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1.  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
2.  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
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.  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
5.  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
6.  Fluconazole Resistance Patterns in Candida Species that Colonize Women with HIV Infection 
The Women’s Interagency HIV Study was established in 1993 to study the natural history of HIV disease among women in the United States. It currently has enrolled 2,895 women testing positive for HIV infection and 972 women without HIV infection recruited from 6 national metropolitan locations. The clinical database information collected for each HIV-positive individual included CD4 cell counts, viral load, and antiviral treatment to evaluate HIV prognosis and related conditions in women.
To provide a baseline for fluconazole treatment prospects in women who test positive for HIV infection. As part of the ongoing Women’s Interagency HIV Study project, we investigated the fluconazole susceptibility of Candida spp. isolated from women with HIV in comparison to volunteer women without HIV. The implication of antifungal treatment on fluconazole susceptibility was evaluated by reviewing antifungal medication use for the past 2 years in each participant. In addition, genotyping of Candida spp. at oral and vaginal sites was monitored for 4 months in 9 patients.
In a cohort of 59 women with HIV and 24 women without HIV, colonization by Candida albicans and non-albicans species of the oral and vaginal sites was first determined. Fluconazole susceptibility was surveyed in vitro according to Clinical and Laboratory Standards Institute protocol. Antifungal drug treatment history was investigated for each patient to correspond with fluconazole susceptibility. Finally, series of isolates from several patients were followed for resistance and susceptibility. Their lineage was verified by genotyping multilocus sequence typing (MLST).
A total of 280 Candida strains were recovered from oral and vaginal swabs of women with and without HIV infection. We found that patients with HIV were colonized with Candida spp. more frequently than women without HIV. The percent of isolates that were susceptibility dose dependent or resistant to fluconazole was higher in Candida glabrata compared with C. albicans isolates, but higher for C. albicans than other published data. Resistance was noted to be more common in vaginal sites. Fluconazole resistance in either species was not associated with relative CD4 cell counts or viral load. However an association with systemic application of fluconazole and resistance was noted.
Systemic antifungal therapy, including a vaginal topical regimen in women with HIV infection correlated with reduced fluconazole susceptibility of oral and vaginal isolates. Genotype profiling has disclosed that a majority of isolates from the same individual are clustered together, suggesting the likelihood of an original strain with some microevolution. We observed a change from a susceptibility dose dependent to a resistant phenotype of isolates in 2 women with HIV infection, even though no treatments were received during the 4-month study and the prior 2 years.
PMCID: PMC4209509  PMID: 25352939
Candida spp; fluconazole resistance; HIV-positive women
7.  Antifungal Activities of R-135853, a Sordarin Derivative, in Experimental Candidiasis in Mice 
The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 μg/ml, respectively. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 μg/ml. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against experimental murine hematogenous candidiasis induced by C. albicans when it was administered by both the subcutaneous and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body weight/dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. Subcutaneous administration of R-135853 exhibited dose-dependent efficacy against experimental murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, respectively. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.
PMCID: PMC538903  PMID: 15616275
8.  Cross-species discovery of syncretic drug combinations that potentiate the antifungal fluconazole 
The authors screen for compounds that show synergistic antifungal activity when combined with the widely-used fungistatic drug fluconazole. Chemogenomic profiling explains the mode of action of synergistic drugs and allows the prediction of additional drug synergies.
The authors screen for compounds that show synergistic antifungal activity when combined with the widely-used fungistatic drug fluconazole. Chemogenomic profiling explains the mode of action of synergistic drugs and allows the prediction of additional drug synergies.
Chemical screens with a library enriched for known drugs identified a diverse set of 148 compounds that potentiated the action of the antifungal drug fluconazole against the fungal pathogens Cryptococcus neoformans, Cryptococcus gattii and Candida albicans, and the model yeast Saccharomyces cerevisiae, often in a species-specific manner.Chemogenomic profiles of six confirmed hits in S. cerevisiae revealed different modes of action and enabled the prediction of additional synergistic combinations; three-way synergistic interactions exhibited even stronger synergies at low doses of fluconazole.The synergistic combination of fluconazole and the antidepressant sertraline was active against fluconazole-resistant clinical fungal isolates and in an in vivo model of Cryptococcal infection.
Rising fungal infection rates, especially among immune-suppressed individuals, represent a serious clinical challenge (Gullo, 2009). Cancer, organ transplant and HIV patients, for example, often succumb to opportunistic fungal pathogens. The limited repertoire of approved antifungal agents and emerging drug resistance in the clinic further complicate the effective treatment of systemic fungal infections. At the molecular level, the paucity of fungal-specific essential targets arises from the conserved nature of cellular functions from yeast to humans, as well as from the fact that many essential yeast genes can confer viability at a fraction of wild-type dosage (Yan et al, 2009). Although only ∼1100 of the ∼6000 genes in yeast are essential, almost all genes become essential in specific genetic backgrounds in which another non-essential gene has been deleted or otherwise attenuated, an effect termed synthetic lethality (Tong et al, 2001). Genome-scale surveys suggest that over 200 000 binary synthetic lethal gene combinations dominate the yeast genetic landscape (Costanzo et al, 2010). The genetic buffering phenomenon is also manifest as a plethora of differential chemical–genetic interactions in the presence of sublethal doses of bioactive compounds (Hillenmeyer et al, 2008). These observations frame the difficulty of interdicting network functions in eukaryotic pathogens with single agent therapeutics. At the same time, however, this genetic network organization suggests that judicious combinations of small molecule inhibitors of both essential and non-essential targets may elicit additive or synergistic effects on cell growth (Sharom et al, 2004; Lehar et al, 2008). Unbiased screens for drugs that synergistically enhance a specific bioactive effect, but which are not themselves individually active—termed a syncretic combination—are one means to substantially elaborate chemical space (Keith et al, 2005). Indeed, compounds that enhance the activity of known agents in model yeast and cancer cell line systems have been identified both by focused small molecule library screens and by computational methods (Borisy et al, 2003; Lehar et al, 2007; Nelander et al, 2008; Jansen et al, 2009; Zinner et al, 2009).
To extend the stratagem of chemical synthetic lethality to clinically relevant fungal pathogens, we screened a bioactive library of known drugs for synergistic enhancers of the widely used fungistatic drug fluconazole against the clinically relevant pathogens C. albicans, C. neoformans and C. gattii, as well as the genetically tractable budding yeast S. cerevisiae. Fluconazole is an azole drug that inhibits lanosterol 14α-demethylase, the gene product of ERG11, an essential cytochrome P450 enzyme in the ergosterol biosynthetic pathway (Groll et al, 1998). We identified 148 drugs that potentiate the antifungal action of fluconazole against the four species. These syncretic compounds had not been previously recognized in the clinic as antifungal agents, and many acted in a species-specific manner, often in a potent fungicidal manner.
To understand the mechanisms of synergism, we interrogated six syncretic drugs—trifluoperazine, tamoxifen, clomiphene, sertraline, suloctidil and L-cycloserine—in genome-wide chemogenomic profiles of the S. cerevisiae deletion strain collection (Giaever et al, 1999). These profiles revealed that membrane, vesicle trafficking and lipid biosynthesis pathways are targeted by five of the synergizers, whereas the sphingolipid biosynthesis pathway is targeted by L-cycloserine. Cell biological assays confirmed the predicted membrane disruption effects of the former group of compounds, which may perturb ergosterol metabolism, impair fluconazole export by drug efflux pumps and/or affect active import of fluconazole (Kuo et al, 2010; Mansfield et al, 2010). Based on the integration of chemical–genetic and genetic interaction space, a signature set of deletion strains that are sensitive to the membrane active synergizers correctly predicted additional drug synergies with fluconazole. Similarly, the L-cycloserine chemogenomic profile correctly predicted a synergistic interaction between fluconazole and myriocin, another inhibitor of sphingolipid biosynthesis. The structure of genetic networks suggests that it should be possible to devise higher order drug combinations with even greater selectivity and potency (Sharom et al, 2004). In an initial test of this concept, we found that the combination of a non-synergistic pair drawn from the membrane active and sphingolipid target classes exhibited potent three-way synergism with a low dose of fluconazole. Finally, the combination of sertraline and fluconazole was active in a G. mellonella model of Cryptococcal infection, and was also efficacious against fluconazole-resistant clinical isolates of C. albicans and C. glabrata.
Collectively, these results demonstrate that the combinatorial redeployment of known drugs defines a powerful antifungal strategy and establish a number of potential lead combinations for future clinical assessment.
Resistance to widely used fungistatic drugs, particularly to the ergosterol biosynthesis inhibitor fluconazole, threatens millions of immunocompromised patients susceptible to invasive fungal infections. The dense network structure of synthetic lethal genetic interactions in yeast suggests that combinatorial network inhibition may afford increased drug efficacy and specificity. We carried out systematic screens with a bioactive library enriched for off-patent drugs to identify compounds that potentiate fluconazole action in pathogenic Candida and Cryptococcus strains and the model yeast Saccharomyces. Many compounds exhibited species- or genus-specific synergism, and often improved fluconazole from fungistatic to fungicidal activity. Mode of action studies revealed two classes of synergistic compound, which either perturbed membrane permeability or inhibited sphingolipid biosynthesis. Synergistic drug interactions were rationalized by global genetic interaction networks and, notably, higher order drug combinations further potentiated the activity of fluconazole. Synergistic combinations were active against fluconazole-resistant clinical isolates and an in vivo model of Cryptococcus infection. The systematic repurposing of approved drugs against a spectrum of pathogens thus identifies network vulnerabilities that may be exploited to increase the activity and repertoire of antifungal agents.
PMCID: PMC3159983  PMID: 21694716
antifungal; combination; pathogen; resistance; synergism
9.  In Vitro and In Vivo Antifungal Activities of TAK-456, a Novel Oral Triazole with a Broad Antifungal Spectrum 
TAK-456 is a novel oral triazole compound with potent and broad-spectrum in vitro antifungal activity and strong in vivo efficacy against Candida albicans and Aspergillus fumigatus. TAK-456 inhibited sterol synthesis of C. albicans and A. fumigatus by 50% at 3 to 11 ng/ml. TAK-456 showed strong in vitro activity against clinical isolates of Candida spp., Aspergillus spp., and Cryptococcus neoformans, except for Candida glabrata. The MICs at which 90% of the isolates tested were inhibited byTAK-456, fluconazole, itraconazole, voriconazole, and amphotericin B were 0.25, 4, 0.5, 0.13, and 0.5 μg/ml, respectively, for clinical isolates of C. albicans and 1, >64, 0.5, 0.5, and 0.5 μg/ml, respectively, for clinical isolates of A. fumigatus. Therapeutic activities of TAK-456 and reference triazoles against systemic lethal infections caused by C. albicans and A. fumigatus in mice were investigated by orally administering drugs once daily for 5 days, and efficacies of the compounds were evaluated by the prolongation of survival. In normal mice, TAK-456 and fluconazole were effective against infection caused by fluconazole-susceptible C. albicans at a dose of 1 mg/kg. In transiently neutropenic mice, therapeutic activity of TAK-456 at 1 mg/kg of body weight against infection with the same strain was stronger than those at 1 mg/kg of fluconazole. TAK-456 was effective against infections with two strains of fluconazole-resistant C. albicans at a dose of 10 mg/kg. TAK-456 also expressed activities similar to or higher than those of itraconazole against the infections caused by two strains of A. fumigatus in neutropenic mice at a dose of 10 mg/kg. These results suggest that TAK-456 is a promising candidate for development for the treatment of candidiasis and aspergillosis in humans.
PMCID: PMC127141  PMID: 11959573
10.  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
11.  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.
PMCID: PMC151753  PMID: 12543666
12.  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.
PMCID: PMC148960  PMID: 12499165
13.  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
14.  Efficacy of D0870 compared with those of itraconazole and amphotericin B in two murine models of invasive aspergillosis. 
D0870 is a novel azole antifungal compound. It was compared with conventional amphotericin B and itraconazole therapy in two murine models of invasive aspergillosis, one a systemic nonimmunocompromised mouse model and the other a temporarily neutropenic mouse respiratory model. D0870 was given orally and achieved measurable concentrations in serum approximately proportional to the daily dose with accumulation over time if it was given twice daily. Amphotericin B at 3.3 mg/kg of body weight was given intraperitoneally for four to six doses, and itraconazole was given orally in a cyclodextrin suspension at 5 to 50 mg/kg daily or twice daily (BID). The duration of therapy varied from 7 to 14 days. In the nonimmunocompromised mouse model, D0870 at 25 mg/kg BID was slightly inferior to amphotericin B and itraconazole with regard to mortality, with a median survival of 20 days for the three groups (P = 0.03 compared with amphotericin B). However, D0870 at 25 mg/kg BID was inferior to amphotericin B (but not itraconazole) with respect to renal culture (P = 0.01) and brain culture (P = 0.0001) results. Only amphotericin B was statistically superior to controls with regard to mortality. In the neutropenic mouse respiratory model, D0870 at 50 mg/kg/day was superior to amphotericin B, itraconazole, and controls with regard to mortality. D0870 at both 25 and 50 mg/kg/day was statistically superior to controls with regard to lung culture results (P = 0.004 to 0.04). A second experiment with a higher inoculum showed that no drug regimen was effective in that model. In all models low doses and concentrations of D0870 in serum were ineffective. D0870 has some efficacy for the treatment of invasive aspergillosis when it is given at modest doses.
PMCID: PMC162830  PMID: 7486923
15.  In vitro and in vivo antifungal activities of D0870, a new triazole agent. 
Antimicrobial Agents and Chemotherapy  1993;37(11):2412-2417.
In vitro and in vivo antifungal activities of D0870 were evaluated in comparison with those of fluconazole. D0870, which is the R-enantiomer of ICI195,739, was found to be the mycologically active enantiomer by comparing the activities of D0870 with those of M16355 (S-enantiomer of ICI195,739). D0870 showed a broad spectrum of antifungal activity and MICs and minimum antibiotic concentrations 4- to 2,000-fold lower in synthetic amino acid medium (fungal) agar than those of fluconazole for various fungi. Although MICs of D0870 were affected by variation of the test conditions, such as type of medium, inoculum size of fungi, supplementation with fetal bovine serum, and pH of medium, they were consistently much lower than those of fluconazole under any condition. In vivo activities of D0870 in the systemic infection models with Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in normal mice and in the mice immunosuppressed with cyclophosphamide or cortisone acetate were 2- to 7-fold and 3- to 89-fold greater than those of fluconazole, respectively. In these infection models in immunosuppressed mice, the therapeutic efficacy of D0870 was almost equivalent to that in normal mice, whereas the efficacy of fluconazole was 2- to 50-fold lower than that in normal mice.
PMCID: PMC192400  PMID: 8285626
16.  Candidiasis (oropharyngeal) 
BMJ Clinical Evidence  2013;2013:1304.
Candida is a fungus present in the mouths of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, and corticosteroid use. In most people, untreated candidiasis persists for months or years unless associated risk factors are treated or eliminated. In neonates, spontaneous cure of oropharyngeal candidiasis usually occurs after 3 to 8 weeks.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent and treat oropharyngeal candidiasis in: adults undergoing treatments that cause immunosuppression; infants and children; people with dentures; and people with HIV infection? Which antifungal regimens reduce the risk of acquiring resistance to antifungal drugs? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 47 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: antifungals (absorbed, partially or topically absorbed, or non-absorbed; for example, imidazole [ketoconazole, clotrimazole, toiconazole, miconazole], polyene [amphotericin B, nystatin], triazole [fluconazole, itraconazole], melaleuca and posaconazole), intermittent or continuous prophylaxis, or treatment, and denture hygiene.
Key Points
Opportunistic infection with the fungus Candida albicans causes painful red or white lesions of the oropharynx, which can affect taste, speech, and the act of eating. Candida is present in the mouth of up to 60% of healthy people, but overt infection is associated with immunosuppression, diabetes, broad-spectrum antibiotics, corticosteroid use, haematinic deficiencies, and denture wear.
In people with immunosuppression following cancer treatment, absorbed (ketoconazole, itraconazole, or fluconazole) or partially absorbed antifungal drugs (miconazole, clotrimazole) prevent oropharyngeal candidiasis compared with placebo or non-absorbed antifungal drugs. We don't know whether antifungal treatment is effective in this group. Non-absorbed antifungal drugs (nystatin or amphotericin B) may be no more effective than placebo at preventing candidiasis.We don't know whether antifungal prophylaxis is effective in adults having tissue transplants, as we found few studies.
CAUTION: there have been drug safety alerts that oral ketoconazole can cause severe liver injury, adrenal gland problems, can lead to harmful drug interactions (, and that the benefits do not outweigh the risks in treating fungal infections ( It has been suspended in some countries and restrictions placed on its use in others.
Prophylaxis with fluconazole is more effective than oral nystatin or amphotericin B at preventing candidiasis in immunocompromised infants and children, while treatment with fluconazole and miconazole increases cure rates compared with nystatin in both immunocompromised and immunocompetent infants and children.
Antifungal drugs may increase clinical improvement or cure in people with oropharyngeal candidiasis caused by wearing dentures. We don't know whether denture hygiene or removing dentures at night reduces the risk of developing oropharyngeal candidiasis.
Daily or weekly prophylaxis with fluconazole or itraconazole reduces the incidence of candidiasis in people with HIV infection. Prophylaxis with nystatin may not be effective. Topical treatments with clotrimazole lozenges and miconazole buccal slow-release tablets may be as effective as oral tablets/suspensions of oral antifungals (fluconazole/itraconazole/ketoconazole) at reducing symptoms of candidiasis in people with HIV infection.A single dose of fluconazole (750 mg) may be as effective as a 14-day course of fluconazole in reducing symptoms of candidiasis in people with HIV infection.
Resistance to antifungal drugs, particularly azole drugs, is an increasing problem. Continuous prophylaxis with antifungal agents may not increase the risk of developing antifungal resistance compared with intermittent prophylaxis, but it may be no more effective at reducing the number of attacks in people with HIV infection, the majority of whom were receiving highly active antiretroviral treatment (HAART).
PMCID: PMC3821534  PMID: 24209593
17.  Efficacy of the Clinical Agent VT-1161 against Fluconazole-Sensitive and -Resistant Candida albicans in a Murine Model of Vaginal Candidiasis 
Vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC) remain major health problems for women. VT-1161, a novel fungal CYP51 inhibitor which has potent antifungal activity against fluconazole-sensitive Candida albicans, retained its in vitro potency (MIC50 of ≤0.015 and MIC90 of 0.12 μg/ml) against 10 clinical isolates from VVC or RVVC patients resistant to fluconazole (MIC50 of 8 and MIC90 of 64 μg/ml). VT-1161 pharmacokinetics in mice displayed a high volume of distribution (1.4 liters/kg), high oral absorption (73%), and a long half-life (>48 h) and showed rapid penetration into vaginal tissue. In a murine model of vaginal candidiasis using fluconazole-sensitive yeast, oral doses as low as 4 mg/kg VT-1161 significantly reduced the fungal burden 1 and 4 days posttreatment (P < 0.0001). Similar VT-1161 efficacy was measured when an isolate highly resistant to fluconazole (MIC of 64 μg/ml) but fully sensitive in vitro to VT-1161 was used. When an isolate partially sensitive to VT-1161 (MIC of 0.12 μg/ml) and moderately resistant to fluconazole (MIC of 8 μg/ml) was used, VT-1161 remained efficacious, whereas fluconazole was efficacious on day 1 but did not sustain efficacy 4 days posttreatment. Both agents were inactive in treating an infection with an isolate that demonstrated weaker potency (MICs of 2 and 64 μg/ml for VT-1161 and fluconazole, respectively). Finally, the plasma concentrations of free VT-1161 were predictive of efficacy when in excess of the in vitro MIC values. These data support the clinical development of VT-1161 as a potentially more efficacious treatment for VVC and RVVC.
PMCID: PMC4538529  PMID: 26124165
18.  Effect of pH on In Vitro Susceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use 
The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility 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. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90 for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0.
PMCID: PMC3294902  PMID: 22232293
19.  Association of Fluconazole Area under the Concentration-Time Curve/MIC and Dose/MIC Ratios with Mortality in Nonneutropenic Patients with Candidemia▿  
The present study tested in vitro susceptibility of Candida bloodstream isolates to fluconazole to determine if the ratio of the fluconazole area under the concentration-time curve (AUC) or weight-normalized daily dose (dosewn) to MIC correlated with mortality. Fluconazole susceptibility and outcome data were determined for 77 patients with a positive Candida blood culture between 2002 and 2005. The most commonly isolated Candida species were C. albicans (64%), C. glabrata (14%), C. parapsilosis (8%), C. tropicalis (6%), and C. lusitaniae (4%). Only two isolates were classified as fluconazole resistant by the CLSI M27-A2 method. Fluconazole MICs were highest against C. glabrata relative to other Candida species. Overall the crude mortality assessed at hospital discharge was 19.4% (n = 15). Mortality rates by species were as follows: C. albicans, 16.3%; C. glabrata, 36.4%; C. parapsilosis, 0%; C. tropicalis, 0%; C. lusitaniae, 33.3%. A mortality rate of 50% was noted among patients infected with nonsusceptible isolates (MIC ≥ 16 μg/ml) compared to 18% for patients infected with susceptible (MIC ≤ 8 μg/ml) isolates (P = 0.17). The fluconazole dosewn/MIC (24-h) values were significantly higher for the 62 survivors (13.3 ± 10.5 [mean ± standard deviation]) compared to the 15 nonsurvivors (7.0 ± 8.0) (P = 0.03). The fluconazole AUC/MIC (24 h) values also trended higher for survivors (775 ± 739) compared to nonsurvivors (589 ± 715) (P = 0.09). These data support the dose-dependent properties of fluconazole. Underdosing fluconazole against less-susceptible Candida isolates has the potential to increase the risk of mortality associated with candidemia.
PMCID: PMC1797664  PMID: 17101684
20.  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
21.  Microdilution in vitro Antifungal Susceptibility Patterns of Candida Species, From Mild Cutaneous to Bloodstream Infections 
Candida species, as opportunistic organisms, can cause various clinical manifestations, ranging from mild cutaneous infections to systemic candidiasis in otherwise healthy individuals. Remarkably, the incidence and mortality rates of candidemia have significantly increased worldwide, even after advances in medical interventions and the development of novel antifungal drugs.
Given the possible resistance to antifungal agents, susceptibility testing can be useful in defining the activity spectrum of antifungals and determining the appropriate treatment regime.
Materials and Methods
The in vitro susceptibilities of molecularly identified Candida strains (n = 150) belonging to seven species recovered from clinical specimens, including vaginal, cutaneous, sputum, bronchoalveolar lavage (BAL), and blood samples, were determined for six antifungal drugs (amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, and caspofungin), based on the clinical and laboratory standards institute’s M27-A3 and M27-S4 documents.
Candida albicans was the most frequently isolated species (44.66%), followed by non-albicans Candida, including C. glabrata (20%), C. parapsilosis (13.33%), C. krusei (8%), C. tropicalis (7.3%), C. dubliniensis (4%), and C. africana (3.33%). Posaconazole had the lowest geometric mean minimum inhibitory concentration (MIC) (0.0122 µg/ml), followed by amphotericin B (0.0217 µg/mL), voriconazole (0.1022 µg/mL), itraconazole (0.1612 µg/mL), caspofungin (0.2525 µg/mL), and fluconazole (0.4874 µg/mL) against all isolated Candida species. Candida africana and C. parapsilosis were significantly more susceptible to fluconazole, compared to C. albicans and other Candida species (P < 0.001). However, their clinical effectiveness in the treatment of Candida infections remains to be determined.
These findings highlight the importance of precise and correct species identification of clinical yeast isolates via molecular approaches, and of monitoring the antifungal susceptibility of Candida species recovered from clinical sources. Laboratories should consider routine MIC testing of C. glabrata isolates collected from sterile sites. Surveillance studies of Candida species and new analyses of antifungal treatment outcomes will allow more informed determinations of the value of these drugs in the antifungal armamentarium.
PMCID: PMC5035436  PMID: 27679703
Candidiasis; Antifungal Susceptibility; Candida Species
22.  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
23.  In Vivo Activity of Amphotericin B Lipid Complex in Immunocompromised Mice against Fluconazole-Resistant or Fluconazole-Susceptible Candida tropicalis 
Antimicrobial Agents and Chemotherapy  2000;44(10):2664-2671.
We compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates of Candida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalis for which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P = <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P = 0.006). In the fluconazole-resistant C. tropicalis model (MIC, 128 μg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P = <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P = <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P = 0.02) in all models at reducing C. tropicalis counts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalis at all doses tested.
PMCID: PMC90132  PMID: 10991841
24.  Correlation between In Vitro and In Vivo Antifungal Activities in Experimental Fluconazole-Resistant Oropharyngeal and Esophageal Candidiasis 
Journal of Clinical Microbiology  2000;38(6):2369-2373.
Oropharyngeal and esophageal candidiasis (OPEC) is a frequent opportunistic mycosis in immunocompromised patients. Azole-resistant OPEC is a refractory form of this infection occurring particularly in human immunodeficiency virus (HIV)-infected patients. The procedures developed by the Antifungal Subcommittee of the National Committee for Clinical Laboratory Standards (NCCLS) are an important advance in standardization of in vitro antifungal susceptibility methodology. In order to further understand the relationship between NCCLS methodology and antifungal therapeutic response, we studied the potential correlation between in vitro susceptibility to fluconazole and in vivo response in a rabbit model of fluconazole-resistant OPEC. MICs of fluconazole were determined by NCCLS methods. Three fluconazole-susceptible (FS) (MIC, ≤0.125 μg/ml) and three fluconazole-resistant (FR) (MIC, ≥64 μg/ml) isolates of Candida albicans from prospectively monitored HIV-infected children with OPEC were studied. FR isolates were recovered from children with severe OPEC refractory to fluconazole, and FS isolates were recovered from those with mucosal candidiasis responsive to fluconazole. Fluconazole at 2 mg/kg of body weight/day was administered to infected animals for 7 days. The concentrations of fluconazole in plasma were maintained above the MICs for FS isolates throughout the dosing interval. Fluconazole concentrations in the esophagus were greater than or equal to those in plasma. Rabbits infected with FS isolates and treated with fluconazole had significant reductions in oral mucosal quantitative cultures (P < 0.001) and tissue burden of C. albicans in tongue, soft palate, and esophagus (P < 0.001). In comparison, rabbits infected with FR isolates were unresponsive to fluconazole and had no reduction in oral mucosal quantitative cultures or tissue burden of C. albicans versus untreated controls. We conclude that there is a strong correlation between in vitro fluconazole susceptibility by NCCLS methods and in vivo response to fluconazole therapy of OPEC due to C. albicans.
PMCID: PMC86806  PMID: 10835005
25.  Candidiasis (vulvovaginal) 
BMJ Clinical Evidence  2010;2010:0815.
Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of alternative or complementary treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of treating a male sexual partner to resolve symptoms and prevent recurrence in non-pregnant women with symptomatic acute vulvovaginal candidiasis? What are the effects of alternative or complementary treatments for symptomatic recurrent vulvovaginal candidiasis in non-pregnant women? What are the effects of treating a male sexual partner in non-pregnant women with symptomatic recurrent vulvovaginal candidiasis? What are the effects of treating asymptomatic non-pregnant women with a positive swab for candidiasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 61 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alternative or complementary treatments; douching; drug treatments; garlic; intravaginal preparations (boric acid, nystatin, imidazoles, tea tree oil); oral fluconazole; oral itraconazole; treating a male sexual partner; and yoghurt containing Lactobacillus acidophilus (oral or vaginal).
Key Points
Vulvovaginal candidiasis is characterised by vulval itching and abnormal "cheese-like" or watery vaginal discharge. Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.Risk factors include pregnancy, diabetes mellitus, and systemic antibiotics. Incidence increases with the onset of sexual activity, but associations with different types of contraceptives are unclear.Recurrent symptoms are common, but are caused by candidiasis in only one third of cases.
Intravaginal imidazoles reduce symptoms of acute vulvovaginal candidiasis in non-pregnant women. Intravaginal imidazoles (butoconazole, clotrimazole, miconazole) reduce symptoms compared with placebo and all seem to have similar efficacy compared with each other. RCTs suggest that single-dose regimens may be as effective as multiple-dose regimens.Intravaginal imidazoles and oral fluconazole or itraconazole seem equally effective in treating acute attacks.
Intravaginal nystatin reduces symptoms compared with placebo, but we don't know how it compares with intravaginal imidazoles or oral fluconazole or itraconazole.
The benefits of other intravaginal treatments, to treat acute attacks or prevent recurrence, remain unclear, and some may be associated with serious adverse effects. We found no RCT evidence assessing intravaginal boric acid or tea tree oil.We found no RCT evidence assessing garlic or yoghurt, used intravaginally or orally.We found no RCT evidence on efficacy of douching, but it is associated with serious adverse effects such as PID and infections, endometritis, and ectopic pregnancy. Oral fluconazole and itraconazole are likely to be beneficial in preventing recurrence of infection. Treating the woman's male sexual partner does not reduce symptoms or prevent recurrence in the woman.
PMCID: PMC2907618  PMID: 21718579

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