Antifungal Resistance
| Term | Meaning |
|---|---|
| Intrinsic (primary) resistance | A property of the species, present before any exposure (for example Candida krusei to fluconazole, Cryptococcus to echinocandins, Mucorales to voriconazole, Aspergillus terreus to amphotericin B, Scedosporium species to amphotericin B) |
| Acquired (secondary) resistance | Arises in a previously susceptible isolate through mutation or gene regulation, under drug pressure in the patient or in the environment |
| Microbiological resistance | An MIC above the clinical breakpoint or above the epidemiological cut off value (a wild type distribution marker, which flags non wild type isolates with acquired mechanisms even when no clinical breakpoint exists) |
| Clinical resistance | Treatment failure despite appropriate dosing; it depends on drug exposure, host immunity, site of infection, source control, and the organism |
| Tolerance | Slow growth or survival at drug concentrations above the MIC, without a change in the MIC itself; a contributor to persistence and relapse |
| Heteroresistance | A resistant subpopulation within an apparently susceptible population |
| Cross resistance | Resistance to one drug that confers resistance to others of the same class (azoles) or sharing a target |
| Multidrug resistance | Resistance to two antifungal classes; pan resistance is resistance to all available classes |
| Breakpoint | The MIC value separating isolates likely to respond (susceptible) from those unlikely to respond (resistant), set from MIC distributions, pharmacokinetic and pharmacodynamic data, and clinical outcomes |
| Factor | Consequence |
|---|---|
| Few drug classes | Only four systemic classes (polyenes, azoles, echinocandins, flucytosine) are in general use, so resistance to one class removes a large part of the options |
| Eukaryotic targets | Fungal and human cells share biochemistry, which limits selective targets and lowers the therapeutic index |
| Fungistatic activity | Azoles are fungistatic against yeasts, which favours persistence and selection of resistant clones |
| Environmental exposure | Agricultural azole fungicides select resistance in environmental moulds |
| Immunosuppressed hosts | Prolonged exposure, poor immune clearance, and biofilm growth increase selection |
| Diagnostic gaps | Susceptibility testing is not routine in many centres, and for many species breakpoints do not exist |
| Prophylaxis | Widespread azole and echinocandin prophylaxis shifts species distribution (for example towards Candida glabrata and Candida auris) |
| Healthcare transmission | Candida auris spreads between patients and carries multidrug resistance |
Overview
| Mechanism | Examples |
|---|---|
| Target alteration | Point mutations in ERG11 (yeasts) or cyp51A (Aspergillus) for azoles; FKS1 and FKS2 hot spot mutations for echinocandins; SQLE mutations for terbinafine; FCY1, FCY2, and FUR1 mutations for flucytosine |
| Target overexpression | ERG11 up regulation through gain of function mutations in the transcription factor UPC2; tandem repeats in the cyp51A promoter (TR34, TR46) |
| Efflux pump overexpression | ATP binding cassette transporters (CDR1, CDR2) and major facilitator superfamily transporters (MDR1), driven by gain of function mutations in the transcription factors TAC1 (CDR1 and CDR2) and MRR1 (MDR1) in Candida, and by atrF and AfuMDR pumps in Aspergillus |
| Altered sterol pathway | Loss of function mutations in ERG3 (no toxic sterol is made, so azole exposure is tolerated and cross resistance to polyenes may arise through reduced ergosterol); ERG2, ERG6, and ERG11 changes in polyene resistance |
| Chromosomal change | Aneuploidy (isochromosome 5L in Candida albicans raises ERG11 and TAC1 dosage) and loss of heterozygosity |
| Stress responses | Calcineurin, heat shock protein 90, and cell wall integrity pathways support tolerance to azoles and echinocandins |
| Biofilm formation | Matrix beta 1,3 glucan binds drug, persister cells, and upregulated pumps give high resistance to azoles, polyenes, and echinocandins |
| Cell wall remodelling | Chitin up regulation compensates for glucan loss under echinocandins |
| Hypermutation | Mismatch repair gene defects (MSH2 in Candida glabrata) raise the mutation rate and the chance of multidrug resistance |
| Drug uptake and activation | Reduced permeases and enzymes needed to activate flucytosine |
Class specific mechanisms
| Class | Principal mechanisms | Typical organisms and comments |
|---|---|---|
| Azoles | ERG11 or cyp51A mutations; target overexpression; efflux pumps; ERG3 loss; biofilm; aneuploidy | Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata (PDR1 mutations raising CDR1, CDR2, and SNQ2), Candida auris, Aspergillus fumigatus (TR34/L98H, TR46/Y121F/T289A), Cryptococcus (heteroresistance), dermatophytes |
| Echinocandins | FKS1 and FKS2 hot spot mutations (for example S645P in Candida albicans and Candida auris, S663P in Candida glabrata) reduce enzyme sensitivity 10 to 100 fold; adaptive stress responses | Candida glabrata (most frequent), Candida auris, Candida albicans, Candida tropicalis; emerges after prolonged exposure; intrinsic reduced susceptibility in Candida parapsilosis, Candida guilliermondii (FKS polymorphism) and Candida kefyr |
| Polyenes | Reduced or altered ergosterol (ERG2, ERG3, ERG6, ERG11 mutations), increased catalase activity and oxidative stress defence, and membrane changes | Rare in Candida; intrinsic in Aspergillus terreus, Scedosporium, Lomentosporium prolificans, Fusarium solani species complex (variable), Candida lusitaniae (variable), Candida auris (some isolates), and Trichosporon |
| Flucytosine | Loss of cytosine permease (FCY2), cytosine deaminase (FCY1), or uracil phosphoribosyltransferase (FUR1) | Rapid emergence in monotherapy; resistance in Candida albicans is mostly through FUR1 mutations |
| Terbinafine | SQLE point mutations (F397L, L393F or S, F415S, H440Y); efflux | Trichophyton rubrum, Trichophyton indotineae (a rapidly spreading cause of recalcitrant tinea), Trichophyton mentagrophytes genotype VIII |
| Griseofulvin | Poorly characterised; tubulin and efflux | Clinical failures in Trichophyton tonsurans and Microsporum |
| Ibrexafungerp | Overlapping FKS mutations, with some cross resistance to echinocandins | Many echinocandin resistant isolates remain susceptible to ibrexafungerp, but not all |
| Pathogen | Resistance pattern | Notes |
|---|---|---|
| Candida albicans | Low rates of azole and echinocandin resistance (under 2 percent in most surveillance) | Fluconazole resistance occurs after prolonged exposure in HIV (oropharyngeal and oesophageal disease) and is mediated by pump overexpression and ERG11 changes |
| Candida glabrata (Nakaseomyces glabratus) | Dose dependent susceptibility to fluconazole (intrinsically reduced), acquired azole cross resistance through PDR1, and echinocandin resistance in 3 to 10 percent or more of invasive isolates in some centres | Hypermutator strains with MSH2 defects; multidrug resistance is described; prior echinocandin exposure is a risk factor |
| Candida krusei (Pichia kudriavzevii) | Intrinsic fluconazole resistance, with reduced itraconazole and flucytosine susceptibility | Voriconazole is active in most isolates; echinocandins and amphotericin B are active |
| Candida parapsilosis | Rising fluconazole resistance (ERG11 Y132F, with clonal outbreaks in some regions), and intrinsically higher echinocandin MICs | Outcomes on echinocandins remain acceptable in most data; fluconazole resistant clonal outbreaks are a concern in neonatal and intensive care settings |
| Candida tropicalis | Azole resistance through ERG11 and UPC2 mutations, with cross resistance to all azoles in some isolates | Rising in South and East Asia |
| Candida auris | Fluconazole resistance in over 90 percent of isolates, amphotericin B resistance in 10 to 30 percent (varies by clade), echinocandin resistance in 2 to 5 percent or more, and pan resistance reported | Clade differences (clade I South Asian and clade III African isolates generally have the highest fluconazole resistance; clade II East Asian isolates less so); efflux (CDR1, MDR1), ERG11 (Y132F, K143R, F126L, VF125AL), and FKS1 (S639F, S639P) |
| Candida lusitaniae | Variable amphotericin B resistance (ERG6 changes) | Susceptibility testing is advised before choosing amphotericin B |
| Cryptococcus | Intrinsic resistance to echinocandins; heteroresistance to fluconazole (ERG11 duplication, disomy of chromosome 1, and efflux); clinical relapse during fluconazole monotherapy | Combination induction with flucytosine reduces relapse; in vitro resistance to flucytosine appears rapidly in monotherapy |
| Aspergillus fumigatus | Azole resistance through cyp51A alterations (TR34/L98H, TR46/Y121F/T289A, G54, M220, and others), more than 10 percent of isolates in some regions of Europe, Asia, and the Middle East | Environmental selection by agricultural azole fungicides, and also arises in patients on prolonged therapy (cavitary disease); a pan azole resistant phenotype is typical for TR34 and TR46 |
| Aspergillus terreus | Intrinsic amphotericin B resistance | Voriconazole and echinocandins are used |
| Aspergillus flavus | Reduced amphotericin B susceptibility in some isolates | Voriconazole remains first line |
| Cryptic Aspergillus species (Aspergillus lentulus, Aspergillus calidoustus, Aspergillus udagawae) | Reduced susceptibility to azoles, amphotericin B, or both | Not separable by morphology; need sequencing |
| Mucorales | Intrinsic resistance to voriconazole, echinocandins, and fluconazole; variable posaconazole and isavuconazole MICs | Liposomal amphotericin B is the first line; some isolates have high amphotericin B MICs (Cunninghamella, Apophysomyces) |
| Fusarium | Resistance to many drugs, with species complex variation in susceptibility (Fusarium solani species complex has the highest resistance) | Voriconazole, liposomal amphotericin B, or both |
| Scedosporium and Lomentosporium prolificans | Intrinsic resistance to amphotericin B (Lomentosporium is resistant to nearly all agents), echinocandins, and often azoles | Voriconazole is first line for Scedosporium apiospermum; combination therapy is used for Lomentosporium |
| Trichosporon | Intrinsic resistance to echinocandins, and to amphotericin B to some degree | Voriconazole is first line |
| Rhodotorula, Malassezia, and Saprochaete | Intrinsic resistance to echinocandins in all three, and to fluconazole in Rhodotorula | Breakthrough infection during echinocandin exposure is a clue |
| Dermatophytes | Terbinafine resistance (Trichophyton rubrum and Trichophyton indotineae), azole cross resistance, and griseofulvin failure | Trichophyton indotineae is spreading internationally; itraconazole at higher doses and longer courses is used, with testing where available |
| Histoplasma, Blastomyces, Coccidioides, and Talaromyces | Fluconazole is less active than itraconazole, and acquired resistance is rare | Relapse arises more from inadequate immune reconstitution or drug exposure |
| Pneumocystis jirovecii | Cannot be cultured, so susceptibility cannot be tested; mutations in the dihydropteroate synthase gene (DHPS) are linked to sulphonamide exposure | The clinical effect of DHPS mutations on treatment with trimethoprim sulphamethoxazole is unclear |
| Source | Features |
|---|---|
| Drug exposure in the patient | Prolonged or repeated exposure (HIV with fluconazole, cystic fibrosis and chronic pulmonary aspergillosis with itraconazole, prophylaxis in haematological malignancy), subtherapeutic levels, poor adherence, and drugs with poor tissue penetration |
| Environmental exposure | Agricultural fungicides (tebuconazole, propiconazole, difenoconazole, epoxiconazole, and bromuconazole) share the target with medical triazoles, and select Aspergillus fumigatus with TR34/L98H and TR46/Y121F/T289A in compost, bulb farms, crop residues, and wood chip; also industrial waste and flower beds |
| Healthcare spread | Candida auris by colonised skin, the environment, and shared equipment; fluconazole resistant Candida parapsilosis clones |
| Veterinary and other uses | Azole use in animals and in material preservation |
| Mutational dynamics | Hypermutator phenotypes, genome plasticity, and transposable elements |
| Resistance | Risk factors |
|---|---|
| Azole resistant Candida | Prior azole exposure (including prophylaxis), prior hospitalisation in an endemic region, central venous catheters, parenteral nutrition, abdominal surgery, and neutropenia |
| Echinocandin resistant Candida | Prior echinocandin exposure (typically more than 2 to 3 weeks), intra-abdominal abscess (poor source control and drug penetration), Candida glabrata infection, and Candida auris colonisation |
| Azole resistant Aspergillus | Prior azole therapy, residence or travel in a region with a high environmental burden, chronic cavitary disease, cystic fibrosis, and agricultural or compost exposure |
| Candida auris | Prior hospitalisation or long term care (ventilator units), invasive devices, broad spectrum antibiotic and antifungal exposure, and colonisation |
| Terbinafine resistant dermatophytes | Travel to or contact with South Asia, household transmission, and prior terbinafine failure |
| Approach | Details |
|---|---|
| Phenotypic susceptibility testing | Broth microdilution (reference method), commercial gradient strips, and automated colourimetric systems; use species level identification and current breakpoints; testing is advised for all invasive Candida isolates and for Aspergillus in invasive disease, prior azole exposure, or failure |
| Cut off values | Epidemiological cut off values separate wild type from non wild type isolates in species without breakpoints (for example Aspergillus, many moulds) |
| Screening agar | Azole containing agar plates (itraconazole, voriconazole, and posaconazole wells) identify azole resistant Aspergillus fumigatus quickly from cultures |
| Molecular detection | Polymerase chain reaction with melting curve analysis or sequencing for cyp51A alterations (TR34, TR46, and point mutations) directly on respiratory samples where culture is negative; FKS hot spot sequencing for Candida; ERG11 sequencing; SQLE sequencing for dermatophytes; whole genome sequencing in outbreaks |
| Species identification | Mass spectrometry or sequencing identifies Candida auris (misidentified as Candida haemulonii, Candida famata, Rhodotorula, Saccharomyces, or Candida lusitaniae by biochemical systems) and cryptic Aspergillus species |
| Therapeutic drug monitoring | Low levels mimic resistance, and levels guide dose changes (voriconazole trough 1 to 5.5 micrograms per mL, posaconazole above 0.7 for prophylaxis and above 1 for treatment, itraconazole above 1, and flucytosine peak 30 to 80) |
| Limits | In vitro and in vivo correlation is imperfect; breakpoints are lacking for several drug and species pairs; and results do not capture tolerance, biofilm, or heteroresistance |
Candida
| Situation | Approach |
|---|---|
| Suspected resistance in candidaemia | Repeat blood cultures, remove or replace the catheter, send the isolate for species identification and susceptibility testing, and image for a deep focus (abdomen, eye, heart); persistence of fever or positive cultures after 3 to 5 days of appropriate therapy prompts a search for a source and resistance |
| Echinocandin resistant Candida | Liposomal amphotericin B 3 to 5 mg per kg daily (if susceptible), or high dose fluconazole or voriconazole if the isolate is susceptible; flucytosine in combination; ibrexafungerp or fosmanogepix are options in investigational or compassionate settings; surgical source control |
| Candida auris | An echinocandin as first line; liposomal amphotericin B 5 mg per kg daily for echinocandin resistance or non response (with resistance to amphotericin B in some isolates); combination of amphotericin B with flucytosine, or an echinocandin with amphotericin B, for pan resistant isolates; contact isolation, screening, environmental cleaning with sporicidal or chlorine based disinfectants, and chlorhexidine skin decolonisation |
| Candida glabrata | Echinocandin first line; high dose fluconazole (12 mg per kg, 800 mg) only if susceptible; liposomal amphotericin B if echinocandin resistant |
| Candida krusei | Echinocandin or liposomal amphotericin B; voriconazole as step down |
| Candida parapsilosis (fluconazole resistant) | Echinocandin remains useful (despite higher MICs), or liposomal amphotericin B |
| Oropharyngeal and oesophageal candidiasis (azole refractory) | Itraconazole solution, posaconazole, voriconazole, then echinocandin or liposomal amphotericin B; optimise antiretroviral therapy |
| Prevention | Restrict unnecessary azole prophylaxis, de-escalate and stop therapy when cultures are negative, and use stewardship |
Aspergillus
| Situation | Approach |
|---|---|
| Local resistance above 10 percent | Voriconazole with an echinocandin, or liposomal amphotericin B 3 to 5 mg per kg daily alone, as initial therapy until susceptibility is known |
| Known azole resistant invasive aspergillosis | Liposomal amphotericin B as first line (3 to 5 mg per kg daily; mortality is high and may reach 50 percent or more with azole therapy alone) |
| Chronic pulmonary aspergillosis with resistance | Switch the azole (voriconazole, posaconazole, isavuconazole) according to MICs and levels, then an echinocandin or intravenous amphotericin B, with surgery when feasible |
| Prevention | Take cultures and susceptibility before and during azole therapy, check levels, and monitor for breakthrough |
| Prophylaxis breakthrough | Test for resistance, check levels, and change class (liposomal amphotericin B or an echinocandin) |
Other organisms
| Organism | Approach |
|---|---|
| Cryptococcus relapse on fluconazole | Reinduce with liposomal amphotericin B and flucytosine, check adherence and levels, and give consolidation fluconazole 800 mg daily (higher than the maintenance dose); susceptibility testing is not widely available |
| Mucorales | Liposomal amphotericin B 5 to 10 mg per kg daily, with posaconazole or isavuconazole step down; avoid voriconazole as it can select Mucorales |
| Lomentosporium prolificans | Voriconazole with terbinafine (and possibly an echinocandin or liposomal amphotericin B), surgery, and immune recovery; olorofim is investigational |
| Terbinafine resistant dermatophytosis | Itraconazole 200 mg once or twice daily for 4 to 8 weeks or longer (tinea corporis and cruris), higher dose terbinafine (500 mg daily) with limited evidence, topical azoles, avoidance of combination steroid creams, household treatment, and testing by SQLE sequencing where available |
| Griseofulvin failure | Terbinafine or itraconazole |
| Measure | Details |
|---|---|
| Diagnostic stewardship | Culture before therapy, species identification, early susceptibility testing, and use of biomarkers to guide treatment and de-escalation |
| Treatment stewardship | Indication specific therapy, optimal dosing and duration, de-escalation within 48 to 72 hours when cultures are negative, and prompt source control |
| Prophylaxis | Limit to proven high risk groups, avoid long azole courses without need, and monitor drug levels |
| Therapeutic drug monitoring | Avoid subtherapeutic exposure with voriconazole, posaconazole, itraconazole, and flucytosine |
| Infection control | Screening and isolation for Candida auris (axilla and groin swabs, with nares and rectum where required), hand hygiene, contact precautions, chlorine releasing disinfectants, dedicated equipment, and outbreak investigation |
| Surveillance | Local resistance rates, species distribution, and azole resistance in environmental and clinical Aspergillus |
| Agricultural measures | Limit the use of azole fungicides that cross select for medical azole resistance; manage compost and crop waste; and develop fungicides with new targets |
| Combination therapy | Used for pathogens in which resistance emerges during monotherapy (flucytosine in cryptococcosis) |
| Research | New classes (olorofim, fosmanogepix, ibrexafungerp, opelconazole, rezafungin) and rapid resistance diagnostics |
| Question | Answer |
|---|---|
| Which drug classes does intrinsic resistance remove? | Echinocandins (Cryptococcus, Mucorales, Fusarium, Scedosporium, Trichosporon); azoles (fluconazole in Candida krusei; voriconazole in Mucorales); amphotericin B (Aspergillus terreus, Scedosporium, Lomentosporium) |
| Which species is the greatest concern for multidrug resistance? | Candida auris, then Candida glabrata |
| Main mechanism of azole resistance in Candida? | Efflux pump up regulation, ERG11 mutation or overexpression |
| Main mechanism of azole resistance in Aspergillus fumigatus? | cyp51A alterations (TR34/L98H and TR46/Y121F/T289A), selected by environmental fungicides |
| Main mechanism of echinocandin resistance? | FKS1 and FKS2 hot spot mutations |
| Main mechanism of terbinafine resistance? | SQLE point mutations |
| Main mechanism of flucytosine resistance? | Loss of FCY2, FCY1, or FUR1 |
| What prevents resistance during treatment? | Adequate dose and levels, combination therapy where indicated, source control, and avoidance of prolonged unnecessary exposure |
