Antifungal Agents

Antifungal Agents

Polyene antibiotic
The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. Nystatin Amphotericin B (may be administered liposomally) Natamycin Rimocidin Filipin Pimaricin

Antifungal Agents

Imidazole and triazole

The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans.

Imidazoles:

Miconazole Ketoconazole Clotrimazole Mebendazole Isoconazole Sertaconazole Thiabendazole

Bifonazole Butoconazole Econazole Fenticonazole Oxiconazole Sulconazole Tiaconazole

Antifungal Agents
The

triazoles are newer, and are less toxic and more effective:
Fluconazole Itraconazole Ravuconazole Posaconazole Voriconazole

Antifungal Agents

Allylamines
Allylamines inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis:
Terbinafine - marketed as Lamisil Amorolfine Naftifine

Butenafine

Antifungal Agents

Echinocandin
Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3- glucan synthase:
Anidulafungin Caspofungin Micafungin

Antifungal agents
Increase of human fungal infections mainly due to advances in surgery, cancer treatment, critical care, increase in the use of broad spectrum antibiotics and HIV Increased number of patients at risk Antifungals available : systemic drugs, oral drugs for mucocutaneous infections and topical drugs

Antifungal Agents

Polyene antibiotic
The polyene antibiotics bind with sterols in the fungal cell membrane, principally ergosterol. This causes the cell's contents to leak out and the cell dies. Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. Nystatin Amphotericin B (may be administered liposomally) Natamycin Rimocidin Filipin Pimaricin

POLYENE ANTIFUNGALS
AMPHOTERICIN B NYSTATIN Fungicidal against both filamentous and yeastlike fungi, Histoplasma, Blastomyces, Coccidioides, Cryptococcus, Cnadida, Aspergillus and Sporotrichum In vitro activity against some protozoa

POLYENE ANTIFUNGALS

Generally acts on sterols in the cytoplasmic membrane of fungi leading to rapid leakage and fungal death

AMPHOTERICIN B: CHEMISTRY
Produced by Streptomyces nodosus Polyene macrolide Water insoluble, prepared as a colloidal suspension or in a lipid associated delivery system

AMPHOTERICIN B: PHARMACOKINETICS

Poor GI absorption Oral administration is effective for fungal infections on the lumen of the GI tract >90% protein bound Serum t1/2 15 days Large Vd but CSF concentrations is only 2-3% of plasma concentrations Poor CSF penetration, may require intrathecal administration in cases of meningitis Fugicidal and fungistatic

AMPHOTERICIN B: LIPID FORMULATIONS

Therapy is limited by toxicity Lipid binding of the drug causes less binding to mammalian membranes permitting the use of effective doses of the drug. Lipid vehicle serves as a reservoir

AMPHOTERICIN B: ADR
Infusion related toxicity: fever, chills, muscle spasms, vomiting, headache , hypotension Ameliorated by slow IV infusion or decreasing the dose Premedications with antihistamines Start with a test dose

AMPHOTERICIN B: ADR
Slower toxicity: Azotemia is variable but can be serious enough to necessitate dialysis Renal toxicity commonly presents with RTA ( renal tubular acidosis with severe K and MG wasting) Attenuated by preloading with saline After intrathecal administration: seizures, chemical arachoidits

AMPHOTERICIN B: Antifungal activity

BROADEST SPECTRUM OF ACTIVITY Candida albicans Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatidis Coccidioides imimtis Aspergillus fumigatus Candida lusitaniae and Pseudallescheria boydii are resistant

AMPHOTERICIN B: Clinical Use

Drug of choice for nearly all life threathening mycotic infections Initial induction therapy for serious fungal infections and is concomitantly replaced by azoles Fungal pneumonia, cryptococcal meningitis, sepsis, systemic fungal disease Local application: Fungal keratitis, fungal arthritis, bladder irrigation in Candiduria

PolyenesAmphotericin B

MOA: Binds to ergosterol within the fungal cell membrane resulting in depolarization of the membrane and the formation of pores. The pores permit leakage of intracellular contents. Exhibits concentration dependent killing.

Zygomycetes

+ +

Scedosporidium

PolyenesAmphotericin B

Tricosporon

+
+ +++ ++ +++

Spectrum of Activity Broad spectrum antifungal Active against most molds and yeasts Holes: C. lusitanae, Fusarium, Tricosporon, Fusarium Histoplasma Blastomyces Coccidioides

Cryptococcus
Aspergillus lusitanae parapsilosis Candida tropicalis krusei glabrata albicans

+++
++ -+++ +++ +++ ++ +++

Scedosporium

PolyenesAmphotericin B

Resistance
Susceptibility testing methods have not been standardized Development of resistance in a previously susceptible species is uncommon Mechanisms of Resistance
Reductions in ergosterol biosynthesis Synthesis of alternative sterols that lessen the ability of amphotericin B to interact with the fungal membrane

PolyenesAmphotericin B

Soluble in both basic and acidic environments Insoluble in water Formulations Amphotericin B deoxycholate
Fungizone

Isolated from Streptococcus nodosus in 1955 Amphotericin B is amphoteric

Amphotericin B colloidal dispersion

Amphotec, Amphocil

Amphotericin B lipid complex

Abelect

Liposomal amphotericin B
Ambisome

Amphotericin B deoxycholate

Distributes quickly out of blood and into liver and other organs and slowly re-enters circulation Penetrates poorly into CNS, saliva, bronchial secretions, pancreas, muscle, and bone Disadvantages
Glomerular NephrotoxicityDose-dependent decrease in GFR because of vasoconstrictive effect on afferent renal arterioles Tubular NephrotoxicityK, Mg+, and bicarbonate wasting Decreased erythropoietin production Acute Reactionschills, fevers, tachypnea
Permanent loss of renal function is related to the total cumulative dose

Long terminal-phase half-life (15 days)

Support

Dose: 0.3 to 1 mg/kg once daily

Fluids Potassium replacement Avoid concurrent nephrotoxic agents Premed with acetaminophen, diphenhydramine or hydrocortisone Meperidine for rigors

Amphotericin B Colloidal Dispersion (Amphotec) Cholesterol sulfate in equimolar amounts to amphotericin B Similar kinetics to amphotericin B deoxycholate Acute infusion related reactions similar to amphotericin B deoxycholate Reduced rates of nephrotoxicity compared to amphotericin B deoxycholate Dose
3 to 4 mg/kg once daily

Amphotericin B Lipid Complex (Abelcet)

Equimolar concentrations of amphotericin and lipid Distributed into tissues more rapidly than amphotericin B deoxycholate
Lower Cmax and smaller AUC than amphotericin deoxycholate
Highest levels achieved in spleen, liver, and lungs Delivers drug into the lung more rapidly than Ambisome Lowest levels in lymph nodes, kidneys, heart, and brain

Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity Dose
5 mg/kg once daily

Liposomal Amphotericin B (AmBisome)

Liposomal product
One molecule of amphotericin B per 9 molecules of lipid

Distribution
Higher Cmax and larger AUC Higher concentrations achieved in liver, lung, and spleen Lower concentrations in kidneys, brain, lymph nodes and heart May achieve higher brain concentrations compared to other amphotericin B formulations

Reduced frequency and severity of infusion related reactions Reduced rate of nephrotoxicity

Dose
3 to 6 mg/kg once daily

NYSTATIN
More soluble than Amphotericin B Used primarily as a topical preparation Active against most Candida species Not absorbed from skin or GI tract No parenteral administration due to toxicity

Flucytosine

MOA
Converted by cytosine deaminase into 5-fluorouracil which is then converted through a series of steps to 5fluorouridine triphosphate and incorporated into fungal RNA leading to miscoding Also converted by a series of steps to 5-fluorodeoxyuridine monophosphate which is a noncompetitive inhibitor of thymidylate synthase, interfering with DNA synthesis

Fluorinated pyrimidine

Flucytosine

Spectrum of Activity
Active against
Candida species except C. krusei Cryptococcus neoformans Aspergillus species

Synergy with amphotericin B has been demonstrated

The altered permeability of the fungal cell membrane produced by amphotericin allows enhanced uptake of flucytosine

Mechanisms of Resistance
Loss of cytosine permease that permits flucytosine to cross the fungal cell membrane Loss of any of the enzymes required to produce the active forms that interfere with DNA synthesis Resistance occurs frequently and rapidly when flucytosine is given as monotherapy Combination therapy is necessary

Flucytosine

Half-life
2 to 5 hours in normal renal function 85 hours in patients with anuria

Distributes into tissues, CSF, and body fluids Toxicities

Bone marrow suppression (dose dependent) Hepatotoxicity (dose dependent) Enterocolitis Toxicities occur more commonly in patients with renal impairment

Dose
Administered orally (available in 250 and 500 mg capsules) 100 to 150 mg/kg/day in 4 divided doses Dose adjust for creatinine clearance

Flucytosine concentrations should be monitored especially in patients with changing renal function Contraindicated in pregnancy

Antifungal Agents

Imidazole and triazole

The imidazole and triazole groups of antifungal drugs inhibit the enzyme cytochrome P450 14-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell membrane synthesis. These drugs also block steroid synthesis in humans.

Imidazoles:

Miconazole Ketoconazole Clotrimazole Mebendazole Isoconazole Sertaconazole Thiabendazole

Bifonazole Butoconazole Econazole Fenticonazole Oxiconazole Sulconazole Tiaconazole

AZOLES
Synthetic compounds Imidazoles: Ketoconazole, Miconazole, Clotrimazole Triazoles: Itraconazole, Fluconazole, Vorioconazole

AZOLES: Mechanism of Action

Reduction of ergosterol synthesis by ionhibition of fungal cytochrome P450 enzymes

AZOLES: Clinical use

Candida species Cryptococus neoformasns B;astomyces Coccidiomycosis Histoplasmosis Dermatophytes Aspergillus for Itraconazole and Voriconazole Pseudallscheria boydii

AZOLES: ADRs
Relatively non toxic Minor GI upset Abnormalities in liver enzymes

Triazoles

MOA: Inhibits 14-sterol demethylase, which is a microsomal CYP450 enzyme. This enzyme is responsible for conversion of lanosterol to ergosterol, the major sterol of most fungal cell membranes

TriazolesSpectrum of Activity
Fluconazole Itraconazole Voriconazole Posaconazole

C. albicans C. glabrata C. krusei C. tropicalis C. parapsilosis C. lusitanae

+++ + -+++ +++ ++

++ + + ++ ++ ++

+++ ++ +++ +++ +++ +++

+++ ++ ++ +++ +++ +++

Aspergillus
Cryptococcus Coccidioides Blastomyces Histoplasma Fusarium Scedosporium Zygomycetes

-+++ +++ ++ + ---

++
+++ +++ +++ +++ -+/-

+++
+++ +++ ++ ++ ++ + -

+++
+++ +++ +++ +++ ++ +/++

TriazolesADME
Fluconazole
Absorption IV and PO Good bioavailability PO
Capsule Suspension

Itraconazole

Voriconazole
IV and PO 90% oral bioavailability

Posaconazole
PO--Absorption enhanced with high fat meal

Capsules best absorbed with food. Suspension best absorbed on empty stomach. Low urinary levels Poor CNS penetration
Hepatic

Distribution Wide. Good CNS penetration

Metabolism Hepatic/Renal

Wide. Good CNS penetration

CYP 2C9, 2C19, 3A4 Saturable metabolism

Widely distributed into tissues

Not a substrate of or metabolized by P450, but it is an Inhibitor of 3A4
Minimal renal excretion of parent compound 66% excreted in feces

Elimination 80% excreted Excreted in feces unchanged in the urine

Minimal renal excretion

TriazolesFluconazole

Dose
100 to 400 mg daily Renal impairment:
CrCl >50 ml/min, give full dose CrCl<50 ml/min, give 50% of dose Dialysis: replace full dose after each session

Drug Interactions
Minor inhibitor of CYP 3A4 Moderate inhibitor of CYP 2C9
Warfarin, phenytoin, cyclosporine, tacrolimus, rifampin/rifabutin, sulfonylureas

Adverse Drug Reactions

Well tolerated Nausea Elevated LFTs
UNC Hospital Formulary

Dose

TriazolesItraconazole

200 to 400 mg/day (capsules)

doses exceeding 200 mg/day are given in 2 divided doses Loading dose: 200 mg 3 times daily can be given for the first 3 days

Oral solution is 60% more bioavailable than the capsules

Drug Interactions
Major substrate of CYP 3A4 Strong inhibitor of CYP 3A4 Many Drug Interactions

Adverse Drug Reactions

Contraindicated in patients with CHF due to negative inotropic effects QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of drug interactions Hepatotoxicity Rash Hypokalemia Nausea and vomiting

TriazolesVoriconazole

Dose
IV
6 mg/kg IV for 2 doses, then 3 to 4 mg/kg IV every 12 hours

PO
> 40 kg200-300 mg PO every 12 hours < 40 kg100-150 mg PO every 12 hours

Cirrhosis:
IV
6 mg /kg IV for 2 doses, then 2 mg/kg IV every 12 hours

PO
> 40 kg100 mg PO every 12 hours < 40 kg 50 mg PO every 12 hours

Renal impairment:
if CrCl<50 ml/min, use oral formulation to avoid accumulation of cyclodextrin solubilizer

TriazolesVoriconazole
Drug Interactions Major substrate of CYP 2CD and 2C19 Minor substrate of CYP 3A4 Weak inhibitor of CYP 2C9 and 2C19 Moderate inhibitor of CYP 3A4 Common Adverse Effects Peripheral edema Rash (6%) N/V/D Hepatotoxicity Headache Visual disturbance (30%) Fever Dose Adjustments Efavirenz Phenytoin Cyclosporine Warfarin Tacrolimus

Serious Adverse Events Stevens-Johnson Syndrome Liver failure Anaphylaxis Renal failure QTc prolongation

TriazolesPosaconazole

Dosing (only available PO)

Prophylaxis of invasive Aspergillus and Candida species
200 mg 3 times/day

Treatment of oropharyngeal candidiasis

100 mg twice daily for 1 day, then 100 mg once daily for 13 days

Treatment or refractory oropharyngeal candidiasis

400 mg twice daily

Treatment of refractory invasive fungal infections (unlabeled use)

800 mg/day in divided doses

Drug Interactions
Moderate inhibitor of CYP3A4

Adverse Reactions
Hepatotoxicity QTc prolongation GI: Diarrhea

Echinocandins
MOA Irreversibly inhibits B-1,3 D glucan synthase, the enzyme complex that forms glucan polymers in the fungal cell wall. Glucan polymers are responsible for providing rigidity to the cell wall. Disruption of B1,3-D glucan synthesis leads to reduced cell wall integrity, cell rupture, and cell death.

Zygomycetes

EchinocandinsSpectrum of Activity

Scedosporidium
Fusarium Histoplasma Blastomyces Coccidioides Cryptococcus Aspergillus guilliermondii lusitanae Candida parapsilosis tropicalis krusei glabrata + +++ + +++ +++ +++ -+++ ++ ++ --

albicans

+++

Gallagher JC, et al. Expert Rev Anti-Infect Ther 2004;2:253-268

Echinocandins
Caspofungin Absorption Distribution Metabolism Micafungin Anidulafungin Not orally absorbed. IV only Extensive into the tissues, minimal CNS penetration spontaneous degradation, hydrolysis and N-acetylation Chemical degradated Not hepatically metabolized 26.5 hours 200 mg IV on day 1, then 100 mg IV daily thereafter

Elimination Half-life Dose

Limited urinary excretion. Not dialyzable 9-23 hours 70 mg IV on day 1, then 50 mg IV daily thereafter 11-21 hours 100 mg IV once daily

Dose Adjustment

Child-Pugh 7-9 70 mg IV on day 1, then 35 mg IV daily thereafter CYP inducers 70 mg IV daily

None

None

Caspofungin

EchinocandinDrug Interactions
Reduced caspofungin levels
Increase caspofungin dose

Not an inducer or inhibitor of CYP enzymes CYP inducers (i.e. phenytoin, rifampin, carbamazepine) Cyclosporine

Increases AUC of caspofungin Hepatotoxicity

Avoid or monitor LFTs

Tacrolimus

Reduced tacrolimus levels by 20%

Monitor levels of tacrolimus

Micafungin

Minor substrate and weak inhibitor of CYP3A4 Nifedipine Sirolimus

Increased concentration of sirolimus

Increased AUC (18%) and Cmax (42%) of nifedipine

Anidulafungin

No clinically significant interactions

Cappelletty et al. Pharmacotherapy 2007;27:369-88

EchinocandinsAdverse Effects
Generally well tolerated Phlebitis, GI side effects, Hypokalemia Abnormal liver function tests Caspofungin

Tends to have higher frequency of liver related laboratory abnormalities Higher frequency of infusion related pain and phlebitis

Itraconazole

Available in oral and IV formulations Drug absorption is increased by food or low gastric pH Reduced bioavailability when taken with Rifampicin, Rifabutin, Rifapentine Poor CSF penetration Drug of choice for HIstoplasma, Blastomyces and Sporotrix infections Used extensively in the treatment of dematophytoses and onychomycosis

Fluconazole

Highly water soluble and high CSF penetration High oral bioavailability Better GI tolerance, fewer hepatic enzyme interactions: widest therapeutic index Azole of choice in the treatment and secondary prophylaxis of Cryptococcal infections Equivalent to Amphotericin B in the treatment of Candidemia Reduce fungal disease in bone marrow transplant and AIDS patients

Voriconazole
Good oral bioavailability Low propensity for mammalian cytochrome P 450 inhibition Causes Blurring of vision and altered color perceptions Excellent activity against Candida, effective in the treatment of invasive Aspergillosis

MICONAZOLE/ CLOTRIMAZOLE
Topically active Fungicidal when administered topically Poor CSF penetration Used in ringworm infections and vulvovaginal candidiasis

FLUCYTOSINE
Water soluble pyrimidine analog related to 5 FU 09% absorbed with peak serum concentrations 1-2 hours after oral administration Poor protein binding, penetrates well into all body fluid compartments including CSF Eliminated by glomerular filtration, levels rise rapidly in renally impaired patients

FLUCYTOSINE: ADRs

Toxicity related to the formation of 5 FU

Anemia, leukopenia, thrombocytopoenia Narrow therapeutic window Used in Cryptococcal infections

Griseofulvin
Used in the systemic treatment of dermatophytosis, Epidermophyton, Microsporum, Trichophyton, Binds to keratin and is deposited in newly forming skin

Terbinafine
Used in the treatment of dermatophytosis, specifically onychiomycosis Like Griseofulvin, it is Keratophyllic Does not seem to affect cytochrome P450 enzymes

Echinocandins/ Capsofungin
Newest class of antifungals Cyclic peptides linked to a long chain fatty acid Acts at the level of the fungal wall by inhibiting the synthesis of beta 1-3 glucan, resulting in cell wall disruption Used in Invasive Aspergillosis who have failed to respond to Amphotericin B.

Voriconazole
Voriconazole is available in oral and intravenous (IV) formulations FDA approval in May 2002

Invasive aspergillosis Scedosporium apiospermum (asexual form of Pseudallescheria boydii) Fusarium spp. infections in patients intolerant of, or refractory to, other therapy

Voriconazole

A synthetic derivative of fluconazole

Substitution of a triazole group with a fluoropyrimidine moiety
increase potency and in vivo efficacy

Addition of a methyl group to the propyl backbone

increasing the affinity of the drug for the target enzyme (14--sterol demethylase)

Voriconazole

Pharmacokinetics
Maximum plasma concentrations
within 1 or 2 hours following dosing (similar for IV and oral route of administration)

The oral bioavailability: 96% Extensive distribution in humans

a steady-state volume of approximately 4.6 L/kg

Serum levels: 2 to 6 g/mL Moderate binding to plasma proteins: 58% Metabolized by the hepatic cytochrome P-450 enzymes
especially CYP2C19, CYP2C9, and CYP3A4

Voriconazole

In vitro susceptibility testing

Broad-spectrum in vitro activity
Candida spp Cryptococcus Scedosporium spp. Trichosporon spp. Aspergillus spp. including AmB-resistant clinical isolates Blastomyces dermatitidis Coccidioides immitis Histoplasma capsulatum Dermatophytes
Epidermophyton floccosum Microsporum spp Trichophyton spp.

Ravuconazole
Ravuconazole is similar to fluconazole with a thiazole in the place of a second triazole Ravuconazole is available only in an oral formulation

Phase II clinical trials Long terminal half-life

100 hours

Well tolerated in
single doses of 800 mg/d 400 mg/d for up to 14 days

Headache being the most reported adverse event

Ravuconazole

In vitro susceptibility testing

Broad spectrum of activity against
Aspergillus spp. C neoformans Candida spp. Trichosporon spp. Dermatophytes
Trichophyton mentagrophytes Trichophyton rubrum Microsporum gypseum Microsporum canis Epidermophyton floccossum

Ravuconazole

In vivo studies
Safety and dose-dependent efficacy were demonstrated in several animal models
Invasive and pulmonary aspergillosis Candidiasis Cryptococcosis Histoplasmosis

Ravuconazole
Oropharyngeal and esophageal candidiasis in immunocompromised humans
400 mg once daily Response rate
Ravuconazole: 86% Fluconazole: 78%

Adverse events
abdominal pain (8%) diarrhea (6%) pruritus (6%) rash (6%)

Ravuconazole
Dermatophyte infections
A phase I-II study of toenail onychomycosis After 48 weeks, effective treatment rates
200 mg/d: 56% effective and safe therapy for onychomycosis 100 mg/wk: 10% 400 mg/wk: 8% Placebo: 15%

Steady-state serum levels: 3000 ng/mL

successful clinical and mycologic response

Posaconazole
An analogue of itraconazole with a 1,3dioxolone backbone In phase III trials

Posaconazole

Pharmacokinetics
Well absorbed at oral concentrations of
200 mg every day 400 mg every day 200 mg four times a day

Half-life: 22 hours Maximum concentrations: 3 hours after dosing

Posaconazole

In vitro susceptibility testing

Broad spectrum of activity against
Aspergillus spp. Candida spp.
including strains resistant to fluconazole

C neoformans Trichosporon spp. Zygomycetes Dermatophytes

more effective against yeast and nondermatophyte fungi

Posaconazole

In vivo studies
In murine models
Invasive aspergillosis Histoplasmosis Coccidioidomycosis Disseminated fusariosis P boydii infections Mucor spp.

Posaconazole
Animal models of superficial fungal infections
Single oral dose of 2.5 or 10 mg
more effective than fluconazole

Topical administration at 0.25 or 0.5%

more effective than oral fluconazole oral itraconazole topical miconazole

More effective in reducing fungal burden

Posaconazole
Oropharyngeal candidiasis in a multicenter trial
a single dose of 200 mg followed by 100 mg/d posaconazole vs fluconazole
similar clinical and mycologic responses similar safety profiles

Azole cross-resistance

Mechanisms of resistance to drug action

Modification of the drug itself Modification in quantity or quality of the drug target Reduced access to the target

The resistance may result from a combination of these mechanisms

Azole cross-resistance

Factors in resistance
Overexpression of 14--demethylase
an azole-resistant strain of C glabrata the mechanism of cross-resistance exhibited with itraconazole and fluconazole

Altered membrane sterol composition

methylated sterols, such as methylfecosterol replacing ergosterol an azole-resistant and polyene-resistant C albicans mutant

Azole cross-resistance

These mechanisms may not be azolespecific

Reduced susceptibility of fluconazoleresistant isolates of Candida spp. to voriconazole and itraconazole
an indication that azole cross-resistance is developing specific to isolates of C tropicalis cross-resistance can be species-specific

Potential cross-resistance of itraconazole with fluconazole

50 isolates of C neoformans

Azole cross-resistance
Cross-resistance to itraconazole, miconazole, and voriconazole
13 isolates of S apiospermum

Posaconazole
Not show cross-resistance with other four azoles May have a mechanism of action or mechanism of resistance that differs from the other azoles

Azole cross-resistance
Heterogeneity

the azoles

in susceptibility to

The similarity of MIC values for voriconazole and ravuconazole

similar modes of action similar mechanisms of resistance

Posaconazole
not show elevations of MIC in conjunction with increased MIC values of the azoles itraconazole, miconazole, and voriconazole

Azole cross-resistance
Heterogeneity

the azoles

in susceptibility to

differences in activity of azoles different mechanisms of resistance to the azoles

explain the lack of cross-resistance between some azoles despite apparent structural similarities

Further studies into azole susceptibility patterns are required