Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance

ABSTRACT Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility...

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Autores principales:	William Hope, Neil R. H. Stone, Adam Johnson, Laura McEntee, Nicola Farrington, Anahi Santoro-Castelazo, Xuan Liu, Anita Lucaci, Margaret Hughes, Jason D. Oliver, Charles Giamberardino, Sayoki Mfinanga, Thomas S. Harrison, John R. Perfect, Tihana Bicanic
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	antifungal resistance antimicrobial resistance cryptococcus fluconazole fungus meningitis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e5efbbfe83444538a96051c24f13cb8a
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spelling	oai:doaj.org-article:e5efbbfe83444538a96051c24f13cb8a2021-11-15T15:54:46ZFluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance10.1128/mBio.02575-192150-7511https://doaj.org/article/e5efbbfe83444538a96051c24f13cb8a2019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02575-19https://doaj.org/toc/2150-7511ABSTRACT Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility, which are associated with the development of aneuploidy. The implications of this phenomenon for pharmacodynamics of fluconazole for cryptococcal meningitis are poorly understood. The pharmacodynamics of fluconazole were studied using a hollow-fiber infection model (HFIM) and a well-characterized murine model of cryptococcal meningoencephalitis. The relationship between drug exposure and both antifungal killing and the emergence of resistance was quantified. The same relationships were further evaluated in a recently described group of patients with cryptococcal meningitis undergoing induction therapy with fluconazole at 800 to 1,200 mg/day. The pattern of emergence of fluconazole resistance followed an “inverted U.” Resistance amplification was maximal and suppressed at ratios of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC:MIC) of 34.5 to 138 and 305.6, respectively. Emergence of resistance was observed in vivo with an fAUC:MIC of 231.4. Aneuploidy with duplication of chromosome 1 was demonstrated to be the underlying mechanism in both experimental models. The pharmacokinetic (PK)-pharmacodynamic model accurately described the PK, antifungal killing, and emergence of resistance. Monte Carlo simulations from the clinical pharmacokinetic-pharmacodynamic model showed that only 12.8% of simulated patients receiving fluconazole at 1,200 mg/day achieved sterilization of the cerebrospinal fluid (CSF) after 2 weeks and that 83.4% had a persistent subpopulation that was resistant to fluconazole. Fluconazole is primarily ineffective due to the emergence of resistance. Treatment with 1,200 mg/day leads to the killing of a susceptible subpopulation but is compromised by the emergence of resistance. IMPORTANCE Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy.William HopeNeil R. H. StoneAdam JohnsonLaura McEnteeNicola FarringtonAnahi Santoro-CastelazoXuan LiuAnita LucaciMargaret HughesJason D. OliverCharles GiamberardinoSayoki MfinangaThomas S. HarrisonJohn R. PerfectTihana BicanicAmerican Society for Microbiologyarticleantifungal resistanceantimicrobial resistancecryptococcusfluconazolefungusmeningitisMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	antifungal resistance antimicrobial resistance cryptococcus fluconazole fungus meningitis Microbiology QR1-502
spellingShingle	antifungal resistance antimicrobial resistance cryptococcus fluconazole fungus meningitis Microbiology QR1-502 William Hope Neil R. H. Stone Adam Johnson Laura McEntee Nicola Farrington Anahi Santoro-Castelazo Xuan Liu Anita Lucaci Margaret Hughes Jason D. Oliver Charles Giamberardino Sayoki Mfinanga Thomas S. Harrison John R. Perfect Tihana Bicanic Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
description	ABSTRACT Cryptococcal meningitis is a lethal disease with few therapeutic options. Induction therapy with fluconazole has been consistently demonstrated to be associated with suboptimal microbiological and clinical outcomes. Exposure to fluconazole causes dynamic changes in antifungal susceptibility, which are associated with the development of aneuploidy. The implications of this phenomenon for pharmacodynamics of fluconazole for cryptococcal meningitis are poorly understood. The pharmacodynamics of fluconazole were studied using a hollow-fiber infection model (HFIM) and a well-characterized murine model of cryptococcal meningoencephalitis. The relationship between drug exposure and both antifungal killing and the emergence of resistance was quantified. The same relationships were further evaluated in a recently described group of patients with cryptococcal meningitis undergoing induction therapy with fluconazole at 800 to 1,200 mg/day. The pattern of emergence of fluconazole resistance followed an “inverted U.” Resistance amplification was maximal and suppressed at ratios of the area under the concentration-time curve for the free, unbound fraction of the drug to the MIC (fAUC:MIC) of 34.5 to 138 and 305.6, respectively. Emergence of resistance was observed in vivo with an fAUC:MIC of 231.4. Aneuploidy with duplication of chromosome 1 was demonstrated to be the underlying mechanism in both experimental models. The pharmacokinetic (PK)-pharmacodynamic model accurately described the PK, antifungal killing, and emergence of resistance. Monte Carlo simulations from the clinical pharmacokinetic-pharmacodynamic model showed that only 12.8% of simulated patients receiving fluconazole at 1,200 mg/day achieved sterilization of the cerebrospinal fluid (CSF) after 2 weeks and that 83.4% had a persistent subpopulation that was resistant to fluconazole. Fluconazole is primarily ineffective due to the emergence of resistance. Treatment with 1,200 mg/day leads to the killing of a susceptible subpopulation but is compromised by the emergence of resistance. IMPORTANCE Cryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it predominantly inhibits growth rather than causing fungal killing. Our work shows that the pattern of fluconazole activity is caused by the emergence of resistance in Cryptococcus not detected by standard susceptibility tests, with chromosomal duplication/aneuploidy as the main mechanism. Resistance emergence is related to drug exposure and occurs with the use of clinically relevant regimens. Hence, fluconazole (and potentially other agents that target 14-alpha-demethylase) is compromised by an intrinsic property that limits its effectiveness. However, this resistance may be potentially overcome by dosage escalation or the use of combination therapy.
format	article
author	William Hope Neil R. H. Stone Adam Johnson Laura McEntee Nicola Farrington Anahi Santoro-Castelazo Xuan Liu Anita Lucaci Margaret Hughes Jason D. Oliver Charles Giamberardino Sayoki Mfinanga Thomas S. Harrison John R. Perfect Tihana Bicanic
author_facet	William Hope Neil R. H. Stone Adam Johnson Laura McEntee Nicola Farrington Anahi Santoro-Castelazo Xuan Liu Anita Lucaci Margaret Hughes Jason D. Oliver Charles Giamberardino Sayoki Mfinanga Thomas S. Harrison John R. Perfect Tihana Bicanic
author_sort	William Hope
title	Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
title_short	Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
title_full	Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
title_fullStr	Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
title_full_unstemmed	Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance
title_sort	fluconazole monotherapy is a suboptimal option for initial treatment of cryptococcal meningitis because of emergence of resistance
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e5efbbfe83444538a96051c24f13cb8a
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Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance

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