Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model

Zhao, Yanan; Prideaux, Brendan; Nagasaki, Yoji; Lee, Min Hee; Chen, Pei-Yu; Blanc, Landry; Ho, Hsinpin; Clancy, Cornelius J.; Nguyen, M. Hong; Dartois, Véronique; Perlin, David S.

doi:10.1128/aac.01009-17

Cited by 82 publications

(81 citation statements)

References 42 publications

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“…Our data suggest that caspofungin MPCs exceed clinically achievable levels at these sites, whereas anidulafungin and micafungin MPCs are lower. New technology such as matrix-assisted laser desorption/ionization mass spectrometry imaging now allow the visualization of drug disposition within target organs (25). Using a murine model of IAC, we demonstrated that micafungin is quickly distributed into liver and kidney tissue, but the drug concentrates around the outer rim, rather than inside, fungal lesions.…”

Section: Discussionmentioning

confidence: 95%

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Shields

Kline

Healey

et al. 2019

Antimicrob Agents Chemother

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Echinocandins are front-line agents for treatment of invasive candidiasis. There are no reported agent-specific differences in Candida mutational frequency of resistance or propensity to develop FKS mutations. The objective of this study was to measure spontaneous and FKS mutation rates among Candida glabrata strains. Twenty bloodstream isolates from patients with or without prior echinocandin exposure were included. Minimum inhibitory concentrations (MICs), minimum fungicidal concentrations (MFCs), and mutation prevention concentrations were higher for caspofungin than for anidulafungin (P < 0.0001) and micafungin (P < 0.0001). Mutational frequencies of resistance at 3× the baseline MIC were highest for caspofungin and lowest for micafungin. A total of 247 isolates were recovered at or above the MFC for caspofungin (n = 159), anidulafungin (n = 74), or micafungin (n = 14). Agent-specific MIC increases were noted for anidulafungin and caspofungin, but not micafungin. Thirty-three percent of isolates harbored hot spot mutations in FKS1 (n = 6) or FKS2 (n = 76). Mutations at the Ser629 (Fks1) or Ser663 (Fks2) loci were more common after selection with anidulafungin or micafungin than with caspofungin (P = 0.003). Four isolates demonstrated >4-fold increases in MICs without FKS hot spot mutations; three of these harbored Fks2 mutations upstream of hot spot 1. The final isolate was FKS1 and FKS2 wild-type, but the 50% inhibitory concentrations of caspofungin and micafungin were increased 2.7- and 8-fold, respectively. In conclusion, micafungin may be superior in vitro to the other agents in limiting the emergence of resistance among C. glabrata. Caspofungin exposure may be most likely to promote resistance development. These data provide a foundation for future investigations of newly developed echinocandin agents.

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Section: Discussionmentioning

confidence: 95%

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Shields

Kline

Healey

et al. 2019

Antimicrob Agents Chemother

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“…The methodology is tremendously powerful since it can be applied to any small molecule drug used in any disease state. Indeed, we have recently quantified an antifungal drug candidate in a mouse model of abdominal candidiasis 14 . Differential drug partitioning into heterogeneous tumor compartments (including necrotic cores) is a primary concern in the treatment of cancer, and a critical area of research in cancer drug discovery 15 .…”

Section: Discussionmentioning

confidence: 99%

Spatial Quantification of Drugs in Pulmonary Tuberculosis Lesions by Laser Capture Microdissection Liquid Chromatography Mass Spectrometry (LCM-LC/MS)

Zimmerman

Blanc

Chen

et al. 2018

JoVE

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Tuberculosis is still a leading cause of morbidity and mortality worldwide. Improvements to existing drug regimens and the development of novel therapeutics are urgently required. The ability of dosed TB drugs to reach and sterilize bacteria within poorly-vascularized necrotic regions (caseum) of pulmonary granulomas is crucial for successful therapeutic intervention. Effective therapeutic regimens must therefore contain drugs with favorable caseum penetration properties. Current LC/MS methods for quantifying drug levels in biological tissues have limited spatial resolution capabilities, making it difficult to accurately determine absolute drug concentrations within small tissue compartments such as those found within necrotic granulomas. Here we present a protocol combining laser capture microdissection (LCM) of pathologically-distinct tissue regions with LC/MS quantification. This technique provides absolute quantification of drugs within granuloma caseum, surrounding cellular lesion and uninvolved lung tissue and, therefore, accurately determines whether bactericidal concentrations are being achieved. In addition to tuberculosis research, the technique has many potential applications for spatially-resolved quantification of drugs in diseased tissues.

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“…FKS mutations that impart echinocandin resistance has been reported to also impact rezafungin MICs, although not in all isolates. Broad cross-resistance was seen between rezafungin, caspofungin, and anidulafungin, although rezafungin's "front-loaded" dosing regimen utilized in studies is suggested to lower development of resistance [16]. In vitro studies have also found rezafungin to have potent activity against C. auris, superior to both caspofungin and micafungin [17].…”

Section: Rezafunginmentioning

confidence: 99%

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

Gintjee

Donnelley

Thompson

2020

JoF

170

161

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Invasive fungal infections are associated with significant morbidity and mortality, and their management is restricted to a variety of agents from five established classes of antifungal medication. In practice, existing antifungal agents are often constrained by dose-limiting toxicities, drug interactions, and the routes of administration. An increasing prevalence of invasive fungal infections along with rising rates of resistance and the practical limitations of existing agents has created a demand for the development of new antifungals, particularly those with novel mechanisms of action. This article reviews antifungal agents currently in various stages of clinical development. New additions to existing antifungal classes will be discussed, including SUBA-itraconazole, a highly bioavailable azole, and amphotericin B cochleate, an oral amphotericin formulation, as well as rezafungin, a long-acting echinocandin capable of once-weekly administration. Additionally, novel first-in-class agents such as ibrexafungerp, an oral glucan synthase inhibitor with activity against various resistant fungal isolates, and olorofim, a pyrimidine synthesis inhibitor with a broad spectrum of activity and oral formulation, will be reviewed. Various other innovative antifungal agents and classes, including MGCD290, tetrazoles, and fosmanogepix, will also be examined.

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Unraveling Drug Penetration of Echinocandin Antifungals at the Site of Infection in an Intra-abdominal Abscess Model

Cited by 82 publications

References 42 publications

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Spontaneous Mutational Frequency and FKS Mutation Rates Vary by Echinocandin Agent against Candida glabrata

Spatial Quantification of Drugs in Pulmonary Tuberculosis Lesions by Laser Capture Microdissection Liquid Chromatography Mass Spectrometry (LCM-LC/MS)

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

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