antifungal agents against Trichophyton rubrum.

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1 AAC Accepted Manuscript Posted Online 20 April 2015 Antimicrob. Agents Chemother. doi: /aac Copyright 2015, American Society for Microbiology. All Rights Reserved. 1 2 Comparison of in vitro susceptibility of newer triazoles and established antifungal agents against Trichophyton rubrum Shuwen Deng 1*, Chao Zhang 1*, Seyedmojtaba Seyedmousavi 2, 3, 4, Shuang Zhu 1,Xin Tan 5, Yiyang Wen 6, Xin Huang 6, Wenzhi Lei 6, Zhaojing Zhou 1, Wenjie Fang 1, Shuaishuai Shen 6, Danqi Deng 5, Weihua Pan 1#, Wanqing Liao 1# Shanghai Institute of Medical Mycology, Changzheng Hospital, Second Military Medical University, Shanghai, China 2 Department of Medical Microbiology, Radboudumc, Nijmegen, The Netherlands 3 Department of Medical Microbiology and Infectious Diseases, ErasmusMC, The Netherlands 4 Invasive Fungi Research Center, Mazandaran University Medical Center, Sari, Iran 5 Department of Dermatology, The second affiliated hospital of Kunming Medical University, Kunming, China 6 Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China Running title: Antifungal susceptibility of Trichophyton rubrum 1

2 23 24 Key words: Trichophyton rubrum, dermatophytosis, antifungal susceptibility testing *Correspondence: Prof. Wanqing Liao Shanghai Institute of Medical Mycology, Changzheng Hospital, Second Military Medical University, Shanghai, China Address: Fengyang Rd No.415, Shanghai, China, Tel: + 86 (21) liaowanqing@sohu.com Co - Corresponding: Dr. Weihua Pan, panweihua@medmail.com.cn *Shuwen Deng and *Chao Zhang contributed equally to this study clinical Trichophyton rubrum isolates were tested against 7 antifungal agents. Geometric mean MIC of all isolates were in increasing order: terbinafine ( 0.03 mg/l ), voriconazole ( 0.05 mg/l ), posaconazole ( 0.11 mg/l ), isavuconazole ( 0.13 mg/l ), itraconazole ( 0.26 mg/l ), griseofulvin ( 1.65 mg/l ), fluconazole ( 2.12 mg/l ) Wordcount abstract: 56 Wordcount maintext: Dermatophytosis caused by Trichophyton rubrum are the most common 2

3 cutaneous fungal infections worldwide(1), which represents the cause of between 80% and 90% of all chronic and recurrent infections(2). These infections establish an important public health problem because of prolonged treatment of the disease, usual recurrence infection are generally considered difficult to manage(3). Reliable in vitro susceptibility testing would therefore be useful for selecting the most suitable antifungal treatment. For many years, griseofulvin was the only approved systemic anti-dermatophytic agent(4). However, nowadays many potent antifungal agents are available for the treatment of dermatophytosis, such as allylamines, and triazoles with the more potent activity and less side effects(5-19). Expansion of information on in vitro susceptibility testing of dermatophytes to new antifungal agents will help in selecting or developing antifungal drug regimens. The aim of the study was to compare in vitro the susceptibility of three newer triazoles including voriconazole, posaconazole and isavuconazole and four established antifungal agents against. T. rubrum. 111 clinical isolates of T. rubrum were collected from seven dermatology clinics in Shanghai, China. Morphological identifications were confirmed by sequence-based analysis of the internal transcribed spacer of the rdna region. In vitro activity of seven antifungal agents was determined with the reference guideline M38-A2 (20) with minor modification. Two reference strains, Trichophyton mentagrophytes (ATCC-MYA-4439) and Candida parapsilosis ( ATCC ) were included as quality controls. Student s t test with the statistical SPSS package (version 3

4 ) were used and P values of 0.05 were considered statistically significant. Table 1 listed the results of the MIC ranges, geometric mean MICs, MIC 50 and MIC 90 values of seven antifungal agents against 111 T. rubrum strains. Terbinafine, voriconazole, posaconazole, isavuconazole, itraconazole, griseofulvin, had low MICs, against all tested strains, whereas fluconazole did not show inhibitory effects. Similarly, it has been shown in several studies (table 2), however, limited data are available for newer triazoles isavuconazole, posaconazole. Terbinafine was one of the most effective antifungal agents against T.rubrum among the 7 fungal agents tested and our findings confirmed those of previous studies(5-19) (table 2). We compared the in vitro activities of 3 newer triazoles isavuconazole, posaconazole and voriconazole with itraconazole. Three newer triazoles offered good in vitro activity against T. rubrum ( table 1 ). All isolates were far more susceptible to the 3 newer triazoles than itraconazole (table 1), and comparable to those reported by other studies(7, 9, 10, 14, 17, 18). Isavuconazole is a novel broad-spectrum triazole agent and shares the same mechanism of action with the other triazoles. Several studies supported its efficacy in invasive Candida species, Cryptococcus neoformans, Aspergillus species, Mucorales isolates(5-19, 21). However, the antifungal-susceptibility profile of dermatophytes remains poorly examined. Ghannoum M et al. reported that isavuconazole had shown potent in vitro activity against the 4

5 dermatophytes(22) and was more active than other triazoles tested (itroconazole, voriconazole ), but had higher MIC value than terbinafine, however, against T. rubrum isolates with high MIC to terbinafine, isavuconazole remained low (0.06 mg/l for all tested isolates )(23). In our study, MIC values of isavuconazole ( GM 0.13 mg/l, MIC mg/l ) were similar to posaconazole (GM 0.11 mg/l, MIC mg/l ), and voriconazole (GM 0.05 mg/l, MIC mg/l ), the difference was within 1 log 2-dilution step, much lower than itraconazole (GM 0.26 mg/l, MIC 90 2 mg/l) for the majority of T. rubrum tested. Posaconazole showed similar activity as those published by A.K. Gupta who reported posaconazole as the most active compound with MIC 90 <=1.0 mg/l(14), similarly, it was 0.5 mg/l in our study. Similar data was reported by Singh et al.(10), however the MIC value was greater than those by us and Gupta et al(14). This variation may be a result of the different methods used (table 2). The potent activity of posaconazole against T. violaceum ( T. rubrum complex spp.) has been reported by us as well(24). The excellent activity of voriconazole against T.rubrum has been observed by B.fernandez and A. J.Carrillo-Muñoz et al. with a sample set of 144 and 139 respectively ( both GM 0.06 mg/l). Our findings, with 111 isolates, have also confirmed this good activity ( GM 0.05 mg/l ). There were, however, some discrepancies, in two of the previous reports, voriconazole appeared to be less active than itraconazole(7, 18). This could be attributed, at least partially, to the 5

6 different methodology employed and the lack of standardized protocols. Voriconazole had revealed potent activity against T. violaceum in our previous study(24). For itraconazole, significant variations are shown among published literature in table 2. Overall, half of the geometric mean MIC of itraconazole was less than 0.1mg/L, the highest GM was 0.42 mg/l (16), followed by 0.24 mg/l(8). Our results showed good in vitro activity of itraconazole against T. rubrum (GM 0.26 mg/l), however, itraconazole was less active than the three new triazoles tested. Griseofulvin has been the first-line antifungal agent for the treatment of dermatophytoses for many years, but today it is not widely used(4) due to griseofulvin-resistant isolates of dermatophytes and existence of strains with elevated MIC levels to griseofulvin(6, 25-27). With our results, the MIC values of griseofulvin for T.rubrum was in agreement with those reported by Adimi et al(7) and Perea et al(18). Griseofulvin was less active than rest agents tested except fluconazole against T. rubrum. Nevertheless, all strains were more susceptible to griseofulvin than fluconazole (table 1 ). Among reported studies( table 2 ), fluconazole also was effective against T. rubrum, except one by Adimi(7). Of all agents tested in current study, fluconazole showed lowest susceptibility which was consistent with previous studies (9, 10, 16), although T. rubrum is not susceptible to fluconazole, it is recommended for the management of some dermatophytoses(28-30). 6

7 In conclusion, terbinafine, voriconazole, posaconazole, isavuconazole were shown in vitro to be the most potent antifungal agents against T. rubrum isolates investigated. These results might help clinicians in developing appropriate therapies for treating dermatophytosis caused by T.rubrum. However, further clinical investigations must be conducted in order to develop interpretive breakpoints ACKNOWLEDGMENTS This study was supported in part by Program no. 973 (2013CB531601, 2013CB531606), Fund no. 2013ZX of Severe Infectious Disease of China and in part by and Fund no. 14dz from Shanghai key Laboratory of Molecular Medical Mycology; partially by the Chinese National Nature Science Fund No and Seyedmojtaba Seyedmousavi received travel grants from Astellas and Gilead sciences. All the others have no conflict of interests REFERENCES Zaias N, Rebell G Chronic dermatophytosis syndrome due to Trichophyton rubrum. Int J Dermatol 35: Decroix J Tinea pedis (mocassin-type) treated with itraconazole. Int J Dermatol 34: Yang J, Chen L, Wang L, Zhang W, Liu T, Jin Q TrED: the Trichophyton rubrum Expression Database. BMC Genomics 8: Gupta AK, Cooper EA Update in antifungal therapy of dermatophytosis. Mycopathologia 166:

8 Jo Siu WJ, Tatsumi Y, Senda H, Pillai R, Nakamura T, Sone D, Fothergill A Comparison of In Vitro Antifungal Activities of Efinaconazole and Currently Available Antifungal Agents against a Variety of Pathogenic Fungi Associated with Onychomycosis. Antimicrobial Agents and Chemotherapy 57: Yenisehirli G, Tuncoglu E, Yenisehirli A, Bulut Y In vitro activities of antifungal drugs against dermatophytes isolated in Tokat, Turkey. Int J Dermatol 52: Adimi P, Hashemi SJ, Mahmoudi M, Mirhendi H, Shidfar MR, Emmami M, Rezaei-Matehkolaei A, Gramishoar M, Kordbacheh P In-vitro Activity of 10 Antifungal Agents against 320 Dermatophyte Strains Using Microdilution Method in Tehran. Iran J Pharm Res 12: Ataides FS, Chaul MH, El Essal FE, Costa CR, Souza LK, Fernandes OF, Silva MR Antifungal susceptibility patterns of yeasts and filamentous fungi isolated from nail infection. J Eur Acad Dermatol Venereol 26: Carrillo-Muñoz AJ, Giusiano G, Guarro J, Quindós G, Guardia C, del Valle O, Rodríguez V, Estivill D, Cárdenes CD In vitro activity of voriconazole against dermatophytes, Scopulariopsis brevicaulis and other opportunistic fungi as agents of onychomycosis. International Journal of Antimicrobial Agents 30: Singh J, Zaman M, Gupta AK Evaluation of microdilution and disk diffusion methods for antifungal susceptibility testing of dermatophytes. Med Mycol 45: Barros MEdS, Santos DdA, Hamdan JS In vitro methods for antifungal susceptibility testing of Trichophyton spp. Mycological Research 110: Sarifakioglu E, Seckin D, Demirbilek M, Can F In vitro antifungal susceptibility patterns of dermatophyte strains causing tinea unguium. Clin Exp Dermatol 32: Santos DA, Hamdan JS In vitro activities of four antifungal drugs against Trichophyton rubrum isolates exhibiting resistance to fluconazole. Mycoses 50: Gupta AK, Kohli Y, Batra R In vitro activities of posaconazole, ravuconazole, terbinafine, itraconazole and fluconazole against dermatophyte, yeast and non-dermatophyte species. Med Mycol 43: Gupta AK, Kohli Y In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity. Br J Dermatol 149: Fernandez-Torres B, Cabanes FJ, Carrillo-Munoz AJ, Esteban A, Inza I, Abarca L, Guarro J Collaborative Evaluation of Optimal Antifungal Susceptibility Testing Conditions for Dermatophytes. Journal of Clinical Microbiology 40: Fernandez-Torres B, Carrillo AJ, Martin E, Del Palacio A, Moore MK, Valverde A, Serrano M, Guarro J In Vitro Activities of 10 Antifungal Drugs against 508 Dermatophyte Strains. Antimicrobial Agents and Chemotherapy 45: Perea S, Fothergill AW, Sutton DA, Rinaldi MG Comparison of In Vitro Activities of Voriconazole and Five Established Antifungal Agents against Different Species of Dermatophytes Using a Broth Macrodilution Method. Journal of Clinical Microbiology 39: Fernandez-Torres B, Vazquez-Veiga H, Llovo X, Pereiro M, Jr., Guarro J In vitro susceptibility to itraconazole, clotrimazole, ketoconazole and terbinafine of 100 isolates of Trichophyton rubrum. Chemotherapy 46:

9 Clinical and Laboratory Standards Institute Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard, 2nd ed CLSI document M38-A2. Clinical and Laboratory Standards Institute, Wayne, PA 21. Seyedmousavi S, Verweij PE, Mouton JW Isavuconazole, a broad-spectrum triazole for the treatment of systemic fungal diseases. Expert Rev Anti Infect Ther 13: Ghannoum M, Isham N Antifungal activity of BAL4815, a novel azole, against dermatophytes, Poster P-009. Programs and abstracts of the 2nd annual trends in medical mycology (TIMM). TIMM, Berlin, Germany. 23. Thompson GR, 3rd, Wiederhold NP Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia 170: Deng S, de Hoog GS, Verweij PE, Zoll J, Ilkit M, Morsali F, Abliz P, Wang X, Zhan P, Yang L, Hasimu H, Liao W, Pan W, Seyedmousavi S In vitro antifungal susceptibility of Trichophyton violaceum isolated from tinea capitis patients. J Antimicrob Chemother doi: /jac/dku Artis WM, Odle BM, Jones HE Griseofulvin-resistant dermatophytosis correlates with in vitro resistance. Arch Dermatol 117: Korting HC, Rosenkranz S In vitro susceptibility of dermatophytes from Munich to griseofulvin, miconazole and ketoconazole. Mycoses 33: Chadeganipour M, Nilipour S, Havaei A In vitro evaluation of griseofulvin against clinical isolates of dermatophytes from Isfahan. Mycoses 47: Wildfeuer A, Seidl HP, Paule I, Haberreiter A In vitro activity of voriconazole against yeasts, moulds and dermatophytes in comparison with fluconazole, amphotericin B and griseofulvin. Arzneimittelforschung 47: Shemer A, Plotnik IB, Davidovici B, Grunwald MH, Magun R, Amichai B Treatment of tinea capitis - griseofulvin versus fluconazole - a comparative study. J Dtsch Dermatol Ges 11: , Korting HC, Ollert M, Abeck D Results of German multicenter study of antimicrobial susceptibilities of Trichophyton rubrum and Trichophyton mentagrophytes strains causing tinea unguium. German Collaborative Dermatophyte Drug Susceptibility Study Group. Antimicrob Agents Chemother 39: Legends: 234 Table1 Geometric mean MICs, MIC ranges, MIC50s and MIC90s obtained by susceptibility 235 testing of antifungal agents against 111 Trichophyton rubrum clinical isolates Table 2 Summarized the susceptibility data of T. rubrum to antifungal drugs in different studies from

10 Table 1. Geometric mean MICs, MIC ranges, MIC50s and MIC90s obtained by susceptibility testing of antifungal agents against 111 Trichophyton rubrum clinical isolates. Organism (no. of strains) and drug T.rubrum isolates ( n = 111 ) MIC/MEC ( mg/l ) Range 50% 90% Geometric mean Griseofulvin Fluconazole Itraconazole Voriconazole Posaconazole Isavuconazole Terbinafine

11 1 Table 2. Summarized the susceptibility data of T. rubrum to antifungal drugs in different studies from Method Terbinafine Itroconazole Voriconazole Fluconazole Posaconazole Griseofulvin Str. Range GM Range GM Range GM Range GM Range GM Range GM N. RT Md TP Reference M38-A PDA 28 This paper M38-A OA 30 Jo Siu, W.J., et al.(,2013) M38-A OA 30 Yenisehirli, G., et al.(2013) M38-A >168 PDA 28 Adimi, P., et al. (2013) M38-A PDA 28 Ataides, F.S., et al.(2011) M38-A ,72,96,longer PDA 28 Carrillo-Muñoz, A.J., et al. (2007) M-38-A PDA 30 Singh, J., M, et al.(2007) M-38-A < PDA 28 Barros, M.E.d.S., et al.(2007) M-38-P < PDA 35 Sarifakioglu, E., et al.(2007) M-38-A <0.031 < > PDA 28 Santos, D.A., et al.(2007) M-38-P > > > OA 35 Gupta, A.K., et al.(2005) M-27-A OA 35 Gupta, A.K., et al.(2003) M-38-P < PDA 28 Fernandez-Torres, B., et al.(2002) M-38-P > > PDA 28 Fernandez-Torres, B., et al.(2001) M-27-A < days PDA - Perea, S., et al.(2001) M-38-P < PDA 28 Fernandez-Torres, B., et al.(2000) 2 3 Note: GM: geometric means; Str.N.: strains number; RT: incubation time; Md: media; TP: incubation temperature

Antifungal susceptibility pattern of dermatomycosis in a tertiary care hospital of North India

International Journal of Research in Dermatology http://www.ijord.com Original Research Article DOI: http://dx.doi.org/10.18203/issn.2455-4529.intjresdermatol20181827 Antifungal susceptibility pattern