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

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.

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, penetrates into the nail bed, and is clinically effective in the treatment of a wide variety of fungal infections. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of oral fluconazole 150, 300, and 450 mg administered once weekly compared with placebo in the treatment of distal subungual onychomycosis of the fingernail caused by dermatophytes. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study enrolling 349 patients with onychomycosis of the fingernails. Clinical and mycologic efficacy as well as measures of safety were assessed monthly for a maximum of 9 months of treatment, with additional safety visits occurring at weeks 2 and 6. For inclusion, patients were required to have clinically and mycologically documented onychomycosis of the fingernail caused by dermatophytes with at least 25% involvement of the target fingernail. After end of therapy, patients with improved or cured fingernails entered a blinded 6-month follow-up without drug treatment during which efficacy was assessed every 2 months. Efficacy was assessed by clinical (visual) and mycologic (microscopic and culture) measures. Clinical measures included assessments of the percentage of target nail involvement, measurement of the distance from the nail fold to the proximal onychomycotic border, and signs and symptoms of onychomycosis. RESULTS: Fluconazole was significantly superior to placebo in eradicating clinical and mycologic symptoms of onychomycosis, both at the end of active treatment and at 6 months after treatment (p=0.0001 for all efficacy measures). At the end of therapy, 91% to 100% of patients in the fluconazole groups were judged clinical successes, defined as reduction of the affected area of the target nail to less than 25% or cure, compared with 8% for placebo. Clinical cure rates at end of therapy were 76%, 85%, and 90% for fluconazole 150, 300, and 450 mg, respectively, compared with 3% for placebo. These clinical success and cure rates were largely maintained or improved during follow-up. Clinical relapse in cured patients during the follow-up period was very low (1.5% to 3.3%). Fluconazole demonstrated mycologic eradication rates of 89% to 100% at the end of treatment and 90% to 99% at the end of follow-up; for placebo the rates were 8% and 12%, respectively. CONCLUSION: Fluconazole administered once weekly is safe and effective in eradicating distal subungual onychomycosis of the fingernail caused by dermatophytes.

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 fluconazole's 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.

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 fluconazole's 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.

Clobetasol propionate emollient 0.05% in the treatment of atopic dermatitis.

A 4-week, double-blind, randomized clinical trial, comparing the efficacy and safety of clobetasol propionate emollient cream 0.05% and its vehicle, was conducted at four private dermatology clinics in 81 non-hospitalized patients (> or = 12 years old) with moderate-to-severe atopic dermatitis covering 2% or more of their body surface. All patients had at least one lesion 2 cm or more in diameter. Three signs/symptoms of target lesions (erythema, pruritus, and induration/papulation) were scored by investigators on a scale of 0-3 (in 0.5-point increments; 0 = absent, 1 = mild, 2 = moderate, and 3 = severe); the total of the three scores had to be > or = 6 for patients to qualify for study entry. Patients were excluded if they were immunocompromised, pregnant, or nursing; had skin atrophy, telangiectasia or striae in skin areas to be treated; or had received topical treatments for atopic dermatitis within 1 week prestudy, intramuscular triamcinolone within 6 weeks prestudy, or long-term systemic corticosteroid usage within 6 months prestudy. Patients were randomized in a 1:1 ratio to receive either clobetasol propionate emollient 0.05% twice daily (n = 41), or the emollient vehicle twice daily (n = 40), for 4 weeks. A fingertip unit, equaling approximately 0.5 g in males and 0.43 g in females (enough to cover approximately 2% of the body), was used to measure and apply a thin film of study drug to the affected areas. The efficacy was evaluated by investigators and patients on days 4, 8, 15, and 29 after initiation of therapy, and 2 weeks after the end of treatment (day 43). Investigators performed a physician's gross assessment based on the percentage improvement of the target lesion. They also rated changes from baseline in mean severity scores for six individual signs/symptoms (erythema, pruritus, induration/papulation, lichenification, erosion/oozing/crusting, and scaling/dryness) and for total signs/symptoms according to the severity scoring system described above. Patients rated their response to treatment as excellent, good, fair, poor, or worse. Laboratory assessments were made on days 15, 29, and (if necessary) day 43.

Efficacy and safety of twice-daily augmented betamethasone dipropionate lotion versus clobetasol propionate solution in patients with moderate-to-severe scalp psoriasis.

This 2-week, randomized, multicenter, investigator-blinded, parallel-group study was conducted to compare the efficacy and safety of augmented betamethasone dipropionate 0.05% lotion and clobetasol propionate 0.05% solution in the treatment of moderate-to-severe scalp psoriasis among 197 (193 assessable) healthy adult patients with at least 20% scalp-surface involvement. The patients received one of two treatments applied twice a day for 2 weeks. Signs and symptoms were evaluated at baseline, after 3 days (day 4), and after weeks 1 (day 8) and 2 (day 15) of treatment. As early as 3 days after treatment, scaling and induration were improved significantly faster by betamethasone dipropionate than by clobetasol propionate. Both treatments also reduced erythema and pruritus. Patients receiving betamethasone dipropionate had a significantly greater mean percent improvement in total sign/symptom scores (P < or = 0.015) at all visits and better mean global clinical response scores at the early visits (days 4 and 8) (P < or = 0.017). At the end of the study, only mild disease was present in both groups. Adverse events were reported by 34.0% and 36.4% of patients receiving betamethasone dipropionate and clobetasol propionate, respectively. All events were transient, most were mild and local, and no discontinuations resulted. The effects of treatment on the hypothalamic-pituitary-adrenal axis were not measured. In conclusion, augmented betamethasone dipropionate lotion and clobetasol propionate solution were equally effective, but betamethasone dipropionate lotion provided a faster onset of relief for scaling and induration, which may enhance patient compliance and patient satisfaction with treatment.

Ofloxacin versus cephalexin for treating skin and soft tissue infections.

Patients with acute localized skin or soft tissue infections were randomized to receive either ofloxacin (300 mg orally, b.i.d.) or cephalexin (500 mg orally, b.i.d.). Among 401 enrolled patients, 382 were evaluable for safety and 148 for microbiologic response. Microbiologic cure occurred in 93.4% of ofloxacin-treated patients and in 94.0% of those treated with cephalexin. Clinical cure or improvement, respectively, was found in 85.2% and 11.1% of patients treated with ofloxacin, and 83.6% and 14.9% of patients receiving cephalexin. Adverse effects (primarily associated with the gastrointestinal tract and central nervous system) were considered to be drug-related in 7.9% of those receiving ofloxacin and 4.8% of those receiving cephalexin. Thus, ofloxacin is as effective and well tolerated as cephalexin and a good alternate antibiotic for treating skin and skin structure infections caused by a variety of pathogens.

Clinical comparison of cefuroxime axetil, cephalexin and cefadroxil in the treatment of patients with primary infections of the skin or skin structures.

This study was designed to compare the clinical and bacteriological efficacy of three oral cephalosporins, cefuroxime axetil, cephalexin and cefadroxil, in the treatment of patients with mild to moderate infections of the skin or skin structures. A total of 330 patients were enrolled at 10 centers and were randomly assigned to receive cefuroxime axetil 250 mg (n = 107), cephalexin 500 mg (n = 111) or cefadroxil 500 mg (n = 112), twice daily for 10 days. Patients were assessed for their clinical and bacteriological responses once during treatment (3-5 days) and twice after treatment (1-3 and 10-14 days). A total of 353 bacterial isolates were obtained: Staphylococcus aureus (41%), Staphylococcus epidermidis (33%) and Streptococcus pyogenes (5%). A satisfactory clinical outcome (cure or improvement) was achieved in 97% (89/92), 89% (80/90) and 94% (82/87) of the clinically evaluable patients treated with cefuroxime axetil, cephalexin or cefadroxil, respectively (p = 0.047, cefuroxime axetil vs. cephalexin). With respect to the eradication of the bacterial pathogens, a satisfactory outcome (cure or presumed cure) was obtained in 96% (69/72), 85% (60/71) and 93% (63/68) of bacteriologically evaluable patients treated with cefuroxime axetil, cephalexin and cefadroxil, respectively (p = 0.026, cefuroxime axetil vs. cephalexin). All three study drugs were well tolerated, with adverse events affecting the gastrointestinal system most commonly reported. There were no significant differences between treatment groups in the incidence of drug-related adverse events.

Mohs micrographic surgery.

Mohs micrographic surgery is a procedure used to treat recurrent or difficult skin cancers by the sequential removal of thin, saucerized layers of tissue. These excised layers are sectioned on a microtome and examined microscopically, and maps are prepared to delineate areas of residual tumor as well as normal, uninvolved tissue. Due to this microscopic control, cure rates are extremely high for basal and squamous cell cancers. Because the technique spares as much normal skin as possible, the wounds produced are well suited for healing by secondary intention alone or by surgical reconstruction. A further benefit of the technique is that almost all cases can be done under local anesthesia alone and in an outpatient setting as well. This results in less morbidity and greatly reduced cost.

Possible side effects of topical steroids.

When used properly in controlled situations, topical corticosteroids provide dramatic relief in distressing disorders such as eczema, psoriasis and seborrheic dermatitis. The fluorinated preparations are associated with a variety of side effects, including acne, striae, premature aging of the skin, hypertrichosis, perioral dermatitis, glaucoma and even adrenal suppression. Except for the severe, acute dermatoses, a nonfluorinated steroid is the better choice because of the relative lack of side effects and lower cost.

Cutaneous Hodgkin's disease.

The case reported herein documents the occurrence of cutaneous involvement in a patient with a long history of Hodgkin's disease. Despite severe pruritus and intermittent exacerbations of a multitude of specific and nonspecific skin lesions, associated with his underlying malignancy, the patient has done remarkably well for more than seven years. This demonstrates quite well that cutaneous involvement in Hodgkin's disease is not necessarily an ominous prognostic indicator. More intensive systemic chemotherapy and/or topical therapy is frequently effective in such patients.

Phospholipid composition and metabolism of Micrococcus denitrificans.

The phospholipid composition of Micrococcus denitrificans was unusual in that phosphatidyl choline (PC) was a major phospholipid (30.9%). Other phospholipids were phosphatidyl glycerol (PG, 52.4%), phosphatidyl ethanolamine (PE, 5.8%), an unknown phospholipid (5.3%), cardiolipin (CL, 3.2%), phosphatidyl dimethylethanolamine (PDME, 0.9%), phosphatidyl monomethylethanolamine (PMME, 0.6%), phosphatidyl serine (PS, 0.5%), and phosphatidic acid (0.4%). Kinetics of (32)P incorporation suggested that PC was formed by the successive methylations of PE. Pulse-chase experiments with pulses of (32)P or acetate-1-(14)C to exponentially growing cells showed loss of isotopes from PMME, PDME, PS, and CL with biphasic kinetics suggesting the same type of multiple pools of these lipids as proposed in other bacteria. The major phospholipids, PC, PG, and PE, were metabolically stable under these conditions. The fatty acids isolated from the complex lipids were also unusual in being a simple mixture of seven fatty acids with oleic acid representing 86% of the total. Few free fatty acids and no non-extractable fatty acids associated with the cell wall or membrane were found.

Phospholipid metabolism during penicillinase production in Bacillus licheniformis.

During membrane-bound penicillinase production, Bacillus licheniformis forms vesicles and tubules that do not appear in the absence of penicillinase production. The major lipids of B. licheniformis were shown to be phospholipids. The proportions, metabolism, and the total phospholipid per cell were shown to be essentially the same in the uninduced control, induced and constitutive penicillinase forming cells during both the exponential and stationary growth phases. Membrane phospholipids were not secreted into the medium during penicillinase formation. In the shift from the exponential to the stationary growth phase, there was an accumulation of phosphatidyl glycerol and a marked decrease in cardiolipin. These two lipids had the most active turnover of their phospholipid phosphate of all the lipids studied.