SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

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

Hope, W; Stone, NRH; Johnson, A; McEntee, L; Farrington, N; Santoro-Castelazo, A; Liu, X; Lucaci, A; Hughes, M; Oliver, JD; et al. Hope, W; Stone, NRH; Johnson, A; McEntee, L; Farrington, N; Santoro-Castelazo, A; Liu, X; Lucaci, A; Hughes, M; Oliver, JD; Giamberardino, C; Mfinanga, S; Harrison, TS; Perfect, JR; Bicanic, T (2019) Fluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of Resistance. MBio, 10 (6). ISSN 2150-7511 https://doi.org/10.1128/mBio.02575-19
SGUL Authors: Harrison, Thomas Stephen

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (2MB) | Preview

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.

Item Type: Article
Additional Information: © 2019 Hope et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/).
Keywords: antifungal resistance, antimicrobial resistance, cryptococcus, fluconazole, fungus, meningitis, yeast, antifungal resistance, antimicrobial resistance, cryptococcus, fluconazole, fungus, meningitis, yeast, 0605 Microbiology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: MBio
ISSN: 2150-7511
Language: eng
Dates:
DateEvent
3 December 2019Published
23 October 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
097377/Z/11/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 31796539
Web of Science ID: WOS:000500484800023
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111559
Publisher's version: https://doi.org/10.1128/mBio.02575-19

Actions (login required)

Edit Item Edit Item