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Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of vulvovaginal candidiasis (thrush). OBJECTIVES: The primary objective of this review was to assess the relative effectiveness of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. The secondary objectives of the review were to assess the cost-effectiveness, safety and patient preference of oral versus intra-vaginal anti-fungals. SEARCH STRATEGY: The following sources were searched: The Cochrane Library (Issue 4, 1999), MEDLINE (January 1985 to May 2000), EMBASE (January 1980 to January 2000) and the Cochrane Collaboration Sexually Transmitted Disease Group Specialised Register of Controlled Trials. The reference lists of retrieved articles were reviewed manually. The manufacturers of anti-fungals available in the UK were contacted. SELECTION CRITERIA: ~Bullet~Randomised controlled trials published in any language. ~Bullet~Trials had to compare at least one oral anti-fungal with one intra-vaginal anti-fungal. ~Bullet~Women (aged 16 years or over) with uncomplicated vulvovaginal candidiasis. ~Bullet~The diagnosis of vulvovaginal candidiasis to be made mycologically (i.e. a positive culture and / or microscopy for yeast). ~Bullet~Trials were excluded if they solely involved subjects who were HIV positive, immunocompromised, pregnant, breastfeeding or diabetic. ~Bullet~The primary outcome measure was clinical cure. DATA COLLECTION AND ANALYSIS: Duplicate scrutiny was performed of the titles and abstracts of the electronic search results. Full article formats of all selected abstracts were retrieved and independently assessed by two reviewers. Independent duplicate abstraction was performed by four reviewers. Disagreements regarding trial inclusion or data abstraction were resolved by discussion between the reviewers. Odds ratios were pooled using the random effects model. Chi-squared tests with a p-value of less than 0.1 indicated heterogeneity in the results. MAIN RESULTS: Seventeen trials are included in the review, reporting 19 oral versus intra-vaginal anti-fungal comparisons. No statistically significant differences were shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short term (OR 1.00 (95% CI, 0.72 to 1.40)) and long term (OR 1.03 (95% CI, 0.72 to 1.49)) follow-up. No statistically significant differences for mycological cure were observed between oral and intra-vaginal treatment at short term (OR 1.20(95% CI, 0.87 to 1.65)) or long term follow-up (OR 1.30 (95% CI, 0.99 to 1.71)). Two trials each reported one withdrawal from treatment due to an adverse reaction. Treatment preference data were poorly reported. REVIEWER'S CONCLUSIONS: No differences exist in terms of the relative effectiveness (measured as clinical and mycological cure) of anti-fungals administered by the oral and intra-vaginal routes for the treatment of uncomplicated vaginal candidiasis. No definitive conclusion can be made regarding the relative safety of oral and intra-vaginal anti-fungals for uncomplicated vaginal candidiasis. The oral route of administration is the preferred route for anti-fungals for the treatment of vulvovaginal candidiasis. The decision to prescribe or recommend the purchase of an anti-fungal for oral or intra-vaginal administration should take into consideration: safety, cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications: if women are purchasing their own treatment, they should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of oral anti-fungal administration is worth the gain in convenience, if this is the patient's preference.

Administration, Intravaginal↗

Topical treatment for vaginal candidiasis in pregnancy.

BACKGROUND: Vaginal candidiasis (moniliasis or thrush) is a common and frequently distressing infection for many women. It is even more common in pregnancy. OBJECTIVES: The objective of this review was to assess the effects of different methods of treating vaginal candidiasis in pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register. In addition, the Cochrane Controlled Trials Register (CENTRAL/CCTR) was searched. Date of last search: April 1999. SELECTION CRITERIA: Randomised trials of any treatment for vaginal candidiasis in pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Twelve trials were included. Based on five trials, imidazole drugs were more effective than nystatin when treating vaginal candidiasis in pregnancy (odds ratio 0.21, 95% confidence interval 0.16 to 0.29). Nystatin,in turn was more effective than hydrargaphen in one trial.A trial of clotrimazole was more effective than placebo (odds ratio 0.14, 95% confidence interval 0.06 to 0.31). Single dose treatment was less effective than three or four days treatment when assessed by culture and by symptoms in three different trials and treatment lasting for four days was less effective than treatment for seven days (odds ratio 10.6, 95% confidence interval 4.01 to 28.05). Based on two trials, treatment for seven days was no more or less effective than treatment for 14 days (odds ratio 0.41, 95% confidence interval 0.16 to 1.05). REVIEWER'S CONCLUSIONS: Topical imidazole appears to be more effective than nystatin for treating symptomatic vaginal candidiasis in pregnancy. Treatments for seven days may be necessary.

Administration, Topical↗

Caspofungin susceptibility testing of isolates from patients with esophageal candidiasis or invasive candidiasis: relationship of MIC to treatment outcome.

The caspofungin clinical trial database offers an opportunity to assess susceptibility results for Candida pathogens obtained from patients with candidiasis and allows for correlations between efficacy outcomes and MICs. Candida isolates have been identified from patients enrolled in four studies of esophageal candidiasis and two studies of invasive candidiasis. The MICs of caspofungin for all baseline isolates were measured at a central laboratory using NCCLS criteria (document M-27A); MICs for caspofungin were defined as the lowest concentration inhibiting prominent growth at 24 h. MICs were then compared to clinical and microbiological outcomes across the two diseases. Susceptibility testing for caspofungin was performed on 515 unique baseline isolates of Candida spp. obtained from patients with esophageal candidiasis. MICs for caspofungin ranged from 0.008 to 4 microg/ml; the MIC50 and MIC90 were 0.5 and 1.0 microg/ml, respectively. Susceptibility testing was also performed on 231 unique baseline isolates of Candida spp. from patients with invasive candidiasis. The majority (approximately 96%) of MICs were between 0.125 and 2 microg/ml, with MIC50 and MIC90 for caspofungin being 0.5 and 2.0 microg/ml, respectively. Overall, caspofungin demonstrated potent in vitro activity against clinical isolates of Candida species. A relationship between MIC for caspofungin and treatment outcome was not seen for patients with either esophageal candidiasis or invasive candidiasis. Patients with isolates for which the MICs were highest (>2 microg/ml) had better outcomes than patients with isolates for which the MICs were lower (<1 microg/ml). Additionally, no correlation between MIC and outcome was identified for specific Candida species.

Antifungal Agents↗

Caspofungin: a review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis.

Echinocandins are a new class of antifungal agents with a novel mechanism of action (interference with fungal cell wall synthesis). Caspofungin (Cancidas), Caspofungin MSD) is the first echinocandin to be approved and is administered intravenously. Caspofungin 50 mg/day had similar efficacy to intravenous fluconazole 200 mg/day and was at least as effective as intravenous amphotericin B 0.5 mg/kg/day in patients with oesophageal candidiasis in two randomised, double-blind studies. A favourable combined clinical and endoscopic response occurred in 81% of caspofungin recipients versus 85% of fluconazole recipients and in 74% of caspofungin recipients versus 63% of amphotericin B recipients. A favourable combined response rate of approximate, equals 90% and approximate, equals 60% occurred in the stratum of patients with oesophageal candidiasis who received caspofungin or amphotericin B in a third randomised, double-blind study. Caspofungin (70 mg loading dose followed by 50 mg/day) had similar efficacy to intravenous amphotericin B (0.7-1.0 mg/kg/day in patients with neutropenia and 0.6-0.7 mg/kg/day in patients without neutropenia) in patients with invasive candidiasis in a double-blind, randomised trial. A favourable overall response occurred in 73.4% of caspofungin recipients and in 61.7% of amphotericin B recipients. In a noncomparative study, salvage therapy with caspofungin (70 mg loading dose followed by 50 mg/day) was effective in patients with invasive aspergillosis who were refractory to or did not tolerate standard antifungal therapy. A favourable response (complete plus partial response) occurred in 37 of 83 patients (45%). Caspofungin was generally well tolerated in clinical trials; it had similar tolerability to intravenous fluconazole and was better tolerated than intravenous amphotericin B. Significantly fewer caspofungin than amphotericin B recipients reported chills, fever, nausea or infusion-related adverse events. In conclusion, caspofungin is a valuable new antifungal agent with a novel mechanism of action. In comparative trials, caspofungin had similar efficacy to fluconazole and was at least as effective as amphotericin B in oesophageal candidiasis and had similar efficacy to amphotericin B in invasive candidiasis. In addition, caspofungin had similar tolerability to fluconazole and was better tolerated than amphotericin B in these indications. Caspofungin was also effective in patients with invasive aspergillosis who were refractory to or intolerant of standard antifungal agents. Thus, caspofungin provides an alternative to triazoles or amphotericin B in oesophageal candidiasis and an alternative to amphotericin B in invasive candidiasis, as well as being an effective salvage therapy in invasive aspergillosis.

Animals↗

Oral candidiasis in HIV infection: pseudomembranous and erythematous candidiasis show similar rates of progression to AIDS.

Candidiasis is the most common oral fungal infection seen in association with HIV infection. It may present in a number of clinical forms, including pseudomembranous and erythematous candidiasis. To determine whether erythematous candidiasis, like the pseudomembranous form, is predictive of the development of AIDS, we reviewed the records of 169 HIV-seropositive patients seen at clinic of the Oral AIDS Center, University of California, San Francisco who were diagnosed with pseudomembranous or erythematous (or both) forms of oral candidiasis at their first examination. Kaplan-Meier analysis showed a rapid rate of progression to AIDS (median, 25 months) and to death (median, 43.8 months) in all three groups. We conclude that erythematous candidiasis is as serious a prognostic indicator as pseudomembranous candidiasis. Because the erythematous form is more difficult to recognize and hence is underdiagnosed, efforts should be made to teach non-dental clinicians who care for HIV-infected patients to diagnose and treat this lesion.

Acquired Immunodeficiency Syndrome↗

Focal hepatic candidiasis: a distinct clinical variant of candidiasis in immunocompromised patients.

Focal hepatic candidiasis is a distinct clinical variant of candidiasis in immunocompromised hosts. Although affected patients may exhibit previous evidence of extra-hepatic candidal infection, manifestations of disease at the time hepatic involvement is documented are localized to the liver. Five cases of focal hepatic candidiasis in immunocompromised patients were diagnosed antemortem in the past 15 months at our institution. Clinical, laboratory, and radiologic findings from those five patients, as well as from 20 additional cases reported in the medical literature, are reviewed. Patients with focal hepatic candidiasis had fever unresponsive to antimicrobial therapy, prominent gastrointestinal symptoms and signs, elevated levels of alkaline phosphatase, and hepatic, with or without accompanying splenic, defects noted on abdominal computed tomography. Liver biopsy usually revealed yeast and/or hyphal forms, but cultures were frequently negative. Response to therapy occurred in only 13 (59%) of 22 assessable patients. The apparent increasing incidence of focal hepatic candidiasis may be due to the recent use of more intensely cytotoxic chemotherapies for cancer.

Adult↗

Global distribution and outcomes for Candida species causing invasive candidiasis: results from an international randomized double-blind study of caspofungin versus amphotericin B for the treatment of invasive candidiasis.

In a randomized study, caspofungin was compared with amphotericin B for the treatment of invasive candidiasis in a total of 239 adults from 56 sites in 20 countries. This study provided a unique opportunity to assess the frequency and outcome of invasive candidiasis caused by different Candida species worldwide, and the results are presented here. Efficacy was primarily assessed at the end of intravenous therapy using a modified intent-to-treat (MITT) analysis. This analysis was performed on 224 of the 239 patients enrolled in the study. Attempts were made to collect baseline Candida isolates from all patients for species identification at a central laboratory. Yeasts were identified to the species level using two commercial systems and microscopic examination. Viable baseline isolates were recovered from 210 of the 224 (94%) patients included in the MITT analysis. Candida albicans was the most frequently isolated species in all regions and was responsible for 45% of cases overall. Nevertheless, the majority of cases of infection were caused by non- albicans Candida species. In the USA and Canada, Candida glabrata was the second most commonly isolated pathogen (18%). In contrast, Candida parapsilosis and Candida tropicalis accounted for 55% of cases in Latin America. Outcomes were comparable for patients treated with caspofungin (74% overall; 64% and 80% for infections due to Candida albicans and non- albicans species) and amphotericin B (62% overall; 58% and 68% for infections due to Candida albicans and non- albicans species), and were generally similar across continents. The distribution of Candida species isolated from patients enrolled in a clinical trial may not be representative of pathogens causing invasive candidiasis in the general population. Nevertheless, our findings may affect the regional choice of empirical antifungal therapy for seriously ill patients with suspected or documented invasive candidiasis since different Candida species have varying susceptibility to conventional antifungal drugs.

Adult↗

Oropharyngeal candidiasis as a marker for esophageal candidiasis in patients with cancer.

The present study was designed to determine the frequency of candidal esophagitis in cancer patients with oral thrush. Patients with clinically and microbiologically diagnosed oral candidiasis were evaluated by endoscopy for concurrent esophageal candidiasis. Esophageal involvement was documented by mucosal lesions, microbiological findings of candidal infection in smears of brushing material, positive cultures of brushing material, and histological evidence of mucosal invasion by the yeast. For 21 of the 22 patients studied, there were endoscopic and microbiological findings of candidal esophagitis. Cultures of the brushing material from all 22 patients were positive, while histological evidence was found for 14 patients. Only 10 of the patients had mild esophageal symptoms. It is concluded that oral thrush represents a reliable marker for esophageal candidiasis in patients with cancer. Routine endoscopy is not necessary to confirm the diagnosis; this procedure should be reserved for patients with persistent thrush and symptoms despite antifungal therapy.

Aged↗

Primary renal candidiasis in two preterm neonates. Report of cases and review of literature on renal candidiasis in infancy.

Primary renal candidiasis and hydronephrosis were diagnosed in two premature neonates in whom systemic hypertension developed. The clinical course in these patients and in 16 patients with renal candidiasis described in the literature indicated that prematurity, use of broad-spectrum antibiotics, and use of intravenous (IV) catheters are predisposing factors. Anuria and flank mass were the initial manifestations in the reviewed cases. Only four of the 16 patients survived following either antifungal therapy or nephrectomy. Both of our patients survived after antifungal therapy with amphotericin B and flucytosine for systemic effect as well as topical instillation of amphotericin B solution via a nephrostomy. We believe that a high index of suspicion in infants at risk and early institution of antifungal therapy for systemic as well as topical effect can improve the outcome in infants with renal candidiasis.

Amphotericin B↗

Management of neonatal candidiasis. Neonatal Candidiasis Study Group.

OBJECTIVE: To identify areas of consensus and controversy in the management of neonatal candidiasis. METHODS: A questionnaire was distributed to US-based members of the Pediatric Infectious Diseases Society and a sampling of US neonatologists. RESULTS: Three hundred eighty evaluable questionnaires were returned (42% of those mailed). Ninety-five percent of respondents have cared for an infant with systemic candidiasis in the past 2 years. Fluconazole and liposomal amphotericin are used to some extent by 90 and 69% of respondents, respectively. A single blood culture positive for Candida led to a recommendation for immediate treatment by 99%; amphotericin B was the preferred therapy for candidemia (88%). More than 80% of respondents would request cerebrospinal fluid, urine and repeat blood cultures and ophthalmologic examination in the evaluation of candidemia. If a cerebrospinal fluid culture is positive, 25% would use amphotericin B alone whereas 62% would add flucytosine. For candiduria Society members chose fluconazole therapy more often than did neonatologists, 23% vs. 3.4% (P<0.001). There was no consensus concerning duration of therapy, use of an amphotericin B test dose or management of a central catheter in place during candidemia. CONCLUSIONS: Systemic candidiasis in neonates is a frequently encountered clinical problem. There is agreement that prompt therapy with amphotericin B is required if a blood culture is positive for Candida and that such infants require additional evaluations. Other antifungals (fluconazole, liposomal amphotericin B) are used to some extent in this population. Many issues in management have no clear consensus and warrant further research.

Amphotericin B↗

B cell knockout mice are resistant to mucosal and systemic candidiasis of endogenous origin but susceptible to experimental systemic candidiasis.

Germfree J(H)D mice, which lack functional B cells and antibodies, were as resistant to orogastric and disseminated candidiasis of endogenous origin as were immunocompetent controls. Newborn J(H)D mice, in contrast to adult mice, were resistant to alimentary tract colonization by Candida albicans for 5-7 days after birth. C. albicans-colonized J(H)D mice were more resistant to intravenous challenge with C. albicans and had greater splenocyte proliferative responses to C. albicans antigens than did germfree mice or conventional controls. Thus, innate and acquired T cell-mediated immune responses induced after oral immunization are sufficient to protect J(H)D mice from mucosal and systemic candidiasis of endogenous origin; however, functional B cells may be required to protect mice from a primary intravenous challenge with C. albicans.

Animals↗

[Systemic candidiasis and ureteral fungus ball. Ketoconazole and irrigating solutions in the management of urinary candidiasis].

A case of systemic candidiasis is presented in a patient with one kidney in the post-operative period from a cysto-prostatouretrectomy with Bricker ureteroileal derivation, performed due to multifocal superficial vesical tumour non controllable by endoscopy. The clinical picture developed with anuria and temporary diuresis periods associated to a severe septic picture; a deep Candida albicans infection was demonstrated by laboratory tests and a fungus ball ureteral obstruction was demonstrated by radiology. Urinary derivation by means of percutaneous nephrostomy, associated with oral treatment with ketoconazole and local treatment with amphotericin B solution intermittently irrigated through the nephrostomy allowed the patient's resuperation and the fungus ball was spontaneously ejected after 30 days of treatment. The different forms of presentation of urinary candidiasis are discussed together with the diagnostic methods and present therapeutical options, with special reference to the imidazole derivative ketoconazole and irrigation solutions.

Amphotericin B↗

Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis.

Much progress has been made over the last decade in diagnosing and treating CDC, a chronic and debilitating infection that interferes with the delivery of intensive cytotoxic chemotherapy in patients with leukemia. The use of fluconazole prophylaxis in these patients has decreased the incidence of CDC dramatically. The greatest future challenges are gaining a better understanding of its pathophysiology, and the continued development of effective diagnostic and therapeutic strategies to treat this unusual manifestation of systemic candidiasis.

Antifungal Agents↗

Effect of abrogation of natural killer cell activity on the course of candidiasis induced by intraperitoneal administration and gastrointestinal candidiasis in mice with severe combined immunodeficiency.

Candida albicans CFU per gram of tissue recovered from livers, spleens, and kidneys of 12 severe combined immunodeficiency (scid) and 12 BALB/c mice 5 days after intraperitoneal (i.p.) administration of 10(7) C. albicans cells were not significantly different. Nine scid mice given normal rabbit serum (NRS) as a control and eight scid mice given anti-asialo-GM1 (alpha-ASGM1) had C. albicans CFU per gram recovered from livers and spleens 1 week after i.p. administration of C. albicans that were not significantly different, despite virtual elimination of natural killer (NK) cell activity in mice treated with alpha-ASGM1. At 2 weeks after i.p. administration, despite significantly increased NK cell activity in eight infected NRS-treated scid mice and virtual elimination of NK cell activity by alpha-ASGM1 treatment of eight scid mice, C. albicans CFU per gram recovered from livers and kidneys were not significantly different. At 2 weeks after intragastric administration of 2 x 10(6) C. albicans cells, eight NRS- and eight alpha-ASGM1-treated scid mice had identical proportions colonized with C. albicans and similar C. albicans CFU per gram recovered from feces. There was no evidence of hematogenous dissemination in either group. Similar results were seen 1 week after intragastric administration of 10(7) C. albicans cells. We conclude that NK cell activity is increased by i.p. administration of C. albicans in scid mice, but nontheless, abrogation of NK cell activity is not associated with enhanced susceptibility to candidiasis induced by i.p. administration and also is not associated with enhanced susceptibility to gastrointestinal colonization or hematogenous dissemination after intragastric administration of C. albicans.

Animals↗

[Orointestinal candidiasis with special emphasis on esophageal candidiasis].

Orointestinal mycoses are localized mainly in the oral cavity and in the oesophagus. Candida oesophagitis is not only found in AIDS-patients, also in patients of risk admitted to intensive care units. Upper intestinoscopies were made in 124 patients. Oesophageal candidosis was found in 6 patients, two of them had also Candida plaques in the stomach. The patients of the intensive care unit had an Apache-II-score of 26.7, those with Candida oesophagitis were 29.5. A significant increase in Candida antibodies was observed with 59 of 124 patients (47.6%), including all patients with oesophageal candidosis. Obviously also Candida infections of other localisations must be suspected. There was a correlation between the severity of endoscopic aspects and the invasiveness observed microscopically.

Candida↗