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Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species

  • PHARMACOLOGY AND PHARMACODYNAMICS OF ANTIFUNGAL AGENTS (P GUBBINS, SECTION EDITOR)
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Abstract

Invasive Candida infections have increased fivefold over the past 20 years. During this time, the incidence of antifungal resistance and infection due to non-albicans species has risen with the increasing use of broad spectrum antifungals. As few new antifungal agents are in development, strategies to improve outcomes in the treatment of Candida infections are sorely needed. The use of immunotherapy to augment the host immune response as an adjunctive treatment for Candida infections is a potentially robust and promising approach. The purpose of this review is to focus on new developments in the use of adjunctive immunotherapy for the treatment of Candida infections, and discuss the potential impact of antifungal resistance on the host immune response.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Gow NA, van de Veerdonk FL, Brown AJ, Netea MG. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat Rev Microbiol. 2011;10:112–22.

    PubMed  Google Scholar 

  2. Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol. 2008;6:67–78.

    Article  PubMed  CAS  Google Scholar 

  3. •• Romani L. Immunity to fungal infections. Nat Rev Immunol. 2011;11:275–88. An in-depth review of antifungal immunity focusing on innate immunity, pathogen recognition, and immune homeostasis.

    Article  PubMed  CAS  Google Scholar 

  4. Netea MG, Marodi L. Innate immune mechanisms for recognition and uptake of Candida species. Trends Immunol. 2010;31:346–53.

    Article  PubMed  CAS  Google Scholar 

  5. Arendrup MC. Epidemiology of invasive candidiasis. Curr Opin Crit Care. 2010;16:445–52.

    Article  PubMed  Google Scholar 

  6. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008–2009. Antimicrob Agents Chemother. 2011;55:561–6.

    Article  PubMed  CAS  Google Scholar 

  7. Lockhart SR, Iqbal N, Cleveland AA, et al. Species identification and antifungal susceptibility testing of Candida bloodstream isolates from population-based surveillance studies in two U.S. cities from 2008 to 2011. J Clin Microbiol. 2012;50:3435–42.

    Article  PubMed  CAS  Google Scholar 

  8. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY Antimicrobial Surveillance Program (2008 to 2009). J Clin Microbiol. 2011;49:396–9.

    Article  PubMed  Google Scholar 

  9. Beyda ND, Lewis RE, Garey KW. Echinocandin resistance in Candida species: mechanisms of reduced susceptibility and therapeutic approaches. Ann Pharmacother. 2012;46:1086–96.

    Article  PubMed  Google Scholar 

  10. Pfaller MA, Castanheira M, Lockhart SR, Ahlquist AM, Messer SA, Jones RN. Frequency of decreased susceptibility and resistance to echinocandins among fluconazole-resistant bloodstream isolates of Candida glabrata. J Clin Microbiol. 2012;50:1199–203.

    Article  PubMed  CAS  Google Scholar 

  11. Chapeland-Leclerc F, Hennequin C, Papon N, et al. Acquisition of flucytosine, azole, and caspofungin resistance in Candida glabrata bloodstream isolates serially obtained from a hematopoietic stem cell transplant recipient. Antimicrob Agents Chemother. 2010;54:1360–2.

    Article  PubMed  CAS  Google Scholar 

  12. Pfeiffer CD, Garcia-Effron G, Zaas AK, Perfect JR, Perlin DS, Alexander BD. Breakthrough invasive candidiasis in patients on Micafungin. J Clin Microbiol. 2010;48:2373–80.

    Article  PubMed  CAS  Google Scholar 

  13. Silva S, Negri M, Henriques M, Oliveira R, Williams DW, Azeredo J. Candida glabrata, Candida parapsilosis and Candida tropicalis: biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiol Rev. 2012;36:288–305.

    Article  PubMed  CAS  Google Scholar 

  14. Jacobsen ID, Brunke S, Seider K, et al. Candida glabrata persistence in mice does not depend on host immunosuppression and is unaffected by fungal amino acid auxotrophy. Infect Immun. 2010;78:1066–77.

    Article  PubMed  CAS  Google Scholar 

  15. Maccallum DM. Hosting infection: experimental models to assay Candida virulence. Int J Microbiol. 2012;2012:363764.

    PubMed  Google Scholar 

  16. Kaur R, Ma B, Cormack BP. A family of glycosylphosphatidylinositol-linked aspartyl proteases is required for virulence of Candida glabrata. Proc Natl Acad Sci U S A. 2007;104:7628–33.

    Article  PubMed  CAS  Google Scholar 

  17. •• Seider K, Brunke S, Schild L, et al. The facultative intracellular pathogen Candida glabrata subverts macrophage cytokine production and phagolysosome maturation. J Immunol. 2011;187:3072–86. Report demonstrates the ability of C. glabrata to survive and replicate inside macrophages while limiting the proinflammatory response.

    Article  PubMed  CAS  Google Scholar 

  18. • Rai MN, Balusu S, Gorityala N, Dandu L, Kaur R. Functional genomic analysis of Candida glabrata-marcophage interaction: role of chromatin remodeling in virulence. PLoS Pathog. 2012;8e1002863. Report identifies chromatin remodeling as a key factor in the ability of C. glabrata to survive ROS mediated damage after phagocytosis by macrophages.

  19. Lewis RE, Viale P, Kontoyiannis DP. The potential impact of antifungal drug resistance mechanisms on the host immune response to Candida. Virulence. 2012;3:368–76.

    Article  PubMed  Google Scholar 

  20. Ferrari S, Ischer F, Calabrese D, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5:e1000268.

    Article  PubMed  Google Scholar 

  21. Ferrari S, Sanguinetti M, De Bernardis F, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55:1852–60.

    Article  PubMed  CAS  Google Scholar 

  22. Stevens DA. Combination immunotherapy and antifungal chemotherapy. Clin Infect Dis. 1998;26:1266–9.

    Article  PubMed  CAS  Google Scholar 

  23. Hubel K, Dale DC, Liles WC. Therapeutic use of cytokines to modulate phagocyte function for the treatment of infectious diseases: current status of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and interferon-gamma. J Infect Dis. 2002;185:1490–501.

    Article  PubMed  CAS  Google Scholar 

  24. Kullberg BJ, van’t Wout JW, Hoogstraten C, van Furth R. Recombinant interferon-gamma enhances resistance to acute disseminated Candida albicans infection in mice. J Infect Dis. 1993;168:436–43.

    Article  PubMed  CAS  Google Scholar 

  25. Stuyt RJ, Netea MG, van Krieken JH, van der Meer JW, Kullberg BJ. Recombinant interleukin-18 protects against disseminated Candida albicans infection in mice. J Infect Dis. 2004;189:1524–7.

    Article  PubMed  CAS  Google Scholar 

  26. Dignani MC, Rex JH, Chan KW, et al. Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia. Cancer. 2005;104:199–204.

    Article  PubMed  CAS  Google Scholar 

  27. Armstrong-James D, Teo IA, Shrivastava S, et al. Exogenous interferon-gamma immunotherapy for invasive fungal infections in kidney transplant patients. Am J Transplant. 2010;10:1796–803.

    Article  PubMed  CAS  Google Scholar 

  28. Bodasing N, Seaton RA, Shankland GS, Pithie A. Gamma-interferon treatment for resistant oropharyngeal candidiasis in an HIV-positive patient. J Antimicrob Chemother. 2002;50:765–6.

    Article  PubMed  CAS  Google Scholar 

  29. Baltch AL, Bopp LH, Smith RP, Ritz WJ, Carlyn CJ, Michelsen PB. Effects of voriconazole, granulocyte-macrophage colony-stimulating factor, and interferon gamma on intracellular fluconazole-resistant Candida glabrata and Candida krusei in human monocyte-derived macrophages. Diagn Microbiol Infect Dis. 2005;52:299–304.

    Article  PubMed  CAS  Google Scholar 

  30. Netea MG, van der Meer JW, van Deuren M, Kullberg BJ. Proinflammatory cytokines and sepsis syndrome: not enough, or too much of a good thing? Trends Immunol. 2003;24:254–8.

    Article  PubMed  CAS  Google Scholar 

  31. Roilides E, Holmes A, Blake C, Pizzo PA, Walsh TJ. Effects of granulocyte colony-stimulating factor and interferon-gamma on antifungal activity of human polymorphonuclear neutrophils against pseudohyphae of different medically important Candida species. J Leukoc Biol. 1995;57:651–6.

    PubMed  CAS  Google Scholar 

  32. Kullberg BJ, Netea MG, Curfs JH, Keuter M, Meis JF, van der Meer JW. Recombinant murine granulocyte colony-stimulating factor protects against acute disseminated Candida albicans infection in nonneutropenic mice. J Infect Dis. 1998;177:175–81.

    Article  PubMed  CAS  Google Scholar 

  33. Hamood M, Bluche PF, De Vroey C, Corazza F, Bujan W, Fondu P. Effects of recombinant human granulocyte-colony stimulating factor on neutropenic mice infected with Candida albicans: acceleration of recovery from neutropenia and potentiation of anti-C. albicans resistance. Mycoses. 1994;37:93–9.

    Article  PubMed  CAS  Google Scholar 

  34. van Spriel AB, van den Herik-Oudijk IE, van de Winkel JG. A single injection of polyethylene-glycol granulocyte colony-stimulating factor strongly prolongs survival of mice with systemic candidiasis. Cytokine. 2000;12:666–70.

    Article  PubMed  Google Scholar 

  35. Gaviria JM, van Burik JA, Dale DC, Root RK, Liles WC. Modulation of neutrophil-mediated activity against the pseudohyphal form of Candida albicans by granulocyte colony-stimulating factor (G-CSF) administered in vivo. J Infect Dis. 1999;179:1301–4.

    Article  PubMed  CAS  Google Scholar 

  36. Richardson MD, Brownlie CE, Shankland GS. Enhanced phagocytosis and intracellular killing of Candida albicans by GM-CSF-activated human neutrophils. J Med Vet Mycol. 1992;30:433–41.

    Article  PubMed  CAS  Google Scholar 

  37. Willment JA, Lin HH, Reid DM, et al. Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide. J Immunol. 2003;171:4569–73.

    PubMed  CAS  Google Scholar 

  38. Brach MA, de Vos S, Gruss HJ, Herrmann F. Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death. Blood. 1992;80:2920–4.

    PubMed  CAS  Google Scholar 

  39. Lechner AJ, Lamprech KE, Potthoff LH, Tredway TL, Matuschak GM. Recombinant GM-CSF reduces lung injury and mortality during neutropenic Candida sepsis. Am J Physiol. 1994;266:L561–8.

    PubMed  CAS  Google Scholar 

  40. Rokusz L, Liptay L, Kadar K. Successful treatment of chronic disseminated candidiasis with fluconazole and a granulocyte-macrophage colony-stimulating factor combination. Scand J Infect Dis. 2001;33:784–6.

    Article  PubMed  CAS  Google Scholar 

  41. Baltch AL, Bopp LH, Smith RP, Ritz WJ, Michelsen PB. Anticandidal effects of voriconazole and caspofungin, singly and in combination, against Candida glabrata, extracellularly and intracellularly in granulocyte-macrophage colony stimulating factor (GM-CSF)-activated human monocytes. J Antimicrob Chemother. 2008;62:1285–90.

    Article  PubMed  CAS  Google Scholar 

  42. Casadevall A. Antibody immunity and invasive fungal infections. Infect Immun. 1995;63:4211–8.

    PubMed  CAS  Google Scholar 

  43. Matthews R, Burnie J. Antibodies against Candida: potential therapeutics? Trends Microbiol. 1996;4:354–8.

    Article  PubMed  CAS  Google Scholar 

  44. Cowen LE, Singh SD, Kohler JR, et al. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci U S A. 2009;106:2818–23.

    Article  PubMed  CAS  Google Scholar 

  45. Mitchell AP, Singh SD, Robbins N, et al. Hsp90 governs Echinocandin resistance in the pathogenic yeast Candida albicans via Calcineurin. PLoS Pathog. 2009;5:e1000532.

    Article  Google Scholar 

  46. Matthews R, Burnie J. Antifungal antibodies: a new approach to the treatment of systemic candidiasis. Curr Opin Investig Drugs. 2001;2:472–6.

    PubMed  CAS  Google Scholar 

  47. Matthews RC, Rigg G, Hodgetts S, et al. Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HSP90. Antimicrob Agents Chemother. 2003;47:2208–16.

    Article  PubMed  CAS  Google Scholar 

  48. Hodgetts S, Nooney L, Al-Akeel R, et al. Efungumab and caspofungin: pre-clinical data supporting synergy. J Antimicrob Chemother. 2008;61:1132–9.

    Article  PubMed  CAS  Google Scholar 

  49. Pachl J, Svoboda P, Jacobs F, et al. A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis. Clin Infect Dis. 2006;42:1404–13.

    Article  PubMed  CAS  Google Scholar 

  50. Louie A, Stein DS, Zack JZ, et al. Dose range evaluation of Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, in combination with amphotericin B-desoxycholate for treatment of murine systemic candidiasis. Antimicrob Agents Chemother. 2011;55:3295–304.

    Article  PubMed  CAS  Google Scholar 

  51. Cassone A, Casadevall A. Recent progress in vaccines against fungal diseases. Curr Opin Microbiol. 2012;15:427–33.

    Article  PubMed  CAS  Google Scholar 

  52. Ibrahim AS, Spellberg BJ, Avanesian V, Fu Y, Edwards Jr JE. The anti-Candida vaccine based on the recombinant N-terminal domain of Als1p is broadly active against disseminated candidiasis. Infect Immun. 2006;74:3039–41.

    Article  PubMed  CAS  Google Scholar 

  53. Spellberg BJ, Ibrahim AS, Avanesian V, et al. Efficacy of the anti-Candida rAls3p-N or rAls1p-N vaccines against disseminated and mucosal candidiasis. J Infect Dis. 2006;194:256–60.

    Article  PubMed  CAS  Google Scholar 

  54. Schmidt CS, White CJ, Ibrahim AS, et al. NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. Vaccine. 2012;30:7594–600.

    Article  PubMed  CAS  Google Scholar 

  55. De Bernardis F, Arancia S, Morelli L, et al. Evidence that members of the secretory aspartyl proteinase gene family, in particular SAP2, are virulence factors for Candida vaginitis. J Infect Dis. 1999;179:201–8.

    Article  PubMed  Google Scholar 

  56. • Sandini S, La Valle R, Deaglio S, Malavasi F, Cassone A, De Bernardis F. A highly immunogenic recombinant and truncated protein of the secreted aspartic proteases family (rSap2t) of Candida albicans as a mucosal anticandidal vaccine. FEMS Immunol Med Microbiol. 2011;62:215–24. Report describes a new antibody-mediated vaccine against C. albicans that elicits antibodies which neutralize the fungal protease Sap2.

    Article  PubMed  CAS  Google Scholar 

  57. Pevion Biotech AG: PEV7 Active immunotherapy against RVVC. Available at http://pevion.com/images/content/Pevion%20PEV7%20RVVC%20Immunotherapy.pdf. Accessed November 2012.

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Conflict of Interest

Nicholas D. Beyda declares that he has no conflict of interest.

Sloan Regen declares that he has no conflict of interest.

Russell E. Lewis has received research grant from Merck and has received payment for development of educational presentations from Gilead Inc.

Kevin W. Garey has received research grant from Astellas.

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Authors and Affiliations

  1. Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, 1441 Moursund Street, Houston, TX, 77030, USA

    Nicholas D. Beyda, Sloan Regen, Russell E. Lewis & Kevin W. Garey

  2. Infectious Diseases Unit, Policlinico S. Orsola Malpighi, Alma Mater Studiorum Università di Bologna, Via Massarenti 11, Bologna, 40138, Italy

    Russell E. Lewis

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  1. Nicholas D. Beyda
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  2. Sloan Regen
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Correspondence to Kevin W. Garey.

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Beyda, N.D., Regen, S., Lewis, R.E. et al. Immunomodulatory Agents as Adjunctive Therapy for the Treatment of Resistant Candida Species. Curr Fungal Infect Rep 7, 119–125 (2013). https://doi.org/10.1007/s12281-013-0132-3

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