scholarly journals Madurella mycetomatis Is Not Susceptible to the Echinocandin Class of Antifungal Agents

2010 ◽  
Vol 54 (6) ◽  
pp. 2738-2740 ◽  
Author(s):  
Wendy W. J. van de Sande ◽  
Ahmed H. Fahal ◽  
Irma A. J. M. Bakker-Woudenberg ◽  
Alex van Belkum
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Agents ◽  
Recurrent Infections ◽  
Madurella Mycetomatis ◽  
High Doses ◽  
Therapeutic Alternatives ◽  
Therapeutic Responses

ABSTRACT Eumycetoma caused by Madurella mycetomatis is treated surgically and with high doses of ketoconazole. Therapeutic responses are poor, and recurrent infections are common. In search of therapeutic alternatives in the treatment of mycetoma, we determined the in vitro susceptibilities of M. mycetomatis isolates against caspofungin, anidulafungin, and micafungin. As a comparator fungus, Aspergillus fumigatus was used. Minimal effective concentrations (MECs) and MICs were assessed and compared to those of ketoconazole. M. mycetomatis isolates were not susceptible to the echinocandins.

scholarly journals In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus Isolates from Transplant and Nontransplant Patients

2004 ◽  
Vol 48 (12) ◽  
pp. 4922-4925 ◽  
Author(s):  
William J. Steinbach ◽  
Nina Singh ◽  
Jackie L. Miller ◽  
Daniel K. Benjamin ◽  
Wiley A. Schell ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Calcineurin Inhibitor ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Transplant Recipients ◽  
In Vitro Interactions

ABSTRACT We performed in vitro antifungal checkerboard testing on 12 Aspergillus fumigatus clinical isolates (6 transplant recipients and 6 nontransplant patients) with three antifungal agents (amphotericin B, voriconazole, and caspofungin) and three immunosuppressants (FK506, cyclosporine, and rapamycin). We were not able to detect a difference in calcineurin inhibitor antifungal activity against isolates from transplant recipients and nontransplant patients.

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

2008 ◽  
Vol 52 (6) ◽  
pp. 2196-2204 ◽  
Author(s):  
Theodouli Stergiopoulou ◽  
Joseph Meletiadis ◽  
Tin Sein ◽  
Paraskevi Papaioannidou ◽  
Ioannis Tsiouris ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Topoisomerase Ii ◽  
Antibacterial Agents ◽  
Antifungal Agents ◽  
Management Strategies ◽  
Isobolographic Analysis ◽  
Pharmacodynamic Interactions ◽  
In Vitro Interaction

ABSTRACT 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.

scholarly journals Comparative Study of Susceptibilities of Germinated and Ungerminated Conidia of Aspergillus fumigatus to Various Antifungal Agents

1999 ◽  
Vol 37 (3) ◽  
pp. 858-861 ◽  
Author(s):  
Elias K. Manavathu ◽  
Jessica Cutright ◽  
Pranatharthi H. Chandrasekar
Keyword(s):  
Comparative Study ◽  
Growth Inhibition ◽  
Aspergillus Fumigatus ◽  
Mycelial Growth ◽  
Fungicidal Activity ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
In Vitro Susceptibility ◽  
In Vitro Susceptibility Testing

Conidia are used as inocula for the in vitro susceptibility testing of Aspergillus fumigatus. Since the MIC is defined on the basis of visible mycelial growth, conidia should germinate and produce sporelings (germinated conidia) for monitoring of the growth inhibition and fungicidal activity of a drug. If a compound is capable of inhibiting germination of conidia while affecting or not affecting the growth of the organism, the MIC obtained will be the concentration of the drug required for the inhibition of conidial germination but not necessarily that required for inhibition of the growth of the organism. We investigated the susceptibility of germinated and ungerminated conidia to amphotericin B, itraconazole, voriconazole, and SCH56592. The MICs of various antifungal agents for germinated conidia were almost identical to those obtained for ungerminated conidia. In addition, both the germinated and ungerminated conidia were killed with almost equal efficiency by all of the compounds tested when exposed to the drugs for 24 h. These results suggest that either germinated or ungerminated conidia could be used as inocula for in vitro susceptibility studies of A. fumigatus with identical results.

scholarly journals In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus

2004 ◽  
Vol 48 (5) ◽  
pp. 1664-1669 ◽  
Author(s):  
William J. Steinbach ◽  
Wiley A. Schell ◽  
Jill R. Blankenship ◽  
Chiatogu Onyewu ◽  
Joseph Heitman ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Potential Role ◽  
Antifungal Agents ◽  
Calcineurin Inhibitors ◽  
Positive Interaction ◽  
Azole Antifungals ◽  
Calcineurin Pathway ◽  
In Vitro Interactions

ABSTRACT The optimal treatment for invasive aspergillosis remains elusive, despite the increased efficacy of newer agents. The immunosuppressants cyclosporine (CY), tacrolimus (FK506), and sirolimus (formerly called rapamycin) exhibit in vitro and in vivo activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae, including fungicidal synergy with azole antifungals. We report here that both FK506 and CY exhibit a clear in vitro positive interaction with caspofungin against Aspergillus fumigatus by disk diffusion, microdilution checkerboard, and gross and microscopic morphological analyses. Microscopic morphological analyses indicate that the calcineurin inhibitors delay filamentation, and in combination with caspofungin there is a positive interaction. Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and existing antifungal agents to augment activity against A. fumigatus.

scholarly journals In VitroSusceptibility ofMadurella mycetomatisto Posaconazole and Terbinafine

2011 ◽  
Vol 55 (4) ◽  
pp. 1771-1773 ◽  
Author(s):  
Alex van Belkum ◽  
Ahmed H. Fahal ◽  
Wendy W. J. van de Sande
Keyword(s):  
Clinical Outcome ◽  
Safety Profile ◽  
Poor Clinical Outcome ◽  
Highly Active ◽  
Excellent Safety Profile ◽  
Madurella Mycetomatis ◽  
Therapeutic Alternatives

ABSTRACTPresently, therapy of eumycetoma in Sudan is still based on surgery combined with prolonged ketoconazole therapy. This usually results in a poor clinical outcome. To determine if posaconazole and terbinafine could offer better therapeutic alternatives, thein vitrosusceptibilities of 34Madurella mycetomatisstrains were determined. It appeared that posaconazole was highly active againstM. mycetomatisbut terbinafine was only moderately active. Since posaconazole has an excellent safety profile, it might provide an important alternative in mycetoma therapy.

scholarly journals Testing of the In Vitro Susceptibilities of Madurella mycetomatis to Six Antifungal Agents by Using the Sensititre System in Comparison with a Viability-Based 2,3-Bis(2-Methoxy-4-Nitro-5-Sulfophenyl)-5- [(Phenylamino)Carbonyl]-2H-Tetrazolium Hydroxide (XTT) Assay and a Modified NCCLS Method

2005 ◽  
Vol 49 (4) ◽  
pp. 1364-1368 ◽  
Author(s):  
Wendy W. J. van de Sande ◽  
Ad Luijendijk ◽  
Abdalla O. A. Ahmed ◽  
Irma A. J. M. Bakker-Woudenberg ◽  
Alex van Belkum
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Therapeutic Management ◽  
Xtt Assay ◽  
Routine Testing ◽  
Antifungal Activities ◽  
Madurella Mycetomatis ◽  
Relevant Range

ABSTRACT The in vitro susceptibilities of 36 clinical isolates of Madurella mycetomatis, the prime agent of eumycetoma in Africa, to ketoconazole, itraconazole, fluconazole, voriconazole, amphotericin B, and flucytosine were determined by the Sensititre YeastOne system. This system appeared to be a rapid and easy test, and by use of hyphal suspensions it generated results comparable to those of a modified NCCLS method. After 10 days of incubation, the antifungal activities of ketoconazole (MIC at which 90% of isolates were inhibited [MIC90], 0.125 μg/ml), itraconazole (MIC90, 0.064 μg/ml), and voriconazole (MIC90, 0.125 μg/ml) appeared superior to those of fluconazole (MIC90, 128 μg/ml) and amphotericin B (MIC90, 1 μg/ml), with MICs in the clinically relevant range. All isolates were resistant to flucytosine (all MICs above 64 μg/ml). Based on the relatively broad range of MICs obtained for the antifungal agents, routine testing of M. mycetomatis isolates for susceptibility to antifungal agents seems to be relevant to adequate therapeutic management.

scholarly journals Potency of Olorofim (F901318) Compared to Contemporary Antifungal Agents against Clinical Aspergillus fumigatus Isolates and Review of Azole Resistance Phenotype and Genotype Epidemiology in China

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Huilin Su ◽  
Min Zhu ◽  
Clement Kin-Ming Tsui ◽  
Henrich van der Lee ◽  
Marlou Tehupeiory-Kooreman ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Drug Targets ◽  
Antifungal Agents ◽  
Single Point ◽  
Resistance Mechanism ◽  
Antifungal Drugs ◽  
Single Point Mutation ◽  
Content Type ◽  
Novel Drug

ABSTRACT Triazole resistance in Aspergillus fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed, with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated the potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and we reviewed the literature on triazole-resistant A. fumigatus (TRAF) published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates, with a MIC90 of 0.031 mg/liter (range, 0.008 to 0.062 mg/liter). For 4 triazole-resistant A. fumigatus isolates, the olorofim MIC ranged between 0.016 and 0.062 mg/liter. The reported rates of TRAF in China are 2.5 to 5.56% for clinical isolates and 0 to 1.4% for environmental isolates. TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non-TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due to TR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets, such as olorofim.

scholarly journals PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections

2020 ◽  
Vol 6 (4) ◽  
pp. 373
Author(s):  
Alison Murray ◽  
Lindsey Cass ◽  
Kazuhiro Ito ◽  
Nicole Pagani ◽  
Darius Armstrong-James ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Antifungal Agent ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Unmet Need ◽  
Systemic Exposure ◽  
Candida Spp ◽  
Aspergillus Infection ◽  
Chronic Lung Diseases

Disease due to pulmonary Aspergillus infection remains a significant unmet need, particularly in immunocompromised patients, patients in critical care and those with underlying chronic lung diseases. To date, treatment using inhaled antifungal agents has been limited to repurposing available systemic medicines. PC945 is a novel triazole antifungal agent, a potent inhibitor of CYP51, purpose-designed to be administered via inhalation for high local lung concentrations and limited systemic exposure. In preclinical testing, PC945 is potent versus Aspergillus spp. and Candida spp. and showed two remarkable properties in preclinical studies, in vitro and in vivo. The antifungal effects against Aspergillus fumigatus accumulate on repeat dosing and improved efficacy has been demonstrated when PC945 is dosed in combination with systemic anti-fungal agents of multiple classes. Resistance to PC945 has been induced in Aspergillus fumigatus in vitro, resulting in a strain which remained susceptible to other antifungal triazoles. In healthy volunteers and asthmatics, nebulised PC945 was well tolerated, with limited systemic exposure and an apparently long lung residency time. In two lung transplant patients, PC945 treated an invasive pulmonary Aspergillus infection that had been unresponsive to multiple antifungal agents (systemic ± inhaled) without systemic side effects or detected drug–drug interactions.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

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