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

Abstract

BackgroundIntra-abdominal candidiasis (IAC) is a prominent invasive fungal infection associated with high mortality. Prompt antifungal therapy and source control are crucial for successful treatment. Echinocandin antifungal drugs are first-line agents. Yet, their clinical effectiveness is highly variable with known potential for breakthrough resistance, and little is known about drug exposure at the site of infection. Using matrix-assisted desorption/ionization (MALDI) mass spectrometry imaging as well as standard analytical techniques, we investigated the spatial and quantitative distribution in tissue lesions for two echinocandin drugs, micafungin and CD101, in a clinically relevant IAC mouse model.MethodsFemale 6–8 week old CD1 mice weighing 18–22 g were infected intraperitoneally (IP) with 1 × 107 CFU of C. albicans SC5314 mixed with sterile stool matrix. Single IP doses of CD101 at 5 or 20 mg/kg (equivalent to humanized therapeutic dose) or micafungin at 5 mg/kg (therapeutic dose) were administered to mice at day 3 post-inoculation. Mice were sacrificed at just before antifungal treatment (n= 1), and at 1, 3, 6, 24, and 48 hours post-dose (n = 3 per group per time point). Liver and kidney lesions were collected for MALDI imaging. Laser capture microdissection (LCM) followed by liquid chromatography coupled tandem mass spectrometry (LC/MS-MS) was applied to 6 and 24 hours samples for drug exposure measurement. In a separate experiment, mice were treated with 2 or 3 doses of micafungin (5 mg/kg), or a single dose of CD101 (20 mg/kg). Drug accumulation was analyzed at 48 and 72hours post the first dose.ResultsDrug accumulation within lesions was observed with both drugs at their humanized therapeutic dose. However, micafungin, even at steady-state, failed to approach the mutant prevention concentration (MPC) (16 µg/mL) of the infecting strain. CD101 demonstrated extensive penetration into the lesions after a single dose administration and persisted in lesions at above MPC level of 29.7 µg/mL at 72 hours postdose.ConclusionThese findings indicate that current echinocandin drugs may be limited by penetration at the site of infection, which have implications for clinical outcomes and emergence of resistance in patients with IAC.Disclosures C. J. Clancy, Merck: Received research funding, Research support; Astellas: Received research funding, Research support; Cidara: Received research funding, Research support; Astellas: Scientific Advisor, Advisory board; Merck: Scientific Advisor, Advisory board; Cidara: Scientific Advisor, Advisory board; Medicines Company: Scientific Advisor, Advisory board; D. Perlin, Cidara: Research Contractor and Scientific Advisor, Research grant; Amplyx: Research Contractor and Scientific Advisor, Research grant; Matinas: Scientific Advisor, Research support; Scynexis: Research Contractor and Scientific Advisor, Research grant; Merck: Research Contractor, Research grant; Astellas: Research Contractor, Research grant

Elevated Vacuolar Uptake of Fluorescently Labeled Antifungal Drug Caspofungin Predicts Echinocandin Resistance in Pathogenic Yeast

“…29−32 This may be due their hydrophobicity and differences in the distribution of these drugs at different infection sites. 33,34 Other possible explanations for efficacy limitations and the continued appearance of echinocandin-tolerant and resistant isolates have not been ruled out. Here, we investigated the mechanisms and dynamics with which echinocandins enter the yeast cells of Candida and the relationship between drug uptake and antifungal activity.…”

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy

“…16 The PK/ PD profile of rezafungin, namely its high plasma drug exposure and wide safety margin, may also be relevant to preventing resistance, as postulated by the mutant selection window hypothesis and mutant prevention concentration (MPC; the minimal concentration of a drug that inhibits development of mutant subpopulations) determined for rezafungin. 15 While prevention of resistance remains hypothetical, PK/PD determinants of efficacy clearly favor the ability to readily achieve and safely maintain high levels of drug in plasma.…”

“…[9][10][11][12] Recent studies have evaluated pharmacokinetic/pharmacodynamic (PK/PD) factors relating to rezafungin efficacy. 11,[13][14][15] The PK/PD index of AUC/MIC for rezafungin correlated well with efficacy and, compared with other echinocandins, rezafungin had lower PK/PD target exposures against Candida spp., including strains with resistance or reduced susceptibility to echinocandins. 11 While C max also predicted rezafungin efficacy, AUC was selected as it is more reliably measured.…”

“…The in vivo efficacy of rezafungin reported herein against azole-resistant C. albicans (R357) expands the database on rezafungin against less susceptible and resistant Candida spp., 11,12,15 including the inherently multidrug-resistant and difficult-to-treat Candida auris (Table 1). 9,10,[26][27][28][29] O RCI D Voon Ong https://orcid.org/0000-0001-8676-6717…”

“…14 Rezafungin also demonstrated extensive distribution to tissue and penetration at the site of infection, as compared with micafungin in an intra-abdominal abscess candidiasis mouse model. 15 A series of in vivo studies using a mouse model of disseminated candidiasis were conducted to further evaluate rezafungin efficacy:…”