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Dermatophytoma is a little-known, difficult to treat fungal infection that complicates onychomycosis. First described by Roberts and Evans in the late 1990's, dermatophytoma presents as a dense concentration of fungal hyphae within or under the nail plate and is generally white or yellow/brown in color, and linear (streaks) or round (patches) in shape; primary etiologic organisms are dermatophytes. Oral antifungals have limited success in treating dermatophytoma owing to difficulties accessing and penetrating what is hypothesized to be a fungal biofilm. In this respect, dermatophytoma is generally treated with a combination therapy approach, often including both surgical and pharmacologic intervention for improved outcomes. A post-hoc assessment of Phase II tavaborole onychomycosis studies was conducted in order to assess the prevalence of dermatophytoma and outcomes in patients treated with topical tavaborole. Of the 366 subjects enrolled in the Phase II onychomycosis studies, we identified 102 cases of dermatophytoma; 21 of 86 (24.4%) subjects treated with tavaborole were able to achieve complete resolution of dermatophytoma by day 180, while no subjects on vehicle obtained resolution. Similarly, 23 of 86 subjects (26.7%) treated with tavaborole solution had complete resolution of dermatophytoma by day 360, while only 1 of 16 subjects (6.3%) on vehicle obtained resolution. Moreover, 13 of 19 subjects (68.4%) treated with tavaborole solution were able to sustain resolution, while only 6 of 19 (31.6%) had reoccurrence, of dermatophytoma during the 180-day washout period (day 360). We present 5 cases of dermatophytoma identified in Phase II trials that responded in a positive manner following treatment with tavaborole solution for onychomycosis of the great toenail. Although not representative of all subject outcomes, these findings provide insight into the use of topical tavaborole for dermatophytoma, a condition previously thought to respond only to oral or combination therapy.pemJ Drugs Dermatol. 2018;17(3):347-354./em/p.

BackgroundOnychomycosis, a fungal nail infection, can impact quality of life.ObjectiveWe sought to evaluate the efficacy and safety of tavaborole topical solution, 5% for treatment of toenail onychomycosis.MethodsIn 2 phase-III trials, adults with distal subungual onychomycosis affecting 20% to 60% of a target great toenail were randomized 2:1 to tavaborole or vehicle once daily for 48 weeks. The primary end point was complete cure of the target great toenail (completely clear nail with negative mycology) at week 52. Secondary end points included completely or almost clear nail, negative mycology, completely or almost clear nail plus negative mycology, and safety.ResultsRates of negative mycology (31.1%-35.9% vs 7.2%-12.2%) and complete cure (6.5% and 9.1% vs 0.5% and 1.5%) significantly favored tavaborole versus vehicle (P ≤ .001). Completely or almost clear nail rates also significantly favored tavaborole versus vehicle (26.1%-27.5% vs 9.3%-14.6%; P

Toenail onychomycosis is a chronic fungal infection that often requires prolonged treatment in order to effectively manage pathogenic organisms and obtain a clear nail. Traditionally, certain clinical features of onychomycosis, including the presence of substantial lateral disease, focal fungal masses, yellow/brown streaks, and extensive nail involvement (ie,50%), indicate a poor treatment prognosis and have proven difficult-to-treat with oral or traditional topical therapies. Owing to the novel features of topical tavaborole, we sought to understand the potential utility of tavaborole in difficult-to-treat onychomycosis. A blinded, post-hoc assessment of Phase III trials was conducted, focusing on initial presentation, midpoint assessment (24 weeks), and final outcomes (52 weeks) in subjects identified as having difficult-to-treat onychomycosis and treated for 48 weeks with once-daily application of either tavaborole 5% solution or vehicle. Our post-hoc analysis identified 84 difficult-to-treat cases (tavaborole 5%; n=60; vehicle, n=24) in subjects with toenail onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes. No subjects identified as difficult-to-treat and treated with vehicle achieved a complete cure, while 6 subjects treated with tavaborole 5% attained a completely clear nail and negative mycology. Similarly, 7 subjects treated with tavaborole 5% solution achieved an almost complete cure (≤10% involvement and negative mycology) while 1 subject on vehicle achieved an almost complete cure. We present a case series of 4 patients, of varying age and difficult-to-treat clinical features, which responded positively to tavaborole 5% solution. Three of the subjects achieved complete cure after being treated with tavaborole 5%, with one additional subject (an 88-year-old female) achieving an almost complete clear nail by treatment end. The outcomes presented here may not be reflective of patients that may present with these clinical characteristics. Additional investigations would be useful in order to assess the value of topical tavaborole 5% solution in difficult-to-treat clinical presentations of onychomycosis.pemJ Drugs Dermatol. 2017;16(10):1016-1021./em/p.

Background It is not known whether human immunodeficiency virus (HIV) infection is associated with an increased susceptibility to dermatophytes. Methods In this study, we determined the prevalence of cutaneous fungal infection in a cohort of HIV-infected patients and HIV-negative controls, and examined the factors associated with an increased risk of infection. Results Using a multiple regression analysis, we found that the strongest independent predictor of cutaneous fungal infection in both groups was a self-reported history of homosexual sex. There was no relationship between HIV infection or reduced CD4 count and the prevalence of dermatophyte infection. Conclusions HIV infection is not independently associated with an increased risk of cutaneous fungal disease.

Background Tinea pedis (athlete’s foot) is the most common fungal infection in the general population. Ciclopirox, a broad-spectrum hydroxypyridone antifungal, has proven efficacy against the organisms commonly implicated in tinea pedis: Trichophyton rubrum, T. mentagrophytes and Epidermophyton floccosum. Objective Two multicenter, double-blind, clinical studies compared the efficacy and safety of ciclopirox gel with that of its vehicle base in subjects with moderate interdigital tinea pedis with or without plantar involvement. Methods Three hundred and seventy-four subjects were enrolled and randomized to one of two treatment groups: ciclopirox gel 0.77%, or ciclopirox gel vehicle, applied twice daily for 28 days, with a final visit up to day 50. The primary efficacy variable was Treatment Success defined as combined mycological cure and clinical improvement 75%. Secondary measures of effectiveness were Global Clinical Response, Sign and Symptom Severity Scores, Mycological Evaluation (KOH examination and final culture result), Mycological Cure (negative KOH and negative final culture results) and Treatment Cure (combined clinical and mycological cure). Results At endpoint (final post-baseline visit), 60% of the ciclopirox subjects achieved treatment success compared to 6% of the vehicle subjects. At the same time point, 66% of ciclopirox subjects compared with 19% of vehicle subjects were either cleared or had excellent improvement. Pooled data showed that 85% of ciclopirox subjects were mycologically cured, compared to only 16% of vehicle subjects at day 43, 2 weeks post-treatment. Conclusions Ciclopirox gel 0.77% applied twice daily for 4 weeks is an effective treatment of moderate interdigital tinea pedis due to T. rubrum, T. mentagrophytes and E. floccosum and is associated with a low incidence of minor adverse effects.

The severity of tinea pedis infection determines the course of treatment required. Mild infections may be resolved using a topical agent. More severe presentations (eg, dermatophytosis complex) may require treatment that eliminates the bacterial and fungal infection. Some topical monotherapies may exhibit both antifungal and antibacterial activity. In other instances, it may be necessary to combine an antifungal agent with an antibacterial agent. If inflammation is present, an agent with known anti-inflammatory action may need to be used. The chronic presentation of tinea pedis (dry type) sometimes does not respond well to topical therapy. In such instances, systemic antifungal therapy is required to ensure that adequate concentrations of the therapeutic agent are present at the site of infection.

Objectives. Terbinafine has been shown to be effective in tinea capitis, using different treatment durations. However, no direct comparison of treatment duration has previously been investigated. This randomized, double-blind, parallel-group, multicenter study was designed to assess the effect of terbinafine treatment duration on the outcome of Trichophyton tinea capitis in a North American population. Methods. A total of 176 patients with a clinical diagnosis of tinea capitis were enrolled in this study and treated with oral terbinafine (3–6 mg/kg/d) for 1, 2, or 4 weeks. All patients were to be followed until week 12. A total of 159 patients had culture-confirmed tinea capitis attributable to Trichophyton species and constituted the intent-to-treat population used for efficacy analysis (50, 55, and 54 patients in the 1-, 2-, and 4-week arms, respectively). Results. At the end of study, effective treatment, defined as negative culture and low scores on signs and symptoms, was achieved in 56%, 69%, and 65% of patients who were treated with terbinafine for 1, 2, and 4 weeks, respectively. A negative culture was achieved in 60%, 76%, and 72%, respectively. Overall, the efficacy data showed that both the 2- and 4-week treatment regimens are clinically superior to the 1-week regimen. Terbinafine was well tolerated, and the incidence of adverse events showed no relationship to the duration of therapy. Conclusion. When efficacy, cost, and compliance are taken into consideration, 2 weeks of terbinafine therapy appears to be the optimal treatment duration for patients with Trichophyton tonsurans tinea capitis.

While Microsporum canis is an infrequent cause of tinea infections in the USA, it should remain in the differential diagnosis when a fungal infection presents in an atypical fashion. We describe an outbreak of M. canis affecting 15 people and 2 dogs with rapid transmission. Family pets may have acted as intermediate hosts in this outbreak, facilitating transmission between human contacts.

Background: Among the ways to reduce the incidence of iatrogenic infectious disease is the use of efficacious preoperative antiseptics. Iodophors and chlorhexidines, the chief presurgical disinfectants today, have various problems with practicality. A new preoperative skin antiseptic has been developed (Alcide Corporation, Redmond, Wash) that involves the mixture of a 0.1% sodium chlorite formulation and an activating preparation of 0.5% mandelic acid to produce chlorous acid and other antimicrobial degradation products. Methods: Under clinical conditions, the antimicrobial effectiveness of this blended preparation was compared with a chlorhexidine gluconate scrub solution. Using a Latin-square randomization scheme, we treated 2 contralateral abdominal sites and 2 contralateral inguinal sites of healthy male and female volunteers with these antiseptics or the controls of vehicle or activator alone. Microorganisms were harvested and quantified by a standard cylinder-scrub technique. Results: Of 85 volunteers (170 possible sites per test region) screened to meet the US Food and Drug Administration baseline criteria on population densities of normal flora, 61 abnominal sites and 107 inguinal sites provided suitable data. Against chlorhexidine, the chlorous acid presurgical skin preparation produced superior but statistically equivalent reductions ( P > .05) of each volunteer's normal flora at 10 minutes, 30 minutes, and 6 hours after treatment. As many as 4 log reductions were achieved, and activity persisted as long as 6 hours. Compared with chlorhexidine, the chlorous acid product has the practical advantages of a shorter scrub time, less foam, air drying (instead of wiping), and no perceivable residue. Conclusions: An activated chlorous acid product statistically matched the performance of chlorhexidine gluconate in reducing populations of resident flora on treated skin sites. With an easier and shorter application procedure and strong, long-term antimicrobial activity, this new halogenated antiseptic seems to be a useful and possible efficacious preoperative skin disinfectant. (AJIC Am J Infect Control 1998;26:406-412)

Fungal infections of the skin, hair and nails are among the most common skin diseases. The increased incidence of these infections in recent years has been attributed to the large number of immunocompromised patients, life-style changes (greater attendance at gymnasiums, public baths, etc.), the use of chemotherapeutic agents, and the greater presence of elderly people in the general population. Superficial fungal infections were also the most frequent and troublesome dermatological condition occurring among US forces during the war in Vietnam.

Background: Onychomycosis is the most frequent cause of nail disease and represents 30% of all mycotic infections of the skin. Objective: Our purpose was to compare the effectiveness and tolerability of intermittent dosing of itraconazole ("pulse therapy") with placebo in fingernail onychomycosis. Methods: Seventy-three patients with clinically and mycologically diagnosed fingernailonychomycosis were randomly selected to receive itraconazole, 200 mg twice daily, or placebo for the first week of each month for 2 consecutive months; patients were observed for 19 weeks. Seventy-one patients received the study medication and were included in the safety analysis. Efficacy of treatment was evaluated in 46 patients. Results: A significantly greater proportion of itraconazole-treated patients than placebo-treated patients achieved clinical success (77% vs 0%), mycologic success (73% vs 13%), and overall success (68% vs 0%). No itraconazole-treated patient had a clinical or mycologic relapse during the follow-up period. Ten itraconazole-treated patients (28%) and nine placebo-treated patients (26%) had adverse events. Three patients discontinued treatment for safety reasons. Conclusion: Pulse therapy with itraconazole for 2 consecutive months produces significantly greater clinical, mycologic, and overall success than placebo. Short-term itraconazole pulse therapy for fingernail onychomycosis is effective and well tolerated. (J Am Acad Dermatol 1997;36:231-5.)

Our knowledge of ecology and epidemiology of dermatophytes and the factors influencing their transmission has helped us understand better the natural history of dermatophytoses. It seems that the anthropophilic agents of scalp infection are being eradicated in developing nations. The exception is Trichophyton tonsurans-related tinea capitis in North America. Microsporum canis is a prevalent agent of tinea capitis in many regions of the world, and this could be related to close association of humans with their pets. Trichophyton violaceum is endemic in certain parts of Eastern Europe, Africa, Asia, and South America but not in North America. Trichophyton rubrum is the most common cause worldwide of tinea pedis, nail infection, tinea cruris, and tinea corporis. Although the incidence of tinea capitis is declining in developed nations, tinea pedis and onychomycosis are becoming more common. The increased use of athletic shoes both by men and women and communal bathing could be contributing factors. Five or six species account for most dermatophytoses globally.

Whether griseofulvin, which pioneered oral antifungal therapy, works topically has long been an open question. The effectiveness of a 1% griseofulvin spray formulation and the vehicle alone against experimentally induced Trichophyton mentagrophytes lesions on the forearms of 16 healthy volunteers and in the treatment of 100 tinea pedis patients (various dermatophytes) was evaluated in a double-blind study. After treatment of the 58 induced lesions twice daily for 14 days with topical griseofulvin (28) or placebo (30), 89% of lesions receiving griseofulvin were mycologically negative compared with 30% in the placebo group (P < 0.0001). In the tinea pedis patients who applied medication once daily for 4 weeks the mycological cure was 79.2% on the fourth week and 80.9% 2 weeks post-treatment. Resurgence of dermatophytes quickly followed the end of treatment in the placebo group only, which had a mycological cure rate of 34% (week 6). Administration of a topical formulation of griseofulvin thus may be an effective treatment for interdigital dermatophyte infections.

Six double-blind, independently randomized studies evaluated the efficacy and safety of calcium mupirocin ointment in eliminating nasal carriage of Staphylococcus aureus among health care workers. Healthy volunteers with stable nasal carriage of S. aureus (n=339) received either calcium mupirocin ointment (n=170) or an identical placebo ointment (n=169) intranasally for 5 days. Nasal carriage was eliminated 48-96 hours after completion of treatment in 130 (91%) of 143 evaluable volunteers receiving mupirocin but in only 8 (6%) of 142 evaluable volunteers receiving placebo. The 85% crude difference represents a 90% pooled (adjusted) estimate of the risk difference (95% confidence interval, 0.86-0.95) and a risk ratio of 16 (P

The antimicrobial activity of stratum corneum lipids was examined by screening in vitro various representative phospholipids and sphingolipids. Of mixed galacto-cerebrosides; phosphatidic acid; phosphatidic acid-monomethylester-dioleoyl; phosphatidylethanolamine; phosphatidylethanolamine-beta-oleoyl-gamma-palmitoyl; phosphatidylcholine; D-sphingosine; D,L-sphinganine; 4-D-hydroxysphinganine; oleoyl-sphingosine; N,N-dimethylsphingosine; and stearylamine, only the sphingosines and, to a lesser extent, stearylamine were clearly and profoundly effective against Staphylococcus aureus (4-log reduction at 6.25 micrograms/ml [20 microM]; 2-log reduction at 0.78 mu/ml [2.5 microM]). The sphingosines were similarly active against Streptococcus pyogenes, Micrococcus luteus, Propionibacterium acnes, Brevibacterium epidermidis, and Candida albicans, moderately active against Pseudomonas aeruginosa, and ineffective against Escherichia coli and Serratia marcescens. Both erythro- and threo-isomers were effective. Optimal inhibition was at 60 min incubation at 37 degrees C and at pH 6.5. Antimicrobial activity, which was Ca++ dependent, was confirmed in vivo by topical application and microbial challenge. Because free sphingosines are available in the stratum corneum and other epidermal layers, these lipids may contribute to the cutaneous antimicrobial barrier.

To investigate the early events of opportunistic infection in AIDS, microorganisms inhabiting the cheek and groin skin and nasal vestibule of 19 male HIV-infected patients in various stages of illness were identified and quantified quarterly for 1 y. During the course of their infection, HIV-positive patients tended to decrease their carriage of microorganisms, by populations on the skin and by fewer species on all sites, especially the groin. Nasal carriage of Staphylococcus aureus was 56 per cent, compared to 22 per cent in healthy subjects. About 35 per cent of HIV-positive patients carried Candida albicans in the oral cavity, compared to 5 per cent in HIV-negative subjects. Enhancement of staphylococcal adherence to nasal and cutaneous cells in HIV-positive subjects was, in thigh cells, related to the severity of infection. The sequelae of HIV-infection seems to include hazardous alterations of the epithelial habitats of microorganisms. Keywords: AIDS; HIV; Staphylococcus aureus ; Candida albicans ; Skin flora.

Ciclopirox olamine is a synthetic hydroxypiridone derived, broad spectrum, antifungal agent which has been used effectively to treat seborrheic dermatitis. Seborrheic dermatitis is a chronic dermatosis, more common in men than women, which usually occurs in sites dense with sebaceous glands in the form of mild inflammatory desquamate erythema. Treatment modalities for seborrheic dermatitis include keratolytic agents, corticosteroids and antifungal agents. Due to its antimycotic and anti-inflammatory activities, ciclopirox olamine is established as an effective treatment for this condition.

BACKGROUND Tinea pedis (athlete's foot) is the most common fungal infection in the general population. Ciclopirox, a broad-spectrum hydroxypyridone antifungal, has proven efficacy against the organisms commonly implicated in tinea pedis; Trichophyton rubrum, T.mentagrophytes and Epidermophyton floccosum.Two multicenter, double-blind, clinical studies compared the efficacy and safety of ciclopirox gel with that of its vehicle base in subjects with moderate interdigital tinea pedis with or without plantar involvement.Three hundred and seventy-four subjects were enrolled and randomized to one of two treatment groups: ciclopirox gel 0.77%, or ciclopirox gel vehicle, applied twice daily for 28 days, with a final visit up to day 50. The primary efficacy variable was Treatment Success defined as combined mycological cure and clinical improvement/= 75%. Secondary measures of effectiveness were Global Clinical Response, Sign and Symptom Severity Scores, Mycological Evaluation (KOH examination and final culture result), Mycological Cure (negative KOH and negative final culture results) and Treatment Cure (combined clinical and mycological cure).At endpoint (final post-baseline visit), 60% of the ciclopirox subjects achieved treatment success compared to 6% of the vehicle subjects. At the same time point, 66% of ciclopirox subjects compared with 19% of vehicle subjects were either cleared or had excellent improvement. Pooled data showed that 85% of ciclopirox subjects were mycologically cured, compared to only 16% of vehicle subjects at day 43, 2 weeks post-treatment.Ciclopirox gel 0.77% applied twice daily for 4 weeks is an effective treatment of moderate interdigital tinea pedis due to T. rubrum, T. mentagrophytes and E. floccosum and is associated with a low incidence of minor adverse effects.

Seborrheic dermatitis is a common inflammatory skin disorder that usually occurs in patients with pre-existing seborrhea. The etiology of seborrheic dermatitis is uncertain. Typically, sites dense with sebaceous glands support growth of the lipophilic yeast Malassezia furfur. Ciclopirox (Loprox) gel is a hydroxypyridone, broad-spectrum antifungal agent proven effective against the yeast M. furfur.A multicenter, randomized, double-blind, vehicle controlled study of 178 subjects evaluated the efficacy of ciclopirox gel in treating seborrheic dermatitis of the scalp.One hundred and seventy-eight subjects were randomized to apply either ciclopirox gel 0.77% twice daily, or vehicle twice daily for 28 days. Subjects' signs and symptoms of severity (erythema, scaling, pruritus and burning) were rated on a scale of 0-3 (none to severe); for inclusion, a minimum score of 4, for the sum of the individual ratings was required. Efficacy evaluations were performed at baseline, days 4, 8, 15, 22, 29, and at end-point (final visit, up to day 33). The primary efficacy variable was clinical response assessed by a global improvement, based on a scale of 0-5 (100% clearance to flare of treatment area). Changes in signs/symptoms severity scores within the target lesion were also evaluated.Global evaluation scores demonstrated that significantly more ciclopirox-treated subjects achieved over 75% improvement compared with vehicle at days 22, 29, and endpoint (P0.01). Change-from-baseline mean score for total signs and symptoms was significantly greater in ciclopirox subjects compared with vehicle subjects at the same time points as above (P0.001), as well as day 15 (P0.01). Twenty-nine percent of subjects rated ciclopirox as having excellent cosmetic acceptability. There were only mild adverse events, with the most common being burning sensation in 13% of ciclopirox subjects and 9% of vehicle subjects.Ciclopirox gel is effective and safe in the treatment of seborrheic dermatitis of the scalp.

We describe an 8-year-old Hispanic female who presented with distal subungual onychomycosis and tinea capitis. Both foci of infection yielded Trichophyton tonsurans upon culture, and were clinically and mycologically cured with terbinafine 125 mg, once daily for 1 week [DOSAGE ERROR CORRECTED]. This aspect of treatment with terbinafine has not previously been reported.

Infants wearing breathable disposable diapers experienced significantly less diaper dermatitis (DD) compared to infants wearing standard, nonbreathable disposable diapers in a series of double-blind clinical trials. Severe DD, including confirmed infection with Candida albicans, was reduced by 38-50% among infants wearing highly breathable (HB) diapers. The prevalence of DD was inversely related to the breathability of the garments. The inhibitory effect of breathable diapers on the survival of Candida was further confirmed in controlled experiments with adult volunteers. A suspension of C. albicans cells was applied to delineated sites on the volar forearm. Each site was then covered by a full-thickness patch from either an HB or a standard diaper. Survival of Candida colonies was reduced by almost two-thirds in the breathable diaper-covered sites compared to the control sites.

Sphingosines (precursors and degeneration products of complex sphingolipids) are mediators in membrane second-messenger cascades and in a wide variety of functions in eukaryotic cells. Sphingosines are also lethal for gram-positive microorganisms. In addition to its direct effect, sphinganine is here reported to affect the adherence of Streptococcus mitis to buccal epithelial cells and of Staphylococcus aureus to nasal mucosal cells after incubation for 90 min at 37 °C. When the bacteria were pretreated with 8.1, 16.2, 32.5, or (for Strep. mitis) 65 μM sphinganine for 60 min at 37 °C, adherence counts were reduced for Staph. aureus by 27, 37, and 60% and for Strep. mitis by 19, 44, 54, and 73%, respectively (p

Background: Onychomycosis, a fungal infection of the nail bed, is responsible for up to 50% of nail disorders. Although several surveys have been conducted in different parts of the world, there have been no multicenter epidemiologic surveys of onychomycosis in North America. Objective: A 12-center study was undertaken to (1) determine the frequency of onychomycosis, (2) identify organisms recovered from the nails, and (3) determine the antifungal susceptibility of isolates. Methods: A total of 1832 subjects participated in this study and completed a comprehensive questionnaire, and nail clippings were collected for potassium hydroxide examination and culturing. Results: The frequency of onychomycosis, as defined by the presence of septate hyphae on direct microscopy and/or the recovery of a dermatophyte, was found to be 13.8%. In general, the dermatophyte isolates were susceptible to the antifungals tested. Conclusion: Because of the limited number of large-scale studies, the baseline incidence is not firmly established. However, the higher frequency of onychomycosis in this study may confirm the suspected increase in incidence of disease in North America. (J Am Acad Dermatol 2000;43:641-8.).

Superficial fungal infections are among the world’s most common diseases. A group of specialized fungi, the dermatophytes, are responsible for cutaneous mycoses such as tinea pedis (athlete's foot), tinea corporis (ringworm), and tinea cruris. Dermatophytes penetrate and parasitize the fully keratinized tissues of the body, i.e., the skin, hair, and nails; however, in immunocompetent hosts, they do not normally invade the subcutaneous or deeper tissues of the body. Yeasts also may cause cutaneous fungal infections e.g., cutaneous can-didiasis (Candida albicans) and Pityriasis versicolor (Malassezia furfur). Superficial fungal infections typically induce mild to severe symptoms, most commonly erythema, desquamation, and pruritus. In the more severe infections, maceration, vesicles, cracking, and Assuring may be present, accompanied by secondary bacterial invasion. A topical preparation is an appropriate treatment mode for most superficial fungal skin infections because the therapy is applied directly to the locus of infection, and because the major symptoms are susceptible to relief with a topical formulation.

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. (J Am Acad Dermatol 1998;38:S110-6.)

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.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.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.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.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.

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. (J Am Acad Dermatol 1998;38:S103-9.)

Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred.To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea.A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study).Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers.One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel.Subjects were evaluated monthly for up to 6 months to determine relapse rates.Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed.In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%).In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.

Onychomycosis accounts for up to 50% of all nail infections I and can be chronic and resistant to treatment. 2-4 Itraconazole has antifungal activity against a broad range of dermatophyte infections. 5 It has a high affinity for keratin and penetrates the nail plate by diffusion through the nail bed. It appears in the distal nail within 7 days of initiating therapy and persists in the nail at inhibitory levels for an extended period, 69 up to 9 months in one study. 6 In our study, 75 patients with cfinically and mycologically diagnosed onychomycosis of the toenail were enrolled for treatment with itraconazole, 200 mg, or placebo once daily for 12 weeks. Patients were reexamined at weeks 24, 36, and 48.

Superficial mycotic infections such as seborrheic dermatitis, tinea pedis, tinea corporis, and onychomycosis are common in patients infected with human immunodeficiency virus (HIV). In communities where HIV infections are frequent, some of these clinical presentations serve as markers of the stage of HIV infection. The diagnosis of superficial fungal infection in HIV-positive patients may be difficult because of atypical clinical manifestations. Therefore, to ensure a correct diagnosis, skin scrapings should be collected for potassium hydroxide preparations and cultures. Most forms of dermatophytosis in HIV-positive patients respond well to many topical antifungal agents, such as azoles, terbinafine, and ciclopirox olamine. If the disease is chronic and extensive, then ketoconazole, fluconazole, and itraconazole are each effective.

Sphingosine and sphinganine, free sphingolipids of the stratum corneum, are, in vitro, strongly inhibitory for both bacteria and fungi. Whether or not they are suitable, indeed active, in vivo was examined: (i) on human volunteers, first as a preventative antiseptic against subsequently applied Staphylococcus aureus and Candida albicans, and second as a restorative antiseptic against the previously expanded normal skin flora; and (ii) on guinea-pigs as therapy for experimental C. albicans and Trichophyton mentagrophytes infections. In the antiseptic studies, which involved 200 micrograms/cm2 of sphinganine in ethanol (50 microliters of a 1.6% solution), up to three-log reductions in the population of target micro-organisms were obtained, compared with vehicle and untreated controls (P < 0.001). The daily application of sphingosine as 1.5% ethanol-petrolatum ointment was able to diminish inflammation slightly in dermatophyte-infected guinea-pigs (P = 0.02-0.05), although the animals remained culture positive over the 3-week sampling period. The candida infections, treated daily with 1.5% sphinganine in ethanol, showed no improvement in inflammation compared with controls, except for 2 days of the 2-week observation period (P = 0.01-0.03); however, by the fourth day of therapy the yeast was eliminated in 75% of animals. No gross toxicity was observed among animals or human volunteers. These experiments further support simple sphingolipids as important antimicrobial agents of the cutaneous barrier and point toward a new biochemical approach in treating infectious disease.

In addition to being keratinophilic, dermatophytes are characterized by the following: (1) production and tolerance of an alkaline pH in culture media, (2) resistance to 500 p.g/ml or less of cycloheximide, and (3) sensitivity to 20 p.gjml or less of griseofulvin. These properties are useful to devise special culture media for their selective isolation and recognition. Most media for general diagnostic mycology are available commercially. The standard medium for growing dermatophytes is Sabouraud's dextrose agar containing chloramphenicol and cycloheximide, which inhibit bacteria and saprophytic fungi, respectively. Four-percent glucose is added to Sabouraud's dextrose agar. Dermatophytes do not necessarily grow best on this agar, but for consistency, colonial morphology is determined on this medium. The addition of cycloheximide inhibits saprophytic fungi such as Scytalidium and Hendersonula (Natrassia), Scopulariopsis brevicaulis, Candida species, and Cryptococcus neoformans. Therefore a second medium without this antifungal agent should be included to avoid elimination of some relevant fungi, especially when nail specimens are being cultured. Media containing cycloheximide and chloramphenicol are commercially known as Mycobiotic or Mycosel agar (BBL, Baltimore, Md.). For poorly sporulating dermatophytes (for example, Trichophyton rubrum), a I: 10 dilution of 2% Sabouraud's dextrose agar is used to stimulate the pro

The authors have improved and simplified previous methods for producing localized mycotic skin infections in an attempt to compare topical antifungal agents for their bioequivalency. Healthy human volunteers who had negative results for commercial, purified Trichophyton antigen (Trichophytin) were inoculated with Trichophyton mentagrophytes on two sites on each forearm in a randomized study designed to compare the antifungal activities of two ciclopirox olamine formulations. The lesions, easily induced by the authors' method, were localized and did not spread under the occlusive dressings. Infections established at the four sites on 26 subjects were treated twice daily for 14 days with the two active drug formulations and their vehicles. There were no significant differences in culture-documented cure rates or alleviation of clinical signs and symptoms between ciclopirox olamine lotion and cream. Each drug was significantly better than its vehicle. The authors' method seems to be effective and suitable for therapeutic studies.

A total of 1,101 patients was studied for the incidence and distribution of dermatophytes in the San Francisco Bay Area from 1974 to 1978. 267 dermatophytes were isolated and identified. Trichophyton rubrum and Triehophyton tonsurans were the most prevalent dermatophytes. T. rubrum caused 83% of tinea pedis, 82% of tinea unguium, 80% of tinea manuum and 66% of tinea cruris. T. tonsurans was the major cause of tinea capitis (60%) followed by Microsporum canis. Microsporum audouinii was not encountered in this survey.

Among the cutaneous effects of an essential fatty acid deficient (EFAD) diet are hyperdesquamation, increased trans-epidermal water loss (TEWL), and altered lipid profiles, characteristics also common to inflammatory dermatoses. Because fatty acids are antimicrobial, we examined the indigenous skin flora of normal and EFAD hairless mice, and compared the antimicrobial efficacy of lipids extracted from their stratum corneum. EFAD mice supported 100-fold more bacteria than normal mice, and were the only group from which staphylococcus aureus were routinely isolated. Despite this greater carriage, in vitro experiments demonstrated that EFAD lipids are more lethal than normal lipids against Streptococcus pyogenes, S. aureus, S. epidermidis, Micrococcus sp., and a coryneform. Skin fungi were equally susceptible to both extracts. After thin layer chromatography, the most active fractions were found to be glycophingolipids and phsopholipids. EFAD extracts had 35% more free fatty acids and 75% more glycophingolipids; normal extracts had more triglycerides and phospholipids. S. aureus strain 502A survived equally well on EFAD as on normal mice, normal lipids applied on EFAD mice had no additional effect, but EFAD lipids on normal mice brought about a 35% reduction of the inoculated bacteria. If the mice were pretreated with alcohol, carriage of strain 502A was reduced by 71%. If instead the mice were previously washed with acetone to increase TEWL, a 97% reduction of the staphylococcus occurred. The application of normal flora to such acetone-washed mice decreased the efficacy to 76%. EFAD and normal lipids on human subjects were equally ineffective in eliminating strain 502A. Results suggest that in vivo the normal flora regulates the killing of pathogenic microorganisms by potent EFAD skin lipids.

Summary Two antimicrobial preparations for handwashing were compared by the‘gloved handwash method’ in seventy-two subjects. The test preparation was 0.5% chlorhexidine gluconate alcoholic-emollient handwash (Hibistat®); the reference agent was 70% isopropyl alcohol. The hands were contaminated with Serratia marcescens and disinfected with each antiseptic twenty-five times over an 8 h day. Bacterial counts were obtained for each hand after initial contamination, and after 5, 10, 15, 20 and 25 contamination treatment procedures. There was a statistically significant reduction in recovery of S. marcescens after chlorhexidine treatment compared to alcohol (P < 0.01). When recovery of organisms was plotted against the number of handwashes, there was a significant linear reduction in transient flora for chlorhexidine treated hands (P < 0.01) but not for alcohol treated hands (P < 0.20).

There was no significant difference in serological titers when different groups of guinea pigs (Hartley strain) infected with varying doses of mycelial phase of Histoplasma duboisii (one, two, seven, and no injections) were superinfected with Listeria monocytogenes 6 months later. The immunological response of infected animals which received two biweekly intraperitoneal injections of Histoplasma duboisii and were superinfected after 40 days with homologous and heterologous organisms was used for comparison. In general, animals receiving a single injection of Histoplasma duboisii had no complement-fixing antibodies against this antigen; however, positive skin and precipitin reactions did occur. Animals receiving several injections of Histoplasma duboisii had a higher complement-fixation titer (1:16 to 1:256) than those with two injections (1:8 to 1:32). After superinfection with Listeria monocytogenes, animals which received seven injections of Histoplasma duboisii showed a slight reduction in the number of rosette-forming cells against Listeria monocytogenes antigens when compared with the controls.

The aerobic bacterial flora of psoriatic plaques, uninvolved skin and the anterior nares of forty psoriatic patients was studied. The incidence od Staphylococcus aureus was 30% in the anterior nares, 20% on the plaques and 13% on the uninvolved skin. S. aureus counts were 3 x 10(2)/cm2 on the plaques and 1-5 x 10/cm2 on the normal skin. The total bacterial counts were also higher on plaques (7-9 x 10(3)/cm2) than on normal skin (3-0 x 10(3)/cm2). The incidence of lipophilic diphtheroids was significantly lower on the plaques (4%) than the normal skin (30%). Eighty percent of the strains of S. aureus isolated from psoriatic patients were resistant to 10 units of penicillin. Because of increased desquamation, psoriatic skin is a public health hazard.

the presence of antimicrobial substances on human skin was investigated. Staphyloccus aureus (10-4 colony-forming units) was applied on the forearm of 50 subjects and covered with a semiocclusive device for 24 hr. In 54% of the subjects the organisms persisted, and in 34% S. aureus was inhibited on the skin. Subjects with persistent S. aureus also had persistent Candida albicans, and vice persa. This correlation was not noted with Streptococcus pyogenes. Skin lipids from the two groups of subjects were extracted with acetone and assayed against S. aureus, S. pyogenes, and C. albicans. The percentage of S. aureus or C. albicans recovered was higher (79% and 55%, respectively) in subjects with persistent microrgamisms on their skin than in those without (47% and 28%, respectively). Subjects with persistent S. aureus and C. albicans had higher counts of normal flora (average, 9.2 times 10-3) than those on whose skin these organisms did not persist (average, 7.4 times 10-2). Coagulase-negative Staphylococcus and Micrococcus were found in higher proportions in subjects with persistent test organisms than in those without. Subjects with lower counts of their normal flora had a higher proportion of diphtheroids (34%) than the high-count group (12%).

This study was designed to establish in vivo the possible presence of antimicrobial substance(s) in human skin. If such agents are present on the skin surface, their removal might allow increased multiplication of applied organisms. One forearm was washed repeatedly for 5 minutes with lipid solvents; the other served as the control. The organisms applied (3 × 10 3 -7 × 10 4 in 0.01 ml Ringer's solution) on the forearms were not allowed to dry and were covered immediately with plastic protective cups for 5 hours. The microorganisms were harvested using a modified Pachtman-Burtenshaw method. With Staphylococcus aureus and Streptococcus pyogenes , acetone washed forearms had 2- to 510-fold more organisms than the control arm (P = 0.0008 and 0.08, respectively). Similar results were noted with ether (average 1:62, p=0.005). Candida albicans increased 2- to 200-fold (average 1:37, p=0.002). This effect did not occur with Escherichia coli and Pseudomonas aeruginosa (P = 0.8). To determine the time required for natural replenishment of the antimicrobial substances, bacteria were applied 2, 3, and 5 hours after washing with acetone. Increased numbers were seen at 2 (P = 0.04), but not at 5 (P = 0.2) hours. On the contrary, microbial flora removed by acetone washing were not restored during the 5 hour period. Regional variation studies showed that the forehead did not inhibit S. aureus persistence (as did the forearms) (P = 0.003). Forearms treated with acetone and the extracts not removed did not show increase of S. aureus counts when compared with untreated arms (average ratio 1 : 1, p=0.6). When acetone extracts of the skin surface were removed, evaporated, and then replaced on the skin, the increased bacterial counts noted above were no longer found.