P2419Terbinafine nail solution in onychomycosis: Baseline patient profile ofa large cohort of patients

Bardur Sigurgeirsson, MD, Department of Dermatology, University of Iceland,Reykjavik, Iceland; Anne Parneix-Spake, MD, Novartis PharmaceuticalsCorporation, East Hanover, NJ, United States; Boni Elewski, MD, University ofAlabama, Birmingham, AL, United States; Erika Zahn, MD, private practice,Berlin, Germany

Introduction: We present the baseline description of a large cohort of patients withonychomycosis enrolled in two pivotal clinical studies of terbinafine HCL nailsolution, a new water-soluble formulation for topical application to the affectednails.

Objectives: The objectives of the studies were to demonstrate the superiority ofterbinafine HCL nail solution over vehicle in patients with onychomycosis and todemonstrate its efficacy in terms of cure rate and safety in terms of reported adverseevents.

Methods: Two randomized, double-blind, vehicle-controlled, multicenter, parallel-group studies of identical design were conducted. In these studies, patients were tobe 12 to 75 years old with dermatophyte nail infection affecting 25% to 75% of thetarget toenail without matrix involvement and confirmed with positive potassiumhydroxide microscopy and culture. Eligible patients were randomized either toactive or to vehicle treatment. In study 1, 518 patients were enrolled (373 from theUnited States, 47 from Canada, and 98 from Iceland), and in study 2, 526 patientswere enrolled (334 in the United States, 174 in Germany, and 18 in France). In bothstudies, the predominant causative microorganism was Trichophyton rubrum (97%and 93%, respectively). In study 1, 82% of patients were 18 to 64 years of age and18% were 65 years of age or older. A similar distribution was observed in study 2 (15-64 years of age [74%] and 65 years of age or older [26%]). About 58% (study 1) and56% (study 2) of patients had[40% nail involvement. There were 57% (study 1) and47% (study 2) of patients who had the current infection for longer than 65 months.

Conclusion: The study baseline patient and disease characteristics confirm thatT rubrum is the causative organism of toenail dermatophytes onychomycosis inthe vast majority of the cases (more than 90%) and that onychomycosis is achronic disease with increasing prevalence with age.

AB116

cial support: None identified.

Commer

P2420Disseminated Pencillium marneffei infection as the presenting symptomof HIV/AIDS in a Vietnamese female

Thanh-Nga T. Tran, MD, Harvard Department of Dermatology, Boston, MA,United States; Minh Van Hoang, MD, University of Medicine and Pharmacy of HoChi Minh City, Ho Chi Minh City, Vietnam; Thanh Thai Van Le, MD, University ofMedicine and Pharmacy of Ho Chi Minh City, Ho Chi Minh City, Vietnam;Timothy R. Quinn, MD, Pathology Services Inc, Cambridge, MA, United States

Penicillium marneffei (PM) infection is an AIDS-defining opportunistic infection.The rate of HIV/AIDS in Vietnam has increased rapidly since first reported in 1990with concurrent increase in opportunistic infections. PM is a dimorphic fungus thatexists in tissue as both intracellular and extracellular yeast-like forms at 378C.Histologically, penicillinosis resembles histoplasmosis with both having smallintracellular yeast forms in macrophages except for the presence of septae inpenicillium that results from binary fission. Culture at 258C, PM grows as a fluffy graycolony with diffusible red pigment on Saboraud glucose agar. Clinically, dissemi-nated penicillinosis present as molluscum contagiosumelike or acneiform pap-ules/nodules on the face and upper chest and extremities and occasionally themucosa. The patient presented with a 3-week history of disseminated umbilicatedpapules on her face and arms, fever, chills, sore throat, difficulty swallowing, and arecent weight loss of 8 kg. Lesions became more numerous and coalesced. Hermedical history included herpes zoster 1 year before presentation. On examination,disseminated and confluent umbilicated papules were widespread. Thrush wasnoted on the tongue and hard palate. Lymphadenopathy was detected in theabdomen. HIV serology was positive. She had a CD4 T-cell count of 24 cells/mm3.Lesional skin biopsy was reported to show intracellular yeast-like forms.Itraconazole 200 mg twice daily was given with great improvement for her faciallesions. She was subsequently referred for antiretroviral therapy. PM infectionshould be considered in patients from Southeast Asia presenting with molluscumcontagiosumelike lesions, previous herpes zoster, oral candidiasis, and intracellularyeast forms on histopathology.

cial support: None identified.

Commer

J AM ACAD DERMATOL

P2421Cutaneous Cryptococcus in a renal transplant patient with mental statuschange: A case report and review of the literature

Jessica Liggett, Henry Ford Health Systems Department of Dermatology, Detroit,MI, United States; David Ozog, MD, Henry Ford Health System, Detroit, MI,United States

Cryptococcus is a systemic infection caused by the encapsulated yeast Cryptococcusneoformans, which is ubiquitously found in our environment. Cutaneous lesions inCryptococcus can occur 2 to 8 months before other symptoms of disseminateddisease and as dermatologists we can aid in the diagnosis of patients before theydevelop more serious visceral involvement. As organ transplantation, HIV, andtreatment of other diseases with immunosuppressive medications increases,opportunistic infections such as Cryptococcus also increases. The index ofsuspicion for an immunosuppressed patient with new skin lesions must be higherand should prompt a more complete review of symptoms. We present the case of a59-year-old African American male with a history of a deceased donor kidneytransplant in 2006. Immunosuppressive medications included mycophenolatemofetil, tacrolimus, and methylprednisolone. He presented with a 1-week historyof headaches, mental status change, difficulty walking and a 2- to 4-week history ofan enlarging plaque on the right cheek. A lumbar puncture was performed and thepatient was found to have cryptococcal meningitis. A biopsy revealed multiple yeast-like organisms in the dermis and within histiocytes in a pauci inflammatory, foamystroma. Capsules were seen with mucicarmine stain. A diagnosis of secondarycutaneous cryptococcus from disseminated disease was made. We will provide areview of the literature on the symptoms, diagnosis and treatment of cutaneouscryptococcus. Specifically, we would like to discuss the adjuvant treatment ofremaining cutaneous lesions after oral antifungal medications have beenadministered.

cial support: None identified.

Commer

P2422AN2718 has broad spectrum antifungal activity necessary for the topicaltreatment of skin and nail fungal infections

Weimin Mao, MD, Anacor Pharmaceuticals, Inc, Palo Alto, CA, United States;Elena Seiradake, PhD, EMBL Grenoble Outstation, Cedex, France; StephenCusack, PhD, EMBL Grenoble Outstation, Cedex, France; Thibaut Crepin, PhD,EMBL Grenoble Outstation, Cedex, France; Yasheen Zhou, PhD, MS, AnacorPharmaceuticals, Inc, Palo Alto, CA, United States

AN2718 (5-chloro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole) is a broad spectrumantifungal compound currently in development for the topical treatment of skin andnail fungal infections. AN2718 inhibits fungal growth by blocking the first step inprotein synthesis, the aminoacylation of tRNA-LEU by leucyl-tRNA synthetase(LeuRS). AN2718 has a broad-spectrum of antifungal activity against yeasts, moldsand dermatophytes. AN2718 has an MIC90 of 1 �g/mL, 0.25 �g/mL, 1 �g/mL, and0.5 �g/mL for Candida albicans (n ¼ 100), C glabrata (n ¼ 100), Trichophytonmentagrophytes (n ¼ 100), and T rubrum (n ¼ 100), respectively. AN2718 inhibitscytoplasmic LeuRS from the mold, Aspergillus fumigatus, and from the yeast,C albicans, with an IC50 of 2 �M and 4.2 �M, respectively. A fumigatus enzyme wasused as surrogate for the Trichophyton enzyme, because Trichophyton, being afilamentous fungi, is more closely related to A fumigatus than the yeast C albicans.To further understand the mechanism of inhibition, its mode of binding to LeuRSwas determined. This was accomplished by obtaining a cocrystal structure of abenzoxaborole with the editing domain of LeuRS from C albicans. An analogue ofAN2718, AN3018, was shown by cocrystal structure determination to bind to theediting active site as an adduct with AMP, a surrogate for the terminal ribonucleotideof tRNA. The boron in AN3018 was bound to the cis-diol on the ribose of AMP in theactive site. These data confirm that AN2718 inhibits LeuRS by trapping tRNA-LEU inthe editing active site, which prevents the synthesis of leucyl-tRNA-LEU, ultimatelyleading to a block in protein synthesis. AN2718, a LeuRS inhibitor, is a broadspectrum antifungal which shows promise for the topical treatment of skin and nailfungal infections.

cial support: None identified.

Commer

MARCH 2009