drug susceptibility and resistance of fungal isolates in onychomycosis against efinaconazole

1
P7037 Disseminated mucormycosis Ha Do, MD, MS, Indiana University, Dermatology Department, Indianapolis, IN, United States; Lori Sanford, MD, Indiana University, Dermatology Department, Indianapolis, IN, United States; Yongxue Yao, MD, PhD, Indiana University, Dermatology Department, Indianapolis, IN, United States We present a case of a 55-year-old man with a history of metastatic pancreatic neuroendocrine tumor statusepost-multivisceral (liver, stomach, pancreas, and intestine) transplant in March 2011. He subsequently developed hepatic EBV- associated monomorphic posttransplant lymphoproliferative disorder in June 2011 and was treated with 4 cycles of weekly Rituxan. He was admitted in February 2012 for severe dyspnea related to persistent pancytopenia since transplant. During this hospitalization, the patient developed a 4-day history of generalized tender rash associated with arthralgia. Examination revealed multiple tender erythematous, indurated dermal nodules, some with central dusky erosions, on the trunk and extremities. Skin biopsy showed large fungal hyphae and spores in the dermis. Fungal morphology evaluation and skin tissue culture confirmed mucormycosis species. Pan-CT imaging showed multifocal cutaneous and paranasal involvement. Ambisome and micafungin were initiated for disseminated mucormycosis. He underwent several surgical debridements in addition to medical therapy. Mucormycosis is a rare fungal infection that often occurs in diabetics, chronic renal failure patients, or immunosuppressed population such as leukemia, lymphoma, AIDS, burns, and organ transplant patients. The clinical course is acute with rapid deterioration and associated with high mortality rate up to 80%. All 5 major clinical forms (cutaneous, rhinocerebral, pulmonary, gastrointestinal, and disseminated) are characterized by blood vessel invasion which leads to tissue infarction and necrotic purulent eschar. Commercial support: None identified. P6538 Drug susceptibility and resistance of fungal isolates in onychomycosis against efinaconazole William Jo, PhD, Dow Pharmaceutical Sciences (a division of Valeant Pharmaceuticals International), Petaluma, CA, United States; Atsushi Iwata, MS, Kaken Pharmaceutical Co Ltd, Kyoto, Japan; Hisato Senda, DVM, Kaken Pharmaceutical Co Ltd, Kyoto, Japan; Takashi Nakamura, MS, Kaken Pharmaceutical Co Ltd, Tokyo, Japan Background: Efinaconazole 10% solution is a new triazole antifungal in development for topical treatment of onychomycosis. Many antifungals have been widely used for mycoses with inherent drug resistance concerns. However, few studies assess the potential for drug resistance in onychomycosis therapy. Objective: To investigate in vitro susceptibility of onychomycosis clinical isolates against efinaconazole and their potential to develop drug resistance. Methods: The in vitro susceptibility to efinaconazole was determined for isolates recovered in 2 multicenter, vehicle-controlled onychomycosis clinical studies with topical efinaconazole 10% solution, using the broth micro dilution minimum inhibitory concentration (MIC) assay (CLSI M38-A2). Isolates were from the United States, Canada and Japan collected at screening (N ¼ 1498), end of treatment (N ¼ 45, week 48) and follow-up (N ¼ 121, week 52) visits. The potential of dermatophytes acquiring resistance to efinaconazole was also examined in vitro with serial subculturing of 6 T rubrum strains and 1 T mentagrophytes strain in the presence of subinhibitory efinaconazole concentrations for 10-12 passages. The MIC was determined for each strain before the first passage and after each passage to monitor changes in MIC. Results: The species distribution of isolates at screening included T rubrum (N ¼ 1387, 92.6%) T mentagrophytes (N ¼ 106, 7.1%), and Epidermophyton floccosum (N ¼ 5, 0.3%). The efinaconazole MICs against T rubrum and T mentagrophytes were # 0.002-0.03 and # 0.002-0.06 g/mL, respectively. Only 3 and 10 T rubrum isolates were recovered from efinaconazole 10% solution treatment arms at weeks 48 and 52, respectively (MIC # 0.002-0.015 g/mL). After serial subculturing with efinaconazole, only 2 T rubrum and 1 T mentagrophytes strains exhibited a 2- to 4- fold increase in MIC. The MIC increases were similar to those observed with itraconazole and clotrimazole. Conclusion: Efinaconazole demonstrated potent antifungal activity within a narrow range of MICs in recently-collected dermatophyte isolates from onychomycosis patients from different geographical locations. The MICs for T rubrum isolates recovered were within the screening MIC range. No significant increases in MIC were observed in T rubrum and T mentagrophytes strains after serial subculturing. These data suggest that the potential of dermatophytes developing resistance to efinaconazole in onychomycosis therapy is low. 100% sponsored by Valeant Dermatology a division of Valeant Pharmaceuticals North America LLC. P6794 Feline sporotrichosis: Family case report Lily Paola Belmonte Casta~ neda, MD, Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil; Glaura Plata, MD, Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil; Marcos Vinicius Lima Galles, MD, Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil; Mayra Alejandra Carillo Uribe, MD, Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil; M onica Daniela Gauto Nu~ nez, MD, Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil Sporotrichosis is described as a disease of low incidence in Brazil; however, recent reports show that the state of Rio de Janeiro has been the scene of an urban epidemic area. In this especificy area, cases have been reported related to scratch or bite of domestic animals (dogs, cats), leading to family outbreaks, affecting individuals of all ages and sex, becoming an emerging zoonosis and thus a public health problem due to the significant increase in cases. With the increased incidence, also increases the incidence of severe clinical forms or atypical form of the disease. Case 1: Female, 14 years, born and raised in Rio de Janeiro, presenting 20 days ago, ulcerated lesion in the left malar region, with the later onset of other painful and erythematous nodules in the same lymph hemiface following the path. Reported a scratch by a domestic cat. Culture: isolated Sporothrix schenckii. Histopatologic: pseudoepitheliomatous hyperplasia of the epidermis, dermis with marked mononuclear cell infiltration, and giant cell granulomatous reaction multinucleadas. Treatment: Itraconazole 100 mg daily, with complete resolution of lesions in one month. Case 2: Patient, 45 years, mother and resident of the same household, housewife. Report that 1 month after domestic cat scratch, she presented ulcerated nodules in the proximal portion of the right leg, later had smaller lesions on thigh of the same limb, following the lymphatic path. Culture: isolated Sporothrix schenckii. Histopatologic: granulomatous, epi- thelioid histiocytes, multinucleated giant cells and necrose. Treatment: Itraconazole 100 mg daily and thermotherapy, progressing to healing of lesions in 2 months. The occurrence of sporotrichosis and increased incidence in the metropolitan area of the state, is strongly related to social, environmental, and behavioral factors that influence their frequency, transmission, and geographic distribution. This strains have slightly different characteristics of the strains studied in Spain and S~ ao Paulo. We need further studies to determine the epidemiologic and social transcendence of human sporotrichosis in the state of Rio de Janeiro, perhaps it is necessary to implement this as a state and municipal reportable disease. Commercial support: None identified. P6481 Juvenile form of paracoccidioidomycosis associated with exuberant hypoalbuminemia Adriana T aquez Munoz, Policl ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil; Aline Sarkis dos Santos, Policl ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil; Ant^ onio Francesconi do Valle, Fundac ¸~ ao Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil; Carlos Alberto Cer on, Policl ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil; Ludimila Noleto de Rezende, Policl ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil; Raquel Noschang Pereira, Policl ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil Background: Paracoccidioidomycosis (PCM) is a suppurative and granulomatous systemic mycosis caused by thermodimorphic Paracoccidioides brasiliensis (Pb) fungus. It is shown in the following clinical forms: chronic adult (90%) and juvenile (10%). Case report: Male patient, 26 years, farmer, showed multiple lymphadenopathy during 8 months, bilateral, in the cervical, axillary and inguinal regions, and also nodular lesions on the face and ulceration in the groin, associated to afternoon fever, anorexia and weight loss. Exams: Serology for fungi: non-reactive, direct mycologic examination and culture of lymph node aspirated: positive for Pb, lymph node biopsy: paracoccidiodiomicose, albumin: 1.8 (hypoalbuminemia). Evolution: Started the treatment with itraconazole 200 mg/day, showing improvement on the skin lesions but with significant lymphedema of the penis, scrotum, pubic region, and lower limbs. Was treated with corticosteroids but without improve- ment. Only after 5 months showed gradual clinical improvement and results in the edema with antifungal medication and oral protein replacement. Discussion: The PCM runs with great clinical polymorphism and the lymph nodes are the organs most frequently involved in the juvenile form, as seen in this case. The hypoalbuminemia affects great part of the patients, especially in the juvenile form, what can interfere in the clinical course and in the treatment response. The patient had a very important protein calorie depletion, which was responsible for the edema and only relented with spare protein. The double immunodiffusion test is the most used in diagnosis because of its ease execution and high sensitivity and specificity; however, it may have false-negative results, being significantly higher in juvenile clinical form, which is what happened with this patient. The treatment of PCM juvenile type can be done with Itraconazole, trimethoprim + sulfamethoxa- zole, and in malabsorptive syndrome case it shall be used intravenous medication (amphotericin B). Drug combinations can also be used, because of the low responses from the use of only one drug. In patients with PCM it is used the term ‘‘apparent cure or clinical cure’’ because of the impossibility of Pb eradication, and the potential risk of a late revival. After the treatment, patients should be monitored once a year, during three years, at least, with clinical, radiologic, and serologic examinations. Commercial support: None identified. AB128 JAM ACAD DERMATOL APRIL 2013

Upload: ngodat

Post on 31-Dec-2016

218 views

Category:

Documents


3 download

TRANSCRIPT

Page 1: Drug susceptibility and resistance of fungal isolates in onychomycosis against efinaconazole

P7037Disseminated mucormycosis

Ha Do, MD, MS, Indiana University, Dermatology Department, Indianapolis, IN,United States; Lori Sanford, MD, Indiana University, Dermatology Department,Indianapolis, IN, United States; Yongxue Yao, MD, PhD, Indiana University,Dermatology Department, Indianapolis, IN, United States

We present a case of a 55-year-old man with a history of metastatic pancreaticneuroendocrine tumor statusepost-multivisceral (liver, stomach, pancreas, andintestine) transplant in March 2011. He subsequently developed hepatic EBV-associated monomorphic posttransplant lymphoproliferative disorder in June 2011and was treated with 4 cycles of weekly Rituxan. He was admitted in February 2012for severe dyspnea related to persistent pancytopenia since transplant. During thishospitalization, the patient developed a 4-day history of generalized tender rashassociated with arthralgia. Examination revealed multiple tender erythematous,indurated dermal nodules, some with central dusky erosions, on the trunk andextremities. Skin biopsy showed large fungal hyphae and spores in the dermis.Fungal morphology evaluation and skin tissue culture confirmed mucormycosisspecies. Pan-CT imaging showed multifocal cutaneous and paranasal involvement.Ambisome and micafungin were initiated for disseminated mucormycosis. Heunderwent several surgical debridements in addition to medical therapy.Mucormycosis is a rare fungal infection that often occurs in diabetics, chronic renalfailure patients, or immunosuppressed population such as leukemia, lymphoma,AIDS, burns, and organ transplant patients. The clinical course is acute with rapiddeterioration and associated with high mortality rate up to 80%. All 5 major clinicalforms (cutaneous, rhinocerebral, pulmonary, gastrointestinal, and disseminated) arecharacterized by blood vessel invasion which leads to tissue infarction and necroticpurulent eschar.

AB128

cial support: None identified.

Commer

P6538Drug susceptibility and resistance of fungal isolates in onychomycosisagainst efinaconazole

William Jo, PhD, Dow Pharmaceutical Sciences (a division of ValeantPharmaceuticals International), Petaluma, CA, United States; Atsushi Iwata, MS,Kaken Pharmaceutical Co Ltd, Kyoto, Japan; Hisato Senda, DVM, KakenPharmaceutical Co Ltd, Kyoto, Japan; Takashi Nakamura, MS, KakenPharmaceutical Co Ltd, Tokyo, Japan

Background: Efinaconazole 10% solution is a new triazole antifungal in developmentfor topical treatment of onychomycosis. Many antifungals have been widely used formycoses with inherent drug resistance concerns. However, few studies assess thepotential for drug resistance in onychomycosis therapy.

Objective: To investigate in vitro susceptibility of onychomycosis clinical isolatesagainst efinaconazole and their potential to develop drug resistance.

Methods: The in vitro susceptibility to efinaconazole was determined for isolatesrecovered in 2 multicenter, vehicle-controlled onychomycosis clinical studies withtopical efinaconazole 10% solution, using the broth micro dilution minimuminhibitory concentration (MIC) assay (CLSI M38-A2). Isolates were from theUnited States, Canada and Japan collected at screening (N¼ 1498), end of treatment(N ¼ 45, week 48) and follow-up (N ¼ 121, week 52) visits. The potential ofdermatophytes acquiring resistance to efinaconazole was also examined in vitrowith serial subculturing of 6 T rubrum strains and 1 T mentagrophytes strain in thepresence of subinhibitory efinaconazole concentrations for 10-12 passages. TheMICwas determined for each strain before the first passage and after each passage tomonitor changes in MIC.

Results: The species distribution of isolates at screening included T rubrum (N ¼1387, 92.6%) T mentagrophytes (N ¼ 106, 7.1%), and Epidermophyton floccosum(N ¼ 5, 0.3%). The efinaconazole MICs against T rubrum and T mentagrophyteswere # 0.002-0.03 and # 0.002-0.06 �g/mL, respectively. Only 3 and 10 T rubrumisolates were recovered from efinaconazole 10% solution treatment arms at weeks48 and 52, respectively (MIC # 0.002-0.015 �g/mL). After serial subculturing withefinaconazole, only 2 T rubrum and 1 T mentagrophytes strains exhibited a 2- to 4-fold increase in MIC. The MIC increases were similar to those observed withitraconazole and clotrimazole.

Conclusion: Efinaconazole demonstrated potent antifungal activity within a narrowrange of MICs in recently-collected dermatophyte isolates from onychomycosispatients from different geographical locations. The MICs for T rubrum isolatesrecovered were within the screening MIC range. No significant increases in MICwere observed in T rubrum and T mentagrophytes strains after serial subculturing.These data suggest that the potential of dermatophytes developing resistance toefinaconazole in onychomycosis therapy is low.

nsored by Valeant Dermatology a division of Valeant Pharmacerica LLC.

100% spo euticalsNorth Am

J AM ACAD DERMATOL

P6794Feline sporotrichosis: Family case report

Lily Paola Belmonte Casta~neda, MD, Policlinica Geral Do Rio de Janeiro, Rio deJaneiro, Brazil; Glaura Plata, MD, Policlinica Geral Do Rio de Janeiro, Rio deJaneiro, Brazil; Marcos Vinicius Lima Galles, MD, Policlinica Geral Do Rio deJaneiro, Rio de Janeiro, Brazil; Mayra Alejandra Carillo Uribe, MD, PoliclinicaGeral Do Rio de Janeiro, Rio de Janeiro, Brazil; M�onica Daniela Gauto Nu~nez, MD,Policlinica Geral Do Rio de Janeiro, Rio de Janeiro, Brazil

Sporotrichosis is described as a disease of low incidence in Brazil; however, recentreports show that the state of Rio de Janeiro has been the scene of an urban epidemicarea. In this especificy area, cases have been reported related to scratch or bite ofdomestic animals (dogs, cats), leading to family outbreaks, affecting individuals of allages and sex, becoming an emerging zoonosis and thus a public health problem dueto the significant increase in cases. With the increased incidence, also increases theincidence of severe clinical forms or atypical form of the disease. Case 1: Female, 14years, born and raised in Rio de Janeiro, presenting 20 days ago, ulcerated lesion inthe left malar region, with the later onset of other painful and erythematous nodulesin the same lymph hemiface following the path. Reported a scratch by a domesticcat. Culture: isolated Sporothrix schenckii. Histopatologic: pseudoepitheliomatoushyperplasia of the epidermis, dermis with marked mononuclear cell infiltration, andgiant cell granulomatous reaction multinucleadas. Treatment: Itraconazole 100 mgdaily, with complete resolution of lesions in one month. Case 2: Patient, 45 years,mother and resident of the same household, housewife. Report that 1 month afterdomestic cat scratch, she presented ulcerated nodules in the proximal portion of theright leg, later had smaller lesions on thigh of the same limb, following the lymphaticpath. Culture: isolated Sporothrix schenckii. Histopatologic: granulomatous, epi-thelioid histiocytes, multinucleated giant cells and necrose. Treatment: Itraconazole100 mg daily and thermotherapy, progressing to healing of lesions in 2 months. Theoccurrence of sporotrichosis and increased incidence in the metropolitan area ofthe state, is strongly related to social, environmental, and behavioral factors thatinfluence their frequency, transmission, and geographic distribution. This strainshave slightly different characteristics of the strains studied in Spain and S~ao Paulo.We need further studies to determine the epidemiologic and social transcendence ofhuman sporotrichosis in the state of Rio de Janeiro, perhaps it is necessary toimplement this as a state and municipal reportable disease.

cial support: None identified.

Commer

P6481Juvenile form of paracoccidioidomycosis associated with exuberanthypoalbuminemia

Adriana T�aquez Munoz, Policl�ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil;Aline Sarkis dos Santos, Policl�ınica Geral do Rio de Janeiro, Rio de Janeiro, Brazil;Antonio Francesconi do Valle, Fundac~ao Oswaldo Cruz (FIOCRUZ), Rio deJaneiro, Brazil; Carlos Alberto Cer�on, Policl�ınica Geral do Rio de Janeiro, Rio deJaneiro, Brazil; Ludimila Noleto de Rezende, Policl�ınica Geral do Rio de Janeiro,Rio de Janeiro, Brazil; Raquel Noschang Pereira, Policl�ınica Geral do Rio deJaneiro, Rio de Janeiro, Brazil

Background: Paracoccidioidomycosis (PCM) is a suppurative and granulomatoussystemic mycosis caused by thermodimorphic Paracoccidioides brasiliensis (Pb)fungus. It is shown in the following clinical forms: chronic adult (90%) and juvenile(10%).

Case report: Male patient, 26 years, farmer, showed multiple lymphadenopathyduring 8 months, bilateral, in the cervical, axillary and inguinal regions, and alsonodular lesions on the face and ulceration in the groin, associated to afternoon fever,anorexia and weight loss. Exams: Serology for fungi: non-reactive, direct mycologicexamination and culture of lymph node aspirated: positive for Pb, lymph nodebiopsy: paracoccidiodiomicose, albumin: 1.8 (hypoalbuminemia). Evolution:Started the treatment with itraconazole 200 mg/day, showing improvement onthe skin lesions but with significant lymphedema of the penis, scrotum, pubicregion, and lower limbs. Was treated with corticosteroids but without improve-ment. Only after 5 months showed gradual clinical improvement and results in theedema with antifungal medication and oral protein replacement.

Discussion: The PCM runs with great clinical polymorphism and the lymph nodesare the organsmost frequently involved in the juvenile form, as seen in this case. Thehypoalbuminemia affects great part of the patients, especially in the juvenile form,what can interfere in the clinical course and in the treatment response. The patienthad a very important protein calorie depletion, which was responsible for theedema and only relented with spare protein. The double immunodiffusion test is themost used in diagnosis because of its ease execution and high sensitivity andspecificity; however, it may have false-negative results, being significantly higher injuvenile clinical form, which is what happened with this patient. The treatment ofPCM juvenile type can be done with Itraconazole, trimethoprim + sulfamethoxa-zole, and in malabsorptive syndrome case it shall be used intravenous medication(amphotericin B). Drug combinations can also be used, because of the lowresponses from the use of only one drug. In patients with PCM it is used the term‘‘apparent cure or clinical cure’’ because of the impossibility of Pb eradication, andthe potential risk of a late revival. After the treatment, patients should be monitoredonce a year, during three years, at least, with clinical, radiologic, and serologicexaminations.

cial support: None identified.

Commer

APRIL 2013