ANTIFUNGAL AGENTS
Katrien Lagrou
0
1
2
3
4
5
6
7
8
1980 1985 1990 1995 1997
Dea
ths
per 1
00,0
00 p
opul
atio
n
Trends in mortality due to invasive mycosis in the US
0-4
5-24
25-44
45-64
≥65
McNeil et al., Clin Infect Dis, 2001: 33, 641-7
The fungal ‘players’• Opportunistic fungi
– Normal flora• Candida spp.
– Ubiquitous in our environment• Aspergillus spp.• Cryptococcus spp.• Mucor spp.
• Newly emerging fungi- Fusarium spp.- Scedosporium spp.
• Endemic geographically restricted- Blastomyces spp.- Coccidioides spp.- Histoplasma spp.
Risk factors for candidemia• Prolonged stay in ICU• Use of broad spectrum antibiotics • Abdominal surgery • Candida colonization (>2 sites)• Central venous and urinary catheters• Total parenteral nutrition• Renal failure (hemodialysis)• Immunosuppression (underlying condition,
immunosuppressive agents)• Intravenous drug use• Severe pancreatitis• Prematurity in neonates
General risk factors for invasive aspergillosis
Major• Neutropenia (+ monocytopenia)• Corticosteroid treatment
Minor• CD4penia• Inherited immunodeficiency (i.e. CGD)• Lung or sinus damage/disease• Severe liver disease• Exposure to high inocula
New• Genetic risk assessment• TLR, INF, MBL, IL-10, ….
Invasive fungal infections in adult HSCT recipientsSpecies distribution for IFI in HSCT recipients 2004-2007
59%25%
7% 9%
Aspergillus CandidaZygomycetes Others
71%
25%
4%Aspergillus Candida Others
Neofytos et al. CID 2009; 48: 265 Pagano et al. CID 2007; 45: 1161
02468
101214
1950 1960 1970 1980 1990 2000
Nysta
tinAm
phot
erici
nB
(195
8)
Griseo
fulvi
n
5-FCMiconazole
KetoconazoleFluconazole
Itraconazole
L-AmBABCDABLC
Terbinafine
Voriconazole
Posaconazole
Cas
pofu
ngin
MicafunginIsavuconazole
Ani
dula
fung
in
Mannoproteins
β-(1→6)-glucan
β-(1→3)-glucan
ChitinPhospholipid bilayer of cellmembrane
Ergosterol
Ergosterolsynthesispathway
AZOLES
POLYENES
β-(1→3)-glucan synthaseECHINOCANDINS
Squalene
ALLYLAMINES
FLUOROPYRIMIDINES
DNA/RNA synthesis
Antifungal agents active on fungal cell membrane
Classic amphotericin B deoxycholate formulation is a colloidal suspension of amphotericin B. A bile salt, deoxycholate, is used as the solubilizing agent.
Amphotericin B deoxycholate
Binds to sterols (preferentially ergosterol)
↓Disruption osmotic integrity
of fungal membrane ↓
Leakage of intracellular components
↓Fungal death
Amphotericin B: Spectrum and Recommended Dose• Spectrum:
• Very broad, active against most fungi except Aspergillusterreus, Scedosporium, Trichosporon and Candida lusitaniae (Candida glabrata)
• Fungicidal
• Amphotericin B: 1 mg/kg IV (after a test dose of 1 mg)
• Lipid-based Amphotericin B
• amphotericin B lipid complex (ABLC): 5 mg/kg IV
• liposomal amphotericin B (L-Amb): 3 mg/kg IV
Amphotericin B: Pharmacokinetics
• No oral bioavailability• Undetectable in CSF (but mainstay for
treatment of Cryptococcal meningitis)• Highly (>90%) protein bound • Exact routes of metabolism (minor hepatic)
and elimination (feces) are largely unknown• Half-life: 24-48 h
Amphotericin B: Tolerability and Safety
• Chills, rigors, fever (during infusion)• Nausea, vomiting• Phlebitis• Nephrotoxicity: incidence: 49-65%• Hypokalemia
can be explained by mode of action: ampho B binds cholesterol in distal tubular membrane leading to wasting of Na+, K+ and Mg++
Amphotericin B: Tolerability and Safety
• Acute renal failure = contra-indication• Can be used in patients with irreversible
terminal renal failure on hemodialysis →renal elimination only 20% of total clearance → low risk of accumulation
• No dose adjustment in patients with hepatic failure
• No risk for the fetus (↔ azoles)
• amphotericin B lipid complex: phospholipid ribbons(1.6-11µm)
• amphotericin B colloidal dispersion:cholesteryl sulfate complex(0.12-0.14 µm)
• liposomal amphotericin B(0.08 µm)
Lipid-Formulated amphotericin B:pharmacokinetics
L-Amb ABLC
Cmax 83.0 mg/L 1.7 mg/L
Toxicity 20 mg/kg: minimal nephrotoxicity (rats)
10 mg/kg: mild nephrotoxicity (rats)
Mode of action Liposome targeting to fungal cell wall with release of AMB into fungus
Release of AMB from complexes by phospholipases?
Drug localisation –therapeutic effect
Comparable efficacy to ABLC even with lower tissue concentrations
Higher concentrations in lung, liver and spleenTaken primarily up by tissues of RES
Amphotericin B: Pharmacodynamics
• Time-kill kinetics in vitro: concentration-dependent fungicidal activity against Candida, Cryptococcus and A. fumigatus
• PK/PD relationship in vivo associated with effective therapy:AMB: Cmax/MIC 4-10L-AMB: Cmax/MIC >40
Lewis, Curr Opinion Pharmacol 2007; 7:491-497
AZOLES
1. Imidazoles
2. Triazoles
(1979)
Voriconazole
Active (cidal) against
Aspergillusspp.
Newer triazolesbetter activity (static)
against Candida spp.
No activity againstZygomycetes except
posaconazole
Fluconazole: PharmacokineticsBio-availability - > 80%
- not dependent of gastric pH or food: IV-PO switch possible!
Distribution - extensive: Vd 0.7-1.0 L/kg- protein binding: 11%- CSF levels: >70% of plasma levels- good penetration in bone
Metabolism - minor hepaticExcretion - mainly renal: dose reduction in severe renal failure
- removed by dialysis- reliable urine concentrations- half-life: 27-34 hrs
Charlier C. JAC 2006; 57:384-410.
Fluconazole: drug interactions
Inhibits CYP2C9, CYP2C19 and CYP3A4• cyclosporine: TDM• midazolam: excessive sedation• phenytoin: TDM• tacrolimus: TDM• warfarin: monitor INR
Rifampin induces fluconazole metabolism:• increase fluconazole dose with 25%
Charlier C. JAC 2006; 57:384-410.
• Generally very well tolerated• Side effects occur especially in high doses (>400
mg/day)– Common: headache, nausea, abdominal pain,
alopecia– Elevated AST/ALT levels: generally mild
• Reported in 10% of leukemia patients with fluconazole prophylaxis• Reported in 20% of ICU patients with fluconazole prophylaxis
– Rare: case reports of fulminant hepatitis– Very rare: neurotoxicity (high doses > 1200 mg/day)
Charlier C. JAC 2006; 57:384-410.
Fluconazole: Tolerability and Safety
Voriconazole: PharmacokineticsBio-availability >90% on empty stomach (↓ with food)Steady state - 5-6 days
- loading dose necessary!Distribution - extensive (Vd: 4.6 L/kg)
- CSF concentration ~ 50% of plasma concentration- vitreal penetration 38%- protein binding 58%
Metabolism - hepatic (CYP2C19, CYP3A4, CYP2C9)
Elimination -80% via urine-20% via feces-Half-life: 6h
Non-linear kinetics: saturable metabolism!• Small increases in dose result in exponential
increases in blood levels• In children: linear pharmacokinetics, higher
metabolizing capacity
Purkins L et al. AAC 2002; 46:2546-53.
Voriconazole serum levels: high interindividualvariability: difficult pharmacokinetics!
Voriconazole: Interindividual variability
Genetic polymorphism CYP2C19• 3 genotypes: extensive metabolizers,
heterozygous extensive metabolizers, poor metabolizers
• PM especially in Asian population: 18-23%• PM in Caucasian population: 3-5%• Plasma levels up to 2-fold (HM) or 4-fold (PM)
higher!
Voriconazole: PharmacokineticsExtensive CYP-metabolism: drug interactions!
• Other drugs affecting voriconazole plasma levels– Contra-indicated with potent inducers
» Rifampin, ritonavir, carbamazepine, phenobarbital– Dose adjustments needed if combined with phenytoin
and rifabutin (↑ 5 mg/kg bid)• Voriconazole affecting plasma levels of others (inhibition)
– Contra-indicated with sirolimus, terfenadine, astemizole, cisapride, …
– Dose adjustments needed if combined with» Cyclosporine: TDM» Tacrolimus: TDM
• Visual disturbances: (20%)• Altered perception of light, photophobia, blurred vision, color
vision changes: mechanism unknown• Transient, infusion related• More in patients with higher levels
• Hepatotoxicity (13%)• AST, ALT, alkaline phosphatases, bilirubin elevations• Correlating with higher vorico plasma levels
• Phototoxicity (6%): erythema, Steven-Johnson syndrome, toxic epidermal necrolysis
• Neurological changes: confusion and hallucinations
Voriconazole: Safety
• IV vials contain sulphobutylether-[beta]-cyclodextrin, a solubilizer
• In patients with moderate to severe renal failure (CrCl < 50 ml/min): accumulation of SBECD →oral therapy if possible!
• In patients on intermittent dialysis therapy• No toxic effects observed• Systematic monitoring of the level of consciousness,
hemodynamic stability, dermal reactions, and liver function tests required
Von Mach MA et al. BMC Clin Pharamacol 2006; 6:6
Voriconazole: Nephrotoxicity of SBECD
• Loading dose: 2 x 6 mg/kg• Maintenance dose: 2 x 4 mg/kg• Child A and B cirrhosis (Child C: no data)
– Loading dose idem– Maintenance dose: 2 x 2 mg/kg
• Children (2-12 yrs)– 2 x 7 mg/kg
Voriconazole: Recommended doses
Pascual A. CID 2008;46:201-211.
Voriconazole: Therapeutic Drug Monitoring
52 adult patients: 181 samples
25%: levels < 1 mg/L
31%: levels ≥ 5.5 mg/L
31% CNS toxicity19% hepatitis
• Consensus and specific recommendations not yet available but accumulating evidence that TDM may play an important role in optimizing the safety and efficacy
• Supported by IDSA in selected cases
• Subset of patients need to be defined:e.g. Children, patients with a high BMI, abnormal liver function, drug-drug
interactions, patients with marked toxicity
• Validated assay necessary• Plasma through levels preferred, provisional therapeutic
range: 1-6 mg/L• Frequent monitoring after dose adjustments is warranted
Walsh et al. ,CID, 2008, 46: 327-60.
Voriconazole: Therapeutic Drug Monitoring
Bio-availability - 52-100%- Dependent on dosing frequency and intake with meal (↑ with high-fat meal)- Saturation in absorption if daily dose > 800 mg
Distribution - Extensive (Vd ~ 25 L/kg)- Tissue penetration: limited data- Protein binding > 98%
Metabolism - Hepatic: metabolized as glucuronide conjugates
Elimination - Majority via feces as unchanged drug- Minimal renal elimination (14%)- Half-life 35 hr
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Posaconazole: Pharmacokinetics
• Posaconazole inhibits CYP3A4• Tacrolimus: TDM (dose reduction)• Cyclosporine: TDM (dose reduction)• Increase in serum concentrations of benzodiazepines,
calcium channel blockers, statines,…
• Posaconazole is substrate of uridine diphosphate-glucuronosyltransferase
• Induction by phenytoin: contra-indicated!• Induction by rifabutin: contra-indicated! (+ rifabutin levels
increased)
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Posaconazole: Drug Interactions
• Dosing in patients with hepatic impairment?• Posaconazole should be used with caution• Not studied using Child score
• Dosing in patients with renal impairment?• Dose adjustment not necessary• Drug is not cleared with hemodialysis
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Goodwin M et al. JAC 2008, 61:17-25.
Posaconazole: Pharmacokinetics
• Seems to be more favorable compared to voriconazole
• Headaches (8%)• Gastro-intestinal side effects: abdominal pain,
diarrhea, nausea: 3-12%• Elevated liver function tests and hepatotoxicity
(<3%)• Rash• Hypokalemia
Posaconazole: Tolerability and Safety
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Goodwin M et al. JAC 2008, 61:17-25.
• Available only as a suspension for oral use• Treatment:
• 400 mg 2x/day with food or nutritional supplement• 200 mg 4x/day if no intake of food
• Prophylaxis: 200 mg 3x/day
Posaconazole: Recommended Doses
Triazoles: Pharmacodynamics
• Time-kill kinetics in vitro: • Concentration-independent fungistatic activity
against Candida, Cryptococcus • Time-dependent and concentration-dependent
fungicidal activity against A. fumigatus
• PK/PD relationship in vivo associated with effective therapy: AUC/MIC ≥ 25 (Candida spp.)
Lewis, Curr Opinion Pharmacol 2007; 7:491-497
Antifungal agents active on fungal cell wall
Phospholipid bilayerof the fungal cell
membrane
Fungalcell wall
β-(1,3)-glucan
β-(1,6)-glucan
β-(1,3)-glucan synthaseErgosterol
PK is specific for each echinocandin
HO
NH
O
HO
OH
HN
O
N
H3C
HO
H3C
HO
NH
O
HN
CH3
OH
N
O
OOH
O
NH
O
HO OH
O
H3C
NO
NHO
HO
HO
NH
O
OH
HN
H2N
OH
H2N
O
OH
HN
OH
HO
H
H
H HNH O
H
CH3
OHO NH
O
H3C
CH3 CH3
caspofungin HO
O
NH
O
HO
OH
HN
O
N
HO
H2N
O
H3C
HO
NH
O
HN
CH3
OH
N
O
OOH
O
NH
O
O
N
HO OH
O
H3C
S
OH
O
O
micafunginanidulafungin
Sidechain determines:‐ Activity: interaction with the cell wall‐Farmacokinetics: more lipophilic→ higher distribution volume
ECHINOCANDINS
Active (static) against
Aspergillus spp.
Active (cidal) against
Candida spp.
Bio-availability <2%: only IVDistribution -Protein binding: 96%, no elimination via dialysis
-Linear pharmacokinetics-Good distribution into most tissues (minimal urine, CSF, brain and ocular fluid penetration)
Metabolism - Hepatic: hydrolysis and N-acetylation: no active metabolites- not CYP450 dependent
Excretion -Via urine and feces (only 2% unchanged)-Half-life: 9-11h
Caspofungin: Pharmacokinetics
• No dose adjustments in renal insufficiency• No CYP-mediated metabolism
• No CYP-mediated drug interactions• No genetic polymorphisms
• Uptake via hepatic transporter: OATP• OATP= organic anion transporting polypeptide• Reduced uptake in patients with hepatic insufficiency
• Dose reduction in Child B liver cirrhosis• No recommendations in Child C
• Drug interactions mediated by OATP?Sandhu P et al. DMD 2005; 33: 676-82.
Caspofungin: Pharmacokinetics
OATP = organic anion transporting polypeptide
• drug uptake transporter
•Basolateral membrane of hepatocytes
•Contributes to overall elimination of caspofungin
• Cyclosporine and rifampin are also substrates for OATP1B1
Caspofungin: Pharmacokinetics
• Co-administration with cyclosporine• AUC caspo + 25%• Competitive inhibition at OATP?
• Co-administration with rifampin• Inhibition and induction effect on caspofungin• First days: rifampin blocks uptake by OATP• After continued dosing: rifampin induces OATP• Net effect: AUC caspo ↓: increase MD to 70mg/day
• Other inducers: efavirenz, nevirapine, dexamethasone, phenytoin, carbamazepine– Increase MD to 70 mg/day
Caspofungin: Pharmacokinetics
• Excellent safety and tolerability• Can be explained by mode of action: human
cells do not have a cell wall
• Adverse events = unspecific drug reactions• Histamine-mediated: headache, fever, nausea• Elevation of hepatic enzyme levels
• AST, ALT and ALP• < 5-fold ULN
Caspofungin: Tolerability and Safety
• Loading dose: 70 mg• Maintenance dose: 50 mg
• Patients > 80 kg: 70 mg
• Child B liver cirrhosis• Loading dose: 70 mg• Maintenance dose: 35 mg
• Children: 3 months-17 year• LD: 70 mg/m2/d, MD: 50 mg/m2/d
• Infants < 3 months• LD: 25 mg/m2/d, MD: 25 mg/m2/d
Caspofungin: Recommended Dose
Anidulafungin MicafunginBio-availability
Low, only IV administration Low, only IV administration
Distribution - Vd: 0.57 L/kg- Protein binding: 99%- Poor CNS and urine penetration
- Vd: 0.39 L/kg- Protein binding: 99%- Poor CNS and urine penetration
Metabolism - No hepatic metabolism- No CYP involvement- Metabolism by slow chemical degradation
- Hepatic (COMT)- Weak substrate for CYP450
Elimination - Half-life : 24hrs- Via feces
- Half-life: 13 hrs- Via feces, > 90% unchanged
Metabolism of echinocandinsAnidulafungin
ChemicalDegradation
HepaticMetabolism
Micafungin
EnzymaticBiotransformation
Renal Elimination
Caspofungin
HepaticMetabolism
ChemicalDegradation
Anidulafungin Micafungin
Dose adjustments in hepatic insufficiency?
NoStudied in Child A,B,C: no increase in plasma levels
NoNot studied in Child C
Dose adjustments in renal insufficiency/dialysis?
No No
Drug interactions? Small increase in anidulafungin levels if combined with cyclosporine
Possibly mild inhibition of CYP3A with small increase in cyclosporine, sirolimus and nifedipin levels
• Adverse reactions = mild• Infusion (histamine-mediated) related reactions
(especially at high infusion rates): flushing, pruritus, rash, urticaria
• Diarrhea, vomiting, nausea• Hepatic enzyme elevation: ALT, ALP, bilirubin
• In 5-10% of patients• Usually < 3-fold ULN
Anidulafungin - Micafungin: Tolerability and Safety
Micafungin
http://www.emea.europa.eu/humandocs/PDFs/EPAR/mycamine/H-734-PI-en.pdf
Warning EMEA – risk hepatocellular tumor formation
• discontinuation if persistent elevation ALT/AST
• consider alternative in patients with severe liver function impairment or chronic liver diseases or concomitant hepatotoxic therapy
Echinocandins: Pharmacodynamics
• Time-kill kinetics in vitro: • Concentration-dependent fungicidal against
Candida• Concentration-dependent fungistatic against
Aspergillus
• PK/PD relationship in vivo associated with effective therapy:• Cmax/MIC >4 (Candida spp.) • Cmax/MEC =10 (Aspergillus spp.)
Lewis, Curr Opinion Pharmacol 2007; 7:491-497
Overzicht prijzen – patiënt 70 kgSpecialiteit Stofnaam Dosering Prijs 1 dag (€) Prijs 14 dagen
(€)Fungizone IV Amfotericine B 1 mg/kg 11.54 161
Abelcet IV Amfo B lipid complex 5 mg/kg 489 6848
Ambisome IV Amfo B liposomaal 3 mg/kg 889 12455
Diflucan IV fluconazole LD 800 mg - OD 400 mg 24 366
Diflucan PO fluconazole LD 800 mg - OD 400 mg 11 168
Vfend IV voriconazole LD 2x 6 mg/kg – OD 2x 4 mg/kg 626 9080
Vfend PO voriconazole LD 2x 6 mg/kg – OD 2x 4 mg/kg 84 1348
Noxafil PO posaconazole 2 x 400 mg 127 1781
Cancidas IV caspofungin LD 70 mg – OD 50 mg 483 7389
Ecalta IV anidulafungin LD 200 mg – OD 100 mg 429 6435
Belgian situation
• Only Fungizone (AmB) en Diflucan(fluconazole) can be prescribed without reimbursement restrictions
• For all other antifungals: reimbursement criteria
• See www.riziv.be
INVASIVE FUNGAL DISEASE: EORTC/MSG CRITERIA
De Pauw B et al., CID 2008: 1813-1821
PROVEN
POSSIBLE
PROBABLE Host factors
Host factors
Clinicalfeatures
Clinicalfeatures
Mycology
Sterile material microscopy and/or culture positive
+ +
+
Host factors
Clinical features
Mycology
NeutropeniaaHSCTCorticosteroidsT cell immunosuppressants
CT/MRI signsClinical criteria
MicroscopyCultureAntigen (galactomannan, β-D-glucan)
Treatment
• Invasive aspergillosis– First line: voriconazole– Second line: caspofungin/ liposomal amphotericin B/
posaconazole
• Candidemia– First line: fluconazole– Candida glabrata R to fluconazole, Candida krusei:
caspofungin or anidulafungin
Antifungal resistance development
Candida resistance• Development of resistance in C. albicans
– Mainly in HIV-infected patients during long term fluconazole treatment for oropharyngeal candidiasis (also resistant to itraconazole)
– Candidemia due to C. albicans resistant to fluconazole in cancer patients on azole prophylaxis remains limited
• Resistance to amphotericin B– C. lusitaniae: usually intrinsically resistant– C.guilliermondii: some isolates are intrinsically resistant– C. glabrata en C. krusei: probably less susceptible– Secondary resistance development is
Etest
Sensititre antifungal panel
Complete concentration range of different antifungal agents (amphotericinB, fluconazole, itraconazole,flucytosine, voriconazole, posaconazole, caspofungin, anidulafungin)
Interpretative breakpoints CLSIBreakpoints established only for some organism-drug combinations
Antifungal agent S S-DD R
Fluconazole ≤ 8 µg/ml (≥ 19 mm) 16-32 µg/ml (15-18 mm) ≥ 64 µg/ml (≤ 14 mm)
Itraconazole ≤ 0,125 µg/ml 0,25-0,5 µg/ml ≥ 1 µg/ml
Voriconazole ≤ 1 µg/ml (≥ 17 mm) 2 µg/ml (14-16 mm) ≥ 4 µg/ml (≤ 13 mm)
Echinocandins (caspofungin, micafungin, anidulafungin)
S: MIC ≤ 2 µg/mLNS: MIC > 2 µg/mL
Azoles
Clinical breakpoints EUCAST
Fluconazole 2/4 IE - 2/4 2/4
Voriconazole 0.125/0.125 IE - 0.125 0.125
Candida albicans
Candida glabrata
Candida krusei
Candida parapsilosis
Candida tropicalis
Susceptibility patterns
Candida species Fluconazole Voriconazole Amphotericin B Candins
C. albicans S S S S
C. tropicalis S S S S
C. parapsilosis S S S S (tot I?)
C. glabrata S-DD tot R S tot I S tot I S
C. krusei R S tot I S tot I S
C. lusitaniae S S S of R S
Pappas et al., Clin Infect Dis, 2004: 38, 161-189.
Resistance to fluconazole among Candida spp.
Pfaller et al, J Clin Microbiol 2007, 45: 1735-1745.
Resistance to voriconazole among Candida spp.
Pfaller et al, J Clin Microbiol 2007, 45: 1735-1745.
Candida resistance• Voriconazole
– 7191 Candida spp. from worldwide (2004-2007)– MIC (50)/MIC (90): 0.008/0.25 µg/mL (98% susceptible)
• Anidulafungin, caspofungin and micafungin– 5,346 invasive isolates from worldwide (2001-2006)– > 99% of isolates inhibited by < or = 2 µg/mL of all three
agents– No geographical differences in resistance– No significant change over time
Pfaller et al., J Clin Microbiol, 2006, 44: 760-763.
Diekema et al., Diagn Microbiol Infect Dis, 2009, 63: 233-236
1945-1998
Multi-azole resistance in A. fumigatus
• MIC itraconazole > 16 mg/L• MIC voriconazole 2 - > 16 mg/L• MIC posaconazole 0,5 – 1,0 mg/L
2002-200712%
(10/81)
Verweij P et al., N Engl J Med 2007;356:1481-1483
0% (0/170)
Azole resistance in A. fumigatus: The Netherlands
PLoS Med 2008;5:e219
R mechanisms: TR/L98H in 30 of 32 (94%) isolates
NetherlandsNorwayPolandPortugal RussiaSpain SwedenSwitzerlandTaiwan TurkeyUK
AustraliaAustriaBelgiumBrazilChina DenmarkFinland France GermanyGreeceItaly
Global prevalence of resistance in Aspergillusfumigatus: SCARE study
FUNGI DIFFER FROM BACTERIA WITH RESPECT TO THEIR TENDENCY TO DEVELOP RESISTANCE
• Few a priori resistant species and strains exist which could be selected
• Newer antifungal agents display a high affinity for the target
• Some fungi (e.g. C. albicans) are diploid
REASONS
• Mutations are often attended by a loss of fitness
• Genetic transfer of resistance from one fungus to another does not occur
• No drug modifying enzymes are known in fungi