Bacteria and fungi share some common mechanisms of resistance to drugs used in treatment of bacterial or fungal infection. However, bacteria have a resistance mechanism not described in fungi. This mechanism is
(See the below table for further information). Several mechanisms of resistance to antifungal drugs have been identified. These include alterations in the drug target by mutation or overexpression, drug efflux pumps, changes in ergosterol or sterol content, and changes in uptake and metabolism. Alteration of the drug either through modification or degradation to inactive moieties has not been reported. Resistance to tolnaftate and allylamines that inhibit squalene epoxidase is not common but likely mechanisms include efflux pumps, mutation or overexpression of the enzyme and nonspecific stress adaptation. Resistance to flucytosine may occur via alteration of the permease that reduces entry into the fungal cell or at enzymatic steps, cytosine deaminase or uracil phosphoribosyl transferase, involved in metabolism of the drug to the active compounds. Resistance to azole class drugs may develop through expression of drug efflux pumps and alteration or over-expression of the drug target. In some resistant isolates, more than one mechanism may be operative. Resistance to polyenes may reflect a decrease in ergosterol content of the membrane or production of other non-polyene binding sterols.SELECTED ANTIFUNGAL DRUGS, MODE OF ACTION AND MECHANISMS OF RESISTANCEAntifungal AgentRouteMode of ActionMechanism(s) of ResistanceTolnaftate TopicalInhibition of squalene epoxidase. (enzyme in the ergosterol biosynthesis pathway)Resistant isolates very rare; likely mechanisms include efflux pumps, mutation, or over expression target, nonspecific stress adaptationAllylamines NaftifineTopicalTerbinafineOral, topicalFlucytosine (5-flurocytosine)OralInhibition of DNA and RNA synthesisChange in permease, cytosine deaminase, or uracil phosphoribosyl transferase activityEchinocandins AnidalufunginIVInhibition of fungal cell wall glucan synthesisMutation in subunit b-l,3-glucan synthaseCaspofunginMicafunginAzoles Ketoconazole TopicalInhibits a cytochrome P450 enzyme 14-a-demethylase (enzyme in the ergosterol biosynthesis pathway)Mutation or overexpression of 14-a-demethylase Clotrimazole, bifonazole, econazole, miconazole, oxiconazole, sulconazole, terconazole, tioconazoleoral TopicalOverexpression of drug efflux pump(s)FluconaozleOral, IVItraconazoleOral, IVPosaconazoleOralVoriconazoleOral, IVPolyenes AmphotericinIVMain mechanism binds to ergosterol creating channels resulting in metabolite leakageAlteration or decrease in ergosterol contentNatamycinTopical (eye)NystatinTopical, oralOxidative pathways may enhance activityGriseofulvinOralActs on microtubules and interferes mitosis/cell divisionPutative mechanism drug efflux
Alteration in the drug target
Efflux of drug
Inactivation of drug
Influx of drug
Mycology