In vitro synergisms obtained by amphotericin B and voriconazole associated with non-antifungal agents against Fusarium spp

ABSTRACT Fungal keratitis is a common but severe eye infection in tropical and subtropical areas of the world. In regions with a temperate climate, the frequency of infection is rising in patients with contact lenses and following trauma. Early and adequate therapy is important to prevent disease progression and loss of vision. The management of Fusarium keratitis is complex, and the optimal treatment is not well defined. We investigated the in vitro activity of chlorhexidine and seven antifungal agents against a well-characterized collection of Fusarium isolates recovered from patients with Fusarium keratitis. The fungus culture collection of the Center of Expertise in Mycology Radboudumc/CWZ was searched for Fusarium isolates that were cultured from cornea scrapings, ocular biopsy specimens, eye swabs, and contact lens fluid containers from patients with suspected keratitis. The Fusarium isolates that were cultured from patients with confirmed keratitis were all identified using conventional and molecular techniques. Antifungal susceptibility testing was performed according to the EUCAST broth microdilution reference method. The antifungal agents tested included amphotericin B, voriconazole, posaconazole, miconazole, natamycin, 5-fluorocytosine, and caspofungin. In addition, the activity of chlorhexidine was determined. The fungal culture collection contained 98 Fusarium isolates of confirmed fungal keratitis cases from 83 Dutch patients and 15 Tanzanian patients. The isolates were collected between 2007 and 2017. Fusarium oxysporum (n = 24, 24.5%) was the most frequently isolated species followed by Fusarium solani sensu stricto (n = 18, 18.4%) and Fusarium petroliphilum (n = 11, 11.2%). Amphotericin B showed the most favorable in vitro inhibition of Fusarium species followed by natamycin, voriconazole, and chlorhexidine, while 5-fluorocytosine, posaconazole, miconazole, and caspofungin showed no relevant inhibiting effect. However, chlorhexidine showed fungicidal activity against 90% of F. oxysporum strains and 100% of the F. solani strains. Our study supports the clinical efficacy of chlorhexidine and therefore warrants its further clinical evaluation for primary therapy of fungal keratitis, particularly in low and middle income countries where fungal keratitis is much more frequent and, currently, antifungal eye drops are often unavailable.

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In Vitro Activities of Isavuconazole and Other Antifungal Agents against Candida Bloodstream Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01217-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1818-1821 ◽

Cited By ~ 61

Author(s):

H. Seifert ◽

U. Aurbach ◽

D. Stefanik ◽

O. Cornely

Keyword(s):

Amphotericin B ◽

Antifungal Agents ◽

Tertiary Care ◽

Common Species ◽

University Hospital ◽

Phase Iii ◽

Highly Active ◽

Fluconazole Resistant ◽

Resistant Strains

ABSTRACT Isavuconazole is the active component of the new azole antifungal agent BAL8557, which is entering phase III clinical development. This study was conducted to compare the in vitro activities of isavuconazole and five other antifungal agents against 296 Candida isolates that were recovered consecutively from blood cultures between 1995 and 2004 at a tertiary care university hospital. Microdilution testing was done in accordance with CLSI (formerly NCCLS) guideline M27-A2 in RPMI-1640 MOPS (morpholinepropanesulfonic acid) broth. The antifungal agents tested were amphotericin B, flucytosine, fluconazole, itraconazole, voriconazole, and isavuconazole. C. albicans was the most common species, representing 57.1% of all isolates. There was no trend found in favor of non-Candida albicans species over time. In terms of MIC50s, isavuconazole was more active (0.004 mg/liter) than amphotericin B (0.5 mg/liter), itraconazole (0.008 mg/liter), voriconazole (0.03 mg/liter), flucytosine (0.125 mg/liter), and fluconazole (8 mg/liter). For isavuconazole, MIC50s/MIC90s ranged from 000.2/0.004 mg/liter for C. albicans to 0.25/0.5 mg/liter for C. glabrata. Two percent of isolates (C. glabrata and C. krusei) were resistant to fluconazole; C. albicans strains resistant to fluconazole were not detected. There were only two isolates with MICs for isavuconazole that were >0.5 mg/liter: both were C. glabrata isolates, and the MICs were 2 and 4 mg/liter, respectively. In conclusion, isavuconazole is highly active against Candida bloodstream isolates, including fluconazole-resistant strains. It was more active than itraconazole and voriconazole against C. albicans and C. glabrata and appears to be a promising agent against systemic Candida infections.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.5.1264 ◽

1999 ◽

Vol 43 (5) ◽

pp. 1264-1266 ◽

Cited By ~ 37

Author(s):

Karen L. Oakley ◽

Caroline B. Moore ◽

David W. Denning

Keyword(s):

Amphotericin B ◽

Aspergillus Terreus ◽

Antifungal Agents ◽

Geometric Mean ◽

Colloidal Dispersion ◽

Vitro Activity ◽

In Vitro Activity ◽

Lipid Complex

ABSTRACT We compared the in vitro activity of liposomal nystatin (Nyotran) with those of other antifungal agents against 60Aspergillus 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).

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Antifungal Drugs Influence Neutrophil Effector Functions

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02409-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 2

Author(s):

Frederic Ries ◽

Astrid Alflen ◽

Pamela Aranda Lopez ◽

Hendrik Beckert ◽

Matthias Theobald ◽

...

Keyword(s):

Amphotericin B ◽

Antifungal Agents ◽

Antifungal Drugs ◽

Polymorphonuclear Neutrophils ◽

Enzyme Linked Immunosorbent Assay ◽

Activation Markers ◽

Effector Functions ◽

Enhanced Expression ◽

Almost All

ABSTRACTThere is a growing body of evidence for immunomodulatory side effects of antifungal agents on different immune cells, e.g., T cells. Therefore, the aim of our study was to clarify these interactions with regard to the effector functions of polymorphonuclear neutrophils (PMN). Human PMN were preincubated with fluconazole (FLC), voriconazole (VRC), posaconazole (POS), isavuconazole (ISA), caspofungin (CAS), micafungin (MFG), conventional amphotericin B (AMB), and liposomal amphotericin B (LAMB). PMN then were analyzed by flow cytometry for activation, degranulation, and phagocytosis and by dichlorofluorescein assay to detect reactive oxygen species (ROS). Additionally, interleukin-8 (IL-8) release was measured by enzyme-linked immunosorbent assay. POS led to enhanced activation, degranulation, and generation of ROS, whereas IL-8 release was reduced. In contrast, ISA-pretreated PMN showed decreased activation signaling, impaired degranulation, and lower generation of ROS. MFG caused enhanced expression of activation markers but impaired degranulation, phagocytosis, generation of ROS, and IL-8 release. CAS showed increased phagocytosis, whereas degranulation and generation of ROS were reduced. AMB led to activation of almost all effector functions besides impaired phagocytosis, whereas LAMB did not alter any effector functions. Independent from class, antifungal agents show variable influence on neutrophil effector functionsin vitro. Whether this is clinically relevant needs to be clarified.

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Indole-Containing Phytoalexin-Based Bioisosteres as Antifungals: In Vitro and In Silico Evaluation against Fusarium oxysporum

Molecules ◽

10.3390/molecules25010045 ◽

2019 ◽

Vol 25 (1) ◽

pp. 45

Author(s):

Andrea Angarita-Rodríguez ◽

Diego Quiroga ◽

Ericsson Coy-Barrera

Keyword(s):

Fusarium Oxysporum ◽

Mycelial Growth ◽

Plant Pathogens ◽

Antifungal Agents ◽

Molecular Mechanic ◽

Energy Performance ◽

Fusarium Spp ◽

Molecular Interaction Fields ◽

Poisson Boltzmann

There is a continuous search for more reliable and effective alternatives to control phytopathogens through different strategies. In this context, indole-containing phytoalexins are stimuli-induced compounds implicated in plant defense against plant pathogens. However, phytoalexins’ efficacy have been limited by fungal detoxifying mechanisms, thus, the research on bioisosteres-based analogs can be a friendly alternative regarding the control of Fusarium phytopathogens, but there are currently few studies on it. Thus, as part of our research on antifungal agents, a set of 21 synthetic indole-containing phytoalexin analogs were evaluated as inhibitors against the phyopathogen Fusarium oxysporum. Results indicated that analogs of the N,N-dialkylthiourea, N,S-dialkyldithiocarbamate and substituted-1,3-thiazolidin-5-one groups exhibited the best docking scores and interaction profiles within the active site of Fusarium spp. enzymes. Vina scores exhibited correlation with experimental mycelial growth inhibition using supervised statistics, and this antifungal dataset correlated with molecular interaction fields after CoMFA. Compound 24 (tert-butyl (((3-oxo-1,3-diphenylpropyl)thio)carbonothioyl)-l-tryptophanate), a very active analog against F. oxysporum, exhibited the best interaction with lanosterol 14α-demethylase according to molecular docking, molecular dynamics and molecular mechanic/poisson-boltzmann surface area (MM/PBSA) binding energy performance. After data analyses, information on mycelial growth inhibitors, structural requirements and putative enzyme targets may be used in further antifungal development based on phytoalexin analogs for controlling phytopathogens.

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Genotypic variation and antifungal susceptibilities of Candida pelliculosa clinical isolates

Journal of Medical Microbiology ◽

10.1099/jmm.0.45850-0 ◽

2005 ◽

Vol 54 (3) ◽

pp. 279-285 ◽

Cited By ~ 18

Author(s):

F Barchiesi ◽

A M Tortorano ◽

L Falconi Di Francesco ◽

A Rigoni ◽

A Giacometti ◽

...

Keyword(s):

Candida Albicans ◽

Drug Therapy ◽

Amphotericin B ◽

Antifungal Agents ◽

Yeast Species ◽

Genotypic Variation ◽

Optimal Drug ◽

Typing Methods ◽

Dna Types

At the Istituto Ricovero Cura Carattere Scientifico, Ospedale Maggiore di Milano, Italy, Candida pelliculosa accounted for 3.3 and 4.4 % of all Candida species other than Candida albicans collected during 1996 and 1998, respectively. Genetic variability was investigated by electrophoretic karyotyping and inter-repeat PCR, and the susceptibility to five antifungal agents of 46 strains isolated from 37 patients during these 2 years was determined. Combination of the two typing methods yielded 14 different DNA types. Although the majority of DNA types were randomly distributed among different units, one DNA type was significantly more common in patients hospitalized in a given unit compared with those from other wards (P = 0.034), whereas another DNA type was more frequently isolated in patients hospitalized during 1996 than in those hospitalized during 1998 (P = 0.002). Fluconazole, itraconazole and posaconazole MIC90 values were 16, 1 and 4 μg ml−1, respectively. All isolates but three were susceptible in vitro to flucytosine. All isolates were susceptible in vitro to amphotericin B. These data suggest that there are possible relationships among strains of C. pelliculosa, wards and time of isolation. Amphotericin B seems to be the optimal drug therapy in infections due to this yeast species.

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Effect of pH onIn VitroSusceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05025-11 ◽

2012 ◽

Vol 56 (3) ◽

pp. 1403-1406 ◽

Cited By ~ 49

Author(s):

Claire S. Danby ◽

Dina Boikov ◽

Rina Rautemaa-Richardson ◽

Jack D. Sobel

Keyword(s):

Amphotericin B ◽

Candida Glabrata ◽

Antifungal Agents ◽

Susceptibility Testing ◽

Low Ph ◽

Clinical Use ◽

Effect Of Ph ◽

Content Type ◽

Clinical Observations

ABSTRACTThe treatment of vulvovaginal candidiasis (VVC) due toCandida glabratais challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite ofin vitrosusceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on thein vitroactivity of 11 antifungal agents against 40C. glabrataisolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibilityC. albicansstrains.In vitrosusceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH,C. glabrataisolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7,C. albicansstrains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitiveC. albicansisolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrentC. glabratavaginitis, clinicians should recognize the limitations ofin vitrosusceptibility testing utilizing pH 7.0.

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Antifungal Susceptibility Profile of Human-Pathogenic Species of Lichtheimia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01270-09 ◽

2010 ◽

Vol 54 (7) ◽

pp. 3058-3060 ◽

Cited By ~ 15

Author(s):

Ana Alastruey-Izquierdo ◽

Isabel Cuesta ◽

Grit Walther ◽

Manuel Cuenca-Estrella ◽

Juan Luis Rodriguez-Tudela

Keyword(s):

Combination Therapy ◽

Amphotericin B ◽

Potential Role ◽

Antifungal Agents ◽

Active Drug ◽

Antifungal Susceptibility ◽

Pathogenic Species

ABSTRACT Forty-four isolates belonging to human pathogenic species of Lichtheimia were tested against nine antifungal agents by using the EUCAST methodology. No remarkable differences were found between the clinical species, although L. ramosa showed slightly higher MICs for all drugs. Amphotericin B was the most active drug. Among azole drugs, posaconazole had the best activity in vitro and voriconazole was inactive. Echinocandins showed activity for some isolates, suggesting a potential role in combination therapy.

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In Vitro Pharmacodynamic Properties of Three Antifungal Agents against Preformed Candida albicans Biofilms Determined by Time-Kill Studies

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.11.3634-3636.2002 ◽

2002 ◽

Vol 46 (11) ◽

pp. 3634-3636 ◽

Cited By ~ 183

Author(s):

Gordon Ramage ◽

Kacy VandeWalle ◽

Stefano P. Bachmann ◽

Brian L. Wickes ◽

José L. López-Ribot

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Antifungal Agents ◽

Pharmacokinetic Properties ◽

Time Kill ◽

Candida Albicans Biofilms

ABSTRACT We have examined the in vitro activities of fluconazole, amphotericin B, and caspofungin against Candida albicans biofilms by time-kill methodology. Fluconazole was ineffective against biofilms. Killing of biofilm cells was suboptimal at therapeutic concentrations of amphotericin B. Caspofungin displayed the most effective pharmacokinetic properties, with ≥99% killing at physiological concentrations.

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