Abstract
Candidemia and other forms of invasive fungal infections caused by Candida glabrata and to a lesser extent Saccharomyces cerevisiae are a serious health problem, especially if their steadily rising resistance to the limited range of antifungal drugs is taken into consideration. Various drug combinations are an attractive solution to the resistance problem, and some drug combinations are already common in the clinical environment due to the nature of diseases or therapies. We tested a few of the common antifungal-immunomodulatory drug combinations and evaluated their effect on selected strains of C. glabrata and S. cerevisiae. The combinations were performed using the checkerboard microdilution assay and interpreted using the Loewe additivity model and a model based on the Bliss independence criterion. A synergistic interaction was confirmed between calcineurin inhibitors (Fk506 and cyclosporine A) and antifungals (fluconazole, itraconazole, and amphotericin B). A new antagonistic interaction between mycophenolic acid (MPA) and azole antifungals was discovered in non-resistant strains. A possible mechanism that explains this is induction of the Cdr1 efflux pump by MPA in C. glabrata ATCC 2001. The Pdr1 regulatory cascade plays a role in overall resistance to fluconazole, but it is not essential for the antagonistic interaction. This was confirmed by the Cgpdr1Δ mutant still displaying the antagonistic interaction between the drugs, although at lower concentrations of fluconazole. This antagonism calls into question the use of simultaneous therapy with MPA and azoles in the clinical environment.
Highlights
The frequency and associated mortality of candidemia and other forms of invasive candidiasis have not decreased over the past two decades despite the introduction of several extended-spectrum triazole and echinocandin antifungal drugs for use in prophylaxis, empiric therapy, and targeted therapy (Pfaller & Diekema, 2007; Pfaller & Castanheira, 2016).How to cite this article Tome et al (2018), Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals against Candida glabrata and Saccharomyces cerevisiae
These were selected from 96 clinical isolates (40 S. cerevisiae and 56 C. glabrata; full list of strains is in Supplemental Information 5) and nine non-clinical S. cerevisiae isolates based on their minimal inhibitory concentrations (MICs) obtained by the reference method for broth dilution antifungal susceptibility testing of yeasts (CLSI M27-A3) (CLSI, 2008)
For most of the immunomodulatory drugs, the concentration range that was used here, and was based on the range expected in human blood after drug administration, did not obtain a MIC; exceptions were some strains with mycophenolic acid (MPA) (Sc3, Sc4, Sc5, Cg2 at 120 mg/l) and Fk506 (Sc4, Sc6 at 200 mg/l)
Summary
The frequency and associated mortality of candidemia and other forms of invasive candidiasis have not decreased over the past two decades despite the introduction of several extended-spectrum triazole and echinocandin antifungal drugs for use in prophylaxis, empiric therapy, and targeted therapy (Pfaller & Diekema, 2007; Pfaller & Castanheira, 2016).How to cite this article Tome et al (2018), Synergistic and antagonistic effects of immunomodulatory drugs on the action of antifungals against Candida glabrata and Saccharomyces cerevisiae. The frequency and associated mortality of candidemia and other forms of invasive candidiasis have not decreased over the past two decades despite the introduction of several extended-spectrum triazole and echinocandin antifungal drugs for use in prophylaxis, empiric therapy, and targeted therapy (Pfaller & Diekema, 2007; Pfaller & Castanheira, 2016). Candida albicans is the dominant pathogen, but the incidence of invasive infections caused by Candida glabrata has been steadily rising (Pfaller et al, 2012b; Pfaller et al, 2014). C. glabrata even surpasses C. albicans as the leading pathogen; these include patients with hematologic malignancies, diabetes mellitus, and patients with an abdominal source of infection (Hachem et al, 2008; Segireddy et al, 2011; Khatib et al, 2016; Whaley & Rogers, 2016). The reasons for the rise of C. glabrata infections include the introduction of fluconazole in 1990 and its widespread prophylactic use against fungal infections (Berrouane, Herwaldt & Pfaller, 1999), a higher rate of antifungal use and intrinsic or acquired resistance of C. glabrata to both fluconazole and echinocandins (Silva et al, 2012; Pfaller et al, 2012a; Alexander et al, 2013; Pfaller & Castanheira, 2016; Colombo, Júnior & Guinea, 2017), and better identification of non-albicans species in the clinic (Liguori et al, 2009)
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