Oral Antifungal Agents Research Articles

Therapeutic options for the treatment of tinea capitis: Griseofulvin versus fluconazole

Background: Tinea capitis is a relatively common fungal infection of childhood. Griseofulvin has been the mainstay of treatment for many years. However, newer oral antifungal agents are being used more frequently. Objective: Our purpose was to evaluate the therapeutic efficacy of fluconazole in comparison with griseofulvin in the treatment of tinea capitis. Methods: We performed a single‐blind, randomized, prospective evaluation of 40 patients with a clinical and mycologic diagnosis of tinea capitis. One group received fluconazole for 4 weeks. The other group received griseofulvin for 6 weeks. Five clinical parameters were evaluated. Mycologic examinations were performed at baseline and at the end of 8 weeks. Results: Patients ranged in age from 1 to 16 years; 80% were boys and 20% were girls. Mycologic examinations disclosed Trichophyton verrucosum in 40% of patients, T. violaceum in 40% and Microsporum canis in 20%. At week 8, the griseofulvin‐treated group showed a cure rate of 76%, and the fluconazole‐treated group 78%. The cure rates were not statistically significant. Conclusion: Fluconazole constitutes an alternative but, because of greater availability and lower cost, griseofulvin remains the treatment of choice for tinea capitis.

Kokzidioidomykose

Coccidioidomycosis is a systemic mycosis that is acquired by inhalation. It is endemic in desert-like areas of the southwest USA and neighboring regions, but is becoming increasingly prevalent in other regions of the world as a result of widespread travel. The clinical spectrum is broad, ranging from inapparent infections or symptoms of acute respiratory infection with spontaneous recovery to various manifestations of disseminated coccidioidomycosis. Since the majority of patients with disseminated coccidioidomycosis present with cutaneous manifestations, early diagnosis of this potentially life-threatening disease by dermatologists is important. Atypical skin changes, pulmonary infiltrates and a history of travel to areas where the disease is endemic are indicative of coccidioidomycosis. For conclusive diagnosis, identification of the fungus by histopathologic examination or culture is desirable. Serological tests can be helpful for establishing the diagnosis and monitoring the course of the disease. The treatment of choice for cutaneous coccidioidomycosis is currently oral azole antifungal agents, such as itraconazole 400 mg daily, continued for 6 months after clinical response. Since relapses are frequent after discontinuation of the treatment, close clinical, serological and radiological follow-up is required for years.

How to Improve the Design of Trials of Antifungal Prophylaxis among Neutropenic Adults with Acute Leukemia

The risk for invasive fungal infections in patients with acute leukemia is generally low (4%-8%), and the routine use of fungal prophylaxis is not warranted except in specific high-risk groups that should be identified among this population. In a prophylactic study with a new agent, fluconazole or itraconazole oral solution represent good choices for the comparator because they are proven better than placebo or oral nonabsorbable antifungal agents in reducing the risk of invasive fungal infections in patients with acute leukemia. Because prophylaxis is most valuable when the risk of infection is high, patients with well-understood risk factors (severe mucosal disruption caused by chemotherapy, impaired cell-mediated immunity caused by steroids or fludarabine, use of a central venous catheter, and colonization by Candida species) should be selected. The end points for antifungal prophylactic trials should focus on proven and probable invasive fungal infections. Superficial and mucosal fungal infections do not represent a primary end point for these studies. Poor compliance should be considered as an interruption of treatment due to side effects and should be included in the criteria for failure. Fungus-related mortality should be evaluated as a failure of prophylaxis, whereas overall mortality may be influenced by many other cofactors. Differences in gastrointestinal toxicity of antifungal agents may limit the use of double-blind designs in some situations.

Inhibition of human vascular endothelial cells proliferation by terbinafine.

We have demonstrated previously that terbinafine (TB), an oral antifungal agent used in the treatment of superficial mycosis, suppresses proliferation of various cultured human cancer cells in vitro and in vivo by inhibiting DNA synthesis and activating apoptosis. In our study, we further demonstrated that TB at a range of concentrations (0-120 microM) dose-dependently decreased cell number in cultured human umbilical vascular endothelial cells (HUVEC). Terbinafine was not cytotoxic at a concentration of 120 microM, indicating that it may have an inhibitory effect on the cell proliferation in HUVEC. The TB-induced inhibition of cell growth rate is reversible. [(3)H]thymidine incorporation revealed that TB reduced the [(3)H]thymidine incorporation into HUVEC during the S-phase of the cell-cycle. Western blot analysis demonstrated that the protein levels of cyclin A, but not cyclins B, D1, D3, E, CDK2 and CDK4, decreased after TB treatment. The TB-induced cell-cycle arrest in HUVEC occurred when the cyclin-dependent kinase 2 (CDK2) activity was inhibited just as the protein level of p21 was increased and cyclin A was decreased. Pretreatment of HUVEC with a p21 specific antisense oligonucleotide reversed the TB-induced inhibition of [(3)H]thymidine incorporation. Taken together, these results suggest an involvement of the p21-associated signaling pathway in the TB-induced antiproliferation in HUVEC. Capillary-like tube formation and chick embryo chorioallantoic membrane (CAM) assays further demonstrated the anti-angiogenic effect of TB. These findings demonstrate for the first time that TB can inhibit the angiogenesis.

New treatments for tinea capitis.

Tinea capitis, a dermatophyte infection involving the hair shaft on the scalp, is primarily a disease of preadolescent children. The predominant pathogen varies according to the geographical location. Trichophyton tonsurans and Microsporum canis account for the majority of infections in north America and certain parts of Europe. The current standard of care for the treatment of tinea capitis in the USA is oral griseofulvin, but evidence is accumulating that some of the newer antifungal agents may also be useful. The newer oral antifungal agents such as terbinafine, itraconazole and fluconazole seem to be effective, safe, and have the advantage of a shorter treatment duration. Although a significant number of clinical studies and reports have documented experience with terbinafine and itraconazole for the treatment of tinea capitis, it should be noted that only a few trials have been conducted utilizing fluconazole. Both 2% ketoconazole and 1% selenium sulfide shampoos are often recommended as adjuvant topical therapy. Currently, many experts consider griseofulvin to be the drug of choice for tinea capitis. Short-term terbinafine, itraconazole and fluconazole therapy have been shown to be comparable in efficacy and safety with griseofulvin. Regular epidemiological surveillance of causative fungal organisms in the community and their antifungal susceptibility is an essential component in the management of this condition.

A current appraisal of drug interactions of significance in clinical practice: focus on antifungal therapeutic agents used in the treatment of superficial mycoses

The subject of drug-drug interactions has continued to expand in terms of understanding its mechanisms, with potentially significant interactions based on advances in evaluating metabolic pathways and enhanced recognition of the importance of pharmacogenomics. Within dermatology, the clinical significance of drug interactions has been made evident by the withdrawal from the marketplace of the “nonsedating” antihistamines, terfenadine and astemizole, due to the increased propensity for prolongation of the QTc interval with subsequent ventricular arrhythmia when these agents were coadministered with erythromycin, ketoconazole or itraconazole. This “hallmark interaction” association is directly related to inhibition of the cytochrome (CYP) 3A4 metabolic pathway by several macrolide antibiotics and azole antifungal agents. Due to the predominant role of CYP 3A4 in the metabolism of approximately half of currently available drugs, the potential for widespread impact related to CYP3A4 inhibition, as well as other less predominant CYP metabolic isoenzymes, has received significant notoriety. In the US, between 1987 and 1991, 98 drugs received approval for use with 32 inclusive of drug interaction studies. Between 1992 and 1997, although the number of approved drugs doubled, the number of associated drug interaction studies more than tripled. Several warnings and contraindications have emerged related to drug interactions, such as recommendations to avoid coadministration of some macrolide antibiotics or azole antifungal agents with HMG-CoA reductase inhibitors, some benzodiazepines and some cardiac drugs, including digoxin. Considering the widespread prevalence of superficial mycotic infections and associated oral antifungal use, it is rational to periodically revisit the subject of potential drug interactions and oral antifungal agents. Due to variations in metabolic pathways, significant differences in the potential for interactions have been established when comparing griseofulvin, terbinafine, ketoconazole and the triazoles, itraconazole and fluconazole. Overall, compared to other oral antifungal agents, terbinafine is associated with the most favorable safety profile with regard to clinically significant drug interactions. This poster provides an overview and update on potential drug interactions related to the selection of specific oral antifungal agents. Emphasis will be placed on supportive data, clinical significance, and management suggestions for the clinician.

Ciclopirox nail lacquer in the treatment of onychomycosis

Ciclopirox nail lacquer solution 8% is the first and only topical lacquer approved in the US for the treatment of mild to moderate onychomycosis, without lunula involvement, due to Trichophyton rubrum. This antifungal agent is broad-spectrum with activity against dermatophytes, Candida species and some non-dermatophyte molds. In vitro data suggests that a synergy exists between ciclopirox and terbinafine; hence, the combination of these two agents may be more effective than terbinafine alone when treating severe onychomycosis (e.g., nail matrix involvement). Ciclopirox nail lacquer may also be a consideration in children where the nail plate is thinner and the rate of nail outgrowth is faster compared to adults. It should be noted that neither ciclopirox nor the newer antifungal agents, terbinafine and itraconazole, are approved in the US for the treatment of onychomycosis in children. The topical nail lacquer may be preferred to an oral antifungal agent when treating the elderly, diabetics, and those who are immunocompromised since these patients may have limited renal or hepatic reserve, or be taking several drugs, some of which may interact or be contraindicated with one or more of the oral antifungal agents. Ciclopirox nail lacquer may also be of value in prophylactic therapy, helping to prevent relapse of successfully treated onychomycosis especially among diabetics, immunocompromised individuals, and patients with a family history of onychomycosis or chronic fungal infections (e.g., tinea pedis) since these patients are more likely to redevelop onychomycosis following mycological cure.

Assessing the efficacy of the oral antifungal agents in the management of dermatophyte toenail onychomycosis

Assessing the efficacy of the oral antifungal agents in the management of dermatophyte toenail onychomycosis

Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis.

Onychomycosis is a common nail disease that is often chronic, difficult to eradicate, and has a tendency to recur. The most common oral therapies for dermatophyte toenail onychomycosis include terbinafine, itraconazole and fluconazole. A cumulative meta-analysis of the randomized controlled trials (RCTs) for antimycotic agents was performed to determine whether the pooled estimate of the cure rates has remained consistent over the years. Furthermore, for each agent we compared the overall meta-analytical average of both mycological and clinical response rates of RCTs vs. open studies. We searched MEDLINE (1966 to November 2002) for relevant studies evaluating the efficacy of the oral antifungal agents terbinafine, itraconazole (pulse or continuous), fluconazole and griseofulvin for treating dermatophyte toenail onychomycosis. Studies included in this meta-analysis required a standard accepted dosage regimen, treatment duration and follow-up period. To determine the cumulative meta-analytical average, studies were sequentially pooled by adding one study at a time according to the date of publication (i.e. earliest to the most recent). There were 36 studies included in the analyses. For RCTs the change in efficacy of mycological cure rates from the first trial to the overall cumulative meta-average for each drug comparator is as follows (with 95% confidence interval): terbinafine, 78 +/- 6% (n = 2 studies, 79 patients) to 76 +/- 3% (n = 18 studies, 993 patients) (P = 0.68); itraconazole pulse, 75 +/- 10% (n = 1 study, 20 patients) to 63 +/- 7% (n = 6 studies, 318 patients) (P = 0.25); itraconazole continuous, 63 +/- 5% (n = 1 study, 84 patients) to 59 +/- 5% (n = 7 studies, 1131 patients) (P = 0.47); fluconazole, 53 +/- 6% (n = 1 study, 72 patients) to 48 +/- 5% (n = 3 studies, 131 patients) (P = 0.50); and griseofulvin, 55 +/- 8% (n = 2 studies, 109 patients) to 60 +/- 6% (n = 3 studies, 167 patients) (P = 0.41). The cumulative meta-analytical average of mycological cure rates when comparing RCTs vs. open studies was: terbinafine, 76 +/- 3% (n = 18 studies, 993 patients) vs. 83 +/- 12% (n = 2 studies, 391 patients) (P = 0.0028); itraconazole pulse, 63 +/- 7% (n = 6 studies, 318 patients) vs. 84 +/- 9% (n = 3 studies, 194 patients) (P = 0.0001); and fluconazole, 48 +/- 5% (n = 3 studies, 131 patients) vs. 79 +/- 3% (n = 3 studies, 208 patients) (P = 0.0001). The cumulative meta-analysis of cure rates for RCTs suggests that over time, as new RCTs have been conducted, the efficacy rates have remained consistent. The efficacy rates of open studies are substantially higher compared with RCTs and may therefore overestimate cure rates.

Mohs Micrographic Surgery for the Eradication of Phaeohyphomycosis of the Hand

BACKGROUND Phaeohyphomycosis is a rare mycotic infection that is caused by dematiaceous fungi requiring surgical excision or long-term use of oral antifungal agents for treatment. OBJECTIVE To report a case of phaeohyphomycosis of the dorsal hand successfully cleared with Mohs micrographic surgery. METHODS We performed Mohs micrographic surgery on phaeohyphomycosis of the dorsal hand. The fungus was cleared in three stages of surgery. Permanent processing and special stains of the final stage confirmed eradication of the infection. RESULTS The patient remained free of the phaeohyphomycosis, without complications, at the 6-month follow-up. CONCLUSION Mohs micrographic surgery is an effective, tissue-sparing technique for the eradication of phaeohyphomycosis, potentially eliminating the need for costly long-term antifungal therapy.

Treatment of Onychomycosis: Pros and Cons of Antifungal Agents

Antifungal agents are beneficial in the treatment of onychomycosis in the general population, as well as in children, the elderly, and immunocompromised individuals. Special patient populations can be more difficult to treat due to such factors as drug interactions with concomitant medications, adverse events, and poor compliance. In addition, there is limited information about the use of antifungal agents in special populations, e.g., children. The pros and cons of oral and topical antifungal agents are discussed, with focus on special patient populations. We searched MedLine (1966 to April 2003) for clinical studies evaluating the efficacy of oral and topical antifungal agents to treat onychomycosis. The key words used in conjunction with "onychomycosis" include: "terbinafine," "itraconazole," "fluconazole," "amorolfine nail lacquer," "ciclopirox nail lacquer," "HIV," "transplant patients," "diabetes," "children," and "elderly." Studies were excluded if published in a language other than English. Studies have shown that antifungal agents can be of benefit in treating the elderly, children, and immunocompromised individuals (e.g., transplant patients, Down's patients, HIV patients, and diabetics) with onychomycosis. The treatment modality of onychomycosis in special patient populations should take into account the clinical presentation of the onychomycosis, the causative organism, patient and physician preference, the concomitant medications that the patient is on, and the potential for adverse events for that patient if antifungal therapy is undertaken.

Treatment of Onychomycosis: Pros and Cons of Antifungal Agents

Background: Antifungal agents are beneficial in the treatment of onychomycosis in the general population, as well as in children, the elderly, and immunocompromised individuals. Special patient populations can be more difficult to treat due to such factors as drug interactions with concomitant medications, adverse events, and poor compliance. In addition, there is limited information about the use of antifungal agents in special populations, e.g., children. Objective: The pros and cons of oral and topical antifungal agents are discussed, with focus on special patient populations. Methods: We searched MedLine (1966 to April 2003) for clinical studies evaluating the efficacy of oral and topical antifungal agents to treat onychomycosis. The key words used in conjunction with “onychomycosis” include: “terbinafine,” “itraconazole,” “fluconazole,” “amorolfine nail lacquer,” “ciclopirox nail lacquer,” “HIV,” “transplant patients,” “diabetes,” “children,” and “elderly.” Studies were excluded if published in a language other than English. Results: Studies have shown that antifungal agents can be of benefit in treating the elderly, children, and immunocompromised individuals (e.g., transplant patients, Down's patients, HIV patients, and diabetics) with onychomycosis. Conclusion: The treatment modality of onychomycosis in special patient populations should take into account the clinical presentation of the onychomycosis, the causative organism, patient and physician preference, the concomitant medications that the patient is on, and the potential for adverse events for that patient if antifungal therapy is undertaken.

Dermatology for the practicing allergist: Tinea pedis and its complications

Tinea pedis is a chronic fungal infection of the feet, very often observed in patients who are immuno-suppressed or have diabetes mellitus. The practicing allergist may be called upon to treat this disease for various reasons. Sometimes tinea infection may be mistaken for atopic dermatitis or allergic eczema. In other patients, tinea pedis may complicate allergy and asthma and may contribute to refractory atopic disease. Patients with recurrent cellulitis may be referred to the allergist/immunologist for an immune evaluation and discovered to have tinea pedis as a predisposing factor. From a molecular standpoint, superficial fungal infections may induce a type2 T helper cell response (Th2) that can aggravate atopy. Th2 cytokines may induce eosinophil recruitment and immunoglobulin E (IgE) class switching by B cells, thereby leading to exacerbation of atopic conditions. Three groups of fungal pathogens, referred to as dermatophytes, have been shown to cause tinea pedis: Trychophyton sp, Epidermophyton sp, and Microsporum sp. The disease manifests as a pruritic, erythematous, scaly eruption on the foot and depending on its location, three variants have been described: interdigital type, moccasin type, and vesiculobullous type. Tinea pedis may be associated with recurrent cellulitis, as the fungal pathogens provide a portal for bacterial invasion of subcutaneous tissues. In some cases of refractory asthma, treatment of the associated tinea pedis infection may induce remission in airway disease. Very often, protracted topical and/or oral antifungal agents are required to treat this often frustrating and morbid disease. An evaluation for underlying immuno-suppression or diabetes may be indicated in patients with refractory disease.

好中球減少患者における診療指針

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in neutropenic patients with leukemia and those undergoing hematopoietic stem cell transplant (HSCT). Two major IFIs are systemic candidiasis (including candidemia, chronic disseminated candidiasis and pneumonia) and invasive pulmonary aspergillosis. Recently, the incidence of the latter has been increasing. Three levels of diagnosis are specified in the Japanese guidelines for the diagnosis and treatment of IFIs. Proven fungal infections are diagnosed by histological/microbiological evidence of fungi at the site of infection or positive blood culture (fungemia). Clinically documented fungal infections are diagnosed by typical radiological findings such as halo sign on chest CT plus positive serological/molecular evidence of fungi such as Aspergillus galactomannan, beta-glucan or fungal DNA. Possible fungal infections are diagnosed by typical radiological findings or positive serological/molecular evidence of fungi. For patients with high risk such as those undergoing HSCT, antifungal prophylaxis using oral antifungal agents is recommended. For possible fungal infections, empiric therapy with fluconazole (FLCZ) or amphotericin B (AMPH) is recommended. For patients with proven fungal infections or clinically documented fungal infections, targeted therapy is warranted. In case of candidemia, the best choice is FLCZ (400 mg/day) or AMPH (0.5-0.7 mg/kg/day), and for invasive pulmonary aspergillosis, a higher dose of AMPH (1.0-1.5 mg/kg/day) is indicated. Micafungin (MCFG), recently licensed in Japan, is an active agent for both Candida and Aspergillus. This drug seems useful for empiric and targeted therapy of IFIs.

Treating chromoblastomycosis with systemic antifungals

Chromoblastomycosis is a subcutaneous mycosis for which there is no treatment of choice but rather, several treatment options, with low cure rates and many relapses. The choice of treatment should consider several conditions, such as the causal agent (the most common one being Fonsecaea pedrosoi), extension of the lesions, clinical topography and health status of the patient. Most oral and systemic antifungals have been used; the best results have been obtained with itraconazole and terbinafine at high doses, for a mean of 6 – 12 months. In extensive and refractory cases, chemotherapy with oral antifungals may be associated with thermotherapy (local heat and/or cryosurgery). Limited or early cases may be managed with surgical methods, always associated with oral antifungal agents. It is important to determine the in vitro sensitivity of the major causal agents to the various drugs, by estimating the minimum inhibitory concentration, as well as drug tolerability and drug interactions.

同種造血幹細胞移植における深在性真菌感染症予防

Hematopoietic stem cell transplantation has been established as a curative treatment for advanced hematologic malignancies. Transplantation with a reduced-intensity conditioning regimen has been developed. The minimal toxicity of reduced-intensity stem cell transplantation (RIST) has made transplantation available for patients of advanced age or with organ dysfunction. The response of malignant lymphoma and some solid tumors to RIST has been observed. RIST with unrelated donors and umbilical cord blood has been studied. Fungal infection is an important complication of RIST. Since the prognosis of fungal infection is poor, the management has been focused on its prophylaxis. Given recent progression in RIST management, the strategy of infectious prophylaxis has also changed. Equipment in the hospital is important for fungal infection; however, the median day of the development of fungal infection is day 100, when most patients are followed as outpatients. The focus of fungal management after RIST is oral antifungal agents rather than in-hospital equipment. Various antifungal agents have recently been developed and applied for clinical use. Many antifungals have been developed simultaneously for the first time. A major change in antifungal management will probably occur in the next several years.

Optimal management of fungal infections of the skin, hair, and nails.

Superficial fungal infections are chronic and recurring conditions. Tinea capitis is a scalp infection, primarily affecting prepubescent children. Ringworm infections, such as tinea corporis and tinea cruris, involve the glabrous skin. Tinea nigra is a rare mycotic infection that may be related to travel abroad. Piedra, black or white, is limited to the hair shaft without involvement of the adjacent skin. Pityriasis (tinea) versicolor and seborrheic dermatitis are dermatoses associated with yeasts of the genus Malassezia that affect the lipid-rich areas of the body. The taxonomy of the Malassezia yeasts has been revised to include nine species, eight of which have been recovered from humans. Tinea pedis, an infection of the feet and toes, is one of the most common forms of dermatophytosis. Onychomycosis is a fungal infection affecting the nail bed and nail plate; it may be chronic and can be difficult to treat. In instances where the superficial fungal infection is severe or chronic, an oral antifungal agent should be considered. Terbinafine, itraconazole, and fluconazole are oral antifungals that are effective in the treatment of superficial mycoses.

Onychomycosis in Children: A Brief Overview with Treatment Strategies

Onychomycosis in children is uncommon. In those children that are affected, a family history of onychomycosis is not uncommon, giving importance to the examination of the entire family for fungal nail infections. In the United States, the newer oral antifungal agents itraconazole, fluconazole, and terbinafine, and the topical nail lacquers ciclopirox and amorolfine are not approved for this indication. More data are needed on the use of these antifungal agents for the treatment of onychomycosis in children.

Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants.

Systemic fungal infection has increased in prevalence in neonatal intensive care units (NICU) caring for very low birth weight infants. It is associated with a prolonged stay and an increase in morbidity and mortality. An assessment of the use of oral prophylactic antifungals to prevent systemic infection is needed. To assess whether the prophylactic administration of oral antifungal agents to very preterm infants reduces the occurrence of systemic fungal infection. The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Searches were carried out up to July 2003 on the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 2, 2003), MEDLINE from 1966, EMBASE from 1980, CINAHL from 1992. Abstracts from SPR (1993 - 2003) and ESPR (1995 to 2002) were hand searched. Randomized and quasi randomized controlled trials in very low birth weight or very preterm infants in which an oral antifungal agent was compared with placebo or no treatment or another oral antifungal agent Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of the trial quality and data extraction undertaken by each author. Results were reported using relative risk (RR) and risk difference (RD) and weighted mean difference (WMD). 95% confidence intervals were reported. We identified three eligible trials, one comparing nystatin with no treatment (67 infants), one comparing miconazole with placebo (600 infants), and one comparing nystatin with fluconazole (21 infants). As the two trials comparing nystatin or miconazole with placebo or no treatment were clinically quite different, meta-analysis was not performed. In the trial of nystatin versus no treatment, systemic fungal infection was significantly reduced [RR 0.19 (0.04,0.78)] in the group treated with nystatin. In the study comparing miconazole with placebo there was no significant effect on systemic fungal infection [RR 1.32 (0.46,3.75)]. Neither study found a significant effect on mortality, and there was no significant difference in the mean number of days infants received ventilation or stayed in the neonatal intensive care unit. In the small trial comparing oral fluconazole with nystatin, no significant difference in systemic fungal infection [RR 0.17 (0.01, 2.84)] or mortality [RR 0.17 (0.01, 2.84)] was reported. Adverse drug reactions were not reported in any study. There is insufficient evidence to support the use of prophylactic oral antifungal agents in very low birth weight infants in the neonatal intensive care unit. Randomised controlled trials in current neonatal practice settings are needed, comparing oral antifungal agents with placebo and with each other and including an assessment of side effects, in order to determine whether oral antifungal agents have a role in preventing systemic fungal infections in preterm infants.

Onychomycosis in clinical practice: factors contributing to recurrence.

The treatment of onychomycosis has improved in recent years and many patients can now expect a complete and lasting cure. However, for up to 25% of patients, persistent disease remains a problem, thus presenting a particular challenge to the clinician. For these patients, it is obviously important to ensure that a correct diagnosis of onychomycosis has been made, as misdiagnosis will inevitably jeopardize the perception of therapeutic effectiveness. Although onychomycosis accounts for about 50% of all nail diseases seen by physicians, nonfungal causes of similar symptoms include repeated trauma, psoriasis, lichen planus, local tumours vascular disorders and inflammatory diseases. Predisposing factors that contribute to a poor response to topical and/or oral therapy include the presence of a very thick nail, extensive involvement of the entire nail unit, lateral nail disease and yellow spikes. However, poor penetration of systemic agents to the centre of infection, or the inability of topical agents to diffuse between the surface of the nail plate and the active disease below, probably contributes to this. Other factors contributing to recurrence may be related to the patient's family history, occupation, lifestyle or underlying physiology. In addition, patients with concomitant disease (e.g. peripheral vascular disease, diabetes) or patients who are immunosuppressed (e.g. those with human immunodeficiency virus/acquired immunodeficiency syndrome) are more susceptible to onychomycosis. In the elderly, the prevalence of onychomycosis may be as high as 60%, and increases with age; in this population, physical trauma plays a major role in precipitating recurrence, especially in patients with faulty biomechanics due to underlying arthritis and bone abnormalities. It is also possible that recurrence in some cases is due to early termination of treatment or use of an inappropriate dose, and these possibilities should be eliminated before further investigations are undertaken. There is good evidence to suggest that a combination of oral and topical therapies, when given at the same time, yield excellent clinical outcomes, although there remains a need for more effective topical agents with greater nail penetration and more effective oral antifungal agents.