Skip to main content
Top
Published in: Current Infectious Disease Reports 12/2016

01-12-2016 | Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)

Azole Resistance in Candida glabrata

Authors: Sarah G. Whaley, P. David Rogers

Published in: Current Infectious Disease Reports | Issue 12/2016

Login to get access

Abstract

Candida infections have increased due to the growth and expansion of susceptible patient populations. The azole fluconazole is the most widely prescribed antifungal, but rising rates of clinical resistance among Candida glabrata isolates have greatly limited its utility. A better understanding of the mechanisms of azole antifungal resistance will provide information needed to overcome this clinical problem and reclaim this antifungal class as an option for empiric treatment of Candida infections. By far, the most frequent mechanism of azole resistance in C. glabrata is the overexpression of multidrug transporters due to activating mutations in the gene encoding transcription factor Pdr1. In this review, we will discuss the molecular and genetic basis of azole resistance in C. glabrata with particular attention given to the most recent discoveries in this field.
Literature
3.
go back to reference Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309–17. doi:10.1086/421946CID32752.CrossRefPubMed Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004;39(3):309–17. doi:10.​1086/​421946CID32752.CrossRefPubMed
4.
go back to reference Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999;29(2):239–44. doi:10.1086/520192.CrossRefPubMed Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin Infect Dis. 1999;29(2):239–44. doi:10.​1086/​520192.CrossRefPubMed
5.
go back to reference Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37(5):634–43. doi:10.1086/376906.CrossRefPubMed Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al. A prospective observational study of candidemia: epidemiology, therapy, and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis. 2003;37(5):634–43. doi:10.​1086/​376906.CrossRefPubMed
7.
go back to reference Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110–22. doi:10.1093/cid/cis021.CrossRefPubMed Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110–22. doi:10.​1093/​cid/​cis021.CrossRefPubMed
8.
go back to reference Khatib R, Johnson LB, Fakih MG, Riederer K, Briski L. Current trends in candidemia and species distribution among adults: Candida glabrata surpasses C. albicans in diabetic patients and abdominal sources. Mycoses. 2016. doi:10.1111/myc.12531.PubMed Khatib R, Johnson LB, Fakih MG, Riederer K, Briski L. Current trends in candidemia and species distribution among adults: Candida glabrata surpasses C. albicans in diabetic patients and abdominal sources. Mycoses. 2016. doi:10.​1111/​myc.​12531.PubMed
9.
go back to reference Lockhart SR, Iqbal N, Cleveland AA, Farley MM, Harrison LH, Bolden CB, 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(11):3435–42. doi:10.1128/JCM.01283-12.CrossRefPubMedPubMedCentral Lockhart SR, Iqbal N, Cleveland AA, Farley MM, Harrison LH, Bolden CB, 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(11):3435–42. doi:10.​1128/​JCM.​01283-12.CrossRefPubMedPubMedCentral
11.
go back to reference Milazzo L, Peri AM, Mazzali C, Grande R, Cazzani C, Ricaboni D, et al. Candidaemia observed at a university hospital in Milan (northern Italy) and review of published studies from 2010 to 2014. Mycopathologia. 2014;178(3-4):227–41. doi:10.1007/s11046-014-9786-9.CrossRefPubMed Milazzo L, Peri AM, Mazzali C, Grande R, Cazzani C, Ricaboni D, et al. Candidaemia observed at a university hospital in Milan (northern Italy) and review of published studies from 2010 to 2014. Mycopathologia. 2014;178(3-4):227–41. doi:10.​1007/​s11046-014-9786-9.CrossRefPubMed
12.
go back to reference Borg-von Zepelin M, Kunz L, Ruchel R, Reichard U, Weig M, Gross U. Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005. J Antimicrob Chemother. 2007;60(2):424–8. doi:10.1093/jac/dkm145.CrossRefPubMed Borg-von Zepelin M, Kunz L, Ruchel R, Reichard U, Weig M, Gross U. Epidemiology and antifungal susceptibilities of Candida spp. to six antifungal agents: results from a surveillance study on fungaemia in Germany from July 2004 to August 2005. J Antimicrob Chemother. 2007;60(2):424–8. doi:10.​1093/​jac/​dkm145.CrossRefPubMed
15.
go back to reference Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP. National nosocomial infections surveillance system H. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002;35(5):627–30. doi:10.1086/342300.CrossRefPubMed Trick WE, Fridkin SK, Edwards JR, Hajjeh RA, Gaynes RP. National nosocomial infections surveillance system H. Secular trend of hospital-acquired candidemia among intensive care unit patients in the United States during 1989-1999. Clin Infect Dis. 2002;35(5):627–30. doi:10.​1086/​342300.CrossRefPubMed
16.
go back to reference Chow JK, Golan Y, Ruthazer R, Karchmer AW, Carmeli Y, Lichtenberg D, et al. Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis. 2008;46(8):1206–13. doi:10.1086/529435.CrossRefPubMed Chow JK, Golan Y, Ruthazer R, Karchmer AW, Carmeli Y, Lichtenberg D, et al. Factors associated with candidemia caused by non-albicans Candida species versus Candida albicans in the intensive care unit. Clin Infect Dis. 2008;46(8):1206–13. doi:10.​1086/​529435.CrossRefPubMed
17.
go back to reference Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112(11):2493–9. doi:10.1002/cncr.23466.CrossRefPubMed Hachem R, Hanna H, Kontoyiannis D, Jiang Y, Raad I. The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy. Cancer. 2008;112(11):2493–9. doi:10.​1002/​cncr.​23466.CrossRefPubMed
19.
go back to reference Bodey GP, Mardani M, Hanna HA, Boktour M, Abbas J, Girgawy E, et al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med. 2002;112(5):380–5.CrossRefPubMed Bodey GP, Mardani M, Hanna HA, Boktour M, Abbas J, Girgawy E, et al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med. 2002;112(5):380–5.CrossRefPubMed
20.
go back to reference Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis. 2004;39(5):743–6. doi:10.1086/423274.CrossRefPubMed Imhof A, Balajee SA, Fredricks DN, Englund JA, Marr KA. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis. 2004;39(5):743–6. doi:10.​1086/​423274.CrossRefPubMed
21.
go back to reference Kontoyiannis DP, Reddy BT, Hanna H, Bodey GP, Tarrand J, Raad II. Breakthrough candidemia in patients with cancer differs from de novo candidemia in host factors and Candida species but not intensity. Infect Control Hosp Epidemiol. 2002;23(9):542–5. doi:10.1086/502104.CrossRefPubMed Kontoyiannis DP, Reddy BT, Hanna H, Bodey GP, Tarrand J, Raad II. Breakthrough candidemia in patients with cancer differs from de novo candidemia in host factors and Candida species but not intensity. Infect Control Hosp Epidemiol. 2002;23(9):542–5. doi:10.​1086/​502104.CrossRefPubMed
23.
go back to reference Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. doi:10.1093/cid/civ933.CrossRefPubMed Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1–50. doi:10.​1093/​cid/​civ933.CrossRefPubMed
24.
25.
go back to reference Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, 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(3):1360–2. doi:10.1128/AAC.01138-09.CrossRefPubMed Chapeland-Leclerc F, Hennequin C, Papon N, Noel T, Girard A, Socie G, 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(3):1360–2. doi:10.​1128/​AAC.​01138-09.CrossRefPubMed
26.
go back to reference Cho EJ, Shin JH, Kim SH, Kim HK, Park JS, Sung H, et al. Emergence of multiple resistance profiles involving azoles, echinocandins and amphotericin B in Candida glabrata isolates from a neutropenia patient with prolonged fungaemia. J Antimicrob Chemother. 2015;70(4):1268–70. doi:10.1093/jac/dku518.PubMed Cho EJ, Shin JH, Kim SH, Kim HK, Park JS, Sung H, et al. Emergence of multiple resistance profiles involving azoles, echinocandins and amphotericin B in Candida glabrata isolates from a neutropenia patient with prolonged fungaemia. J Antimicrob Chemother. 2015;70(4):1268–70. doi:10.​1093/​jac/​dku518.PubMed
28.
go back to reference Hull CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AG, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrob Agents Chemother. 2012;56(8):4223–32. doi:10.1128/AAC.06253-11.CrossRefPubMedPubMedCentral Hull CM, Parker JE, Bader O, Weig M, Gross U, Warrilow AG, et al. Facultative sterol uptake in an ergosterol-deficient clinical isolate of Candida glabrata harboring a missense mutation in ERG11 and exhibiting cross-resistance to azoles and amphotericin B. Antimicrob Agents Chemother. 2012;56(8):4223–32. doi:10.​1128/​AAC.​06253-11.CrossRefPubMedPubMedCentral
29.
go back to reference Garnaud C, Botterel F, Sertour N, Bougnoux ME, Dannaoui E, Larrat S, et al. Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles. J Antimicrob Chemother. 2015;70(9):2556–65. doi:10.1093/jac/dkv139.CrossRefPubMed Garnaud C, Botterel F, Sertour N, Bougnoux ME, Dannaoui E, Larrat S, et al. Next-generation sequencing offers new insights into the resistance of Candida spp. to echinocandins and azoles. J Antimicrob Chemother. 2015;70(9):2556–65. doi:10.​1093/​jac/​dkv139.CrossRefPubMed
30.
go back to reference • Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock C, Falconer DJ, et al. Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob Agents Chemother. 1998;42(7):1695–701. This represents the first indication of a multidrug transporter contributing to fluconazole resistance in C. glabrata. PubMedPubMedCentral • Miyazaki H, Miyazaki Y, Geber A, Parkinson T, Hitchcock C, Falconer DJ, et al. Fluconazole resistance associated with drug efflux and increased transcription of a drug transporter gene, PDH1, in Candida glabrata. Antimicrob Agents Chemother. 1998;42(7):1695–701. This represents the first indication of a multidrug transporter contributing to fluconazole resistance in C. glabrata. PubMedPubMedCentral
33.
go back to reference •• Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob Agents Chemother. 1999;43(11):2753–65. This paper describes the predominant multidrug transporter involved in fluconazole resistance in C. glabrata. PubMedPubMedCentral •• Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob Agents Chemother. 1999;43(11):2753–65. This paper describes the predominant multidrug transporter involved in fluconazole resistance in C. glabrata. PubMedPubMedCentral
36.
go back to reference • Torelli R, Posteraro B, Ferrari S, La Sorda M, Fadda G, Sanglard D, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol. 2008;68(1):186–201. doi:10.1111/j.1365-2958.2008.06143.x. This paper demonstrates an important role for a third multidrug transporter in fluconazole resistance in C. glabrata.CrossRefPubMed • Torelli R, Posteraro B, Ferrari S, La Sorda M, Fadda G, Sanglard D, et al. The ATP-binding cassette transporter-encoding gene CgSNQ2 is contributing to the CgPDR1-dependent azole resistance of Candida glabrata. Mol Microbiol. 2008;68(1):186–201. doi:10.​1111/​j.​1365-2958.​2008.​06143.​x. This paper demonstrates an important role for a third multidrug transporter in fluconazole resistance in C. glabrata.CrossRefPubMed
37.
go back to reference Sanglard D, Kuchler K, Ischer F, Pagani JL, Monod M, Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995;39(11):2378–86.CrossRefPubMedPubMedCentral Sanglard D, Kuchler K, Ischer F, Pagani JL, Monod M, Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob Agents Chemother. 1995;39(11):2378–86.CrossRefPubMedPubMedCentral
38.
go back to reference Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996;40(10):2300–5.PubMedPubMedCentral Sanglard D, Ischer F, Monod M, Bille J. Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors. Antimicrob Agents Chemother. 1996;40(10):2300–5.PubMedPubMedCentral
39.
go back to reference •• Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol. 2006;61(3):704–22. doi:10.1111/j.1365-2958.2006.05235.x. Along with 44, this paper describes the genetic basis for fluconazole resistance in C. glabrata and delineates the gene regulated by an activating mutation in the gene encoding Pdr1. CrossRefPubMed •• Vermitsky JP, Earhart KD, Smith WL, Homayouni R, Edlind TD, Rogers PD. Pdr1 regulates multidrug resistance in Candida glabrata: gene disruption and genome-wide expression studies. Mol Microbiol. 2006;61(3):704–22. doi:10.​1111/​j.​1365-2958.​2006.​05235.​x. Along with 44, this paper describes the genetic basis for fluconazole resistance in C. glabrata and delineates the gene regulated by an activating mutation in the gene encoding Pdr1. CrossRefPubMed
41.
go back to reference Costa C, Pires C, Cabrito TR, Renaudin A, Ohno M, Chibana H, et al. Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1. Antimicrob Agents Chemother. 2013;57(7):3159–67. doi:10.1128/AAC.00811-12.CrossRefPubMedPubMedCentral Costa C, Pires C, Cabrito TR, Renaudin A, Ohno M, Chibana H, et al. Candida glabrata drug:H+ antiporter CgQdr2 confers imidazole drug resistance, being activated by transcription factor CgPdr1. Antimicrob Agents Chemother. 2013;57(7):3159–67. doi:10.​1128/​AAC.​00811-12.CrossRefPubMedPubMedCentral
43.
go back to reference • Paul S, Bair TB, Moye-Rowley WS. Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and rho0 cells. Antimicrob Agents Chemother. 2014;58(11):6904–12. doi:10.1128/AAC.03921-14. This paper delineates the transcriptional targets of Pdr1 when activated by loss of mitochondrial function. CrossRefPubMedPubMedCentral • Paul S, Bair TB, Moye-Rowley WS. Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and rho0 cells. Antimicrob Agents Chemother. 2014;58(11):6904–12. doi:10.​1128/​AAC.​03921-14. This paper delineates the transcriptional targets of Pdr1 when activated by loss of mitochondrial function. CrossRefPubMedPubMedCentral
44.
go back to reference • Tsai HF, Krol AA, Sarti KE, Bennett JE. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50(4):1384–92. doi:10.1128/AAC.50.4.1384-1392.2006. Along with 39, this paper describes the genetic basis for fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentral • Tsai HF, Krol AA, Sarti KE, Bennett JE. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50(4):1384–92. doi:10.​1128/​AAC.​50.​4.​1384-1392.​2006. Along with 39, this paper describes the genetic basis for fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentral
46.
go back to reference •• Ferrari S, Ischer F, Calabrese D, Posteraro B, Sanguinetti M, Fadda G, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5(1):e1000268. doi:10.1371/journal.ppat.1000268. This paper establishes activating mutations in the gene encoding Pdr1 as the primary mechanism of fluconazole resistance and demonstrates that such mutations enhance fitness and virulence.CrossRefPubMedPubMedCentral •• Ferrari S, Ischer F, Calabrese D, Posteraro B, Sanguinetti M, Fadda G, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5(1):e1000268. doi:10.​1371/​journal.​ppat.​1000268. This paper establishes activating mutations in the gene encoding Pdr1 as the primary mechanism of fluconazole resistance and demonstrates that such mutations enhance fitness and virulence.CrossRefPubMedPubMedCentral
47.
go back to reference Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother. 2004;48(5):1773–7.CrossRefPubMedPubMedCentral Bennett JE, Izumikawa K, Marr KA. Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis. Antimicrob Agents Chemother. 2004;48(5):1773–7.CrossRefPubMedPubMedCentral
48.
go back to reference • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452(7187):604–9. doi:10.1038/nature06836. This paper suggests a mechanism by which Pdr1 is activated by ketoconazole. CrossRefPubMed • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, et al. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature. 2008;452(7187):604–9. doi:10.​1038/​nature06836. This paper suggests a mechanism by which Pdr1 is activated by ketoconazole. CrossRefPubMed
49.
go back to reference •• Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, et al. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016;530(7591):485–9. doi:10.1038/nature16963. This paper demonstrates that the Pdr1-Mediator interaction can be chemically disrupted, thereby pointing to the possibility of a co-therapeutic strategy to overcome fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentral •• Nishikawa JL, Boeszoermenyi A, Vale-Silva LA, Torelli R, Posteraro B, Sohn YJ, et al. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction. Nature. 2016;530(7591):485–9. doi:10.​1038/​nature16963. This paper demonstrates that the Pdr1-Mediator interaction can be chemically disrupted, thereby pointing to the possibility of a co-therapeutic strategy to overcome fluconazole resistance in C. glabrata. CrossRefPubMedPubMedCentral
51.
go back to reference Borah S, Shivarathri R, Srivastava VK, Ferrari S, Sanglard D, Kaur R. Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata. Antimicrob Agents Chemother. 2014;58(10):5976–86. doi:10.1128/AAC.02786-14.CrossRefPubMedPubMedCentral Borah S, Shivarathri R, Srivastava VK, Ferrari S, Sanglard D, Kaur R. Pivotal role for a tail subunit of the RNA polymerase II mediator complex CgMed2 in azole tolerance and adherence in Candida glabrata. Antimicrob Agents Chemother. 2014;58(10):5976–86. doi:10.​1128/​AAC.​02786-14.CrossRefPubMedPubMedCentral
54.
55.
go back to reference Orta-Zavalza E, Guerrero-Serrano G, Gutierrez-Escobedo G, Canas-Villamar I, Juarez-Cepeda J, Castano I, et al. Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata. Mol Microbiol. 2013;88(6):1135–48. doi:10.1111/mmi.12247.CrossRefPubMed Orta-Zavalza E, Guerrero-Serrano G, Gutierrez-Escobedo G, Canas-Villamar I, Juarez-Cepeda J, Castano I, et al. Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata. Mol Microbiol. 2013;88(6):1135–48. doi:10.​1111/​mmi.​12247.CrossRefPubMed
56.
go back to reference vanden Bossche H, Marichal P, Odds FC, Le Jeune L, Coene MC. Characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1992;36(12):2602–10.CrossRef vanden Bossche H, Marichal P, Odds FC, Le Jeune L, Coene MC. Characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1992;36(12):2602–10.CrossRef
57.
go back to reference Marichal P, Vanden Bossche H, Odds FC, Nobels G, Warnock DW, Timmerman V, et al. Molecular biological characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1997;41(10):2229–37.PubMedPubMedCentral Marichal P, Vanden Bossche H, Odds FC, Nobels G, Warnock DW, Timmerman V, et al. Molecular biological characterization of an azole-resistant Candida glabrata isolate. Antimicrob Agents Chemother. 1997;41(10):2229–37.PubMedPubMedCentral
58.
go back to reference Redding SW, Kirkpatrick WR, Saville S, Coco BJ, White W, Fothergill A, et al. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol. 2003;41(2):619–22.CrossRefPubMedPubMedCentral Redding SW, Kirkpatrick WR, Saville S, Coco BJ, White W, Fothergill A, et al. Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol. 2003;41(2):619–22.CrossRefPubMedPubMedCentral
60.
go back to reference •• Whaley SG, Caudle KE, Vermitsky JP, Chadwick SG, Toner G, Barker KS, et al. UPC2A is required for high-level azole antifungal resistance in Candida glabrata. Antimicrob Agents Chemother. 2014;58(8):4543–54. doi:10.1128/AAC.02217-13. This paper demonstrates the importance of the sterol biosynthesis regulator Upc2A in fluconzole resistance in C. glabrata and points to a strategy for overcoming it. CrossRefPubMedPubMedCentral •• Whaley SG, Caudle KE, Vermitsky JP, Chadwick SG, Toner G, Barker KS, et al. UPC2A is required for high-level azole antifungal resistance in Candida glabrata. Antimicrob Agents Chemother. 2014;58(8):4543–54. doi:10.​1128/​AAC.​02217-13. This paper demonstrates the importance of the sterol biosynthesis regulator Upc2A in fluconzole resistance in C. glabrata and points to a strategy for overcoming it. CrossRefPubMedPubMedCentral
61.
go back to reference Nakayama H, Izuta M, Nakayama N, Arisawa M, Aoki Y. Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice. Antimicrob Agents Chemother. 2000;44(9):2411–8.CrossRefPubMedPubMedCentral Nakayama H, Izuta M, Nakayama N, Arisawa M, Aoki Y. Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice. Antimicrob Agents Chemother. 2000;44(9):2411–8.CrossRefPubMedPubMedCentral
66.
go back to reference Nakayama H, Tanabe K, Bard M, Hodgson W, Wu S, Takemori D, et al. The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother. 2007;60(6):1264–72. doi:10.1093/jac/dkm321.CrossRefPubMed Nakayama H, Tanabe K, Bard M, Hodgson W, Wu S, Takemori D, et al. The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum. J Antimicrob Chemother. 2007;60(6):1264–72. doi:10.​1093/​jac/​dkm321.CrossRefPubMed
67.
go back to reference Nagi M, Tanabe K, Ueno K, Nakayama H, Aoyama T, Chibana H, et al. The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation. Mol Microbiol. 2013;88(2):371–81. doi:10.1111/mmi.12189.CrossRefPubMed Nagi M, Tanabe K, Ueno K, Nakayama H, Aoyama T, Chibana H, et al. The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation. Mol Microbiol. 2013;88(2):371–81. doi:10.​1111/​mmi.​12189.CrossRefPubMed
69.
go back to reference • Vale-Silva L, Ischer F, Leibundgut-Landmann S, Sanglard D. Gain-of-function mutations in PDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells. Infect Immun. 2013;81(5):1709–20. doi:10.1128/IAI.00074-13. This paper further establishes the contribution of activating mutations in Pdr1 to virulence through increased adherence to host cells.CrossRefPubMedPubMedCentral • Vale-Silva L, Ischer F, Leibundgut-Landmann S, Sanglard D. Gain-of-function mutations in PDR1, a regulator of antifungal drug resistance in Candida glabrata, control adherence to host cells. Infect Immun. 2013;81(5):1709–20. doi:10.​1128/​IAI.​00074-13. This paper further establishes the contribution of activating mutations in Pdr1 to virulence through increased adherence to host cells.CrossRefPubMedPubMedCentral
70.
go back to reference • Vale-Silva LA, Moeckli B, Torelli R, Posteraro B, Sanguinetti M, Sanglard D. Upregulation of the adhesin gene EPA1 mediated by PDR1 in Candida glabrata leads to enhanced host colonization. mSphere. 2016;1(2). doi:10.1128/mSphere.00065-15. This paper demonstrates a role for Pdr1-mediated EPA1 expression in enhanced host colonization. • Vale-Silva LA, Moeckli B, Torelli R, Posteraro B, Sanguinetti M, Sanglard D. Upregulation of the adhesin gene EPA1 mediated by PDR1 in Candida glabrata leads to enhanced host colonization. mSphere. 2016;1(2). doi:10.​1128/​mSphere.​00065-15. This paper demonstrates a role for Pdr1-mediated EPA1 expression in enhanced host colonization.
72.
go back to reference Devaux F, Carvajal E, Moye-Rowley S, Jacq C. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. FEBS Lett. 2002;515(1-3):25–8.CrossRefPubMed Devaux F, Carvajal E, Moye-Rowley S, Jacq C. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. FEBS Lett. 2002;515(1-3):25–8.CrossRefPubMed
73.
74.
go back to reference Defontaine A, Bouchara JP, Declerk P, Planchenault C, Chabasse D, Hallet JN. In-vitro resistance to azoles associated with mitochondrial DNA deficiency in Candida glabrata. J Med Microbiol. 1999;48(7):663–70. doi:10.1099/00222615-48-7-663.CrossRefPubMed Defontaine A, Bouchara JP, Declerk P, Planchenault C, Chabasse D, Hallet JN. In-vitro resistance to azoles associated with mitochondrial DNA deficiency in Candida glabrata. J Med Microbiol. 1999;48(7):663–70. doi:10.​1099/​00222615-48-7-663.CrossRefPubMed
75.
go back to reference Brun S, Berges T, Poupard P, Vauzelle-Moreau C, Renier G, Chabasse D, et al. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother. 2004;48(5):1788–96.CrossRefPubMedPubMedCentral Brun S, Berges T, Poupard P, Vauzelle-Moreau C, Renier G, Chabasse D, et al. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother. 2004;48(5):1788–96.CrossRefPubMedPubMedCentral
76.
go back to reference Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, Posteraro B, Vandeputte P, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55(5):1852–60. doi:10.1128/AAC.01271-10.CrossRefPubMedPubMedCentral Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, Posteraro B, Vandeputte P, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55(5):1852–60. doi:10.​1128/​AAC.​01271-10.CrossRefPubMedPubMedCentral
77.
80.
go back to reference •• Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun. 2016;7:11128. doi:10.1038/ncomms11128. This work establishes a mechanism by which C. glabrata rapidly develops antifungal resistance. CrossRefPubMed •• Healey KR, Zhao Y, Perez WB, Lockhart SR, Sobel JD, Farmakiotis D, et al. Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance. Nat Commun. 2016;7:11128. doi:10.​1038/​ncomms11128. This work establishes a mechanism by which C. glabrata rapidly develops antifungal resistance. CrossRefPubMed
82.
go back to reference Klempp-Selb B, Rimek D, Kappe R. Karyotyping of Candida albicans and Candida glabrata from patients with Candida sepsis. Mycoses. 2000;43(5):159–63.CrossRefPubMed Klempp-Selb B, Rimek D, Kappe R. Karyotyping of Candida albicans and Candida glabrata from patients with Candida sepsis. Mycoses. 2000;43(5):159–63.CrossRefPubMed
87.
go back to reference •• Ben-Ami R, Zimmerman O, Finn T, Amit S, Novikov A, Wertheimer N, et al. Heteroresistance to fluconazole is a continuously distributed phenotype among Candida glabrata clinical strains associated with in vivo persistence. MBio. 2016;7(4):e00655–16. doi:10.1128/mBio.00655-16. This work establishes the importance of heteroresistance in fluconazole resistance among clinical isolates of C. glabrata. CrossRefPubMedPubMedCentral •• Ben-Ami R, Zimmerman O, Finn T, Amit S, Novikov A, Wertheimer N, et al. Heteroresistance to fluconazole is a continuously distributed phenotype among Candida glabrata clinical strains associated with in vivo persistence. MBio. 2016;7(4):e00655–16. doi:10.​1128/​mBio.​00655-16. This work establishes the importance of heteroresistance in fluconazole resistance among clinical isolates of C. glabrata. CrossRefPubMedPubMedCentral
Metadata
Title
Azole Resistance in Candida glabrata
Authors
Sarah G. Whaley
P. David Rogers
Publication date
01-12-2016
Publisher
Springer US
Published in
Current Infectious Disease Reports / Issue 12/2016
Print ISSN: 1523-3847
Electronic ISSN: 1534-3146
DOI
https://doi.org/10.1007/s11908-016-0554-5

Other articles of this Issue 12/2016

Current Infectious Disease Reports 12/2016 Go to the issue

Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)

Antibiotic Resistance in Pediatric Urinary Tract Infections

Central Nervous System Infections (K Bloch, Section Editor)

Update on the Diagnosis and Management of Neurocysticercosis

Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)

Echinocandin Resistance in Candida Species: a Review of Recent Developments

Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)

Emerging Issues and Treatment Strategies in Carbapenem-Resistant Enterobacteriaceae (CRE)

Antimicrobial Development and Drug Resistance (A Pakyz, Section Editor)

Resistance to Non-glycopeptide Agents in Serious Staphylococcus aureus Infections

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.