scholarly journals Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents

2003 ◽  
Vol 47 (8) ◽  
pp. 2404-2412 ◽  
Author(s):  
Dominique Sanglard ◽  
Françoise Ischer ◽  
Tania Parkinson ◽  
Derek Falconer ◽  
Jacques Bille
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Antifungal Susceptibility ◽  
Wild Type ◽  
Gene Encoding ◽  
Aerobic Conditions ◽  
Targeted Deletion ◽  
Resistant Strains

ABSTRACT The role of sterol mutations in the resistance of Candida albicans to antifungal agents has not been thoroughly investigated. Previous work reported that clinical C. albicans strains resistant to both azole antifungals and amphotericin B were defective in ERG3, a gene encoding sterol Δ5,6-desaturase. It is also believed that a deletion of the lanosterol 14α-demethylase gene, ERG11, is possible only under aerobic conditions when ERG3 is not functional. We tested these hypotheses by creating mutants by targeted deletion of the ERG3 and ERG11 genes and subjecting those mutants to antifungal susceptibility testing and sterol analysis. The homozygous erg3/erg3 mutant created, DSY1751, was resistant to azole derivatives, as expected. This mutant was, however, slightly more susceptible to amphotericin B than the parent wild type. It was possible to generate erg11/erg11 mutants in the DSY1751 background but also, surprisingly, in the background of a wild-type isolate with functional ERG3 alleles under aerobic conditions. This mutant (DSY1769) was obtained by exposure of an ERG11/erg11 heterozygous strain in a medium containing 10 μg of amphotericin B per ml. Amphotericin B-resistant strains were obtained only from ERG11/erg11 heterozygotes at a frequency of approximately 5 × 10−5 to 7 × 10−5, which was consistent with mitotic recombination between the first disrupted erg11 allele and the other remaining functional ERG11 allele. DSY1769 was also resistant to azole derivatives. The main sterol fraction in DSY1769 contained lanosterol and eburicol. These studies showed that erg11/erg11 mutants of a C. albicans strain harboring a defective erg11 allele can be obtained in vitro in the presence of amphotericin B. Amphotericin B-resistant strains could therefore be selected by similar mechanisms during antifungal therapy.

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

2007 ◽  
Vol 51 (5) ◽  
pp. 1818-1821 ◽  
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.

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

1998 ◽  
Vol 42 (10) ◽  
pp. 2503-2510 ◽  
Author(s):  
Maurizio Del Poeta ◽  
Wiley A. Schell ◽  
Christine C. Dykstra ◽  
Susan K. Jones ◽  
Richard R. Tidwell ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Candida Albicans ◽  
Fusarium Solani ◽  
Antifungal Agents ◽  
Antifungal Drugs ◽  
Inhibitory Compounds ◽  
Wide Range ◽  
Fluconazole Resistant ◽  
Resistant Strains

ABSTRACT 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 againstCandida 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 againstAspergillus 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.

scholarly journals Genotypic variation and antifungal susceptibilities of Candida pelliculosa clinical isolates

2005 ◽  
Vol 54 (3) ◽  
pp. 279-285 ◽  
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.

scholarly journals Mutations in the fks1 Gene in Candida albicans, C. tropicalis, and C. krusei Correlate with Elevated Caspofungin MICs Uncovered in AM3 Medium Using the Method of the European Committee on Antibiotic Susceptibility Testing

2008 ◽  
Vol 52 (9) ◽  
pp. 3092-3098 ◽  
Author(s):  
Marie Desnos-Ollivier ◽  
Stéphane Bretagne ◽  
Dorothée Raoux ◽  
Damien Hoinard ◽  
Françoise Dromer ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antibiotic Susceptibility ◽  
Susceptibility Testing ◽  
Antifungal Susceptibility ◽  
Clinical Isolates ◽  
Antibiotic Susceptibility Testing ◽  
Wild Type ◽  
European Committee ◽  
Rpmi Medium

ABSTRACT Mutations in two specific regions of the Fks1 subunit of 1,3-β-d-glucan synthase are known to confer decreased caspofungin susceptibility on Candida spp. Clinical isolates of Candida spp. (404 Candida albicans, 62 C. tropicalis, and 21 C. krusei isolates) sent to the French National Reference Center were prospectively screened for susceptibility to caspofungin in vitro by the broth microdilution reference method of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing (AFST-EUCAST). Twenty-eight isolates (25 C. albicans, 2 C. tropicalis, and 1 C. krusei isolate) for which the caspofungin MIC was above the MIC that inhibited 90% of the isolates of the corresponding species (MIC90) were subjected to molecular analysis in order to identify mutations in the fks1 gene. Substitutions in the deduced protein sequence of Fks1 were found for 8 isolates, and 20 isolates had the wild-type sequence. Among the six C. albicans isolates harboring mutations, six patterns were observed involving amino acid changes at positions 641, 645, 649, and 1358. For C. tropicalis, one isolate showed an L644W mutation, and for one C. krusei isolate, two mutations, L658W and L701M, were found. Two media, RPMI medium and AM3, were tested for their abilities to distinguish between isolates with wild-type Fks1 and those with mutant Fks1. In RPMI medium, caspofungin MICs ranged from 0.25 to 2 μg/ml for wild-type isolates and from 1 to 8 μg/ml for mutant isolates. A sharper difference was observed in AM3: all wild-type isolates were inhibited by 0.25 μg/ml of caspofungin, while caspofungin MICs for all mutant isolates were ≥0.5 μg/ml. These data demonstrate that clinical isolates of C. albicans, C. tropicalis, and C. krusei with decreased susceptibility to caspofungin in vitro have diverse mutations in the fks1 gene and that AM3 is potentially a better medium than RPMI for distinguishing between mutant and wild-type isolates using the AFST-EUCAST method.

scholarly journals Antifungal Susceptibility Profile of Human-Pathogenic Species of Lichtheimia

2010 ◽  
Vol 54 (7) ◽  
pp. 3058-3060 ◽  
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.

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

2002 ◽  
Vol 46 (11) ◽  
pp. 3634-3636 ◽  
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.

scholarly journals In Vitro Susceptibilities of Candida dubliniensisIsolates Tested against the New Triazole and Echinocandin Antifungal Agents

1999 ◽  
Vol 37 (3) ◽  
pp. 870-872 ◽  
Author(s):  
M. A. Pfaller ◽  
S. A. Messer ◽  
S. Gee ◽  
S. Joly ◽  
C. Pujol ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Clinical Laboratory ◽  
National Committee ◽  
Mucosal Disease ◽  
Fluconazole Resistant ◽  
Resistant Strains ◽  
Investigational Agents ◽  
Multidrug Resistance Transporters

Candida dubliniensis is a newly recognized fungal pathogen causing mucosal disease in AIDS patients. Although preliminary studies indicate that most strains of C. dubliniensis are susceptible to established antifungal agents, fluconazole-resistant strains have been detected. Furthermore, fluconazole-resistant strains are easily derived in vitro, and these strains exhibit increased expression of multidrug resistance transporters, especially MDR1. Because of the potential for the development of resistant strains of C. dubliniensis, it is prudent to explore the in vitro activities of several of the newer triazole and echinocandin antifungals against isolates of C. dubliniensis. In this study we tested 71 isolates of C. dubliniensis against the triazoles BMS-207147, Sch 56592, and voriconazole and a representative of the echinocandin class of antifungal agents, MK-0991. We compared the activities of these agents with those of the established antifungal agents fluconazole, itraconazole, amphotericin B, and 5-fluorocytosine (5FC) by using National Committee for Clinical Laboratory Standards microdilution reference methods. Our findings indicate that the vast majority of clinical isolates of C. dubliniensis are highly susceptible to both new and established antifungal agents. Strains with decreased susceptibilities to fluconazole remained susceptible to the investigational agents as well as to amphotericin B and 5FC. The increased potencies of the new triazole and echinocandin antifungal agents may provide effective therapeutic options for the treatment of infections due to C. dubliniensis.

scholarly journals Antifungal susceptibility of Candida albicans isolated from oral mucosa of patients with cancer

1999 ◽  
Vol 13 (3) ◽  
pp. 219-223 ◽  
Author(s):  
Lino João da COSTA ◽  
Esther Goldenberg BIRMAN ◽  
Sidney Hartz ALVES ◽  
Arlete Emily CURY
Keyword(s):  
Candida Albicans ◽  
Cancer Patients ◽  
Amphotericin B ◽  
Oral Mucosa ◽  
Antifungal Susceptibility ◽  
New Drugs ◽  
Local Conditions ◽  
Opportunistic Fungi ◽  
Sabouraud Agar

The increasing number of oral infections due to opportunistic fungi in immunocompromised patients, needs a new evaluation of the drugs in use. The susceptibility in vitro of Candida albicans strains from the oral mucosa of cancer patients to amphotericin B, ketoconazole, miconazole, fluconazole and itraconazole were evaluated. A dilution technique in YNB agar or subculture on Sabouraud agar was utilised for MIC or MFC determinations. With this methodology, the best fungicidal drug for C.albicans collected from the oral mucosa of 40 cancer patients, divided in two groups: one treated by radiotherapy and the other not, the best results were obtained with amphotericin B, presenting low values of MIC compared to azoles and MFC values. However it is important to take into consideration the utilisation in vivo of this polyenic antibiotic and the possible toxic levels necessary to achieve good results. The coexistence of other fungi and the local conditions must also be pondered with these patients, who are mostly undergoing radiotherapy. In order to achieve better results without undesirable consequences, higher levels of MIC are expected with the daily clinical use of new drugs.

scholarly journals Antifungal Susceptibility of Malassezia pachydermatis Isolates from Dogs

2019 ◽  
Vol 63 (2) ◽  
pp. 15-20
Author(s):  
Z. Sihelská ◽  
E. Čonková ◽  
P. Váczi ◽  
M. Harčárová
Keyword(s):  
Antifungal Agents ◽  
Antifungal Susceptibility ◽  
Diffusion Method ◽  
Opportunistic Pathogens ◽  
Ear Canal ◽  
Disk Diffusion Method ◽  
Malassezia Pachydermatis ◽  
Resistant Strains ◽  
Standard Disk

Abstract The genus Malassezia belongs to Basidiomycota and includes 16 species, from which M. pachydermatis is the most common in dogs. M. pachydermatis is a member of the normal mycobiota of the skin and mucosal sites of dogs. Under certain conditions, these yeasts can be opportunistic pathogens and involved skin and ear canal infections of these animals. Topical and oral antifungal agents are used for the therapy of Malassezia dermatitis and otitis. With the expanding use of antifungal agents, resistant strains of Malassezia are increasingly detected. In this study, the susceptibility of 40 M. pachydermatis isolates to fluconazole, itraconazole, ketoconazole, clotrimazole and nystatin were evaluated in vitro based on the modified standard disk diffusion method M44-2A.

Comparative antifungal susceptibility analyses of Cryptococcus neoformans VNI and Cryptococcus gattii VGII from the Brazilian Amazon Region by the Etest, Vitek 2, and the Clinical and Laboratory Standards Institute broth microdilution methods

2019 ◽  
Vol 57 (7) ◽  
pp. 864-873 ◽  
Author(s):  
Marília Martins Nishikawa ◽  
Rodrigo Almeida-Paes ◽  
Fabio Brito-Santos ◽  
Carlos Roberto Nascimento ◽  
Miguel Madi Fialho ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Susceptibility ◽  
Amazon Region ◽  
Antifungal Drugs ◽  
Epidemiological Surveillance ◽  
Broth Microdilution ◽  
Wild Type ◽  
Brazilian Amazon Region ◽  
Vitek 2

AbstractEarly diagnosis, efficient clinical support, and proper antifungal therapy are essential to reduce death and sequels caused by cryptococcosis. The emergence of resistance to the antifungal drugs commonly used for cryptococcosis treatment is an important issue of concern. Thus, the in vitro antifungal susceptibility of clinical strains from northern Brazil, including C. neoformans VNI (n = 62) and C. gattii VGII (n = 37), to amphotericin B (AMB), 5-flucytosine, fluconazole, voriconazole, and itraconazole was evaluated using the Etest and Vitek 2 systems and the standardized broth microdilution (CLSI-BMD) methodology. According to the CLSI-BMD, the most active in vitro azole was voriconazole (C. neoformans VNI modal MIC of 0.06 μg/ml and C. gattii VGII modal MIC of 0.25 μg/ml), and fluconazole was the least active (modal MIC of 4 μg/ml for both fungi). Modal MICs for amphotericin B were 1 μg/ml for both fungi. In general, good essential agreement (EA) values were observed between the methods. However, AMB presented the lowest EA between CLSI-BMD and Etest for C. neoformans VNI and C. gattii VGII (1.6% and 2.56%, respectively, P < .05 for both). Considering the proposed Cryptococcus spp. epidemiological cutoff values, more than 97% of the studied isolates were categorized as wild-type for the azoles. However, the high frequency of C. neoformans VNI isolates in the population described here that displayed non-wild-type susceptibility to AMB is noteworthy. Epidemiological surveillance of the antifungal resistance of cryptococcal strains is relevant due to the potential burden and the high lethality of cryptococcal meningitis in the Amazon region.

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