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Analysis of Candida Antifungal Resistance Using Animal Infection Models

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Antifungal Drug Resistance

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2658))

Abstract

Candida frequently produces three general disease states, including mucosal candidiasis, disseminated candidiasis, and biofilm infection (which can be present with either of the other disease states). Antifungal drug resistance is intrinsic to biofilm growth and has emerged in other disease states. Mechanistic studies have uncovered the genetic pathways governing resistance to a number of antifungal agents. However, analyzing the clinical relevance of distinct mechanisms is fundamental for broadening our knowledge of antifungal drug resistance and for delineating the potential impact of targeting these pathways medically. Also, as drug-resistant strains and biofilms represent important nosocomial problems, preclinical animal models to assess the activity of novel antifungals are of great interest. Here we describe two rodent models that mimic the most common biofilm device and disseminated candidiasis states in patients. The model systems incorporate the anatomical site, immune components, and antifungal exposures relevant for the study of antifungal resistance. The models can be used to analyze mutant strains, assess the extent of drug resistance, examine biofilm formation, test new antimicrobials, and help determine drug exposures that may be linked with clinical failure.

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References

  1. Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20:133–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pappas PG, Kauffman CA, Andes DR et al (2016) Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis 62:e1–e50

    Google Scholar 

  3. Shor E, Perlin DS (2015) Coping with stress and the emergence of multidrug resistance in fungi. PLoS Pathog 11:e1004668

    Article  PubMed  PubMed Central  Google Scholar 

  4. Taff HT, Mitchell KF, Edward JA et al (2013) Mechanisms of Candida biofilm drug resistance. Future Microbiol 8:1325–1337

    Article  CAS  PubMed  Google Scholar 

  5. Chandra J, Kuhn DM, Mukherjee PK et al (2001) Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J Bacteriol 183:5385–5394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kojic EM, Darouiche RO (2004) Candida infections of medical devices. Clin Microbiol Rev 17:255–267

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhao M, Lepak AJ, Andes DR (2016) Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Bioorg Med Chem 24:6390–6400

    Article  CAS  PubMed  Google Scholar 

  8. Spellberg B, Ibrahim AS, Edwards JE Jr et al (2005) Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis 192:336–343

    Article  PubMed  Google Scholar 

  9. Zhao M, Lepak AJ, Vanscoy B et al (2018) In vivo pharmacokinetics and pharmacodynamics of APX001 against Candida spp. in a neutropenic disseminated candidiasis mouse model. Antimicrob Agents Chemother 62

    Google Scholar 

  10. Lepak AJ, Zhao M, Vanscoy B et al (2018) Pharmacodynamics of a long-acting echinocandin, CD101, in a neutropenic invasive-candidiasis murine model using an extended-interval dosing design. Antimicrob Agents Chemother 62

    Google Scholar 

  11. Lepak AJ, Zhao M, Berkow EL et al (2017) Pharmacodynamic optimization for treatment of invasive Candida auris infection. Antimicrob Agents Chemother 61

    Google Scholar 

  12. Nett J, Andes D (2006) Candida albicans biofilm development, modeling a host-pathogen interaction. Curr Opin Microbiol 9:340–345

    Article  CAS  PubMed  Google Scholar 

  13. Nikawa H, Nishimura H, Hamada T et al (1997) Effects of dietary sugars and, saliva and serum on Candida bioflim formation on acrylic surfaces. Mycopathologia 139:87–91

    Article  CAS  PubMed  Google Scholar 

  14. Nobile CJ, Schneider HA, Nett JE et al (2008) Complementary adhesin function in C. albicans biofilm formation. Curr Biol 18:1017–1024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Uppuluri P, Nett J, Heitman J et al (2008) Synergistic effect of calcineurin inhibitors and fluconazole against Candida albicans biofilms. Antimicrob Agents Chemother 52:1127–1132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nett JE, Sanchez H, Cain MT et al (2010) Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J Infect Dis 202:171–175

    Article  CAS  PubMed  Google Scholar 

  17. Andes D, Nett J, Oschel P et al (2004) Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect Immun 72:6023–6031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nett JE, Lepak AJ, Marchillo K et al (2009) Time course global gene expression analysis of an in vivo Candida biofilm. J Infect Dis 200:307–313

    Article  CAS  PubMed  Google Scholar 

  19. Ahrens J, Graybill JR, Craven PC et al (1984) Treatment of experimental murine candidiasis with liposome-associated amphotericin B. Sabouraudia 22:163–166

    Article  CAS  PubMed  Google Scholar 

  20. Maccallum DM, Odds FC (2004) Need for early antifungal treatment confirmed in experimental disseminated Candida albicans infection. Antimicrob Agents Chemother 48:4911–4914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wiederhold NP, Najvar LK, Jaramillo R et al (2018) Oral glucan synthase inhibitor SCY-078 is effective in an experimental murine model of invasive candidiasis caused by WT and echinocandin-resistant Candida glabrata. J Antimicrob Chemother 73:448–451

    Article  CAS  PubMed  Google Scholar 

  22. Wiederhold NP, Najvar LK, Jaramillo R et al (2020) The novel Arylamidine T-2307 demonstrates in vitro and in vivo activity against Candida auris. Antimicrob Agents Chemother 64

    Google Scholar 

  23. Nett J, Lincoln L, Marchillo K et al (2007) Beta −1,3 glucan as a test for central venous catheter biofilm infection. J Infect Dis 195:1705–1712

    Article  CAS  PubMed  Google Scholar 

  24. Andes D, Van Ogtrop M (1999) Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother 43:2116–2120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Andes DR, Diekema DJ, Pfaller MA et al (2008) In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother 52:3497–3503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hogan DA (2006) Talking to themselves: autoregulation and quorum sensing in fungi. Eukaryot Cell 5:613–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hope WW, Drusano GL, Moore CB et al (2007) Effect of neutropenia and treatment delay on the response to antifungal agents in experimental disseminated candidiasis. Antimicrob Agents Chemother 51:285–295

    Article  CAS  PubMed  Google Scholar 

  28. Odds FC, Van Nuffel L, Gow NA (2000) Survival in experimental Candida albicans infections depends on inoculum growth conditions as well as animal host. Microbiology 146(Pt 8):1881–1889

    Article  CAS  PubMed  Google Scholar 

  29. Sasse C, Dunkel N, Schafer T et al (2012) The stepwise acquisition of fluconazole resistance mutations causes a gradual loss of fitness in Candida albicans. Mol Microbiol 86:539

    Article  CAS  PubMed  Google Scholar 

  30. Cowen LE, Kohn LM, Anderson JB (2001) Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans. J Bacteriol 183:2971–2978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ben-Ami R, Kontoyiannis DP (2012) Resistance to echinocandins comes at a cost: the impact of FKS1 hotspot mutations on Candida albicans fitness and virulence. Virulence 3:95–97

    Article  PubMed  PubMed Central  Google Scholar 

  32. Lepak A, Castanheira M, Diekema D et al (2012) Optimizing Echinocandin dosing and susceptibility breakpoint determination via in vivo pharmacodynamic evaluation against Candida glabrata with and without fks mutations. Antimicrob Agents Chemother 56:5875–5882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lepak AJ, Marchillo K, Vanhecker J et al (2013) Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model. Antimicrob Agents Chemother 57:5642–5648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Institutes of Health (U19 AI142720, R01 AI073289).

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Correspondence to David R. Andes .

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© 2023 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

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Andes, D.R., Nett, J.E. (2023). Analysis of Candida Antifungal Resistance Using Animal Infection Models. In: Krysan, D.J., Moye-Rowley, W.S. (eds) Antifungal Drug Resistance. Methods in Molecular Biology, vol 2658. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3155-3_16

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  • DOI: https://doi.org/10.1007/978-1-0716-3155-3_16

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3154-6

  • Online ISBN: 978-1-0716-3155-3

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