ANTIFUNGAL AGENTS

Katrien Lagrou

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1980 1985 1990 1995 1997

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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