Histoplasmosis in Europe: report on an epidemiological survey from the European Confederation of Medical Mycology Working Group.

The purpose of this survey was to systematically collect data on individuals with histoplasmosis in Europe over a 5-year period (from January 1995 to December 1999). This included information on where and how the infection was acquired, the patient's risk factors, the causative organism, how the infection was diagnosed and what therapy the patients received. Data were sent on a standardized survey form via a national convenor to the coordinator. During the survey, 118 cases were reported, with 62 patients having disseminated disease, 31 acute pulmonary infection, chronic pulmonary infection in 6 and localized disease in 2 patients. For 17 patients, the diagnosis of histoplasmosis was incidental, usually secondary to investigations for lung cancer. Most patients had travelled to known endemic areas, but 8 patients (from Italy, Germany and Turkey) indicated that they had not been outside their countries of origin and hence these cases appear to be autochthonous. Notable observations during the survey were the reactivation of the disease up to 50 years after the initial infection in some patients and transmission of the infection by a transplanted liver. Itraconazole was the most commonly used therapy in both pulmonary and disseminated disease. The observation of autochthonous cases of disease suggests that the endemic area of histoplasmosis is wider than classically reported and supports continued surveillance of the disease throughout Europe.

Testing of antifungal combinations against yeasts and dermatophytes.

BACKGROUND: Fungal infections of the nail are a common and chronic problem. The main pathogens responsible for onychomycosis are dermatophytes, yeasts and moulds. Despite significant improvements, approximately 20% of patients with onychomycosis still fail on antifungal therapy. The successful exploitation of drug synergy may provide a useful approach to improve cure rates. METHODS: The minimum inhibitory concentrations (MIC(80)) were recorded for pathogens that are most frequently responsible for onychomycosis against combinations of several antifungal agents, namely, fluconazole, itraconazole, terbinafine and amorolfine. Fractional inhibitory concentrations (FICs) were then calculated from the MIC(80) results and the FIC values for each drug in the combinations added to determine the degree of synergy. A combined value of <1 was taken to suggest synergy; a value of 1-2 indicated an additive effect or indifference; and a combined FIC value of >2 was taken to suggest antagonism. RESULTS: Overall, 46% of amorolfine combinations showed results suggestive of synergy, with the most synergistic results seen against dermatophytes (54%) and moulds (52%). CONCLUSIONS: Some combinations of drugs may have synergistic activity in vitro; however, the importance of this in a clinical setting is yet to be established, and more studies are justified.

Drug synergies and the potential for combination therapy in onychomycosis.

Synergy between antifungal drugs is well recognized. However, combinations of antifungals are yet to be widely adopted to treat onychomycosis. The rationale for the combination of topical and oral therapy in the treatment of onychomycosis is that the systemic antifungal reaches the infection area via the nail bed and the topical agent is absorbed through the nail surface. The combination of antifungals used should ideally be synergistic in their mode of action. Synergy between amorolfine and other antifungals has been demonstrated in vitro. This is presumably due to differences in the precise point of action of the drugs on the fungal cell membrane, where they inhibit the synthesis of ergosterol. Thus, combinations can result in increased antifungal activity at lower concentrations of both drugs. The potential exists therefore for combinations of antifungals to achieve higher cure rates in onychomycosis, in a shorter time than is currently possible. This approach warrants further investigation.

Prediction of outcome in the treatment of onychomycosis.

Patients with toenail onychomycosis remain a therapeutic challenge despite the introduction of new systemic therapies. Around 20% of patients remain uncured even with optimal oral therapy, but the reasons for treatment failure are unclear. Thus far there are no data to suggest that treatment failures can be identified on the basis of their presenting features or progress during treatment. In a series of patients, we have attempted to identify clinical parameters that determine the patient response to 12 weeks of oral terbinafine for confirmed dermatophyte onychomycosis. As part of a dose-defining randomized multicentre study, 35 patients were followed for 48 weeks. The unaffected nail length, growth rate, hyperkeratosis, onycholysis and presence of a dermatophytoma were assessed prospectively. To confirm our findings, at the end of the study period we analysed retrospectively photographs that had been taken regularly throughout the trial. The average degree of hyperkeratosis was less severe in the group achieving a disease-free nail, meaning clinical and mycological cure. For mycological cure alone, no predictive factors could be identified.

Molecular strain typing of Trichophyton rubrum indicates multiple strain involvement in onychomycosis.

BACKGROUND: Trichophyton rubrum is an important cause of onychomycosis. Molecular strain typing methods have recently been developed to address questions of epidemiology and source of relapse following treatment. OBJECTIVES: To determine whether T. rubrum nail infections are caused by one or more strains of this fungus. METHODS: Nail specimens from 10 patients with onychomycosis due to T. rubrum were cultured and five colonies per culture plate were selected for molecular strain typing. DNA was extracted from these isolates and subjected to a polymerase chain reaction-based typing method that analyses variations in numbers of repetitive elements in the non-transcribed spacer region of the ribosomal RNA gene repeats. RESULTS: In six of 10 specimens, there were two or more T. rubrum strain types present. CONCLUSIONS: This preliminary study suggests that in many cases of fungal nail infection by T. rubrum, multiple strains are involved. This has important implications for epidemiological studies and possibly for therapy.

Prognostic factors of mycological cure following treatment of onychomycosis with oral antifungal agents.

BACKGROUND: There is considerable literature on the efficacy and safety of various drugs used in treating onychomycosis; however, little information is available regarding prognostic factors which may be associated with non-response to conventional treatment. OBJECTIVES: To identify parameters influencing mycological cure at 72 weeks following treatment of toenail onychomycosis with oral antifungal agents. METHODS: Univariate and multivariate logistic regression analysis from a randomized double-blind controlled trial including 496 patients with toenail onychomycosis caused by dermatophytes. RESULTS: Baseline parameters including patient's age, gender, weight, number of toenails involved, percentage of nail involvement, duration of infection, history of previous treatment were not associated with mycological cure. In the multivariate prognostic factor analysis based on factors assessed at week 12, positive mycological culture at 12 weeks [odds ratio (OR): 0.583; 95% confidence interval (CI): 0.370-0.918] was negatively associated with mycological cure at 72 weeks. Similarly, in the multivariate prognostic factor analysis based on factors assessed at week 24, positive direct microscopy at 24 weeks (OR: 0.373; 95% CI: 0.211-0.659) and mycological culture at 24 weeks (OR: 0.293; 95% CI: 0.168-0.513) were negatively associated with mycological cure at 72 weeks. CONCLUSIONS: Mycological culture at 12 and 24 weeks and direct microscopic examination at 24 weeks can help in early identification of patients failing to respond to conventional oral antifungal treatment.

The oncogenic potential of Candida in the female genital tract.

The possible role of Candida species in carcinogenesis at the uterine cervix was investigated in 226 females attending a colposcopy clinic. Approximately 34% of the 226 subjects harbored Candida species in cervical/vaginal secretions, but there was no association with any particular histologic abnormality. Two independent analytical procedures were used for strain discrimination of the isolates of C. albicans, but again no relationship was found between individual strains and histologic diagnoses. Only three C. glabrata strains were isolated, but they were all in association with cervical intraepithelial neoplasia (CIN) II or III. A total of 18 strains of C. albicans, one C. glabrata and one C. parapsilosis all inhibited the formation of the nitrosamine nitrosodimethylamine (NDMA) from precursors. Furthermore, C. albicans strains did not convert NDMA to carcinogenic metabolites. The results of this study do not suggest that C. albicans has a role in cervical carcinogenesis.