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Chapter 127 : Mechanisms of Resistance to Antifungal Agents

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Abstract:

This chapter describes the factors that contribute to a recalcitrant or resistant clinical infection. It focuses on the resistance of fungal isolates, as determined by their MIC. There are two types of resistance: intrinsic resistance, which is an inherited characteristic of a species or strain, and acquired resistance, which occurs when a previously susceptible isolate develops a resistant phenotype, usually as a result of prolonged treatment with antifungals. A section of the chapter concentrates on the mechanisms identified in , with discussion of mechanisms identified in other fungi when applicable. Several alterations in ERG11 have been associated with resistance in , including (i) point mutations in the coding regions, (ii) overexpression of the gene, (iii) gene amplification, and (iv) gene conversion or mitotic recombination. The interaction between the azoles and Erg11p can be altered by mutation or overexpression of the ERG11 gene. Alterations in other enzymes in ergosterol biosynthesis can also affect azole susceptibility. New azole drugs, such as posaconazole, need to be carefully monitored for their effect on strains that are resistant to fluconazole. An increased understanding of antifungal drug resistance should allow for the development of new diagnostic strategies to identify resistant clinical isolates in a patient, new treatment strategies to treat these resistant infections, and new prevention strategies that would forestall the development of antifungal drug resistance in these patient populations.

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127

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FIGURE 1

Molecular mechanisms of azole resistance. See text for details. Gene products shown in the figure include Erg11p (pink sphere), the efflux pumps (green tubes) with ATP binding cassette domains (green spheres), the efflux pump (red tubes), and other ergosterol biosynthetic enzymes (spheres of assorted colors). Point mutations are shown as dark slices in pink and blue spheres. Reprinted with modification from reference with permission of the publisher.

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127
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References

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Tables

Generic image for table
TABLE 1

Factors that contribute to clinical antifungal drug resistance

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127
Generic image for table
TABLE 2

Clinical breakpoints for

For a more complete list of clinical breakpoints in other species, refer to chapter 128.

Includes caspofungin, anidulafungin, and micafungin.

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127
Generic image for table
TABLE 3

Transcriptional regulation of resistance

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127
Generic image for table
TABLE 4

Cellular phenotypes associated with resistance

Standard MIC at 48 h.

Citation: White T, Hoot S. 2011. Mechanisms of Resistance to Antifungal Agents, p 2008-2019. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch127

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