1887

Abstract

Vulvovaginal candidiasis, a superficial infection caused predominantly by the pathogenic fungus , is frequently treated with clotrimazole. Some drug formulations contain lactate for improved solubility. Lactate may modify physiology and drug sensitivity by serving as a carbon source for the fungus and/or affecting local pH. Here, we explored the effects of lactate, in combination with pH changes, on proliferation, morphology and clotrimazole sensitivity. Moreover, we determined the influence of growth phase and morphology per se on drug sensitivity. We showed that utilization of lactate as a carbon source did not promote fast fungal proliferation or filamentation. Lactate had no influence on clotrimazole-mediated killing of in standard fungal cultivation medium but had an additive effect on the fungicidal clotrimazole action under vagina-simulative conditions. Moreover, clotrimazole-mediated killing was growth-phase and morphology dependent. Post-exponential cells were resistant to the fungicidal action of clotrimazole, whilst logarithmic cells were sensitive, and hyphae showed the highest susceptibility. Finally, we showed that treatment of pre-formed hyphae with sublethal concentrations of clotrimazole induced a reversion to yeast-phase growth. As hyphae are considered the pathogenic morphology during mucosal infections, these data suggest that elevated fungicidal activity of clotrimazole against hyphae plus clotrimazole-induced hyphae-to-yeast reversion may help to dampen acute vaginal infections by reducing the relative proportion of hyphae and thus shifting to a non-invasive commensal-like population. In addition, lactate as an ingredient of clotrimazole formulations may potentiate clotrimazole killing of in the vaginal microenvironment.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000082
2015-07-01
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/jmm/64/7/714.html?itemId=/content/journal/jmm/10.1099/jmm.0.000082&mimeType=html&fmt=ahah

References

  1. Achkar J.M., Fries B.C. 2010; Candida infections of the genitourinary tract. Clin Microbiol Rev 23:253–273 [View Article][PubMed]
    [Google Scholar]
  2. Beggs W.H., LaSota I.R., Hughes C.E. 1987; Is it morphologic type or physiologic state that governs susceptibility of Candida albicans to clotrimazole kill?. Antimicrob Agents Chemother 31:1864–1865 [View Article][PubMed]
    [Google Scholar]
  3. Biswas S., Van Dijck P., Datta A. 2007; Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans . Microbiol Mol Biol Rev 71:348–376 [View Article][PubMed]
    [Google Scholar]
  4. Boskey E.R., Cone R.A., Whaley K.J., Moench T.R. 2001; Origins of vaginal acidity: high d/l lactate ratio is consistent with bacteria being the primary source. Hum Reprod 16:1809–1813 [View Article][PubMed]
    [Google Scholar]
  5. Costa C., Henriques A., Pires C., Nunes J., Ohno M., Chibana H., Sá-Correia I., Teixeira M.C. 2013; The dual role of Candida glabrata drug : H+ antiporter CgAqr1 (ORF CAGL0J09944g) in antifungal drug and acetic acid resistance. Front Microbiol 4:170 [View Article][PubMed]
    [Google Scholar]
  6. Danby C.S., Boikov D., Rautemaa-Richardson R., Sobel J.D. 2012; Effect of pH on in vitro susceptibility of Candida glabrata Candida albicans to 11 antifungal agents and implications for clinical use. Antimicrob Agents Chemother 56:1403–1406 [View Article][PubMed]
    [Google Scholar]
  7. Davis D.A. 2009; How human pathogenic fungi sense and adapt to pH: the link to virulence. Curr Opin Microbiol 12:365–370 [View Article][PubMed]
    [Google Scholar]
  8. Edelman D.A., Grant S. 1999; One-day therapy for vaginal candidiasis. A review. J Reprod Med 44:543–547[PubMed]
    [Google Scholar]
  9. Ene I.V., Adya A.K., Wehmeier S., Brand A.C., MacCallum D.M., Gow N.A., Brown A.J. 2012a; Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell Microbiol 14:1319–1335 [View Article][PubMed]
    [Google Scholar]
  10. Ene I.V., Heilmann C.J., Sorgo A.G., Walker L.A., de Koster C.G., Munro C.A., Klis F.M., Brown A.J. 2012b; Carbon source-induced reprogramming of the cell wall proteome and secretome modulates the adherence and drug resistance of the fungal pathogen Candida albicans . Proteomics 12:3164–3179 [View Article][PubMed]
    [Google Scholar]
  11. Ene I.V., Cheng S.C., Netea M.G., Brown A.J. 2013; Growth of Candida albicans cells on the physiologically relevant carbon source lactate affects their recognition and phagocytosis by immune cells. Infect Immun 81:238–248 [View Article][PubMed]
    [Google Scholar]
  12. Gillum A.M., Tsay E.Y., Kirsch D.R. 1984; Isolation of the Candida albicans gene for orotidine-5′-phosphate decarboxylase by complementation of S. cerevisiae ura3 E. coli pyrF mutations. Mol Gen Genet 198:179–182 [View Article][PubMed]
    [Google Scholar]
  13. Hornby J.M., Nickerson K.W. 2004; Enhanced production of farnesol by Candida albicans treated with four azoles. Antimicrob Agents Chemother 48:2305–2307 [View Article][PubMed]
    [Google Scholar]
  14. Iwata K., Yamaguchi H., Hiratani T. 1973; Mode of action of clotrimazole. Sabouraudia 11:158–166 [View Article][PubMed]
    [Google Scholar]
  15. Köhler G.A., Assefa S., Reid G. 2012; Probiotic interference of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 with the opportunistic fungal pathogen Candida albicans . Infect Dis Obstet Gynecol 2012:636474 [View Article][PubMed]
    [Google Scholar]
  16. Linhares I.M., Summers P.R., Larsen B., Giraldo P.C., Witkin S.S. 2011; Contemporary perspectives on vaginal pH and lactobacilli. Am J Obstet Gynecol 204:120e1–120e5 [View Article][PubMed]
    [Google Scholar]
  17. Mendling W., Plempel M. 1982; Vaginal secretion levels after 6 days, 3 days and 1 day of treatment with 100, 200 and 500 mg vaginal tablets of clotrimazole and their therapeutic efficacy. Chemotherapy 28:(Suppl 1)43–47 [View Article][PubMed]
    [Google Scholar]
  18. Mendling W., Ritter W., Plempel M. 1982; Intravaginale Wirkstoffverfügbarkeit von Canesten R 100, 200 und 500 mg Vaginaltabletten. Krankenhausarzt 55:716–722
    [Google Scholar]
  19. Mendling W., Brasch J. 2012; Guideline vulvovaginal candidosis (2010) of the German Society for Gynecology and Obstetrics, the Working Group for Infections and Infectimmunology in Gynecology and Obstetrics, the German Society of Dermatology, the Board of German Dermatologists and the German Speaking Mycological Society. Mycoses 55:(Suppl. 3)1–13 [View Article][PubMed]
    [Google Scholar]
  20. Moosa M.Y., Sobel J.D., Elhalis H., Du W., Akins R.A. 2004; Fungicidal activity of fluconazole against Candida albicans in a synthetic vagina-simulative medium. Antimicrob Agents Chemother 48:161–167 [View Article][PubMed]
    [Google Scholar]
  21. Moyes D.L., Runglall M., Murciano C., Shen C., Nayar D., Thavaraj S., Kohli A., Islam A., Mora-Montes H., other authors. 2010; A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8:225–235 [View Article][PubMed]
    [Google Scholar]
  22. Niimi M., Kamiyama A., Tokunaga M., Tokunaga J., Nakayama H. 1985; Germ tube-forming cells of Candida albicans are more susceptible to clotrimazole-induced killing than yeast cells. Sabouraudia 23:63–68 [View Article][PubMed]
    [Google Scholar]
  23. Odds F.C., Cockayne A., Hayward J., Abbott A.B. 1985; Effects of imidazole- and triazole-derivative antifungal compounds on the growth and morphological development of Candida albicans hyphae. J Gen Microbiol 131:2581–2589[PubMed]
    [Google Scholar]
  24. Owen D.H., Katz D.F. 1999; A vaginal fluid simulant. Contraception 59:91–95 [View Article][PubMed]
    [Google Scholar]
  25. Plempel M. 1982; On the action kinetics of clotrimazole. Chemotherapy 28:(Suppl 1)22–31 [View Article][PubMed]
    [Google Scholar]
  26. Sobel J.D. 2007; Vulvovaginal candidosis. Lancet 369:1961–1971 [View Article][PubMed]
    [Google Scholar]
  27. Sobel J.D. 2013; Factors involved in patient choice of oral or vaginal treatment for vulvovaginal candidiasis. Patient Prefer Adherence 8:31–34 [View Article][PubMed]
    [Google Scholar]
  28. Sobel J.D., Muller G., Buckley H.R. 1984; Critical role of germ tube formation in the pathogenesis of candidal vaginitis. Infect Immun 44:576–580[PubMed]
    [Google Scholar]
  29. Sosinska G.J., de Groot P.W., Teixeira de Mattos M.J., Dekker H.L., de Koster C.G., Hellingwerf K.J., Klis F.M. 2008; Hypoxic conditions and iron restriction affect the cell-wall proteome of Candida albicans grown under vagina-simulative conditions. Microbiology 154:510–520 [View Article][PubMed]
    [Google Scholar]
  30. Stevens D.A., Calderon L., Martinez M., Clemons K.V., Wilson S.J., Selitrennikoff C.P. 2002; Zeamatin, clotrimazole and nikkomycin Z in therapy of a Candida vaginitis model. J Antimicrob Chemother 50:361–364 [View Article][PubMed]
    [Google Scholar]
  31. Sud I.J., Feingold D.S. 1981; Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol 76:438–441 [View Article][PubMed]
    [Google Scholar]
  32. Wächtler B., Wilson D., Hube B. 2011; Candida albicans adhesion to and invasion and damage of vaginal epithelial cells: stage-specific inhibition by clotrimazole and bifonazole. Antimicrob Agents Chemother 55:4436–4439 [View Article][PubMed]
    [Google Scholar]
  33. Wilson D., Hebecker B., Moyes D.L., Miramón P., Jablonowski N., Wisgott S., Allert S., Naglik J.R., Hube B. 2013; Clotrimazole dampens vaginal inflammation and neutrophil infiltration in response to Candida albicans infection. Antimicrob Agents Chemother 57:5178–5180 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000082
Loading
/content/journal/jmm/10.1099/jmm.0.000082
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error