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Antimicrobial Agents and Chemotherapy Jul 2008Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have...
Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have recently been detected and the underlying molecular mechanisms of resistance characterized. Three hundred and ninety-three isolates, including 32 itraconazole-resistant strains, were used to define wild-type populations, epidemiological cutoffs, and cross-resistance between azole drugs. The epidemiological cutoff for itraconazole, voriconazole, and ravuconazole for the wild-type populations of A. fumigatus was < or =1 mg/liter. For posaconazole, the epidemiological cutoff was < or =0.25 mg/liter. Up till now, isolates susceptible to itraconazole have not yet displayed resistance to other azole drugs. Cross-resistance between azole drugs depends on specific mutations in cyp51A. Thus, a substitution of glycine in position 54 of Cyp51A confers cross-resistance between itraconazole and posaconazole. A substitution of methionine at position 220 or a duplication in tandem of a 34-bp fragment in the cyp51A promoter combined with a substitution of leucine at position 98 for histidine confers cross-resistance to all azole drugs tested. The results obtained in this study will help to develop clinical breakpoints for azole drugs and A. fumigatus.
Topics: Amino Acid Substitution; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Cytochrome P-450 Enzyme System; Drug Resistance, Fungal; Fungal Proteins; Genes, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Molecular Epidemiology; Molecular Sequence Data; Pyrimidines; Thiazoles; Triazoles; Voriconazole
PubMed: 18474574
DOI: 10.1128/AAC.00156-08 -
Data in Brief Aug 2020The data have been obtained for tautomers and enantiomers of ATTAF-1 and ATTAF-2 that were developed based on antifungal standard drugs with triazole scaffold. These...
The data have been obtained for tautomers and enantiomers of ATTAF-1 and ATTAF-2 that were developed based on antifungal standard drugs with triazole scaffold. These compounds were docked into the human and fungal lanosterol-14α-demethylase. In order to validate the data, 8 standard triazole antifungal drugs (Fluconazole, Itraconazole, Posaconazole, Ravuconazole, Albaconazole, Voriconazole, Isavuconazole and Efinaconazole) were also docked into the human and fungal lanosterol-14α-demethylase. The binding conformations of these molecules and their interactions with lanosterol-14α-demethylase may inform the development of further small molecule lanosterol-14α-demethylase inhibitors with significant selectivity toward this enzyme. The analysis has done on the basis of type of interactions (bond type and distance). The length of the Fe-N coordination bond for ()-N2-ATTAF-1 and ()-N1-ATTAF-2 complexes is obtained 6.36 and 4.19 Å, respectively and about 2 Å in the other tautomer and enantiomer complexes, reflecting the lower basicity of the N-4 atom in the 1,2,4-triazole ring of ()-N2-ATTAF-1 and ()-N1-ATTAF-2 in comparison with the N-4 atom in the 1,2,4-triazole ring in other tautomers and enantiomers and supporting higher selectivity of ()-N2-ATTAF-1 and ()-N1-ATTAF-2 towards the target CYP51 enzymes vs. human. Interestingly, we have investigated unfavorable interactions (donor-donor) with TRP239 and MET378 for ()-N2-ATTAF-1 and ()-N1-ATTAF-2, respectively. These unfavorable interactions also have been seen in case of posaconazole and isavuconazole. The data presented in this article are related to the research paper entitled " prediction of ATTAF-1 and ATTAF-2 selectivity towards human/fungal lanosterol 14α-demethylase using molecular dynamic simulation and docking approaches".
PubMed: 32671150
DOI: 10.1016/j.dib.2020.105942 -
Antimicrobial Agents and Chemotherapy Mar 2002Ravuconazole (RCZ) was evaluated for efficacy in comparison to fluconazole (FCZ) and itraconazole (ITZ) in murine models of disseminated histoplasmosis. All regimens...
Ravuconazole (RCZ) was evaluated for efficacy in comparison to fluconazole (FCZ) and itraconazole (ITZ) in murine models of disseminated histoplasmosis. All regimens tested prolonged survival (P < 0.05 to 0.0001). At equivalent doses of 50 mg/kg of body weight, RCZ and ITZ were equally effective and RCZ was more effective than FCZ (P = 0.02). Clearance of fungal burden from the livers and spleens of mice showed RCZ and ITZ at doses of 50 mg/kg to be efficacious but not curative. These data indicate that RCZ should be studied further.
Topics: Animals; Antifungal Agents; Colony Count, Microbial; Female; Fluconazole; Histoplasmosis; Itraconazole; Liver; Mice; Spleen; Survival; Survival Analysis; Thiazoles; Triazoles
PubMed: 11850289
DOI: 10.1128/AAC.46.3.922-924.2002 -
Antimicrobial Agents and Chemotherapy Jan 2018and are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because...
and are environmental fungi that cause cryptococcosis, which is usually treated with amphotericin B and fluconazole. However, therapeutic failure is increasing because of the emergence of resistant strains. Because these species are constantly isolated from vegetal materials and the usage of agrochemicals is growing, we postulate that pesticides could be responsible for the altered susceptibility of these fungi to clinical drugs. Therefore, we evaluated the influence of the pesticide tebuconazole on the susceptibility to clinical drugs, morphophysiology, and virulence of and strains. The results showed that tebuconazole exposure caused cross-resistance (CR) between the agrochemical and clinical azoles (fluconazole, itraconazole, and ravuconazole) but not with amphotericin B. In some strains, CR was observed even after the exposure ceased. Further, tebuconazole exposure changed the morphology, including formation of pseudohyphae in H99, and the surface charge of the cells. Although the virulence of both species previously exposed to tebuconazole was decreased in mice, the tebuconazole-exposed colonies recovered from the lungs were more resistant to azole drugs than the nonexposed cells. This CR was confirmed when fluconazole was not able to reduce the fungal burden in the lungs of mice. The tolerance to azoles could be due to increased expression of the gene in both species and of efflux pump genes ( and ) in Our study data support the idea that agrochemical usage can significantly affect human pathogens present in the environment by affecting their resistance to clinical drugs.
Topics: Animals; Antifungal Agents; Cryptococcosis; Cryptococcus gattii; Cryptococcus neoformans; Drug Resistance, Multiple, Fungal; Fluconazole; Fungicides, Industrial; Male; Mice, Inbred C57BL; Microbial Sensitivity Tests; Triazoles; Virulence
PubMed: 29109169
DOI: 10.1128/AAC.01179-17 -
Antimicrobial Agents and Chemotherapy Dec 2001A model of orogastric candidosis in SCID mice, which mimics disease seen in AIDS patients, was used to evaluate ravuconazole in comparison with fluconazole for...
A model of orogastric candidosis in SCID mice, which mimics disease seen in AIDS patients, was used to evaluate ravuconazole in comparison with fluconazole for treatment. Mice were infected orally with Candida albicans and received either no treatment or oral treatment once daily for 12 days with 1, 5, or 25 mg of ravuconazole per kg of body weight per day, 5 or 25 mg of fluconazole per kg per day, or diluent (10% dimethyl sulfoxide in 0.5% carboxymethyl cellulose). The numbers of C. albicans CFU in the esophagus, stomach, small intestine, and cecum on day 25 in mice given no treatment and diluent were equivalent. Both doses of fluconazole significantly reduced numbers of CFU in all four tissues but were equivalent to each other. Ravuconazole showed dose-responsive improvement of clearance of CFU. Ravuconazole at 25 mg/kg was superior in reduction of numbers of CFU in all tissues to controls or 25 mg of fluconazole per kg and to other regimens in at least three tissues. Fluconazole at 25 mg/kg cured no infection in any tissue, whereas 25 mg of ravuconazole/kg cleared infection in all tissues from 50% of mice. Ravuconazole has good efficacy and the potential to cure mucosal candidosis in the absence of a functional immune response.
Topics: Administration, Oral; Animals; Antifungal Agents; Candidiasis, Chronic Mucocutaneous; Digestive System; Dose-Response Relationship, Drug; Female; Mice; Mice, SCID; Microbial Sensitivity Tests; Thiazoles; Triazoles
PubMed: 11709320
DOI: 10.1128/AAC.45.12.3433-3436.2001 -
Japanese Journal of Infectious Diseases May 2020Ravuconazole (RVCZ) is a new human anti-fungal azole drug available in Japan since 2018 and is a broad-spectrum agent that exhibits excellent activity against...
Ravuconazole (RVCZ) is a new human anti-fungal azole drug available in Japan since 2018 and is a broad-spectrum agent that exhibits excellent activity against dermatophytes. In the present study, the in vitro RVCZ susceptibility of clinical isolates of anthropophilic dermatophytes, including Trichophyton interdigitale strains with either low susceptibility to itraconazole (ITCZ) or resistance to terbinafine (TEBR), was investigated using the Clinical & Laboratory Standards Institute M38-A2 test. The MICs of RCVZ for 20 clinical isolates of T. interdigitale were < 0.03125-0.125 mg/L; for 4 clinical isolates of T. rubrum, < 0.03125-0.0625 mg/L; and for 20 clinical isolates of T. tonsurans, < 0.03125 mg/L. Similarly, the MICs of RCVZ for the T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR were also < 0.03125 mg/L. To our knowledge, this is first study to investigate the in vitro RVCZ susceptibility of T. interdigitale strains with either low susceptibility to ITCZ or resistance to TEBR. Our results indicated that RVCZ was the most effective drug against these strains.
Topics: Antifungal Agents; Arthrodermataceae; Dermatomycoses; Drug Resistance, Fungal; Humans; Itraconazole; Microbial Sensitivity Tests; Terbinafine; Thiazoles; Triazoles
PubMed: 31875604
DOI: 10.7883/yoken.JJID.2019.265 -
Antimicrobial Agents and Chemotherapy Feb 2019This work evaluated a serial blood sampling procedure to enhance the sensitivity of duplex real-time quantitative PCR (qPCR) for baseline detection and quantification of... (Randomized Controlled Trial)
Randomized Controlled Trial
This work evaluated a serial blood sampling procedure to enhance the sensitivity of duplex real-time quantitative PCR (qPCR) for baseline detection and quantification of parasitic loads and posttreatment identification of failure in the context of clinical trials for treatment of chronic Chagas disease, namely, DNDi-CH-E1224-001 (ClinicalTrials.gov registration no. NCT01489228) and the MSF-DNDi PCR Sampling Optimization Study (NCT01678599). Patients from Cochabamba ( = 294), Tarija ( = 257), and Aiquile ( = 220) were enrolled. Three serial blood samples were collected at each time point, and qPCR triplicates were tested for each sample. The first two samples were collected during the same day and the third one 7 days later. A patient was considered PCR positive if at least one qPCR replicate was detectable. Cumulative results of multiple samples and qPCR replicates enhanced the proportion of pretreatment sample positivity from 54.8% to 76.2%, 59.5% to 77.8%, and 73.5% to 90.2% in Cochabamba, Tarija, and Aiquile cohorts, respectively. This strategy increased the detection of treatment failure from 72.9% to 91.7%, 77.8% to 88.9%, and 42.9% to 69.1% for E1224 low-, short-, and high-dosage regimens, respectively, and from 4.6% to 15.9% and 9.5% to 32.1% for the benznidazole arm in the DNDi-CH-E1224-001 and MSF-DNDi studies, respectively. The addition of the third blood sample and third qPCR replicate in patients with nondetectable PCR results in the first two samples gave a small, non-statistically significant improvement in qPCR positivity. No change in clinical sensitivity was seen with a blood volume increase from 5 to 10 ml. The monitoring of patients treated with placebo in the DNDi-CH-E1224-001 trial revealed fluctuations in parasitic loads and occasionally nondetectable results. In conclusion, a serial sampling strategy enhanced PCR sensitivity to detecting treatment failure during follow-up and has the potential for improving recruitment capacity in Chagas disease trials, which require an initial positive qPCR result for patient admission.
Topics: Adolescent; Adult; Chagas Disease; DNA, Protozoan; Humans; Middle Aged; Monitoring, Physiologic; Nitroimidazoles; Parasite Load; Placebos; Real-Time Polymerase Chain Reaction; Thiazoles; Treatment Outcome; Triazoles; Trypanocidal Agents; Trypanosoma cruzi; Young Adult
PubMed: 30509941
DOI: 10.1128/AAC.01191-18 -
Antimicrobial Agents and Chemotherapy Oct 2008Two clinical isolates of Aspergillus fumigatus, designated AT and DK, were recently obtained from patients failing caspofungin and itraconazole therapy, respectively.... (Comparative Study)
Comparative Study
Two clinical isolates of Aspergillus fumigatus, designated AT and DK, were recently obtained from patients failing caspofungin and itraconazole therapy, respectively. The isolates were tested by microdilution for susceptibility to itraconazole, voriconazole, posaconazole, ravuconazole, and caspofungin and by Etest for susceptibility to amphotericin B and caspofungin. Susceptibility testing documented that the DK isolate was azole resistant (itraconazole and posaconazole MICs, >4 microg/ml; voriconazole MIC, 2 microg/ml; ravuconazole MIC, 4 microg/ml), and the resistance was confirmed in a hematogenous mouse model, with mortality and the galactomannan index as the primary and secondary end points. Sequencing of the cyp51A gene revealed the M220K mutation, conferring multiazole resistance. The Etest, but not microdilution, suggested that the AT isolate was resistant to caspofungin (MIC, >32 microg/ml). In the animal model, this isolate showed reduced susceptibility to caspofungin. Sequencing of the FKS1 gene revealed no mutations; the enzyme retained full sensitivity in vitro; and investigation of the polysaccharide composition showed that the beta-(1,3)-glucan proportion was unchanged. However, gene expression profiling by Northern blotting and real-time PCR demonstrated that the FKS gene was expressed at a higher level in the AT isolate than in the susceptible control isolate. To our knowledge, this is the first report to document the presence of multiazole-resistant clinical isolates in Denmark and to demonstrate reduced susceptibility to caspofungin in a clinical A. fumigatus isolate with increased expression of the FKS gene. Further research to determine the prevalence of resistance in A. fumigatus worldwide, and to develop easier and reliable tools for the identification of such isolates in routine laboratories, is warranted.
Topics: Adult; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Base Sequence; Caspofungin; Cytochrome P-450 Enzyme System; DNA, Fungal; Disease Models, Animal; Drug Resistance, Multiple, Fungal; Echinocandins; Fungal Proteins; Genes, Fungal; Glucosyltransferases; Humans; In Vitro Techniques; Itraconazole; Lipopeptides; Mice; Microbial Sensitivity Tests; Mutation
PubMed: 18644959
DOI: 10.1128/AAC.00190-08 -
Journal of Clinical Microbiology May 2006During 2003, a total of 1,397 Candida isolates, 73 Aspergillus isolates, 53 Cryptococcus neoformans isolates, and 25 other fungal isolates from infected, normally...
During 2003, a total of 1,397 Candida isolates, 73 Aspergillus isolates, 53 Cryptococcus neoformans isolates, and 25 other fungal isolates from infected, normally sterile, body sites in patients hospitalized in North America, Europe, and Latin America were studied as a component of the longitudinal SENTRY Antimicrobial Surveillance Program. The MICs for seven antifungal agents were determined in a central laboratory (JMI Laboratories, North Liberty, IA) using testing methods promulgated by the Clinical and Laboratory Standards Institute (formerly the National Committee for Clinical Laboratory Standards). The rank order of Candida spp. occurrence was as follows: C. albicans (48.7%), C. parapsilosis (17.3%), C. glabrata (17.2%), C. tropicalis (10.9%), C. krusei (1.9%), and other Candida spp. (4.0%). C. albicans accounted for 51.5, 47.8, and 36.5% of candidal infections in North America, Europe, and Latin America, respectively. Ravuconazole, voriconazole, and fluconazole were highly active against C. albicans, C. parapsilosis, and C. tropicalis, with both former agents being more potent (MIC at which 90% of the isolates tested are inhibited [MIC90] of < or =0.008 to 0.12 microg/ml) than fluconazole (MIC90 of 0.5 to 2 microg/ml). C. glabrata isolates were less susceptible to these agents, with MIC90s of 1, 1, and 64 microg/ml, respectively. Ravuconazole and voriconazole were the most active agents tested against C. krusei (MIC90 of 0.5 microg/ml). Among Aspergillus spp., A. fumigatus was the most commonly (71.2% of isolates) recovered species; 96.2, 96.2, 84.6, and 11.5% of strains were inhibited by < or =1 microg/ml of ravuconazole, voriconazole, itraconazole, and amphotericin B, respectively. Of the antifungal agents tested, ravuconazole and voriconazole displayed the greatest spectrum of activity against pathogenic Candida and Aspergillus spp., regardless of geographic origin. These results extend upon previous findings from SENTRY Program reports (1997 to 2000), further characterizing species composition as seen in local clinical practice and demonstrating the potent activity of selected, newer triazole antifungal agents.
Topics: Antifungal Agents; Aspergillosis; Aspergillus; Candida; Candidiasis; Drug Resistance, Fungal; Europe; Humans; Latin America; Microbial Sensitivity Tests; North America; Population Surveillance
PubMed: 16672407
DOI: 10.1128/JCM.44.5.1782-1787.2006 -
Antimicrobial Agents and Chemotherapy Apr 2003In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under...
In vivo studies have characterized the pharmacodynamic characteristics of the triazole fluconazole. These investigations demonstrated that the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (24-h AUC/MIC ratio) is the critical pharmacokinetic/pharmacodynamic (PK/PD) parameter associated with treatment efficacy. Further analysis demonstrated that a fluconazole 24-h AUC/MIC ratio of 20 to 25 was predictive of treatment success in both experimental models and clinical trials. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the time course activity of the new triazole ravuconazole. The PK/PD parameters (percent time above the MIC, AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by organism number in kidney cultures after 24 and 72 h of therapy. Ravuconazole kinetics and protein binding were performed in neutropenic infected mice. Peak/dose and AUC/dose values ranged from 0.03 to 0.04 and 0.30 to 0.34, respectively. Serum elimination half-life ranged from 3.9 to 4.8 h. Protein binding was 95.8%. Single-dose postantifungal effect studies demonstrated prolonged suppression of organism regrowth after serum ravuconazole levels had fallen below the MIC. Treatment efficacies with the five dosing intervals studied were similar, supporting the argument for the AUC/MIC ratio as the PK/PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (AUC/MIC ratio, R(2) = 91%; peak/MIC ratio, R(2) = 85%; percent time above the MIC, R(2) = 47 to 65%). Similar studies were conducted with seven additional C. albicans isolates with various ravuconazole susceptibilities (MIC, 0.016 to 0.12 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The ravuconazole free-drug AUC/MIC ratios were similar for all of the organisms studied (10 to 36; mean +/- SD = 20.3 +/- 8.2; P = 0.43). These free-drug AUC/MIC ratios are similar to those observed for fluconazole in this model.
Topics: Animals; Antifungal Agents; Area Under Curve; Candidiasis; Disease Models, Animal; Female; Humans; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Thiazoles; Triazoles
PubMed: 12654646
DOI: 10.1128/AAC.47.4.1193-1199.2003