1887

Abstract

, the most virulent species in the complex, is responsible for the ongoing epidemics of human and animal sporotrichosis in Brazil. Feline outbreaks are usually driven by and followed by extensive transmission to humans. Itraconazole is the first-line treatment for both feline and human sporotrichosis; however, reduced sensitivity is an emerging issue. Thus, we investigated the effect of the widely used antifungal clotrimazole – alone or in combination with itraconazole – against the pathogenic (yeast) form of feline and human isolates, .

Minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values were determined for treatment with clotrimazole and itraconazole, as monotherapy or in combination. In addition, the effect of the drugs on neutral lipid levels and the yeast ultrastructure were evaluated by flow cytometry and transmission electron microscopy (TEM), respectively.

The MIC and MFC values show that clotrimazole was more effective than itraconazole against feline isolates, while human isolates were more sensitive to itraconazole. Similarly to itraconazole, treatment with clotrimazole induced statistically significant neutral lipid accumulation in yeasts, and treated yeasts displayed irregularities in the cell membrane and a thicker cell wall when observed by TEM. Clotrimazole increased the antifungal activity of itraconazole in combination assays, with a synergistic effect for two feline isolates.

The strong activity of clotrimazole against feline isolates suggests that this drug is potentially a new alternative for the treatment of feline sporotrichosis, alone or in combination with itraconazole.

Erratum

This article contains a correction applying to the following content:
Corrigendum: Clotrimazole is highly effective against feline isolates
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2017-11-01
2020-12-01
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References

  1. Chakrabarti A, Bonifaz A, Gutierrez-Galhardo MC, Mochizuki T, Li S. Global epidemiology of sporotrichosis. Med Mycol 2015;53:3–14 [CrossRef][PubMed]
    [Google Scholar]
  2. Gremião ID, Miranda LH, Reis EG, Rodrigues AM, Pereira SA. Zoonotic epidemic of sporotrichosis: cat to human transmission. PLoS Pathog 2017;13:e1006077 [CrossRef][PubMed]
    [Google Scholar]
  3. Rodrigues AM, de Hoog GS, de Camargo ZP. Sporothrix species causing outbreaks in animals and humans driven by animal-animal transmission. PLoS Pathog 2016;12:e1005638 [CrossRef][PubMed]
    [Google Scholar]
  4. Arrillaga-Moncrieff I, Capilla J, Mayayo E, Marimon R, Mariné M et al. Different virulence levels of the species of Sporothrix in a murine model. Clin Microbiol Infect 2009;15:651–655 [CrossRef][PubMed]
    [Google Scholar]
  5. Fernandes GF, dos Santos PO, Rodrigues AM, Sasaki AA, Burger E et al. Characterization of virulence profile, protein secretion and immunogenicity of different Sporothrix schenckii sensu stricto isolates compared with S. globosa and S. brasiliensis species. Virulence 2013;4:241–249 [CrossRef][PubMed]
    [Google Scholar]
  6. Almeida-Paes R, de Oliveira MM, Freitas DF, do Valle AC, Zancopé-Oliveira RM et al. Sporotrichosis in Rio de Janeiro, Brazil: Sporothrix brasiliensis is associated with atypical clinical presentations. PLoS Negl Trop Dis 2014;8:e3094 [CrossRef][PubMed]
    [Google Scholar]
  7. Schubach TM, Schubach A, Okamoto T, Barros MB, Figueiredo FB et al. Evaluation of an epidemic of sporotrichosis in cats: 347 cases (1998–2001). J Am Vet Med Assoc 2004;224:1623–1629 [CrossRef][PubMed]
    [Google Scholar]
  8. Gremião ID, Menezes RC, Schubach TM, Figueiredo AB, Cavalcanti MC et al. Feline sporotrichosis: epidemiological and clinical aspects. Med Mycol 2015;53:15–21 [CrossRef][PubMed]
    [Google Scholar]
  9. Hirano M, Watanabe K, Murakami M, Kano R, Yanai T et al. A case of feline sporotrichosis. J Vet Med Sci 2006;68:283–284 [CrossRef][PubMed]
    [Google Scholar]
  10. Yegneswaran PP, Sripathi H, Bairy I, Lonikar V, Rao R et al. Zoonotic sporotrichosis of lymphocutaneous type in a man acquired from a domesticated feline source: report of a first case in southern Karnataka, India. Int J Dermatol 2009;48:1198–1200 [CrossRef][PubMed]
    [Google Scholar]
  11. Borba-Santos LP, Visbal G, Gagini T, Rodrigues AM, de Camargo ZP et al. Δ24-Sterol Methyltransferase plays an important role in the growth and development of Sporothrix schenckii and Sporothrix brasiliensis. Front Microbiol 2016;7:311 [CrossRef][PubMed]
    [Google Scholar]
  12. Robbins N, Wright GD, Cowen LE. Antifungal drugs: the current armamentarium and development of new agents. Microbiol Spectr 2016;4:1–20 [CrossRef][PubMed]
    [Google Scholar]
  13. Rodrigues AM, de Hoog GS, de Cássia Pires D, Brihante RS, Sidrim JJ et al. Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis. BMC Infect Dis 2014;14:219 [CrossRef][PubMed]
    [Google Scholar]
  14. Borba-Santos LP, Rodrigues AM, Gagini TB, Fernandes GF, Castro R et al. Susceptibility of Sporothrix brasiliensis isolates to amphotericin B, azoles, and terbinafine. Med Mycol 2015;53:178–188 [CrossRef][PubMed]
    [Google Scholar]
  15. Han HS, Kano R, Chen C, Noli C. Comparison of two in vitro antifungal sensitivity tests and monitoring during therapy of Sporothrix schenckii sensu stricto in Malaysian cats. Vet Dermatol 2017;28:e132e32 [CrossRef][PubMed]
    [Google Scholar]
  16. Kadavakollu S, Stailey C, Kunapareddy CS, White S. Clotrimazole as a cancer drug: a short review. Med Chem 2014;4:722–724 [CrossRef][PubMed]
    [Google Scholar]
  17. Huy NT, Takano R, Hara S, Kamei K. Enhancement of heme-induced membrane damage by the anti-malarial clotrimazole: the role of colloid-osmotic forces. Biol Pharm Bull 2004;27:361–365 [CrossRef][PubMed]
    [Google Scholar]
  18. Mcnaughton-Smith GA, Burns JF, Stocker JW, Rigdon GC, Creech C et al. Novel inhibitors of the Gardos channel for the treatment of sickle cell disease. J Med Chem 2008;51:976–982 [CrossRef][PubMed]
    [Google Scholar]
  19. Buckner FS, Urbina JA. Recent developments in sterol 14-demethylase inhibitors for chagas disease. Int J Parasitol Drugs Drug Resist 2012;2:236–242 [CrossRef][PubMed]
    [Google Scholar]
  20. Czerninski R, Pikovsky A, Gati I, Friedman M, Steinberg D. Comparison of the efficacy of a novel sustained release clotrimazole varnish and clotrimazole troches for the treatment of oral candidiasis. Clin Oral Investig 2015;19:467–473 [CrossRef][PubMed]
    [Google Scholar]
  21. Trivedi V, Chand P, Srivastava K, Puri SK, Maulik PR et al. Clotrimazole inhibits hemoperoxidase of Plasmodium falciparum and induces oxidative stress. Proposed antimalarial mechanism of clotrimazole. J Biol Chem 2005;280:41129–41136 [CrossRef][PubMed]
    [Google Scholar]
  22. Georgopoulos A, Petranyi G, Mieth H, Drews J. In vitro activity of naftifine, a new antifungal agent. Antimicrob Agents Chemother 1981;19:386–389 [CrossRef][PubMed]
    [Google Scholar]
  23. Petranyi G, Meingassner JG, Mieth H. Antifungal activity of the allylamine derivative terbinafine in vitro. Antimicrob Agents Chemother 1987;31:1365–1368 [CrossRef][PubMed]
    [Google Scholar]
  24. Mohd Nizam T, Binting RA, Mohd Saari S, Kumar TV, Muhammad M et al. In vitro antifungal activities against moulds isolated from dermatological specimens. Malays J Med Sci 2016;23:32–39[PubMed]
    [Google Scholar]
  25. Diaz MC, Camponovo R, Araya I, Cerda A, Santander MP et al. [Identification and in vitro antifungal susceptibility of vaginal Candida spp. isolates to fluconazole, clotrimazole and nystatin]. Rev Esp Quimioter 2016;29:151–154[PubMed]
    [Google Scholar]
  26. Shadomy S. In vitro antifungal activity of clotrimazole (Bay b 5097). Infect Immun 1971;4:143–148[PubMed]
    [Google Scholar]
  27. Holt RJ, Newman RL. The treatment of urinary candidosis with the oral antifungal drugs 5-fluorocytosine and 'clotrimazole'. Dev Med Child Neurol Suppl 1972;27:70–79 [CrossRef][PubMed]
    [Google Scholar]
  28. Büchel KH, Draber W, Regel E, Plempel M. [Synthesis and properties of clotrimazole and other antimycotic 1-triphenylmethylimidazoles]. Arzneimittelforschung 1972;22:1260–1272[PubMed]
    [Google Scholar]
  29. Marimon R, Cano J, Gené J, Sutton DA, Kawasaki M et al. Sporothrix brasiliensis, S. globosa, and S. mexicana, three new Sporothrix species of clinical interest. J Clin Microbiol 2007;45:3198–3206 [CrossRef][PubMed]
    [Google Scholar]
  30. Rodrigues AM, de Melo Teixeira M, de Hoog GS, Schubach TM, Pereira SA et al. Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks. PLoS Negl Trop Dis 2013;7:e2281 [CrossRef][PubMed]
    [Google Scholar]
  31. Montenegro H, Rodrigues AM, Dias MA, da Silva EA, Bernardi F et al. Feline sporotrichosis due to Sporothrix brasiliensis: an emerging animal infection in São Paulo, Brazil. BMC Vet Res 2014;10:269 [CrossRef][PubMed]
    [Google Scholar]
  32. Clinical and Laboratory Standards Institute Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts, approved standard, M27-A3, 3rd ed. Vilanova: Clinical and Laboratory Standards Institute; 2008
    [Google Scholar]
  33. Teixeira MM, de Almeida LG, Kubitschek-Barreira P, Alves FL, Kioshima ES et al. Comparative genomics of the major fungal agents of human and animal sporotrichosis: Sporothrix schenckii and Sporothrix brasiliensis. BMC Genomics 2014;15:943 [CrossRef][PubMed]
    [Google Scholar]
  34. Lorian V. Antibiotics in laboratory medicine. In Pillai SK, Moellering RC, Eliopoulos GM. (editors) Antimicrobial Combinations Philadelphia: Lippincott Williams & Wilkins Co; 2005; pp.365–440
    [Google Scholar]
  35. Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003;52:1 [CrossRef][PubMed]
    [Google Scholar]
  36. Lloret A, Hartmann K, Pennisi MG, Ferrer L, Addie D et al. Sporotrichosis in cats: ABCD guidelines on prevention and management. J Feline Med Surg 2013;15:619–623 [CrossRef][PubMed]
    [Google Scholar]
  37. Almeida-Paes R, Brito-Santos F, Figueiredo-Carvalho MHG, Machado ACS, Oliveira MME et al. Minimal inhibitory concentration distributions and epidemiological cutoff values of five antifungal agents against Sporothrix brasiliensis. Mem Inst Oswaldo Cruz 2017;112:376–381 [CrossRef][PubMed]
    [Google Scholar]
  38. Espinel-Ingroff A, Abreu DPB, Almeida-Paes R, Brilhante RSN, Chakrabarti A et al. Multicenter and international study of MIC/MEC distributions for definition of epidemiological cutoff values (ECVs) for species of Sporothrix identified by molecular methods. Antimicrob Agents Chemother 2017;AAC.01057-17 [CrossRef][PubMed]
    [Google Scholar]
  39. Adinolfi B, Carpi S, Romanini A, da Pozzo E, Castagna M et al. Analysis of the antitumor activity of clotrimazole on A375 human melanoma cells. Anticancer Res 2015;35:3781–3786[PubMed]
    [Google Scholar]
  40. Warrilow AG, Price CL, Parker JE, Rolley NJ, Smyrniotis CJ et al. Azole antifungal sensitivity of sterol 14α-demethylase (CYP51) and CYP5218 from Malassezia globosa. Sci Rep 2016;6:27690 [CrossRef][PubMed]
    [Google Scholar]
  41. Gow NAR, Latge JP, Munro CA. The fungal cell wall: structure, biosynthesis, and function. Microbiol Spectr 2017;5:FUNK-0035-2016 [CrossRef][PubMed]
    [Google Scholar]
  42. Kumar SN, Nambisan B, Mohandas C, Sundaresan A. In vitro synergistic activity of diketopiperazines alone and in combination with amphotericin B or clotrimazole against Candida albicans. Folia Microbiol 2013;58:475–482 [CrossRef][PubMed]
    [Google Scholar]
  43. Nishanth Kumar S, Nisha GV, Sudaresan A, Venugopal VV, Sree Kumar MM et al. Synergistic activity of phenazines isolated from Pseudomonas aeruginosa in combination with azoles against Candida species. Med Mycol 2014;52:480–488 [CrossRef][PubMed]
    [Google Scholar]
  44. Reimann H. Clotrimazol in Wirkstoffkombinationen. Der Hautarzt 2015;66:795–796 [CrossRef]
    [Google Scholar]
  45. Anju S, Kumar NS, Krishnakumar B, Kumar BS. Synergistic combination of violacein and azoles that leads to enhanced killing of major human pathogenic dermatophytic fungi Trichophyton rubrum. Front Cell Infect Microbiol 2015;5:57 [CrossRef][PubMed]
    [Google Scholar]
  46. Beggs WH, Sarosi GA, Steele NM. Inhibition of potentially pathogenic yeastlike fungi by clotrimazole in combination with 5-fluorocytosine or amphotericin B. Antimicrob Agents Chemother 1976;9:863–865 [CrossRef][PubMed]
    [Google Scholar]
  47. Tavassoli K, Mattana P. [Topical treatment of vaginal infections by the association of metronidazole-clotrimazole]. Minerva Ginecol 2013;65:707–715[PubMed]
    [Google Scholar]
  48. Crowley PD, Gallagher HC. Clotrimazole as a pharmaceutical: past, present and future. J Appl Microbiol 2014;117:611–617 [CrossRef][PubMed]
    [Google Scholar]
  49. Toll J, Ashe CM, Trepanier LA. Intravesicular administration of clotrimazole for treatment of candiduria in a cat with diabetes mellitus. J Am Vet Med Assoc 2003;223:1156–1158 [CrossRef][PubMed]
    [Google Scholar]
  50. Furrow E, Groman RP. Intranasal infusion of clotrimazole for the treatment of nasal aspergillosis in two cats. J Am Vet Med Assoc 2009;235:1188–1193 [CrossRef][PubMed]
    [Google Scholar]
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