The Effect of Combinations of Antimycotics on Systemic Candidiasis in a Mouse Model

Abstract

Objective: The purpose of this study was to test the hypothesis thThis study was planned to investigate the antipneumocystis activity of terbinafine in a rat model. Material and Methods: Rats were obtained from the Hakan Çetinsaya Experimental and Clinical Research Institutions, Erciyes University, Kayseri, Turkey. Terbinafine administered orally in doses of 40, 80, 120 and 160 mg/kg/day after nine weeks of immunosuppression with dexamethasone to facilitate the development of acute Pneumocystis carinii penumoniae (PCP). Results: Untreated animals showed P. carinii infection levels with a mean (±standard deviation) log number of cysts per gram of lung tissue of 4.6±1.6 at the end of the experiment. Terbinafine administered at a dose of 160 mg/kg/day significantly reduced the log number of cysts per gram to 2.2±1.5. The therapeutic efficacy of terbinafine administered at 160 mg/kg/day (log 2.2±1.5 cysts/lung) was similar to that obtained with trimethoprim-sulfamethoxazole (TMP-SMX), 50/250 mg/kg/day (p<0.001). A reduction in the number of cysts was also observed in infected animals treated with 80, and 120 mg of terbinafine/kg/day, although the results were not statistically significant (p>0.05). Conclusion: In our model, the efficacy of terbinafine in PCP has been found to be dose dependent. Turkish Başlık: Sistemik Fare Kandidoz Modelinde Antifungal Kombinasyonlarının Etkinliği Anahtar Kelimeler: Kandidoz; fare; terbinafin; kombinasyon Amaç: Bu çalışma rat modelinde terbinafinin anti-Pneumocystis aktivitesini belirlemek için planlanmıştır. Gereç ve Yöntemler: Ratlar Erciyes Üniversitesi Deneysel ve Klinik Araştırma Merkezin'den sağlanmıştır. Dokuz hafta boyunca akut Pneumocystis carinii pnömonisi (PCP) oluşturmak üzere, deksamethazon ile immünsüpresyon yapılan ratlara oral olarak 40, 80, 120 ve 160 mg/kg/gün terbinafin verildi. Bulgular: Çalışmanın sonunda tedavi almayan grupda PCP enfeksiyon düzeyi ortalama (±standart sapma) akciğer dokusu gramındaki kist sayısı log 4.6±1.6 idi. Terbinafin 160mg/kg/gün uygulanan grupta gramdaki kist sayısında önemli düşüş gözlendi log 2.2±1.5. Terbinafin 160mg/kg/gün uygulanan tedavi etkinliği, trimetoprim-sulfametoksazol (TMP-SMX), 50/250 mg/kg/gün uygulaması ile benzer sonuç verdi (p<0.001). Terbinafin 80 ve 120 mg/kg/gün uygulamalarında da kist sayısında düşüş görülmekle birlikte bu değerler istatistiksel olarak anlamlı değildi (p>0.05). Sonuç: Bizim modelimizde terbinafinin PCP etkinliği doza bağlı bulundu.

Keywords

• Candidiasis; combination; mice; terbinafine

Sistemik Fare Kandidoz Modelinde Antifungal Kombinasyonlarının Etkinliği

Öz

Anahtar Kelimeler

• Kandidoz, fare, terbinafin, kombinasyon

Kaynakça

1. Loui A, Banerjee P, Drusano GL, et al. Interaction between fluconazole and amphotericin B in mice with systemic infection due to fluconazole-susceptible or –resistant strains of Candida albicans. Antimicrob Agents Chemother. 1999;43:2841-7.
2. Santangelo R, Paderu P, Delmas G, Chen ZW, Mannino R, Zarif L, et al. Efficacy of oral cochleate-amphotericinB in a mouse model of systemic candidiasis. Antimicrob Agents Chemother. 2000;44:2356-60.
3. Sugar AM, Hitchcock CA, Troke PF, Picard M. Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother. 1995;39:598-601.
4. Zarif L, Graybill JR, Perlin D, Najvar L, Bocanegra R, Mannino RJ. Antifungal activity of amphotericin B cochleates against Candida. Antimicrob Agents Chemother. 2000;44:1463-9.
5. Anaissie EJ, Karyotakis NC, Hachem R, Dignani MC, Rex JH, Paetznick V. Correlation between ×n vitro and in vivo activity of antifungal agents against Candida species. J Infect Dis. 1994;170:384-9.
6. Barchiesi F, Di Francessco LF, Scalise G. In vitro activities of terbinafine in combination with fluconazole and itraconazole against isolates of Candida albicans with reduced suspectibility to azoles. Antimicrob Agents Chemother. 1997;41:1812-4.
7. Koç AN, Evrensel N, Gökahmetoglu S, Oguzkaya M. The in vitro effects of antifungal agents against Candida albicans. Antibiyotik ve Kemoterapi Dergisi. 2000;14:15-20.
8. Barchiesi F, Di Francesco LF, Compagnucci P, Arzeni D, Giacometti A, Scalise G. In vitro interaction of terbinafine with amphotericin B, fluconazole and itraconazole against clinical isolates of Candida albicans. J Antimicrob Chemother. 1998;41:59-65.

9. Cacciapuoti A, Loebenberg D, Corcoran E, Menzel F Jr, Moss EL Jr, Norris C, et al. In vitro and in vivo activities os SCH 56592 (posaconazole), a new triazole antifungal agent, against Aspergillus and Candida. Antimicrob Agents Chemother. 2000;44:2017-22.
10. Abdel-Rahman SM, Nahata MC. Oral terbinafine: a new antifungal agent. Ann Pharmacother. 1997;31:445-56.
11. Balfour JA, Faulds D. Terbinafine a review of its pharmacodynamics and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs. 1992;43:259-84.
12. Perea S, Gonzalez G, Fothergill AW, Sutton DA, Rinaldi MG. In vitro activities of terbinafine in combination with fluconazole, itraconazole, voriconazole, and posaconazole against clinical isolates of Candida glabrata with decreased susceptibility to azoles. J Clin Microbiol. 2002;40:1831-3.
13. Sorensen KN, Sobel RA, Clemons KV, Calderon L, Howell KJ, Irani PR, et al. Comparative efficacies of terbinafine and fluconazole in treatment of experimental coccidioidal meningitis in a rabit model. Antimicrob Agents Chemother. 2000;44:3087-91.
14. Warren NG, Hazen KC. Candida, Cryptococcus, and other yeasts of medical importance, In Manuel of Clinical Microbiology, 7th edn (P.R. Murray, E.J. Baron, M.A. Pfaller, F.C. Tenover, & R.H. Yolken, Eds), pp. 1184-1199. American Society for Microbiology, Washington, DC. 1999.
15. Sugar AM, Liu XP. Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis. J Infect Dis. 1997;177:1660-3.
16. Graybill JR, Najvar LK, Luther MF, Fothergill AW. Treatment of murine disseminated candidiasis with L-743, 872. Antimicrob Agents Chemother. 1997;41:1775-7.
17. Walzer PD, Ashbaugh A. Use of terbinafine in mouse and rat models of Pneumocyctis carinii pneumonia. Antimicrob Agents Chemother. 2002;46:514-6.
18. Ghannoum MA, Elewski B. Successfull treatment of fluconazole-resistant oropharyngeal candidiasis by a combination of fluconazole and terbinafine. Clin Diag Lab Immunol. 1999;6:921-3.
19. National Committee for Clinical Laboratory Standarts. Reference method for broth dilution antifungal susceptibility testing of yeast. 1997. Approved standart. Document M27-A. National Committee for Clinical Laboratory Standarts, Wayne, P.
20. Conti C, Angelici E, Canipari R. Structural changes in rat Pneumocystis carinii surface antigens after terbinafine administration in experimental P. carinii pneumonia. J Antimicrob Chemother. 1999;43:301-4.