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1.  Activities of D0870, a novel triazole, against Candida lusitaniae and Trichosporon beigelii in experimental murine infections. 
Candida lusitaniae and Trichosporon beigelii may cause life-threatening infections in the immunocompromised host and may be resistant to amphotericin B. We assessed the activities of a new triazole, D0870, against one T. beigelii and four C. lusitaniae strains, in comparison with those of fluconazole and amphotericin B. Immunosuppressed CF1 mice, intravenously infected with each fungal strain, received 3 days of therapy with oral D0870 (5 or 25 mg/kg of body weight daily), fluconazole (5 to 50 mg/kg daily), or parenteral amphotericin B (1 or 2 mg/kg daily). Survival was significantly prolonged and kidney fungus titers were reduced in mice treated with D0870 compared with untreated mice (P < or = 0.05). Treatment with D0870 was significantly more effective than that with amphotericin B or fluconazole in animals infected with two of the C. lusitaniae strains and equally effective for the remaining two C. lusitaniae strains and the T. beigelii strain. Fluconazole and amphotericin B failed to improve the survival of mice infected with one and two C. lusitaniae strains, respectively. D0870 was active against all the organisms tested, including those resistant to fluconazole and amphotericin B.
PMCID: PMC162585  PMID: 7726538
2.  Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice. 
D0870 is a recently developed triazole with characteristics of a broad spectrum of activity and slow clearance by nonrenal mechanisms. Herein we have evaluated the efficacy of D0870, alone and combined with flucytosine, in a murine model of disseminated Candida tropicalis infection. Four isolates of C. tropicalis were evaluated. Two were highly susceptible in vitro to fluconazole, and two were resistant to fluconazole. All were highly susceptible to flucytosine and D0870. Animals were pretreated with 5-fluorouracil 1 day before infection because C. tropicalis has reduced virulence in immunocompetent mice. This was done to render them neutropenic for > 10 days. Mice were infected intravenously and treated orally with D0870 or fluconazole, alone or combined with flucytosine. Survival and tissue burden of the spleen and kidneys were used to evaluate the efficacy of antifungal therapy. Fluconazole was less effective for treatment of resistant C. tropicalis than susceptible C. tropicalis. D0870 was more potent than fluconazole and was effective in fluconazole-resistant isolates. Flucytosine was consistently effective when used alone but did not consistently add to the benefit of D0870 or fluconazole. D0870 has potential in treatment of candidiasis caused by C. tropicalis, including fluconazole-resistant isolates.
PMCID: PMC162655  PMID: 7785997
3.  In vitro activity of a new antifungal triazole, D0870, against Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. 
Antimicrobial Agents and Chemotherapy  1994;38(11):2553-2556.
We investigated the in vitro activity of a new antifungal triazole, D0870, against 100 Candida albicans isolates from the oral cavities of patients infected with human immunodeficiency virus by using a broth macrodilution method following the recommendations provided by the National Committee for Clinical Laboratory Standards (document M27-P). All of the isolates were chosen from C. albicans isolates already tested for fluconazole susceptibility by the procedure of the National Committee for Clinical Laboratory Standards. Fifty isolates were considered fluconazole susceptible (MICs, < or = 4 micrograms/ml), and 50 isolates were considered fluconazole resistant (MICs, > or = 8 micrograms/ml). The in vitro data demonstrated that D0870 had good activity against isolates tested; for 90% of all strains of C. albicans, MICs were 0.5 micrograms/ml. However, the D0870 MICs for the fluconazole-susceptible isolates were lower than those for the fluconazole-resistant isolates; MICs for 50 and 90% of the isolates tested were < or = 0.0078 and 0.06 micrograms/ml, respectively, for fluconazole-susceptible isolates and 0.25 and 2 micrograms/ml, respectively, for fluconazole-resistant isolates (P < 0.001). Our data suggest that this new triazole could represent a valid alternative in the treatment of oral candidiasis in human immunodeficiency virus-infected patients.
PMCID: PMC188240  PMID: 7872746
4.  Pharmacokinetics of Two Multiple-Dosing Regimens of D0870 in Human Immunodeficiency Virus-Positive Patients: a Phase I Study 
D0870 is a triazole with a broad antifungal spectrum, and it has been shown to have both in vitro and in vivo activities against wild-type and fluconazole-resistant strains of Candida albicans. Twenty-two human immunodeficiency virus (HIV)-positive male subjects were enrolled in an open, nonrandomized trial investigating the pharmacokinetics of two different dosing regimens of D0870 and assessing the safety of multiple oral doses of D0870 in HIV-positive subjects and their ability to tolerate multiple oral doses. Nine subjects received an initial loading dose of 50 mg, followed by four once-daily maintenance doses of 10 mg. A further nine subjects received an initial 200-mg loading dose followed by four daily maintenance doses of 25 mg. All subjects were fasting. A single loading dose of 50 mg of D0870 resulted in a mean maximum concentration in serum (Cmax) of 107 ± 32 ng/ml. Concentrations in plasma were maintained by the 10-mg once-daily dosing regimen as seen by the similar values of the area under the concentration-time curve from 0 to 24 h following dosing on days 1 and 5 and a mean accumulation ratio close to unity (0.90). The terminal plasma half-life of D0870 in plasma following dosing on day 5 ranged from 23 to 85 h (mean, 49 h). A single loading dose of 200 mg of D0870 resulted in a Cmax of 431 ± 186 ng/ml. Concentrations in plasma were again maintained by the 25-mg daily dosing regimen, with the mean accumulation ratio being close to unity (1.17). The terminal half-life of D0870 in plasma following dosing on day 5 of phase II of the study ranged from 34 to 137 h (mean, 71 h). In addition, the concentrations achieved in the plasma of these HIV-positive subjects were similar to the values predicted from simulations based on data derived from normal, healthy subjects. D0870 was well tolerated. No serious adverse events were experienced during the course of the study, and all volunteers completed the trial. A total of 15 adverse events were reported, but none were considered to be related to the administration of D0870 and all had resolved by the end of the trial. No changes in the hematology, clinical chemistry, or urinalysis parameters were considered to be related to dosing with D0870. No clinically significant changes in the electrocardiogram parameters were noted during the trial. The data generated in this trial support further investigation of these regimens with HIV-positive subjects with fluconazole-susceptible or -resistant oropharyngeal candidosis.
PMCID: PMC105564  PMID: 9559805
5.  Fluconazole Susceptibility of Vaginal Isolates Obtained from Women with Complicated Candida Vaginitis: Clinical Implications 
Despite considerable evidence of azole resistance in oral candidiasis due to Candida species, little is known about the azole susceptibilities of the genital tract isolates responsible for vaginitis. The fluconazole susceptibilities of vaginal isolates obtained during a multicenter study of 556 women with complicated Candida vaginitis were determined by evaluating two fluconazole treatment regimens. Of 393 baseline isolates of Candida albicans, 377 (96%) were highly susceptible to fluconazole (MICs, <8 μg/ml) and 14 (3.6%) were resistant (MICs, ≥64 μg/ml). Following fluconazole therapy, one case of in vitro resistance developed during 6 weeks of monitoring. In accordance with the NCCLS definition, in vitro fluconazole resistance correlated poorly with the clinical response, although a trend of a higher mycological failure rate was found (41 versus 19.6% on day 14). By using an alternative breakpoint of 1 μg/ml, based upon the concentrations of fluconazole achievable in vaginal tissue, no significant differences in the clinical and mycological responses were observed when isolates (n = 250) for which MICs were ≤1 μg/ml were compared with isolates (n = 30) for which MICs were >1 μg/ml, although a trend toward an improved clinical outcome was noted on day 14 (odds ratio, >2.7; 95% confidence interval, 0.91, 8.30). Although clinical failure was uncommon, symptomatic recurrence or mycological relapse almost invariably occurred with highly sensitive strains (MICs, <1.0 μg/ml). In vitro fluconazole resistance developed in 2 of 18 initially susceptible C. glabrata isolates following fluconazole exposure. Susceptibility testing for women with complicated Candida vaginitis appears to be unjustified.
doi:10.1128/AAC.47.1.34-38.2003
PMCID: PMC148960  PMID: 12499165
6.  Efficacy of the triazole D0870 in a murine model of systemic histoplasmosis. 
The efficacy of D0870 was studied in a murine model of systemic histoplasmosis and was compared with that of fluconazole. All regimens of D0870 (1 or 10 mg/kg of body weight given daily or 1, 10, or 100 mg/kg given every other day) and 100 mg of fluconazole per kg given daily provided complete protection from lethality. Comparison of the number of viable Histoplasma capsulatum yeasts remaining in the spleen or liver indicated that D0870 was superior to fluconazole in clearing and curing infection. D0870 was 10- to 100-fold more efficacious than fluconazole in the treatment of experimental histoplasmosis.
PMCID: PMC162626  PMID: 7793893
7.  Efficacy of CS-758, a Novel Triazole, against Experimental Fluconazole-Resistant Oropharyngeal Candidiasis in Mice 
The therapeutic efficacy of CS-758, a novel triazole, was evaluated against experimental murine oropharyngeal candidiasis induced by Candida albicans with various susceptibilities to fluconazole. Against infections induced by strains with various susceptibilities to fluconazole, the efficacy of fluconazole was strongly correlated with the MIC of fluconazole, as measured by the NCCLS method, and agreed with the NCCLS interpretive breakpoints, suggesting that the efficacies of new drugs could be predicted by using this model. The results of the fungal burden study corresponded with the results of the histopathological study. CS-758 exhibited potent in vitro activity (MICs, 0.004 to 0.06 μg/ml) against the strains used in this murine model including fluconazole-susceptible dose-dependent and fluconazole-resistant strains (fluconazole MICs, 16 to 64 μg/ml). CS-758 exhibited excellent efficacy against the infections induced by all the strains including a fluconazole-resistant strain, and the reductions in viable cell counts were significant at 10 and 50 mg/kg of body weight/dose. Fluconazole was not effective even at 50 mg/kg/dose against infections induced by a fluconazole-resistant strain (fluconazole MIC, 64 μg/ml). These results suggest that CS-758 is a promising compound for the treatment of oropharyngeal candidiasis including fluconazole-refractory infections.
doi:10.1128/AAC.47.2.601-606.2003
PMCID: PMC151753  PMID: 12543666
8.  In vitro activity of D0870 compared with those of other azoles against fluconazole-resistant Candida spp. 
We compared the in vitro activity of a new triazole, D0870, with those of fluconazole, itraconazole, and ketoconazole against 41 clinical isolates of fluconazole-resistant Candida belonging to nine different species. The 50% inhibitory concentrations (IC50s) were determined by a microdilution method with morpholinopropanesulfonic acid (MOPS)-buffered RPMI medium and an inoculum of approximately 10(4) yeasts per ml. After incubation for 48 h at 37 degrees C the optical density at 550 nm was measured. The IC50 was the lowest drug concentration which reduced the optical density at 550 nm by > or = 50% compared with that for a drug-free control. D0870 had significant activity against many of the isolates. Its activity was comparable to that of ketoconazole, slightly superior to that of itraconazole, and markedly superior to that of fluconazole against Candida albicans. Against Candida glabrata, Candida krusei, and Candida inconspicua, it had activity similar to those of itraconazole and ketoconazole but had activity superior to that of fluconazole. D0870 IC50s for some isolates were increased. This may be due to cross-resistance mechanisms because the IC50s of both itraconazole and ketoconazole for these isolates were often high. When IC50s and IC80s were compared there was a marked organism and drug variation. With C. glabrata much higher endpoints for itraconazole were observed when an IC80 endpoint was used. For C. albicans there was also a significant shift upward in endpoints for itraconazole and ketoconazole. Values were changed little when IC50 and IC80 endpoints of D0870 were compared. For 35 of 41 isolates tested the D0870 IC50 was less than the 2.5-mg/liter breakpoint threshold proposed previously. Therefore, D0870 may be a useful agent for the therapy of infections caused by fluconazole-resistant Candida spp.
PMCID: PMC162644  PMID: 7785986
9.  Comparison of in vivo activity of fluconazole with that of amphotericin B against Candida tropicalis, Candida glabrata, and Candida krusei. 
Fluconazole (UK-49,858) is a new oral bis-triazole antifungal agent with demonstrated activity against Candida albicans. Because of the increasing importance of infections due to other species of Candida, we studied the efficacy of fluconazole in a rat model of established systemic candidiasis, using clinical isolates of C. tropicalis, C. glabrata, and C. Krusei. In normal rats, oral fluconazole at both 20 and 80 mg/kg per day for 7 days reduced both kidney and liver titers of C. tropicalis and C. glabrata compared with those in control animals and was only slightly inferior to amphotericin B. Both fluconazole and amphotericin B were ineffective in reducing kidney titers of C. krusei, but amphotericin B was more effective than fluconazole in reducing liver titers. Fluconazole showed no increased efficacy at the higher dose of 80 mg/kg per day compared with 20 mg/kg per day in any experiment. These results suggest that oral fluconazole may be useful in the treatment of established disseminated candidiasis caused by species other than C. albicans. Further in vivo studies are needed, however, to define minimum effective doses and length of therapy and to test additional Candida isolates.
PMCID: PMC172680  PMID: 2554797
10.  Fluconazole treatment of Candida albicans infection in mice: does in vitro susceptibility predict in vivo response? 
Antimicrobial Agents and Chemotherapy  1995;39(10):2197-2200.
A series of fluconazole-susceptible and-fluconazole resistant Candida albicans fungal isolates were used to infect mice intravenously. Mice were treated with varying doses of fluconazole beginning one day after infection. For all of the 6 fluconazole-susceptible isolates, fluconazole was highly effective at <0.25 mg/kg of body weight twice daily. By contrast, fluconazole was less effective in at least 6 of 10 fluconazole-resistant isolates and was ineffective at > or = 40 mg/kg twice daily in 4 fluconazole-resistant isolates. Although the correlation is not precise, in vitro susceptibility testing of C. albicans can predict in vivo response to fluconazole.
PMCID: PMC162913  PMID: 8619566
11.  Fluconazole-induced Fixed Drug Eruption 
Triazole antifungals are commonly used in the treatment of oral, esophageal, and vaginal candidiasis. Fluconazole is frequently prescribed as the therapy modality for vaginal fungal infections. On rare occasions, fluconazole has been shown to cause fixed drug eruptions. Lesions of fixed drug eruptions vary in size and number, but have the same general appearance and symptoms. The authors report a case of fluconazole-induced fixed drug eruption in a 24-year-old woman with recurrent vaginal candidiasis. The lesion was initially diagnosed as a spider bite. Topical and oral provocation tests with fluconazole were performed. Topical provocation with petroleum/fluconazole and dimethyl sulfoxide/fluonazole were both negative. Oral provocation was positive, thus confirming the diagnosis of fluconazole-induced fixed drug eruption.
PMCID: PMC3613274  PMID: 23556037
12.  Activity of fluconazole (UK 49,858) and ketoconazole against Candida albicans in vitro and in vivo. 
Fluconazole (UK 49,858), a new orally administered bis-triazole, was compared with ketoconazole for activity in synthetic broth dilution susceptibility tests against Candida albicans and also in treatment of experimental systemic candidal infections in rats. In vitro studies indicated that fluconazole activity is less sensitive to acidic medium than is that of ketoconazole. At physiologic pH, fluconazole was approximately 16-fold less active than ketoconazole against 35 representative isolates of C. albicans. Two additional isolates (K-1 and K-3) recovered from patients who had failed ketoconazole therapy were 32- to 64-fold more resistant than the median of each drug for other isolates. In animal studies, fluconazole was very effective in prolonging survival of rats infected with a representative candidal strain. With an inoculum sufficient to kill 29 of 38 sham-treated animals, only 1 of 18 animals treated with 0.5 mg of fluconazole per kg per day died compared with 13 of 20 animals treated with 10.0 mg of ketoconazole per kg per day. However, when similar fluconazole treatment was administered to rats infected with the more resistant strain, K-1, no prolongation of survival was found. Thus, in vivo and in vitro results between strains correlated well for fluconazole. However, in comparing results between drugs, ketoconazole was 16-fold more active in vitro and fluconazole was 20-fold more active in vivo. This discrepancy may be due to drug distribution, modes of drug metabolism, or other pharmacologic differences between the two agents.
PMCID: PMC180572  PMID: 3022641
13.  Activities of the triazole D0870 in vitro and against murine blastomycosis. 
The novel triazole D0870 was tested for in vitro activity, as well as in vivo in a murine model of pulmonary blastomycosis. In vitro, D0870 had inhibitory and fungicidal activity against Blastomyces dermatitidis (MIC = 0.048 microgram/ml; minimal fungicidal concentration = 0.097 microgram/ml). In vivo, D0870 was approximately 100-fold more active than fluconazole on the basis of milligrams per kilogram of body weight given once daily (QD) against blastomycosis. D0870 doses of both 1 or 10 mg/kg given QD and 10 or 100 mg/kg given every other day prolonged survival (P < 0.001) over fluconazole (100 mg/kg given QD). A D0870 dosage of 1 mg/kg QD was equivalent to fluconazole given at 100 mg/kg in reduction of lung burdens of B. dermatitidis, and D0870 administered at 10 mg/kg QD and 10 or 100 mg/kg every other day caused greater reduction (P < 0.001). However, D0870 at 100 mg/kg given QD was lethally toxic, whereas fluconazole at 100 mg/kg was not. These results indicate that D0870 is an effective therapy for murine blastomycosis and should be further tested.
PMCID: PMC187927  PMID: 8517710
14.  Antifungal drug susceptibilities of oral Candida dubliniensis isolates from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro. 
Candida dubliniensis is a recently described species of Candida associated with oral candidiasis in human immunodeficiency virus (HIV)-infected individuals. Nineteen oral isolates of C. dubliniensis recovered from 10 HIV-positive and 4 HIV-negative individuals and one vaginal isolate from an additional HIV-negative subject were assessed for fluconazole susceptibility by broth microdilution (BMD), hyphal elongation assessment, and Etest. The susceptibilities of these 20 isolates to itraconazole and amphotericin B and of 10 isolates to ketoconazole were also determined by BMD only. Sixteen of the C. dubliniensis isolates were susceptible to fluconazole (MIC range, 0.125 to 1.0 microgram ml-1), and four (recovered from two AIDS patients) were fluconazole resistant (MIC range, 8 to 32 micrograms ml-1). Fluconazole susceptibility data obtained by hyphal elongation assessment correlated well with results obtained by BMD, but the corresponding Etest MIC results were one to four times higher. All of the isolates tested were found to be sensitive to itraconazole, ketoconazole, and amphotericin B. Sequential exposure of two fluconazole-sensitive (MIC, 0.5 microgram ml-1) C. dubliniensis isolates to increasing concentrations of fluconazole in agar medium resulted in the recovery of derivatives which expressed a stable fluconazole-resistant phenotype (BMD-determined MIC range, 16 to 64 micrograms ml-1), even after a minimum of 10 consecutive subcultures on drug-free medium and following prolonged storage at -70 degrees C. The clonal relationship between the parental isolates and their respective fluconazole-resistant derivatives was confirmed by genomic DNA fingerprinting and karyotype analysis. The results of this study demonstrate that C. dubliniensis is inherently susceptible to commonly used antifungal drugs, that fluconazole resistance does occur in clinical isolates, and that stable fluconazole resistance can be readily induced in vitro following exposure to the drug.
PMCID: PMC163761  PMID: 9056003
15.  Replacement of Candida albicans with C. dubliniensis in Human Immunodeficiency Virus-Infected Patients with Oropharyngeal Candidiasis Treated with Fluconazole 
Journal of Clinical Microbiology  2002;40(9):3135-3139.
Candida dubliniensis is an opportunistic yeast that has been increasingly implicated in oropharyngeal candidiasis (OPC) in human immunodeficiency virus (HIV)-infected patients but may be underreported due to its similarity with Candida albicans. Although most C. dubliniensis isolates are susceptible to fluconazole, the inducibility of azole resistance in vitro has been reported. Thus, the use of fluconazole prophylaxis in the treatment of these patients may have contributed to the increasing rates of isolation of C. dubliniensis. In this study, yeast strains were collected from the oral cavities of HIV-infected patients enrolled in a longitudinal study of OPC. Patients received fluconazole for the suppression or treatment of OPC, and isolates collected at both study entry and end of study were chosen for analysis. Samples were plated on CHROMagar Candida medium for initial isolation and further identified by Southern blot analysis with the species-specific probes Ca3 (for C. albicans) and Cd25 (for C. dubliniensis). Fluconazole MICs were determined by using NCCLS methods. At study entry, susceptible C. albicans isolates were recovered from oral samples in 42 patients who were followed longitudinally (1 to 36 months). C. albicans strains from 12 of these patients developed fluconazole resistance (fluconazole MIC, ≥64 μg/ml). C. dubliniensis was not detected at end of study in any of these patients. Of the remaining 30 patients, eight (27%) demonstrated a replacement of C. albicans by C. dubliniensis when a comparison of isolates obtained at baseline and those from the last culture was done. For the 22 of these 30 patients in whom no switch in species was detected, the fluconazole MICs for initial and end-of-study C. albicans isolates ranged from 0.125 to 2.0 μg/ml. For the eight patients in whom a switch to C. dubliniensis was detected, the fluconazole MICs for C. dubliniensis isolates at end of study ranged from 0.25 to 64 μg/ml: the fluconazole MICs for isolates from six patients were 0.25 to 2.0 μg/ml and those for the other two were 32 and 64 μg/ml, respectively. In conclusion, a considerable number of patients initially infected with C. albicans strains that failed to develop fluconazole resistance demonstrated a switch to C. dubliniensis. C. dubliniensis in this setting may be underestimated due to lack of identification and may occur due to the impact of fluconazole on the ecology of oral yeast species.
doi:10.1128/JCM.40.9.3135-3139.2002
PMCID: PMC130753  PMID: 12202543
16.  SCH 51048, a new antifungal triazole active against hematogenous Candida krusei infections in neutropenic mice. 
Candida krusei is increasingly recognized as an opportunistic pathogen in immunocompromised patients and is inherently resistant to fluconazole. We tested the in vivo efficacy of SCH 51048, an investigational antifungal triazole, in experimental hematogenous murine infection caused by two C. krusei isolates and compared its activity with those of amphotericin B and fluconazole. CF1 mice were immunosuppressed with cyclophosphamide and cortisone acetate and were challenged intravenously with infecting inocula of each C. krusei isolate. Treatment with SCH 51048 (50 or 100 mg/kg of body weight per day orally) or amphotericin B (2 mg/kg/day intraperitoneally) significantly prolonged the survival of infected mice and significantly reduced fungal titers in the kidneys (P < or = 0.05). Treatment with fluconazole (100 mg/kg/day orally) had no effect. Both dosages of SCH 51048 were as effective as amphotericin B in improving survival, but the higher dosage was significantly (P < or = 0.05) better in reducing the fungal burden in the kidneys of infected animals. A dose-dependent response was observed with SCH 51048 treatment, especially in organ clearance. Our results indicate that SCH 51048 is the first triazole that has in vivo activity against experimental infection with C. krusei and deserves further evaluation.
PMCID: PMC162625  PMID: 7793892
17.  In vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients infected with human immunodeficiency virus. 
A broth macrodilution technique, which was performed by following the recommendations provided by the National Committee for Clinical Laboratory Standards (document M27-P), was applied to study the in vitro activity of itraconazole against fluconazole-susceptible and -resistant Candida albicans isolates from the oral cavities of 100 patients infected with human immunodeficiency virus. The in vitro data demonstrated that itraconazole had good activity against the tested isolates; for 90% of all strains of C. albicans, MICs were 1 microgram/ml, and only one isolate was highly resistant to this triazole (MIC, > 16 micrograms/ml). However, the itraconazole MICs for the fluconazole-susceptible isolates were significantly lower than those for the fluconazole-resistant isolates; the MICs for 50 and 90% of the isolates tested were < or = 0.03 and 0.25 microgram/ml, respectively, for the fluconazole-susceptible isolates and 0.5 and 1 microgram/ml, respectively, for the fluconazole-resistant isolates (P = 0.00001). Our findings could be of clinical relevance because human immunodeficiency virus-infected patients who fail fluconazole therapy for oral and/or esophageal candidiasis may require itraconazole at doses higher than those used in standard therapy.
PMCID: PMC284588  PMID: 7979284
18.  In vivo activity of terpinen-4-ol, the main bioactive component of Melaleuca alternifolia Cheel (tea tree) oil against azole-susceptible and -resistant human pathogenic Candida species 
Background
Recent investigations on the antifungal properties of essential oil of Melaleuca alternifolia Cheel (Tea Tree Oil, TTO) have been performed with reference to the treatment of vaginal candidiasis. However, there is a lack of in vivo data supporting in vitro results, especially regarding the antifungal properties of TTO constituents. Thus, the aim of our study was to investigate the in vitro and the in vivo anti-Candida activity of two critical bioactive constituents of TTO, terpinen-4-ol and 1,8-cineole.
Methods
Oophorectomized, pseudoestrus rats under estrogen treatment were used for experimental vaginal infection with azole (fluconazole, itraconazole) -susceptible or -resistant strains of C. albicans. All these strains were preliminarily tested for in vitro susceptibility to TTO, terpinen-4-ol and 1,8-cineole for their antifungal properties, using a modification of the CLSI (formerly NCCLS) reference M27-A2 broth micro-dilution method.
Results
In vitro minimal inhibitory concentrations (MIC90) values were 0.06% (volume/volume) for terpinen-4-ol and 4% (volume/volume) for 1,8-cineole, regardless of susceptibility or resistance of the strains to fluconazole and itraconazole. Fungicidal concentrations of terpinen-4-ol were equivalent to the candidastatic activity. In the rat vaginal infection model, terpinen-4-ol was as active as TTO in accelerating clearance from the vagina of all Candida strains examined.
Conclusion
Our data suggest that terpinen-4-ol is a likely mediator of the in vitro and in vivo activity of TTO. This is the first in vivo demonstration that terpinen-4-ol could control C. albicans vaginal infections. The purified compound holds promise for the treatment of vaginal candidiasis, and particularly the azole-resistant forms.
doi:10.1186/1471-2334-6-158
PMCID: PMC1637110  PMID: 17083732
19.  Emergence of fluconazole-resistant strains of Candida albicans in patients with recurrent oropharyngeal candidosis and human immunodeficiency virus infection. 
Journal of Clinical Microbiology  1994;32(9):2092-2098.
After repeated use of fluconazole for therapy of oropharyngeal candidosis, the emergence of in vitro fluconazole-resistant Candida albicans isolates (MIC, > or = 25 micrograms/ml) together with oral candidosis unresponsive to oral dosages of up to 400 mg of fluconazole were observed in patients with human immunodeficiency virus (HIV) infection. Antifungal susceptibility testing was done by broth microdilution and agar dilution techniques on C. albicans isolates recovered from a cohort of patients with symptomatic HIV infection who were treated repeatedly with fluconazole for oropharyngeal candidosis. In vitro findings did show a gradual increase in the MICs for C. albicans isolates recovered from selected patients with repeated episodes of oropharyngeal candidosis. Primary resistance of C. albicans to fluconazole was not seen. Cross-resistance in vitro occurred between fluconazole and other azoles (ketoconazole, itraconazole), but to a lesser extent. The results of the study suggest that the development of clinical resistance to fluconazole could be clearly correlated to in vitro resistance to fluconazole. Itraconazole may still serve as an effective antifungal agent in patients with HIV infection and oropharyngeal candidosis nonresponsive to fluconazole.
PMCID: PMC263948  PMID: 7814530
20.  Evaluation of Differential Gene Expression in Fluconazole-Susceptible and -Resistant Isolates of Candida albicans by cDNA Microarray Analysis 
Antimicrobial Agents and Chemotherapy  2002;46(11):3412-3417.
The opportunistic fungal pathogen Candida albicans is the major causative agent of oropharyngeal candidiasis (OPC) in AIDS. The development of azoles, such as fluconazole, for the treatment of OPC has proven effective except in cases where C. albicans develops resistance to fluconazole during the course of treatment. In the present study, we used microarray technology to examine differences in gene expression from a fluconazole-susceptible and a fluconazole-resistant well-characterized, clinically obtained matched set of C. albicans isolates to identify genes which are differentially expressed in association with azole resistance. Among genes found to be differentially expressed were those involved in amino acid and carbohydrate metabolism; cell stress, cell wall maintenance; lipid, fatty acid, and sterol metabolism; and small molecule transport. In addition to CDR1, which has previously been demonstrated to be associated with azole resistance, the drug resistance gene RTA3, the ergosterol biosynthesis gene ERG2, and the cell stress genes CRD2, GPX1, and IFD5 were found to be upregulated. Several genes, such as the mitochondrial aldehyde dehydrogenase gene ALD5, the glycosylphosphatidylinositol synthesis gene GPI1, and the iron transport genes FET34 and FTR2 were found to be downregulated. Further study of these differentially regulated genes is warranted to evaluate how they may be involved in azole resistance. In addition to these novel findings, we demonstrate the utility of microarray analysis for studying the molecular mechanisms of drug resistance in pathogenic organisms.
doi:10.1128/AAC.46.11.3412-3417.2002
PMCID: PMC128735  PMID: 12384344
21.  Susceptibility testing of Candida albicans isolated from oropharyngeal mucosa of HIV+ patients to fluconazole, amphotericin B and Caspofungin. killing kinetics of caspofungin and amphotericin B against fluconazole resistant and susceptible isolates 
Brazilian Journal of Microbiology  2009;40(1):163-169.
A clear understanding of the pharmacodynamic properties of antifungal agents is important for the adequate treatment of fungal infections like candidiasis. For certain antifungal agents, the determination of Minimal Fungicidal Concentration (MFC) and time kill curve could be clinically more relevant than the determination of the Minimal Inhibitory Concentration (MIC). In this study, MIC and MFC to fluconazole, amphotericin B and caspofungin against C. albicans isolates and the killing patterns obtained with caspofungin and amphotericin B against susceptible and resistant strains to fluconazole were determined. The results of MICs showed that all C. albicans isolates were highly susceptible to amphotericin B, but two isolates were fluconazole resistant. The comparative analysis between MIC and MFC showed that MFC of fluconazole was fourfold higher than MIC in 41.9% of the C. albicans isolates. Same values of MFC and MIC of amphotericin B and caspofungin were found for 71% of the isolates. Correlation between time kill curves and MFC of amphotericin B and caspofungin against all 4 isolates tested was observed. The caspofungin killing effect was more evident at MFC in 6 hours of incubation than at MIC in this time, suggesting dependence of concentration. The similarity of results of time-kill curve and MFC values indicate that determination of MFC is an alternative for the detection of the fungicidal activity of these drugs.
doi:10.1590/S1517-838220090001000028
PMCID: PMC3768489  PMID: 24031337
Antifungal susceptibility; Candida albicans; Time kill curves
22.  Activities of fluconazole (UK 49,858) and ketoconazole against ketoconazole-susceptible and -resistant Candida albicans. 
We have compared the activities of fluconazole and ketoconazole against ketoconazole-susceptible and -resistant strains of Candida albicans in a neutropenic-site rabbit model. Oral treatment with fluconazole resulted in much higher serum and extravascular concentrations of this antifungal agent than did comparable doses of ketoconazole. Fluconazole had no additional in vivo activity against the ketoconazole-susceptible strains; no fungicidal activity was observed with peak drug levels as high as approximately 75 micrograms/ml in the infection sites. Significant fungistatic activity against the ketoconazole-resistant strains was observed with fluconazole treatment (80 mg/kg), but not with less fluconazole (20 mg/kg) or with ketoconazole (approximately 67 mg/kg). In vitro susceptibility tests separated the ketoconazole-susceptible strains from the ketoconazole-resistant strains, but the results were variable when the resistant strains were tested with fluconazole.
PMCID: PMC172136  PMID: 2834995
23.  Comparative Study of the Effectiveness of Oral Fluconazole and Intravaginal Clotrimazole in the Treatment of Vaginal Candidiasis 
Objective: A study was carried out to compare 3 treatment regimens for vaginal candidiasis.
Methods: A total of 150 women with clinical and mycological evidence of vaginal candidiasis were randomized to receive 50 mg of oral fluconazole daily for 6 days (50 women), a single oral 150 mg dose of fluconazole (50 women), or 100 mg of intravaginal clotrimazole daily for 6 days (50 women). They were assessed at 5–15 days (short-term assessment) and again at 30–60 days (long-term assessment) after the completion of treatment.
Results: Candida species were completely eradicated from the vagina in 88% or 80% in the 6-day oral fluconzaole group, 76% or 70% in the single oral fluconazole group, and 72% or 60% in the intravaginal clotrimazole group at short-term or long-term assessment, respectively. The rates of clinical effectiveness were 92% or 88% in the 6-day oral fluconzaole group, 80% or 76% in the single oral fluconazole group, and 72% or 58% in the intravaginal clotrimazole group at the short-term or long-term assessment, respectively. Treatment-related side effects were not found in any group.
Conclusions: This study suggests that the treatment of vaginal candidiasis with oral fluconazole is effective and that a single oral fluconazole dose might be one choice in the treatment of vaginal candidiasis.
doi:10.1155/S1064744995000238
PMCID: PMC2364408  PMID: 18475414
24.  Clinical Characteristics of Turkish Women with Candida krusei Vaginitis and Antifungal Susceptibility of the C. krusei Isolates  
Objective. Candida krusei causes approximately 1% of vulvovaginal candidiasis (VVC) cases and is naturally resistant to fluconazole. Antifungal testing may be required if C. krusei vaginitis fails to respond to non-fluconazole therapy, particularly in patients with recurrent infections. Design. We investigated the clinical characteristics and antifungal susceptibility profile of vaginal C. krusei isolates. Between 2009 and 2012, we identified 560 unrelated Candida spp.-positive vaginal cultures, of which 28 (5.0%) were C. krusei. These isolates were analyzed according to host factors and the clinical forms of VVC, and their in vitro susceptibility to 10 antifungal agents was tested using a reference microdilution method. Results. We observed that perineal laceration and increased age (>50 years) were significant predictors of C. krusei in vaginal samples (P < 0.05). All isolates were susceptible to amphotericin B, caspofungin, ketoconazole, and miconazole. Additionally, susceptible dose-dependent and resistant rates were found for fluconazole as 42.9% and 57.1%, respectively. Remarkably, only 42.9% and 67.9% of the isolates were susceptible to itraconazole and voriconazole, respectively. Conclusions. Understanding local susceptibility patterns, especially those of non-C. albicans Candida species, can significantly aid in the selection of an effective antifungal agent. The in vivo response of C. krusei vaginitis to various antifungal therapeutics remains unknown and requires further research.
doi:10.1155/2013/698736
PMCID: PMC3874352  PMID: 24396265
25.  In vitro activities of voriconazole (UK-109,496) against fluconazole-susceptible and -resistant Candida albicans isolates from oral cavities of patients with human immunodeficiency virus infection. 
The susceptibility of Candida albicans to a new antifungal triazole, voriconazole (UK-109,496), was investigated in 105 isolates obtained from the oral cavities of patients with human immunodeficiency virus (HIV) infection to study this drug's activity against fluconazole-susceptible and -resistant isolates. MICs were determined by a broth microdilution technique according to document M27-T from the National Committee for Clinical Laboratory Standards and by using a broth microdilution technique and a synthetic high-resolution medium. These antifungal susceptibility testing methods showed high levels of agreement (93% for fluconazole and 86% for voriconazole). Data from in vitro studies showed that voriconazole has good activity against fluconazole-susceptible and -resistant C. albicans isolates; the MICs at which 90% of all isolates were inhibited were 0.19 to 0.39 microgram/ml. We found that for isolates for which fluconazole MICs were high, voriconazole MICs were proportionally higher than those for fluconazole-susceptible C.albicans (P < 0.001). Pretreatment isolates from six patients with fluconazole-refractory esophageal candidiasis were included in the study. For these isolates the MICs were < or = 0.39 microgram/ml, and all patients responded to voriconazole. These results suggest that voriconazole is effective even in the treatment of fluconazole-refractory esophageal candidiasis and should be studied further to determine its clinical relevance in patients with HIV infection.
PMCID: PMC163753  PMID: 9055995

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