Candidemia, intra-abdominal candidiasis (IAC) and other deeply invasive diseases caused by Candida spp. are the leading fungal infections in U.S. hospitals. Echinocandin antifungals are agents of choice against most types of invasive candidiasis. Nevertheless, treatment failures occur in up to 40% of cases, and echinocandin resistance is evident among 8-18% of Candida glabrata strains at some centers. The data suggest that echinocandin delivery to tissue sites of infection is often insufficient to eliminate . glabrata or suppress emergence of resistance. In both mouse models and humans, Candida invasion of tissues from the bloodstream or peritoneal cavity typically culminates in abscess formation, which limits access of antifungal agents. There are limited data on echinocandin pharmacokinetics-pharmacodynamics (PK-PD) within Candida-infected tissues, and no PK-PD data from within abscesses. Site-specific PK-PD studies are now feasible using an innovative strategy that combines quantification of antimicrobial concentrations within tissues by HPLC tandem mass spectrometry (HPLC-MS/MS) and mapping of unlabeled drug distribution within pathologic lesions by MALDI mass spectrometry imaging (MALDI-MSI). In the present project, we will employ these techniques to study PK-PD of micafungin (the most commonly used echinocandin in the U.S.) within abscesses recovered from a newly-developed mouse model of C. glabrata IAC. We hypothesize that conventional micafungin doses are ineffective at treating C. glabrata IAC due to poor penetration into abscesses. First, we will define micafungin PK and distribution within C. glabrata-infected abscesses from mice with IAC using HPLC-MS/MS and MALDI-MSI, respectively. C. glabrata cells will be co-localized with micafungin by histopathologic staining. We will use results to predict micafungin regimens that are likely to attain PK-PD targets and effectively treat mice with C. glabrata IAC. Second, we will validate our predictions by testing micafungin dosing regimens against IAC caused by different C. glabrata strains, and measuring antifungal activity and emergence of resistance within abscesses. Results will demonstrate whether micafungin dose escalation improves outcomes against IAC caused by at least some C.glabrata strains. To accomplish our aims, we have assembled a research team of internationally-recognized investigators with a history of collaboration, and expertise in mouse models and molecular pathogenesis of candidiasis, antifungal drug resistance and PK-PD, and HPLC-MS/MS and MALDI-MSI techniques. This will be the first study to define the value and limitations of an echinocandin in treating either IAC or abscesses. By using cutting-edge technologies and a novel, clinically-relevant mouse model, we will generate data that will not be obtained in other studies, and that will have far-reaching implications for designing more effective treatment strategies against various types of invasive candidiasis in humans.

Public Health Relevance

Echinocandins are drugs of choice against invasive Candida infections, but treatment failures are common and resistance is emerging. There are limited data on echinocandin pharmacokinetics and pharmacodynamics (PK-PD) at tissue sites of invasive candidiasis, and no PK-PD data from within pathologic lesions like abscesses. We will use new technologies to measure PK and image micafungin (the most commonly used echinocandin) within abscesses recovered from mice with intra-abdominal candidiasis due to Candida glabrata. We will then perform PD studies in mice to validate micafungin regimens that are predicted to reduce C. glabrata burdens and suppress resistance. Results will be used to develop improved treatment strategies.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI121555-02
Application #
9197946
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Franceschi, Francois J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213