Yoh Hayasaki

Penetration of Ravuconazole, a New Triazole Antifungal, into Rat Tissues

Ravuconazole (BMS 207147, ER-30346) is a long-lasting triazole antifungal agent active against a broad spectrum of fungal pathogens including non-albicans Candida, Aspergillus, Cryptococcus and key dermatophytic fungi. The penetration of ravuconazole into rat tissues was examined. Fifty-five 7-week-old specific pathogen free female rats were used in this study. Plasma, lung and uterus tissue of rats were taken at 1, 2, 4, 8, 12, 16, 24, 32, 48, 60, and 72 h (n = 5) after oral administration of 10 mg/kg of ravuconazole. The quantitative assays of ravuconazole by HPLC after the extraction with diethylether were conducted for each tissue sample homogenate. tmax, t 1/2, and Cmax of ravuconazole is 8 h, 16.9 h and 1.68 µg/ml, respectively. The concentrations of ravuconazole in rat uterus and lung tissues were 2–to 6 times higher than the corresponding blood concentrations. The ratio of plasma to lung levels of ravuconazole was superior to the published data of other azoles. Considering its antifungal spectrum, ravuconazole would thus be a good candidate for treatment of deep-seated fungal infections caused by Candida, Aspergillus and Cryptococcus.

Comparative Study on the Effectiveness of Antifungal Agents in Different Regimens against Vaginal Candidiasis

Objective: A study was carried out to compare three treatment regimens for vaginal candidiasis. Methods: A total of 150 women with clinical and mycological evidence of vaginal candidiasis were randomized to receive daily a 200-mg dose of oral itraconazole for 3 days (50 women), a single oral 150 mg dose of fluconazole (50 women), or daily 100 mg dose of intravaginal clotrimazole 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 discontinuation of the treatment. Results: At the short-term or long-term assessment, Candida species were completely eradicated from the vagina in 80 or 74% in the 3-day oral itraconazole group, 76 or 70% in the single oral fluconazole group, and 72 or 60% in the intravaginal clotrimazole group, respectively. The rates of clinical effectiveness were 92 or 88% in the 3-day oral itraconazole group, 80 or 76% in the single oral fluconazole group, and 72 or 58% in the intravaginal clotrimazole group, respectively. Treatment-related side effects were not found in any group. Conclusions: Our study suggests that the treatment of vaginal candidiasis with oral itraconazole or oral fluconazole would be effective and that an oral itraconazole or fluconazole therapy might be one choice in the treatment of vaginal candidiasis.

Effect of ravuconazole, a new triazole antifungal, in a rat intraabdominal abscess model

Background: Ravuconazole (BMS-207147) is a long-lasting triazole antifungal agent active against a broad spectrum of fungal pathogens including non-albicans Candida, Aspergillus, Cryptococcus and key dermatophytic fungi. Methods: The efficacy of ravuconazole was evaluated using an experimental intraabdominal abscess model in rats caused by Candida albicans (E81022). Two hundred milligrams of cyclophosphamide per kilogram was injected intraperitoneally into 40 rats. Four days (96 h) after the injection of cyclophosphamide, a mixture of C. albicans and autoclaved rat cecal contents [C. albicans 1.7 × 108 colony-forming units/rat] was inoculated into the peritoneal cavity. The rats were divided into four groups: ravuconazole treated, fluconazole treated, itraconazole treated and untreated. Each antifungal was given orally at a dose of 10 mg/kg twice a day for 5 days. On the day after the last administration, the rats were dissected and the viable fungi in the abscesses were determined. The number of C. albicans in each abscess was determined by a quantitative culture technique. Results: Ravuconazole inhibited abscess formation and significantly decreased the viable cell counts in abscesses in comparison with the untreated group. It’s efficacy was at least equivalent to fluconazole and itraconazole against this pathogen. The rank order of potency (inhibition) was ravuconazole > itraconazole > fluconazole. Conclusion: Taking into consideration the antifungal spectrum of ravuconazole, which includes non-albicans Candida as well as C. albicans and Aspergillus, it is suggested that ravuconazole would be a good agent for the treatment of fungal peritonitis.

Current Status and Fluconazole Treatment of Pelvic Fungal Gynecological Infections

The incidence of opportunistic fungal infections has recently been increasing in many clinical fields. Fluconazole is commonly used against systemic fungal infections. The present study was undertaken to investigate the current status and the efficacy of fluconazole in pelvic fungal gynecological infections. Thirty-eight patients aged 36–72 years old diagnosed with pelvic peritonitis with positive fungal culture in pelvic ascites were enrolled in this study and given fluconazole treatment. Forty-two pathogens were isolated from the 38 assessable patients. The predominant pathogen was Candida albicans with an incidence of 61.9% (26/42). Others included non-albicans Candida species amounting to 38.1% (16/42): 19.0% (8/42) Candida glabrata, 7.1% (3/42) Candida tropicalis, 7.1% (3/42) Candida parapsilosis and 4.8% (2/42) Candida krusei. The clinical cure rate at the end of fluconazole treatment was assessed as 30/38 (78.9%), and the fungal eradication rate as 26/42 (61.9%). Each rate was 29/38 (76.3%) and 26/42 (61.9%), respectively, at 1 week after the treatment, while the eradication rate of C. albicans and non-albicans species was 20/26 (76.9%) and 6/16 (37.5%), respectively. There was no adverse effect exept for slight elevations of GOT, GPT and LDH observed in 1 patient (2.6%), which returned to normal after the treatment. It seems there may be an increasing trend of non-albicans species in pelvic fungal gynecological infection, against which fluconazole appears to be rather effective.

In vitro Bactericidal Activities of Antimicrobial Agents and Morphologic Changes on Prevotella bivia

Prevotella bivia is common in pelvic inflammatory diseases. Parenteral antimicrobial agents have been widely used against those infections. We investigated the bactericidal activities of three cephalosporins, i.e. cefluprenam (CFLP), ceftazidime (CAZ) and cefotaxime (CTX) and of two other antimicrobial agents, i.e. clindamycin (CLDM) and imipenem (IPM) against P. bivia. We also investigated the in vitro morphological changes induced by these agents in P. bivia. Cephalosporins exhibited bactericidal activities against P. bivia and induced time- and concentration-dependent morphological changes in P. bivia (filamentation). CLDM and IPM also had bactericidal activities, but induced different morphologic alterations: formation of spheroblasts and lysis. These results confirm the fact that each antimicrobial agent has characteristic aspects.

Effects of crude herbal ingredients on serum levels of inflammatory cytokines in a rat uterine endometritis model

The effects of crude herbal ingredients that constitute Juzen-taihoto and Ryutan-shakan-to on serum levels of inflammatory cytokines in a rat uterine endometritis model were investigated. Extracts of Glycyrrhizae Radix, Cnidii Rhizoma, Rehmanniae Radix, Alismatis Rhizoma, Cinnamomi Cortex, Hoelen, and Angelicae Radix significantly inhibited serum levels of the inflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6. The decreased serum levels of inflammatory cytokines appeared to support a previous report on decreased uterine bacterial counts in the rat uterine endometritis model. Based on these results, it is thus speculated that herbal medicines might enhance the host-defense mechanism by decreasing the production of inflammatory cytokines.

Adequate levofloxacin treatment schedules for uterine cervicitis caused by Chlamydia trachomatis

The in vivo efficacy of levofloxacin (LVFX), one of the most standard new quinolone antimicrobial agents, in the different treatment schedules of Chlamydia trachomatis uterine cervicitis in women was evaluated. Cervical C. trachomatis was detected by polymerase chain reaction. LVFX at a dosage of 300 mg t.i.d. for 5, 7 and 14 days was orally administered to 18, 33 and 35 Japanese patients, respectively. The eradication rate and the recurrence rate in the different treatment schedules of C. trachomatis were evaluated. The eradication rate in 5-, 7- or 14-day cases was 44.4, 87.9 or 88.6%, respectively. The recurrence rate of 5-, 7- or 14-day cases was 50.0, 0 or 0%, respectively. Seven-day treatment with LVFX is adequate for and effective in C. trachomatis uterine cervicitis.

In vitro activities of pazufloxacin, a novel injectable quinolone, against bacteria causing infections in obstetric and gynecological patients.

T-3762 is an injectable new quinolone with a broad spectrum of antibacterial activity. Pazufloxacin (T-3761) is an active form of T-3762. The minimal inhibitory concentrations (MICs) of pazufloxacin for 50% of the clinical isolates tested were 3.13 µg/ml for Streptococcus agalactiae, 6.25 µg/ml for Gardnerella vaginalis, 0.025 µg/ml for Escherichia coli, 0.78 µg/ml for Pseudomonas aeruginosa, 6.25 µg/ml for Peptostreptococcus magnus, 6.25 µg/ml for Bacteroides fragilis and 12.5 µg/ml for Prevotella bivia. The MICs of T-3762 for 90% of the clinical isolates tested were 3.13 µg/ml for S. agalactiae, 6.25 µg/ml for G. vaginalis, 0.10 µg/ml for E. coli, 12.5 µg/ml for P. aeruginosa, 25 µg/ml for P. magnus, 12.5 µg/ml for B. fragilis and 25 µg/ml for P. bivia. The results of this study suggest that, subject to confirmation by clinical trials, T-3762, in combination with an agent with reliable activity against anaerobic bacteria, is suitable as an empirical therapy of patients with obstetric and gynecological infections.

In vitro bactericidal activities of a new oral cephalosporin, E1100, and morphologic changes on Escherichia coli

Escherichia coli is one of the most common aerobic bacteria in pelvic inflammatory diseases. Oral cephalosporins have been widely used against those infections. We investigated in vitro morphologic changes induced on E. coli by a new oral cephalosporin, E1100, and its bactericidal activity on this organism. Morphologic changes were observed by electron microscopy. E1100 induced morphologic changes (filamentation) and exerted a bactericidal activity on E. coli. The filamentation induced by E1100 was time and concentration dependent.

MR imaging findings of uterine pyomyoma: radiologic–pathologic correlation

A 69-year-old postmenopausal female with a spontaneously occurring uterine pyomyoma was described with emphasis on the MR imaging findings. On unenhanced T1- and T2-weighted MR images, a huge mottled mass suspected to contain blood products, necrotic tissue, or purulent or viscous fluid was demonstrated within anterior myometrial wall of uterine body. The mass was surrounded by a peripheral rim that was hyperintense on T1-weighted images and hypointense on T2-weighted images. On gadolinium-enhanced MR images, most of the mass was unenhanced, but the peripheral rim was equally enhanced with the surrounding myometrium. Pathological examination revealed an intramural uterine pyomyoma surrounded by fibrous capsules with abundant lymphocytes and neutrophils. Our findings indicate that pyomyoma should be considered when MR images demonstrate a myometrial cystic lesion accompanied by a peripheral rim.