Jorge E. Arrese

Treatment Failures and Relapses in Onychomycosis: A Stubborn Clinical Problem

The therapeutic outcome of onychomycoses is uncertain. Comparative short-term efficacy studies on antifungals abound and report contradictory findings. Few unbiased follow-up studies have scrutinized the long-term outcome. Basically, none of the current antifungals can guarantee cure in all instances. In addition, relapses are not rare. The causes of therapeutic failure in onychomycoses are multiple. The most important are the lack of diagnostic accuracy, inadequate antifungal choice or delivery modality, and presence of dormant conidia, sequestrated mycelium pockets or resistant fungal species. The concept of fungicidal drug derived from selected in vitro studies appears irrelevant in clinical practice.

Present and potential diagnostic techniques in onychomycosis

The problem of onychomycosis has been frequently addressed during recent years. To make the diagnosis of onychomycosis dermatologists have relied on clinical presentation, culture, and microscopy. These approaches are hampered by false-negative and false-positive results that have confused treatment outcomes. Two new diagnostic techniques, immunohistochemistry and flow cytometry, provide an effective means of identifying different dermatophytes, yeasts, and nondermatophytic molds. Immunohistochemistry employs antibodies to certain fungi to enable positive identification in situ, whereas flow cytometry differentiates fungi on the basis of molecular differences. These techniques provide new evidence that nondermatophytic molds and yeasts can actively invade nail tissue and that mixed infections occur. These findings could have important implications for the treatment of onychomycosis.

Fatal hyalohyphomycosis following Fusarium onychomycosis in an immunocompromised patient.

A 35-year-old man with B lymphoblastic lymphoma was treated with bone marrow transplant and aggressive chemotherapy. He developed a Fusarium infection of the great toenail. Septicemic dissemination of a Fusarium sp. occurred 9 months later during a lymphoma relapse. The clinical course of the hyalohyphomycosis was then rapidly fatal despite institution of amphotericin B therapy.

Surfactant-induced dermatitis: Comparison of corneosurfametry with predictive testing on human and reconstructed skin

BACKGROUND Surfactants elicit alterations in the stratum corneum. Predictive tests that avoid animal experimentation are needed. OBJECTIVE This study compares three methods of rating and predicting shampoo-induced irritation. METHODS Corneosurfametry entails collection of stratum corneum followed by brief contact with diluted surfactants and measurement of variations in staining of samples. RESULTS Corneosurfametry appears to correlate well with in vivo testing in volunteers with sensitive skin. However, corneosurfametry presents less interindividual variability than in vivo testing and allows better discrimination among mild products. Morphologic information about surfactant-induced loosening of corneocytes may be increased by testing surfactants on human skin equivalent. Results are similar to those provided by specimens used for corneosurfametry. CONCLUSION The corneosurfametric prediction of surfactant irritancy correlates with in vivo testing and with in vitro evaluation on human skin equivalent.

Facing up to the diagnostic uncertainty and management of onychomycoses

Onychomycoses represent a common and complex medical problem.1–4 In all aspects of everyday practice, from diagnosis and treatment to prognosis, the clinician is beset by questions and may remain uncertain of the answers. It is not possible to dissociate the members of the threesome – diagnosis, treatment, and pharmacoeconomy – without running the risk of totally distorting the perception of this condition. The logical procedure may be summarized in the form of a few questions which lead on from each other like the items in a decision tree.

Treatment and Prophylaxis of Tinea Infections

SummarySuperficial fungal infections affect millions of people throughout the world. Among them, tinea represents cutaneous infections by dermatophytes. Therapeutic strategies depend upon the affected body site. Hence, clinicians distinguish several types of tinea including the corporis, faciei, cruris, pedis, manuum, capitis, barbae and unguium variants. There are several ways of tackling the tinea problem. Numerous topical and oral antifungals are available today. Topical antifungals remain the most commonly recommended treatment for many superficial dermatophytoses. Active compounds include imidazoles, morpholines and allylamines, with a few other miscellaneous drugs. The recent development of new generation oral agents (fluconazole, itraconazole, terbinafine) has enhanced the armamentarium against difficult-to-treat tineas. The antifungal efficacy and pharmacokinetic profiles of these drugs allow shorter durations of treatment and the innovative use of intermittent pulse regimens. The modern formulations fully meet the requirements of being well tolerated, involving little risk and acting specifically against relevant pathogens. However, the response rates to date do not always come up to the high expectations offered by in vitro studies.

Antifungal activity of itraconazole and terbinafine in human stratum corneum: A comparative study

BACKGROUND The evaluation of antifungal agents by in vitro and animal experiments cannot predict clinical efficacy with certainty. New models are needed to assess and compare antifungal activity. OBJECTIVE We compared on human stratum corneum ex vivo the antifungal activity and lingering effect of 200 mg itraconazole daily and twice daily, and 250 mg/day terbinafine. METHODS Three groups of 10 healthy volunteers entered the open comparative trial. Results were evaluated in a blinded manner. Cyanoacrylate skin surface strippings (CSSS) were taken from the back and superficial dermatome skin samples (SDSS) were taken from plantar skin at days 0, 1, 3, 7, 8, 10, 14, 21, 28, and 35. Spores or yeasts of selected fungi (Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, and Candida albicans) were deposited and cultured on the CSSS and SDSS. The 1-week fungal growth on CSSS and SDSS was assessed over time by computerized image analysis to derive the inhibitory effect of the oral antifungal agents administered. Fungitoxic activity was also assessed by the use of 2-day cultures on CSSS followed by a transfer to Sabouraud medium. RESULTS Comparable antifungal activity against dermatophytes was found for all three regimens. Itraconazole at both dosages was always significantly more active than terbinafine against C. albicans on CSSS and SDSS. Overall, 200 mg itraconazole twice daily appeared to be more fungitoxic than 250 mg/day terbinafine and 200 mg/day itraconazole. CONCLUSION The ex vivo culture of fungi on human stratum corneum is very similar to the in vivo situation. Both itraconazole and terbinafine display high antidermatophyte activity. Faster onset and longer posttherapy activity were demonstrated in the itraconazole treatment groups. Terbinafine had marginal activity against C. albicans in this model.

Effect of Ketoconazole 1% and 2% Shampoos on Severe Dandruff and Seborrhoeic Dermatitis: Clinical, Squamometric and Mycological Assessments

Ketoconazole (KET) is active to control dandruff and seborrhoeic dermatitis. Objective assessments comparing the 1% and 2% shampoo formulations are scant. This open, randomized parallel-group trial was carried out to differentiate the effectiveness of KET 1% and 2% in severe dandruff and seborrhoeic dermatitis. A total of 66 patients with severe dandruff or seborrhoeic dermatitis were randomized to each of the two groups. A 2-week run-in phase was followed by a 4-week treatment phase, in turn followed by a 4-week follow-up. The efficacy of treatments was evaluated by combining squamometry X, Malassezia spp. counts and clinical assessments. After 2 and 4 weeks of treatment, KET 2% was significantly superior over KET 1% (p < 0.001) for decreasing both in flakiness and Malassezia density from baseline. The same trend was observed in the mean change from baseline in the overall dandruff severity score. Only 6 mild adverse events were reported. During follow-up KET 2% showed a trend to fewer relapses than KET 1%. KET 2% had superior efficacy compared to KET 1% in the treatment of severe dandruff and scalp seborrhoeic dermatitis. Biometrological evaluations were correlated with the clinical improvements and therefore useful to incorporate in future dandruff studies.

Dermal dendritic cells in anogenital warty lesions unresponsive to an immune-response modifier

Background: Human papilloma viruses (HPV) are responsible for a variety of proliferative epithelial lesions including anogenital condylomas. These lesions may regress during treatment with an immune‐response modifier such as imiquimod. The release of specific cytokines from the monocyte‐macrophage lineage induces a cascade of events abating the HPV replication.

A plea to bridge the gap between antifungals and the management of onychomycosis.

Onychomycosis represents a stubborn problem for the clinician facing up to the realities of antifungal treatments. There are obvious discrepancies between data given by in vitro antifungal testings, pharmacodynamics and pharmacokinetics, and those gathered from clinical experience. This critical review is an attempt at bridging the gap between in vitro and in vivo information about oral antifungals that aim to treat onychomycoses. Common sense shows that the in vitro concept of fungicidy cannot be simply extrapolated into clinical practice. Indeed, chlamidoconidia and arthroconidia present in vivo are much more resistant to antifungals than hyphae. Corneofungimetry may be a realistic bioassay in predicting antifungal activity in human infections. Boosting hyphae growth from conidia while taking antifungals is a new and appealing treatment modality that deserves controlled study.