compared with marketed formulation. Copyright © 2014. Published by Elsevier B.V.

Recent developments in the management of invasive fungal infections in patients with oncohematological diseases.

PubMed

Ruhnke, Markus; Schwartz, Stefan

2016-12-01

Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other non- Aspergillus molds are increasingly be identified in cases of documented IFDs. Important risk factors are long lasting granulocytopenia with neutrophil counts below 500/μl for more than 10 days or graft- versus -host disease resulting from allogeneic stem-cell transplantation. For definite diagnosis of IFD, various diagnostic tools have to be applied, including conventional mycological culture and nonconventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. In the last few years, various laboratory methods, like the Aspergillus GM immunoassay ( Aspergillus GM EIA), 1,3-ß-D-glucan (BG) assay or polymerase chain reaction (PCR) techniques have been developed for better diagnosis. Since no single indirect test, including radiological methods, provides the definite diagnosis of an invasive fungal infection, the combination of different diagnostic procedures, which include microbiological cultures, histological, serological and molecular methods like PCR together with the pattern of clinical presentation, may currently be the best strategy for the prompt diagnosis, initiation and monitoring of IFDs. Early start of antifungal therapy is mandatory, but clinical diagnostics often do not provide clear evidence of IFD. Integrated care pathways have been proposed for management and therapy of IFDs with either the diagnostic driven strategy using the preemptive antifungal therapy as opposed to the clinical or empirical driven strategy using the 'traditional' empirical antifungal therapy. Antifungal agents preferentially used for systemic therapy of invasive fungal infections are amphotericin B preparations, fluconazole, voriconazole, posaconazole, caspofungin, anidulafungin, micafungin, and most recently isavuconazole. Clinical decision making must consider licensing status, local experience and availability, pharmacological and economic aspects.

Synergy between cilofungin and amphotericin B in a murine model of candidiasis.

PubMed Central

Hanson, L H; Perlman, A M; Clemons, K V; Stevens, D A

1991-01-01

The efficacies of cilofungin and amphotericin B separately and together in mice with disseminated candidiasis were studied. Male CD-1 mice (age, 5 weeks) were infected intravenously with 3 X 10(5) CFU of Candida albicans. At 4 days postinfection, intraperitoneal therapy was initiated and was continued for 14 days. Therapy groups included those given cilofungin at 6.25 or 62.5 mg/kg/day (given twice daily), amphotericin B at 0.625 mg/kg/day (given once daily), cilofungin at 6.25 mg/kg/day plus amphotericin B, and cilofungin at 62.5 mg/kg/day plus amphotericin B. Mice were observed through 30 days postinfection. All infected untreated mice died of infection between days 6 and 18. Eighty-five percent of mice receiving cilofungin at 6.25 mg/kg/day died between days 13 and 30. All other mice survived. Quantitative determination of the number of CFU of C. albicans in the spleens and kidneys of all survivors revealed that mice that had received both drugs had lower residual burdens of C. albicans. All mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B had sterile spleens, whereas 42 to 58% of mice given cilofungin or amphotericin B monotherapy had sterile spleens. All kidneys were infected in mice which had received cilofungin at 62.5 mg/kg/day or amphotericin B. Neither organ was infected in 17% of each group receiving combination therapy with cilofungin and amphotericin B. The number of CFU in the kidneys of mice treated with cilofungin at 62.5 mg/kg/day plus amphotericin B was lower than those cultured from mice treated with cilofungin at 62.5 mg/kg/day (P less than 0.001, Mann-Whitney) or amhotericin B (P less than 0.05). Modest synergy was noted in inhibition of the C. albicans isolate in vitro. Pharmacokinetic studies showed elevated levels of cilofungin but not amphotericin B in sera of mice treated with combined therapy compared with those in mice given monotherapy. No overt toxicity was evident with any regimen. The mechanism of increased efficacy may be altered cilofungin distribution, excretion, or metabolism; antifungal synergy; or both. These results indicate that concurrent cilofungin-amphotericin B therapy has synergistic or additive efficacy in vivo. PMID:1929290

Antifungal susceptibility of Malassezia furfur, Malassezia sympodialis, and Malassezia globosa to azole drugs and amphotericin B evaluated using a broth microdilution method.

PubMed

Rojas, Florencia D; Sosa, María de los A; Fernández, Mariana S; Cattana, María E; Córdoba, Susana B; Giusiano, Gustavo E

2014-08-01

We studied the in vitro activity of fluconazole (FCZ), ketoconazole (KTZ), miconazole (MCZ), voriconazole (VCZ), itraconazole (ITZ) and amphotericin B (AMB) against the three major pathogenic Malassezia species, M. globosa, M. sympodialis, and M. furfur. Antifungal susceptibilities were determined using the broth microdilution method in accordance with Clinical and Laboratory Standards Institute reference document M27-A3. To support lipid-dependent yeast development, glucose, peptone, ox bile, malt extract, glycerol, and Tween supplements were added to Roswell Park Memorial Institute RPMI 1640 medium. The supplemented medium allowed good growth of all three species studied. The minimal inhibitory concentrations (MICs) were recorded after 72 h of incubation at 32ºC. The three species showed different susceptibility profiles for the drugs tested. Malassezia sympodialis was the most susceptible and M. furfur the least susceptible species. KTZ, ITZ, and VCZ were the most active drugs, showing low variability among isolates of the same species. FCZ, MCZ, and AMB showed high MICs and wide MIC ranges. Differences observed emphasize the need to accurately identify and evaluate antifungal susceptibility of Malassezia species. Further investigations and collaborative studies are essential for correlating in vitro results with clinical outcomes since the existing limited data do not allow definitive conclusions. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A Fatal Case of Candida auris and Candida tropicalis Candidemia in Neutropenic Patient.

PubMed

Mohd Tap, Ratna; Lim, Teck Choon; Kamarudin, Nur Amalina; Ginsapu, Stephanie Jane; Abd Razak, Mohd Fuat; Ahmad, Norazah; Amran, Fairuz

2018-06-01

We report a fatal case of Candida auris that was involved in mixed candidemia with Candida tropicalis, isolated from the blood of a neutropenic patient. Identification of both isolates was confirmed by amplification and sequencing of internal transcribed spacer and D1/D2 domain of large subunit in rRNA gene. Antifungal susceptibility test by E-test method revealed that C. auris was resistant to amphotericin B, anidulafungin, caspofungin, fluconazole, itraconazole and voriconazole. On the other hand, C. tropicalis was sensitive to all antifungal tested. The use of chromogenic agar as isolation media is vital in detecting mixed candidemia.

Candidaemia and antifungal susceptibility testing in a teaching hospital.

PubMed

Tzar, M N; Shamim, A S

2009-03-01

We reviewed cases of candidaemia at Universiti Kebangsaan Malaysia Medical Centre from 1st January 2005 to 30th June 2006. All blood cultures positive for Candida species or its teleomorphs within the study period were identified and antifungal susceptibility testing was performed. Out of 50 blood isolates, 20 (40%) were identified as Candida albicans, 16 (32%) C. tropicalis, five (10%) C. parapsilosis, three (6%) C. famata, two (4%) C. glabrata, two (4%) Pichia ohmeri, one (2%) C. krusei and one (2%) P. etchell/carsonii. Susceptibility to amphotericin B was 100%, fluconazole 90%, itraconazole 40%, ketoconazole 88%, 5-flucytosine 98% and voriconazole 98%.

Bovine Serum Albumin Nanoparticles Containing Amphotericin B: Characterization, Cytotoxicity and In Vitro Antifungal Evaluation.

PubMed

Casa, Diani Meza; Karam, Thaysa Ksiaskiewcz; Alves, Aline de Cristo Soares; Zgoda, Aline Aparecida; Khalil, Najeh Maissar; Mainardes, Rubiana Mara

2015-12-01

In this study, nanoparticles based on bovine serum albumin (BSA) containing amphotericin B (AmB) were obtained by the desolvation method and characterized with respect to size, size distribution, AmB encapsulation efficiency, AmB state of aggregation, and AmB in vitro release profile. After, the effect of nanoparticles on the cytotoxicity of human erythrocytes in vitro and efficacy over strains of Candida spp. were evaluated. The mean particle size was 156 nm and the AmB encapsulation efficiency was over 82%. The in vitro release profile revealed a sustained release of approximately 48% of AmB over 5 days. AmB is present in BSA nanoparticles as monomer. AmB-loaded nanoparticles showed very low index of hemolysis (less than 8%) in 72 h of assay compared to free AmB, which presented 100% of hemolysis in 2 h of incubation. The AmB-loaded BSA nanoparticles were as effective as free AmB against Candida albicans and Candida tropicalis, considering their sustained release profile. Thus, BSA nanoparticles are potential carriers for AmB, reducing its molecular aggregation and prolonging its release, resulting in lower cytotoxicity while maintaining its antifungal activity.

The antifungal effect of silver nanoparticles on Trichosporon asahii.

PubMed

Xia, Zhi-Kuan; Ma, Qiu-Hua; Li, Shu-Yi; Zhang, De-Quan; Cong, Lin; Tian, Yan-Li; Yang, Rong-Ya

2016-04-01

Silver nanoparticles are receiving increasing attention in biomedical applications. This study aims at evaluating the antifungal properties of silver nanoparticles against the pathogenic fungus Trichosporon asahii. The growth of T. asahii on potato dextrose agar medium containing different concentrations of silver nanoparticles was examined and the antifungal effect was evaluated using minimum inhibitory concentration. Scanning and transmission electron microscopy were also used to investigate the antifungal effect of silver nanoparticles on T. asahii. Silver nanoparticles had a significant inhibitory effect on the growth of T. asahii. The minimum inhibitory concentration of silver nanoparticles against T. asahii was 0.5 μg/mL, which was lower than amphotericin B, 5-flucytosine, caspofungin, terbinafine, fluconazole, and itraconazole and higher than voriconazole. Silver nanoparticles obviously damaged the cell wall, cell membrane, mitochondria, chromatin, and ribosome. Our results demonstrate that silver nanoparticles have good antifungal activity against T. asahii. Based on our electron microscopy observations, silver nanoparticles may inhibit the growth of T. asahii by permeating the fungal cell and damaging the cell wall and cellular components. Copyright © 2014. Published by Elsevier B.V.

Assessing the potential of four cathelicidins for the management of mouse candidiasis and Candida albicans biofilms.

PubMed

Yu, Haining; Liu, Xuelian; Wang, Chen; Qiao, Xue; Wu, Sijin; Wang, Hui; Feng, Lan; Wang, Yipeng

2016-02-01

As the most common fungal pathogen of humans, severe drug resistance has emerged in the clinically isolated Candida albicans, which lead to the urgency to develop novel antifungal agents. Here, four our previously characterized cathelicidins (cathelicidin-BF, Pc-CATH1, Cc-CATH2, Cc-CATH3) were selected and their antifungal activities against C. albicans were evaluated in vitro and in vivo using amphotericin B and LL-37 as control. Results showed that all four cathelicidins could eradicate standard and clinically isolated C. albicans strains with most MIC values ranging from 1 to 16 μg/ml, in less than 0.5 h revealed by time-kill kinetic assay. Four peptides only exhibited slight hemolytic activity with most HC50 > 200 μg/ml, and retained potent anti-C. albicans activity at salt concentrations below and beyond physiological level. In animal experiment, 50 mg/kg administration of the four cathelicidins could significantly reduce the fungal counts in a murine oral candidiasis model induced by clinically isolated C. albicans. The antibiofilm activity of cathelicidin-BF, the most potent among the five peptides was evaluated, and result showed that cathelicidin-BF strongly inhibited C. albicans biofilm formation at 20 μg/ml. Furthermore, cathelicidin-BF also exhibited potent anti-C. albicans activity in established biofilms as measured by metabolic and fluorescent viability assays. Structure-function analyses suggest that they mainly adopt an α-helical conformations, which enable them to act as a membrane-active molecule. Altogether, the four cathelicidins display great potential for antifungal agent development against candidiasis. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Role of bronchoalveolar lavage in immunocompromised patients with pneumonia treated with a broad spectrum antibiotic and antifungal regimen

PubMed Central

Hohenadel, I; Kiworr, M; Genitsariotis, R; Zeidler, D; Lorenz, J

2001-01-01

BACKGROUND—In a retrospective study the value of bronchoalveolar lavage (BAL) in the diagnosis of pneumonia was investigated in 95 immunocompromised patients suffering from haematological disorders and receiving a regimen of broad spectrum antibiotics and antifungal agents (BSAR).
METHODS—With the exception of four afebrile patients, all had fever, raised C reactive protein (CRP) levels, and new infiltrates visible on chest radiography. All patients underwent BAL to identify the organism causing the pneumonia and surveillance cultures were performed regularly for pathogens at different sites. Following classification of the isolates, patients with positive cultures were subdivided into two groups, pathogenic or contaminated. We investigated whether relevant pathogens were cultured only from the BAL fluid and whether they were susceptible to BSAR.
RESULTS—Although 77 of the 95 patients were thrombocytopenic, bleeding during BAL occurred in only 15% of all patients. Ten days after the procedure the fever improved in 88% of patients, radiographic findings improved in 71%, and CRP levels improved in 75% of patients; 22% of patients died within 28 days. Pathologically relevant isolates were found in 65% of all patients. Respiratory pathogens were detected only in the BAL fluid of 29 of the 95 patients (35% Gram positive species, 40% Gram negative species, 11% Mycobacterium, 11% fungi, and 3% cytomegalovirus). In 16 of these 29 patients (55%) the pathogens cultured only from the BAL fluid were resistant to treatment. Pathogens detected only in the BAL fluid were not susceptible to a standard broad spectrum antibiotic and antifungal regimen including teicoplanin, ceftriaxon, tobramycin, and amphotericin B in 12 of the 29 patients (41%).
CONCLUSIONS—Our data suggest that 12 patients were treated with broad spectrum antimicrobial agents which were not directed at the appropriate organism on in vitro sensitivity tests without BAL. BAL is a relatively safe procedure in the diagnosis of pneumonia, supplying important information in immunocompromised patients as well as in immunocompromised patients receiving BSAR.

 PMID:11209099

Growth inhibitory action of ebselen on fluconazole-resistant Candida albicans: role of the plasma membrane H+-ATPase.

PubMed

Billack, Blase; Santoro, Michelle; Lau-Cam, Cesar

2009-06-01

PMA1 is a yeast gene that codes for the plasma membrane H(+)-ATPase, a protein commonly referred to as Pma1p. Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is a synthetic selenium-containing compound that has recently been shown to display antimicrobial activity owing to its ability to inhibit Pma1p. Ebselen is able to block the activity of Pma1p not only in opportunistic pathogens such as Cryptococcus neoformans and Candida albicans but also in nonpathogenic yeasts such as Saccharomyces cerevisiae. A series of in vitro studies aimed at evaluating the antifungal activity of ebselen were performed. At low concentrations (<10 microM), ebselen was fungistatic against three strains of S. cerevisiae (IC(50) approximately 3 microM) and one fluconazole-resistant strain of C. albicans (IC(50) approximately 6 microM), and at a high concentration (30 microM) it was fungicidal against C. albicans. Moreover, ebselen was found to inhibit medium acidification by the fluconazole-resistant strain of C. albicans in a concentration-dependent manner. In comparison to currently used antifungal agents represented by azole (itraconazole, ketoconazole, fluconazole) and polyene (amphotericin B) compounds, ebselen was at least 10-fold more potent than fluconazole but less active than the other compounds tested. The present results suggest that the growth inhibitory activity of ebselen toward fluconazole-resistant yeast cells is due, at least in part, to inhibition of Pma1p. Ebselen may also serve as a useful agent in the treatment of infections caused by fluconazole-resistant fungi.

In Vitro Toxicity and Activity of Dakin’s Solution, Mafenide Acetate, and Amphotericin B on Filamentous Fungi and Human Cells

DTIC Science & Technology

2013-08-01

there are some data alluding to their ability to be used in implantable bone cement placed into wounds.27,28 In this study, we have shown that...2012;46:369 372. 27. Grimsrud C, Raven R, Fothergill AW, et al. The in vitro elution charac- teristics of antifungal-loaded PMMA bone cement and calcium

Theonellamide G, a potent antifungal and cytotoxic bicyclic glycopeptide from the Red Sea marine sponge Theonella swinhoei.

PubMed

Youssef, Diaa T A; Shaala, Lamiaa A; Mohamed, Gamal A; Badr, Jihan M; Bamanie, Faida H; Ibrahim, Sabrin R M

2014-04-01

In our search for bioactive metabolites from marine organisms, we have investigated the polar fraction of the organic extract of the Red Sea sponge Theonella swinhoei. Successive chromatographic separations and final HPLC purification of the potent antifungal fraction afforded a new bicyclic glycopeptide, theonellamide G. The structure of the peptide was determined using extensive 1D and 2D NMR and high-resolution mass spectral determinations. The absolute configuration of theonellamide G was determined by chemical degradation and 2D NMR spectroscopy. Theonellamide G showed potent antifungal activity towards wild and amphotericin B-resistant strains of Candida albicans with IC₅₀ of 4.49 and 2.0 μM, respectively. Additionally, it displayed cytotoxic activity against the human colon adenocarcinoma cell line (HCT-16) with IC₅₀ of 6.0 μM. These findings provide further insight into the chemical diversity and biological activities of this class of compounds.

Effect of Addition of Antifungal Agents on Physical and Biological Properties of a Tissue Conditioner: An In-Vitro Study.

PubMed

Rawat, Pragati; Agarwal, Swatantra; Tripathi, Siddhi

2017-09-01

Purpose: Tissue conditioners are used for healing of abused oral tissues. They may harbour microorganisms causing oral diseases such as candidiasis compromising the health of the patient. Also, addition of antifungal agents into tissue conditioner may alter its properties. This study compares the anti-fungal property and mechanical properties of tissue conditioner containing different antifungal agents. Methods: Three antifungal agents, one synthetic - fluconazole, and two natural - oregano oil and virgin coconut oil were added into the tissue conditioner (Viscogel) in different concentrations. The antifungal property, tensile bond strength and viscoelasticity of Viscogel containing these antifungal agents were assessed after 24 hours, three days and seven days. Results: While, the highest antifungal activity was shown by Viscogel containing fluconazole, the maximum tensile bond strength was found to be of Viscogel alone (control). Although Viscogel alone and in combination of fluconazole showed deterioration in viscoelasticity, Viscogel in combination of natural agents showed no significant changes over the period of seven days. Conclusion: Incorporation of the natural agents in the tissue conditioner can be used as an effective alternative to systemic or topical synthetic antifungal agents.

Detection of dermatophytes in healthy companion dogs and cats in eastern India.

PubMed

Debnath, C; Mitra, T; Kumar, A; Samanta, I

2016-01-01

In recent times increasing occurrence of dermatophytosis, especially among the school children in eastern India was evidenced along with increased tendency of keeping companion animals such as dogs and cats. This study was undertaken to detect the occurrence of dermatophytes with antifungal susceptibility among the companion animals. A total of 1501 healthy companion animals comprising 1209 dogs and 292 cats belonged to individual owners in and around Kolkata (West Bengal, India) were examined for the evidence of dermatophytosis during 2011-2013. The collected samples were subjected to direct examination by standard KOH mount technique. The samples were inoculated into both Sabouraud dextrose agar (SDA) with 0.05% chloramphenicol and 0.5% cycloheximide and dermatophyte test medium (DTM). Each of the fungal isolate was identified based upon its colony characteristics and hyphal and conidial cells it produced. Antifungal susceptibility of the isolates was tested by broth micro dilution assay using fluconazole, ketoconazole, itraconazole, miconazole, griseofulvin and amphotericin-B antifungals. Among the 1209 samples from dogs and 292 samples from cats, 253 (20.93%) and 109 (37.33%) samples were positive for dermatophytes by direct examination. Three identified species of dermatophytes with predominant occurrence were Microsporum canis, Microsporum gypseum and Trichophyton mentagrophytes. Ketoconazole (0.06-0.5 µgm/ml), itraconazole (0.03-0.5 µgm/ml) and amphotericin-B (0.03-0.5 µgm/ml) showed lowest MIC values against M. canis, T. mentagrophytes and M. gypseum, respectively. This is the first systemic report of dermatophytes in healthy companion animals with large numbers of samples in India.

Candida Species From Eye Infections: Drug Susceptibility, Virulence Factors, and Molecular Characterization.

PubMed

Ranjith, Konduri; Sontam, Bhavani; Sharma, Savitri; Joseph, Joveeta; Chathoth, Kanchana N; Sama, Kalyana C; Murthy, Somasheila I; Shivaji, Sisinthy

2017-08-01

To determine the type of Candida species in ocular infections and to investigate the relationship of antifungal susceptibility profile to virulence factors. Fifty isolates of yeast-like fungi from patients with keratitis, endophthalmitis, and orbital cellulitis were identified by Vitek-2 compact system and DNA sequencing of ITS1-5.8S-ITS2 regions of the rRNA gene, followed by phylogenetic analysis for phenotypic and genotypic identification, respectively. Minimum inhibitory concentration of six antifungal drugs was determined by E test/microbroth dilution methods. Phenotypic and genotypic methods were used to determine the virulence factors. Phylogenetic analysis showed the clustering of all isolates into eight distinct groups with a major cluster formed Candida parapsilosis (n = 21), which was the most common species by both Vitek 2 and DNA sequencing. Using χ2 test no significant difference was noted between the techniques except that Vitek 2 did not identify C. viswanathii, C. orthopsilosis, and two non-Candida genera. Of 43 tested Candida isolates high susceptibility to amphotericin B (39/43, 90.6%) and natamycin (43/43, 100%) was noted. While none of the isolates produced coagulase, all produced esterase and catalase. The potential to form biofilm was detected in 23/43 (53.4%) isolates. Distribution of virulence factors by heat map analysis showed difference in metabolic activity of biofilm producers from nonbiofilm producers. Identified by Vitek 2 and DNA sequencing methods C. parapsilosis was the most common species associated with eye infections. Irrespective of the virulence factors elaborated, the Candida isolates were susceptible to commonly used antifungal drugs such as amphotericin B and natamycin.

Dosage-Dependent Antifungal Efficacy of V-Echinocandin (LY303366) against Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis

PubMed Central

Petraitis, Vidmantas; Petraitiene, Ruta; Groll, Andreas H.; Sein, Tin; Schaufele, Robert L.; Lyman, Caron A.; Francesconi, Andrea; Bacher, John; Piscitelli, Stephen C.; Walsh, Thomas J.

2001-01-01

V-echinocandin (VER-002; LY303366) is a semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1, 3)-β-d-glucan synthase. We studied the antifungal efficacy, the concentrations in saliva and tissue, and the safety of VER-002 at escalating dosages against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant Candida albicans in immunocompromised rabbits. Study groups consisted of untreated controls, animals treated with VER-002 at 1, 2.5, and 5 mg/kg of body weight/day intravenously (i.v.), animals treated with fluconazole at 2 mg/kg/day i.v., or animals treated with amphotericin B at 0.3 mg/kg/day. VER-002-treated animals showed a significant dosage-dependent clearance of C. albicans from the tongue, oropharynx, esophagus, stomach, and duodenum in comparison to that for untreated controls. VER-002 also was superior to amphotericin B and fluconazole in clearing the organism from all sites studied. These in vivo findings are consistent with the results of in vitro time-kill assays, which demonstrated that VER-002 has concentration-dependent fungicidal activity. Esophageal tissue VER-002 concentrations were dosage proportional and exceeded the MIC at all dosages. Echinocandin concentrations in saliva were greater than or equal to the MICs at all dosages. There was no elevation of serum hepatic transaminase, alkaline phosphatase, bilirubin, potassium, or creatinine levels in VER-002-treated rabbits. In summary, the echinocandin VER-002 was well tolerated, penetrated the esophagus and salivary glands, and demonstrated dosage-dependent antifungal activity against fluconazole-resistant esophageal candidiasis in immunocompromised rabbits. PMID:11158743

In vitro susceptibility of antifungal drugs against Sporothrix brasiliensis recovered from cats with sporotrichosis in Brazil.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Rodrigues, Anderson Messias; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha; Pereira, Sandro Antonio; Gremião, Isabella Dib Ferreira; Schubach, Tânia Maria Pacheco; de Camargo, Zoilo Pires

2016-03-01

Sporotrichosis is an important subcutaneous mycosis of humans and animals. Classically, the disease is acquired upon traumatic inoculation of Sporothrix propagules from contaminated soil and plant debris. In addition, the direct horizontal transmission of Sporothrix among animals and the resulting zoonotic infection in humans highlight an alternative and efficient rout of transmission through biting and scratching. Sporothrix brasiliensis is the most virulent species of the Sporothrix schenckii complex and is responsible for the long-lasting outbreak of feline sporotrichosis in Brazil. However, antifungal susceptibility data of animal-borne isolates is scarce. Therefore, this study evaluated the in vitro activity of amphotericin B, caspofungin, itraconazole, voriconazole, fluconazole, and ketoconazole against animal-borne isolates of S. brasiliensis. The susceptibility tests were performed through broth microdilution (M38-A2). The results show the relevant activity of itraconazole, amphotericin B, and ketoconazole against S. brasiliensis, with the following MIC ranges: 0.125-2, 0.125-4 and 0.0312-2 μg/ml, respectively. Caspofungin was moderately effective, displaying higher variation in MIC values (0.25-64 μg/ml). Voriconazole (2-64 μg/ml) and fluconazole (62.5-500 μg/ml) showed low activity against S. brasiliensis strains. This study contributed to the characterization of the in vitro antifungal susceptibility of strains of S. brasiliensis recovered from cats with sporotrichosis, which have recently been considered the main source of human infections. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Molecular epidemiology and in vitro antifungal susceptibility testing of 108 clinical Cryptococcus neoformans sensu lato and Cryptococcus gattii sensu lato isolates from Denmark.

PubMed

Hagen, Ferry; Hare Jensen, Rasmus; Meis, Jacques F; Arendrup, Maiken Cavling

2016-09-01

Cryptococcosis is mainly caused by members of the Cryptococcus gattii/Cryptococcus neoformans species complexes. Here, we report the molecular characterisation and in vitro antifungal susceptibility of Danish clinical cryptococcal isolates. Species, genotype, serotype and mating type were determined by amplified fragment length polymorphism (AFLP) fingerprinting and qPCR. EUCAST E.Def 7.2 MICs were determined for amphotericin B, flucytosine, fluconazole, voriconazole and isavuconazole. Most isolates were C. neoformans (serotype A; n = 66) and belonged to genotype AFLP1/VNI (n = 61) or AFLP1B/VNII (n = 5) followed by Cryptococcus deneoformans (serotype D; genotype AFLP2, n = 20), C. neoformans × C. deneoformans hybrids (serotype AD; genotype AFLP3, n = 13) and Cryptococcus curvatus (n = 2). Six isolates were C. gattii sensu lato, and one isolate was a C. deneoformans × C. gattii hybrid (genotype AFLP8). All isolates were amphotericin B susceptible. Flucytosine susceptibility was uniform MIC50 of 4-8 mg l(-1) except for C. curvatus (MICs >32 mg l(-1) ). Cryptococcus gattii sensu lato isolates were somewhat less susceptible to the azoles. MICs of fluconazole (>32 mg l(-1) ), voriconazole (≥0.5 mg l(-1) ) and isavuconazole (0.06 and 0.25 mg l(-1) respectively) were elevated compared to the wild-type population for 1/19 C. deneoformans and 1/2 C. curvatus isolates. Flucytosine MIC was elevated for 1/61 C. neoformans (>32 mg l(-1) ). Antifungal susceptibility revealed species-specific differential susceptibility, but suggested acquired resistance was an infrequent phenomenon. © 2016 Blackwell Verlag GmbH.

Protothecosis.

PubMed

Mayorga, Jorge; Barba-Gómez, José Fernando; Verduzco-Martínez, Ana Paula; Muñoz-Estrada, Víctor Fernando; Welsh, Oliverio

2012-01-01

Protothecosis is a rare infection caused by achlorophyllic algae that are members of the genus Prototheca. They are ubiquitous in nature in organic material. The clinical manifestations can be acute or chronic and local or disseminated. The disease is classified as cutaneous, causing bursitis or disseminated/systemic, affecting both immunocompetent and immunosuppressed patients, with more severe and disseminated infections occurring in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii are the most frequent organisms reported in humans. Diagnosis is made by observing asexual sporangia (thecas) on histopathological examination of tissue. Medical and surgical treatment should be considered. Ketoconazole, itraconazole, fluconazole, voriconazole, posaconazole, and amphotericin B are the most commonly used antifungals. Voriconazole and amphotericin B are highly effective against Prototheca spp. Treatment failure is not uncommon because of the comorbidities that limit the therapeutic outcome. Copyright © 2012. Published by Elsevier Inc.

Role of catalase overproduction in drug resistance and virulence in Candida albicans.

PubMed

Román, Elvira; Prieto, Daniel; Martin, Ry; Correia, Inês; Mesa Arango, Ana Cecilia; Alonso-Monge, Rebeca; Zaragoza, Oscar; Pla, Jesús

2016-10-03

To investigate the role of Cat1 overproduction in Candida albicans. Strains overproducing the CAT1 gene were constructed. Cells overproducing CAT1 were found to be more resistant to some oxidants and mammalian phagocytic cells. They also showed reduced intracellular reactive oxygen species generated by amphotericin B or ciclopirox olamine. CAT1 overproduction did not change the minimum inhibitory concentration of fungal cells to fungistatic or fungicidal azoles nor to amphotericin B although increased twofold the minimum inhibitory concentration to caspofungin. The role of Cat1 overproduction in virulence and colonization was also analyzed in mouse models. The overproduction of Cat1 protects against oxidants, phagocytes and certain antifungals at subinhibitory concentration but does not increase virulence in a systemic infection mouse model.

Invasive candidiasis in intensive care units in China: in vitro antifungal susceptibility in the China-SCAN study.

PubMed

Liu, Wei; Tan, Jingwen; Sun, Jimei; Xu, Zhijiang; Li, Min; Yang, Qing; Shao, Haifeng; Zhang, Liyan; Liu, Weixia; Wan, Zhe; Cui, Wei; Zang, Bin; Jiang, Dongpo; Fang, Qiang; Qin, Bingyu; Qin, Tiehe; Li, Weiqin; Guo, Fengmei; Liu, Dawei; Guan, Xiandong; Yu, Kaijiang; Qiu, Haibo; Li, Ruoyu

2014-01-01

The objectives of this study were to determine species distribution and in vitro antifungal susceptibility of Candida isolates identified in the multicentre China-SCAN study of invasive Candida infection (ICI) in intensive care units (ICUs) across China. Candida isolates from patients in the China-SCAN study with documented ICI were evaluated by a central laboratory. Species were identified using chromogenic culture media or the API 20C AUX kit. Susceptibility to fluconazole, voriconazole, itraconazole, caspofungin and amphotericin B was determined using the CLSI broth microdilution method (M27-A3) and updated clinical breakpoints or epidemiological cut-off values. A total of 389 isolates from 244 patients were analysed. Species identified most frequently were Candida albicans (40.1%), Candida parapsilosis (21.3%), Candida tropicalis (17.2%) and Candida glabrata (12.9%). Rarer species such as Lodderomyces elongisporus and Candida ernobii were also identified. Fluconazole susceptibility was evident in 85.9% (134/156) of C. albicans, 62.7% (42/67) of C. tropicalis and 48.2% (40/83) of C. parapsilosis isolates. Susceptibility to voriconazole was ≥ 90% among all species. All isolates were susceptible to amphotericin B and caspofungin except C. glabrata [86.0% (43/50) susceptible to caspofungin]. Cross-resistance between fluconazole and voriconazole was observed for C. parapsilosis and C. glabrata. Although C. albicans was the predominant single species, non-albicans species constituted >50% of isolates. Fluconazole susceptibility was lower in most non-albicans species, indicating that fluconazole resistance should be closely monitored. Susceptibility to voriconazole, amphotericin B and caspofungin is encouraging. Differences between these data and those from other regions emphasize the importance of assessing regional variations.

Common drug-drug interactions in antifungal treatments for superficial fungal infections.

PubMed

Gupta, Aditya K; Versteeg, Sarah G; Shear, Neil H

2018-04-01

Antifungal agents can be co-administered alongside several other medications for a variety of reasons such as the presence of comorbidities. Pharmacodynamic interactions such as synergistic and antagonistic interactions could be the result of co-administered medications. Pharmacokinetic interactions could also transpire through the inhibition of metabolizing enzymes and drug transport systems, altering the absorption, metabolism and excretion of co-administered medications. Both pharmacodynamic and pharmacokinetic interactions can result in hospitalization due to serious adverse effects associated with antifungal agents, lower therapeutic doses required to achieve desired antifungal activity, and prevent antifungal resistance. Areas covered: The objective of this review is to summarize pharmacodynamic and pharmacokinetic interactions associated with common antifungal agents used to treat superficial fungal infections. Pharmacodynamic and pharmacokinetic interactions that impact the therapeutic effects of antifungal agents and drugs that are influenced by the presence of antifungal agents was the context to which these antifungal agents were addressed. Expert opinion: The potential for drug-drug interactions is minimal for topical antifungals as opposed to oral antifungals as they have minimal exposure to other co-administered medications. Developing non-lipophilic antifungals that have unique metabolizing pathways and are topical applied are suggested properties that could help limit drug-drug interactions associated with future treatments.

Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease.

PubMed

Michot, J M; Gubavu, C; Fourn, E; Maigne, G; Teicher, E; Angoulvant, A; Blanche, S; Lortholary, O; Coilly, A; Duclos-Vallée, J C; Sebagh, M; Guettier, C; Aumont, C; Delfraissy, J F; Lambotte, O

2014-06-01

Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Combination of Amphotericin B and Flucytosine against Neurotropic Species of Melanized Fungi Causing Primary Cerebral Phaeohyphomycosis

PubMed Central

Deng, S.; Pan, W.; Liao, W.; de Hoog, G. S.; Gerrits van den Ende, A. H. G.; Vitale, R. G.; Rafati, H.; Ilkit, M.; Van der Lee, A. H.; Rijs, A. J. M. M.; Verweij, P. E.

2016-01-01

Primary central nervous system phaeohyphomycosis is a fatal fungal infection due mainly to the neurotropic melanized fungi Cladophialophora bantiana, Rhinocladiella mackenziei, and Exophiala dermatitidis. Despite the combination of surgery with antifungal treatment, the prognosis continues to be poor, with mortality rates ranging from 50 to 70%. Therefore, a search for a more-appropriate therapeutic approach is urgently needed. Our in vitro studies showed that with the combination of amphotericin B and flucytosine against these species, the median fractional inhibitory concentration (FIC) indices for strains ranged from 0.25 to 0.38, indicating synergy. By use of Bliss independence analysis, a significant degree of synergy was confirmed for all strains, with the sum ΔE ranging from 90.2 to 698.61%. No antagonism was observed. These results indicate that amphotericin B, in combination with flucytosine, may have a role in the treatment of primary cerebral infections caused by melanized fungi belonging to the order Chaetothyriales. Further in vivo studies and clinical investigations to elucidate and confirm these observations are warranted. PMID:26833164

Interaction of gelatin with polyenes modulates antifungal activity and biocompatibility of electrospun fiber mats

PubMed Central

Lakshminarayanan, Rajamani; Sridhar, Radhakrishnan; Loh, Xian Jun; Nandhakumar, Muruganantham; Barathi, Veluchamy Amutha; Kalaipriya, Madhaiyan; Kwan, Jia Lin; Liu, Shou Ping; Beuerman, Roger Wilmer; Ramakrishna, Seeram

2014-01-01

Topical application of antifungals does not have predictable or well-controlled release characteristics and requires reapplication to achieve therapeutic local concentration in a reasonable time period. In this article, the efficacy of five different US Food and Drug Administration-approved antifungal-loaded (amphotericin B, natamycin, terbinafine, fluconazole, and itraconazole) electrospun gelatin fiber mats were compared. Morphological studies show that incorporation of polyenes resulted in a two-fold increase in fiber diameter and the mats inhibit the growth of yeasts and filamentous fungal pathogens. Terbinafine-loaded mats were effective against three filamentous fungal species. Among the two azole antifungals compared, the itraconazole-loaded mat was potent against Aspergillus strains. However, activity loss was observed for fluconazole-loaded mats against all of the test organisms. The polyene-loaded mats displayed rapid candidacidal activities as well. Biophysical and rheological measurements indicate strong interactions between polyene antifungals and gelatin matrix. As a result, the polyenes stabilized the triple helical conformation of gelatin and the presence of gelatin decreased the hemolytic activity of polyenes. The polyene-loaded fiber mats were noncytotoxic to primary human corneal and sclera fibroblasts. The reduction of toxicity with complete retention of activity of the polyene antifungal-loaded gelatin fiber mats can provide new opportunities in the management of superficial skin infections. PMID:24920895

Antifungal Wound Penetration of Amphotericin and Voriconazole in Combat-related Injuries: Case Report

DTIC Science & Technology

2015-04-15

trauma can have long and challenging recoveries , which may be complicated by infection. Invasive fungal infections are a rare but serious complication...and massive blood transfu- sion [6]. Inoculation of soil-dwelling molds into wounds is proposed to occur at the time of injury, with subsequent growth...microbiological assays in austere field hos- pitals, histopathological confirmation, and positive fungal culture. Thus, the median time from infection

Intrabronchial instillation of amphotericin B lipid complex: a case report.

PubMed

Morales, P; Galán, G; Sanmartín, E; Monte, E; Tarrazona, V; Santos, M

2009-01-01

We sought to present our results of topical intrabronchial installation of amphotericin B lipid complex (AmpB lipid). A deposit of fungal material was observed in a bilateral lung transplant recipient who experienced stenosis of the left anastomosis and have been fitted with a double endobronchial prosthesis. The deposit was adherent to the prosthetic material, causing marked local laceration, risk of perforation, and exacerbation of the bronchial stenosis. Upon cultivation of a bronchial aspirate (BAS), we isolated Aspergillus fumigatus, Scedosporium prolificans, and Candida glabrata. Systemic antifungal treatment was begun with oral voriconazole (200 mg every 12 hours) and inhaled AmpB lipid (25 mg once daily). The fungal deposit on the prosthetic material was treated by topical instillation of a solution of 25 mg AmpB lipid before and after each therapeutic fibrobronchoscopy (FB), which was performed weekly at 5 consecutive examinations. Tolerance was excellent. The improvement obtained after the procedure made it possible to withdraw one of the displaced prostheses. Subsequent cultivation for the fungi found in the BAS was persistently negative over a follow-up of 2 years. Topical intrabronchial instillation of AmpB lipid has proven effective and well tolerated for the treatment of localized fungal colonies. This use could be extended by protocol to FB in the early postoperative period after lung transplantation for antifungal prophylaxis.

Mucor irregularis infection and lethal midline granuloma: a case report and review of published literature.

PubMed

Li, Dong Ming; Lun, Li De

2012-12-01

Mucor irregularis (Rhizomucor variabilis) infection and lethal midline granuloma (LMG) are characterized by progressive swelling, ulceration, and destruction of the central face that is usually fatal. Pathological features are inflammation, necrosis, and granulation. LMG has been called by various names, and in recent years, it has been known as NK/T cell lymphoma. However, diagnosis still relies on the progressive necrosis course rather than malignancy in histology. The disease has long challenged physicians, particularly when it worsens with radiotherapy or chemotherapy but sometimes achieves total remission without anti-malignancy therapies. We describe a 35-year-old man who had typical clinical-pathological symptoms of LMG, which turned out to be primary M. irregularis infection; that was diagnosed by positive tissue culture and fungal elements in histology. The patient was successfully treated with antifungal therapy (liposomal amphotericin B, total 4,600 mg and amphotericin B total 277 mg, over a duration of 70 days). We hereby review current knowledge about the epidemiology, clinical manifestations, radiographic characteristics, and pathologic features of LMG with those of M. irregularis infection and their associations. We conclude that primary M. irregulars infection can mimic the clinico-pathological symptoms of LMG and the condition responds favorably to aggressive antifungal therapy.

Proteomic and Transcriptomic Analysis of Aspergillus fumigatus on Exposure to Amphotericin B▿ †

PubMed Central

Gautam, Poonam; Shankar, Jata; Madan, Taruna; Sirdeshmukh, Ravi; Sundaram, Curam Sreenivasacharlu; Gade, Wasudev Namdeo; Basir, Seemi Farhat; Sarma, Puranam Usha

2008-01-01

Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections, including invasive aspergillosis. It has been our aim to understand the molecular targets of AMB in Aspergillus fumigatus by genomic and proteomic approaches. In transcriptomic analysis, a total of 295 genes were found to be differentially expressed (165 upregulated and 130 downregulated), including many involving the ergosterol pathway, cell stress proteins, cell wall proteins, transport proteins, and hypothetical proteins. Proteomic profiles of A. fumigatus alone or A. fumigatus treated with AMB showed differential expression levels for 85 proteins (76 upregulated and 9 downregulated). Forty-eight of them were identified with high confidence and belonged to the above-mentioned categories. Differential expression levels for Rho-GDP dissociation inhibitor (Rho-GDI), secretory-pathway GDI, clathrin, Sec 31 (a subunit of the exocyst complex), and RAB GTPase Ypt51 in response to an antifungal drug are reported here for the first time and may represent a specific response of A. fumigatus to AMB. The expression of some of these genes was validated by real-time reverse transcription-PCR. The AMB responsive genes/proteins observed to be differentially expressed in A. fumigatus may be further explored for novel drug development. PMID:18838595

Proteomic and transcriptomic analysis of Aspergillus fumigatus on exposure to amphotericin B.

PubMed

Gautam, Poonam; Shankar, Jata; Madan, Taruna; Sirdeshmukh, Ravi; Sundaram, Curam Sreenivasacharlu; Gade, Wasudev Namdeo; Basir, Seemi Farhat; Sarma, Puranam Usha

2008-12-01

Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections, including invasive aspergillosis. It has been our aim to understand the molecular targets of AMB in Aspergillus fumigatus by genomic and proteomic approaches. In transcriptomic analysis, a total of 295 genes were found to be differentially expressed (165 upregulated and 130 downregulated), including many involving the ergosterol pathway, cell stress proteins, cell wall proteins, transport proteins, and hypothetical proteins. Proteomic profiles of A. fumigatus alone or A. fumigatus treated with AMB showed differential expression levels for 85 proteins (76 upregulated and 9 downregulated). Forty-eight of them were identified with high confidence and belonged to the above-mentioned categories. Differential expression levels for Rho-GDP dissociation inhibitor (Rho-GDI), secretory-pathway GDI, clathrin, Sec 31 (a subunit of the exocyst complex), and RAB GTPase Ypt51 in response to an antifungal drug are reported here for the first time and may represent a specific response of A. fumigatus to AMB. The expression of some of these genes was validated by real-time reverse transcription-PCR. The AMB responsive genes/proteins observed to be differentially expressed in A. fumigatus may be further explored for novel drug development.

Molecular Identification, Antifungal Susceptibility Profile, and Biofilm Formation of Clinical and Environmental Rhodotorula Species Isolates

PubMed Central

Nunes, Jorge Meneses; Bizerra, Fernando César; Ferreira, Renata Carmona e

2013-01-01

Rhodotorula species are emergent fungal pathogens capable of causing invasive infections, primarily fungemia. They are particularly problematic in immunosuppressed patients when using a central venous catheter. In this study, we evaluated the species distribution of 51 clinical and 8 environmental Rhodotorula species isolates using the ID32C system and internal transcribed spacer (ITS) sequencing. Antifungal susceptibility testing and biofilm formation capability using a crystal violet staining assay were performed. Using ITS sequencing as the gold standard, the clinical isolates were identified as follows: 44 R. mucilaginosa isolates, 2 R. glutinis isolates, 2 R. minuta isolates, 2 R. dairenensis isolates, and 1 Rhodosporidium fluviale isolate. The environmental isolates included 7 R. mucilaginosa isolates and 1 R. slooffiae isolate. Using the ID32C system, along with a nitrate assimilation test, only 90.3% of the isolates tested were correctly identified. In the biofilm formation assay, R. mucilaginosa and R. minuta exhibited greater biofilm formation ability compared to the other Rhodotorula species; the clinical isolates of R. mucilaginosa showed greater biofilm formation compared to the environmental isolates (P = 0.04). Amphotericin B showed good in vitro activity (MIC ≤ 1 μg/ml) against planktonic cells, whereas voriconazole and posaconazole showed poor activity (MIC50/MIC90, 2/4 μg/ml). Caspofungin and fluconazole MICs were consistently high for all isolates tested (≥64 μg/ml and ≥ 4 μg/ml, respectively). In this study, we emphasized the importance of molecular methods to correctly identify Rhodotorula species isolates and non-R. mucilaginosa species in particular. The antifungal susceptibility profile reinforces amphotericin B as the antifungal drug of choice for the treatment of Rhodotorula infections. To our knowledge, this is the first study evaluating putative differences in the ability of biofilm formation among different Rhodotorula species. PMID:23114761

Molecular identification, antifungal susceptibility profile, and biofilm formation of clinical and environmental Rhodotorula species isolates.

PubMed

Nunes, Jorge Meneses; Bizerra, Fernando César; Ferreira, Renata Carmona E; Colombo, Arnaldo Lopes

2013-01-01

Rhodotorula species are emergent fungal pathogens capable of causing invasive infections, primarily fungemia. They are particularly problematic in immunosuppressed patients when using a central venous catheter. In this study, we evaluated the species distribution of 51 clinical and 8 environmental Rhodotorula species isolates using the ID32C system and internal transcribed spacer (ITS) sequencing. Antifungal susceptibility testing and biofilm formation capability using a crystal violet staining assay were performed. Using ITS sequencing as the gold standard, the clinical isolates were identified as follows: 44 R. mucilaginosa isolates, 2 R. glutinis isolates, 2 R. minuta isolates, 2 R. dairenensis isolates, and 1 Rhodosporidium fluviale isolate. The environmental isolates included 7 R. mucilaginosa isolates and 1 R. slooffiae isolate. Using the ID32C system, along with a nitrate assimilation test, only 90.3% of the isolates tested were correctly identified. In the biofilm formation assay, R. mucilaginosa and R. minuta exhibited greater biofilm formation ability compared to the other Rhodotorula species; the clinical isolates of R. mucilaginosa showed greater biofilm formation compared to the environmental isolates (P = 0.04). Amphotericin B showed good in vitro activity (MIC ≤ 1 μg/ml) against planktonic cells, whereas voriconazole and posaconazole showed poor activity (MIC(50)/MIC(90), 2/4 μg/ml). Caspofungin and fluconazole MICs were consistently high for all isolates tested (≥64 μg/ml and ≥ 4 μg/ml, respectively). In this study, we emphasized the importance of molecular methods to correctly identify Rhodotorula species isolates and non-R. mucilaginosa species in particular. The antifungal susceptibility profile reinforces amphotericin B as the antifungal drug of choice for the treatment of Rhodotorula infections. To our knowledge, this is the first study evaluating putative differences in the ability of biofilm formation among different Rhodotorula species.

Prevalence and susceptibility of Saccharomyces cerevisiae causing vaginitis in Greek women.

PubMed

Papaemmanouil, V; Georgogiannis, N; Plega, M; Lalaki, J; Lydakis, D; Dimitriou, M; Papadimitriou, A

2011-12-01

Saccharomyces cerevisiae is an ascomycetous yeast, that is traditionally used in wine bread and beer production. Vaginitis caused by S. cerevisiae is rare. The aim of this study was to evaluate the frequency of S. cerevisiae isolation from the vagina in two groups of women and determined the in vitro susceptibility of this fungus. Vaginal samples were collected from a total of 262 (asymptomatic and symptomatic) women with vaginitis attending the centre of family planning of General hospital of Piraeus. All blastomycetes that isolated from the vaginal samples were examined for microscopic morphological tests and identified by conventional methods: By API 20 C AUX and ID 32 C (Biomerieux). Antifungal susceptibility testing for amphotericin B,fluconazole itraconazole,voriconazole, posaconazole and caspofungin was performed by E -test (Ab BIODIKS SWEDEN) against S. cerevisiae. A total of 16 isolates of S. cerevisiae derived from vaginal sample of the referred women, average 6.10%. Susceptibility of 16 isolates of S. cerevisiae to a variety of antimycotic agents were obtained. So all isolates of S. cerevisiae were resistant to fluconazole, posaconazole and intraconazole, but they were sensitive to voriconazole caspofungin and Amphotericin B which were found sensitive (except 1/16 strains). None of the 16 patients had a history of occupational domestic use of baker's yeast. Vaginitis caused by S. cerevisiae occur, is rising and cannot be ignored. Treatment of Saccharomyces vaginitis constitutes a major challenge and may require selected and often prolonged therapy. Copyright © 2011 Elsevier Ltd. All rights reserved.

Defining the frontiers between antifungal resistance, tolerance and the concept of persistence.

PubMed

Delarze, Eric; Sanglard, Dominique

2015-11-01

A restricted number of antifungal agents are available for the therapy of fungal diseases. With the introduction of epidemiological cut-off values for each agent in important fungal pathogens based on the distribution of minimal inhibitory concentration (MIC), the distinction between wild type and drug-resistant populations has been facilitated. Antifungal resistance has been described for all currently available antifungal agents in several pathogens and most of the associated resistance mechanisms have been deciphered at the molecular level. Clinical breakpoints for some agents have been proposed and can have predictive value for the success or failure of therapy. Tolerance to antifungals has been a much more ignored area. By definition, tolerance operates at antifungal concentrations above individual intrinsic inhibitory values. Important is that tolerance to antifungal agents favours the emergence of persister cells, which are able to survive antifungal therapy and can cause relapses. Here we will review the current knowledge on antifungal tolerance, its potential mechanisms and also evaluate the role of antifungal tolerance in the efficacy of drug treatments. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.

PubMed Central

Wasan, K M; Vadiei, K; Luke, D R; Keyhani, A; White, R A; McQueen, T J; Mehta, R; Lopez-Berestein, G

1991-01-01

HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice. PMID:1759826

PHARMACOLOGIC PROBING OF AMPHOTERICIN B-INDUCED RENAL DYSFUNCTION IN THE NEONATAL RAT

EPA Science Inventory

Pharmacologic Probing of Amphotericin B-Induced Renal Dysfunction in the Neonatal Rat. Gray, J.A., and Kavlock, R.J. (1988). Toxicol. Appl. Pharmacol. 93, 360-368. Acetazolamide, furosemide, chlorothiazide, and amiloride pharmacologic agents that act primarily in the proximal tub...

[Imported mycosis: a review of paracoccidioidomycosis].

PubMed

Bousquet, A; Dussart, C; Drouillard, I; Charbel, E C; Boiron, P

2007-12-01

Population migration is increasing the number of systemic mycosis cases, a condition little or not present in Metropolitan France, thus often weakly documented for medical teams. Paracoccidioidomycosis is a systemic mycosis geographically confined to Latin America. The causative agent is Paracoccidioides brasiliensis, a dimorphic fungus present at ground level. Discovering that the armadillo was a new host allowed documenting the ideal conditions for this fungus development. The mortality rate is currently 1.45 for one million people and the disease affects mainly farmers. The mode of infection is respiratory and all organs and mucous membranes can be affected by lymphatic dissemination. The chronic form with pulmonary, cutaneous and oral lesions is the most important. The diagnosis can be carried out by direct examination of samples revealing the presence of budding yeasts, as well as culture at 25 and 37 degrees C. Antifungals like the sulfamethoxazole-trimethoprime combination, amphotericin B, but especially azole derivatives are use in the therapeutic management of patients. Detection and gp 43 antigen assay is useful for the patient's follow-up.

Intracranial haemorrhage possibly related to Tipranavir in an HIV-1 patient with cryptococcal meningitis.

PubMed

Chrysos, G; Gerakari, S; Stasini, F; Kokkoris, S; Kourousis, D; Velegraki, A

2008-07-01

A 55-year-old HIV-infected patient on antiretroviral treatment with Ritonavir-boosted Tipranavir as part of HAART developed intracranial haemorrhage during the acute phase of cryptococcal meningitis. CT scan and MRI confirmed the intracranial haemorrhage. Positive cryptococcal antigen and cultures of both blood and CSF confirmed the diagnosis of meningitis caused by Cryptococcus neoformans. There was no evidence of any bleeding disorder, use of aspirin or antiplatelet agents. The patient was treated with Liposomal Amphotericin B for cryptococcal meningitis. No special treatment was needed for the intracranial haemorrhage, but Tipranavir was discontinued and replaced by Kaletra and Saquinavir. Intracranial haemorrhage could be related to Tipranavir and cryptococcal meningitis was a predisposing factor. Headache stopped 3 days after starting antifungal treatment. To the best of our knowledge, this is the first reported case of intracranial haemorrhage related to Tipranavir treatment after the end of the "RESIST" studies and the only one related to meningitis.

A new aurone glycoside with antifungal activity from marine-derived fungus Penicillium sp. FJ-1.

PubMed

Song, Yan-xia; Ma, Qiang; Li, Jie

2015-03-01

Endophytic fungi which reside in the tissue of mangrove plants seem to play an important role in the discovery of new biologically active substances. During the course of screening for the antimicrobial metabolites from the endophytic fugus Penicillium sp. FJ-1 of mangrove plant Avicennia marina, a new aurone glycoside (1) was isolated by repeated column chromatography on silica gel and recrystallization methods. The structure of 1 was elucidated as (Z)-7,4'-dimethoxy-6-hydroxy-aurone-4-O-β-glucopyranoside, on the basis of spectroscopic analysis. Compound 1 exhibited antifungal activity against Candida sp., with the potency comparable to amphotericin B and much better than fluconazole. Compound 1 can also inhibit extracellular phospholipase secretion in a concentration-dependent manner.

Post-traumatic intracranial epidural Aspergillus fumigatus abscess.

PubMed

Letscher, V; Herbrecht, R; Gaudias, J; Taglang, G; Koenig, H; Dupuis, M G; Waller, J

1997-01-01

We report an intracranial epidural abscess caused by Aspergillus fumigatus in an immunocompetent patient. Infection occurred in a 20-year-old man 2 months after a frontal craniotomy following trauma. The abscess was encapsulated by a thickened dura and although the fungus did not invade the brain, frontal bone was infected and the patient presented with a subcutaneous frontal cellulitis. Initial management combined surgical drainage, resection of necrotic bone and liposomal amphotericin B (1 mg kg-1 per day). After 3 weeks of antifungal treatment a second evaluation surgery was performed. A clinically and radiologically unsuspected new abscess was found and evacuated. Treatment was completed with instillation into the cavity of amphotericin B at a concentration of 5 mg ml-1 and prolonged oral itraconazole (400-600 mg day-1). Treatment was successful and the patient is free of infection after 3 years.

Antifungal susceptibility patterns of colonized Candida species isolates from immunocompromised pediatric patients in five university hospitals.

PubMed

Badiee, Parisa; Choopanizadeh, Maral; Moghadam, Abdolkarim Ghadimi; Nasab, Ali Hossaini; Jafarian, Hadis; Shamsizadeh, Ahmad; Soltani, Jafar

2017-12-01

Colonization of Candida species is common in pediatric patients admitted to hematology-oncology wards. The aim of this study was to identify colonized Candida species and their susceptibility patterns in hematologic pediatric patients. Samples were collected from mouth, nose, urine and stool of the patients admitted to five university hospitals and cultured on sabouraud dextrose agar. The isolates were identified by API 20 C AUX system and their susceptibility patterns were evaluated by CLSI M27-A3 and S4. From 650 patients, 320 (49.2%) were colonized with 387 Candida species. Candida albicans was the most prevalent isolated species, followed by Candida glabrata, Candida tropicalis, Candida famata, Candida kefyr and Candida kuresi . The epidemiological cut off value (ECV) for all Candida species to amphotericin B was ≤0.25 μg except C. krusei (4 μg). The resistance rate to fluconazole in this study in C. albicans was 4.9% with ECV 8 μg/ml, followed by C. tropicalis 8.8% with ECV 0.5 μg/ml. Voriconazole and posaconazole were effective antifungal agents for all Candida isolates. The ECV of C. albicans, Candida parapsilosis, C. tropicalis, C. glabrata and C. krusei for itraconazole were 0.5, 0.25, 0.5, 1 and 2 μg, respectively. The resistant and intermediate rates of Candida species to caspofungin in this study were 2.9%, 5.9%, 18.8%, 47.9%, 0.0% and 16.7% in C. tropicalis, C. glabrata and C. parapsilosis respectively. C. albicans was the most prevalent species in pediatric colonized patients. New azole agents like voriconazole and posaconazole are effective against non-albicans Candida species. Increase in intermediate species is alarming to future emerging resistant species.

Histoplasmosis Complicating Tumor Necrosis Factor–α Blocker Therapy: A Retrospective Analysis of 98 Cases

PubMed Central

Vergidis, Paschalis; Avery, Robin K.; Wheat, L. Joseph; Dotson, Jennifer L.; Assi, Maha A.; Antoun, Smyrna A.; Hamoud, Kassem A.; Burdette, Steven D.; Freifeld, Alison G.; McKinsey, David S.; Money, Mary E.; Myint, Thein; Andes, David R.; Hoey, Cynthia A.; Kaul, Daniel A.; Dickter, Jana K.; Liebers, David E.; Miller, Rachel A.; Muth, William E.; Prakash, Vidhya; Steiner, Frederick T.; Walker, Randall C.; Hage, Chadi A.

2015-01-01

Background. Histoplasmosis may complicate tumor necrosis factor (TNF)–α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. Methods. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. Results. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06–14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03–1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1–69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. Conclusions. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months. PMID:25870331

Self-assembled amphotericin B-loaded polyglutamic acid nanoparticles: preparation, characterization and in vitro potential against Candida albicans

PubMed Central

Zia, Qamar; Khan, Aijaz Ahmed; Swaleha, Zubair; Owais, Mohammad

2015-01-01

In the present study, we developed a self-assembled biodegradable polyglutamic acid (PGA)-based formulation of amphotericin B (AmB) and evaluated its in vitro antifungal potential against Candida albicans. The AmB-loaded PGA nanoparticles were prepared in-house and had a mean size dimension of around 98±2 nm with a zeta potential of −35.2±7.3 mV. Spectroscopic studies revealed that the drug predominantly acquires an aggregated form inside the formulation with an aggregation ratio above 2. The PGA-based AmB formulation was shown to be highly stable in phosphate-buffered saline as well as in serum (only 10%–20% of the drug was released after 10 days). The AmB–PGA nanoparticles were less toxic to red blood cells (<15% lysis at an AmB concentration of 100 μg/mL after 24 hours) when compared with Fungizone®, a commercial antifungal product. An MTT assay showed that the viability of mammalian cells (KB and RAW 264.7) was negligibly affected at AmB concentrations as high as 200 μg/mL. Histopathological examination of mouse kidney revealed no signs of tissue necrosis. The AmB–PGA formulation showed potent antimicrobial activity similar to that of Fungizone against C. albicans. Interestingly, AmB-bearing PGA nanoparticles were found to inhibit biofilm formation to a considerable extent. In summary, AmB–PGA nanoparticles showed highly attenuated toxicity when compared with Fungizone, while retaining equivalent active antifungal properties. This study indicates that the AmB–PGA preparation could be a promising treatment for various fungal infections. PMID:25784804

Amphotericin B liposomes with prolonged circulation in blood: in vitro antifungal activity, toxicity, and efficacy in systemic candidiasis in leukopenic mice.

PubMed Central

van Etten, E W; ten Kate, M T; Stearne, L E; Bakker-Woudenberg, I A

1995-01-01

Pegylated amphotericin B (AmB) liposomes (PEG-AmB-LIP) were compared with laboratory-prepared nonpegylated AmB liposomes (AmB-LIP), a formulation with a lipid composition the same as that in AmBisome, as well as with industrially prepared AmBisome regarding their in vitro antifungal activities, toxicities, blood residence times, and therapeutic efficacies. Killing of Candida albicans (> 99.9%) during short-term (6-h) incubation was observed at 0.2 mg of AmB per liter for AmB desoxycholate, 0.4 mg of AmB per liter for PEG-AmB-LIP, 0.8 mg of AmB per liter for AmB-LIP, and 12.8 mg of AmB per liter for AmBisome. The maximum tolerated doses of PEG-AmB-LIP, AmB-LIP, and AmBisome were 15, 19, and > 31 mg of AmB per kg of body weight, respectively. In contrast to AmB-LIP, the blood residence time of PEG-AmB-LIP was prolonged and dose independent. In a model of systemic candidiasis in leukopenic mice at a dose of 5 mg of AmB per kg, PEG-AmB-LIP was completely effective and AmB-LIP was partially effective, whereas AmBisome was not effective. AmB-LIP at 11 mg of AmB per kg was partially effective. AmBisome at 29 mg of AmB per kg was completely effective. In conclusion, the therapeutic efficacies of AmB liposomes can be improved by preparing AmB liposomes in which a substantial reduction in toxicity is achieved while antifungal activity is retained. In addition, therapeutic efficacy is favored by a prolonged residence time of AmB liposomes in blood. PMID:8540697

Tissue Penetration of Antifungal Agents

PubMed Central

Felton, Timothy; Troke, Peter F.

2014-01-01

SUMMARY Understanding the tissue penetration of systemically administered antifungal agents is critical for a proper appreciation of their antifungal efficacy in animals and humans. Both the time course of an antifungal drug and its absolute concentrations within tissues may differ significantly from those observed in the bloodstream. In addition, tissue concentrations must also be interpreted within the context of the pathogenesis of the various invasive fungal infections, which differ significantly. There are major technical obstacles to the estimation of concentrations of antifungal agents in various tissue subcompartments, yet these agents, even those within the same class, may exhibit markedly different tissue distributions. This review explores these issues and provides a summary of tissue concentrations of 11 currently licensed systemic antifungal agents. It also explores the therapeutic implications of their distribution at various sites of infection. PMID:24396137

[Does the sampling locality influence on the antifungal activity of the flavonoids of Marrubium vulgare against Aspergillus niger and Candida albicans?].

PubMed

Bouterfas, K; Mehdadi, Z; Aouad, L; Elaoufi, M M; Khaled, M B; Latreche, A; Benchiha, W

2016-09-01

The study was undertaken to determine the effect of the sampling locality on the antifungal activity of the flavonoids extracted from the leaves of Marrubium vulgare L. against two fungal strains; Aspergillus niger ATCC 16404 and Candida albicans ATCC 10231. The leaves were collected from three different sampling localities belonging northwest Algeria: Tessala mount, M'sila forest and Ain Skhouna. The flavonoid extraction was carried out by using organic solvents with increasing polarity. A phytochemical screening was performed by staining test tubes. The inhibition diameters were measured by solid medium diffusion method. The minimum inhibitory concentrations were determined by dilution method on solid medium. The antifungal activity varied significantly (P<0.001) according to the sampling locality of the leaves, the flavonoid extract and its concentration, and the strain fungal type. The inhibition diameters varied between 8.16 and recorded 37.5mm even recording a total inhibition of fungal growth and often exceed those induced marketed antifungals (Amphotericin, Fluconazole, Terbinafine and econazole nitrate). The minimum inhibitory concentrations (MICs) obtained range between 6.25 and 100μg/mL; experiencing strong antifungal inhibition. The phytochemical screening revealed the existence of certain flavonoids classes such as flavans and flavanols which may be responsible of this remarkable antifungal power. The sampling locality of Marrubium vulgare leaves influenced on the antifungal activity of flavonoids. These have proven very good fungistatic and worth valuing in pharmacology. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

[Multicenter Prospective Observational Study of Fungal Keratitis--Identification and Susceptibility Test of Fungi].

PubMed

Sunada, Atsuko; Asari, Seishi; Inoue, Yoshitsugu; Ohashi, Yuichi; Suzuki, Takashi; Shimomura, Yoshikazu; Fukuda, Masahiko; Sotozono, Chie; Hatano, Hiroshi; Eguchi, Hiroshi; Araki-Sasaki, Kaoru; Hoshi, Saichi; Yaguchi, Takashi; Makimura, Koichi; Yokokura, Shunji; Mochizuki, Kiyofumi; Monden, Yu; Nejima, Ryohei

2016-01-01

To investigate the causative fungi of fungal keratitis in Japan and their drug susceptibility. Identification and antifungal susceptibility test for 8 drugs (micafungin, amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, miconazole and pimaricin) were performed using isolated fungi from patients with fungal keratitis treated at 27 facilities in Japan between November 1, 2011 and October 31, 2013. Fungal strains were detected in 72 (50.7%) out of 142 samples. The major isolates were Fusarium spp. (18), Candida parapsilosis (12), C. albicans (11) and Alternaria spp. (6), in all, fungi of 31 species were identified by gene analysis. In the yeast-like fungi, susceptibility rates were evident for more than 80% in voriconazole, pimaricin, flucytosine, micafungin, amphotericin B and fluconazole. In filamentous fungi, the susceptibility rate was less than 50% except for PMR (90%). Fusarium spp., which were susceptible to amphotericin B and pimaricin, showed lower susceptibility rates compared with other genera. Although various genera and species of fungi cause fungal keratitis, the obtained drug susceptibility data in this study demonstrates the different susceptibility patterns among the major isolates (Fusarium spp., C. parapsilosis, C. albicans and other groups). This is important evidence useful for fungal keratitis treatment.

Targeting and synergistic action of an antifungal peptide in an antibiotic drug-delivery system.

PubMed

Park, Seong-Cheol; Kim, Young-Min; Lee, Jong-Kook; Kim, Nam-Hong; Kim, Eun-Ji; Heo, Hun; Lee, Min-Young; Lee, Jung Ro; Jang, Mi-Kyeong

2017-06-28

Amphotericin B (AmB) has been widely used against fungal infections throughout almost the entire body, including the skin, nails, oral cavity, respiratory tract, and urinary tract. However, the development of AmB-loaded nanoparticles demands a novel technique that reduces its toxicity and other associated problems. Here, we developed a pH-responsive and redox-sensitive polymer-based AmB-delivery carrier system. In particular, this system was functionalized by conjugation with the antifungal peptide histatin 5, which acts both as a targeting ligand and a synergistic antifungal molecule against Candida albicans, a major systemic fungal pathogen of humans. Our results in vitro and in vivo suggest that this drug-delivery system may serve as a novel tool to facilitate the use of antimicrobial peptides as targeting ligands to pathogenic microbes, which would open new avenues of investigation in the field of drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-Candida and anti-Cryptococcus antifungal produced by marine microorganisms.

PubMed

El Amraoui, B; El Amraoui, M; Cohen, N; Fassouane, A

2014-12-01

In order to search for antifungal from biological origin, we performed a screening of marine microorganisms isolated from seawater, seaweed, sediment and marine invertebrates collected from different coastal areas of the Moroccan Atlantic Ocean. The antifungal activities of these isolates were investigated against the pathogenic yeasts involved in medical mycology. Whole cultures of 34 marine microorganisms were screened for antifungal activities using the method of agar diffusion against four yeasts. The results showed that among the 34 isolates studied, 13 (38%) strains have antifungal activity against at least one out of four yeast species, 11 isolates have anti-Candida albicans CIP 48.72 activity, 12 isolates have anti-C. albicans CIP 884.65 activity, 13 isolates have anti-Cryptococcus neoformans activity and only 6 isolates are actives against Candida tropicalis R2 resistant to nystatin and amphotericin B. Nine isolates showed strong fungicidal activity. Fourteen microorganisms were identified and assigned to the genera Acinetobacter, Aeromonas, Alcaligenes, Bacillus, Chromobacterium, Enterococcus, Pantoea, and Pseudomonas. Due to a competitive role for space and nutrient, the marine microorganisms could produce more antimicrobials; therefore these marine microorganisms were expected to be potential resources of natural products such as those we research: anti-Candida and anti-Cryptococcus fungicides. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Biochemical characterization of GM1 micelles-Amphotericin B interaction.

PubMed

Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

2015-01-01

In this work a thorough characterization of the GM1 micelle-Amphotericin B (AmB) interaction was performed. The micelle formation as well as the drug loading occurs spontaneously, although influenced by the physicochemical conditions, pH and temperature. The chromatographic profile of GM1-AmB complexes at different molar ratios shows the existence of two populations. The differential absorbance of GM1, monomeric and aggregate AmB, allowed us to discriminate the presence of all of them in both fractions. Thus, we noted that at higher proportion of AmB in the complex, increases the larger population which is composed mainly of aggregated AmB. The physical behavior of these micelles shows that both GM1- AmB complexes were stable in solution for at least 30 days. However upon freeze-thawing or lyophilization-solubilization cycles, only the smallest population, enriched in monomeric AmB, showed a complete solubilization. In vitro, GM1-AmB micelles were significantly less toxic on cultured cells than other commercial micellar formulations as Fungizone, but had a similar behavior to liposomal formulations as Ambisome. Regarding the antifungal activity of the new formulation, it was very similar to that of other formulations. The characterization of these GM1-AmB complexes is discussed as a potential new formulation able to improve the antifungal therapeutic efficiency of AmB.

Lipoamino acid-based micelles as promising delivery vehicles for monomeric amphotericin B.

PubMed

Serafim, Cláudia; Ferreira, Inês; Rijo, Patrícia; Pinheiro, Lídia; Faustino, Célia; Calado, António; Garcia-Rio, Luis

2016-01-30

Lipoamino acid-based micelles have been developed as delivery vehicles for the hydrophobic drug amphotericin B (AmB). The micellar solubilisation of AmB by a gemini lipoamino acid (LAA) derived from cysteine and its equimolar mixtures with the bile salts sodium cholate (NaC) and sodium deoxycholate (NaDC), as well as the aggregation sate of the drug in the micellar systems, was studied under biomimetic conditions (phosphate buffered-saline, pH 7.4) using UV-vis spectroscopy. Pure surfactant systems and equimolar mixtures were characterized by tensiometry and important parameters were determined, such as critical micelle concentration (CMC), surface tension at the CMC (γCMC), maximum surface excess concentration (Γmax), and minimum area occupied per molecule at the water/air interface (Amin). Rheological behaviour from viscosity measurements at different shear rates was also addressed. Solubilisation capacity was quantified in terms of molar solubilisation ratio (χ), micelle-water partition coefficient (KM) and Gibbs energy of solubilisation (ΔGs°). Formulations of AmB in micellar media were compared in terms of drug loading, encapsulation efficiency, aggregation state of AmB and in vitro antifungal activity against Candida albicans. The LAA-containing micellar systems solubilise AmB in its monomeric and less toxic form and exhibit in vitro antifungal activity comparable to that of the commercial formulation Fungizone. Copyright © 2015 Elsevier B.V. All rights reserved.

Antifungal Resistance and Virulence Among Candida spp. from Captive Amazonian manatees and West Indian Manatees: Potential Impacts on Animal and Environmental Health.

PubMed

Sidrim, José Júlio Costa; Carvalho, Vitor Luz; de Souza Collares Maia Castelo-Branco, Débora; Brilhante, Raimunda Sâmia Nogueira; de Melo Guedes, Gláucia Morgana; Barbosa, Giovanna Riello; Lazzarini, Stella Maris; Oliveira, Daniella Carvalho Ribeiro; de Meirelles, Ana Carolina Oliveira; Attademo, Fernanda Löffler Niemeyer; da Bôaviagem Freire, Augusto Carlos; de Aquino Pereira-Neto, Waldemiro; de Aguiar Cordeiro, Rossana; Moreira, José Luciano Bezerra; Rocha, Marcos Fábio Gadelha

2016-06-01

This work aimed at evaluating the antifungal susceptibility and production of virulence factors by Candida spp. isolated from sirenians in Brazil. The isolates (n = 105) were recovered from the natural cavities of Amazonian and West Indian manatees and were tested for the susceptibility to amphotericin B, itraconazole, and fluconazole and for the production of phospholipases, proteases, and biofilm. The minimum inhibitory concentrations (MICs) for amphotericin B ranged from 0.03 to 1 µg/mL, and no resistant isolates were detected. Itraconazole and fluconazole MICs ranged from 0.03 to 16 µg/mL and from 0.125 to 64 µg/mL, respectively, and 35.2% (37/105) of the isolates were resistant to at least one of these azole drugs. Concerning the production of virulence factors, phospholipase activity was observed in 67.6% (71/105) of the isolates, while protease activity and biofilm production were detected in 50.5% (53/105) and 32.4% (34/105) of the isolates, respectively. Since the natural cavities of manatees are colonized by resistant and virulent strains of Candida spp., these animals can act as sources of resistance and virulence genes for the environment, conspecifics and other animal species, demonstrating the potential environmental impacts associated with their release back into their natural habitat.

Allicin enhances the oxidative damage effect of amphotericin B against Candida albicans.

PubMed

An, MaoMao; Shen, Hui; Cao, YongBing; Zhang, JunDong; Cai, Yun; Wang, Rui; Jiang, YuanYing

2009-03-01

Amphotericin B (AmB) is the gold standard of antifungal treatment for the most severe invasive mycoses. In addition to the interaction of AmB with ergosterol in the fungi cell membrane, several studies have demonstrated oxidative damage involved in the fungicidal activity of AmB. In this study, allicin, an allyl sulphur compound from garlic, was shown to enhance significantly the effect of AmB against Candida albicans in vitro and in vivo, although allicin did not exert a fungicidal effect. Further study first demonstrated that allicin-mediated oxidative damage, such as phospholipid peroxidation in the plasma membrane, via influencing the defence of C. albicans against oxidative damage may be the cause of the synergistic interaction between allicin and AmB. We envision that a combination of AmB with allicin may prove to be a promising strategy for the therapy of disseminated candidiasis.

Human protothecosis.

PubMed

Lass-Flörl, Cornelia; Mayr, Astrid

2007-04-01

Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue.

Human Protothecosis

PubMed Central

Lass-Flörl, Cornelia; Mayr, Astrid

2007-01-01

Human protothecosis is a rare infection caused by members of the genus Prototheca. Prototheca species are generally considered to be achlorophyllic algae and are ubiquitous in nature. The occurrence of protothecosis can be local or disseminated and acute or chronic, with the latter being more common. Diseases have been classified as (i) cutaneous lesions, (ii) olecranon bursitis, or (iii) disseminated or systemic manifestations. Infections can occur in both immunocompetent and immunosuppressed patients, although more severe and disseminated infections tend to occur in immunocompromised individuals. Prototheca wickerhamii and Prototheca zopfii have been associated with human disease. Usually, treatment involves medical and surgical approaches; treatment failure is not uncommon. Antifungals such as ketoconazole, itraconazole, fluconazole, and amphotericin B are the most commonly used drugs to date. Among them, amphotericin B displays the best activity against Prototheca spp. Diagnosis is largely made upon detection of characteristic structures observed on histopathologic examination of tissue. PMID:17428884

Treatment of a critically ill child with disseminated Candida glabrata with a recombinant human antibody specific for fungal heat shock protein 90 and liposomal amphotericin B, caspofungin, and voriconazole.

PubMed

Sutherland, Adam; Ellis, David

2008-07-01

To report a case of fungal sepsis treated prospectively with liposomal amphotericin, caspofungin, and a novel monoclonal antibody specific for candidal heat shock protein 90 (Mycograb, Neutec Pharma, Manchester, UK). Case report. Pediatric intensive care unit in a tertiary care children's hospital. A 7-yr-old male with a history of global developmental delay, epilepsy, and gastroesophageal reflux, who presented to the emergency department with a transdiaphragmatic herniation of bowel and subsequent Candida glabrata infection. Efungumab 1 mg/kg twice daily for 5 days. C-reactive protein fell from 225 mg/L to 99 mg/L, and physiological monitoring parameters improved when Mycograb was used in conjunction with high-dose antifungals. Mycograb therapy was well tolerated, but further experience with this therapy in children is needed.

Anti-transferrin receptor-modified amphotericin B-loaded PLA-PEG nanoparticles cure Candidal meningitis and reduce drug toxicity.

PubMed

Tang, Xiaolong; Liang, Yong; Zhu, Yongqiang; Xie, Chunmei; Yao, Aixia; Chen, Li; Jiang, Qinglin; Liu, Tingting; Wang, Xiaoyu; Qian, Yunyun; Wei, Jia; Ni, Wenxuan; Dai, Jingjing; Jiang, Zhenyou; Hou, Wei

2015-01-01

Fatal fungal infections in central nervous system (CNS) can occur through hematogenous spread or direct extension. At present, hydrophobic amphotericin B (AMB) is the most effective antifungal drug in clinical trials. However, AMB is hydrophobic and therefore penetrates poorly into the CNS, and therapeutic levels of AMB are hard to achieve. The transferrin receptor (TfR/CD71) located at the blood-brain barrier mediates transferrin transcytosis. In order to enhance the receptor-mediated delivery of AMB into CNS with therapeutic level, an anti-TfR antibody (OX26)-modified AMB-loaded PLA (poly[lactic acid])-PEG (polyethylene glycol)-based micellar drug delivery system was constructed. The prepared OX26-modified AMB-loaded nanoparticles (OX26-AMB-NPs) showed significant reduction of CNS fungal burden and an increase of mouse survival time. In conclusion, OX26-AMB-NPs represent a promising novel drug delivery system for intracerebral fungal infection.

Current Perspectives on Ophthalmic Mycoses

PubMed Central

Thomas, Philip A.

2003-01-01

Fungi may infect the cornea, orbit and other ocular structures. Species of Fusarium, Aspergillus, Candida, dematiaceous fungi, and Scedosporium predominate. Diagnosis is aided by recognition of typical clinical features and by direct microscopic detection of fungi in scrapes, biopsy specimens, and other samples. Culture confirms the diagnosis. Histopathological, immunohistochemical, or DNA-based tests may also be needed. Pathogenesis involves agent (invasiveness, toxigenicity) and host factors. Specific antifungal therapy is instituted as soon as the diagnosis is made. Amphotericin B by various routes is the mainstay of treatment for life-threatening and severe ophthalmic mycoses. Topical natamycin is usually the first choice for filamentous fungal keratitis, and topical amphotericin B is the first choice for yeast keratitis. Increasingly, the triazoles itraconazole and fluconazole are being evaluated as therapeutic options in ophthalmic mycoses. Medical therapy alone does not usually suffice for invasive fungal orbital infections, scleritis, and keratitis due to Fusarium spp., Lasiodiplodia theobromae, and Pythium insidiosum. Surgical debridement is essential in orbital infections, while various surgical procedures may be required for other infections not responding to medical therapy. Corticosteroids are contraindicated in most ophthalmic mycoses; therefore, other methods are being sought to control inflammatory tissue damage. Fungal infections following ophthalmic surgical procedures, in patients with AIDS, and due to use of various ocular biomaterials are unique subsets of ophthalmic mycoses. Future research needs to focus on the development of rapid, species-specific diagnostic aids, broad-spectrum fungicidal compounds that are active by various routes, and therapeutic modalities which curtail the harmful effects of fungus- and host tissue-derived factors. PMID:14557297

Trehalose pathway as an antifungal target.

PubMed

Perfect, John R; Tenor, Jennifer L; Miao, Yi; Brennan, Richard G

2017-02-17

With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with widespread use of antifungal agents, drug-resistant fungal infections are on the rise. Therefore, there is some urgency to develop the antifungal pipeline with the goal of new antifungal agent discovery. In this review, a simple metabolic pathway, which forms the disaccharide, trehalose, will be characterized and its potential as a focus for antifungal target(s) explained. It possesses several important features for development of antifungal agents. First, it appears to have fungicidal characteristics and second, it is broad spectrum with importance across both ascomycete and basidiomycete species. Finally, this pathway is not found in mammals so theoretically specific inhibitors of the trehalose pathway and its enzymes in fungi should be relatively non-toxic for mammals. The trehalose pathway and its critical enzymes are now in a position to have directed antifungal discovery initiated in order to find a new class of antifungal drugs.

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

PubMed Central

Debnath, Anjan; Tunac, Josefino B.; Galindo-Gómez, Silvia; Silva-Olivares, Angélica; Shibayama, Mineko

2012-01-01

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM. PMID:22869574

New insights into membrane-active action in plasma membrane of fungal hyphae by the lipopeptide antibiotic bacillomycin L.

PubMed

Zhang, Bao; Dong, Chunjuan; Shang, Qingmao; Han, Yuzhu; Li, Pinglan

2013-09-01

Bacillomycin L, a natural iturinic lipopeptide produced by Bacillus amyloliquefaciens, is characterized by strong antifungal activities against a variety of agronomically important filamentous fungi including Rhizoctonia solani Kühn. Prior to this study, the role of membrane permeabilization in the antimicrobial activity of bacillomycin L against plant pathogenic fungi had not been investigated. To shed light on the mechanism of this antifungal activity, the permeabilization of R. solani hyphae by bacillomycin L was investigated and compared with that by amphotericin B, a polyene antibiotic which is thought to act primarily through membrane disruption. Our results derived from electron microscopy, various fluorescent techniques and gel retardation experiments revealed that the antifungal activity of bacillomycin L may be not solely a consequence of fungal membrane permeabilization, but related to the interaction of it with intracellular targets. Our findings provide more insights into the mode of action of bacillomycin L and other iturins, which could in turn help to develop new or improved antifungal formulations or result in novel strategies to prevent fungal spoilage. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Chemosensitization as a Means to Augment Commercial Antifungal Agents

PubMed Central

Campbell, Bruce C.; Chan, Kathleen L.; Kim, Jong H.

2012-01-01

Antimycotic chemosensitization and its mode of action are of growing interest. Currently, use of antifungal agents in agriculture and medicine has a number of obstacles. Foremost of these is development of resistance or cross-resistance to one or more antifungal agents. The generally high expense and negative impact, or side effects, associated with antifungal agents are two further issues of concern. Collectively, these problems are exacerbated by efforts to control resistant strains, which can evolve into a treadmill of higher dosages for longer periods. This cycle in turn, inflates cost of treatment, dramatically. A further problem is stagnation in development of new and effective antifungal agents, especially for treatment of human mycoses. Efforts to overcome some of these issues have involved using combinations of available antimycotics (e.g., combination therapy for invasive mycoses). However, this approach has had inconsistent success and is often associated with a marked increase in negative side effects. Chemosensitization by natural compounds to increase effectiveness of commercial antimycotics is a somewhat new approach to dealing with the aforementioned problems. The potential for safe natural products to improve antifungal activity has been observed for over three decades. Chemosensitizing agents possess antifungal activity, but at insufficient levels to serve as antimycotics, alone. Their main function is to disrupt fungal stress response, destabilize the structural integrity of cellular and vacuolar membranes or stimulate production of reactive oxygen species, augmenting oxidative stress and apoptosis. Use of safe chemosensitizing agents has potential benefit to both agriculture and medicine. When co-applied with a commercial antifungal agent, an additive or synergistic interaction may occur, augmenting antifungal efficacy. This augmentation, in turn, lowers effective dosages, costs, negative side effects and, in some cases, countermands resistance. PMID:22393330

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

USDA-ARS?s Scientific Manuscript database

Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

[Efficacy of the treatment and secondary antifungal prophylaxis in AIDS-related histoplasmosis. Experience at the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires].

PubMed

Negroni, Ricardo; Messina, Fernando; Arechavala, Alicia; Santiso, Gabriela; Bianchi, Mario

Classic histoplasmosis is a systemic endemic mycosis due to Histoplasma capsulatum var. capsulatum. A significant reduction in the morbidity and mortality of AIDS-related histoplasmosis has been observed since the introduction of highly active antiretroviral therapy (HAART) and secondary antifungal prophylaxis. The aim of this study was to determine the current state of prognosis and treatment response of HIV-positive patients with histoplasmosis in the Francisco J. Muñiz Infectious Diseases Hospital in Buenos Aires City. A retrospective study was conducted using the demographic, clinical, immunological and treatment data of 80 patients suffering from AIDS-related histoplasmosis. Of the 80 cases studied 65 were male, the median age was 36 years, with 73.7% of the patients being drug addicts, 82.5% of the patients was not receiving HAART at diagnosis, and 58.7% of the cases had less than 50 CD4+ cells/μl at the beginning of the treatment. The initial phase of treatment consisted of intravenous amphotericin B and/or oral itraconazole for 3 months, with 78.7% of the cases showing a good clinical response. Only 26/63 patients who were discharged from hospital continued with the follow-up of the HAART, secondary prophylaxis with itraconazole or amphotericin B. Secondary prophylaxis was stopped after more than one year of HAART if the patients were asymptomatic, had two CD 4 + cell counts greater than 150cells/μl, and undetectable viral loads. No relapses were observed during a two-year follow up after prophylaxis was stopped. The treatment of histoplasmosis in HIV-positive patients was effective in 78.8% of the cases. The combination of HAART and secondary antifungal prophylaxis is safe, well tolerated, and effective. The low adherence of patients to HAART and the lack of laboratory kits for rapid histoplasmosis diagnosis should be addressed in the future. The usefulness of primary antifungal prophylaxis for cryptococcosis and histoplasmosis HIV-positive patients should be studied. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Fusarium species causing eumycetoma: Report of two cases and comprehensive review of the literature.

PubMed

Al-Hatmi, Abdullah M S; Bonifaz, Alexandro; Tirado-Sánchez, Andrés; Meis, Jacques F; de Hoog, G Sybren; Ahmed, Sarah A

2017-03-01

Recently, mycetoma was added to the World Health Organization's list of neglected tropical disease priorities. Fusarium as a genus has been reported to cause eumycetoma, but little is known about the species involved in this infection and their identification. In this study, molecular tools were applied to identify Fusarium agents from human eumycetoma cases. The partial translation elongation factor 1-alpha (TEF-1α) gene was used as diagnostic parameter. Two additional cases of eumycetoma, due to F. keratoplasticum and F. pseudensiforme, respectively, are presented. A systematic literature review was performed to assess general features, identification, treatment and outcome of eumycetoma infections due to Fusarium species. Of the 20 reviewed patients, the majority (75%) were male. Most agents belonged to the F. solani species complex, ie F. keratoplasticum, F. pseudensiforme, and an undescribed lineage of F. solani. In addition, F. thapsinum, a member of Fusarium fujikuroi species complex was encountered. The main antifungal drugs used were itraconazole, ketoconazole and amphotericin B, but cure rates were low (15%). Partial response or relapse was observed in some cases, and a case ended in amputation. Clinical management of eumycetoma due to Fusarium is complex and combination therapy might be required to increase cure rates. © 2016 Blackwell Verlag GmbH.

Voriconazole for the treatment of refractory Aspergillus fumigatus keratitis

PubMed Central

Mehta, Hitendra B; Garg, Prashant; Kodial, Harish

2008-01-01

We report a case of Aspergillus fumigatus keratitis in a 53-year-old, well-controlled diabetic female who did not respond to standard antifungal treatment. She was started on topical natamycin eye drops, but the infiltrate continued to progress. Topical amphotericin B and systemic ketoconazole was added, however, there was no response and the infiltrate increased further. She was then switched to topical and systemic voriconazole. Steady resolution of the infiltrate was noted within 2 weeks of therapy. PMID:18417831

Curvularia lunata endophthalmitis after penetrating ocular trauma.

PubMed

Jaramillo, Sergio; Varon, Clara L

2013-01-01

To report a case of Curvularia lunata endophthalmitis that responded to amphotericin B and itraconazole Observational case report of one patient with C. lunata endophthalmitis after penetrating ocular injury with vegetable material. One young adult male patient presented with visual loss after penetrating ocular trauma with vegetable material. Biomicroscopy revealed keratitis and secondary endophthalmitis. Vitreous cultures after vitrectomy were positive for C. lunata and Staphylococcus epidermidis. Patient responded well to intravitreal amphotericin B and moxifloxacin. Fungal endophthalmitis should be suspected after trauma with vegetable material. Curvularia lunata may produce endophthalmitis and keratitis. Amphotericin B and itraconazole should be considered suitable agents for its treatment.

Molecular identification and in vitro antifungal susceptibility of Scedosporium complex isolates from high-human-activity sites in Mexico.

PubMed

Elizondo-Zertuche, Mariana; de J Treviño-Rangel, Rogelio; Robledo-Leal, Efrén; Luna-Rodríguez, Carolina E; Martínez-Fierro, Margarita L; Rodríguez-Sánchez, Iram P; González, Gloria M

2017-01-01

The genus Scedosporium is a complex of ubiquitous moulds associated with a wide spectrum of clinical entities, with high mortality principally in immunocompromised hosts. Ecology of these microorganisms has been studied performing isolations from environmental sources, showing a preference for human-impacted environments. This study aimed to evaluate the presence and antifungal susceptibility of Scedosporium complex species in soil samples collected in high-human-activity sites of Mexico. A total of 97 soil samples from 25 Mexican states were collected. Identifications were performed by microscopic morphology and confirmed by sequencing of the rDNA (internal transcribed spacer [ITS], D1/D2) and β-tubulin partial loci. Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) protocols. Soil samples of urban gardens and industrial parks constituted the best sources for isolation of Scedosporium complex species. S. apiospermum sensu stricto was the most prevalent species (69%), followed by S. boydii (16%). Voriconazole (minimal inhibitory concentration [MIC] geometric mean ≤2.08 µg/mL), followed by posaconazole (MIC geometric mean ≤2.64 µg/mL), exhibited excellent in vitro activity for most species. Amphotericin B and fluconazole demonstrated limited antifungal activity, and all of the strains were resistant to echinocandins. This is the first report in Mexico of environmental distribution and antifungal in vitro susceptibility of these emergent pathogens.

Increased Degree of Unsaturation in the Lipid of Antifungal Cationic Amphiphiles Facilitates Selective Fungal Cell Disruption.

PubMed

Steinbuch, Kfir B; Benhamou, Raphael I; Levin, Lotan; Stein, Reuven; Fridman, Micha

2018-05-11

Antimicrobial cationic amphiphiles derived from aminoglycosides act through cell membrane permeabilization but have limited selectivity for microbial cell membranes. Herein, we report that an increased degree of unsaturation in the fatty acid segment of antifungal cationic amphiphiles derived from the aminoglycoside tobramycin significantly reduced toxicity to mammalian cells. A collection of tobramycin-derived cationic amphiphiles substituted with C 18 lipid chains varying in degree of unsaturation and double bond configuration were synthesized. All had potent activity against a panel of important fungal pathogens including strains with resistance to a variety of antifungal drugs. The tobramycin-derived cationic amphiphile substituted with linolenic acid with three cis double bonds (compound 6) was up to an order of magnitude less toxic to mammalian cells than cationic amphiphiles composed of lipids with a lower degree of unsaturation and than the fungal membrane disrupting drug amphotericin B. Compound 6 was 12-fold more selective (red blood cell hemolysis relative to antifungal activity) than compound 1, the derivative with a fully saturated lipid chain. Notably, compound 6 disrupted the membranes of fungal cells without affecting the viability of cocultured mammalian cells. This study demonstrates that the degree of unsaturation and the configuration of the double bond in lipids of cationic amphiphiles are important parameters that, if optimized, result in compounds with broad spectrum and potent antifungal activity as well as reduced toxicity toward mammalian cells.

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine

PubMed Central

Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

2016-01-01

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies. PMID:27031728

Melanins Protect Sporothrix brasiliensis and Sporothrix schenckii from the Antifungal Effects of Terbinafine.

PubMed

Almeida-Paes, Rodrigo; Figueiredo-Carvalho, Maria Helena Galdino; Brito-Santos, Fábio; Almeida-Silva, Fernando; Oliveira, Manoel Marques Evangelista; Zancopé-Oliveira, Rosely Maria

2016-01-01

Terbinafine is a recommended therapeutic alternative for patients with sporotrichosis who cannot use itraconazole due to drug interactions or side effects. Melanins are involved in resistance to antifungal drugs and Sporothrix species produce three different types of melanin. Therefore, in this study we evaluated whether Sporothrix melanins impact the efficacy of antifungal drugs. Minimal inhibitory concentrations (MIC) and minimal fungicidal concentrations (MFC) of two Sporothrix brasiliensis and four Sporothrix schenckii strains grown in the presence of the melanin precursors L-DOPA and L-tyrosine were similar to the MIC determined by the CLSI standard protocol for S. schenckii susceptibility to amphotericin B, ketoconazole, itraconazole or terbinafine. When MICs were determined in the presence of inhibitors to three pathways of melanin synthesis, we observed, in four strains, an increase in terbinafine susceptibility in the presence of tricyclazole, a DHN-melanin inhibitor. In addition, one S. schenckii strain grown in the presence of L-DOPA had a higher MFC value when compared to the control. Growth curves in presence of 2×MIC concentrations of terbinafine showed that pyomelanin and, to a lesser extent, eumelanin were able to protect the fungi against the fungicidal effect of this antifungal drug. Our results suggest that melanin protects the major pathogenic species of the Sporothrix complex from the effects of terbinafine and that the development of new antifungal drugs targeting melanin synthesis may improve sporotrichosis therapies.

Emerging Drugs and Vaccines for Candidemia

PubMed Central

Moriyama, Brad; Gordon, Lori A.; McCarthy, Matthew; Henning, Stacey A.; Walsh, Thomas J.; Penzak, Scott R.

2014-01-01

Summary Candidemia and other forms of invasive candidiasis are important causes of morbidity and mortality. The evolving challenge of antimicrobial resistance among fungal pathogens continues to highlight the need for potent, new antifungal agents. MEDLINE, EMBASE, Scopus, and Web of Science searches (up to January 2014) of the English-language literature were performed with the keywords “Candida” or “Candidemia” or “Candidiasis” and terms describing investigational drugs with activity against Candida spp. Conference abstracts and the bibliographies of pertinent articles were also reviewed for relevant reports. ClinicalTrials.gov was searched for relevant clinical trials. Currently available antifungal agents for the treatment of candidemia are summarized. Investigational antifungal agents with potential activity against Candida bloodstream infections and other forms of invasive candidiasis and vaccines for prevention of Candida infections are also reviewed as are selected antifungal agents no longer in development. Antifungal agents currently in clinical trials include isavuconazole, albaconazole, SCY-078, VT-1161, and T-2307. Further data are needed to determine the role of these compounds in the treatment of candidemia and other forms of invasive candidiasis. The progressive reduction in antimicrobial drug development may result in a decline in antifungal drug discovery. Still there remains a critical need for new antifungal agents to treat and prevent invasive candidiasis and other life-threatening mycoses. PMID:25294098

[Fungi isolated from the stool in patients with gastrointestinal disorders in 2005 - 2009].

PubMed

Macura, Anna B; Witalis, Jadwiga

2010-01-01

The mycological examination of 2242 stool specimens sampled form patients with non-specific gastrointestinal tract ailments was focused on the spectrum of fungal species isolated in culture, the frequency of isolation of the particular species high enough to indicate microbiological imbalance in the gut flora as well as evaluation of the fungal susceptibility to the antifungal agents. Fungal presence was detected in 61.5% of the specimens tested. The fungal flora isolated was as follows: C. albicans 70.9% of the isolates, Candida non-albicans 20.8% (including C krusei 3.40%, C. parapsilosis 1.88%, C. glabrata 1.59%), other genera 8.34% (including S. cerevisiae 5.58%, Geotrichum sp. 1.16%, and Trichosporon sp. 1.01%). The results of semiquantitative evaluation of the intensity of growth of the fungi isolated from the stool revealed that imbalance in the gut flora occured in 20.8% of the cases. Candida strains tested using Fungitest were less susceptible to azoles than to amphotericin B and 5-fluorocytosine. Decreased susceptibiliy or resistance to antimycotics was relatively often found among Candida non-albicans strains.

Structure-In Vitro Activity Relationships of Pentamidine Analogues and Dication-Substituted Bis-Benzimidazoles as New Antifungal Agents

PubMed Central

Del Poeta, Maurizio; Schell, Wiley A.; Dykstra, Christine C.; Jones, Susan; Tidwell, Richard R.; Czarny, Agnieszka; Bajic, Miroslav; Bajic, Marina; Kumar, Arvind; Boykin, David; Perfect, John R.

1998-01-01

Twenty analogues of pentamidine, 7 primary metabolites of pentamidine, and 30 dicationic substituted bis-benzimidazoles were screened for their inhibitory and fungicidal activities against Candida albicans and Cryptococcus neoformans. A majority of the compounds had MICs at which 80% of the strains were inhibited (MIC80s) comparable to those of amphotericin B and fluconazole. Unlike fluconazole, many of these compounds were found to have potent fungicidal activity. The most potent compound against C. albicans had an MIC80 of ≤0.09 μg/ml, and the most potent compound against C. neoformans had an MIC80 of 0.19 μg/ml. Selected compounds were also found to be active against Aspergillus fumigatus, Fusarium solani, Candida species other than C. albicans, and fluconazole-resistant strains of C. albicans and C. neoformans. It is clear from the data presented here that further studies on the structure-activity relationships, mechanisms of action and toxicities, and in vivo efficacies of these compounds are warranted to determine their clinical potential. PMID:9756747

Protothecal peritonitis in child after bone marrow transplantation: case report and literature review of paediatric cases.

PubMed

Sykora, T; Horakova, J; Buzzasyova, D; Sladekova, M; Poczova, M; Sufliarska, S

2014-11-01

The case presented here illustrates a protothecal infection caused by Prototheca wickerhamii in a paediatric haematopoietic stem cell recipient followed by a review of the literature of all 13 paediatric cases published since 1980. Protothecosis is a rare disease caused by algae, not described in this setting before. Infection was proven additionally post-mortem from peritoneal dialysis fluid. Even though no death of a paediatric patient due to this infection has been reported and the mortality rate associated with protothecosis is low, our patient died from multiorgan failure as a result of numerous post-transplant complications and a strain of cultivated alga that was highly resistant to antifungal agents. Prototheca spp. show various susceptibility profiles, and there is no direct correlation between in vitro activity and clinical response. There are different treatment regimens described but there are no clear published guidelines of specific therapy of protothecosis. Paediatric cases were successfully treated mostly with amphotericin B and azoles. As the number of immunocompromised patients increases, it is necessary to think more about unusual pathogens such as Prototheca.

[In vitro activity of voriconazole and three other antifungal agents against dermatophytes].

PubMed

Serrano-Martino, María del Carmen; Chávez-Caballero, Mónica; Valverde-Conde, Anastasio; Claro, Rosa María; Pemán, Javier; Martín-Mazuelos, Estrella

2003-11-01

The increase in infections due to dermatophytes in recent years led us to study the effectiveness of new antifungal formulations against these microorganisms. The in vitro activity of a new antifungal agent, voriconazole, was compared with three other antifungal agents, itraconazole, fluconazole and terbinafine, against 120 dermatophytes belonging to four species (61 Trichophyton mentagrophytes, 34 Microsporum canis, 13 M. gypseum and 12 T. rubrum). A broth microdilution method was used following the recommendations of the NCCLS document M38-P with some modifications. Terbinafine was the most active agent against the dermatophytes studied (MIC90 < or = 0.03 mg/ml), followed by voriconazole (MIC90, 0.25 micro g/ml) and itraconazole (MIC90, 0.5 micro g/ml). Fluconazole was the least active antifungal agent. The most susceptible species was M. canis. Voriconazole was found to have effective activity against dermatophytes.

The efficacy of gaseous ozone against different forms of Candida albicans

PubMed Central

Zargaran, M; Fatahinia, M; Zarei Mahmoudabadi, A

2017-01-01

Background and Purpose: Ozone is an inorganic molecule with effective antimicrobial properties. Clinical treatment of ozonated water was used for the elimination of Candida albicans, Enterococcus faecalis, endotoxins, and biofilms from root canals. In addition, its therapeutic effects for tinea pedis, ulcers, and leishmaniasis were investigated. The purpose of the present study was to evaluate the fungicidal effects of ozone on different forms of C. albicans. In addition, antifungal susceptibility profile of strains was assessed before and after exposure to ozone. Materials and Methods: Fifty strains of C. albicans were exposed to gaseous ozone at different times. Furthermore, biofilm formation and germ tube production were evaluated when yeast suspensions were exposed to ozone. In addition, antifungal susceptibility of ozone resistant colonies was investiagted as compared to controls. Results: Ozone was highly effective in killing C. albicans in yeast form and inhibition of germ tube formation during 210 and 180 s, respectively. Although with increasing exposure time biofilm production was considerably decreased, resistance to ozone was much higher among vaginal and nail isolates even after 60 min. All the strains were sensitive to fluconazole, caspofungin, and terbinafine pre- and post-ozone exposure. Resistance to amphotericin B was significantly enhanced after exposure to ozone. Conclusion: Although ozone was highly effective on the yeast form of C. albicans and it can inhibit the formation of germ tubes in C. albicans, the complete removal of biofilms did not happen even after 60 min. It seems that ozone therapy induces resistance to amphotericin B. PMID:29354778

Interaction of amphotericin B and its low toxic derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester, with fungal, mammalian and bacterial cells measured by the energy transfer method.

PubMed

Szlinder-Richert, Joanna; Cybulska, Barbara; Grzybowska, Jolanta; Bolard, Jacques; Borowski, Edward

2004-04-01

Amphotericin B (AMB) derivative, N-methyl-N-D-fructosyl amphotericin B methyl ester (MFAME) retains the broad antifungal spectrum and potency of the parent antibiotic, whereas its toxicity towards mammalian cells is reduced by about two orders of magnitude. The purpose of this work was to find out whether the differences observed in the toxicity of MFAME and native AMB are due to the differential drugs affinity to fungal and mammalian cell membranes. Comparative studies on AMB and MFAME biological activity and their affinity to fungal, mammalian and bacterial cells were performed. The interaction of AMB and MFAME with cells have been studied by fluorescence method based on the energy transfer between membrane fluorescent probe (donor) and the polyenic chromophore of the antibiotic (acceptor) simultaneously present in the cell membrane. The amount of the antibiotic bound to cells was indicated by the extent of fluorescence quenching of 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH) or 1,6-diphenyl-1,3,5-hexatriene (DPH) by polyenic chromophore of the antibiotic. The results obtained indicate that binding extent and characteristics for both antibiotics are comparable in the three types of cells studied. Dramatically lower toxicity of MFAME as compared to AMB towards mammalian cells is not related to the antibiotic-cell affinity, but rather to different consequences of these interactions for cells, reflected in membrane permeabilization. MFAME is definitely less effective than parent AMB in the permeabilizing species formation in mammalian cell membrane.

In Vitro Activities of 35 Double Combinations of Antifungal Agents against Scedosporium apiospermum and Scedosporium prolificans▿

PubMed Central

Cuenca-Estrella, Manuel; Alastruey-Izquierdo, Ana; Alcazar-Fuoli, Laura; Bernal-Martinez, Leticia; Gomez-Lopez, Alicia; Buitrago, Maria J.; Mellado, Emilia; Rodriguez-Tudela, Juan L.

2008-01-01

Activities of 35 combinations of antifungal agents against Scedosporium spp. were analyzed by a checkerboard microdilution design and the summation of fractional concentration index. An average indifferent effect was detected apart from combinations of azole agents and echinocandins against Scedosporium apiospermum. Antagonism was absent for all antifungal combinations against both species. PMID:18195067

Efficacy of an Abbreviated Induction Regimen of Amphotericin B Deoxycholate for Cryptococcal Meningoencephalitis: 3 Days of Therapy Is Equivalent to 14 Days

PubMed Central

Livermore, Joanne; Howard, Susan J.; Sharp, Andrew D.; Goodwin, Joanne; Gregson, Lea; Felton, Timothy; Schwartz, Julie A.; Walker, Catherine; Moser, Bill; Müller, Werner; Harrison, Thomas S.; Perfect, John R.; Hope, William W.

2014-01-01

ABSTRACT Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log10 CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3+ CD4+ or CD3+ CD8+ cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis. PMID:24473125

The diversity and antifungal susceptibility of the yeasts isolated from coconut water and reconstituted fruit juices in Brazil.

PubMed

Maciel, Natália O P; Piló, Fernanda B; Freitas, Larissa F D; Gomes, Fátima C O; Johann, Susana; Nardi, Regina M D; Lachance, Marc-André; Rosa, Carlos A

2013-01-01

The aims of this study were to characterise the yeasts present in the reconstituted fruit juices and coconut water extracted with "coconut machines", both collected from commercial outlets in a Brazilian city, and to investigate the antifungal resistance of isolates from these beverages that were able to grow at 37°C. The yeast population counts in the coconut water samples ranged from 1.7 to >6.5logcfu/ml, and in the reconstituted fruit juices, the counts ranged from 1.5 to >5.5logcfu/ml. Aureobasidium pullulans, Candida boidinii, Candidaintermedia, Candidaoleophila, Candidaparapsilosis, Candidasantamariae, Candidatropicalis, Clavispora lusitaniae, Kloeckera apis, Lachancea fermentati, Pichia fermentans and Rhodotorula mucilaginosa were the most frequent species isolated from these beverages. At least 18 yeast species isolated from these beverages have been reported as opportunistic pathogens. Eight yeast isolates were resistant to fluconazole, seven were resistant to itraconazole, and 26 to amphotericin B. Some yeast species were resistant to more than one of the antifungal drugs tested. Two isolates of C. tropicalis from the reconstituted fruit juices exhibited resistance to all three drugs. The presence of yeast strains that are resistant to commonly used antifungal drugs suggests a potential risk, at least to immunocompromised individuals who consume these beverages. Copyright © 2012 Elsevier B.V. All rights reserved.

Complications of hematopoietic stem transplantation: Fungal infections.

PubMed

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Species distribution and antifungal susceptibility patterns of Candida isolates from a public tertiary teaching hospital in the Eastern Cape Province, South Africa.

PubMed

Mnge, P; Okeleye, B I; Vasaikar, S D; Apalata, T

2017-05-15

Candida species are the leading cause of invasive fungal infections, and over the past decade there has been an increased isolation of drug resistant Candida species. This study aimed to identify the species distribution of Candida isolates and to determine their unique antifungal susceptibility and resistance patterns. During a cross-sectional study, 209 Candida isolates (recovered from 206 clinical samples) were collected and their species distribution was determined using ChromAgar Candida. The Vitek-2 system (Biomerieux, South Africa) was used to determine minimum inhibitory concentrations (MICs) to azoles (fluconazole, voriconazole), echinocandins (caspofungin, micafungin), polyenes (amphotericin B) and flucytosine. Four species of Candida were isolated, of which C. albicans was the most frequent, isolated in 45.4% (95/209) of the isolates, followed by C. glabrata: 31.1% (65/209). The MICs of the different antifungal drugs varied amongst the species of Candida. From the 130 isolates tested for MICs, 90.77% (112/130) were susceptible to all antifungal drugs and 6.9% (9/130) of the isolates were multi-drug resistant. C. dubliniensis (n=2) isolates were susceptible to all the above mentioned antifungal drugs. There was no significant difference in species distribution amongst clinical specimens and between patients' genders (P>0.05). An increase in MIC values for fluconazole and flucytosine towards the resistance range was observed. To our knowledge, this is the first report on surveillance of Candida species distribution and antifungal susceptibility at a public tertiary teaching hospital in Eastern Cape, South Africa.

Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

PubMed

Vergidis, Paschalis; Avery, Robin K; Wheat, L Joseph; Dotson, Jennifer L; Assi, Maha A; Antoun, Smyrna A; Hamoud, Kassem A; Burdette, Steven D; Freifeld, Alison G; McKinsey, David S; Money, Mary E; Myint, Thein; Andes, David R; Hoey, Cynthia A; Kaul, Daniel A; Dickter, Jana K; Liebers, David E; Miller, Rachel A; Muth, William E; Prakash, Vidhya; Steiner, Frederick T; Walker, Randall C; Hage, Chadi A

2015-08-01

Histoplasmosis may complicate tumor necrosis factor (TNF)-α blocker therapy. Published case series provide limited guidance on disease management. We sought to determine the need for long-term antifungal therapy and the safety of resuming TNF-α blocker therapy after successful treatment of histoplasmosis. We conducted a multicenter retrospective review of 98 patients diagnosed with histoplasmosis between January 2000 and June 2011. Multivariate logistic regression was used to evaluate risk factors for severe disease. The most commonly used biologic agent was infliximab (67.3%). Concomitant corticosteroid use (odds ratio [OR], 3.94 [95% confidence interval {CI}, 1.06-14.60]) and higher urine Histoplasma antigen levels (OR, 1.14 [95% CI, 1.03-1.25]) were found to be independent predictors of severe disease. Forty-six (47.4%) patients were initially treated with an amphotericin B formulation for a median duration of 2 weeks. Azole treatment was given for a median of 12 months. TNF-α blocker therapy was initially discontinued in 95 of 98 (96.9%) patients and later resumed in 25 of 74 (33.8%) patients at a median of 12 months (range, 1-69 months). The recurrence rate was 3.2% at a median follow-up period of 32 months. Of the 3 patients with recurrence, 2 had restarted TNF-α blocker therapy, 1 of whom died. Mortality rate was 3.2%. In this study, disease outcomes were generally favorable. Discontinuation of antifungal treatment after clinical response and an appropriate duration of therapy, probably at least 12 months, appears safe if pharmacologic immunosuppression has been held. Resumption of TNF-α blocker therapy also appears safe, assuming that the initial antifungal therapy was administered for 12 months. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery.

PubMed

Liu, Shuyuan; Hou, Yinglong; Chen, Xu; Gao, Yuan; Li, Hui; Sun, Shujuan

2014-05-01

The past decades have witnessed a dramatic increase in invasive fungal infections, especially candidiasis. Despite the development of more effective new antifungal agents, fluconazole (FLC) is still widely used in the clinic because of its efficacy and low toxicity. However, as the number of patients treated with FLC has increased, FLC-resistant Candida albicans isolates emerge more frequently. In addition, biofilm-associated infections are commonly encountered and their resistance poses a great challenge to antifungal treatment. Various approaches have been proposed to increase the susceptibility of C. albicans to FLC in order to cope with treatment failures, among which is the combination of FLC with different classes of non-antifungal agents such as antibacterials, calcineurin inhibitors, heat shock protein 90 inhibitors, calcium homeostasis regulators and traditional Chinese medicine drugs. Interestingly, many of these combinations showed synergistic effects against C. albicans, especially resistant strains. The main mechanisms of these synergistic effects appear to be increasing the permeability of the membrane, reducing the efflux of antifungal drugs, interfering with intracellular ion homeostasis, inhibiting the activity of proteins and enzymes required for fungal survival, and inhibiting biofilm formation. These modes of action and the antifungal mechanisms of various compounds referenced in this paper highlight the idea that the reversal of fungal resistance can be achieved through various mechanisms. Studies examining drug interactions will hopefully provide new approaches against antifungal drug resistance as well as insight into antifungal agent discovery. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Coexistence of aspergilloma and pulmonary hydatid cyst in an immunocompetent individual.

PubMed

Aala, F; Badali, H; Hashemi Fesharaki, S; Boroumand, M; Sotoudeh Anvari, M; Davari, H; Agha Kuchak Afshari, S; Khodavaisy, S

2017-09-01

Echinococcosis is a zoonotic disease caused by Echinococcus granulosus sensu lato. The liver and lungs are the most commonly sites of infections, but involvements of other organs were also observed. Recently, the coinfection of pulmonary hydatid cyst with aspergilloma has been reported in the literature. Herein, we report a successful treatment of coinfection of cystic echinoccosis with aspergilloma due to Aspergillus flavus in a 34-year-old female. In vitro antifungal susceptibility tests revealed that the MIC values for antifungals employed in this case were posaconazole (0.031μg/ml), itraconazole (0.125μg/ml), voriconazole (0.25μg/ml), and amphotericin B (1μg/ml). The minimum effective concentration for caspofungin was 0.008μg/ml. This coexistence of active pulmonary echinococcosis and aspergillosis is being reported because of its rarity and clinical importance for its management. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

In vitro antifungal susceptibility and molecular identity of 99 clinical isolates of the opportunistic fungal genus Curvularia.

PubMed

da Cunha, Keith C; Sutton, Deanna A; Fothergill, Annette W; Gené, Josepa; Cano, Josep; Madrid, Hugo; Hoog, Sybren de; Crous, Pedro W; Guarro, Josep

2013-06-01

The in vitro antifungal susceptibility of a set of 99 clinical isolates of Curvularia was tested against 9 drugs using a reference microdilution method. The isolates had been identified previously to species level by comparing their ITS rDNA and glyceraldehyde-3-phosphate dehydrogenase gene sequences with those of reference strains. We were able to reliably identify 73.2% of the isolates, the most frequent species being Curvularia aeria, Curvularia geniculata/Curvularia senegalensis, Curvularia lunata, Curvularia inaequalis, Curvularia verruculosa, and Curvularia borreriae. Most of these isolates had been recovered from nasal sinus, which is generally considered one of the most frequent sites of infection by these fungi. In addition, at least 3 phylogenetic species that have not yet been formally described were detected. The most active drugs were the echinocandins, amphotericin B, and posaconazole, whereas voriconazole and itraconazole showed poor activity. Copyright © 2013 Elsevier Inc. All rights reserved.

Candida Arthritis: Analysis of 112 Pediatric and Adult Cases

PubMed Central

Gamaletsou, Maria N.; Rammaert, Blandine; Bueno, Marimelle A.; Sipsas, Nikolaos V.; Moriyama, Brad; Kontoyiannis, Dimitrios P.; Roilides, Emmanuel; Zeller, Valerie; Taj-Aldeen, Saad J.; Miller, Andy O.; Petraitiene, Ruta; Lortholary, Olivier; Walsh, Thomas J.

2016-01-01

Background. Candida arthritis is a debilitating form of deeply invasive candidiasis. However, its epidemiology, clinical manifestations, management, and outcome are not well understood. Methods. Cases of Candida arthritis were reviewed from 1967 through 2014. Variables included Candida spp in joint and/or adjacent bone, underlying conditions, clinical manifestations, inflammatory biomarkers, diagnostic imaging, management, and outcome. Results. Among 112 evaluable cases, 62% were males and 36% were pediatric. Median age was 40 years (range, <1–84 years). Most patients (65%) were not pharmacologically immunosuppressed. Polyarticular infection (≥3 joints) occurred in 31% of cases. Clinical manifestations included pain (82%), edema (71%), limited function (39%), and erythema (22%) with knees (75%) and hips (15%) most commonly infected. Median erythrocyte sedimentation rate was 62 mm/hr (10–141) and C reactive protein 26 mg/dL (0.5–95). Synovial fluid median white blood cell count was 27 500/µL (range, 100–220 000/µL) with 90% polymorphonuclear neutrophils (range, 24–98). Adjacent osteomyelitis was present in 30% of cases. Candida albicans constituted 63%, Candida tropicalis 14%, and Candida parapsilosis 11%. Most cases (66%) arose de novo, whereas 34% emerged during antifungal therapy. Osteolysis occurred in 42%, joint-effusion in 31%, and soft tissue extension in 21%. Amphotericin and fluconazole were the most commonly used agents. Surgical interventions included debridement in 25%, irrigation 10%, and drainage 12%. Complete or partial response was achieved in 96% and relapse in 16%. Conclusion. Candida arthritis mainly emerges as a de novo infection in usually non-immunosuppressed patients with hips and knees being most commonly infected. Localizing symptoms are frequent, and the most common etiologic agents are C albicans, C tropicalis, and C parapsilosis. Management of Candida arthritis remains challenging with a clear risk of relapse, despite antifungal therapy. PMID:26858961

Potent Inhibition of Pseudogymnoascus destructans, the Causative Agent of White-Nose Syndrome in Bats, by Cold-Pressed, Terpeneless, Valencia Orange Oil.

PubMed

Boire, Nicholas; Zhang, Sean; Khuvis, Joshua; Lee, Rick; Rivers, Jennifer; Crandall, Philip; Keel, M Kevin; Parrish, Nicole

2016-01-01

The causative agent of White-nose Syndrome (WNS), Pseudogymnoascus destructans, has been shown to be fatal to several species of bats in North America. To date, no compounds or chemical control measures have been developed which eliminates the growth of the fungus in the environment or in affected animals. In the current study, we evaluated the activity of cold-pressed, terpeneless orange oil (CPT) against multiple isolates of P. destructans in vitro. For all assays, a modified Kirby-Bauer disk diffusion assay was used. Standardized spore suspensions were prepared, adjusted to a specific optical density, and used to plate fungal lawns. Plates were incubated at either 15°C or 4°C for up to 6 months and checked at regular intervals for growth. Once controls had grown, zones of inhibition were measured (mm) on test plates and compared to those obtained using current antifungal drugs. All P. destructans isolates were completely inhibited by 100% CPT (10 μL) at 1 month of incubation regardless of temperature (4°C and 15°C). Complete inhibition persisted up to 6 months following a single exposure at this concentration. Of the standard antifungals, only amphotericin B demonstrated any activity, resulting in zone diameters ranging from 58 mm to 74 mm. CPT, at the highest concentration tested (100%), had no significant effect against a variety of other environmental organisms including various filamentous fungi, bacteria and aerobic actinomycetes. Given that CPT is relatively non-toxic, the possibility exists that the all-natural, mixture could be used as an environmental pre-treatment to eradicate P. destructans from bat habitats. Additional studies are needed to assess any undesirable effects of CPT on bat behavior and health and overall impacts on other members of the interconnected ecosystem(s).

Potent Inhibition of Pseudogymnoascus destructans, the Causative Agent of White-Nose Syndrome in Bats, by Cold-Pressed, Terpeneless, Valencia Orange Oil

PubMed Central

Boire, Nicholas; Zhang, Sean; Khuvis, Joshua; Lee, Rick; Rivers, Jennifer; Crandall, Philip; Keel, M. Kevin; Parrish, Nicole

2016-01-01

The causative agent of White-nose Syndrome (WNS), Pseudogymnoascus destructans, has been shown to be fatal to several species of bats in North America. To date, no compounds or chemical control measures have been developed which eliminates the growth of the fungus in the environment or in affected animals. In the current study, we evaluated the activity of cold-pressed, terpeneless orange oil (CPT) against multiple isolates of P. destructans in vitro. For all assays, a modified Kirby-Bauer disk diffusion assay was used. Standardized spore suspensions were prepared, adjusted to a specific optical density, and used to plate fungal lawns. Plates were incubated at either 15°C or 4°C for up to 6 months and checked at regular intervals for growth. Once controls had grown, zones of inhibition were measured (mm) on test plates and compared to those obtained using current antifungal drugs. All P. destructans isolates were completely inhibited by 100% CPT (10 μL) at 1 month of incubation regardless of temperature (4°C and 15°C). Complete inhibition persisted up to 6 months following a single exposure at this concentration. Of the standard antifungals, only amphotericin B demonstrated any activity, resulting in zone diameters ranging from 58 mm to 74 mm. CPT, at the highest concentration tested (100%), had no significant effect against a variety of other environmental organisms including various filamentous fungi, bacteria and aerobic actinomycetes. Given that CPT is relatively non-toxic, the possibility exists that the all-natural, mixture could be used as an environmental pre-treatment to eradicate P. destructans from bat habitats. Additional studies are needed to assess any undesirable effects of CPT on bat behavior and health and overall impacts on other members of the interconnected ecosystem(s). PMID:26849057

Antifungal Indole and Pyrrolidine-2,4-Dione Derivative Peptidomimetic Lead Design Based on In Silico Study of Bioactive Peptide Families

PubMed Central

Moradi, Shoeib; Azerang, Parisa; Khalaj, Vahid; Sardari, Soroush

2013-01-01

Background The rise of opportunistic fungal infections highlights the need for development of new antimicrobial agents. Antimicrobial Peptides (AMPs) and Antifungal Peptides (AFPs) are among the agents with minimal resistance being developed against them, therefore they can be used as structural templates for design of new antimicrobial agents. Methods In the present study four antifungal peptidomimetic structures named C1 to C4 were designed based on plant defensin of Pisum sativum. Minimum inhibitory concentrations (MICs) for these structures were determined against Aspergillus niger N402, Candida albicans ATCC 10231, and Saccharomyces cerevisiae PTCC 5052. Results C1 and C2 showed more potent antifungal activity against these fungal strains compared to C3 and C4. The structure C2 demonstrated a potent antifungal activity among them and could be used as a template for future study on antifungal peptidomemetics design. Sequences alignments led to identifying antifungal decapeptide (KTCENLADTY) named KTC-Y, which its MIC was determined on fungal protoplast showing 25 (µg/ml) against Aspergillus fumigatus Af293. Conclusion The present approach to reach the antifungal molecules seems to be a powerful approach in design of bioactive agents based on AMP mimetic identification. PMID:23626876

Isatis tinctoria mediated synthesis of amphotericin B-bound silver nanoparticles with enhanced photoinduced antileishmanial activity: A novel green approach.

PubMed

Ahmad, Aftab; Wei, Yun; Syed, Fatima; Khan, Shafiullah; Khan, Gul Majid; Tahir, Kamran; Khan, Arif Ullah; Raza, Muslim; Khan, Faheem Ullah; Yuan, Qiping

2016-08-01

After malaria, Leishmaniasis is the most prevalent infectious disease in terms of fatality and geographical distribution. The availability of a limited number of antileishmanial agents, emerging resistance to the available drugs, and the high cost of treatment complicate the treatment of leishmaniasis. To overcome these issues, critical research for new therapeutic agents with enhanced antileishmanial potential and low treatment cost is needed. In this contribution, we developed a green protocol to prepare biogenic silver nanoparticles (AgNPs) and amphotericin B-bound biogenic silver nanoparticles (AmB-AgNPs). Phytochemicals from the aqueous extract of Isatis tinctoria were used as reducing and capping agents to prepare silver nanoparticles. Amphotericin B was successfully adsorbed on the surface of biogenic silver nanoparticles. The prepared nanoparticles were characterized by various analytical techniques. UV-Visible spectroscopy was employed to detect the characteristic localized surface plasmon resonance peaks (LSPR) for the prepared nanoparticles. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) studies revealed the formation of spherical silver nanoparticles with an average particle size of 10-20nm. The cubic crystalline structure of the prepared nanoparticles was confirmed by X-ray diffraction (XRD) study. FTIR spectroscopic analysis revealed that plant polyphenolic compounds are mainly involved in metal reduction and capping. Under visible light irradiation, biogenic silver nanoparticles exhibited significant activity against Leishmania tropica with an IC50 value of 4.2μg/mL. The leishmanicidal activity of these nanoparticles was considerably enhanced by conjugation with amphotericin B (IC50=2.43μg/mL). In conclusion, the findings of this study reveal that adsorption of amphotericin B, an antileishmanial drug, to biogenic silver nanoparticles, could be a safe, more effective and economic alternative to the available antileishmanial strategies. Copyright © 2016 Elsevier B.V. All rights reserved.

Candidiasis and the impact of flow cytometry on antifungal drug discovery.

PubMed

Ku, Tsun Sheng N; Bernardo, Stella; Walraven, Carla J; Lee, Samuel A

2017-11-01

Invasive candidiasis continues to be associated with significant morbidity and mortality as well as substantial health care costs nationally and globally. One of the contributing factors is the development of resistance to antifungal agents that are already in clinical use. Moreover, there are known treatment limitations with all of the available antifungal agents. Since traditional techniques in novel drug discovery are time consuming, high-throughput screening using flow cytometry presents as a potential tool to identify new antifungal agents that would be useful in the management of these patients. Areas covered: In this review, the authors discuss the use of automated high-throughput screening assays based upon flow cytometry to identify potential antifungals from a library comprised of a large number of bioactive compounds. They also review studies that employed the use of this research methodology that has identified compounds with antifungal activity. Expert opinion: High-throughput screening using flow cytometry has substantially decreased the processing time necessary for screening thousands of compounds, and has helped enhance our understanding of fungal pathogenesis. Indeed, the authors see this technology as a powerful tool to help scientists identify new antifungal agents that can be added to the clinician's arsenal in their fight against invasive candidiasis.

Antifungal Susceptibility Patterns of Opportunistic Fungi in the Genera Verruconis and Ochroconis

PubMed Central

Samerpitak, K.; Rijs, A. J. M. M.; Melchers, W. J. G.; Mouton, J. W.; Verweij, P. E.; de Hoog, G. S.

2014-01-01

Species of Verruconis and species of Ochroconis are dematiaceous fungi generally found in the environment but having the ability to infect humans, dogs, cats, poultry, and fish. This study presents the antifungal susceptibility patterns of these fungi at the species level. Forty strains originating from clinical and environmental sources were phylogenetically identified at the species level by using sequences of the ribosomal DNA internal transcribed spacer (rDNA ITS). In vitro antifungal susceptibility testing was performed against eight antifungals, using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method. The geometric mean MICs for amphotericin B (AMB), flucytosine (5FC), fluconazole (FLC), itraconazole (ITC), voriconazole (VRC), and posaconazole (POS) and minimum effective concentrations (MECs) for caspofungin (CAS) and anidulafungin (AFG) across the Ochroconis and Verruconis species were as follows, in increasing order. For Verruconis species, the values (μg/ml) were as follows: AFG, 0.04; POS, 0.25; ITC, 0.37; AMB, 0.50; CAS, 0.65; VRC, 0.96; 5FC, 10.45; and FLC, 47.25. For Ochroconis species, the values (μg/ml) were as follows: AFG, 0.06; POS, 0.11; CAS, 0.67; VRC, 2.76; ITC, 3.94; AMB, 5.68; 5FC, 34.48; and FLC, 61.33. Antifungal susceptibility of Ochroconis and Verruconis was linked with phylogenetic distance and thermotolerance. Echinocandins and POS showed the greatest in vitro activity, providing possible treatment options for Ochroconis and Verruconis infections. PMID:24687495

Distribution and Drug Susceptibility of Candida spp. Associated With Female Genital Tract Infection, Chongqing, China

PubMed Central

Luo, Xiaodong; Dong, Xiaojing; Pen, Zhi

2015-01-01

Background Vulvovaginal candidiasis is defined as vulvovaginitis associated with vaginal carriage of Candida spp. and is a common problem with a high rate of morbidity. Objectives To investigate the distribution of Candida spp. and evaluate the corresponding antifungal susceptibility in women with genital tract infection in Chongqing, southwestern China. Patients and Methods Samples (n = 2.129) were obtained from female patients with symptoms of genital tract infection. Candida spp. were isolated from the specimens and were identified using a coloration medium and the VITEK 2 Compact automatic microbial identification system. Antifungal susceptibility testing was performed using the ATB FUNGUS drug susceptibility testing system. Results From 2,129 samples, 478 (22.45%) isolates of Candida were isolated, of which 395 (82.64%) were Candida albicans, 39 (8.16%) were C. glabrata, 21 (4.39%) were C. tropicalis, 9 (1.88%) were C. parapsilosis, and 14 (2.93%) were other Candida spp. The resistance of C. albicans, C. glabrata, and C. tropicalis to 5 antifungal drugs (amphotericin B, voriconazole, fluconazole, 5-fluorocytosine, and itraconazole) ranged from 0.5% to 6.4%, 0% to 7.7%, and 0% to 9.6%, respectively. Conclusions Candida albicans was the major pathogen associated with candidiasis of the female genital tract in patients in Chongqing. The results of the antifungal sensitivity of the isolates suggest that it is important for clinicians to administer appropriate antifungals for the treatment of Candida spp. infections. PMID:28138369

Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals against Candida glabrata and Saccharomyces cerevisiae.

PubMed

Tome, Miha; Zupan, Jure; Tomičić, Zorica; Matos, Tadeja; Raspor, Peter

2018-01-01

Candidemia and other forms of invasive fungal infections caused by Candida glabrata and to a lesser extent Saccharomyces cerevisiae are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of C. glabrata and S. cerevisiae . The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in C. glabrata ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the Cg pdr1 Δ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.

Consumption of systemic antifungal agents among acute care hospitals in Catalonia (Spain), 2008-2013.

PubMed

Fondevilla, Esther; Grau, Santiago; Mojal, Sergi; Palomar, Mercedes; Matas, Lurdes; Gudiol, Francesc

2016-01-01

Objective To know the patterns and consumption trends (2008-2013) of antifungal agents for systemic use in 52 acute care hospitals affiliated to VINCat Program in Catalonia (Spain). Methods Consumption was calculated in defined daily doses (DDD)/100 patient-days and analyzed according to hospital size and complexity and clinical departments. Results Antifungal consumption was higher in intensive care units (ICU) (14.79) than in medical (3.08) and surgical departments (1.19). Fluconazole was the most consumed agent in all type of hospitals and departments. Overall antifungal consumption increased by 20.5%during the study period (p = 0.066); a significant upward trend was observed in the consumption of both azoles and echinocandins. In ICUs, antifungal consumption increased by 12.4% (p = 0.019). Conclusions The study showed a sustained increase in the overall consumption of systemic antifungals in a large number of acute care hospitals of different characteristics in Catalonia. In ICUs there was a trend towards the substitution of older agents by the new ones.

[Molecular epidemiology and antifungal susceptibility of Candida species isolated from urine samples of patients in intensive care unit].

PubMed

Yüksekkaya, Serife; Fındık, Duygu; Arslan, Uğur

2011-01-01

The aims of this study were to analyse the amphotericin B and fluconazole susceptibility and molecular epidemiology of Candida strains (Candida albicans, Candida tropicalis and Candida glabrata) isolated from the urine samples of patients hospitalized in the intensive care unit. Identification of the isolates was done according to microscopic morphology (chlamydospor, blastospor, pseudohyphae and true hyphae) on cornmeal agar, germ tube formation and carbohydrate assimilation patterns (API ID 32C bioMérieux, France). Antifungal susceptibilities of the isolates were determined by in vitro broth microdilution method recommended by Clinical and Laboratory Standards Institute (CLSI). To investigate the clonal relationship of the isolates, randomly amplified polymorphic DNA (RAPD) analysis was performed by using Cnd3 primer. Of the 56 Candida isolates minimum inhibitory concentration (MIC) ranges, MIC50 and MIC90 values for amphotericin B were 0.125-1 µg/ml, 0.125 and 0.5 µg/ml for C.albicans, 0.125-1 µg/ml, 0.25 and 1 µg/ml for C.tropicalis and 0.125-1 µg/ml, 0.25 and 1 µg/ml for C.glabrata, respectively. Fluconazole MIC ranges, MIC50 and MIC90 values were 0.25-4 µg/ml, 0.25 and 0.5 µg/ml for C.albicans, 0.25-16 µg/ml, 0.5 and 1 µg/ml for C.tropicalis and 0.5-64 µg/ml, 8 and 16 µg/ml for C.glabrata, respectively. For amphotericin B, none of the isolates had high MIC values (MIC > 1 µg/ml). While one of the C.glabrata isolates was resistant to fluconazole (MIC ≥ 64 µg/ml), one C.tropicalis and two C.glabrata isolates were dose-dependent susceptible (MIC: 16-32 µg/ml). The results of RAPD analysis indicated an exogenous spread from two clones for C.albicans, one clone for C.glabrata and one clone for C.tropicalis. This study underlines the importance of molecular epidemiological analysis of clinical samples together with hospital environmental samples in terms of Candida spp. To determine the exogenous origin for the related strains and to prevent nosocomial Candida infections.

Occurrence and characterization of Candida nivariensis from a culture collection of Candida glabrata clinical isolates in Malaysia.

PubMed

Tay, Sun Tee; Lotfalikhani, Azadeh; Sabet, Negar Shafiei; Ponnampalavanar, Sasheela; Sulaiman, Sofiah; Na, Shiang Ling; Ng, Kee Peng

2014-10-01

Candida nivariensis and C. bracarensis have been recently identified as emerging yeast pathogens which are phenotypically indistinguishable from C. glabrata. However, there is little data on the prevalence and antifungal susceptibilities of these species. This study investigated the occurrence of C. nivariensis and C. bracarensis in a culture collection of 185 C. glabrata isolates at a Malaysian teaching hospital. C. nivariensis was discriminated from C. glabrata using a PCR assay as described by Enache-Angoulvant et al. (J Clin Microbiol 49:3375-9, 2011). The identity of the isolates was confirmed by sequence analysis of the D1D2 domain and internal transcribed spacer region of the yeasts. The isolates were cultured on Chromogenic CHROMagar Candida (®) agar (Difco, USA), and their biochemical and enzymic profiles were determined. Antifungal susceptibilities of the isolates against amphotericin B, fluconazole, voriconazole and caspofungin were determined using E tests. Clotrimazole MICs were determined using a microbroth dilution method. There was a low prevalence (1.1 %) of C. nivariensis in our culture collection of C. glabrata. C. nivariensis was isolated from a blood culture and vaginal swab of two patients. C. nivariensis grew as white colonies on Chromogenic agar and demonstrated few positive reactions using biochemical tests. Enzymatic profiles of the C. nivariensis isolates were similar to that of C. glabrata. The isolates were susceptible to amphotericin B, fluconazole, voriconazole and caspofungin. Clotrimazole resistance is suspected in one isolate. This study reports for the first time the emergence of C. nivariensis in our clinical setting.

Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans.

PubMed

Cui, Jinhui; Ren, Biao; Tong, Yaojun; Dai, Huanqin; Zhang, Lixin

2015-01-01

Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections.

In vitro susceptibility of 137 Candida sp. isolates from HIV positive patients to several antifungal drugs.

PubMed

Magaldi, S; Mata, S; Hartung, C; Verde, G; Deibis, L; Roldán, Y; Marcano, C

2001-01-01

Oropharyngeal candidiasis caused by various species of Candida is one of the most common infections in HIV seropositive or AIDS patients. Drug resistance among these yeasts is an increasing problem. We studied the frequency of resistance profile to fluconazole, itraconazole, ketoconazole, amphotericin B and terbinafine of 137 isolates of Candida sp. From HIV positive or AIDS patients with oropharyngeal candidiasis at Instituto de Inmunología, U.C.V. and the Hospital "Jose Ignacio Baldó", Caracas Venezuela, using the well diffusion susceptibility test (Magaldi et al.). We found that nearly 10% of C. albicans isolates were primarily fluconazole resistant, 45% of C. albicans isolates from patients with previous treatment were resistant to fluconazole, of which 93% showed cross-resistance to itraconazole, and even about 30% of C. tropicalis (n = 13) were resistant to fluconazole and/or itraconazole. To this respect, several recent reports have been described antifungal cross-resistance among azoles. Therefore, we consider that C. tropicalis should be added to the growing list of yeast in which antifungal drug resistance is common. This report could be useful for therapeutic aspect in AIDS patients with oral candidiasis.

Synergistic anticandidal activity of pure polyphenol curcumin I in combination with azoles and polyenes generates reactive oxygen species leading to apoptosis.

PubMed

Sharma, Monika; Manoharlal, Raman; Negi, Arvind Singh; Prasad, Rajendra

2010-08-01

We have shown previously that pure polyphenol curcumin I (CUR-I) shows antifungal activity against Candida species. By employing the chequerboard method, filter disc and time-kill assays, in the present study we demonstrate that CUR-I at non-antifungal concentration interacts synergistically with azoles and polyenes. For this, pure polyphenol CUR-I was tested for synergy with five azole and two polyene drugs - fluconazole (FLC), miconazole, ketoconazole (KTC), itraconazole (ITR), voriconazole (VRC), nystatin (NYS) and amphotericin B (AMB) - against 21 clinical isolates of Candida albicans with reduced antifungal sensitivity, as well as a drug-sensitive laboratory strain. Notably, there was a 10-35-fold drop in the MIC(80) values of the drugs when CUR-I was used in combination with azoles and polyenes, with fractional inhibitory concentration index (FICI) values ranging between 0.09 and 0.5. Interestingly, the synergistic effect of CUR-I with FLC and AMB was associated with the accumulation of reactive oxygen species, which could be reversed by the addition of an antioxidant such as ascorbic acid. Furthermore, the combination of CUR-I and FLC/AMB triggered apoptosis that could also be reversed by ascorbic acid. We provide the first evidence that pure CUR-I in combination with azoles and polyenes represents a novel therapeutic strategy to improve the activity of common antifungals.

Central nervous system infection due to Cryptococcus gattii sensu lato in India: Analysis of clinical features, molecular profile and antifungal susceptibility.

PubMed

Lahiri Mukhopadhyay, Shayanki; Bahubali, Veenakumari H; Manjunath, Netravathi; Swaminathan, Aarthi; Maji, Sayani; Palaniappan, Marimuthu; Parthasarathy, Satishchandra; Chandrashekar, Nagarathna

2017-11-01

Cryptococcus gattii species complex has evolved as a pathogen in the last two decades causing infection among both immunocompetent and immunocompromised hosts. We aimed to analyse the clinical features of CNS infection caused by C. gattii sensu lato, molecular and antifungal susceptibility profile of this pathogen. Cases diagnosed to have CNS cryptococcosis were included in the study. Cryptococcus recovered from patient's specimen was identified by standard protocol. Species confirmation, mating type and molecular type determination were performed by PCR based methods. Antifungal susceptibility was tested in VITEK2C to amphotericin B, 5-flucytosine, fluconazole and voriconazole. Among 199 cases, 20 (10%) were due to C. gattii, comprising of 75% cryptococcal meningitis and 25% cryptococcoma cases. Young adult males were commonly affected. Headache and vomiting were prominent symptoms and 50% were immunocompromised. Among the isolates, 75%, 20% and 5% were C. tetragattii, C. gattii sensu stricto and C. bacillisporus respectively and all had mating type α. Four (20%) isolates of C. tetragattii and the only isolate of C. bacillisporus were resistant to fluconazole. The most common species isolated from south India is C. tetragattii. The study contributes to the epidemiology of C. gattii and reiterates the need for genotyping and antifungal susceptibility testing. © 2017 Blackwell Verlag GmbH.

D-Cateslytin: a new antifungal agent for the treatment of oral Candida albicans associated infections.

PubMed

Dartevelle, Pauline; Ehlinger, Claire; Zaet, Abdurraouf; Boehler, Christian; Rabineau, Morgane; Westermann, Benoit; Strub, Jean-Marc; Cianferani, Sarah; Haïkel, Youssef; Metz-Boutigue, Marie-Hélène; Marban, Céline

2018-06-18

The excessive use of antifungal agents, compounded by the shortage of new drugs being introduced into the market, is causing the accumulation of multi-resistance phenotypes in many fungal strains. Consequently, new alternative molecules to conventional antifungal agents are urgently needed to prevent the emergence of fungal resistance. In this context, Cateslytin (Ctl), a natural peptide derived from the processing of Chromogranin A, has already been described as an effective antimicrobial agent against several pathogens including Candida albicans. In the present study, we compared the antimicrobial activity of two conformations of Ctl, L-Ctl and D-Ctl against Candida albicans. Our results show that both D-Ctl and L-Ctl were potent and safe antifungal agents. However, in contrast to L-Ctl, D-Ctl was not degraded by proteases secreted by Candida albicans and was also stable in saliva. Using video microscopy, we also demonstrated that D-Ctl can rapidly enter C. albicans, but is unable to spread within a yeast colony unless from a mother cell to a daughter cell during cellular division. Besides, we revealed that the antifungal activity of D-Ctl could be synergized by voriconazole, an antifungal of reference in the treatment of Candida albicans related infections. In conclusion, D-Ctl can be considered as an effective, safe and stable antifungal and could be used alone or in a combination therapy with voriconazole to treat Candida albicans related diseases including oral candidosis.

Antifungal stewardship considerations for adults and pediatrics.

PubMed

Hamdy, Rana F; Zaoutis, Theoklis E; Seo, Susan K

2017-08-18

Antifungal stewardship refers to coordinated interventions to monitor and direct the appropriate use of antifungal agents in order to achieve the best clinical outcomes and minimize selective pressure and adverse events. Antifungal utilization has steadily risen over time in concert with the increase in number of immunocompromised adults and children at risk for invasive fungal infections (IFI). Challenges in diagnosing IFI often lead to delays in treatment and poorer outcomes. There are also emerging data linking prior antifungal exposure and suboptimal dosing to the emergence of antifungal resistance, particularly for Candida. Antimicrobial stewardship programs can take a multi-pronged bundle approach to ensure suitable prescribing of antifungals via post-prescription review and feedback and/or prior authorization. Institutional guidelines can also be developed to guide diagnostic testing in at-risk populations; appropriate choice, dose, and duration of antifungal agent; therapeutic drug monitoring; and opportunities for de-escalation and intravenous-to-oral conversion.

Antifungal effect and action mechanism of antimicrobial peptide polybia-CP.

PubMed

Wang, Kairong; Jia, Fengjing; Dang, Wen; Zhao, Yanyan; Zhu, Ranran; Sun, Mengyang; Qiu, Shuai; An, Xiaoping; Ma, Zelin; Zhu, Yuanyuan; Yan, Jiexi; Kong, Ziqing; Yan, Wenjin; Wang, Rui

2016-01-01

The incidence of life-threatening invasive fungal infections increased significantly in recent years. However, the antifungal therapeutic options are very limited. Antimicrobial peptides are a class of potential lead chemical for the development of novel antifungal agents. Antimicrobial peptide polybia-CP was purified from the venom of the social wasp Polybia paulista. In this study, we synthesized polybia-CP and determined its antifungal effects against a series of Candidian species. Our results showed that polybia-CP has potent antifungal activity and fungicidal activity against the tested fungal cells with a proposed membrane-active action mode. In addition, polybia-CP could induce the increase of cellular reactive oxygen species production, which would attribute to its antifungal activity. In conclusion, the present study suggests that polybia-CP has potential as an antifungal agent or may offer a new strategy for antifungal therapeutic option. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Endogenous Cryptococcus neoformans endophthalmitis with subretinal abscess in a HIV-infected man.

PubMed

Joseph, Joveeta; Sharma, Savitri; Narayanan, Raja

2018-07-01

To report a rare case of Cryptococcus neoformans endogenous endophthalmitis with subretinal abscess in a 36-year-old HIV-positive man, referred with progressive blurred vision in his right eye for the last 6 months. Vitreous biopsy followed by intravitreal ganciclovir did not result in significant improvement. Microbiology revealed the presence of C. neoformans, and intravitreal amphotericin B was then administered. The patient was treated aggressively with systemic and intravitreal antifungals but had a poor visual and anatomical outcome. A high degree of clinical suspicion combined with microbiological evaluation helped to arrive at an appropriate diagnosis.

Paracoccidioidomycosis: case report and review.

PubMed

Manns, B J; Baylis, B W; Urbanski, S J; Gibb, A P; Rabin, H R

1996-11-01

A previously well 59-year-old man presented with paracoccidioidomycosis, more than 15 years after leaving South America. He failed to respond to conventional therapies, first with oral itraconazole and then with amphotericin B plus sulfadiazine, and eventually died of recurrent arterial emboli possibly due to paracoccidioidomycotic aortitis. This patient's presentation demonstrates the difficulties that may be encountered in diagnosing and managing this disease. Paracoccidioidomycosis should be suspected in patients with an appropriate travel history who experience weight loss and have pulmonary, mucosal, and cutaneous lesions. This article comprehensively reviews the literature, with emphasis on epidemiology, clinical presentation, diagnosis, and therapy with imidazole antifungal medications.

Systemic chlorellosis, an emerging infection in humans caused by algae.

PubMed

Krcméry, V

2000-08-01

One hundred and eight cases of human protothecosis occurring over 25 years are reviewed. The most common species isolated was Prototheca wickerhamii, The algae have been isolated from a large number of sites but seem to have low virulence. In the majority of systemic infections there have been few symptoms. Cutaneous manifestations may vary from patient to patient but infections of immunosuppressed patients tend to be more florid. Most cases have been successfully treated by excising the lesion or with antifungals. Most strains are sensitive to 5-fluorocytosine, amphotericin B and the azoles but resistance does occur.

Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans

PubMed Central

Cui, Jinhui; Ren, Biao; Tong, Yaojun; Dai, Huanqin; Zhang, Lixin

2015-01-01

Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections. PMID:26048362

[Aspergillus lumbar discitis in a patient with acute lymphoblastic leukemia following induction therapy].

PubMed

Kawamura, M; Takeuchi, J; Hatta, Y; Aiso, M; Horikoshi, A; Ohshima, T; Horie, T

1995-03-01

A 47-year-old female was admitted in October 1988 because of anemia and lymphoblastic cells in peripheral blood. A bone marrow aspirate was hypercellular with 93.9% lymphoblasts negative for peroxidase staining. The case was diagnosed as ALL (L2), and treated with JALSG ALL-87 regimen. She developed spiky fever and endotoxin shock due to bacteremia caused by pseudomonas aeruginosa, then was treated with several antibiotics. With the recovery of leukocytes, the chest X-ray showed an infiltrative shadow and a cavity forming lung abscess resembling aspergilloma in her left lung. The cavity improved of transbronchial infusion following amphotericin B (AMPH-B). Although she achieved complete remission, she felt severe lumbago accompanied by a marked erosion of the vertebral body with disc space narrowing on her X-ray. Then she underwent surgery to remove a disc abscess, and 1 colony of the aspergillus species was cultured from the specimen. She was treated with intravenous AMPH-B, and post remission therapies were performed under the injection of anti-fungal agents. No remarkable symptoms of complications were recognized during the chemotherapy. AMPH-B is useful and safe for the management of aspergillus discitis.

Lecythophora hoffmannii isolated from a case of canine osteomyelitis in Japan.

PubMed

Sakaeyama, Shin-Ichi; Sano, Ayako; Murata, Yoshiteru; Kamei, Katsuhiko; Nishimura, Kazuko; Hatai, Kishio

2007-05-01

A 2-year-old spayed female mongrel dog showed claudication with abnormal ossification containing fungal cells detected by biopsy. The dog was treated with ketoconazole and itraconazole perorally for 5 months; however, the osteomyelitis became aggravated, and an amputation from the scapula was performed. The right superficial cervical lymph node became swollen 5 months after the operation. The lymph node contained PAS positive fungal elements and a portion of tissue produced mycelial fungal growth on potato dextrose agar supplemented with chloramphenicol. The culture was identified as Lecythophora hoffmannii based on morphology, physiology and 100% identity in the sequence of the D1/D2 domain of the large subunit ribosomal RNA gene of the fungal species in the GenBank database (accession number AB100627). In addition, the sequence from the present isolate was submitted as AB189164. The isolate showed resistance to antifungal agents, i.e., amphotericin B, 5-FC, fluconazole, itraconazole, miconazole and micafungin. The dog developed cachexia 2 months after the onset of lymphadenopathy, and was euthanized on the 459th day after onset of clinical symptoms. This was the first disseminated case of L. hoffmannii infection in Japan.

Molecular characterization and antifungal susceptibility of Cryptococcus neoformans strains collected from a single institution in Lima, Peru.

PubMed

Bejar, Vilma; Tello, Mercedes; García, Ruth; Guevara, José M; Gonzales, Sofia; Vergaray, German; Valencia, Esther; Abanto, Enma; Ortega-Loayza, Alex G; Hagen, Ferry; Gutierrez, Ericson L

2015-01-01

Cryptococcosis is a fungal infection with a worldwide distribution, mainly caused by Cryptococcus neoformans and Cryptococcus gattii. To molecularly characterize the mating-types, serotypes, genotypes and antifungal susceptibility profiles of a set of retrospectively isolated C. neoformans strains from Lima, Peru. A set of 32 Cryptococcus spp. strains from the Institute of Tropical Medicine of the National University of San Marcos, Lima, Peru, were included in this retrospective study. Twenty-four strains were isolated from patients, while the remaining 8 were isolated from the environment. Using conventional PCR, 27 (84.4%) of the isolates were identified as C. neoformans var. grubii mating-type alpha and serotype A. Using the AFLP fingerprinting, it was shown that 16 (50%) of the C. neoformans strains were genotype AFLP1, 13 (40.6%) were genotype AFLP1B, 2 (6.3%) were genotype AFLP2, and 1 (3.1%) was found to be a hybrid between both C. neoformans varieties (genotype AFLP3). The antifungal susceptibility profiles for amphotericin B, fluconazole and voriconazole showed that all the 32 C. neoformans are sensitive to these antifungal compounds. In this study we observed that C. neoformans var. grubii (AFLP1 and AFLP1B) and C. neoformans var. neoformans (AFLP2) were the only cryptococcal varieties involved. All strains were found to be sensitive to the antifungals tested, results that are consistent with those found in the international literature. Copyright © 2013 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Determining Antifungal Target Sites in the Sterol Pathway of the Yeast Candida and Saccharomyces

DTIC Science & Technology

1997-10-01

interaction of the azole antifungal agent SCH39304 with the cytochrome P-450 monooxygenase system isolated from Cryptococcus neoformans. Antimicrob. Agents...isolates of Cryptococcus neoformans. Antimicrob. Agents Chemother. 41: 748-751. 16. Wheat, J., Marichal, P., Vanden Bossche, H., Le Monte, A., and

Carboxymethylated ɩ-carrageenan conjugated amphotericin B loaded gelatin nanoparticles for treating intracellular Candida glabrata infections.

PubMed

Aparna, V; Melge, Anu Rohit; Rajan, V K; Biswas, Raja; Jayakumar, R; Gopi Mohan, C

2018-04-15

Intercellular Candida glabrata infections are difficult to treat due to poor penetration of drugs into the fungal niche. Delivering amphotericin B (Amp B) into the macrophages where the pathogen inhabits is an effective solution. We are studying the macrophage targeting proficiency of ɩ-carrageenan for the delivery of Amp B using gelatin A nanoparticles (GNPs). The choice of gelatin A was the outcome of in silico inspections where the amino functionalized polymer having the best docking score with Amp B was selected. We prepared a sustained release formulation of amp B loaded carboxymethyl ɩ-carrageenan conjugated gelatin nanoparticles (CMC-Amp B-GNPs) with size 343±12nm and -25±5.3mV zeta potential. The formulations were found to be stable, biocompatible and non-haemolytic. Flow cytometry analysis showed 3 fold higher uptake of CMC-GNPs compared to the GNPs by RAW 264.7 cells. CMC-Amp B-GNPs showed enhanced antifungal activity than bare Amp B and Amp B-GNPs. Copyright © 2017 Elsevier B.V. All rights reserved.

Antifungal Drug Susceptibility of Candida Species Isolated from HIV-Positive Patients Recruited at a Public Hospital in São Luís, Maranhão, Brazil.

PubMed

Terças, Ana L G; Marques, Sirlei G; Moffa, Eduardo B; Alves, Márcia B; de Azevedo, Conceição M P S; Siqueira, Walter L; Monteiro, Cristina A

2017-01-01

Oropharyngeal candidiasis is the most common fungal infection in hospitalized patients with acquired immune deficiency syndrome (AIDS). Its progression results in invasive infections, which are a significant cause of morbidity and mortality. This study aimed to quickly and accurately identify Candida spp. from oral mucosa of AIDS patients recruited at Presidente Vargas Hospital, in São Luís city, Brazil and to evaluate the sensitivity profile of these fungi to antifungals by using an automated system. Isolates were collected from oropharyngeal mucosa of 52 hospitalized AIDS patients, under anti-viral and antifungal therapies. Patients were included in research if they were HIV-positive, above 18 years of age and after obtaining their written consent. CHROMagar ® Candida and the automated ViteK-2 ® system were used to isolate and identify Candida spp., respectively. Antifungal susceptibility testing was performed using the ViteK-2 ® system, complemented with the Etest ® , using the drugs amphotericin B, fluconazole, flucytosine, and voriconazole. Oropharyngeal candidiasis had a high prevalence in these hospitalized AIDS patients (83%), and the most prevalent species was Candida albicans (56%). Antifungal susceptibility test showed that 64.7% of the Candida spp. were susceptible, 11.8% were dose-dependent sensitive, and 23.5% were resistant. All the Candida krusei and Candida famata isolates and two of Candida glabrata were resistant to fluconazole. Most of AIDS patients presented oropharyngeal candidiasis and C. albicans was the most frequently isolated species. The results showed high variability in resistance among isolated species and indicates the need to identify the Candida spp. involved in the infection and the need to test antifungal susceptibility as a guide in drug therapy in patients hospitalized with AIDS. This is the first relate about AIDS patients monitoring in a public hospital in São Luís concerning the precise identification and establishing of antifungal profile of Candida spp..

A case of Candida albicans fungus balls in the urinary tract appeared during the course of antifungal treatment for Candida endophthalmitis.

PubMed

Onozawa, Kyoko; Miyake, Noriko; Iwasaki, Noriko; Nishida, Ruriko; Chong, Yong; Shimoda, Shinji; Shimono, Nobuyuki; Akashi, Koichi

2015-09-01

Fungus balls have been rarely implicated as a cause of urinary tract obstruction. Here, we report a case of Candida albicans fungus balls in the urinary tract after the treatment of Candida endophthalmitis that has enough periods and adequate amount of antifungal agents. The patient completely recovered from this rare complication by irrigating through single-J stent and changing antifungal agents. Here we emphasize that we should take into account not only the susceptibility test results but also the difference in excretion route and tissue distribution of antifungal agents. Copyright © 2015 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Analysis Of Volatile Fingerprints: A Rapid Screening Method For Antifungal Agents For Efficacy Against Dermatophytes

NASA Astrophysics Data System (ADS)

Naraghi, Kamran; Sahgal, Natasha; Adriaans, Beverley; Barr, Hugh; Magan, Naresh

2009-05-01

The potential of using an electronic nose (E. nose) for rapid screening dermatophytes to antifungal agents was studied. In vitro, the 50 and 90% effective concentration (EC) values of five antifungal agents for T. rubrum and T. mentagrophytes were obtained by mycelial growth assays. Then, the qualitative volatile production patterns of the growth responses of these fungi to these values were incorporated into solid medium were analysed after 96-120 hrs incubation at 25° C using headspace analyses. Overall, results, using PCA and CA demonstrated that it is possible to differentiate between various treatments within 96-120 hrs. This study showed that potential exists for using qualitative volatile patterns as a rapid screening method for antifungal agents for microorganism. This approach could also facilitate the monitoring of antimicrobial drug activities and infection control programmes and perhaps drug resistance build up in microbial species.

Clinical implications of globally emerging azole resistance in Aspergillus fumigatus

PubMed Central

Verweij, Paul E.

2016-01-01

Aspergillus fungi are the cause of an array of diseases affecting humans, animals and plants. The triazole antifungal agents itraconazole, voriconazole, isavuconazole and posaconazole are treatment options against diseases caused by Aspergillus. However, resistance to azoles has recently emerged as a new therapeutic challenge in six continents. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main burden is the aquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides. Although ubiquitously distributed, A. fumigatus is not a phytopathogen. However, agricultural fungicides deployed against plant pathogenic moulds such as Fusarium, Mycospaerella and A. flavus also show activity against A. fumigatus in the environment and exposure of non-target fungi is inevitable. Further, similarity in molecule structure between azole fungicides and antifungal drugs results in cross-resistance of A. fumigatus to medical azoles. Clinical studies have shown that two-thirds of patients with azole-resistant infections had no previous history of azole therapy and high mortality rates between 50% and 100% are reported in azole-resistant invasive aspergillosis. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR34/L98H, TR53 and TR46/Y121F/T289A resistance mechanisms. Early detection of resistance is of paramount importance and if demonstrated, either with susceptibility testing or through molecular analysis, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin are recomended for azole-resistant aspergillosis. This article is part of the themed issue ‘Tackling emerging fungal threats to animal health, food security and ecosystem resilience’. PMID:28080986

Candida periprosthetic joint infection: A rare and difficult-to-treat infection.

PubMed

Escolà-Vergé, Laura; Rodríguez-Pardo, Dolors; Lora-Tamayo, Jaime; Morata, Laura; Murillo, Oscar; Vilchez, Helem; Sorli, Luisa; Carrión, Laura Guío; Barbero, José Mª; Palomino-Nicás, Julián; Bahamonde, Alberto; Jover-Sáenz, Alfredo; Benito, Natividad; Escudero, Rosa; Sampedro, Marta Fernandez; Vidal, Rafael Pérez; Gómez, Lucía; Corona, Pablo S; Almirante, Benito; Ariza, Javier; Pigrau, Carles

2018-05-08

Candida periprosthetic joint infection (CPJI) is a rare, difficult-to-treat disease. The purpose of this study was to evaluate the clinical characteristics and outcomes of CPJI treated with various surgical and antifungal strategies. We conducted a multicenter retrospective study of all CPJI diagnosed between 2003 and 2015 in 16 Spanish hospitals. Forty-three patients included: median age, 75 years, and median Charlson Comorbidity Index score, 4. Thirty-four (79.1%) patients had ≥1 risk factor for Candida infection. Most common causative species were C. albicans and C. parapsilosis. Thirty-five patients were evaluable for outcome: overall, treatment succeeded in 17 (48.6%) and failed in 18 (51.4%). Success was 13/20 (67%) in patients with prosthesis removal and 4/15 (27%) with debridement and prosthesis retention (p = 0.041). All 3 patients who received an amphotericin B-impregnated cement spacer cured. In the prosthesis removal group, success was 5/6 (83%) with an antibiofilm regimen and 8/13 (62%) with azoles (p = 0.605). In the debridement and prosthesis retention group, success was 3/10 (30%) with azoles and 1/5 (20%) with antibiofilm agents. Therapeutic failure was due to relapse in 9 patients, need for suppressive treatment in 5, persistent infection in 2, and CPJI-related death in 2; overall attributable mortality was 6%. CPJI is usually a chronic disease in patients with comorbidities and risk factors for Candida infection. Treatment success is low, and prosthesis removal improves outcome. Although there is insufficient evidence that use of antifungals with antibiofilm activity has additional benefits, our experience indicates it may be recommendable. Copyright © 2018 Elsevier Ltd. All rights reserved.

Surveillance of Candida spp Bloodstream Infections: Epidemiological Trends and Risk Factors of Death in Two Mexican Tertiary Care Hospitals

PubMed Central

Corzo-Leon, Dora E.; Alvarado-Matute, Tito; Colombo, Arnaldo L.; Cornejo-Juarez, Patricia; Cortes, Jorge; Echevarria, Juan I.; Guzman-Blanco, Manuel; Macias, Alejandro E.; Nucci, Marcio; Ostrosky-Zeichner, Luis; Ponce-de-Leon, Alfredo; Queiroz-Telles, Flavio; Santolaya, Maria E.; Thompson-Moya, Luis; Tiraboschi, Iris N.; Zurita, Jeannete; Sifuentes-Osornio, Jose

2014-01-01

Introduction Larger populations at risk, broader use of antibiotics and longer hospital stays have impacted on the incidence of Candida sp. bloodstream infections (CBSI). Objective To determine clinical and epidemiologic characteristics of patients with CBSI in two tertiary care reference medical institutions in Mexico City. Design Prospective and observational laboratory-based surveillance study conducted from 07/2008 to 06/2010. Methods All patients with CBSI were included. Identification and antifungal susceptibility were performed using CLSI M27-A3 standard procedures. Frequencies, Mann-Whitney U test or T test were used as needed. Risk factors were determined with multivariable analysis and binary logistic regression analysis. Results CBSI represented 3.8% of nosocomial bloodstream infections. Cumulative incidence was 2.8 per 1000 discharges (incidence rate: 0.38 per 1000 patient-days). C. albicans was the predominant species (46%), followed by C. tropicalis (26%). C. glabrata was isolated from patients with diabetes (50%), and elderly patients. Sixty-four patients (86%) received antifungals. Amphotericin-B deoxycholate (AmBD) was the most commonly used agent (66%). Overall mortality rate reached 46%, and risk factors for death were APACHE II score ≥16 (OR = 6.94, CI95% = 2.34–20.58, p<0.0001), and liver disease (OR = 186.11, CI95% = 7.61–4550.20, p = 0.001). Full susceptibility to fluconazole, AmBD and echinocandins among C. albicans, C. tropicalis, and C. parapsilosis was observed. Conclusions The cumulative incidence rate in these centers was higher than other reports from tertiary care hospitals from Latin America. Knowledge of local epidemiologic patterns permits the design of more specific strategies for prevention and preemptive therapy of CBSI. PMID:24830654

Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

USDA-ARS?s Scientific Manuscript database

Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

Treatment of candidosis in severely injured adults with short-course, low-dose amphotericin B.

PubMed

Rosemurgy, A S; Drost, T F; Murphy, C G; Kearney, R E; Albrink, M H

1990-12-01

Thirty-three (0.7%) of 4,818 trauma patients admitted between January 1, 1987, and July 1, 1989, developed invasive candidosis requiring IV antifungal therapy. All patients were seriously traumatized. Before developing candidosis, all patients had documented bacterial infections. These infections were generally polymicrobial and were treated with multiple broad-spectrum antibiotics (an average of 5.4 antibiotics for 17.2 days). Twenty-eight (85%) of 33 patients received enteral feedings for an average of 11 days +/- 1.5 (SEM) before developing candidosis and 24 (73%) received NG/oral nystatin for an average of 7.6 days +/- 0.9 before developing candidosis. All patients with candidosis were treated with intravenous amphotericin B: cumulative dose of 157.3 mg +/- 31.3 mg given over 10 days +/- 1.1. One patient developed recurrent candidosis despite NG/oral prophylaxis and enteral feedings. Six patients (18%) died due to sepsis and multiple organ failure. The patients who died did not objectively differ from the survivors. Candidosis is an infrequent infection in severely injured patients. Candidosis was invariably preceded by treatment with multiple broad-spectrum antibiotics for a variety of polymicrobial bacterial infections. NG/oral nystatin and enteral feedings did not prevent candidosis, in contrast to widely accepted beliefs. Amphotericin B therapy was safe. Recurrent candidosis was unusual. Candida infections had a high mortality rate associated with multiple blood transfusions and prolonged hospitalization. Candidosis represents a sign of severe injury and illness but can be amenable to prompt, aggressive treatment.

Emerging multidrug-resistant Candida duobushaemulonii infections in Panama hospitals: importance of laboratory surveillance and accurate identification.

PubMed

Ramos, Ruben; Caceres, Diego H; Perez, Marilyn; Garcia, Nicole; Castillo, Wendy; Santiago, Erika; Borace, Jovanna; Lockhart, Shawn R; Berkow, Elizabeth L; Hayer, Lizbeth; Espinosa-Bode, Andres; Moreno, Jose; Jackson, Brendan R; Moran, Jackeline; Chiller, Tom; de Villarreal, Gloriela; Sosa, Nestor; Vallabhaneni, Snigdha

2018-04-25

Candida duobushaemulonii , a yeast closely related to Candida auris, is thought to rarely cause infections, and is often misidentified. In October 2016, the Panamanian Ministry of Health implemented laboratory surveillance for C. auris Suspected C. auris isolates were forwarded to the national reference laboratory for identification by Matrix Assisted Laser Desorption Ionization-Time of Flight mass spectrometry and antifungal susceptibility testing. During November 2016-May 2017, 17 of 36 (47%) isolates suspected to be C. auris were identified as C. duobushaemulonii. These 17 isolates were obtained from 14 patients at six hospitals. Ten patients, including three children, had bloodstream infections, MICs for fluconazole, voriconazole, and amphotericin B were elevated. No resistance to echinocandins was observed. C. duobushaemulonii causes more invasive infections than previously appreciated, and poses a substantial problem given it is resistant to multiple antifungals. Expanded laboratory surveillance is an important step in the detection and control of such emerging pathogens. Copyright © 2018 American Society for Microbiology.

New spiro-oxindole constructed with pyrrolidine/thioxothiazolidin-4-one derivatives: Regioselective synthesis, X-ray crystal structures, Hirshfeld surface analysis, DFT, docking and antimicrobial studies

NASA Astrophysics Data System (ADS)

Barakat, Assem; Soliman, Saied M.; Al-Majid, Abdullah Mohammed; Ali, M.; Islam, Mohammad Shahidul; Elshaier, Yaseen A. M. M.; Ghabbour, Hazem A.

2018-01-01

In this work, polycyclic heterocycles containing spirooxindole, pyrrolidine, and thioxothiazolidin-4-one rings have been synthesized via the regioselective 1,3-dipolar cycloaddition of azomethine ylide, which is generated in situ by the condensation of the dicarbonyl compound isatin and the secondary amino acid (L-proline), with 5-arylidine-2-thioxothiazolidin-4-one as the dipolarophile. The structure of the synthesized compounds 4a and 4b were determined by using X-ray single crystal diffraction, and also, Hirshfeld surface analysis were reported. Their geometric parameters were calculated using density functional theory at the B3LYP/6-311G (d,p) level of theory. Both compounds showed antimicrobial and antifungal activity better than selected standards (ampicillin and gentamicin in case of antibacterial activity and Amphotericin A and fluconazole in case of antifungal activity). Molecular docking study of the synthesized compounds indicated that phenyl group plays an important role in determination of compound interaction inside the receptors.

Oral administration of amphotericin B nanoparticles: antifungal activity, bioavailability and toxicity in rats.

PubMed

Radwan, Mahasen A; AlQuadeib, Bushra T; Šiller, Lidija; Wright, Matthew C; Horrocks, Benjamin

2017-11-01

Amphotericin B (AMB) is used most commonly in severe systemic life-threatening fungal infections. There is currently an unmet need for an efficacious (AMB) formulation amenable to oral administration with better bioavailability and lower nephrotoxicity. Novel PEGylated polylactic-polyglycolic acid copolymer (PLGA-PEG) nanoparticles (NPs) formulations of AMB were therefore studied for their ability to kill Candida albicans (C. albicans). The antifungal activity of AMB formulations was assessed in C. albicans. Its bioavalability was investigated in nine groups of rats (n = 6). Toxicity was examined by an in vitro blood hemolysis assay, and in vivo nephrotoxicity after single and multiple dosing for a week by blood urea nitrogen (BUN) and plasma creatinine (PCr) measurements. The MIC of AMB loaded to PLGA-PEG NPs against C. albicans was reduced two to threefold compared with free AMB. Novel oral AMB delivery loaded to PLGA-PEG NPs was markedly systemically available compared to Fungizone® in rats. The addition of 2% of GA to the AMB formulation significantly (p < 0.05) improved the bioavailability from 1.5 to 10.5% and the relative bioavailability was > 790% that of Fungizone®. The novel AMB formulations showed minimal toxicity and better efficacy compared to Fungizone®. No nephrotoxicity in rats was detected after a week of multiple dosing of AMB NPs based on BUN and PCr, which remained at normal levels. An oral delivery system of AMB-loaded to PLGA-PEG NPs with better efficacy and minimal toxicity was formulated. The addition of glycyrrhizic acid (GA) to AMB NPs formulation resulted in a significant oral absorption and improved bioavailability in rats.

Trichosporon inkin biofilms produce extracellular proteases and exhibit resistance to antifungals.

PubMed

de Aguiar Cordeiro, Rossana; Serpa, Rosana; Flávia Uchoa Alexandre, Camila; de Farias Marques, Francisca Jakelyne; Vladia Silva de Melo, Charlline; da Silva Franco, Jônatas; José de Jesus Evangelista, Antonio; Pires de Camargo, Zoilo; Samia Nogueira Brilhante, Raimunda; Fabio Gadelha Rocha, Marcos; Luciano Bezerra Moreira, José; de Jesus Pinheiro Gomes Bandeira, Tereza; Júlio Costa Sidrim, José

2015-11-01

The aim of this study was to determine experimental conditions for in vitro biofilm formation of clinical isolates of Trichosporon inkin, an important opportunistic pathogen in immunocompromised patients. Biofilms were formed in microtitre plates in three different media (RPMI, Sabouraud and CLED), with inocula of 104, 105 or 106 cells ml- 1, at pH 5.5 and 7.0, and at 35 and 28 °C, under static and shaking conditions for 72 h. Growth kinetics of biofilms were evaluated at 6, 24, 48 and 72 h. Biofilm milieu analysis were assessed by counting viable cells and quantification of nucleic acids released into biofilm supernatants. Biofilms were also analysed for proteolytic activity and antifungal resistance against amphotericin B, caspofungin, fluconazole, itraconazole and voriconazole. Finally, ultrastructural characterization of biofilms formed in microtitre plates and catheter disks was performed by scanning electron microscopy. Greater biofilm formation was observed with a starter inoculum of 106 cells ml- 1, at pH 7.0 at 35 °C and 80 r.p.m., in both RPMI and Sabouraud media. Growth kinetics showed an increase in both viable cells and biomass with increasing incubation time, with maximum production at 48 h. Biofilms were able to disperse viable cells and nucleic acids into the supernatant throughout the developmental cycle. T. inkin biofilms produced more protease than planktonic cells and showed high tolerance to amphotericin B, caspofungin and azole derivatives. Mature biofilms were formed by different morphotypes, such as blastoconidia, arthroconidia and hyphae, in a strain-specific manner. The present article details the multicellular lifestyle of T. inkin and provides perspectives for further research.

Identification, antifungal resistance profile, in vitro biofilm formation and ultrastructural characteristics of Candida species isolated from diabetic foot patients in Northern India.

PubMed

Kumar, D; Banerjee, T; Chakravarty, J; Singh, S K; Dwivedi, A; Tilak, R

2016-01-01

Diabetic foot ulcers are a serious cause of diagnostic and therapeutic concern. The following study was undertaken to determine the fungal causes of diabetic foot ulcers, with their phenotypic and genotypic characterisation. A total of 155 diabetic foot ulcers were studied for 1 year. Deep tissue specimen was collected from the wounds, and crushed samples were plated on Sabouraud dextrose agar with chloramphenicol (0.05 g). Identification was done by growth on cornmeal agar, germ tube formation and urease test. For molecular identification, conserved portion of the 18S rDNA region, the adjacent internal transcribed spacer 1 (ITS1) and a portion of the 28S rDNA region were amplified, using the ITS1 and ITS2 primers. Antifungal susceptibility against voriconazole, fluconazole and amphotericin B was determined by standard broth microdilution method. Biofilm formation was studied in three steps. First, on the surface of wells of microtiter plates followed by quantification of growth by fungal metabolism measurement. Finally, biofilms were analysed by scanning electron microscopy (SEM). Fungal aetiology was found in 75 patients (48.38%). All were identified as Candida species (100%). The prevalence of different species was Candida tropicalis (34.6%), Candida albicans (29.3%), Candida krusei (16.0%), Candida parapsilosis (10.6%), Candida glabrata (9.33%). All were susceptible to amphotericin B (100%). On microtiter plate, all the isolates were viable within 48 h showing biofilms. The metabolic activity of cells in the biofilm increased with cellular mass, especially in the first 24 h. On SEM, majority showed budding yeast form. Non-albicans Candida spp. with potential biofilm forming ability are emerging as a predominant cause of diabetic foot ulcers.

Identification and Antifungal Susceptibility Testing of Candida Species: A Comparison of Vitek-2 System with Conventional and Molecular Methods.

PubMed

Kaur, Ravinder; Dhakad, Megh Singh; Goyal, Ritu; Haque, Absarul; Mukhopadhyay, Gauranga

2016-01-01

Candida infection is a major cause of morbidity and mortality in immunocompromised patients; an accurate and early identification is a prerequisite need to be taken as an effective measure for the management of patients. The purpose of this study was to compare the conventional identification of Candida species with identification by Vitek-2 system and the antifungal susceptibility testing (AST) by broth microdilution method with Vitek-2 AST system. A total of 172 Candida isolates were subjected for identification by the conventional methods, Vitek-2 system, restriction fragment length polymorphism, and random amplified polymorphic DNA analysis. AST was carried out as per the Clinical and Laboratory Standards Institute M27-A3 document and by Vitek-2 system. Candida albicans (82.51%) was the most common Candida species followed by Candida tropicalis (6.29%), Candida krusei (4.89%), Candida parapsilosis (3.49%), and Candida glabrata (2.79%). With Vitek-2 system, of the 172 isolates, 155 Candida isolates were correctly identified, 13 were misidentified, and four were with low discrimination. Whereas with conventional methods, 171 Candida isolates were correctly identified and only a single isolate of C. albicans was misidentified as C. tropicalis . The average measurement of agreement between the Vitek-2 system and conventional methods was >94%. Most of the isolates were susceptible to fluconazole (88.95%) and amphotericin B (97.67%). The measurement of agreement between the methods of AST was >94% for fluconazole and >99% for amphotericin B, which was statistically significant ( P < 0.01). The study confirmed the importance and reliability of conventional and molecular methods, and the acceptable agreements suggest Vitek-2 system an alternative method for speciation and sensitivity testing of Candida species infections.

Potential Use of Alginate-Based Carriers As Antifungal Delivery System

PubMed Central

Spadari, Cristina de Castro; Lopes, Luciana B.; Ishida, Kelly

2017-01-01

Fungal infections have become a major public health problem, growing in number and severity in recent decades due to an increase of immunocompromised patients. The use of therapeutic agents available to treat these fungal infections is limited by their toxicity, low bioavailability, antifungal resistance, and high cost of treatment. Thus, it becomes extremely important to search for new therapeutic options. The use of polymeric systems as drug carriers has emerged as a promising alternative to conventional formulations for antifungals. Alginate is a natural polymer that has been explored in the last decade for development of drug delivery systems due to its non-toxicity, biodegradability, biocompatibility, low cost, mucoadhesive, and non-immunogenic properties. Several antifungal agents have been incorporated in alginate-based delivery systems, including micro and nanoparticles, with great success, displaying promising in vitro and in vivo results for antifungal activities, reduction in the toxicity and the total drug dose used in the treatment, and improved bioavailability. This review aims at discussing the potential use and benefits of alginate-based nanocarriers and other delivery systems containing antifungal agents in the therapy of fungal infections. PMID:28194145

The rationale of combination antifungal therapy in severely immunocompromised patients: empiricism versus evidence-based medicine.

PubMed

Chamilos, Georgios; Kontoyiannis, Dimitrios P

2006-08-01

Despite expansion of the antifungal armamentarium over the past decade, the mortality rate for invasive fungal infections remains high in severely immunocompromised patients. Furthermore, in recent years, difficult-to-treat invasive infections caused by rare molds and yeasts have emerged in high-risk patients receiving antifungal prophylaxis or empirical treatment. Antifungal combinations are increasingly used in clinical practice to improve outcomes for refractory mycoses because of the suboptimal efficacy of current antifungal agents. Herein we review recent advances in the area of antifungal combinations in high-risk patients to separate empiricism from evidence-based medicine. Thus far, the benefits of combination antifungal therapy have been difficult to prove for invasive fungal infections other than cryptococcal meningitis. The recent introduction of a new class of antifungal agents (the echinocandins) and extended-spectrum triazoles has rejuvenated interest in studying those combinations for difficult-to-treat aspergillosis, as recent observational studies show promise. In view of the evolving epidemiology of invasive fungal infections, combination antifungal therapy could be most valuable in preemptive management of carefully selected high-risk patients; however, this should be studied in appropriate trials.

Portrait of Matrix Gene Expression in Candida glabrata Biofilms with Stress Induced by Different Drugs

PubMed Central

2018-01-01

(1) Background: Candida glabrata is one of the most significant Candida species associated with severe cases of candidiasis. Biofilm formation is an important feature, closely associated with antifungal resistance, involving alterations of gene expression or mutations, which can result in the failure of antifungal treatments. Hence, the main goal of this work was to evaluate the role of a set of genes, associated with matrix production, in the resistance of C. glabrata biofilms to antifungal drugs. (2) Methods: the determination of the expression of BGL2, XOG1, FKS1, FKS2, GAS2, KNH1, UGP1, and MNN2 genes in 48-h biofilm’s cells of three C. glabrata strains was performed through quantitative real-time PCR (RT-qPCR), after contact with Fluconazole (Flu), Amphotericin B (AmB), Caspofungin (Csf), or Micafungin (Mcf). (3) Results: Mcf induced a general overexpression of the selected genes. It was verified that the genes related to the production of β-1,3-glucans (BGL2, XOG1, GAS2) had the highest expressions. (4) Conclusion: though β-1,6-glucans and mannans are an essential part of the cell and biofilm matrix, C. glabrata biofilm cells seem to contribute more to the replacement of β-1,3-glucans. Thus, these biopolymers seem to have a greater impact on the biofilm matrix composition and, consequently, a role in the biofilm resistance to antifungal drugs. PMID:29642649

Alkylphenol Activity against Candida spp. and Microsporum canis: A Focus on the Antifungal Activity of Thymol, Eugenol and O-Methyl Derivatives.

PubMed

Fontenelle, Raquel O S; Morais, Selene M; Brito, Erika H S; Brilhante, Raimunda S N; Cordeiro, Rossana A; Lima, Ynayara C; Brasil, Nilce V G P S; Monteiro, André J; Sidrim, José J C; Rocha, Marcos F G

2011-07-29

In recent years there has been an increasing search for new antifungal compounds due to the side effects of conventional antifungal drugs and fungal resistance. The aims of this study were to test in vitro the activity of thymol, eugenol, estragole and anethole and some O-methyl-derivatives (methylthymol and methyleugenol) against Candida spp. and Microsporum canis. The broth microdilution method was used to determine the minimum inhibitory concentration (MIC). The minimum fungicidal concentrations (MFC) for both Candida spp. and M. canis were found by subculturing each fungal suspension on potato dextrose agar. Thymol, methylthymol, eugenol, methyl-eugenol, anethole, estragole and griseofulvin respectively, presented the following MIC values against M. canis: 4.8-9.7; 78-150; 39; 78-150; 78-150; 19-39 µg/mL and 0.006-2.5 mg/mL. The MFC values for all compounds ranged from 9.7 to 31 µg/mL. Concerning Candida spp, thymol, methylthymol, eugenol, methyleugenol, anethole, estragole and amphotericin, respectively, showed the following MIC values: 39; 620-1250; 150-620; 310-620; 620; 620-1250 and 0.25-2.0 mg/mL. The MFC values varied from 78 to 2500 µg/mL. All tested compounds thus showed in vitro antifungal activity against Candida spp. and M. canis. Therefore, further studies should be carried out to confirm the usefulness of these alkylphenols in vivo.

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients.

PubMed

Billaud, Eliane M; Guillemain, Romain; Berge, Maud; Amrein, Catherine; Lefeuvre, Sandrine; Louët, Agnès Lillo-Le; Boussaud, Véronique; Chevalier, Patrick

2010-11-01

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Caetano, Erica Pacheco de; Oliveira, Jonathas Sales; Castelo-Branco, Débora de Souza Collares Maia; Souza, Elizabeth Ribeiro Yokobatake; Alencar, Lucas Pereira de; Cordeiro, Rossana de Aguiar; Bandeira, Tereza de Jesus Pinheiro Gomes; Sidrim, José Júlio Costa; Rocha, Marcos Fábio Gadelha

2015-01-01

The antifungal activity of some statins against different fungal species has been reported. Thus, at the first moment, the in vitro antifungal activity of simvastatin, atorvastatin and pravastatin was tested against Candida spp. and Cryptococcus spp. Then, in a second approach, considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of Candida spp. and Cryptococcus spp. Drug susceptibility testing was performed using the microdilution broth method, as described by the Clinical and Laboratory Standards Institute. The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index. Regarding biofilm susceptibility, simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species. Simvastatin showed inhibitory effect against Candida spp. and Cryptococcus spp. with minimum inhibitory concentration values ranging from 15.6 to 1000 mg L(-1) and from 62.5 to 1000 mg L(-1), respectively. The combination of simvastatin with itraconazole and fluconazole showed synergism against Candida spp. and Cryptococcus spp., while the combination of simvastatin with amphotericin B was synergistic only against Cryptococcus spp. Concerning the biofilm assays, simvastatin was able to inhibit both growing biofilm and mature biofilm of Candida spp. and Cryptococcus spp. The present study showed that simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

The antifungal action of dandruff shampoos.

PubMed

Bulmer, A C; Bulmer, G S

1999-01-01

The disease commonly known as "dandruff" is caused by numerous host factors in conjunction with the normal flora yeast Malassezia furfur (Pityrosporum ovale). Indeed, clinical studies have shown that administration of antifungal agents correlates with an improved clinical condition. Almost all commercially available hair shampoos publicize that they contain some form of antifungal agent(s). However, few studies have been published in which antifungal activity of commercially available hair shampoos have been contrasted experimentally. In this study six commercially available shampoos (in the Philippines) were assessed for antifungal activity against a human (dandruff) isolate of M. furfur: (a) Head & Shoulders (Proctor & Gamble); (b) Gard Violet (Colgate-Palmolive); (c) Nizoral 1% (Janssen); (d) Nizoral 2% (Janssen); (e) Pantene Blue (Proctor & Gamble); and (f) Selsun Blue (Abbott). The results demonstrated that all six of the assayed hair shampoos have some antifungal effect on the test yeast. However, there was consider variation in potency of antifungal activity. Nizoral 1% and Nizoral 2% shampoo preparations were the most effective. The 1% Nizoral shampoo was consistently 10X better at killing yeast cells than the next closest rival shampoo. The 2% Nizoral shampoo was 10X better than the Nizoral 1% product and 100 times better than any of the other products assayed. The study demonstrated that shampoos containing a proven antifungal compound were the most effective in controlling the causative yeast.

Epidemiological investigation of Candida species causing bloodstream infection in paediatric small bowel transplant recipients.

PubMed

Suhr, Mallory J; Gomes-Neto, João Carlos; Banjara, Nabaraj; Florescu, Diana F; Mercer, David F; Iwen, Peter C; Hallen-Adams, Heather E

2017-06-01

Small bowel transplantation (SBT) can be a life-saving medical procedure. However, these recipients experience high risk of bloodstream infections caused by Candida. This research aims to characterise the SBT recipient gut microbiota over time following transplantation and investigate the epidemiology of candidaemia in seven paediatric patients. Candida species from the recipients' ileum and bloodstream were identified by internal transcribed spacer sequence and distinguished to strain by multilocus sequence typing and randomly amplified polymorphic DNA. Antifungal susceptibility of bloodstream isolates was determined against nine antifungals. Twenty-two ileostomy samples harboured at least one Candida species. Fungaemia were caused by Candida parapsilosis, Candida albicans, Candida glabrata, Candida orthopsilosis and Candida pelliculosa. All but three bloodstream isolates showed susceptibility to all the antifungals tested. One C. glabrata isolate showed multidrug resistance to itraconazole, amphotericin B and posaconazole and intermediate resistance to caspofungin. Results are congruent with both endogenous (C. albicans, C. glabrata) and exogenous (C. parapsilosis) infections; results also suggest two patients were infected by the same strain of C. parapsilosis. Continuing to work towards a better understanding of sources of infection-particularly the exogenous sources-would lead to targeted prevention strategies. © 2017 Blackwell Verlag GmbH.

Environmental isolation, biochemical identification, and antifungal drug susceptibility of Cryptococcus species.

PubMed

Teodoro, Valter Luis Iost; Gullo, Fernanda Patrícia; Sardi, Janaína de Cássia Orlandi; Torres, Edson Maria; Fusco-Almeida, Ana Marisa; Mendes-Giannini, Maria José Soares

2013-01-01

The incidence of opportunistic fungal infections has increased in recent years and is considered an important public health problem. Among systemic and opportunistic mycoses, cryptococcosis is distinguished by its clinical importance due to the increased risk of infection in individuals infected by human immunodeficiency virus. To determine the occurrence of pathogenic Cryptococcus in pigeon excrement in the City of Araraquara, samples were collected from nine environments, including state and municipal schools, abandoned buildings, parks, and a hospital. The isolates were identified using classical tests, and susceptibility testing for the antifungal drugs (fluconazole, itraconazole, voriconazole, and amphotericin B) independently was also performed. After collection, the excrement samples were plated on Niger agar and incubated at room temperature. A total of 87 bird dropping samples were collected, and 66.6% were positive for the genus Cryptococcus. The following species were identified: Cryptococcus neoformans (17.2%), Cryptococcus gattii (5.2%), Cryptococcus ater (3.5%), Cryptococcus laurentti (1.7%), and Cryptococcus luteolus (1.7%). A total of 70.7% of the isolates were not identified to the species level and are referred to as Cryptococcus spp. throughout the manuscript. Although none of the isolates demonstrated resistance to antifungal drugs, the identification of infested areas, the proper control of birds, and the disinfection of these environments are essential for the epidemiological control of cryptococcosis.

Augmenting the efficacy of antifungal intervention via chemo-biological approaches

USDA-ARS?s Scientific Manuscript database

Mycotic infection is becoming a serious health problem since effective antifungal agents for control of pathogenic fungi, especially drug-resistant pathogens, is often very limited. Fungal resistance to antimycotic agents frequently involves mutations caused by environmental stressors. In fungal pat...

In vitro antifungal susceptibility to six antifungal agents of 229 Candida isolates from patients with diabetes mellitus.

PubMed

Manfredi, M; McCullough, M J; Polonelli, L; Conti, S; Al-Karaawi, Z M; Vescovi, P; Porter, S R

2006-06-01

The most common antifungal drugs in current clinical use for the treatment of oral candidosis are polyenes and azoles, mainly used topically. Poor glycaemic control in association with other local factors, such as the presence of oral dental prostheses, salivary pH, salivary flow rate and tobacco habits, may lead to the development of oral candidosis. Topical antifungal agents are frequently used to prevent the development of candidal infections in patients with poor metabolic control, particularly in the elderly wearing dentures. The aim of this study was to assess the antifungal susceptibility of Candida isolates to six antifungal agents using a commercially available kit, Fungitest. The isolated were collected from patients affected by diabetes mellitus from two different geographic localities (London, UK, and Parma, Italy) and from a group of healthy non-diabetic subjects. No differences in antifungal susceptibility to the six agents tested were observed between Candida isolates from diabetic and non-diabetic subjects. However, differences were observed between the two geographically different diabetes mellitus populations. Oral yeast isolates from diabetes mellitus patients in the UK more often displayed resistance or intermediate resistance to fluconazole (P=0.02), miconazole (P<0.0001), and ketoconazole (P=0.01) than did isolates from diabetes mellitus patients in Italy. In addition, more C. albicans isolates were found in diabetic and non-diabetic subjects that were susceptible to fluconazole (P=0.0008 and P=0.01, respectively) than non-albicans isolates. The difference in the antifungal resistance of isolates from the two populations of diabetes mellitus patients may be related to differences in the therapeutic management of candidal infections between the two centres.

Population-Based Survey of Filamentous Fungi and Antifungal Resistance in Spain (FILPOP Study)

PubMed Central

Mellado, E.; Peláez, T.; Pemán, J.; Zapico, S.; Alvarez, M.; Rodríguez-Tudela, J. L.; Cuenca-Estrella, M.

2013-01-01

A population-based survey was conducted to investigate the epidemiology of and antifungal resistance in Spanish clinical strains of filamentous fungi isolated from deep tissue samples, blood cultures, and respiratory samples. The study was conducted in two different periods (October 2010 and May 2011) to analyze seasonal variations. A total of 325 strains were isolated in 29 different hospitals. The average prevalence was 0.0016/1,000 inhabitants. Strains were identified by sequencing of DNA targets and susceptibility testing by the European Committee for Antimicrobial Susceptibility Testing reference procedure. The most frequently isolated genus was Aspergillus, accounting for 86.3% of the isolates, followed by Scedosporium at 4.7%; the order Mucorales at 2.5%; Penicillium at 2.2%, and Fusarium at 1.2%. The most frequent species was Aspergillus fumigatus (48.5%), followed by A. flavus (8.4%), A. terreus (8.1%), A. tubingensis (6.8%), and A. niger (6.5%). Cryptic/sibling Aspergillus species accounted for 12% of the cases. Resistance to amphotericin B was found in 10.8% of the isolates tested, while extended-spectrum triazole resistance ranged from 10 to 12.7%, depending on the azole tested. Antifungal resistance was more common among emerging species such as those of Scedosporium and Mucorales and also among cryptic species of Aspergillus, with 40% of these isolates showing resistance to all of the antifungal compounds tested. Cryptic Aspergillus species seem to be underestimated, and their correct classification could be clinically relevant. The performance of antifungal susceptibility testing of the strains implicated in deep infections and multicentric studies is recommended to evaluate the incidence of these cryptic species in other geographic areas. PMID:23669377

Yeasts from Scarlet ibises (Eudocimus ruber): A focus on monitoring the antifungal susceptibility of Candida famata and closely related species.

PubMed

Brilhante, Raimunda Sâmia Nogueira; Silva, Aline Lobão da; Monteiro, Frederico Ozanan Barros; Guedes, Glaucia Morgana de Melo; Sales, Jamille Alencar; Oliveira, Jonathas Sales de; Maia Junior, José Erisvaldo; Miranda, Stefânia Araújo; Sidrim, José Júlio Costa; Alencar, Lucas Pereira de; Castelo-Branco, Débora Souza Collares Maia; Cordeiro, Rossana de Aguiar; Pereira Neto, Waldemiro de Aquino; Rocha, Marcos Fábio Gadelha

2017-10-01

This study aimed to identify yeasts from the gastrointestinal tract of scarlet ibises (Eudocimus ruber) and from plant material collected from the environment where they live. Then, the isolates phenotypically identified as Candida famata were submitted to molecular identification of their closely related species and evaluated for their antifungal susceptibility and possible resistance mechanisms to antifungal drugs. Cloacal swabs from 20 scarlet ibises kept in captivity at Mangal das Garças Park (Brazil), pooled stool samples (n = 20) and samples of trunks and hollow of trees (n = 20) obtained from their enclosures were collected. The samples were seeded on Sabouraud agar supplemented with chloramphenicol. The 48 recovered isolates were phenotypically identified as 15 Candida famata, 13 Candida catenulata, 2 Candida intermedia, 1 Candida lusitaniae, 2 Candida guilliermondii, 1 Candida kefyr, 1 Candida amapae, 1 Candida krusei, 8 Trichosporon spp., and 4 Rhodotorula spp. The C. famata isolates were further identified as 3 C. famata, 8 Debaryomyces nepalensis, and 4 C. palmioleophila. All C. famata and C. palmioleophila were susceptible to caspofungin and itraconazole, while one D. nepalensis was resistant to fluconazole and voriconazole. This same isolate and another D. nepalensis had lower amphotericin B susceptibility. The azole resistant strain had an increased efflux of rhodamine 6G and an alteration in the membrane sterol content, demonstrating multifactorial resistance mechanism. Finally, this research shows that scarlet ibises and their environment harbor C. famata and closely related species, including antifungal resistant isolates, emphasizing the need of monitoring the antifungal susceptibility of these yeast species. © The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Investigating the antifungal activity and mechanism(s) of geraniol against Candida albicans strains.

PubMed

Leite, Maria Clerya Alvino; de Brito Bezerra, André Parente; de Sousa, Janiere Pereira; de Oliveira Lima, Edeltrudes

2015-04-01

Candida albicans can be a yeast that is a commensal on the human body but can cause opportunistic or pathogenic infections. Candida infections may create serious health problems and as a result has initiated a search for new drugs with an antifungal action. Geraniol is an acyclic monoterpene alcohol with known pharmacological properties, including antimicrobial activity. The aim of this work was to evaluate the antifungal activity and mechanism(s) of geraniol against C. albicans strains. The minimum inhibitory concentration (MIC) was determined through broth microdilution techniques. We investigated possible geraniol activity on the fungal cell wall (sorbitol protect effect), cell membrane (geraniol to ergosterol binding), the time-kill curve, and its biological activity on the yeast's morphology. Amphotericin B was used as control, and all tests were performed in duplicate. The MIC of geraniol was 16 μg/ml (for 90% of isolates) but its probable mechanism of action did not involve the cell wall and ergosterol binding. In the morphological interference assay, we observed that the product inhibited pseudohyphae and chlamydoconidia formation. Time-dependent kill curve assay demonstrated that the fungicidal activity for MIC × 2 started at 2 h for the ATCC 76485 strain, and at 4 h for the LM-70 strain. Geraniol showed in vitro antifungal potential against strains of C. albicans but did not involve action on the cell wall or ergosterol. This study contributes to the development of new antifungal drugs, especially against Candida spp. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Problems found in the isolation of mycelial fungi (Fusarium solani) from blood culture (Bacter NR-860)].

PubMed

Sanz, F; Soledad Cuétara, M; del Palacio, A; Campbell, C K; Johnson, L; Urruzunu, P; Pía Roiz, M

1993-11-01

F. solani fungemia is unusual. Patients at risk are immunosuppressed, have underlying malignancy or severe debilitating diseases. We report two cases of F. solani fungemia in two non neutropenic patients who had been treated with wide-spectrum antibiotics an/or systemic corticosteroids, parenteral nutrition and intravenous lines. Bactec NR-860 (Becton-Dickinson) system was used, and growth was detected in aerobic conditions (between 3-7 days of incubation). Removal of the catheters with or without i.v. amphotericin B were used successfully. The spectrum of Fusarium sp. fungemia is discussed. Current available antifungal therapy is also reviewed.

Simple fluorescence-based high throughput cell viability assay for filamentous fungi.

PubMed

Chadha, S; Kale, S P

2015-09-01

Filamentous fungi are important model organisms to understand the eukaryotic process and have been frequently exploited in research and industry. These fungi are also causative agents of serious diseases in plants and humans. Disease management strategies include in vitro susceptibility testing of the fungal pathogens to environmental conditions and antifungal agents. Conventional methods used for antifungal susceptibilities are cumbersome, time-consuming and are not suitable for a large-scale analysis. Here, we report a rapid, high throughput microplate-based fluorescence method for investigating the toxicity of antifungal and stress (osmotic, salt and oxidative) agents on Magnaporthe oryzae and compared it with agar dilution method. This bioassay is optimized for the resazurin reduction to fluorescent resorufin by the fungal hyphae. Resazurin bioassay showed inhibitory rates and IC50 values comparable to the agar dilution method and to previously reported IC50 or MICs for M. oryzae and other fungi. The present method can screen range of test agents from different chemical classes with different modes of action for antifungal activities in a simple, sensitive, time and cost effective manner. A simple fluorescence-based high throughput method is developed to test the effects of stress and antifungal agents on viability of filamentous fungus Magnaporthe oryzae. This resazurin fluorescence assay can detect inhibitory effects comparable to those obtained using the growth inhibition assay with added advantages of simplicity, time and cost effectiveness. This high throughput viability assay has a great potential in large-scale screening of the chemical libraries of antifungal agents, for evaluating the effects of environmental conditions and hyphal kinetic studies in mutant and natural populations of filamentous fungi. © 2015 The Society for Applied Microbiology.

Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

PubMed Central

Parente-Rocha, Juliana Alves; Bailão, Alexandre Melo; Amaral, André Correa; Paccez, Juliano Domiraci; Borges, Clayton Luiz

2017-01-01

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs. PMID:28694566

Combination of different antifungal agents in oil-in-water emulsions to control strawberry jam spoilage.

PubMed

Ribes, Susana; Fuentes, Ana; Talens, Pau; Barat, Jose Manuel

2018-01-15

The combination of antifungal agents (cinnamon bark oil, zinc gluconate and trans-ferulic acid) in oil-in-water emulsions to control the fungal spoilage of strawberry jams, minimising essential oil's sensory impact, was evaluated in this work. The in vitro assays of free antifungal agents were performed against five fungal strains; meanwhile, the emulsions assays were conducted against Aspergillus niger given its strong resistance and its relevance in strawberry products. The emulsion formulated with 0.08mg/g of essential oil was able to inhibit mould growth after the incubation period. The incorporation of zinc gluconate or trans-ferulic acid, independently of the concentration used, allowed to reduce a 25% the amount of essential oil needed to inhibit the microbial growth. The combination of antifungal agents in the emulsions has demonstrated to be an effective alternative to reduce the amount of essential oil employed, maintaining the hygienic quality and sensory profile of the strawberry jam. Copyright © 2017 Elsevier Ltd. All rights reserved.

In Vitro and In Vivo Activity of a Novel Antifungal Small Molecule against Candida Infections

PubMed Central

Yuen, Kwok Yong; Wang, Yu; Yang, Dan; Samaranayake, Lakshman Perera

2014-01-01

Candida is the most common fungal pathogen of humans worldwide and has become a major clinical problem because of the growing number of immunocompromised patients, who are susceptible to infection. Moreover, the number of available antifungals is limited, and antifungal-resistant Candida strains are emerging. New and effective antifungals are therefore urgently needed. Here, we discovered a small molecule with activity against Candida spp. both in vitro and in vivo. We screened a library of 50,240 small molecules for inhibitors of yeast-to-hypha transition, a major virulence attribute of Candida albicans. This screening identified 20 active compounds. Further examination of the in vitro antifungal and anti-biofilm properties of these compounds, using a range of Candida spp., led to the discovery of SM21, a highly potent antifungal molecule (minimum inhibitory concentration (MIC) 0.2 – 1.6 µg/ml). In vitro, SM21 was toxic to fungi but not to various human cell lines or bacterial species and was active against Candida isolates that are resistant to existing antifungal agents. Moreover, SM21 was relatively more effective against biofilms of Candida spp. than the current antifungal agents. In vivo, SM21 prevented the death of mice in a systemic candidiasis model and was also more effective than the common antifungal nystatin at reducing the extent of tongue lesions in a mouse model of oral candidiasis. Propidium iodide uptake assay showed that SM21 affected the integrity of the cell membrane. Taken together, our results indicate that SM21 has the potential to be developed as a novel antifungal agent for clinical use. PMID:24465737

Imaging microscopic distribution of antifungal agents in dandruff treatments with stimulated Raman scattering microscopy

NASA Astrophysics Data System (ADS)

Garrett, Natalie L.; Singh, Bhumika; Jones, Andrew; Moger, Julian

2017-06-01

Treatment of dandruff condition usually involves use of antidandruff shampoos containing antifungal agents. Different antifungal agents show variable clinical efficacy based on their cutaneous distribution and bioavailability. Using stimulated Raman scattering (SRS), we mapped the distribution of unlabeled low-molecular weight antifungal compounds zinc pyrithione (ZnPT) and climbazole (CBZ) on the surface of intact porcine skin with cellular precision. SRS has sufficient chemical selectivity and sensitivity to detect the agents on the skin surface based on their unique chemical motifs that do not occur naturally in biological tissues. Moreover, SRS is able to correlate the distribution of the agents with the morphological features of the skin using the CH2 stretch mode, which is abundant in skin lipids. This is a significant strength of the technique since it allows the microscopic accumulation of the agents to be correlated with physiological features and their chemical environment without the use of counter stains. Our findings show that due to its lower solubility, ZnPT coats the surface of the skin with a sparse layer of crystals in the size range of 1 to 4 μm. This is consistent with the current understanding of the mode of action of ZnPT. In contrast, CBZ being more soluble and hydrophobic resulted in diffuse homogeneous distribution. It predominantly resided in microscopic lipid-rich crevasses and penetrated up to 60 μm into the infundibular spaces surrounding the hair shaft. The ability of the SRS to selectively map the distribution of agents on the skin's surface has the potential to provide insight into the mechanisms underpinning the topical application of antifungal or skin-active agents that could lead to the rational engineering of enhanced formulations.

Comparison of two in vitro antifungal sensitivity tests and monitoring during therapy of Sporothrix schenckii sensu stricto in Malaysian cats.

PubMed

Han, Hock Siew; Kano, Rui; Chen, Charles; Noli, Chiara

2017-02-01

Feline sporotrichosis is common in Malaysia. Thermosensitivity and effects of azole treatment on fungal susceptibility are unknown. To evaluate thermotolerance and antifungal susceptibility of feline Malaysian Sporothrix isolates, compare microdilution (MD) and E-test results, and investigate changes in susceptibility during azole therapy. Sporothrix schenckii sensu stricto was isolated from 44 cats. Thermotolerance was determined via culture at 37°C for 7 days. Susceptibility to itraconazole (ITZ), ketoconazole (KTZ) and terbinafine (TRB) was assessed in 40 isolates by MD; to amphotericin B (AMB), KTZ, ITZ, fluconazole (FLC) and posaconazole (POS) by E-test. Results were statistically compared by Pearson's Product Moment. In eight ketoconazole treated cats, susceptibility testing to itraconazole and ketoconazole was repeated every two months for six months. Thermotolerance was observed in 36 of 44 (82%) isolates. Assuming that isolates growing at antifungal concentrations ≥4 mg/mL were resistant, all were resistant on E-test to FLC and AMB, 11 (28%) to POS, 6 (15%) to ITZ and 1 (3%) to KTZ. On MD, 27 of 40 (68%) were resistant to TRB, 2 (5%) to ITZ and 3 (8%) to KTZ. There was no correlation between E-test and MD results (KTZ r = 0.10, P = 0.54, and ITZ r = 0.11, P = 0.48). MD values for ITZ and KTZ did not exceed 4 mg/L during KTZ therapy. The majority of feline isolates in Malaysia are thermosensitive. Lack of correlation between E-test and MD suggests that the E-test is unreliable to test antifungal susceptibility for Sporothrix spp. compared to MD. KTZ was the antifungal drug with the lowest MIC. Prolonged KTZ administration may not induce changes in antifungal susceptibility. © 2017 ESVD and ACVD.

In vitro susceptibility of Scedosporium isolates to N-acetyl-L-cysteine alone and in combination with conventional antifungal agents.

PubMed

Homa, Mónika; Galgóczy, László; Tóth, Eszter; Virágh, Máté; Chandrasekaran, Muthusamy; Vágvölgyi, Csaba; Papp, Tamás

2016-10-01

In recent years, Scedosporium species have been more commonly recognized from severe, difficult-to-treat human infections, such as upper respiratory tract and pulmonary infections. To select an appropriate therapeutic approach for these infections is challenging, because of the commonly observed resistance of the causative agents to several antifungal drugs. Therefore, to find a novel strategy for the treatment of pulmonary Scedosporium infections the in vitro antifungal effect of a mucolytic agent, N-acetyl-L-cysteine and its in vitro combinations with conventional antifungals were investigated. Synergistic and indifferent interactions were registered in 23 and 13 cases, respectively. Antagonism was not revealed between the compounds. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Retrospective study of Candida sp. contaminations of endoscopes at the University Hospital of Tlemcen (Algeria).

PubMed

Hassaine-Lahfa, I; Boucherit-Otmani, Z; Sari-Belkherroubi, L; Boucherit, K

2017-06-01

Improper cleaning and disinfection of endoscopes has been responsible for multiple nosocomial outbreaks and sometimes serious life-threatening infections. The aim of our study is, at first, to identify Candida species responsible for the contamination of endoscopes, and to determine the minimal inhibitory concentrations of planktonic (MIC) and sessile cells (SMIC) of amphotericin B (AmB) against our isolated strains. The present study was performed on four endoscopes in the department of gastroenterology at the University Hospital of Tlemcen (Algeria). A total of 300 samples from endoscopes were examined over a period of 3years. Thirty-four strains of Candida sp. were isolated, representing 11.33% of the considered samples. The number of isolated strains dropped significantly in the second and the third year compared to the first year of our study. After testing the antifungal property of amphotericin B, we showed clearly that the sessile cells of Candida sp. were much more resistant than their planktonic counterparts (suspended cells). The methods of sterilization of the endoscopes are very important; drying by compressed air is a critical step that reduces significantly the number of yeasts contamination. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Candida albicans biofilms formed into catheters and probes and their resistance to amphotericin B.

PubMed

Boucherit-Atmani, Z; Seddiki, S M L; Boucherit, K; Sari-Belkharoubi, L; Kunkel, D

2011-09-01

In Algeria, many bacterial biofilms have been studied but those of fungal origin, particularly those due to the yeast Candida albicans remained unidentified. The present study was performed at the Chabane Hamdoune hospital in Maghnia (Algeria), where 51 strains of C. albicans representing 16.94% of all taken samples were isolated. They were collected from catheters and probes used in different hospital services with variable rates; the most concerned service was ICU (40.74%) followed by gynecology department (17.39%), while general surgery came third (15.79%). Testing the antifungal property of amphotericin B (AmB) we showed clearly that the sessile cells of C. albicans were much more resistant than their planktonic counterparts (suspended cells), especially when the resistance increased during the different phases of biofilm formation until it reached its threshold at the ripening stage (at 48h). Furthermore, scanning electron microscopy of the isolated strains in the laboratory revealed the formation of biofilms on catheters by C. albicans. Surprisingly, observations revealed the presence of a new structure in these biofilms: a chlamydospore? Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Rational Discovery of (+) (S) Abscisic Acid as a Potential Antifungal Agent: a Repurposing Approach.

PubMed

Khedr, Mohammed A; Massarotti, Alberto; Mohamed, Maged E

2018-06-04

Fungal infections are spreading widely worldwide, and the types of treatment are limited due to the lack of diverse therapeutic agents and their associated side effects and toxicity. The discovery of new antifungal classes is vital and critical. We discovered the antifungal activity of abscisic acid through a rational drug design methodology that included the building of homology models for fungal chorismate mutases and a pharmacophore model derived from a transition state inhibitor. Ligand-based virtual screening resulted in some hits that were filtered using molecular docking and molecular dynamic simulations studies. Both in silico methods and in vitro antifungal assays were used as tools to select and validate the abscisic acid repurposing. Abscisic acid inhibition assays confirmed the inhibitory effect of abscisic acid on chorismate mutase through the inhibition of phenylpyruvate production. The repositioning of abscisic acid, the well-known and naturally occurring plant growth regulator, as a potential antifungal agent because of its suggested action as an inhibitor to several fungal chorismate mutases was the main result of this work.

[Saccharomyces cerevisiae infections].

PubMed

Souza Goebel, Cristine; de Mattos Oliveira, Flávio; Severo, Luiz Carlos

2013-01-01

Saccharomyces cerevisiae is an ubiquitous yeast widely used in industry and it is also a common colonizer of the human mucosae. However, the incidence of invasive infection by these fungi has significantly increased in the last decades. To evaluate the infection by S. cerevisiae in a hospital in southern Brazil during a period of 10 years (2000-2010). Review of medical records of patients infected by this fungus. In this period, 6 patients were found to be infected by S. cerevisiae. The age range of the patients was from 10 years to 84. Urine, blood, ascitic fluid, peritoneal dialysis fluid, and esophageal biopsy samples were analyzed. The predisposing factors were cancer, transplant, surgical procedures, renal failure, use of venous catheters, mechanical ventilation, hospitalization in Intensive Care Unit, diabetes mellitus, chemotherapy, corticosteroid use, and parenteral nutrition. Amphotericin B and fluconazole were the treatments of choice. Three of the patients died and the other 3 were discharged from hospital. We must take special precautions in emerging infections, especially when there are predisposing conditions such as immunosuppression or patients with serious illnesses. The rapid and specific diagnosis of S. cerevisiae infections is important for therapeutic decision. Furthermore, epidemiological and efficacy studies of antifungal agents are necessary for a better therapeutic approach. Copyright © 2012 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

Central Nervous System Histoplasmosis in Acquired Immunodeficiency Syndrome.

PubMed

Nyalakonda, Harita; Albuerne, Marisol; Suazo Hernandez, Lia Patricia; Sarria, Juan C

2016-02-01

Involvement of the central nervous system (CNS) by Histoplasma capsulatum in AIDS is uncommon and not easily recognized. CNS histoplasmosis cases from our institution were identified by a retrospective chart review from 2004-2014. A thorough literature search was performed for additional cases and their characteristics were compared. Clinical findings, treatment and outcomes are discussed. A total of 5 cases from our institution were identified. They had a clinical presentation that included classic signs of meningitis, often with evidence of disseminated involvement, and was typically severe with important neurological impairment. These cases were treated with antifungal agents, including a lipid amphotericin B formulation and azole drugs, but eventually 3 experienced nonresolution of their disease likely because of lack of adherence to therapy and died from their infection. The clinical presentation, treatment and outcome of these cases did not significantly differ from cases found in the review of the literature. Clinicians practicing in endemic areas should be aware of this rare but serious form of histoplasmosis. The recognition of 5 cases of CNS histoplasmosis in AIDS patients from a single institution suggests that histoplasmosis should be included in the differential diagnosis of the CNS complications of AIDS. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Disseminated Exophiala dermatitidis causing septic arthritis and osteomyelitis.

PubMed

Lang, Raynell; Minion, Jessica; Skinner, Stuart; Wong, Alexander

2018-06-04

Exophiala dermatitidis is a melanized fungus isolated from many environmental sources. Infections caused by Exophiala species are typically seen in immunocompromised hosts and manifest most commonly as cutaneous or subcutaneous disease. Systemic infections are exceedingly rare and associated with significant morbidity and mortality CASE PRESENTATION: A 28-year-old female originally from India presented with fevers, chills, weight loss and increasing back pain. She had a recent diffuse maculopapular rash that resulted in skin biopsy and a tentative diagnosis of sarcoidosis, leading to administration of azathioprine and prednisone. An MRI of her spine revealed a large paraspinal abscess requiring surgical intervention and hardware placement. Cultures from the paraspinal abscess grew a colony of dark pigmented mold. Microscopy of the culture revealed a melanized fungus, identified as Exophiala dermatitidis. Voriconazole was initially utilized, but due to relapse of infection involving the right iliac crest and left proximal humerus, she received a prolonged course of amphotericin B and posaconazole in combination and required 7 separate surgical interventions. Prolonged disease stability following discontinuation of therapy was achieved. Described is the first identified case of disseminated Exophiala dermatitidis causing osteomyelitis and septic arthritis in a patient on immunosuppressive therapy. A positive outcome was achieved through aggressive surgical intervention and prolonged treatment with broad-spectrum antifungal agents.

The In Vitro Efficacy of Essential Oils and Antifungal Drugs Against Prototheca zopfii.

PubMed

Grzesiak, Barbara; Głowacka, Anna; Krukowski, Henryk; Lisowski, Andrzej; Lassa, Henryka; Sienkiewicz, Monika

2016-08-01

The algae of the genus Prototheca are environmental pathogens whose main reservoir is the habitat of cows. They can cause protothecosis in domestic and wild animals, as well as human beings, with the main etiological agents being Prototheca zopfii in animals and Prototheca wickerhamii in humans. The aim of the study was to evaluate the in vitro activity of selected essential oils and antifungal antibiotics against P. zopfii isolates. The material consisted of nine P. zopfii strains isolated from the milk of cows suffering from mastitis. Eight essential oils produced by POLLENA-AROMA, Poland, and nine antifungal agents were tested. The effects of essential oils on P. zopfii were evaluated by microdilution with liquid Sabouraud dextrose broth, and susceptibility to antifungal agents was tested using the disk-diffusion method. All used essential oils inhibited the activity of P. zopfii isolates, with MIC values ranging from 0.2 to 10.5 μl/ml. Cinnamon, clove, and thyme demonstrated the highest activity against the tested P. zopfii strains at concentrations ranging from 0.6 to 1.0 μl/ml. Of the antifungal agents, the tested strains were the most sensitive to nystatin (100 %). The tested essential oils can be used to complement protothecosis therapy in animals and human beings.

Exploring the molecular basis of antifungal synergies using genome-wide approaches

USDA-ARS?s Scientific Manuscript database

This is a review article summarizing genomic profiling strategies for determining the mechanism of action of antifungal synergies, and highlighting the potential applications of these technologies. Given the limitations of currently available antifungal agents and the development of drug resistance...

Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

PubMed Central

Takei-Masuda, Naomi; Kubota, Natsuki; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, Maiko; Maebashi, Kazunori

2015-01-01

Fungal nail infection (onychomycosis) is a prevalent disease in many areas of the world, with a high incidence approaching 23%. Available antifungals to treat the disease suffer from a number of disadvantages, necessitating the discovery of new efficacious and safe antifungals. Here, we evaluate the in vitro antifungal activity and nail penetration ability of ME1111, a novel antifungal agent, along with comparator drugs, including ciclopirox, amorolfine, terbinafine, and itraconazole. ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and an MIC50 and MIC90 of 0.5 mg/liter for both. Importantly, none of the tested isolates showed an elevated ME1111 MIC. Moreover, the antifungal activity of ME1111 was minimally affected by 5% wool keratin powder in comparison to the other antifungals tested. The ME1111 solution was able to penetrate human nails and inhibit fungal growth in a dose-dependent manner according to the TurChub assay. In contrast, 8% ciclopirox and 5% amorolfine nail lacquers showed no activity under the same conditions. ME1111 demonstrated approximately 60-fold-greater selectivity in inhibition of Trichophyton spp. than of human cell lines. Our findings demonstrate that ME1111 possesses potent antidermatophyte activity, maintains this activity in the presence of keratin, and possesses excellent human nail permeability. These results suggest that ME1111 is a promising topical medication for the treatment of onychomycosis and therefore warrants further clinical evaluation. PMID:26643333

Syngonanthus nitens Bong. (Rhul.)-Loaded Nanostructured System for Vulvovaginal Candidiasis Treatment.

PubMed

Dos Santos Ramos, Matheus Aparecido; de Toledo, Luciani Gaspar; Calixto, Giovana Maria Fioramonti; Bonifácio, Bruna Vidal; de Freitas Araújo, Marcelo Gonzaga; Dos Santos, Lourdes Campaner; de Almeida, Margarete Teresa Gottardo; Chorilli, Marlus; Bauab, Taís Maria

2016-08-22

Herbal-loaded drug delivery nanotechnological systems have been extensively studied recently. The antimicrobial activity of medicinal plants has shown better pharmacological action when such plants are loaded into a drug delivery system than when they are not loaded. Syngonanthus nitens Bong. (Rhul.) belongs to the Eriocaulaceae family and presents antiulcerogenic, antioxidant, antibacterial, and antifungal activity. The aim of this study was to evaluate the antifungal activity of Syngonanthus nitens (S. nitens) extract that was not loaded (E) or loaded (SE) into a liquid crystal precursor system (S) for the treatment of vulvovaginal candidiasis (VVC) with Candida albicans. The minimal inhibitory concentration (MIC) was determined by the microdilution technique. Additionally, we performed hyphae inhibition and biofilm tests. Finally, experimental candidiasis was evaluated in in vivo models with Wistar female rats. The results showed effective antifungal activity after incorporation into S for all strains tested, with MICs ranging from 31.2 to 62.5 μg/mL. Microscopic observation of SE revealed an absence of filamentous cells 24 h of exposure to a concentration of 31.2 μg/mL. E demonstrated no effective action against biofilms, though SE showed inhibition against biofilms of all strains. In the in vivo experiment, SE was effective in the treatment of infection after only two days of treatment and was more effective than E and amphotericin B. The S. nitens is active against Candida albicans (C. albicans) and the antifungal potential is being enhanced after incorporation into liquid crystal precursor systems (LCPS). These findings represent a promising application of SE in the treatment of VVC.

The antibiotic polymyxin B exhibits novel antifungal activity against Fusarium species.

PubMed

Hsu, Li-Hang; Wang, Hsuan-Fu; Sun, Pei-Lun; Hu, Fung-Rong; Chen, Ying-Lien

2017-06-01

The genus Fusarium comprises many species, including Fusarium oxysporum, Fusarium solani, Fusarium graminearum and Fusarium verticillioides, and causes severe infections in plants and humans. In clinical settings, Fusarium is the third most frequent mould to cause invasive fungal infections after Aspergillus and the Mucorales. F. solani and F. oxysporum are the most prevalent Fusarium spp. causing clinical disease. However, few effective antifungal drugs are available to treat human and plant Fusarium infections. The cationic peptide antibiotic polymyxin B (PMB) exhibits antifungal activity against the human fungal pathogens Candida albicans and Cryptococcus neoformans, but its efficacy against Fusarium spp. is unknown. In this study, the antifungal activity of PMB was tested against 12 Fusarium strains that infect humans and plants (banana, tomato, melon, pea, wheat and maize). PMB was fungicidal against all 12 Fusarium strains, with minimum fungicidal concentrations of 32 µg/mL or 64 µg/mL for most strains tested, as evidenced by broth dilution, methylene blue staining and XTT reduction assays. PMB can reduce the germination rates of conidia, but not chlamydospores, and can cause defects in cell membrane integrity in Fusarium strains. PMB exhibits synergistic activity with posaconazole and can potentiate the effect of fluconazole, voriconazole or amphotericin B against Fusarium spp. However, PMB does not show synergistic effects with fluconazole against Fusarium spp. as it does against Candida glabrata and C. neoformans, indicating evolutionary divergence of mechanisms between yeast pathogens and the filamentous fungus Fusarium. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Syngonanthus nitens Bong. (Rhul.)-Loaded Nanostructured System for Vulvovaginal Candidiasis Treatment

PubMed Central

dos Santos Ramos, Matheus Aparecido; de Toledo, Luciani Gaspar; Calixto, Giovana Maria Fioramonti; Bonifácio, Bruna Vidal; de Freitas Araújo, Marcelo Gonzaga; dos Santos, Lourdes Campaner; de Almeida, Margarete Teresa Gottardo; Chorilli, Marlus; Bauab, Taís Maria

2016-01-01

Herbal-loaded drug delivery nanotechnological systems have been extensively studied recently. The antimicrobial activity of medicinal plants has shown better pharmacological action when such plants are loaded into a drug delivery system than when they are not loaded. Syngonanthus nitens Bong. (Rhul.) belongs to the Eriocaulaceae family and presents antiulcerogenic, antioxidant, antibacterial, and antifungal activity. The aim of this study was to evaluate the antifungal activity of Syngonanthus nitens (S. nitens) extract that was not loaded (E) or loaded (SE) into a liquid crystal precursor system (S) for the treatment of vulvovaginal candidiasis (VVC) with Candida albicans. The minimal inhibitory concentration (MIC) was determined by the microdilution technique. Additionally, we performed hyphae inhibition and biofilm tests. Finally, experimental candidiasis was evaluated in in vivo models with Wistar female rats. The results showed effective antifungal activity after incorporation into S for all strains tested, with MICs ranging from 31.2 to 62.5 μg/mL. Microscopic observation of SE revealed an absence of filamentous cells 24 h of exposure to a concentration of 31.2 μg/mL. E demonstrated no effective action against biofilms, though SE showed inhibition against biofilms of all strains. In the in vivo experiment, SE was effective in the treatment of infection after only two days of treatment and was more effective than E and amphotericin B. The S. nitens is active against Candida albicans (C. albicans) and the antifungal potential is being enhanced after incorporation into liquid crystal precursor systems (LCPS). These findings represent a promising application of SE in the treatment of VVC. PMID:27556451

Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis.

PubMed

Elphick, Heather E; Southern, Kevin W

2012-06-13

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, their many side effects are well-documented. A group of compounds, the azoles, have activity against Aspergillus fumigatus and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been employed in aerosolised form to treat invasive infection with Aspergillus fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); 2. do not have unacceptable adverse effects.If benefit was demonstrated, we aimed to assess the optimal type, duration and dose of antifungal therapy. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.In addition, pharmaceutical companies were approached.Date of the most recent search of the Group's Trials Register: 09 February 2012. Published or unpublished randomised controlled trials, where antifungal treatments have been compared to either placebo or no treatment, or where different doses of the same treatment have been used in the treatment of ABPA in people with cystic fibrosis. Two trials were identified by the searches; neither was judged eligible for inclusion in the review. No completed randomised controlled trials were included. At present, there are no randomised controlled trials to evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis. Trials with clear outcome measures are needed to properly evaluate this potentially useful treatment for cystic fibrosis.

Nosocomial Candidiasis: Antifungal Stewardship and the Importance of Rapid Diagnosis.

PubMed

Pfaller, Michael A; Castanheira, Mariana

2016-01-01

Candidemia and other forms of candidiasis are associated with considerable excess mortality and costs. Despite the addition of several new antifungal agents with improved spectrum and potency, the frequency of Candida infection and associated mortality have not decreased in the past two decades. The lack of rapid and sensitive diagnostic tests has led to considerable overuse of antifungal agents resulting in increased costs, selection pressure for resistance, unnecessary drug toxicity, and adverse drug interactions. Both the lack of timely diagnostic tests and emergence of antifungal resistance pose considerable problems for antifungal stewardship. Whereas antifungal stewardship with a focus on nosocomial candidiasis should be able to improve the administration of antifungal therapy in terms of drug selection, proper dose and duration, source control and de-escalation therapy, an important parameter, timeliness of antifungal therapy, remains a victim of slow and insensitive diagnostic tests. Fortunately, new proteomic and molecular diagnostic tools are improving the time to species identification and detection. In this review we will describe the potential impact that rapid diagnostic testing and antifungal stewardship can have on the management of nosocomial candidiasis. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Osteomyelitis caused by Aspergillus species: a review of 310 reported cases.

PubMed

Gabrielli, E; Fothergill, A W; Brescini, L; Sutton, D A; Marchionni, E; Orsetti, E; Staffolani, S; Castelli, P; Gesuita, R; Barchiesi, F

2014-06-01

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 per cent 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%. © 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.

Antidermatophytic properties of extracts from the leaves of Aristolochia paucinervis Pomel.

PubMed

Gadhi, C A; Benharref, A; Jana, M; Basile, A M; Contet-Audonneau, N; Fortier, B

2001-02-01

Several fractions of a methanol extract from the leaves of Aristolochia paucinervis Pomel (Aristolochiaceae) were screened for their antidermatophytic efficiency against different human pathogenic fungi responsible for tinea and other skin infections. The antifungal study was carried out by the macrodilution agar method and the results showed that, with the exception of the aqueous fraction, all the fractions exhibited antifungal activities against the dermatophytic fungi tested. The hexane fraction was found to be the most effective (MIC range: 64-2048 microg/mL), whereas the butanol fraction was the least active (MIC range: 1024 microg/mL to more than 2048 microg/mL). The most susceptible fungi were Epidermophyton floccosum and Trichophyton violaceum in contrast to Trichophyton mentagrophytes and Trychophyton rubrum which were less sensitive to the fractions tested. The effects were compared with those of ketoconazole, amphotericin B and griseofulvin, for which MIC ranges were, respectively, 0.12-4 microg/mL, 0.5-4 microg/mL and 0.5-2 microg/mL. Copyright 2001 John Wiley & Sons, Ltd.

Cutaneous mucormycosis secondary to penetrative trauma.

PubMed

Zahoor, Bilal; Kent, Stephen; Wall, Daryl

2016-07-01

Mucormycosis is a rare but serious sequelae of penetrating trauma [1-5]. In spite of aggressive management, mortality remains high due to dissemination of infection. We completed a review of literature to determine the most optimal treatment of cutaneous mucormycosis which occurs secondary to penetrating trauma. We completed a review regarding the management of mucormycosis in trauma patients. We selected a total of 36 reports, of which 18 were case-based, for review. Surgical debridement is a primary predictor of improved outcomes in the treatment of mucormycosis [3,6,7]. Anti-fungal therapy, especially lipid soluble formulation of Amphotericin B, is helpful as an adjunct or when surgical debridement has been maximally achieved. Further research is needed to fully evaluate the impact of topical dressings; negative pressure wound therapy is helpful. An aggressive and early surgical approach, even at the expense of disfigurement, is necessary to reduce mortality in the setting of cutaneous mucormycosis that results from penetrating trauma [4,8,9]. Anti-fungal therapy and negative pressure wound therapy are formidable adjuncts. Copyright © 2016 Elsevier Ltd. All rights reserved.

Polymer Multilayers Loaded with Antifungal β-Peptides Kill Planktonic Candida albicans and Reduce Formation of Fungal Biofilms on the Surfaces of Flexible Catheter Tubes

PubMed Central

Raman, Namrata; Lee, Myung-Ryul

2014-01-01

Candida albicans is the most common fungal pathogen responsible for hospital-acquired infections. Most C albicans infections are associated with the implantation of medical devices that act as points of entry for the pathogen and as substrates for the growth of fungal biofilms that are notoriously difficult to eliminate by systemic administration of conventional antifungal agents. In this study, we report a fill-and-purge approach to the layer-by-layer fabrication of biocompatible, nanoscale ‘polyelectrolyte multilayers’ (PEMs) on the luminal surfaces of flexible catheters, and an investigation of this platform for the localized, intraluminal release of a cationic β-peptide-based antifungal agent. We demonstrate that polyethylene catheter tubes with luminal surfaces coated with multilayers ~700 nm thick fabricated from poly-L-glutamic acid (PGA) and poly-L-lysine (PLL) can be loaded, post-fabrication, by infusion with β-peptide, and that this approach promotes extended intraluminal release of this agent (over ~4 months) when incubated in physiological media. The β-peptide remained potent against intraluminal inoculation of the catheters with C albicans and substantially reduced the formation of C albicans biofilms on the inner surfaces of film-coated catheters. Finally, we report that these β-peptide-loaded coatings exhibit antifungal activity under conditions that simulate intermittent catheter use and microbial challenge for at least three weeks. We conclude that β-peptide-loaded PEMs offer a novel and promising approach to kill C albicans and prevent fungal biofilm formation on surfaces, with the potential to substantially reduce the incidence of device-associated infections in indwelling catheters. β-Peptides comprise a promising new class of antifungal agents that could help address problems associated with the use of conventional antifungal agents. The versatility of the layer-by-layer approach used here thus suggests additional opportunities to exploit these new agents in other biomedical and personal care applications in which fungal infections are endemic. PMID:24862322

[Emerging pathogen: Candida kefyr (Kluvyeromyces marxianus)].

PubMed

Çuhadar, Tuğba; Kalkancı, Ayşe

2017-10-01

In the central microbiology laboratory of Gazi University Hospital Candida kefyr was isolated from different clinical samples as 5.3% in 2016 and in 2017 this rate increased to 9.3% which was nearly two-fold and this has drawn our attention. The aim of this study was to evaluate the special characteristics, antifungal susceptibility and virulence properties of C.keyfr species. Germ tube, corn meal-tween 80 agar morphology and carbohydrate assimilation profiles on ID32C yeast identification system were used for the diagnosis of Candida species. In this study, DNA sequencing was performed using ITS1 and ITS4 primers amplifying fungal gene between 5.8S and 18S regions of rRNA. Antifungal susceptibility was performed using M27A microdilution method recommended by Clinical and Laboratory Standards Institute (CLSI). Minimum inhibitory concentration (MIC) values for amphotericin B, fluconazole, voriconazole and itraconazole were determined. MIC distribution, MIC50 and MIC90 values and geometric mean (GM) were detected. The existence of virulence factors caseinase, secreted aspartyl proteinase, esterase and phospholipase were investigated in vitro. A total of 865 Candida species were isolated from different clinical samples in the central microbiology laboratory of Gazi University Hospital in 2016. Among them, 46 (5.3%) were C.kefyr. In the first four months of 2017, 30 (9.3%) C.kefyr were identified among 320 Candida isolates. Ten isolates which have shown atypical morphology on corn meal agar were selected. Among these 10 isolates, nine of them were identified as C.kefyr by using ID32C system and DNA sequencing method. Amphotericin B MIC value was 2 µg/ml for one isolate, and fluconazole MIC value was 8 µg/ml for another isolate among 46 isolates. Among the 30 isolates of the year 2017, one of them presented MIC value for fluconazole as 8 µg/ml. No marked antifungal resistance was detected in our isolate group. Caseinase was positive in one C.kefyr isolate, and phospholipase were positive in eight of nine isolates. As a result, the reason of increase in the incidence of this Candida species, which does not show significant resistance and presents mostly phospholipase activity as a virulence factor, should be investigated in more detail.

Genotyping and antifungal susceptibility testing of multiple Malassezia pachydermatis isolates from otitis and dermatitis cases in pets: is it really worth the effort?

PubMed

Álvarez-Pérez, Sergio; García, Marta E; Peláez, Teresa; Blanco, José L

2016-01-01

A total of 216 colonies of Malassezia pachydermatis from 28 cases of fungal otitis or dermatitis in pets were genotyped by M13 fingerprinting and tested for antifungal susceptibility. A huge genetic diversity was found (157 M13 types in total), with all animals having a polyclonal pattern of infection (5.4 ± 1.5 genotypes/sample). Furthermore, analysis of molecular variance (AMOVA) revealed that most genetic diversity (44%) was found at the within sample level. In contrast, variability in antifungal susceptibility among isolates from the same sample was less important, with different M13 types displaying in most cases identical or very similar MIC results. Most isolates displayed high in vitro susceptibility to amphotericin B, terbinafine and all azoles tested except fluconazole, for which MIC values were always ≥4 μg/ml and a 26.9% of isolates displayed values ≥32 μg/ml. We conclude that although characterization of multiple yeast isolates results in a considerable increase in laboratory workload and expenses, it may help to get a better understanding of the epidemiology of M. pachydermatis in a given patient population. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Polymorphism in Mitochondrial Group I Introns among Cryptococcus neoformans and Cryptococcus gattii Genotypes and Its Association with Drug Susceptibility.

PubMed

Gomes, Felipe E E S; Arantes, Thales D; Fernandes, José A L; Ferreira, Leonardo C; Romero, Héctor; Bosco, Sandra M G; Oliveira, Maria T B; Del Negro, Gilda M B; Theodoro, Raquel C

2018-01-01

Cryptococcosis, one of the most important systemic mycosis in the world, is caused by different genotypes of Cryptococcus neoformans and Cryptococcus gattii , which differ in their ecology, epidemiology, and antifungal susceptibility. Therefore, the search for new molecular markers for genotyping, pathogenicity and drug susceptibility is necessary. Group I introns fulfill the requisites for such task because (i) they are polymorphic sequences; (ii) their self-splicing is inhibited by some drugs; and (iii) their correct splicing under parasitic conditions is indispensable for pathogen survival. Here, we investigated the presence of group I introns in the mitochondrial LSU rRNA gene in 77 Cryptococcus isolates and its possible relation to drug susceptibility. Sequencing revealed two new introns in the LSU rRNA gene. All the introns showed high sequence similarity to other mitochondrial introns from distinct fungi, supporting the hypothesis of an ancient non-allelic invasion. Intron presence was statistically associated with those genotypes reported to be less pathogenic ( p < 0.001). Further virulence assays are needed to confirm this finding. In addition, in vitro antifungal tests indicated that the presence of LSU rRNA introns may influence the minimum inhibitory concentration (MIC) of amphotericin B and 5-fluorocytosine. These findings point to group I introns in the mitochondrial genome of Cryptococcus as potential molecular markers for antifungal resistance, as well as therapeutic targets.

Characterization of Prototheca zopfii Genotypes Isolated from Cases of Bovine Mastitis and Cow Barns in China.

PubMed

Shahid, Muhammad; Ali, Tariq; Zhang, Limei; Hou, Rongguang; Zhang, Shiyao; Ding, Laidi; Han, Dandan; Deng, Zhaoju; Rahman, Abdur; Han, Bo

2016-04-01

Protothecal mastitis, caused mostly by Prototheca zopfii (P. zopfii), is increasing in dairy herds and is being reported globally. The present study was aimed at studying the epidemiology of mastitis and at molecular characterization of P. zopfii isolates from dairy herds and their surroundings in three provinces of China using microbiological, biochemical and molecular methods, and antibiotic susceptibility tests. Samples from milk (n = 620) of mastitic cows and their barns sources (n = 410) including feces, feed, bedding materials and drinking water were analyzed. Among other pathogens recovered from mastitic milk, 84 (13.5%) of the isolates were identified as P. zopfii. All of the P. zopfii isolates recovered from milk were recognized as genotype 2, whereas 58 (73.4%) and 21 (26.6%) isolates from environmental sources were found to be P. zopfii genotypes 1 and 2, respectively. The isolates were susceptible to some antibiotics and antifungal agents, including amikacin (78.1%), streptomycin (58.5%), gentamicin (17.8%), amphotericin B (68.6%) and nystatin (64.4%). Additionally, the two genotypes displayed versatile patterns of susceptibility to different antimicrobials agents. Phylogeny of the genotypes on the basis of 18S SSU rDNA and 28S SSU rDNA was also investigated. The isolates of the two genotypes separated into different clades, and no interrelationship was observed among these as shown by phylogenetic analysis. The genotype 1 isolates from cow barn sources were non-pathogenic and may not present any risk of mastitis. We conclude that P. zopfii genotype 2 might play an important role in bovine mastitis in China.

Cell-Type–Specific Transcriptional Profiles of the Dimorphic Pathogen Penicillium marneffei Reflect Distinct Reproductive, Morphological, and Environmental Demands

PubMed Central

Pasricha, Shivani; Payne, Michael; Canovas, David; Pase, Luke; Ngaosuwankul, Nathamon; Beard, Sally; Oshlack, Alicia; Smyth, Gordon K.; Chaiyaroj, Sansanee C.; Boyce, Kylie J.; Andrianopoulos, Alex

2013-01-01

Penicillium marneffei is an opportunistic human pathogen endemic to Southeast Asia. At 25° P. marneffei grows in a filamentous hyphal form and can undergo asexual development (conidiation) to produce spores (conidia), the infectious agent. At 37° P. marneffei grows in the pathogenic yeast cell form that replicates by fission. Switching between these growth forms, known as dimorphic switching, is dependent on temperature. To understand the process of dimorphic switching and the physiological capacity of the different cell types, two microarray-based profiling experiments covering approximately 42% of the genome were performed. The first experiment compared cells from the hyphal, yeast, and conidiation phases to identify “phase or cell-state–specific” gene expression. The second experiment examined gene expression during the dimorphic switch from one morphological state to another. The data identified a variety of differentially expressed genes that have been organized into metabolic clusters based on predicted function and expression patterns. In particular, C-14 sterol reductase–encoding gene ergM of the ergosterol biosynthesis pathway showed high-level expression throughout yeast morphogenesis compared to hyphal. Deletion of ergM resulted in severe growth defects with increased sensitivity to azole-type antifungal agents but not amphotericin B. The data defined gene classes based on spatio-temporal expression such as those expressed early in the dimorphic switch but not in the terminal cell types and those expressed late. Such classifications have been helpful in linking a given gene of interest to its expression pattern throughout the P. marneffei dimorphic life cycle and its likely role in pathogenicity. PMID:24062530

Evaluation of conformity of a first prescription of lipid-based formulation of amphotericin B in a university-teaching pediatric hospital.

PubMed

Agogué, Claire; Bussières, Jean-François; Dehaut, Catherine; Lebel, Denis; Brochet, Marie-Sophie

2006-04-01

Invasive fungal infections are an important cause of morbidity and mortality in immunodeficient children. Amphotericin B is an important therapeutic agent for the treatment of invasive fungal infections but is associated with significant toxicities and high acquisition costs. The purpose of this study was to evaluate physician adherence to a local guideline for the use of lipid-based amphotericin B. The study was approved through Pharmacology & Therapeutics (P&T) committee activities. A retrospective drug utilization review (DUR) was conducted. All orders written between January 1, 2003, and December 31, 2004, were reviewed. Demographic and descriptive clinical data were collected as well as variables related to the drug order process. Conformity rates were calculated for the primary objective criteria (authorized prescribers - infectious disease members; recommended drug of choice-Abelcet; accepted indications; and presence of underlying conditions). A total of 109 orders for 70 patients were reviewed by a single research assistant for a 2-year period. Global conformity rate for all four criteria was calculated at 7.3%. Non-conformity was mostly associated with the absence of underlying conditions (e.g., prerenal insufficiency or presence of nephrotoxicity due to amphotericin B desoxycholate) in 84.5% of the cases. Infusionrelated adverse drug reactions partly explained a switch to a non-formulary lipid-based amphotericin B product. External factors (newly published results since the adoption of the guideline and continuous marketing practices) and internal factors (availability of non-formulary process, inefficient DUR process) could have contributed to non-adherence to a local guideline. This study shows low adherence to P&T committee drug guidelines on lipid-based amphotericin B. Continuous and efficient DUR processes should be in place to monitor drug guideline adherence.

Treatment Outcomes for Malassezia Folliculitis in theDermatology Department of a University Hospital in Japan.

PubMed

Suzuki, Chikako; Hase, Midori; Shimoyama, Harunari; Sei, Yoshihiro

2016-01-01

Topical or systemic antifungal therapy was administered to patients diagnosed with Malassezia folliculitis during the 5-year period between March 2007 and October 2013. The diagnosis of Malassezia folliculitis was established on the basis of characteristic clinical features and direct microscopic findings (10 or more yeast-like fungi per follicle). Treatment consisted of topical application of 2% ketoconazole cream or 100 mg oral itraconazole based on symptom severity and patients' preferences. Treatment was given until papules flattened, and flat papules were examined to determine whether the patient's clinical condition had "improved" and the treatment had been "effective". The subjects were 44 patients (35 men, 9 women), with a mean disease period of 25±15 days. In regard to the lesion site, the frontal portion of the chest was the most common, accounting for 60% of all patients. The mean period required for improvement was 27±16 days in 37 patients receiving the topical antifungal agent and 14±4 days in the 7 patients receiving the systemic antifungal agent. The results were "improved" and the treatment was "effective" in all patients. Neither treatment resulted in any adverse reactions. Although administration of oral agents has been recommended for the treatment of Malassezia folliculitis, this study revealed that beneficial results are safely obtained with topical antifungal therapy alone, similar to those of systemic antifungal agents.

The epidemiology of mycotic vulvovaginitis and the use of antifungal agents in suspected mycotic vulvovaginitis and its implications for clinical practice.

PubMed

Jackson, S T; Mullings, A M; Rainford, L; Miller, A

2005-06-01

Data in the Caribbean documenting the speciation of yeast associated with vulvovaginitis are lacking. The widespread use of antibiotics and increased availability of antimycotic agents, both prescribed and over-the-counter, predisposes both to a change in the epidemiologic patterns and the possible development of secondary resistance among previously susceptible yeast. This study was conducted to evaluate the aetiologic agents associated with mycotic vulvovaginitis and to review the appropriateness of prescribed antifungal therapy. Of 134 positive isolates, the most frequent yeast isolate was C. albicans accounting for 78%, C. tropicalis 10%, Prototheca wickerhamii (P. wickerhamii) 5%, C. glabrata 4%, Cryptococcus albidus (C. albidus) 2% and C. lusitaniae (1%) were also isolated. Of the positive cases, 75% were treated with antifungals, 17% with antibiotics and 8% were not treated. The azole group was the most frequently prescribed antifungal (71%). Of cases with negative yeast cultures, 83% were treated with antifungals. The presence of non-albicans Candida species and other opportunistic fungi is an important finding and combined with the pattern of therapy, represents a major challenge for future empirical therapeutic and prophylactic strategies in the treatment of mycotic vulvovaginitis.

Prevention of fungal spoilage in food products using natural compounds: A review.

PubMed

Ribes, Susana; Fuentes, Ana; Talens, Pau; Barat, Jose Manuel

2017-04-10

The kingdom Fungi is the most important group of microorganism contaminating food commodities, and chemical additives are commonly used in the food industry to prevent fungal spoilage. However, the increasing consumer concern about synthetic additives has led to their substitution by natural compounds in foods. The current review provides an overview of using natural agents isolated from different sources (plants, animals, and microorganisms) as promising antifungal compounds, including information about their mechanism of action and their use in foods to preserve and prolong shelf life. Compounds derived from plants, chitosan, lactoferrin, and biocontrol agents (lactic acid bacteria, antagonistic yeast, and their metabolites) are able to control the decay caused by fungi in a wide variety of foods. Several strategies are employed to reduce the drawbacks of some antifungal agents, like their incorporation into oil-in-water emulsions and nanoemulsions, edible films and active packaging, and their combination with other natural preservatives. These strategies facilitate the addition of volatile agents into food products and, improve their antifungal effectiveness. Moreover, biological agents have been investigated as one of the most promising options in the control of postharvest decay. Numerous mechanisms of action have been elucidated and different approaches have been studied to enhance their antifungal effectiveness.

Correlation of Culture with Histopathology in Fungal Burn Wound Colonization and Infection

DTIC Science & Technology

2007-01-01

Echinocandin Anidulafungin, caspofungin, micafungin Candidal yeasts and Aspergillus Zygomycetes, Cryptococcus , Trichosporon, Fusarium Candida...less common moulds, as well as Cryptococcus and Trichosporon species. Of the currently approved agents, only amphotericin B has proven efficacy

New record of Scedosporium dehoogii from Chile: Phylogeny and susceptibility profiles to classic and novel putative antifungal agents.

PubMed

Alvarez, Eduardo; Sanhueza, Camila

Scedosporium species are considered emerging agents causing illness in immunocompromised patients. In Chile, only Scedosporium apiospermum, Scedosporium boydii and Lomentospora prolificans haven been reported previously. The study aimed to characterize genetically Scedosporium dehoogii strains from Chilean soil samples, and assessed the antifungal susceptibility profile to classic and novel putative antifungal molecules. In 2014, several samples were obtained during a survey of soil fungi in urban areas from Chile. Morphological and phylogenetic analyses of the internal transcribed spacer region (ITS), tubulin (TUB), and calmodulin (CAL) sequences were performed. In addition, the susceptibility profiles to classic antifungal and new putative antifungal molecules were determined. Four strains of Scedosporium dehoogii were isolated from soil samples. The methodology confirmed the species (reported here as a new record for Chile). Antifungal susceptibility testing demonstrates the low activity of terpenes (α-pinene and geraniol) against this species. Voriconazole (VRC), posaconazole (PSC), and the hydroxyquinolines (clioquinol, and 5,7-dibromo-8-hydroxyquinoline) showed the best antifungal activity. Our results demonstrate that Scedosporium dehoogii is present in soil samples from Chile. This study shows also that hydroxyquinolines have potential as putative antifungal molecules. Copyright © 2016 Asociación Española de Micología. Publicado por Elsevier España, S.L.U. All rights reserved.

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi

PubMed Central

Pinheiro, Ana M.; Carreira, Alexandra; Prescott, Thomas A. K.; Ferreira, Ricardo B.; Monteiro, Sara A.

2017-01-01

The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans, however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans. HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn2+, Zn2+, and Fe2+. The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans. Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections. PMID:28702011

Bridging the Gap to Non-toxic Fungal Control: Lupinus-Derived Blad-Containing Oligomer as a Novel Candidate to Combat Human Pathogenic Fungi.

PubMed

Pinheiro, Ana M; Carreira, Alexandra; Prescott, Thomas A K; Ferreira, Ricardo B; Monteiro, Sara A

2017-01-01

The lack of antifungal drugs with novel modes of action reaching the clinic is a serious concern. Recently a novel antifungal protein referred to as Blad-containing oligomer (BCO) has received regulatory approval as an agricultural antifungal agent. Interestingly its spectrum of antifungal activity includes human pathogens such as Candida albicans , however, its mode of action has yet to be elucidated. Here we demonstrate that BCO exerts its antifungal activity through inhibition of metal ion homeostasis which results in apoptotic cell death in C. albicans . HIP HOP profiling in Saccharomyces cerevisiae using a panel of signature strains that are characteristic for common modes of action identified hypersensitivity in yeast lacking the iron-dependent transcription factor Aft1 suggesting restricted iron uptake as a mode of action. Furthermore, global transcriptome profiling in C. albicans also identified disruption of metal ion homeostasis as a potential mode of action. Experiments were carried out to assess the effect of divalent metal ions on the antifungal activity of BCO revealing that BCO activity is antagonized by metal ions such as Mn 2+ , Zn 2+ , and Fe 2+ . The transcriptome profile also implicated sterol synthesis as a possible secondary mode of action which was subsequently confirmed in sterol synthesis assays in C. albicans . Animal models for toxicity showed that BCO is generally well tolerated and presents a promising safety profile as a topical applied agent. Given its potent broad spectrum antifungal activity and novel multitarget mode of action, we propose BCO as a promising new antifungal agent for the topical treatment of fungal infections.

[Invasive fungal disease due to Scedosporium, Fusarium and mucorales].

PubMed

Pemán, Javier; Salavert, Miguel

2014-01-01

The number of emerging organisms causing invasive fungal infections has increased in the last decades. These etiological agents include Scedosporium, Fusarium and mucorales. All of them can cause disseminated, virulent, and difficult-to treat infections in immunosuppressed patients, the most affected, due to their resistance to most available antifungal agents. Current trends in transplantation including the use of new immunosuppressive treatments, the common prescription of antifungal agents for prophylaxis, and new ecological niches could explain the emergence of these fungal pathogens. These pathogens can also affect immunocompetent individuals, especially after natural disasters (earthquakes, floods, tsunamis), combat wounds or near drowning. All the invasive infections caused by Scedosporium, Fusarium, and mucorales are potentially lethal and a favourable outcome is associated with rapid diagnosis by direct microscopic examination of the involved tissue, wide debridement of infected material, early use of antifungal agents including combination therapy, and an improvement in host defenses, especially neutropenia. Copyright © 2014. Published by Elsevier Espana.

Improved efficacy in onychomycosis therapy.

PubMed

Gupta, Aditya K; Paquet, Maryse

2013-01-01

The success rate of onychomycosis treatment is limited by several factors, including the access of the therapeutic agent to the fungal mass, the presence of conidia, and the susceptibility of the different infectious agents to the antifungals. Different strategies used to improve efficacy of the currently available antifungal treatments, their rationale, and the published evidence of their beneficial effects are reviewed. An improved efficacy was demonstrated for some of these strategies, such as combined oral and topical antifungal therapies, whereas most of them lack clear and direct evidence of an increase in therapeutic success. © 2013 Elsevier Inc. All rights reserved.

Oxidized forms of polyene antibiotic amphotericin B

NASA Astrophysics Data System (ADS)

Gagoś, Mariusz; Czernel, Grzegorz

2014-04-01

Amphotericin B (AmB) is one of the most important drug for the medical treatment of internal fungal infections. In this work we study electronic absorption and fluorescence properties of AmB in aqueous solution upon adding strong oxidizing agent. Particularly, we focus on the origin of the emission band ˜470 nm, which has been previously assigned to either formation of AmB dimers or to tetraene and pentaenes impurities. We find clear correlation between appearance of this band and oxidation of AmB, therefore, we conclude that the emission with maximum ˜470 nm is mainly related to the oxidation of AmB chromophore.

Novel oral amphotericin B formulation (iCo-010) remains highly effective against murine systemic candidiasis following exposure to tropical temperature.

PubMed

Wasan, Kishor M; Sivak, Olena; Bartlett, Karen; Wasan, Ellen K; Gershkovich, Pavel

2015-01-01

To evaluate the antifungal activity of amphotericin B (AmB) in a mouse model of systemic candidiasis following administration of a novel oral AmB formulation (iCo-010) that has been pre-exposed to tropical temperatures. Amphotericin B (AmB) was prepared as a 5 mg/mL dispersion in a mixture of Peceol, Gelucire 44/14 and VitE-TPGS 2,3 (iCo-010). The formulation was protected from light and incubated in a sealed container at 43 °C for 60 days. Mice infected with Candida albicans were treated with either iCo-010 formulation pre-incubated at 43 °C for 60 days or freshly prepared iCo-010 formulation at doses of 5, 10 and 20 mg/kg once daily for five consecutive days. Single intravenous 5 mg/kg dose of AmBisome® was used as a positive control group. Seven days following the last dose, the kidney, liver, spleen, lung, heart and brain were removed and the number of colony forming units (CFUs) was determined as a measure of tissue fungal load. In addition, the concentration of AmB within each tissue was determined using high performance liquid chromatography (HPLC). There were no significant differences in the reduction of CFUs and the concentration of AmB recovered in all organs at all iCo-010 doses tested between the freshly prepared iCo-010 formulation compared to the formulation that was incubated at 43 °C for 60 days. A novel oral AmB formulation, iCo-010, incubated at 43 °C for 60 days to simulate the exposure of the formulation to tropical temperatures remained highly effective against murine systemic candidiasis.

Safety of a weekly high dose of liposomal amphotericin B for prophylaxis of invasive fungal infection in immunocompromised patients: PROPHYSOME Study.

PubMed

Cordonnier, Catherine; Mohty, Mohamad; Faucher, Catherine; Pautas, Cécile; Robin, Marie; Vey, Norbert; Monchecourt, Françoise; Mahi, Lamine; Ribaud, Patricia

2008-02-01

With its broad spectrum of activity and better tolerability profile than conventional amphotericin B, liposomal amphotericin B (L-AmB) may be the drug of choice for antifungal prophylaxis in haematological patients. An open-label, multicentre, prospective, pilot study was conducted in adult patients receiving chemotherapy for acute leukaemia (AL) or myeloablative allogeneic stem cell transplantation (SCT). Patients received weekly 10mg/kg infusions of L-AmB for 4 weeks for AL and 8 weeks for SCT. The primary objective was safety, with particular attention to infusion-related reactions and nephrotoxicity. Twenty-nine adult patients were included: 21 AL (median age 52 years) and 8 SCT (median age 37 years). The most frequent adverse events (AEs) related to study drug were infusion-related reactions, 12 of which (from a total of 76 infusions) led to increased infusion duration for better tolerance. No AE related to the study drug led to discontinuation of prophylactic treatment in AL patients. In SCT patients, eight AEs (in six patients) reported to be related to study treatment led to treatment discontinuation. Enrolment was discontinued in the SCT group as recommended by the independent data review committee in accordance with the 10% limit of AEs (CTC grade 3-4) fixed by the protocol. The appropriate timing of high-dose prophylactic L-AmB remains to be determined in the SCT setting to optimise the safety profile of this regimen. For AL, a 10mg/kg weekly dose appears to be well tolerated during chemotherapy and may represent an important tool towards improving AL patient outcome.

Efficacy of a poly-aggregated formulation of amphotericin B in treating systemic sporotrichosis caused by Sporothrix brasiliensis.

PubMed

Ishida, Kelly; Castro, Rafaela Alves; Torrado, Juan J; Serrano, Dolores Remedios; Borba-Santos, Luana Pereira; Quintella, Leonardo Pereira; de Souza, Wanderley; Rozental, Sonia; Lopes-Bezerra, Leila M

2018-04-01

In severe cases of sporotrichosis, it is recommended to use amphotericin B deoxycholate (D-AMB) or its lipid formulations and/or in association with itraconazole (ITC). Our aim was to evaluate the antifungal efficacy of a poly-aggregated amphotericin B (P-AMB), a nonlipid formulation, compared with D-AMB on systemic sporotrichosis caused by Sporothrix brasiliensis. In vitro assays showed that Sporothrix schenckii sensu stricto and S. brasiliensis yeast clinical isolates were susceptible to low concentrations of P-AMB and D-AMB. Although P-AMB presented a higher minimal inhibitory concentration (MIC) compared to D-AMB, its cytotoxic effect on renal cells and erythrocytes was lower. For the in vivo assays, male BALB/c mice were intravenously infected with S. brasiliensis yeasts, and P-AMB or D-AMB was administered 3 days post-infection. The efficacy of five therapeutic regimens was tested: intravenous monotherapy with P-AMB or D-AMB, intravenous pulsed-therapy with P-AMB or D-AMB, and intravenous therapy with P-AMB, followed by oral ITC. These treatments increased murine survival and controlled the fungal burden in the liver, spleen, lungs, and kidneys. However, only D-AMB monotherapy or the pulsed-therapies with D-AMB or P-AMB led to 100% survival of the mice 45 days post-infection; only pulsed administration of D-AMB was able to control the fungal load in all organs 45 days post-infection. Accordingly, the histopathological findings showed reductions in the fungal burden and inflammatory reactions in these treatment regimens. Together, our results suggest that the P-AMB formulation could be considered as an alternative drug to D-AMB for treating disseminated sporotrichosis.

[In vitro synergistic effect of moxifloxacin and amphotericin B combination against Candida strains].

PubMed

Yalçin, Burçe; Kalkanci, Ayşe; Gürelik, Feryal; Fidan, Işil; Kustimur, Semra; Ozdek, Sengül

2010-01-01

Contradictory results such as synergy or indifferent effect, have been reported about the interactions between quinolones and antifungal drugs in different studies. The aim of this study was to investigate the in vitro susceptibilities of Candida spp. to moxifloxacin (MOX) alone and MOX + amphotericin B (AmB) combination. A total of 20 strains were included to the study, of which 19 were clinical isolates (10 Candida albicans, 4 Candida glabrata, 2 Candida parapsilosis, 1 Candida tropicalis, 1 Candida pelliculosa ve 1 Candida sake) and 1 was a standard strain (C. albicans ATCC 90028). In vitro susceptibilities of the strains to MOX with AmB were investigated by broth microdilution method according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI), and in vitro interaction of these drugs were determined by a chequerboard titration method. Minimal inhibitory concentration (MIC) values of Candida spp. for MOX were found > or = 400 microg/ml indicating that MOX, by itself has no antifungal activity. AmB MIC values were found 1 microg/ml in 11 of the clinical isolates, and < or = 0.5 microg/ml in the other 8 clinical isolates and 1 standard strain. The inhibitor activity of AmB was slightly enhanced when combined with MOX, there being a decrease of 1-4 fold dilutions in the AmB MICs against all isolates tested. Synergistic effect between MOX and AmB, defined as a fractional inhibitory concentration (FIC) index as < or = 0.5, was observed in 90% (18/20; all were clinical isolates) of the strains, whereas indifferent effect (FIC = 1) was detected in 10% (2/20; 1 was clinical and 1 was standard strain) of the strains. Antagonistic effect was not observed for this combination even at 48th hours. It was concluded that these preliminary results should be confirmed by large-scaled in vitro and in vivo studies to evaluate MOX + AmB combination as a therapeutic option for the treatment of Candida infections.

Dose Range Evaluation of Mycograb C28Y Variant, a Human Recombinant Antibody Fragment to Heat Shock Protein 90, in Combination with Amphotericin B-Desoxycholate for Treatment of Murine Systemic Candidiasis ▿

PubMed Central

Louie, Arnold; Stein, Daniel S.; Zack, Julia Z.; Liu, Weiguo; Conde, Haley; Fregeau, Christine; VanScoy, Brian D.; Drusano, George L.

2011-01-01

Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg of body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t1/2α of ∼0.198 h and a t1/2β of ∼1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis. PMID:21502626

Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

USDA-ARS?s Scientific Manuscript database

Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

Candida Species Biofilms’ Antifungal Resistance

PubMed Central

Silva, Sónia; Rodrigues, Célia F.; Araújo, Daniela; Rodrigues, Maria Elisa; Henriques, Mariana

2017-01-01

Candida infections (candidiasis) are the most prevalent opportunistic fungal infection on humans and, as such, a major public health problem. In recent decades, candidiasis has been associated to Candida species other than Candida albicans. Moreover, biofilms have been considered the most prevalent growth form of Candida cells and a strong causative agent of the intensification of antifungal resistance. As yet, no specific resistance factor has been identified as the sole responsible for the increased recalcitrance to antifungal agents exhibited by biofilms. Instead, biofilm antifungal resistance is a complex multifactorial phenomenon, which still remains to be fully elucidated and understood. The different mechanisms, which may be responsible for the intrinsic resistance of Candida species biofilms, include the high density of cells within the biofilm, the growth and nutrient limitation, the effects of the biofilm matrix, the presence of persister cells, the antifungal resistance gene expression and the increase of sterols on the membrane of biofilm cells. Thus, this review intends to provide information on the recent advances about Candida species biofilm antifungal resistance and its implication on intensification of the candidiasis. PMID:29371527

Comparison of the Vitek 2 Antifungal Susceptibility System with the Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) Broth Microdilution Reference Methods and with the Sensititre YeastOne and Etest Techniques for In Vitro Detection of Antifungal Resistance in Yeast Isolates ▿ ‖

PubMed Central

Cuenca-Estrella, Manuel; Gomez-Lopez, Alicia; Alastruey-Izquierdo, Ana; Bernal-Martinez, Leticia; Cuesta, Isabel; Buitrago, Maria J.; Rodriguez-Tudela, Juan L.

2010-01-01

The commercial technique Vitek 2 system for antifungal susceptibility testing of yeast species was evaluated. A collection of 154 clinical yeast isolates, including amphotericin B- and azole-resistant organisms, was tested. Results were compared with those obtained by the reference procedures of both the CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Two other commercial techniques approved for clinical use, the Etest and the Sensititre YeastOne, were included in the comparative exercise as well. The average essential agreement (EA) between the Vitek 2 system and the reference procedures was >95%, comparable with the average EAs observed between the reference procedures and the Sensititre YeastOne and Etest. The EA values were >97% for Candida spp. and stood at 92% for Cryptococcus neoformans. Intraclass correlation coefficients (ICC) between the commercial techniques and the reference procedures were statistically significant (P < 0.01). Percentages of very major errors were 2.6% between Vitek 2 and the EUCAST technique and 1.6% between Vitek 2 and the CLSI technique. The Vitek 2 MIC results were available after 14 to 18 h of incubation for all Candida spp. (average time to reading, 15.5 h). The Vitek 2 system was shown to be a reliable technique to determine antifungal susceptibility testing of yeast species and a more rapid and easier alternative for clinical laboratories than the procedures developed by either the CLSI or EUCAST. PMID:20220169

Oropharyngeal candidiasis in HIV-infected patients under treatment with protease inhibitors.

PubMed

Migliorati, Cesar Augusto; Birman, Esther Goldenberg; Cury, Arlete Emily

2004-09-01

Oropharyngeal candidiasis decreased when protease inhibitors were included with other antiretrovirals to treat HIV infection. We tested oral yeast isolates of Brazilian HIV-infected individuals receiving antiretroviral therapy for protease secretion and susceptibility to ritonavir and some antifungals. We collected oral samples and identified yeasts from 19 HIV-infected patients receiving highly active antiretroviral therapy (HAART) and suspected of having oral candidiasis. Ritonavir and its excipients' effects on the isolated yeasts were tested for protease secretion by Rüchel's technique. The yeasts' susceptibility to amphotericin B (AnB), fluorocitosine (5FC), fluconazole (FZL), ketoconazole (KZL), and itraconazole (IZL) was determined by E-test (AB Biodisk). Chi-squared test determined the statistical differences. Twenty-five different positive isolates were obtained. Sixty-eight percent were C. albicans. Other isolates included C. famata (16%), C. glabrata (4%), C. tropicalis (4%), T. capitatum (4%), and 1 isolate not identified. High protease secretion was observed for most of the isolates (20/25). Ritonavir only altered enzyme secretion in 6/20 of the protease-secreting isolates. All isolates were highly sensitive to both AnB and 5FC. Antifungal activity did not change when ritonavir was added to the culture media. Some isolates were highly resistant to studied antifungals (52.2% KZL, 30.4% FZL, and 26% IZL). Resistance significantly decreased when ritonavir was added to the medium with KZL and IZL (P <.5 by chi-squared). A trend to decreased resistance was also observed with FZL but the results were not statistically significant. Candida continues to be the most prevalent fungus in the oral cavity. Although oral candidal isolates secrete protease, ritonavir does not inhibit all protease-secreting oral yeast isolates. There seems to be a synergistic effect between ritonavir and oral antifungals against fungal resistance.

Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis▿

PubMed Central

Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

2011-01-01

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated. PMID:21788462

Characterization of Scedosporium apiospermum Glucosylceramides and Their Involvement in Fungal Development and Macrophage Functions

PubMed Central

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; de Souza, Lauro M.; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2′-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy. PMID:24878570

Characterization of Scedosporium apiospermum glucosylceramides and their involvement in fungal development and macrophage functions.

PubMed

Rollin-Pinheiro, Rodrigo; Liporagi-Lopes, Livia Cristina; de Meirelles, Jardel Vieira; Souza, Lauro M de; Barreto-Bergter, Eliana

2014-01-01

Scedosporium apiospermum is an emerging fungal pathogen that causes both localized and disseminated infections in immunocompromised patients. Glucosylceramides (CMH, GlcCer) are the main neutral glycosphingolipids expressed in fungal cells. In this study, glucosylceramides (GlcCer) were extracted and purified in several chromatographic steps. Using high-performance thin layer chromatography (HPTLC) and electrospray ionization mass spectrometry (ESI-MS), N-2'-hydroxyhexadecanoyl-1-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine was identified as the main GlcCer in S. apiospermum. A monoclonal antibody (Mab) against this molecule was used for indirect immunofluorescence experiments, which revealed that this CMH is present on the surface of the mycelial and conidial forms of S. apiospermum. Treatment of S. apiospermum conidia with the Mab significantly reduced fungal growth. In addition, the Mab also enhanced the phagocytosis and killing of S. apiospermum by murine cells. In vitro assays were performed to evaluate the CMHs for their cytotoxic activities against the mammalian cell lines L.929 and RAW, and an inhibitory effect on cell proliferation was observed. Synergistic in vitro interactions were observed between the Mab against GlcCer and both amphotericin B (AmB) and itraconazole. Because Scedosporium species develop drug resistance, the number of available antifungal drugs is limited; our data indicate that combining immunotherapy with the available drugs might be a viable treatment option. These results suggest that in S. apiospermum, GlcCer are most likely cell wall components that are targeted by antifungal antibodies, which directly inhibit fungal development and enhance macrophage function; furthermore, these results suggest the combined use of monoclonal antibodies against GlcCer and antifungal drugs for antifungal immunotherapy.

Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis.

PubMed

Hata, Katsura; Horii, Takaaki; Miyazaki, Mamiko; Watanabe, Nao-Aki; Okubo, Miyuki; Sonoda, Jiro; Nakamoto, Kazutaka; Tanaka, Keigo; Shirotori, Syuji; Murai, Norio; Inoue, Satoshi; Matsukura, Masayuki; Abe, Shinya; Yoshimatsu, Kentaro; Asada, Makoto

2011-10-01

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.

In vitro susceptibility of Sporothrix brasiliensis: Comparison of yeast and mycelial phases.

PubMed

Sanchotene, Karine Ortiz; Brandolt, Tchana Martinez; Klafke, Gabriel Baracy; Poester, Vanice Rodrigues; Xavier, Melissa Orzechowski

2017-11-01

Sporothrix brasiliensis has emerged as an important cause of sporotrichosis, particularly associated with feline and zoonotic cases. Owing to the paucity of data on antifungal activity against this species, the present study aimed to evaluate the in vitro susceptibility of clinical isolates of S. brasiliensis in the mycelial and yeast phases to itraconazole (ITZ), terbinafine (TRB), and amphotericin B (AMB). Thirty-five isolates from an outbreak of feline sporotrichosis in Southern Brazil were used. All of them were assessed in the yeast and filamentous phases using the broth microdilution technique in accordance with the respective reference protocols M27-A3 and M38-A2 of the Clinical and Laboratory Standards Institute (CLSI). In our study, TRB was the most active antifungal against both the filamentous and yeast phases, showing GM of the MIC of 0.343 μg/ml and 0.127 μg/ml, respectively. In the yeast phase, the GM of the MIC for TRB was significantly lower than that for both ITZ (P = .009) and AMB (P < .001). However, in the filamentous phase, the GM of the MIC for TRB was significantly lower than that of AMB (P < .001), but not different from that of ITZ (P = .091). AMB was the antifungal with the highest GM of the MIC for both phases (1.486 μg/ml for the filamentous phase and 0.660 μg/ml for the yeast). Our results may contribute to a better understanding of antifungal susceptibility profiles of clinical isolates of S. brasiliensis in the mycelial and yeast phases in further studies. © The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Studies on Antifungal Potential, Primary Characterization and Mode of Action of a De Novo Cytoplasmic Protein (EAF) from Human Commensal Escherichia coli Against Aspergillus spp.

PubMed

Balhara, Meenakshi; Ruhil, Sonam; Dhankhar, Sandeep; Chhillar, Anil K

2015-01-01

A de novo protein named as EAF (Escherichia antifungal protein) from the cytoplasmic pool of an Escherichia coli strain (MTCC 1652), has been purified to homogeneity using anion exchange (Q-XL Sepharose) and cation exchange (SP-Sepharose) chromatography. The MIC (minimum inhibitory concentration) values of purified protein against A. fumigatus (the major pathogenic species) were found to be comparable with standard drugs i.e. 3.90 µg/ml, 3.90 µg/ml and 1.25 µg/disc via microbroth dilution assay (MDA), percentage spore germination inhibition (PSGI) and disc diffusion assay (DDA) respectively. Toxicity results confirmed that it causes no haemolysis against human RBCs upto a concentration of 1000.0 µg/ml as compared to Amphotericin B (conventional antifungal drug) that causes hundred percent haemolysis at a concentration of 37.50 µg/ml only.The purified protein demonstrated a molecular mass of 28 kDa on SDS-PAGE which was further authenticated by MALDI-TOF. Proteomic and bioinformatics studies deciphered its significant homology (72 %) with chain A-D-ribose binding protein (cluster 2 sugar binding periplasmic proteins; sequence homologues of transcription regulatory proteins) from E. coli. Single dimensional page analysis of A. fumigatusproteins with due effect of EAF (at MIC50) revealed the inhibition of two major proteins; a heat shock protein 70-Hsp70 (68 kDa); having role in protein folding and functioning andphenylanalyl-t RNA synthetase PodG subunit protein (74 kDa); involved in growth polarity in fungi. Scanning electron microscopic studies depicted homologous results. We suggest that EAF most likely belongs to a new group of proteins with potent antifungal characteristics, negligible toxicity and targeting vital proteins of fungal metabolism.

Diffusion of Antimicrobials Across Silicone Hydrogel Contact Lenses

PubMed Central

Zambelli, Alison M.; Brothers, Kimberly M.; Hunt, Kristin M.; Romanowski, Eric G.; Nau, Amy C.; Dhaliwal, Deepinder K.; Shanks, Robert M. Q.

2014-01-01

Objectives To measure the diffusion of topical preparations of moxifloxacin, amphotericin B (AmB), and polyhexamethylene biguanide (PHMB) through silicone hydrogel (SH) contact lenses in vitro. Methods Using an in vitro model, the diffusion of three antimicrobials through SH contact lenses was measured. Diffused compounds were measured using a spectrophotometer at set time points over a period of four hours. The amount of each diffused antimicrobial was determined by comparing the experimental value to a standard curve. A biological assay was performed to validate the contact lens diffusion assay by testing antimicrobial activity of diffused material against lawns of susceptible bacteria (Staphylococcus epidermidis) and yeast (Saccharomyces cerevisiae). Experiments were repeated at least two times with a total of at least 4 independent replicates. Results Our data show detectable moxifloxacin and PHMB diffusion through SH contact lenses at 30 minutes, while amphotericin B diffusion remained below the limit of detection within the 4 hour experimental period. In the biological assay, diffused moxifloxacin demonstrated microbial killing starting at 20 minutes on bacterial lawns, whereas PHMB and amphotericin B failed to demonstrate killing on microbial lawns over the course of the 60 minute experiment. Conclusions In vitro diffusion assays demonstrate limited penetration of certain anti-infective agents through silicone hydrogel contact lenses. Further studies regarding the clinical benefit of using these agents along with bandage contact lens use for corneal pathology are warranted. PMID:25806673

Chemical composition and antifungal activity of Carica papaya Linn. seed essential oil against Candida spp.

PubMed

He, X; Ma, Y; Yi, G; Wu, J; Zhou, L; Guo, H

2017-05-01

In recent years, the incidence of clinical yeast infections has increased dramatically. Due to the extensive use of broad-spectrum antifungal agents, there has been a notable increase in drug resistance among infections yeast species. As one of the most popular natural antimicrobial agents, essential oils (EOs) have attracted a lot of attention from the scientific community. The aim of this study was to analyse the chemical composition and examine the antifungal activity of the EO extracted from the seeds of Carica papaya Linn. The papaya seed EO was analysed by gas chromatography-mass spectrometry. The major constituent is benzyl isothiocyanate (99·36%). The filter paper disc diffusion method and broth dilution method were employed. The EO showed inhibitory effect against all the tested Candida strains including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropical with inhibition zone diameters in the range of 14·2-33·2 mm, the minimal inhibitory concentrations (MICs) in the range of 4·0-16·0 μg ml -1 and the minimum fungicidal concentrations (MFCs) in the range of 16·0-64·0 μg ml -1 . Here, we found that the papaya seed EO has promising anticandida activity and identify C. papaya L. as a potential natural source of antifungal agents. The chemical composition and antifungal activity of essential oil of Carica papaya seeds were studied. The oil of papaya seeds could inhibit the growth of Candida spp. for the first report. Carica Papaya may be recognized as a possible new source of natural antifungal agents. © 2017 The Society for Applied Microbiology.

C. albicans growth, transition, biofilm formation, and gene expression modulation by antimicrobial decapeptide KSL-W

PubMed Central

2013-01-01

Background Antimicrobial peptides have been the focus of much research over the last decade because of their effectiveness and broad-spectrum activity against microbial pathogens. These peptides also participate in inflammation and the innate host defense system by modulating the immune function that promotes immune cell adhesion and migration as well as the respiratory burst, which makes them even more attractive as therapeutic agents. This has led to the synthesis of various antimicrobial peptides, including KSL-W (KKVVFWVKFK-NH2), for potential clinical use. Because this peptide displays antimicrobial activity against bacteria, we sought to determine its antifungal effect on C. albicans. Growth, hyphal form, biofilm formation, and degradation were thus examined along with EFG1, NRG1, EAP1, HWP1, and SAP 2-4-5-6 gene expression by quantitative RT-PCR. Results This study demonstrates that KSL-W markedly reduced C. albicans growth at both early and late incubation times. The significant effect of KSL-W on C. albicans growth was observed beginning at 10 μg/ml after 5 h of contact by reducing C. albicans transition and at 25 μg/ml by completely inhibiting C. albicans transition. Cultured C. albicans under biofilm-inducing conditions revealed that both KSL-W and amphotericin B significantly decreased biofilm formation at 2, 4, and 6 days of culture. KSL-W also disrupted mature C. albicans biofilms. The effect of KSL-W on C. albicans growth, transition, and biofilm formation/disruption may thus occur through gene modulation, as the expression of various genes involved in C. albicans growth, transition and biofilm formation were all downregulated when C. albicans was treated with KSL-W. The effect was greater when C. albicans was cultured under hyphae-inducing conditions. Conclusions These data provide new insight into the efficacy of KSL-W against C. albicans and its potential use as an antifungal therapy. PMID:24195531

Identification by Molecular Methods and Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and Antifungal Susceptibility Profiles of Clinically Significant Rare Aspergillus Species in a Referral Chest Hospital in Delhi, India.

PubMed

Masih, Aradhana; Singh, Pradeep K; Kathuria, Shallu; Agarwal, Kshitij; Meis, Jacques F; Chowdhary, Anuradha

2016-09-01

Aspergillus species cause a wide spectrum of clinical infections. Although Aspergillus fumigatus and Aspergillus flavus remain the most commonly isolated species in aspergillosis, in the last decade, rare and cryptic Aspergillus species have emerged in diverse clinical settings. The present study analyzed the distribution and in vitro antifungal susceptibility profiles of rare Aspergillus species in clinical samples from patients with suspected aspergillosis in 8 medical centers in India. Further, a matrix-assisted laser desorption ionization-time of flight mass spectrometry in-house database was developed to identify these clinically relevant Aspergillus species. β-Tubulin and calmodulin gene sequencing identified 45 rare Aspergillus isolates to the species level, except for a solitary isolate. They included 23 less common Aspergillus species belonging to 12 sections, mainly in Circumdati, Nidulantes, Flavi, Terrei, Versicolores, Aspergillus, and Nigri Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) identified only 8 (38%) of the 23 rare Aspergillus isolates to the species level. Following the creation of an in-house database with the remaining 14 species not available in the Bruker database, the MALDI-TOF MS identification rate increased to 95%. Overall, high MICs of ≥2 μg/ml were noted for amphotericin B in 29% of the rare Aspergillus species, followed by voriconazole in 20% and isavuconazole in 7%, whereas MICs of >0.5 μg/ml for posaconazole were observed in 15% of the isolates. Regarding the clinical diagnoses in 45 patients with positive rare Aspergillus species cultures, 19 (42%) were regarded to represent colonization. In the remaining 26 patients, rare Aspergillus species were the etiologic agent of invasive, chronic, and allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, keratitis, and mycetoma. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Identification by Molecular Methods and Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry and Antifungal Susceptibility Profiles of Clinically Significant Rare Aspergillus Species in a Referral Chest Hospital in Delhi, India

PubMed Central

Masih, Aradhana; Singh, Pradeep K.; Kathuria, Shallu; Agarwal, Kshitij

2016-01-01

Aspergillus species cause a wide spectrum of clinical infections. Although Aspergillus fumigatus and Aspergillus flavus remain the most commonly isolated species in aspergillosis, in the last decade, rare and cryptic Aspergillus species have emerged in diverse clinical settings. The present study analyzed the distribution and in vitro antifungal susceptibility profiles of rare Aspergillus species in clinical samples from patients with suspected aspergillosis in 8 medical centers in India. Further, a matrix-assisted laser desorption ionization–time of flight mass spectrometry in-house database was developed to identify these clinically relevant Aspergillus species. β-Tubulin and calmodulin gene sequencing identified 45 rare Aspergillus isolates to the species level, except for a solitary isolate. They included 23 less common Aspergillus species belonging to 12 sections, mainly in Circumdati, Nidulantes, Flavi, Terrei, Versicolores, Aspergillus, and Nigri. Matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) identified only 8 (38%) of the 23 rare Aspergillus isolates to the species level. Following the creation of an in-house database with the remaining 14 species not available in the Bruker database, the MALDI-TOF MS identification rate increased to 95%. Overall, high MICs of ≥2 μg/ml were noted for amphotericin B in 29% of the rare Aspergillus species, followed by voriconazole in 20% and isavuconazole in 7%, whereas MICs of >0.5 μg/ml for posaconazole were observed in 15% of the isolates. Regarding the clinical diagnoses in 45 patients with positive rare Aspergillus species cultures, 19 (42%) were regarded to represent colonization. In the remaining 26 patients, rare Aspergillus species were the etiologic agent of invasive, chronic, and allergic bronchopulmonary aspergillosis, allergic fungal rhinosinusitis, keratitis, and mycetoma. PMID:27413188

Candidemia in acute leukemia patients.

PubMed

Ribeiro, P; Sousa, A B; Nunes, O; Aveiro, F; Fernandes, J P; Gouveia, J

1997-05-01

Fungal infections are an important cause of morbidity and mortality in patients with acute leukemia (AL). Candidemia, once rare, is now a common nosocomial infection because of the intensity of chemotherapy, prolonged neutropenia, administration of broad-spectrum antibiotics and use of central venous catheters (CVC). We retrospectively identified patients treated for AL from 6/86 to 6/95 who also had candidemia. We describe 28 patients (incidence 6.3%) with a median age of 39 years, 24 of whom were on remission induction and 4 on postremission chemotherapy. All patients had CVC and empiric antimicrobial therapy, 4 had been given prophylactic antifungal drugs, and 2 had parenteral nutrition. Neutropenia was profound (median leukocyte nadir 200/microliters, median duration 19 days). Candida was isolated in blood cultures 10 days (median) after the start of neutropenia. The clinical presentation included fever (100%), respiratory symptoms (71.4%), skin lesions (39.2%) and septic shock (17.8%). Amphotericin B was given to 17 patients and liposomal amphotericin to 5 patients. Infection resolved in 18 patients (64.2%). 10 of whom were in complete remission. Mortality from candidemia was 17.8% (5/28). In conclusion, fungal infections are responsible for death in a significant number of patients. In our series treatment success was related to its rapid onset and to the recovery of neutropenia.