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Antimicrob Agents Chemother. 2009 October; 53(10): 4540–4541.
Published online 2009 July 27. doi:  10.1128/AAC.00565-09
PMCID: PMC2764185

Efficacy of Albaconazole against Candida albicans in a Vaginitis Model[down-pointing small open triangle]

Abstract

The efficacy of albaconazole (ABC) was evaluated using a murine model of vaginal Candida albicans infection. Both ABC and fluconazole (FLC) were effective in reducing the fungal load from vaginas of infected mice; however, ABC demonstrated encouraging activities against an FLC-resistant strain, with trends toward superiority over FLC in some treatment groups.

Vulvovaginal candidosis is a common infection among healthy women and is caused by members of the genus Candida, predominately Candida albicans (12). Current treatments for Candida vulvovaginitis include a wide range of intravaginal azole preparations, usually administered over several days. No evidence exists to suggest that any one formulation results in a better cure rate; overall cure rates for topical azoles range from 80% to 90% (13). Recent reports on the comparative efficacies of local versus oral treatments of uncomplicated vulvovaginal candidosis found no significant difference between either treatment modality (8); however, many patients prefer the convenience of oral administration. Oral fluconazole (FLC), a triazole, with its marked in vitro activity against Candida species, clinical efficacy, and ease of administration, is a convenient alternative to topical therapy in a single-dose regimen (11, 14) and is the most-prescribed treatment for vulvovaginal candidosis.

Albaconazole (ABC) (formerly UR-9825) is also a triazole antifungal molecule, under development by Stiefel Laboratories, Inc. (Coral Gables, FL). ABC has potent and broad-spectrum antifungal activity, with good in vitro activity against yeast (4, 6, 9), dermatophytes (3), and some filamentous and opportunistic fungi, such as Aspergillus spp., Paecilomyces spp., and Chaetomium spp. (2). ABC also has activity against the protozoon Trypanosoma cruzi (15).

In the present study, we compared the effectiveness of ABC and FLC for the treatment of experimental C. albicans vaginitis caused by an FLC-resistant isolate.

C. albicans isolate 03-2718 has been used previously in our laboratory for studies of vaginal candidosis (5). The 48-h MICs of ABC and FLC were 0.5 μg/ml and >64 μg/ml, respectively. This indicates that in vitro, the isolate is resistant to FLC (7). The yeast was grown in sterile bottles, each containing 100 ml of RPMI-1640 with l-glutamine (Hardy Diagnostics, Santa Maria, CA), and incubated for 24 h at 35°C on a gyratory shaker. C. albicans was harvested by centrifugation, and the cells were counted in a hemocytometer. Quantitative cultures by serial dilution were used to confirm the inoculum size.

Five-week-old BALB/c mice (weight, 18 g) were purchased from Harlan Mexico. A total of 10 mice were randomly assigned to each treatment or control group. Mice were housed five per cage and were provided food and water ad libitum. All animal research procedures were approved by the ethics committee of our university. Care, maintenance, and handling of the animals were in accordance with the Mexican government license conditions for animal experimentation. Two confirmatory animal studies were performed.

A previously described model of vaginal candidosis was utilized (1). Three days prior to infection and on day 4 postchallenge, mice were given 0.5 mg of estradiol valerate (Delestrogen, King Pharmaceuticals) subcutaneously to maintain pseudoestrus. On the day of infection, the mice were anesthetized intraperitoneally with 80 mg/kg of body weight ketamine hydrochloride and then inoculated intravaginally with 20 μl of a suspension of 2 × 108/ml CFU of C. albicans isolate 03-2718. The vaginal cavity of each mouse was swabbed (prior to treatment) 1 day after inoculation with C. albicans to ensure infection was consistently distributed among animals (10). Mice were swabbed on day 6 to evaluate the early treatment effects. Each alginate swab was placed in 0.9 ml sterile saline; serial 10-fold dilutions were made, and 100 μl was placed on Sabouraud dextrose agar supplemented with 0.5% (wt/vol) chloramphenicol to quantify the CFU/ml.

ABC (Stiefel Laboratories, Inc., Coral Gables, FL) and FLC (Pfizer, Inc., New York, NY) were obtained in powder form from the manufacturers. ABC was prepared fresh daily and dissolved in 0.2% carboxymethylcellulose (low viscosity) with 1% Tween 80 (Sigma-Aldrich, St. Louis, MO). FLC was dissolved in distilled water. ABC was given by gavage once or twice daily at 5, 10, 20, or 40 mg/kg orally on days 1 through 5 postinoculation. FLC was administered by oral gavage once or twice daily at 20 mg/kg of body weight. All treatments were given in a volume of 0.2 ml. Control mice were infected but received no active treatment; one group received 0.2% carboxymethylcellulose with 1% Tween 80 and another sterile distilled water as vehicle controls.

Comparisons were performed using the Mann-Whitney U test, with significance set at a P value of <0.05.

The effects of ABC were compared with those of FLC for treatment of experimental vaginitis induced by an FLC-resistant isolate of C. albicans. The infection was evaluated 6 days after vaginal inoculation. The drug treatments were administered orally either once or twice daily for five consecutive days (days 1 to 5 postinoculation). Compared with results for vehicle-treated control mice, mice given doses of ABC at ≥20 mg/kg once daily greatly reduced vaginal loads of C. albicans (Table (Table1)1) (P < 0.01 to 0.0001). In addition, twice-daily administration of ABC at ≥10 mg/kg resulted in significant reductions of the vaginal load of C. albicans compared to results for single-dose administration. Oral administration with FLC at 20 mg/kg given once or twice a day significantly reduced the vaginal load of C. albicans (P < 0.008 to 0.001). A significant difference was found between the group that received ABC at 20 mg/kg once daily versus mice which received FLC at 20 mg/kg once daily (P = 0.02). However, there was no statistically significant difference in the fungal burden with the dose of 20 mg/kg twice daily of ABC or FLC (P = 0.07). Sterilization of the vaginal cavity was not observed with either the ABC or FLC regimen.

TABLE 1.
Recovery of C. albicans strain 03-2718 from vaginas of mice treated orally with ABC or FLC

ABC may therefore have a place in the treatment of vulvovaginal candidosis based on data from this in vivo study, which indicate that ABC has relevant activity and an overall greater therapeutic effect against azole-resistant Candida spp. To our knowledge, this is the first report evaluating the efficacy of ABC against C. albicans in a murine model of vaginal infection. Further studies are needed to confirm the clinical relevance of these data.

Acknowledgments

We declare that we have no conflict of interest.

We thank Timothy Raczniak for his helpful suggestions on the manuscript.

Footnotes

[down-pointing small open triangle]Published ahead of print on 27 July 2009.

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