Defining the frontiers between antifungal resistance, tolerance and the concept of persistence

Trailing growth depends on growth conditions; clinical isolates differ in this sensitivity, causing substantial variation between laboratories in its measurement.

“Like tolerance, trailing growth is sensitive to growth conditions17–19; the degree of sensitivity to these conditions differs for different clinical isolates9,(reviewed in 20), and leads to considerable laboratory-to-laboratory variation in the estimation of trailing growth.”

MIC measurements have been optimized to minimize or ignore residual fungal growth, termed tolerance or trailing growth, which is detected in 25-60% of clinical isolates.

“MIC measurements have been optimized to minimize or ignore residual fungal growth 4,18 , termed”

Antifungal tolerance and persistence are often overlooked in clinical practice.

“However, antifungal tolerance and persistence are often overlooked [17,47].”

Because azoles are fungistatic to most yeast pathogens, it is challenging to determine whether azole tolerance is associated with persistence or with inherent properties of the drug itself.

“Given that azoles are fungistatic to most yeast pathogens, it can be challenging to determine whether azole tolerance is associated with persistence or the inherent properties of the drug itself [17].”

Antifungal persistence is non-heritable, although progeny of persisters may still divide into persistent and non-persistent subpopulations.

“Thirdly, antifungal persistence is non-heritable, although the progeny of persisters may still divide into persistent subpopulations and non-persistent subpopulations.”

Persistent strains require longer MDK99.99 because a persistent subpopulation emerges and maintains viability.

“Over time, the persistent subpopulation emerges and maintains viability, leading to longer minimum treatment durations required for 99.99% population eradication (MDK99.99) [15,17,20,21] (Fig 1).”

Antifungal persistence is a heterogeneous trait in which only a small fraction of the population, generally much less than 1%, survives drug exposure, while the majority of non-persistent cells are rapidly killed.

“Antifungal persistence is a heterogeneous trait, where only a small fraction of the population (generally <<1%) is able to survive drug exposure, while the majority of non-persistent cells are rapidly killed by the treatment.”

Fungal persisters exhibit a powerful antioxidant system to cope with the challenge of ROS produced by drugs or the host environment.

“Above all, fungal persisters exhibit a powerful antioxidant system to cope with the challenge of ROS produced by drugs or host environment [17].”

The reversible nature of heteroresistance distinguishes it from conventional resistance, suggesting a non-stably heritable, potentially adaptive basis.

“The reversible nature of HR distinguishes it from conventional resistance [11], suggesting a non‐stably heritable, potentially adaptive basis.”

Infection outcomes are influenced by host factors as well as features of the pathogen that are not reflected by the MIC.

“This implies that infection outcomes are influenced by host factors as well as features of the pathogen that are not reflected by the MIC 5,6 .”

Antifungal resistance is linked to specific molecular mechanisms and can be stably inherited by progeny.

“In contrast, resistance is linked to specific molecular mechanisms and can be stably inherited by progeny [15,17–19].”

In time-kill assays, persistent and susceptible strains take similar time to reach MDK99.

“Persistent strain and susceptible strain take similar time to reach the minimum duration of treatment that kills 99% of the population (MDK99), because initially most of the persistent strain population is susceptible to antifungal treatment and is eliminated in a manner similar to a susceptible strain.”

Tolerance is reversible and results from epigenetic mechanisms, while resistance is an inheritable property determined by genes and their mutations.

“Furthermore, tolerance is reversible and results from epigenetic mechanisms, while resistance is an inheritable property determined by genes and their mutations [139].”

Trailing growth phenomenon is related to azole tolerance and has been well documented in C. albicans.

“The ‘trailing growth’ phenomenon, describing the residual population of cells that grow at supra-MIC levels observed in broth dilution assays, can be considered related to azole tolerance and has been well documented in C. albicans.”