The terms resistance, tolerance, persistence and heteroresistance have been used very generally in the current literature to describe the ability of an organism to survive and grow in the presence of an antimicrobial drug. Furthermore, clinical failures are often due to non-resistant (susceptible) strains that persist in vivo and likely seed recurrent infections. Resistance is heritable, with growth of ~ all cells in the population up to a given drug concentration. Studies in bacteria have started to define tolerance and persistence much more precisely. By contrast, the use of these terms remains very vague in studies of fungal pathogens such as Candida species. Within different Candida albicans isolates we detect different degrees of subpopulations of cells that grow slowly but consistently in drug. We developed and adapted assays to measure this subpopulation and, based on its growth dynamics, we call it "Perseverance". Perseverence is slow, steady growth in drug that is seen for >10% of the population, is concentration-independent, but time-dependent. Furthermore, and in contrast to tolerance in bacteria, these subpopulations exhibit shorter lag times in drug relative to sensitive strains. The degree to which high perseverence is connected to the rate of appearance of frank resistance will be presented.
By contrast, in Candida glabrata, we find that clinical strains exhibit hetero-resistance, in which very small subpopulations (<0.1%) survive in drug. Hetero-resistance is also heritable and it allows subpopulations of a clinical strain to persist in the host. Furthermore, genomic analysis indicates that different subpopulations exhibit different gene expression profiles.
Importantly, clinical assays currently measure neither persistance or hetero-resistance and thus these properties of strains are not considered in clinical decisions. We suggest that perseverance and hetero-resistance are important parameters contributing to the evolution of resistance and thus the persistence and recurrence of and infection, which must be considered in the clinical setting. .