Donald L. Greer

Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the fingernail.

BACKGROUND Onychomycosis is a prevalent infection of the nail caused primarily by dermatophytes. Fluconazole is active in vitro against the most common pathogens of onychomycosis, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of superficial fungal infections. OBJECTIVE The purpose of this study was to compare the efficacy and safety of three different doses of fluconazole (150, 300, and 450 mg) given orally once weekly to that of placebo in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. METHODS In this multicenter, double-blind study, 362 patients with mycologically confirmed onychomycosis were randomized to treatment with fluconazole, 150, 300, or 450 mg once weekly, or placebo once weekly for a maximum of 12 months. To enter the study, patients were required to have at least 25% involvement of the target nail with at least 2 mm of healthy nail from the nail fold to the proximal onychomycotic border. Patients who were clinically cured or improved at the end of treatment were further evaluated over a 6 month follow-up period. At both the end of therapy and the end of follow-up, clinical success of the target nail was defined as reduction of the affected area to less than 25% or cure. RESULTS At the end of therapy, 86% to 89% of patients in the fluconazole treatment groups were judged clinical successes as defined above compared with 8% of placebo-treated patients. Clinical cure (completely healthy nail) was achieved in 28% to 36% of fluconazole-treated patients compared with 3% of placebo-treated patients. Fluconazole demonstrated mycologic eradication rates of 47% to 62% at the end of therapy compared with 14% for placebo. The rates at the end of follow-up were very similar, indicating that eradication of the dermatophyte was maintained over the 6-month period. All efficacy measures for the fluconazole groups were significantly superior to placebo (p=0.0001); there were no significant differences between the fluconazole groups on these efficacy measures. The clinical relapse rate among cured patients over 6 months of follow-up was low at 4%. Fluconazole was well tolerated at all doses over the 12-month treatment period, with the incidence and severity of adverse events being similar between the fluconazole and placebo treatment groups. Mean time to clinical success in the fluconazole treatment groups was 6 to 7 months. This time frame may be used as a guideline for fluconazole treatment duration. CONCLUSION The results of this study support the use of fluconazole in the treatment of distal subungual onychomycosis of the toenail caused by dermatophytes. Doses between 150 to 450 mg weekly for 6 months were clinically and mycologically effective as well as safe and well tolerated.

Successful treatment of tinea capitis with 2% ketoconazole shampoo.

Background Oral antifungal drugs are required for effective treatment of tinea capitis. Topical antifungal shampoos, namely ketoconazole 2% shampoo or products with selenium sulfide or salicylic acid are recommended as adjunctive therapy. Topical antifungal monotherapy has not been successful in the treated of tinea capitis. The purpose of this open study was to evaluate ketoconazole 2% shampoo as a monotherapy for the treatment of tinea capitis.

Cryptococcus neoformans pulmonary infection in HIV-1-infected patients

Cryptococcus neoformans (Cn) is a frequent pathogen in patients infected with the human immunodeficiency virus (HIV-1). We review the initial presentation and clinical course of 18 HIV-1-infected (HIV +) patients with a Cn pulmonary infection. Simultaneous positive cerebrospinal fluid (CSF) cultures were found in 10 (63%) of 16 examined. The most frequent presenting symptoms were fever (87%) and pulmonary complaints (60%). Although the most common chest radiographic finding was bilateral diffuse interstitial infiltrates, nodules and cavitary lesions were also seen. Nine (50%) of the 18 patients died within 6 weeks of diagnosis. Of six patients with an isolated Cn pulmonary infection, five have subsequently died. Three of these five patients did not receive maintenance therapy and had confirmed or probable relapse. Patients initially presenting with an isolated Cn pulmonary infection may later show disseminated disease, suggesting that such patients should receive both acute and maintenance therapy.

Pharmacokinetics of three doses of once-weekly fluconazole (150, 300, and 450 mg) in distal subungual onychomycosis of the toenail

BACKGROUND Preliminary clinical data suggest that fluconazole is effective in the treatment of patients with onychomycosis. To design optimum dosage regimens, a better understanding of fluconazoles distribution into and elimination from nails is needed. OBJECTIVE The purpose of this study was to determine plasma and toenail concentrations of fluconazole. METHODS In this multicenter, randomized, double-blind investigation, fluconazole (150 mg, 300 mg, or 450 mg) or matching placebo was administered once a week for a maximum of 12 months to patients with onychomycosis of the toenail. A total of 151 subjects participated in the pharmacokinetic assessment. Blood samples and distal toenail clippings from both affected and healthy nails were obtained for fluconazole concentration determinations at baseline, at the 2-week visit, at each monthly visit until the end of treatment, and then at 2, 4, and 6 months (nail samples only at the latter two) after fluconazole was discontinued. RESULTS Fluconazole was detected in healthy and affected nails at the 2-week assessment in nearly all subjects. The median time to reach steady-state fluconazole concentrations in healthy nails was 4 to 5 months in the three fluconazole dose groups. In affected nails, steady-state fluconazole concentrations were achieved more slowly, with a median time of 6 to 7 months. At the 8-month assessment, affected toenail fluconazole concentrations were higher than corresponding plasma fluconazole concentrations, with ratios of 1.31 to 1.50 in the three active treatment groups. Toenail concentrations of fluconazole declined slowly after treatment was discontinued, with elimination half-lives of 2.5, 2.4, and 3.7 months for the 150, 300, and 450 mg doses, respectively. Measurable fluconazole concentrations were still present in toenails at 6 months after treatment in most subjects. CONCLUSION Fluconazole penetrates healthy and diseased nails rapidly, yielding detectable concentrations after two weekly doses. Once it penetrates nail, fluconazole persists for up to 6 months or longer after therapy is stopped. These favorable pharmacokinetic characteristics support a once-weekly fluconazole dosage regimen for the treatment of patients with onychomycosis.

Tinea pedis caused by Hendersonula toruloidea:A new problem in dermatology

We report the first case of tinea pedis and onychomycosis caused by Hendersonula toruloidea in the United States and, to our knowledge, the third such case reported in North America. The clinical picture is one of chronic, hyperkeratotic, recalcitrant tinea pedis similar to that caused by Trichophyton rubrum . Except for 2 years in Alaska, our 46-year-old patient had never lived outside the state of Louisiana. Previous treatment with griseofulvin and treatment with 1 % bifonazole cream for 4 weeks were both ineffective. The patient did not respond to further treatment with a variety of topical antifungal preparations. This fungus is endemic to the tropical and subtropical regions; our case suggests that it may be endemic to the southern part of the United States as well. Dermatologists should be alerted to this overlooked disease entity.

Treatment of tinea cruris with topical terbinafine

Twenty-three patients were enrolled in a randomized, double-blind trial of terbinafine 1% cream versus its vehicle (placebo) in the treatment of tinea cruris. One patient had a negative initial culture and was excluded, and two patients were dropouts, one because of poor study compliance (terbinafine) and one because of an adverse event (placebo). Twenty patients were examined for efficacy of treatment (9 terbinafine-treated, 11 placebo-treated). Both groups were similar in age, sex, duration of disease, prior therapy, size and location of lesion, infecting organism, and predisposing factors. Terbinafine 1% cream was more effective than vehicle cream in the reduction of the signs and symptoms of tinea cruris. In addition, there was a higher conversion rate to negative culture and normal microscopy findings in the terbinafine-treated group. Clinical results combined with evaluation of mycologic tests at end of therapy showed terbinafine to be a rapid and significantly more effective treatment for tinea cruris than placebo (78% vs 18% cure rate, respectively). Follow-up cure rates confirmed these findings (89% and 18%, respectively). No significant adverse events occurred during terbinafine treatment.

Primary cutaneous phaeohyphomycosis. Report of three cases

Dematiaceous fungi have a diverse clinical spectrum that presents a difficult problem in diagnosis and treatment. These opportunistic pathogens are of concern in healthy, debilitated, or immunocompromised individuals. We describe three patients with localized cutaneous infections produced by dematiaceous filamentous fungal organisms with varying clinical presentations. Two patients were immunocompromised, and a third was otherwise healthy. The unusual clinical and unique histologic features of these difficult infections are reported in detail, as is their successful medical management with ketoconazole (Nizoral) and an experimental antifungal agent, fluconazole.

Pharmacokinetics of three once-weekly dosages of fluconazole (150, 300, or 450 mg) in distal subungual onychomycosis of the fingernail ☆ ☆☆

BACKGROUND Fluconazole has proven to be safe and effective for a variety of superficial and systemic fungal infections. Preliminary analysis of extensive Phase III studies suggests that it is very effective for the treatment of onychomycosis. Its pharmacokinetic properties, including low molecular weight and high water-solubility, suggest a unique ability to penetrate the nail. This feature is likely to account in part for fluconazoles effectiveness in the treatment of onychomycosis. OBJECTIVE Determinations of plasma and fingernail concentrations of fluconazole were performed as part of a larger study comparing the safety and efficacy of once-weekly fluconazole (150, 300, and 450 mg) to placebo in the treatment of distal subungual onychomycosis of the fingernails caused by dermatophytes. The relationship between fluconazole concentrations and efficacy was also examined. METHODS Pharmacokinetic studies were performed by means of plasma and fingernail samples from 133 patients, a subset of 349 patients participating in a double-blind, placebo-controlled clinical trial of fluconazole administered in once-weekly doses of 150, 300, or 450 mg until cure of onychomycosis or for a maximum of 9 months. Blood and fingernail samples for pharmacokinetic analysis were taken at baseline, at week 2, and at monthly intervals during the treatment phase of the study. Patients considered clinically cured or improved also participated in a 6-month follow-up study. During this phase, patients were monitored and samples taken every 2 months. RESULTS Significant amounts of fluconazole were detected in the earliest fingernail samples taken (after 2 weeks of treatment). After two weekly doses, 30% to 33% of steady-state concentrations had been achieved in healthy nails and 22% to 29% in affected nails. Steady state was achieved in 3 to 5 months. Fluconazole concentration in nails as well as plasma followed dose-proportional pharmacokinetics. Nail:plasma ratios in affected nails were 0.4 to 0.6 at 2 weeks and 1.7 to 1.8 at 6 months. Fluconazole concentrations fell slowly after drug discontinuation and were still detectable 4 months after end of treatment. A statistically significant correlation was found between steady-state concentration and clinical and global outcomes. CONCLUSION Fluconazole rapidly penetrates the fingernail, where it is retained at detectable levels for at least 4 months after drug discontinuation. A significant correlation exists between fluconazole concentration in the fingernails and clinical and global outcomes.

Cutaneous zygomycosis in a diabetic HTLV-I–seropositive man

Zygomycosis, an invasive fungal infection, is usually seen in persons with diabetes, particularly in those with diabetic ketoacidosis. The infection most frequently occurs in the rhinocerebral region and rapidly spreads, causing a swift demise. Rarely, the infection is confined to the cutaneous tissues. We describe a 31-year-old man seropositive for human T lymphotropic virus type I who had diabetic ketoacidosis with zygomycosis confined to the right arm. The lesion was presumed initially to be a bacterial infection but did not respond to conventional antimicrobial therapy. The arm lesion was cultured, and Rhizopus arrhizus was isolated. The patient responded well to a combination of amphotericin B and extensive surgical debridements. Our case emphasizes the importance of maintaining a high index of suspicion of cutaneous zygomycotic infections in the impaired host, especially of those in patients with diabetes, who do not respond to initial antimicrobial treatment.

Comparative trial of a two-dosage schedule of ketoconazole 2% cream for the treatment of tinea pedis

Sixty-two patients with mycologically confirmed tinea pedis received two different treatment regimens of ketoconazole 2% cream on a randomized double-blind basis for 1 month with weekly evaluations. A 4-week posttreatment follow-up permitted an assessment of recurrence or improvement. After 1 month of treatment, 90% of the patients treated once daily responded clinically, in comparison with 83% of those treated twice daily. The cure rate was 63% for the once-daily and 60% for the twice-daily group. This rate substantially improved at follow-up (77% and 73%, respectively). One patient from each group discontinued therapy for an adverse reaction. On the basis of both clinical and mycologic assessments, topical treatment with ketoconazole 2% cream was effective as a once-daily therapy.