Clinical and mycological efficacy of single-day oral treatment with itraconazole (400 mg) in acute vulvovaginal candidosis

This study aimed to investigate the effectiveness of single-day oral treatment with itraconazole in acute vulvovaginal candidosis (VVC). Vaginitis was demonstrated by both detection of yeast cells and pseudohyphae formation on microscopic examination of vaginal discharge and mycological culture as well as by the clinical signs and symptoms. Clinical and mycological examinations of the 52 patients were performed before, 1 week (short-term) and 4 weeks (long-term) after single-day oral treatment with itraconazole 200 mg b.i.d. The causative yeast fungi were: Candida albicans (76.9%), C. glabrata (9.6%), C. kefyr (9.6%) and C. krusei (3.9%), respectively. In short- and long-term examinations, clinical cure rates were found to be 61.5% and 90.4%, and mycological cure rates were 63.5% and 90.4%, respectively. Itraconazole was found to be 95.0% effective with C. albicans and 75.0% with other Candida species. It is concluded that treatment of acute VVC with itraconazole is safe and effective in the long-term.     

Itraconazole in the treatment of acute and recurrent vulvovaginal candidosis: comparison of a 1-day and a 3-day regimen

Itraconazole is a systemic triazole with a broad-spectrum antifungal effect which belongs to a standard choice for the treatment of vulvovaginal candidosis. Thirty-four patients with acute and 26 patients with recurrent form of culture documented attacks of vulvovaginal candidosis were evaluated. There was frequent discrepancy between severe symptoms and weaker signs in patients with recurrent form than in the group with acute sporadic form. Eighteen patients with the acute form and 13 patients with the recurrent form of vulvovaginal candidosis received 1-day therapy (twice 200 mg of itraconazole in 1 day). Sixteen patients with the acute form and 13 patients with the recurrent form received 3-day therapy (200 mg of itraconazole daily for three following days). The cure rates 1 month after treatment were 97.1 and 76.9% in patients with the acute sporadic and recurrent form of vulvovaginal candidosis, respectively. Positive cultures in the latter group documented relapses. These clinical failures were not related to the resistance of yeasts to itraconazole. With the exception of one case of alopecia areata, side effects were minimal. The application of the long-term regimens and suppressive therapy with azole drugs is suggested in patients with recurrent vulvovaginal candidosis.     

The Clinical Pharmacokinetics of Itraconazole: An Overview

Summary: Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole.
The pharmacokinetics of itraconazole in man are characterized by a good oral absorption, an extensive tissue distribution with tissue concentrations many times higher than in plasma, a relatively long elimination half-life of about one day and a biotransformation into a large number of metabolites. One of them, hydroxy-itraconazole, is antifungally active and explains why antifungal plasma levels, when measured by bioassay, are about three times the itraconazole levels measured by a specific HPLC-method.
Distribution studies have shown that therapeutically active levels of itraconazole are maintained much longer in some infected tissues than in plasma. For instance, active levels persist for four days in the vaginal epithelium after a one-day treatment and for 3 weeks in the stratum cor-neum of the skin after treatment has been stopped. Unlike fluconazole, itraconazole does not interfere with mammalian drug metabolizing enzymes, minimizing the risk of interaction with concomitantly administered drugs. These pharmacokinetic properties may contribute to the high eficacy and safety of itraconazole in patients with various mycotic infections. New pharmaceutical formulations are being explored in order to broaden the application field of itraconazole to intravenous and oral therapy of patients with malabsorption.     

A clinical multicenter study comparing efficacy and tolerability of topical combination therapy with clotrimazole (Canesten, two formats) with oral single dose fluconazole (Diflucan) in vulvovaginal mycoses

Two topical formats containing clotrimazole [500 mg single dose vaginal tablet (VT) or 10% single dose vaginal cream (VC) for intravaginal use] combined with additional clotrimazole cream for topical application to the vulval area (Canesten 1 Combi, Bayer AG, Leverkusen, Germany) were compared with oral fluconazole 150 mg single dose treatment of vulvovaginal mycosis (VVM) in a single-blind clinical study. The objective of the study was to demonstrate the equivalent efficacy of the clotrimazole combination therapies (VT + 1% cream and VC + 2% cream), and fluconazole 150 mg oral capsule (Diflucan 1, Pfizer Gmbh, Karlsruhe, Germany) in terms of overall response defined as clinical cure and mycological resolution. Overall, combination therapies containing either clotrimazole 500 mg VTs or clotrimazole 10% VC were as effective as a single dose fluconazole 150 mg oral tablet in treating VVM with rates for overall response being 66%, 61% and 60%, respectively, after 14 days. There were no significant differences in the time to onset of symptom relief in the clotrimazole 500 mg tablet group and clotrimazole 10% VC compared with fluconazole 150 mg oral capsules. Only 50% of 88 patients across treatment groups with mycological recurrence also experienced return of symptoms over the entire 8 week follow-up period. All treatments administered were safe and well-tolerated and the number of patients experiencing adverse events was low.     

Oral and Gastrointestinal Candidosis: Prophylaxis During Immunosuppressive Therapy.

Summary: Patients with acute leukaemia and malignant lymphomas often are severely affected by fungal infections. There is in particular growing concern about disseminated candidosis. Oral, gastrointestinal and systemic candidosis seem to be closely linked. Predisposing factors are damaged mucosal barriers due to chemotherapy, protracted periods of neutropenia, and prolonged use of antibiotics and steroids.
Oropharyngeal candidosis is very frequent. This can be prevented or controlled by the application of topical antifungals such as nystatin. The systemic application of antifungals is an alternative for patients who do not respond. Both oral ketoconazole and intravenous amphotericin B have been proven effective. Candida oesophagitis is also an important problem. Oral nystatin suspension can be helpful in mild cases. In others oral ketoconazole and intravenous amphotericin B have to be used. A whole range of measures has to be taken to prevent spread of the disease, i.e. H,-antagonists should be used only if definitely needed. Specific antifungal prophylaxis has also been discussed. Oral amphotericin B seems to be helpful. The azole itraconazole might be especially promising.     

Prophylaxis of Fungal Infections with Itraconazole during Remission-Induction Therapy

Summary: Deep fungal infections are an increasing problem in the treatment of acute leukemias and malignant lympho-mas. Risk factors are known but unavoidable. Because of diagnostic difficulties most patients are treated empirically with intravenous amphotericin B. This drug's toxicity increases morbidity and mortality. An orally absorbable triazole derivative, itraconazole, may offer effective and safe prophylaxis against deep candidosis and aspergillosis in these patients.
Such infections have been treated successfully with oral itraconazole even when resistant to intravenous amphotericin B. In retrospective comparative studies there are significantly less deep fungal infections in patients given itraconazole. The significance of the difference varies between studies. Pharmaco-kinetic data confirm therapeutic plasma levels of itraconazole but with wide variation within and between patients.
The current large, multi-centre, randomised, double-blind, prospective trial of oral itraconazole versus placebo in the U.K. will test its prophylactic efficacy against deep fungal infections during treatment of haematological malignancies.     

Non‐response to fluconazole maintenance treatment (ReCiDiF regimen) for recurrent vulvovaginal candidosis is not related to impaired glucose metabolism

Is non‐response to maintenance treatment for recurrent vulvovaginal candidosis (RCVV) related to the impaired glucose metabolism? In the ReCiDiF trial, women with RCVV were given a degressive regimen with fluconazole according to their clinical, microscopic and mycologic response. Data obtained from optimal, suboptimal and non‐reponding patients were used for secondary analysis of medical history, physical status and family history for potential glucose impairment. Results were presented in means and percentages. Pearson chi‐square, Fisher exact, Mann‐Whitney U, Kruskal‐Wallis and Spearman's correlation coefficient was calculated. P<.05 were interpreted as statistically significant. Sociodemographic characteristics and family and personal history of diabetes were not different between optimal, suboptimal and non‐responders. The average HbA1c concentration was 5.1±0.3% in optimal, 5.0±0.4% in sub‐optimal, and 5.1±0.3% in non‐responding patients (P=1.0). There are no statistical differences between optimal, sub‐optimal and non‐respondents to treatment in all deciles of HbA1c among patients with recurrent candidosis (P=1.0). There was no difference among groups in fasting glucose concentration, nor after 30 min, 60 min or 120 min during the oral glucose tolerance test (OGTT) (P=.6). Area under the OGTT curve did not differ within groups (P=.8), nor was the deviation from the normal cut‐off value any different (P=.8). Glucose concentration in vaginal rinsing fluid showed no correlation with responsiveness to treatment (P=.7). Glucose metabolism, BMI, personal or family history of diabetes are not related to non‐response to maintenance treatment with fluconazole for patients with RVVC.     

Day-to-day follow-up after a short oral treatment of acute vaginal candidosis with itraconazole

Seventeen patients with acute vaginal candidosis were treated for 2 days with itraconazole (200 mg daily). During 5 days after the start of the treatment, patients were daily screened for the presence of Candida (culture and microscopy) and the presence of signs and symptoms. Four days after treatment, no Candida could be detected in smears of vaginal fluid and cultures from these patients. At that time leucorrhoea, pruritus, vulvitis, and erythema were strongly reduced but had not completely disappeared.     

Oral candidosis: treatment with absorbable and non-absorbable antifungal agents in children

Oral candidosis in neonates and children is a common infection which occurs often during the first few months after birth, but occasionally also in older children with certain predisposing factors. In neonates, oral candidosis is usually benign, although the symptoms of such an acute infection can be disturbing to both the patient and the parents. In older children developing oral candidosis, specific predisposing factors may be present (e.g. immunodeficiency, chemotherapy, etc.). In such cases, the infection may constitute a source for further dissemination, leading to occasionally fatal Candida sepsis or to widespread chronic mucocutaneous candidosis. Treatment modalities to date include drugs with limited or no absorption from the gastrointestinal tract (e.g. nystatin and miconazole) and agents that are absorbed, combining local effect with systemic therapy (e.g. clotrimazole, ketoconazole, itraconazole and fluconazole). Overall, it appears that treatment of neonatal oral candidosis should be performed with non-absorbable drugs, while the systemically active agents should be used primarily if a risk of dissemination exists or if widespread disease is present. In general, side-effects and toxicity are not major causes of concern with non-absorbed or absorbed antifungals in children with oral candidosis, since treatment is usually of relatively short duration. When the systemically active agents are used in premature infants with sub-optimal liver function, the risk of drug-induced liver toxicity may be increased.     

Shorter treatment for vaginal candidosis: comparison between single-dose oral fluconazole and three-day treatment with local miconazole.

Fluconazole is an effective, simple and safe, although slightly expensive, agent for the treatment of vaginal candidosis. Single-dose fluconazole (150 mg) administered orally in capsule form was compared with three-day local treatment with miconazole pessaries in the treatment of vaginal candidosis in a randomized study in Finland. Cure rates were good (> 80%) in randomized patient groups assessed both clinically and by the results of yeast cultures. Oral administration was preferred to local therapy by patients in both the miconazole and fluconazole groups. For the time being, fluconazole is not recommended for use during pregnancy or lactation.     

Change of Causative Organisms under Antifungal Treatment in Immunosuppressed Patients with HIV-Infections

Summary: Oral and esophageal candidosis are very common in HIV-infected patients. Due to the lack of efficacy of topical antimy-cotics in advanced stages of HIV-infection oral azoles are mainly used for treatment. holes most often used are ketoconazole and fluconazole. While Candida albicans clearly is the most frequently encountered yeast before and after treatment other species can be found somewhat less frequently after treatment. This especially applies to Candida glabrata. Candida spp. other than C. albicans obviously may cause manifest oral candidosis. This shift of microbes deserves the more interest as they are less susceptible to azole drugs.     

Guideline vulvovaginal candidosis (2010) of the German Society for Gynecology and Obstetrics, the Working Group for Infections and Infectimmunology in Gynecology and Obstetrics, the German Society of Dermatology, the Board of German Dermatologists and the German Speaking Mycological Society

Candida (C.) species colonize the estrogenized vagina in at least 20% of all women. This statistic rises to 30% in late pregnancy and in immunosuppressed patients. The most often occurring species is Candida albicans. Host factors, especially local defense deficiencies, gene polymorphisms, allergic factors, serum glucose levels, antibiotics, psychosocial stress and estrogens influence the risk for a Candida vulvovaginitis. In less than 10% of all cases, non-albicans species, especially C. glabrata, but in rare cases also Saccharomyces cerevisiae, cause a vulvovaginitis, often with fewer clinical signs and symptoms. Typical symptoms include premenstrual itching, burning, redness and non-odorous discharge. Although pruritus and inflammation of the vaginal introitus are typical symptoms, only less than 50% of women with genital pruritus suffer from a Candida vulvovaginitis. Diagnostic tools are anamnesis, evaluation of clinical signs, the microscopic investigation of the vaginal fluid by phase contrast (400 x), vaginal pH-value and, in clinically and microscopically uncertain or in recurrent cases, yeast culture with species determination. The success rate for treatment of acute vaginal candidosis is approximately 80%. Vaginal preparations containing polyenes, imidazoles and ciclopiroxolamine or oral triazoles, which are not allowed during pregnancy, are all equally effective. C. glabrata is resistant to the usual dosages of all local antimycotics. Therefore, vaginal boric acid suppositories or vaginal flucytosine are recommended, but not allowed or available in all countries. Therefore, high doses of 800 mg fluconazole/day for 2-3 weeks are recommended in Germany. Due to increasing resistence, oral posaconazole 2 × 400 mg/day plus local ciclopiroxolamine or nystatin for 15 days was discussed. C. krusei is resistant to triazoles. Side effects, toxicity, embryotoxicity and allergy are not clinically important. A vaginal clotrimazole treatment in the first trimester of pregnancy has shown to reduce the rate of preterm births in two studies. Resistance of C. albicans does not play a clinically important role in vulvovaginal candidosis. Although it is not necessary to treat vaginal candida colonization in healthy women, it is recommended in the third trimester of pregnancy in Germany, because the rate of oral thrush and diaper dermatitis in mature healthy newborns, induced by the colonization during vaginal delivery, is significantly reduced through prophylaxis. Chronic recurrent vulvovaginal candidosis requires a "chronic recurrent" suppression therapy, until immunological treatment becomes available. Weekly to monthly oral fluconazole regimes suppress relapses well, but cessation of therapy after 6 or 12 months leads to relapses in 50% of cases. Decreasing-dose maintenance regime of 200 mg fluconazole from an initial 3 times a week to once monthly (Donders 2008) leads to more acceptable results. Future studies should include candida autovaccination, antibodies against candida virulence factors and other immunological trials. Probiotics should also be considered in further studies. Over the counter (OTC) treatment must be reduced.     

Introduction

Summary: Oral candidosis is the manifestation of candidosis earliest described. In fact pertinent cases are already to be found in the corpus hippocraticum. Exactly 150 years ago a fungus was found in lesions of orogastrointestinal candidosis by the German surgeon Langenbeck. For a long time, there was much dispute on the proper term for the most important causative organism of thrush and correspondingly for the proper name of the diseases caused. Today, Candida albicans is accepted by virtually everybody and the discussion on the name of the disease only focuses on the terms can-didiasis and candidosis of which the latter seems preferable. Facing the scientific progress in the field of Candida and candidosis research and the permanent change of both the causative organism and the corresponding disease in the age of the HIV-infection (AIDS), it seems rewarding to review epidemiology, microbiology, nosology and treatment of oral and gastrointestinal candidosis.     

Introduction

Summary: Oral candidosis is the manifestation of candidosis earliest described. In fact pertinent cases are already to be found in the corpus hippocraticum. Exactly 150 years ago a fungus was found in lesions of orogastrointestinal candidosis by the German surgeon Langenbeck. For a long time, there was much dispute on the proper term for the most important causative organism of thrush and correspondingly for the proper name of the diseases caused. Today, Candida albicans is accepted by virtually everybody and the discussion on the name of the disease only focuses on the terms can-didiasis and candidosis of which the latter seems preferable. Facing the scientific progress in the field of Candida and candidosis research and the permanent change of both the causative organism and the corresponding disease in the age of the HIV-infection (AIDS), it seems rewarding to review epidemiology, microbiology, nosology and treatment of oral and gastrointestinal candidosis.     

In vitro fluconazole and nystatin susceptibility and clinical outcome in complicated vulvovaginal candidosis

To correlate fluconazole and nystatin susceptibility with clinical outcome for complicated vulvovaginal candidosis (VVC), 287 Candida isolates were collected from 283 patients with complicated VVC. In vitro fluconazole and nystatin susceptibility was tested using E‐test or commercial agar diffusion method. The patients were treated with fluconazole or nystatin. The fluconazole‐resistant and ‐susceptible dose‐dependent (SDD) rates of Candida species were 0.8% (1/132) and 5.3% (7/132) respectively. The mycological cure rate at days 7–14 and days 30–35 in fluconazole SDD isolates was lower than that in fluconazole‐susceptible isolates (42.9% vs. 88.7% and 28.6% vs. 76.6%, P < 0.05). The mycological cure rate at days 7–14 and days 30–35 in VVC caused by Candida albicans and non‐albicans Candida species was 85.6% (219/256) vs. 88.9% (24/27) and 79.3% (203/256) vs. 81.5% (22/27), P > 0.05. All C. albicans and non‐albicans Candida species were susceptible to nystatin in vitro. The mycological cure rate of the patients treated with nystatin at days 7–14 and days 30–35 in VVC was 85.4% (129/151) and 83.4% (126/151) respectively. We conclude that fluconazole resistance was rare and both C. albicans and non‐albicans Candida species were susceptible to nystatin in vitro. The decrease in fluconazole susceptibility or a low concentration of fluconazole in the vagina was probably related to fluconazole therapeutic failure.     

Utility of the oestrogen-dependent vaginal candidosis murine model in evaluating the efficacy of various therapies against vaginal Candida albicans infection

The efficacy of yogurt treatment against vaginal candidosis (VC) was examined using an oestrogen‐dependent vaginal candidosis (EDVC) murine model. The EDVC mouse model was constructed by inoculating mice with viable Candida albicans cells under pseudo‐oestrus conditions. Vaginal fungal burden in the various mouse groups was evaluated at several time points following the induction of VC. Untreated and yogurt‐treated naïve mice exhibited background levels of VC (<6000 CFU per mouse). Candida albicans colonisation in untreated EDVC mice was significantly higher (P < 0.05) than that in yogurt‐treated EDVC mice at days 20–30. Metronidazole‐treated naïve mice developed persistent C. albicans vaginal colonisation at significantly lower levels (P < 0.05) than that in untreated or metronidazole‐treated EDVC mice. Lactobacillus was only detected in the reproductive tracts of yogurt‐treated naïve and EDVC mice. These findings suggest that the presence of Lactobacillus in the reproductive tract can suppress C. albicans growth and the antibiotics may predispose to VC.     

Clinical Spectrum of Oral Candidosis and its Role in HIV-Infected Patients

Summary: Oral candidosis is a very frequent diseased state occurring mainly together with severe underlying disease. Clinical manifestation is variable. One can distinguish between oral thrush, denture stomatitis, angular cheilitis, leukoplakia and midline glossitis.
Nowadays oral candidosis is also important in connection with HIV-infection. Here the clinical spectrum does not seem to be totaly different. Apart from oral thrush (or pseudomembraneous type) a chronic atro-phic type, a chronic hyperplastic type, papillary hyperplasia and angular cheilitis are distinguished. Oral candidosis is the most frequent opportunistic infection in HIV-infected patients. Frequency of overt disease is linked to the T4/T8 ratio. In patients with AIDS-related complex oral candidosis seems to be indicative of rapid progression. Cadida albicans is the prevailing microorganism. There is, however, a change of biotypes during the course of HIV-infection. There seems to be a selection of certain phenotypes as can be judged from the increasing resistance to 5-fluorocytosine.     

A case of oral erosive candidosis in a kidney transplant patient

A case of oral erosive candidosis due to Candida albicans in a 64-year-old female patient, who had undergone kidney transplant 20 days earlier, is reported. Concomitant herpes infection was excluded. The patient achieved clinical and mycological recovery after treatment with topical and systemic antimycotics (200 mg fluconazole per day) for 50 days. The case is reported because of the erosive ulcerating aspect and extent of the lesions, usually only reported in immunodepressed subjects, especially those with neutropenia or AIDS.     

Use of Dermasilk briefs in recurrent vulvovaginal candidosis: safety and effectiveness

Despite the generally excellent results achieved with fluconazole 150 mg weekly in recurrent vulvovaginal candidosis (RVVC), some patients with a long history of disease do not achieve complete resolution of symptoms following antimycotic treatment. It is thought that use of tight synthetic fabric underwear could be a significant factor in causing recurrence. We decided to compare underwear made of Dermasilk^®, a pure fibroin fabric impregnated with a permanent antimicrobial protection, with a cotton placebo to see whether it could be a useful adjunctive tool in the management of RVVC. We recruited 96 women who had a long‐term history of RVVC and had not responded to oral antimycotics with complete satisfaction. The patients were randomly divided into two groups and instructed to use either white cotton placebo briefs or Dermasilk^® briefs. Both groups were treated with fluconazole 150 mg once weekly for 6 months. After 6 months, the Dermasilk group showed a statistically significant greater decrease of itching, burning, erythema and a smaller number of recurrences than the cotton group. Our work suggests that Dermasilk^® briefs could be a useful adjunctive tool in addition to antimycotic treatment to help relieve the discomfort of recurrent vulvovaginitis.     

Oral Candidosis and its Role in Immunocompromised Patients

Summary: The increased incidence of invasive candidosis in numerous categories of patients, including neonates, cancer patients, AIDS patients and patients who have undergone organ transplantation, is of great concern for the physicians involved. The manifestations of candidosis are numerous, and various clinical entities such as localized and disseminated infection have to be considered separately. All types of localized candidosis per se are usually not the main cause of disseminated disease. However, spreading of the mycotic pathogens in the gastrointestinal tract could induce disseminated candidosis. Prophylactic measurements in risk patients and consequent local and, if necessary, systemic treatment is recommended in these clinical entities.