Weekly fluconazole for the prevention of mucosal candidiasis in women with HIV infection. A randomized, double-blind, placebo-controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS

BACKGROUND: Candidiasis is a frequent complication of infection with the human immunodeficiency virus (HIV); however, few data exist about the natural history, prevention, and treatment of mucosal candidiasis in women. OBJECTIVE: To evaluate the safety and effectiveness of weekly fluconazole prophylaxis for mucosal candidiasis in women infected with HIV. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 14 sites participating in the Community Programs for Clinical Research on AIDS (CPCRA). PATIENTS: 323 women with HIV infection and CD4+ cell counts of 300 cells/mm3 or less. INTERVENTION: 200 mg of fluconazole per week or placebo. Open-label fluconazole for candidiasis prophylaxis was permitted after two oropharyngeal or vaginal episodes or one esophageal episode. MEASUREMENTS: Development of mucosal candidiasis, clinical and in vitro resistance of Candida species to fluconazole, survival, and adverse events. RESULTS: After a median follow-up of 29 months, 72 of 162 patients receiving fluconazole and 93 of 161 patients receiving placebo had at least one episode of candidiasis (relative risk [RR], 0.56 [95% Cl, 0.41 to 0.77); P < 0.001). Weekly fluconazole was effective in preventing oropharyngeal candidiasis (RR, 0.50 [Cl, 0.33 to 0.74]; P < 0.001) and vaginal candidiasis (RR, 0.64 [Cl, 0.40 to 1.00]; P = 0.05) but not esophageal candidiasis (RR, 0.91 [Cl, 0.48 to 1.72]; P > 0.2). Relative risks were similar for women who had a history of mucosal candidiasis (RR, 0.5 [Cl, 0.35 to 0.75]) and those who did not (RR, 0.69 [Cl, 0.35 to 1.34]). Absolute risk reduction for patients with a history of infection was 25.6 per 100 person-years, which is more than twice the reduction of 11.2 per 100 person-years seen in patients with no history of infection. This difference reflects the higher risk of patients who previously had an infection. Candida albicans was not usually resistant to fluconazole in vaginal specimens in clinical or in vitro settings; such resistance occurred in less than 5% of patients in each group. CONCLUSIONS: Weekly fluconazole (200 mg) seems to be safe and effective in preventing oropharyngeal and vaginal candidiasis. This regimen has a useful role in the management of HIV-infected women who are at risk for recurrent mucosal candidiasis.     

Fluconazole. An update of its antimicrobial activity, pharmacokinetic properties, and therapeutic use in vaginal candidiasis

Fluconazole is a bis-triazole antifungal drug which has a pharmacokinetic profile characterised by its high water solubility, low affinity for plasma proteins, and metabolic stability. After a single 150 mg oral dose, therapeutic concentrations in vaginal secretions are rapidly achieved and are sustained for a duration sufficient to produce high clinical and mycological responses in nonimmunocompromised patients with vaginal candidiasis (candidosis). At this dosage, clinical and mycological responses have compared favourably with responses achieved after multiple dose regimens of other oral and intravaginal antifungal agents. Clinical efficacy rates have ranged between 92 and 99% at short term evaluation (5 days post-treatment). At 80 to 100 days post-treatment clinical efficacy rates of 91% have been reported. In addition, limited data indicate that fluconazole is more effective than placebo as prophylactic treatment of frequently recurring vaginal candidiasis. Single oral doses of fluconazole 150 mg are well tolerated. Most frequently observed adverse events are gastrointestinal symptoms, which are generally mild and transient in nature. Thus, fluconazole is a valuable alternative to established systemic and intravaginal azole antifungal drugs which are used to treat vaginal candidiasis. Moreover, in view of its favourable patient acceptability and compliance profile compared with alternative treatments, single-dose oral fluconazole should be considered as a first-line therapeutic choice for the treatment of women with vaginal candidiasis.     

Oral contraceptive use and vaginal candida colonization

Fungal vaginal infections/colonisations can be divided into a symptomatic vaginal candidiasis and an asymptomatic vaginal Candida-carriage. The latter seems to be a predisposing factor for the development of a symptomatic vaginal candidiasis. The fungal organism isolated most frequently is Candida albicans, followed by Candida glabrata, which was previously also known as Torulopsis glabrata. To a lower extend, other Candida species such as Candida tropicalis and Candida krusei can be prevalent in the vulvovaginal region. Predisposing factors for vaginal candidiasis are gravidity, diabetes mellitus or a therapy with immunosuppressive agents. Also gestagenes showed to be a pre-disposing factor for vaginal candidiasis. Divergent results concerning the predisposition to vaginal candidiasis or colonisation due to oral contraception have so far been reported. Therefore we performed a study with two healthy collectives of female volunteers (n = 2 x 60) which were different concerning the taking of oral contraceptives. Overall, in 17% of the subjects (20/120) yeast could be cultured out of the vaginal secretions. There was no evidence for a higher rate of Candida-colonisation in subjects taking oral contraceptives. Further, there was no evidence for a relationship between the length of the taking of oral contraceptives and the rate of vaginal yeast-carriage. Also the type of oral contraceptive (combination or sequential contraceptive) had no influence on the frequency of Candida-carriage. Candida albicans was the most prevalent yeast (16/20), followed by Candida glabrata (4/20).     

Gynaecological conditions associated with HIV infection in women who are partners of HIV-positive Thai blood donors

Women who were partners of HIV-positive blood donors were enrolled in a study of heterosexual HIV transmission between March 1992 and December 1996 and were interviewed and examined. Gynaecological conditions, including cervical dysplasia, human papillomavirus (HPV) infection, gonorrhoea, chlamydial infection, trichomoniasis, bacterial vaginosis, vaginal candidiasis and syphilis were assessed in addition to HIV status and CD4 level. Of 481 women enrolled, 224 (46.6%) were HIV seropositive. HIV-infected women were more likely to have abnormal vaginal discharge on physical examination (OR=2.6, P <0.01), HPV infection with a high-risk type (OR=6.9, P <0.01), and cervical dysplasia (OR=5.3, P <0.01). The prevalence of other gynaecological conditions detected at the enrolment visit did not differ by HIV status. History of prior STD (OR=2.0, P <0.01) was more common among HIV-infected women. The median CD4 count was 400 cells/microl among HIV-infected women. The prevalence of abnormal vaginal discharge and bacterial vaginosis increased significantly with decreasing CD4 count. The prevalence of ectopy, vaginal candidiasis, and cervical dysplasia increased with decreasing CD4 count, but these trends were not significant. We conclude that HIV-infected Thai women appear to have increased prevalences of abnormal vaginal discharge, squamous intraepithelial lesions and self-reported history of STD.     

HIV infection in women: an escalating health concern

The proportion of women infected with the human immunodeficiency virus (HIV) continues to increase. Over one-half of women acquire the virus through heterosexual contact. The diagnoses that define the acquired immunodeficiency syndrome and the use of antiretroviral therapy are similar in men and women, except in pregnancy. However, management decisions differ significantly regarding contraceptive and gynecologic care. Besides abstinence, use of the latex condom continues to be the most effective way of preventing transmission of HIV. The management of human papillomavirus-associated disease, pelvic inflammatory disease and vaginal candidiasis is especially challenging in women with HIV infection. A positive status for the virus does not appear to affect pregnancy outcome. Each year, up to 2,000 infants are born infected with HIV. Transmission can occur by transplacental or intrapartum spread or through breast milk. Since 1994, prophylaxis with zidovudine has been shown to be an effective method of limiting transmission to infants. It is important to offer all pregnant women a test for HIV, with counseling provided both before and after the test, even if testing does not become mandatory under the law.     

Vulvovaginitis

Candidiasis, infection due to Trichomonas vaginalis and bacterial vaginosis (Gardnerella vaginalis and/or other species) represent the major three causes of vulvo-vaginitis. Other are rare bacterial infections and non infectious vaginitis such as allergic and post-menopausal vaginitis with epithelial atrophy. Clues for the diagnosis include the clinical features of vaginal discharge, cytological examinations, bacterial and fungal cultures. Only T. vaginalis seems to be responsible of sexually transmitted disease. All appropriate antibacterial or anticandidosic treatment are immediately effective, but the mechanisms of recurrent candidiasis and vaginosis are still unclear.     

The viability and blood supply of experimental autografts on a venous vascular pedicle

In 87 patients with a missed abortion prior to 13 weeks, the application of a prostaglandin (PG) E1 derivative (1 mg gemeprost, Cergem) was compared to conventional surgical termination of pregnancy by cervical dilatation and curettage. In 33 patients with PGE1 application, complete expulsion of the abnormal pregnancy occurred after an average of 2.8 +/- 1.5 vaginal suppositories. PGE1 treatment was effective in 76.7%, and surgical management was effective in 90.9% of patients. Sixty percent of the patients in the PGE1 group required analgesia because of uterine pain in comparison to 4.5% in the surgical group. The possibility of medical termination with synthetic PG derivatives should be further investigated.     

Control of Candida albicans murine vaginitis by topical administration of polycarbophil-econazole complex

The complexation of econazole with the mucoadhesive polycarbophil was found to significantly improve the therapeutic benefit of the drug in the topical treatment of experimental vaginal candidiasis in mice, while no difference in the antimycotic activity exerted by econazole and polycarbophil-econazole could be detected in vitro.     

Acute neutropenia decreases inflammation associated with murine vaginal candidiasis but has no effect on the course of infection

We have used a mouse model of vaginal candidiasis to determine the effect of neutrophil depletion on (a) the clearance of Candida albicans and (b) the degree of inflammation associated with infection. No differences in recoverable yeast number or rate of clearance were observed between normal and neutrophil-depleted mice; however, vaginal inflammation was significantly decreased in neutrophil-depleted animals.     

Bacterial vaginosis: an update

Bacterial vaginosis is the most common cause of vaginal discharge. Recent studies have confirmed its association with pelvic inflammatory disease and adverse pregnancy outcomes. Bacterial vaginosis is treated with oral metronidazole (given either as a single dose or a seven-day course) or clindamycin. Treatment with topical clindamycin or metronidazole is also effective in returning the vaginal flora to normal but may be less effective in preventing the increased incidence of adverse pregnancy outcomes.     

Parasitic diseases control in the 21st century in China

The aim of this study was to determine whether the endometrium acts as a reservoir for Candida albicans in cases of recurrent vaginal candidiasis. Twenty-five women with documented history of recurrent vaginal candidiasis were enrolled in the study and endometrial samples were cultured for Candida albicans. Only two patients had positive cultures for Candida albicans. Therefore, we concluded that the endometrium is not a common reservoir for Candida albicans.     

Oral fluconazole for vaginal candidiasis

The recent surge of interest in fluconazole is due to its approval by the U.S. Food and Drug Administration for use as a single 150-mg oral dose in the treatment of vaginal candidiasis. Fluconazole is a triazole antifungal agent that acts primarily by inhibiting sterol synthesis in the fungal cell membrane. Recent studies have shown that a single dose of oral fluconazole is as effective as intravaginal antifungal agents. Many physicians and patients prefer this single-dose regimen because of its low rate of side effects, cost-effectiveness and ease of administration.     

Candida-specific Th1-type responsiveness in mice with experimental vaginal candidiasis

The role of systemic cell-mediated immunity (CMI) as a host defense mechanism in the vagina is poorly understood. Using a murine pseudoestrus model of experimental vaginal candidiasis, we previously found that animals given a vaginal inoculum of viable Candida albicans blastoconidia acquired a persistent vaginal infection and developed Candida-specific delayed-type hypersensitivity (DTH) responses. The present study was designed to characterize the peripheral CMI reactivity generated from the vaginal infection in mice and to determine whether pseudoestrus is a prerequisite for the induction of peripheral CMI reactivity. Mice treated or not treated with estrogen and given a vaginal inoculum of C. albicans blastoconidia were examined for 4 weeks for their vaginal Candida burden and peripheral CMI reactivity, including DTH responsiveness and in vitro Th1 (interleukin-2 [IL-2], gamma interferon [IFN-gamma]/Th2 (IL-4, IL-10)-type lymphokine production in response to Candida antigens. Results showed that although mice not treated with estrogen before being given a vaginal inoculum of C. albicans blastoconidia developed only a short-lived vaginal infection and harbored significantly fewer Candida CFU in the vagina compared with those given estrogen and then infected; DTH reactivity was equivalent in both groups. In vitro measurement of CMI reactivity further showed that lymph node cells from both estrogen- and non-estrogen-treated infected mice produced elevated levels of IL-2 and IFN-gamma in response to Candida antigens during the 4 weeks after vaginal inoculation. In contrast, lymph node cells from the same vaginally infected mice showed no IL-10 production and only small elevations of IL-4 during week 4 of infection. These results suggest that mice with experimental vaginal candidiasis develop predominantly Th1-type Candida-specific peripheral CMI reactivity and that similar patterns of Th1-type reactivity occur in mice regardless of the persistence of infection and the estrogen status of the infected mice.     

Managing patients with vulvovaginal candidiasis

Epidemiologic studies have demonstrated a continuing increase in the prevalence of vulvovaginal candidiasis. Although in the past most of these infections were caused by Candida albicans, an increasing percentage are caused by non-albicans Candida species that are less sensitive to the most frequently used antifungal agents. An accurate diagnosis of these infections and the subsequent choice of the most appropriate therapy can only be made after a thorough evaluation of the patient. Successful treatment of vulvovaginal candidiasis is dependent on compliance with therapy; thus, the treatment regimen chosen should fit the patient's daily lifestyle. Newer single-dose regimens offer the option of completing therapy with a single treatment for most patients with uncomplicated vaginal candidiasis. Use of topical agents avoids the potential systemic adverse effects and drug interactions that have been noted with oral antifungals. Patient education and support can also enhance satisfaction with the treatment plan and promote compliance.     

Comparison of the influence of spermicidal and non-spermicidal contraception on bacterial vaginosis, candidal infection and inflammation of the vagina--a preliminary study

This preliminary study compared the signs, symptoms and prevalence of bacterial vaginosis (BV) and candidal infections in women using spermicides, with those using other forms of contraception, to establish whether nonoxynol-9 had any therapeutic value against BV or gave rise to vaginal candidiasis and inflammation. Overall results showed that the prevalence of BV in non-spermicide users was 35/113 (31%) but was significantly less in spermicide users, 10/66 (15%), P < 0.05. Nonoxynol-9 was not associated with increased isolation of Candida albicans, which was found in 16/113 (14%) of non-spermicide users, and in 8/66 (12%) of those using spermicides, P > 0.1. Vaginal inflammation and discharge were significantly less in spermicide users, 19/66 (29%) than in the non-spermicide group, 50/113 (44%), P < 0.05. Nonoxynol-9 contraception was associated with a significantly reduced prevalence of BV, but not with increased candidiasis or vaginal inflammation.     

Miconazole per os in tinea and deep mycosis

For the last 6 years we have been using Miconazole cream in the treatment of tinea and vaginal candidiasis. We think that it is at least as good as the best drugs for this purpose, but consider it difficult to decide about its superiority. Therefore we refrain from describing this part of our experience in detail. We have employed Miconazole "per os" at the daily doses of 24-28 mg./kg. in treating 3 cases of tinea corporis or cruris by "Trichophyton rubrum". Symptoms ceased in 3 days; mycologic examination turned negative in 2 weeks; treatment ended in apparent cure in 3 weeks. We have employed Miconazole "per venam" and "per os" in the treatment of: mycetomata (2) by "Streptomyces somaliensis", without success; mycetoma by "Madurella grisea" (1), without success; chromomycosis by a 5-flucytosine resistant strain of "Cladosporium carrionii" (1), without success; paracoccidioidosis (5) with lesions in mouth and lungs, with good results; leishmaniasis by "Leishmania brasiliensis" (1), without success; mucocutaneous disseminated candidiasis (1), with very good results. Tolerance has been excellent: but pruritus appeared from the third week with 600 or more mg. "per venam", in several patients. Doses varied between 10 and 50 mg./kg./day. One patient, who suffered with candidiasis, is taking 50 to 30 mg./kg./day since more than a year ago and, being a child, he is feeling well and growing to be normal. We recommend employing Miconazole against systemic canidiasis, sulpharesistant paracoccidioidosis and assaying it further in tinea (at least, in griseofulvin-resistant cases).     

Menstrual induction by the vaginal application of ICI 81008 gel

After approximately 2 weeks menstrual delay (positive Pregnosticon Tests) "menstrual induction" was attempted in 75 gravidas by repeated vaginal application of a gel, containing 200 or 400 mug/ml ICI 81008. After approximately 10 minutes, following the 1st vaginal delivery of 400 mug ICI 81008, the uterus responded to this PGF2alpha analogue with sustained contracture. The highest success rate in induced bleeding (93%) and pregnancy termination (79%), without supportive therapy, was achieved when 400 mug ICI 81008 was administered 2 to 5 times at 4 hour intervals. Those gravidas (21%), who failed in induced menstruation, or stopped bleeding within 24 hour- after treatment, had positive Pregnosticon Tests on day 14 and were curetted. The side effects, mostly vomiting and increased blood pressure, were transient and subjectively and medically acceptable. While the vaginal application of the drug is apparently less effective than the intrauterine (1), it has the advantage of simple delivery and the potential of self-administration.     

Prevalence and susceptibility of vaginal yeast isolates in Jordan

The prevalence of vaginal yeast species has been studied in 140 women (41 pregnant, 66 infertile and 33 healthy controls) attending a gynaecological private clinic in Amman, Jordan. Yeast species were isolated from pregnant (68.2%), infertile (51.5%) and healthy control (48.4%) women. Patients manifesting one, two or three symptoms of vulvovaginitis were 22.1%, 26.8% or 24.2% respectively. Asymptomatic cases and cases with more than three symptoms were 22.4% and 4.5% respectively. Candida albicans was the dominant species (in 51.3% of the patients) followed by C. glabrata (17.9%). The percentage occurrence as well as the pattern of Candida species differed among the different groups of patients. Candida kefyr was found to be significantly higher in the infertile women. In vitro sensitivity tests using amphotericin B, nystatin, miconazole nitrate and chlorhexidine were carried out; amphotericin B was the most effective and miconazole nitrate the least.     

Matrix metalloproteases and their inhibitors in the pleura

Vulvovaginal candidiasis is a frequent inflammatory process in women but it has not been widely studied in female sex workers (FSWs). To estimate the frequency of Candida species infection in FSWs and to identify related risk factors and clinical findings, we carried out a retrospective study of 1923 FSWs over 11 years. We also performed a prospective study of 163 consecutive FSWs with a history of candidiasis during a 4-year period. Candida species were isolated in 1967 samples (18.5% of the total). Candida albicans (89.3%) was the most frequent species, followed by Candida glabrata (2.7%), Candida parapsilosis (1.2%) and Saccharomyces cerevisiae (0.4%). In the prospective study of 163 patients, we found vaginal discharge in 76.1% of cases, soreness in 52.1% and vulval pruritus in 32.5%. We identified 12 patients (7.4%) with recurrent vulvovaginal candidiasis. No statistical difference was found between recurrent vulvovaginitis and the use of oral contraceptives, oral sex, tight-fitting clothing and synthetic underwear. FSWs have the same prevalence of candidiasis as other groups of women described in published literature. The proportion of albicans and non-albicans species does not differ between women with recurrent and non-recurrent vulvovaginal candidiasis (VVC).