Clumping Morphology Influences Virulence Uncoupled from Echinocandin Resistance in \u3cem\u3eCandida glabrata\u3c/em\u3e

Here, we report two paired sets of an index wild-type Candida glabrata bloodstream isolate and subsequent echinocandin-resistant FKS mutant. One paired set exhibited a higher proportion of clumping cells and was more virulent in the invertebrate host Galleria mellonella than the other paired set. No virulence difference between the paired index and FKS strains was observed. These findings imply a potential link of clumping morphology with virulence in C. glabrata that is uncoupled from FKS-mediated echinocandin resistance. IMPORTANCE Candida glabrata is a leading cause of invasive candidiasis. In contrast to other species, it has a high propensity for developing resistance to echinocandins, which are the first-line treatment. Unlike the dimorphic Candida albicans which can grow invasive filamentous hyphae, C. glabrata lacks this ability. Here, we report a link between virulence and clumping cell morphology in two different sets of clinical C. glabrata strains obtained from patients failing echinocandin therapy. One set of paired strains (echinocandin-susceptible and subsequent resistant mutant) had a high proportion of clumping cells in the population and were significantly more virulent than another set which had fewer clumping cells. Additionally, we corroborate that echinocandin resistance does not impart a significant fitness cost. Our findings suggest that clumping morphology may be an important but previously underestimated virulence factor for C. glabrata and also aid our understand for the high prevalence of resistance observed in this species

Innate inflammatory response and immunopharmacologic activity of micafungin, caspofungin, and voriconazole against wild-type and FKS mutant Candida glabrata isolates

The direct or indirect interactions that antifungals have with the host immune response may play a significant role in defining their activity in vivo. However, the impact that acquired antifungal resistance has on the immunopharmacologic activity of antifungals is not well described. We assessed the immunopharmacologic activity of caspofungin, micafungin, and voriconazole among isolates of Candida glabrata with or without FKS-mediated echinocandin resistance. Clinical bloodstream isolates of C. glabrata from patients who did (n = 5) or did not (n = 3) develop persistent candidemia and who did (n = 2) or did not (n = 11) harbor FKS gene mutations were included. A cell-based assay was used to compare differences in macrophage activation among isolates when grown in the presence or absence of subinhibitory concentrations of caspofungin, micafungin, or voriconazole. In the absence of antifungals, macrophage activation was significantly lower for index C. glabrata isolates obtained from persistent candidemia patients than for those from nonpersistent patients (33% versus 79% increase over negative controls, respectively; P < 0.01). Growth of isolates possessing wild-type FKS genes in subinhibitory concentrations of micafungin or caspofungin, but not voriconazole, significantly increased macrophage inflammatory responses compared to untreated controls (1.25- to 2.75-fold increase, P < 0.01). For isolates harboring the FKS2 hot spot 1 (HS1) S663P mutation, however, a significant increase was observed only with micafungin treatment (1.75-fold increase versus negative control, P < 0.01). Macrophage activation correlated with the level of unmasking of \u3b2-glucan in the cell wall. The diminished macrophage inflammatory response to isolates that caused persistent candidemia and differential immunopharmacologic activity of echinocandins among FKS mutants suggest that certain strains of C. glabrata may have a higher propensity for immunoevasion and development of antifungal resistance during treatment

Adjuvant β-lactam therapy combined with vancomycin for methicillin-resistantStaphylococcus aureus bacteremia: does β-lactam class matter?

We analyzed the impact of vancomycin (VAN) combined with adjuvant β-lactam therapy (Combo) on persistent (≥5 days) methicillin-resistant Staphylococcus aureus bacteremia versus VAN alone by using pooled data from two previously published observational studies (n = 156). Combo was inversely associated with persistent bacteremia (adjusted odds ratio, 0.460; 95% confidence interval, 0.229 to 0.923). Acute kidney injury was more common with Combo than with VAN (18.9% and 7.6%, respectively; P = 0.062)