Resistance to Antifungal Agents

RESISTANCE TO ANTIFUNGAL AGENTS

Definition of Resistance

The concepts, definitions, and laboratory methods described for bacterial resistance are generally applicable to fungi. Quantitative susceptibility is measured by the minimal inhibitory concentration (MIC) under conditions that favor the growth of fungi. The diversity of growth rates and metabolic activity in the various fungi has made appli-cation of the MIC to therapy more difficult than in bacteria. The MICs performed in dif-ferent types of fungal growth media can vary as much as 1000-fold. Although which medium is “right” cannot be determined, there has now been agreement on a standardized broth dilution method so experimental and clinical results can be reliably compared. Most of this work is with yeasts; molds are more difficult to work with and not suited to testing in broth. As with bacteria, fungi with MICs in the pharmacologically achievable range may or may not be clinically susceptible. Because of the variables cited above, high MICs do not predict resistance with the same certainty they do with bacteria. For these reasons, antifungal susceptibility testing is still considered investigational and not offered in hospi-tal laboratories.

Mechanisms of Resistance

The cell wall and cytoplasmic membrane present a barrier for antifungal agents to access the fungal interior. While this is generally considered a mechanism of innate resistance, there have been examples in which changes in membrane sterols appear to have restricted perme-ability to azoles. 5FC requires entry of a permease into the cell, and the absence of this en-zyme is a significant mechanism of acquired resistance. Energy-requiring efflux pumps, which remove the drug from the cytoplasm, appear to be an even more important mecha-nism of resistance with the azoles. The efflux mechanism may confer resistance to multiple agents, and the mechanisms and genes involved are similar to the human P-glycoprotein pump associated with resistance to antineoplastic chemotherapeutics.

Alterations in the target of the antifungal agent are an important means of acquired re-sistance. Although resistance to polyenes is rare, it has been traced to the appearance in the cytoplasmic membrane of sterols that have a decreased affinity for these agents. The production of cytochrome demethylases with lower affinity for azoles is also associated with resistance. Other mechanisms of resistance involve the absence or overproduction of crucial enzymes. Isolates resistant to 5FC lack either the permease or the cytosine deami-nase that converts it to its active form. Resistance to both azoles and allylamines has been associated with overproduction of their target enzymes. It is surprising that enzymatic inactivation, the most potent bacterial resistance mechanism, is not important for any of the antifungals in current use.