Antifungals: Clinical Aspects

Antifungals: Clinical Aspects II

Jerika T. Lam, Pharm.D., AAHIVP, FCSHPAssociate Professor

PHRM 555: Infectious Diseases II

Learning Objectives

• Review the 5 classes of antifungals: polyenes, azoles, nucleic acid synthesis inhibitor, echinocandins and triterpenoids

• Discuss the spectrum of activity and clinical uses for each antifungal class

• Differentiate the advantages and disadvantages between each antifungal class

Types of Fungal Infections – Mycoses

• Superficial mycoses• Affect the skin, hair and nails

• Subcutaneous mycoses (tropical)• Affect the muscle and connective tissue immediately below the skin

• Systemic (invasive) mycoses• Involve the internal organs• Primary vs. opportunistic

• Allergic mycoses• Affect lungs or sinuses • Patients may have chronic asthma, cystic fibrosis or sinusitis

There is some overlap between these groups

Timeline of Antifungal Development

1957

Amphotericin B (AMB)

1989

Lipid AMB

2005

Micafungin

1979

Miconazole

1992

Itraconazole2001

Caspofungin

2006

Anidulafungin

1964

Flucytosine

1980

Ketoconazole

1990

Fluconazole

2002

Voriconazole

1995-97

Lipid AMB SalvageAspergillosis

2015

Isavuconazole

2006

Posaconazole

Adapted from: Chapman SW, et al. Trans Am Clin Climatol Assoc. 2008;119:197-215.

2021Ibrexafungerp

Fungal cell

Mannoproteins

β-(1,6)-glucanβ-(1,3)-glucan

Chitin

Phospholipid bilayer of cell membrane

Cell membrane and cell wall

Ergosterolβ-(1,3)-glucan synthase

Squalene

ErgosterolSynthesisPathway

DNA/RNA Synthesis

Recap: Fungal Structure

Targets of Antifungal Therapy

Adapted from: Moriyama B, et al. Mycoses. 2014;57(12):718-733.

Cell wall synthesis(Echinocandins + triterpenoids)

Membrane function(Polyenes) Ergosterol synthesis

(Azoles)

Nucleic acid synthesis(Flucytosine)

Targets of Antifungal TherapyMembrane function

(Polyenes)

PolyenesAmphotericin B (1958)Abelcet® (1995)Ambisome® (1997)Nystatin (1998)

Polyenes

• MOA: binds to ergosterol in the fungal cell membrane leakage of the intracellular cations and cell death

• Fungicidal and fungistatic (lower doses)• Selectivity based on the difference in

fungal vs. mammalian cell membrane (ergosterol vs. cholesterol)

• Resistance rare and mediated by changes in ergosterol content in fungal cell membrane

Nystatin (Mycostatin®, Bio-Statin®)MOA Binds to ergosterol causes leakage of essential cellular

cations = fungal cell death

Indications Treatment of susceptible cutaneous, mucocutaneous, and oral cavity fungal infections caused by Candida spp.

Dosages Oral candidiasis (suspension): 400,000 – 600,000 units QID (swish and swallow)Intestinal infections (tablets): 500,000 – 1,000,000 units Q8H

Adverse Effects Diarrhea, nausea, stomach pain, and/or vomiting; hypersensitivity reaction (rare)

Notes • Suspension: shake well before using; should be swished about the mouth and retained in mouth for as long as possible (several minutes) before swallowing

• Powder for compounding: 1/8 teaspoon (500,000 units/bottle) to equal approximately ½ cup of water; give QID

Amphotericin B

• Spectrum of activity: against most Candida, Aspergillus spp., Mucorales,Cryptococcus spp., and dimorphic fungi

• Does NOT have activity against• C. lusitaniae and C. guilliermondii• A. terreus and some A. flavus• Fusarium and Scedosporidium

• Fungizone®: conventional formulation; has lots of serious adverse effects

• Lipid formulations: liposomal amphotericin B, amphotericin B colloidal dispersion and amphotericin B lipid complex

Amphotericin B – Clinical Uses

• Cryptococcal meningitis, mucormycosis, aspergillosis (second-line), and other systemic infections caused by dimorphic fungi

• Invasive or systemic mycoses, including candidiasis not responding to other antifungal therapy

• Bladder irrigation (off-label): cystitis; fungal balls associated with UTI due to Candida

• Other methods of delivery• Intranasal• Aerosolized

Amphotericin B – Pharmacokinetics

• Absorption from the GI tract is negligible• Oral solution sometimes used to decontaminate gut; few side effects

• Only reliable method of administration is IV• Conventional amphotericin B (Fungizone®)• Amphotericin B lipid complex (ABLC; Abelcet®)• Liposomal amphotericin B (L-AMB; Ambisome®)• Amphotericin B colloidal dispersion (ABCD; Amphotec®)

• Selective distribution into deep tissue sites, with slow release of drug

kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye

LowHigh

Lipid-Based Formulations of Amphotericin B

• Advantages: less nephrotoxicity; higher doses can be administered, and decreased severity and frequency of acute infusion reactions

Lipid Formulation Dosage

Ambisome® (unilamellar liposomal product)

3 – 5 mg/kg/day

Abelcet®(lipid complex)

5 mg/kg/day

Amphotec® (cholesteryl sulfate complex)

3 – 4 mg/kg/day

Amphotericin B Lipid Formulations (cont’d)

• Lower incidence of nephrotoxicity• Infusion related reactions can still occur

• Ambisome® & Abelcet® << Amphotec®• Premedication with APAP and diphenhydramine with 1st dose

• Preferred therapy for patients intolerant of, or refractory to conventional amphotericin B

• Therapeutic failure• Initial renal insufficiency (SCr > 2.5 mg/dL, or CrCl < 25 mL/min)• Significant rise in SCr during conventional amphotericin B therapy

Afferent arteriole

Efferent arteriole

Proximaltubule Distal

tubule

Glomerulus

Direct damage of distal tubularmembranes leading to wastingof Na+, K+, and Mg++

Constriction of the afferent arterioles leading to decreased glomerular filtration

Tubular-glomerular feedback: Further constriction of arterioles

Amphotericin B – Nephrotoxicity

Amphotericin B – Nephrotoxicity (cont’d)

Renovascular & tubular mechanisms

• Vascular-decrease in renal blood flow leading to drop in GFR, azotemia• Tubular-distal tubular ischemia: wasting of K+ and Mg2+

Enhanced in patients who are volume depleted, or who are on concomitant nephrotoxic agents

Amphotericin B – Drug Interactions

• Nephrotoxic drugs• Aminoglycosides• Cyclosporine• Foscarnet• Pentamidine

• Cisplatin – nitrogen mustards increases renal toxicity of amphotericin

• Flucytosine (5-FC) – additive toxicity• Ampho B decreases 5-FC’s renal excretion increased [5-FC],

resulting in BM suppression risk

Amphotericin B – ADRs and Toxicities

• Infusion-related reactions (chills, HA, malaise)• Hypokalemia, hypomagnesemia• Hypotension• Anemia (normochromic-normocytic)• Pain at injection site• Tachypnea• Anorexia, diarrhea, nausea, vomiting, epigastric pain

Amphotericin B – Monitoring Parameters

• Electrolyte abnormalities – K+, Mg2+, Na+

• Electrolyte abnormalities – potassium, magnesium, Na & bicarbonate wasting

• Nephrotoxicity – dose dependent • Sodium loading (500 mL to 1 liter of 0.9% NaCl before and/or after dose) may suppress

tubulo-glomerular feedback• Avoid coadministration with nephrotoxic drugs• Reversible after discontinuation

• Thrombophlebitis – central line administration if possible

• Pregnancy category B


Ergosterol synthesis(Azoles)

AzolesMiconazole (1978)Ketoconazole (1981) Fluconazole (1990) Itraconazole (1992) Voriconazole (2002)Posaconazole (2006)Efinaconazole (2014)Isavuconazonium (2015)(Isavuconazole)

Azoles• 5-membered organic ring with either 2

or 3 nitrogen molecules• 2 = imidazoles• 3 = triazoles

• MOA: inhibits the fungal CYP450 enzyme lanosterol 14-α demethylase

• Fungistatic activity

• Spectrum: Candida, Cryptococcus, Coccidioides, Histoplasma, Blastomyces, & some Aspergillus spp.

• Resistance – increasing

Cell membrane

Ergosterol

ErgosterolSynthesisPathway

Squalene

Azole

Accumulation of toxic sterols in cell membrane

Toxic sterolsInhibition of14-alpha-demethylase

Azole Antifungals

• Clotrimazole (Mycelex®, etc.)• Miconazole (Monistat®, etc.)• Ketoconazole (Nizoril®)

• Fluconazole (Diflucan®)• Itraconazole (Sporanox®)

• Voriconazole (Vfend®)• Posaconazole (Noxafil®)• Isavuconazonium (Cresemba®)

Imidazoles

“1st generation triazoles”

“2nd generation triazoles”

Clotrimazole – Clinical Uses

• Buccal/oral (Mycelex®) 10 mg troche • Prophylaxis of oropharyngeal candidiasis

• 1 troche PO TID for the duration of chemotherapy, or until steroids are reduced to maintenance levels

• Treatment of oropharyngeal candidiasis• 1 troche PO 5 times daily x14 days

*Allow troche to dissolve slowly in the mouth*

Clotrimazole & Miconazole – Topical

• Clinical uses: vaginal candidiasis, cutaneous or superficial fungal infections

• Clotrimazole topical (Clotrim®, Lotrimin®, Lotrimin®AF, Gyne-Lotrimin®, Gyne-Lotrimin®3)

• Cream, solution, and vaginal cream

• Miconazole nitrate topical (Lotrimin®AF, Monistat® 1, Monistat® 3, Monistat® 7, Zeasorb-AF®, etc.)

• Cream, ointment, powder, spray, vaginal cream & suppository

Ketoconazole (Nizoral®)

• Oral formulation NOT used anymore for systemic fungal infections• CYP3A4 substrate & inhibitor: lots of drug-drug interactions!• Resistance

• High MICs in Candida spp. reported during prolonged use in patients with AIDS

• ADR profile• Nausea & vomiting: common and dose-related• Hepatotoxicity• Rash• Gynecomastia, oligospermia, decreased libido

Triazole Antifungals

• Fluconazole• Itraconazole1st generation

• Voriconazole• Posaconazole• Isavuconazonium

2nd generation (“broad spectrum”)

Fluconazole (Diflucan®)

• Spectrum of activity: most Candida spp. and Cryptococcus neoformans

• Emerging resistance to C. tropicalis & C. glabrata (dose-dependent resistance)

• Less active against dimorphic fungi• H. capsulatum, B. dermatitidis & C. immitis

• NO activity against:• C. krusei (intrinsically resistant), C. auris• Molds (Aspergillus spp., Mucorales, Fusarium and

Scedosporidium)

Fluconazole (Diflucan®) – Clinical Uses• Mucosal or vulvovaginal candidiasis• Alternative to ampho B: systemic, deep, or hepatosplenic candidiasis• Cryptococcal and coccidioidal meningitis: high doses• Eliminated by the kidneys – dose adjustments required!• Dosages

• Oropharyngeal (“thrush”): 200 mg PO/IV x1 (LD), then 100 mg PO/IV daily (MD) x2 weeks

• Vaginal infections: 150 mg PO x1• Serious infections: 400 – 800 mg IV daily• Adjustments in renal impairment

• CrCl (21-50 mL/min): give 50% of dose• CrCl (<20 mL/min): give 25% of dose • HD: replace full dose after each session

Fluconazole (Diflucan®) – PK and ADRs

• Excellent bioavailability (PO and IV)• Renally eliminated (use with caution and adjust dose)• Effectively penetrates organs and tissues, including CNS• Drug-drug interactions: CYP3A4 substrate

• CYP3A4 inhibitor (weak)• CYP2C9 inhibitor (moderate)• Monitor when coadministered with drugs that are potent CYP3A4

inducers/inhibitors• ADRs

• GI discomfort, HA, dizziness• Alopecia (at high doses and/or prolonged regimens)• C/I with drugs known to cause QT prolongation (e.g., erythromycin, quinidine,

pimozide), patients w/a history of QT prolongation

Itraconazole (Sporanox®)

• Spectrum of activity: Aspergillus spp., Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma, Trichophyton spp.

• Pharmacokinetics• Oral absorption dependent on acidic pH and

improved with food for capsule formulation, not for solution (best absorbed on empty stomach)

• Oral solution: 60% more bioavailable than capsules• Poor CNS penetration!

• CYP3A4 substrate and inhibitor (strong)

Itraconazole (Sporanox®)• Clinical uses

• Aspergillosis (intolerant or refractory to ampho B), candidiasis, coccidioidomycosis, blastomycosis, histoplasmosis, fingernail and toenail onychomycosis

• Dosages• Uncomplicated: 200 mg PO daily for 3-7 days, except for onychomycosis• Moderate to severe: 200 mg PO TID x3 days, then 200 mg PO BID x 12 months

(as stepdown therapy after initial therapy with amphotericin B)• C/I: patients with CHF due to negative inotropic effects• ADR profile

• Nausea, vomiting• Increased transaminases• Higher doses: hypokalemia, HTN (possible)• Rash

Voriconazole (Vfend®)

• Spectrum of activity: Aspergillus, Candida spp. (including fluconazole-resistant species), Fusarium, Scedosporidium

• DOC: Invasive pulmonary aspergillosis• Does NOT have activity against Mucormycetes (in the

Mucorales family)• Pharmacokinetics

• Good CNS penetration!• Bioavailability >95%• Renal impairment: use oral formulation only

Voriconazole (Vfend®) – Dosages • Standard dosing (weight-based)

• IV formulation: 6 mg/kg IV x2 doses (LD), then 3 – 4 mg/kg IV Q12H (MD)• Oral formulation

• >40 kg: 200 – 300 mg PO Q12H• <40 kg: 100 – 150 mg PO Q12H

• Hepatic impairment (mild-to-moderate)• IV formulation: 6 mg/kg IV x2 doses, then 2 mg/kg IV Q12H• Oral formulation

• >40 kg: 100 mg PO Q12H• <40 kg: 50 mg PO Q12H

• Renal impairment (CrCl <50 mL/min): use oral formulation to avoid accumulation of cyclodextrin solubilizer (SBECD) in IV formulation

Voriconazole (Vfend®)

• ADR profile• Nausea, vomiting, diarrhea -HA• Rash -Hepatoxicity• Visual disturbances/hallucinations -QTc prolongation• Photosensitivity -Risk for squamous cell skin cancer

• Consider pharmacogenomics [CYP2C19*1 (WT) vs. CYP2C19*2 and *3 (homozygous or poor metabolizer)]

• Take on empty stomach for best absorption

Voriconazole (Vfend®) – Drug Interactions

• Metabolized by CYP2C19 (major), 2C9 & 3A4 (minor)• CYP3A4 inhibitor (moderate)• CYP2C9 & 2C19 inhibitor (minor)

• Decrease voriconazole’s dose when co-administered with:• Cyclosporine• Phenytoin• Tacrolimus• Warfarin

• Should NOT be co-administered with sirolimus

Posaconazole (Noxafil®)

• Spectrum of activity: • Similar spectrum as voriconazole, but

broader to include mucormycetes(Mucorales family)

• Clinical uses• Prophylaxis: invasive Aspergillus and

Candida infections in patients who are severely immunocompromised

• Treatment: oropharyngeal candidiasis, invasive Aspergillosis


• Dosages• IV: 300 mg IV BID (Day 1), then 300 mg IV daily• Delayed-release tablet: 300 mg PO BID (Day 1), then 300 mg PO daily (with

food)• Suspension (high-fat meal increases bioavailability by 2-4 fold)

• 200 mg q6h in fasting state achieves same concentrations as 400 mg q12h with high fat meal

• Absorption is reduced if coadministered with H2RAs and PPIs

• FDA recommends using the delayed-release tablet and IV formulations• Tablet formulation is not pH dependent

• Renal impairment (CrCl <50 mL/min): use oral formulation to avoid accumulation of cyclodextrin solubilizer (SBECD) in IV formulation


• Pharmacokinetics• Absorption: enhanced with food, preferably high fat meal (suspension)• Bioavailability >95%• Metabolized via glucuronidation and P-gp

• CYP3A4 inhibitor (moderate)

• ADR profile• Hypokalemia, diarrhea, nausea• QTc prolongation, hepatotoxicity (rare)

Isavuconazonium (Cresemba®)

Isavuconazonium (prodrug) isavuconazole (active drug)

Spectrum of activity: Mucorales and Aspergillus spp.

Clinical indications Invasive mucormycosis and aspergillosis (in patients for whom amphotericin B is inappropriate)

Dosages*LD not required when switching between formulations

Loading: 2 capsules (186 mg x2) PO Q8H for 6 doses (2 days), OR 372 mg IV Q8H for 6 doses (2 days)Maintenance: 2 capsules (186 mg x2) PO daily, OR372 mg IV daily

Comments Does NOT contain SBECD can be given to patients with renal impairment

Isavuconazole (active moiety)

• Pharmacokinetics• Bioavailability >95%• Metabolized via CYP3A4 enzyme

• CYP3A4 inhibitor (moderate); also inhibits 2C9, 2C19, and 2D6

• CYP3A4, 2C9 and 2B6 inducer

• ADR profile• Peripheral edema, hypokalemia, N/V/D• Constipation (less than diarrhea), HA, dyspnea, cough and backache

Fungus Fluconazole Itraconazole Voriconazole Posaconazole IsavuconazoleC. albicans +++ ++ +++ +++ -

C. glabrata + + ++ ++ -

C. krusei -- + +++ ++ -

C. tropicalis +++ ++ +++ +++ -

C. parapsilosis +++ ++ +++ +++ -

C. lusitanae ++ ++ +++ +++ -

Aspergillus -- ++ +++ +++ +++Cryptococcus +++ +++ +++ +++ -

Coccidioides +++ +++ +++ +++ -

Blastomyces ++ +++ ++ +++ -

Histoplasma + +++ ++ +++ -

Fusarium -- -- ++ ++ +/-

Scedosporium -- +/- + +/- +/-

Mucorales - - - ++ +++

Comparison of ADRs

ADR AzoleDiarrhea/vomiting Itraconazole > Posaconazole > Fluconazole

Nausea Itraconazole > Posaconazole ≈ Fluconazole

Hypokalemia Itraconazole > Posaconazole > Fluconazole

Hypertension Posaconazole > Fluconazole > Itraconazole

Rash Itraconazole > Posaconazole ≈ Fluconazole

Summary 1: Azoles’ Spectrum of Activity

• Fluconazole – preferred to treat Candida spp (i.e., C. albicans)• Except for C. krusei and C. auris

• Voriconazole, posaconazole and isavuconazole are ACTIVE against Aspergillus

• Fluconazole is NOT active

• Voriconazole and posaconazole and isavuconazole (maybe) have some promise in the treatment of Scedosporium and Fusarium

• Posaconazole and isavuconazole are most active against Mucorales• Consider their use if patient is intolerant or failed amphotericin B

Summary 2: Azoles – Pharmacodynamics

Concentration-independent fungistatic activity • Dosage escalation may be necessary when faced with more

resistant fungal species (i.e., C. glabrata)

Goal of dosing is to maintain AUC:MIC > 50• Maintain concentrations 1-2 x MIC for the entire dosing interval

Summary 3: Azoles’ PharmacokineticsFluconazole, voriconazole, posaconazole (DR tabs), isavuconazole have oral bioavailability >95% and are not affected by increases in gastric pH

Itraconazole capsules and tablets can be affected by H2RAs and PPIs

Posaconazole DR tablets and IV formulation are preferred• Posaconazole suspension is affected by H2RAs and PPIs; bioavailability dependent on high fat meal• Metabolized by glucuronidation and P-gp

Fluconazole, voriconazole and isavuconazole can achieve therapeutic CSF concentrations• Itraconazole and posaconazole cannot

Posaconazole and isavuconazole have high plasma protein binding >95%• Fluconazole and voriconazole have low plasma protein binding

Summary 3: Azoles’ Pharmacokinetics (cont’d)Fluconazole is dependent on the kidney for elimination• Itraconazole, voriconazole, Posaconazole and isavuconazole are NOT

Voriconazole and posaconazole contain SBECD excipient• Avoid IV use in eGFR <50 mL/min/1.73

Fluconazole, itraconazole, voriconazole and isavuconazole are metabolized by CYP3A4

Voriconazole is also metabolized by CYP2C19 (PGx testing) and CYP2C9

All azoles inhibit CYP3A4 substrates (itraconazole is strongest)

Fluconazole and isavuconazole inhibit CYP2C9 substrates

Summary 4: Azoles’ Adverse Effects

Dose-related upper GI (N/V)Alopecia (fluconazole at high dose or chronic use)Altered LFTs (particularly voriconazole)Visual disturbances (voriconazole)Photosensitivity (voriconazole)QT prolongation & Torsades de Pointes (fluconazole, voriconazole, posaconazole)Nephrotoxicity (voriconazole, posaconazole)Squamous cell carcinoma (voriconazole possible over long-term use)Periostitis (voriconazole)

Summary 5: Azoles’ Other Points

• Hepatotoxicity• CYP450 drug-drug interactions• Rash• Pregnancy category D


Nucleic acid synthesis(Flucytosine)

Flucytosine (Ancobon®, 5-FC)

MOA Inhibits thymidylate synthetase interrupts nucleic acid and protein synthesis = fungal cell death

Indications Adjunctive treatment of systemic Candida and Cryptococcus infections (e.g., septicemia, endocarditis, UTI, meningitis, or pulmonary)

Dosages 50 – 150 mg/kg/day PO Q6H

Adverse Effects Abdominal pain, diarrhea, nausea, vomiting, confusion, HA, hallucinations; nephrotoxicity and bone marrow toxicity (rare)

Notes • Well distributed in the CNS• Used for fluconazole- or voriconazole-resistant isolates• Synergistic clinical activity in combination with amphotericin B

-Potential additive 5-FC toxicity BM suppression risk• Should NOT be used as monotherapy – resistance!

Flucytosine (Ancobon®, 5-FC)

• Fungistatic activity

• Pharmacokinetics• Rapid GI absorption; bioavailability >80%• Protein binding ~10%• Vd: 0.7 – 1 L/kg; CSF concentrations 63-88% of serum• t1/2: 3 – 5 hours • Elimination: >90% renal

Flucytosine (Ancobon®, 5-FC) – ADRs and Toxicities

• Concentration-dependent BM suppression• Neutropenia, leukopenia, pancytopenia• Caution in renal impairment

• Increased hepatic transaminases (hepatotoxicity)

• Nausea, vomiting and/or diarrhea• Dose dependent• Use smaller divided doses

Flucytosine – Monitoring Parameters

LFTs Renal

WBC Pregnancy


Cell wall synthesis(Echinocandins + triterpenoid)

EchinocandinsCaspofungin (2001)Micafungin (2005)Anidulafungin (2006)

TriterpenoidsIbrexafungerp (2021)

Echinocandins

• Spectrum of activity: Candida spp. (cidal activity), Aspergillus spp., Blastomyces, Coccidioides,

• MOA: inhibits β(1,3) glucan synthase blocks fungal cell wall synthesis

• Caspofungin (Cancidas®)• Micafungin (Mycamine®)• Anidulafungin (Eraxis®)

Echinocandins – Spectrum of ActivityFungus Potency

Aspergillus +++Candida spp.

guilliermondiilusitanaeparapsilosistropicaliskruseiglabrataalbicansauris

++++

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

Histoplasma --Blastomyces ++Coccidioides ++Cryptococcus --Mucorales, Scedosporidium, Fusarium --

Echinocandins - ComparisonCaspofungin (Cancidas®) Micafungin (Mycamine®) Anidulafungin (Eraxis®)

Absorption Not orally absorbed. IV administration onlyDistribution Extensive into the tissues. Minimal CNS penetrationMetabolism Hydrolysis and N-acetylation. Spontaneous

degradationNot hepatically metabolized.

Chemical degradation

Elimination Limited urinary excretion. Not dialyzableDose 70 mg IV on day 1, then

50 mg IV daily100 – 150 mg IV daily *200 mg IV on day 1,

then 100 mg IV dailyDose adjustments

Child-Pugh 7-970 mg IV on day 1, then

35 mg IV daily

None None

*Dose is for disseminated candidiasis and candidemia. Dose will vary depending on fungal infection

Caspofungin (Cancidas®)

• ADR profile• Diarrhea• Nausea• Pyrexia• Chills• Rash

• Drug-drug interactions• Potent CYP inducers (PHT, CBZ, rifampin): reduce caspofungin levels• Cyclosporine: increases AUC of caspofungin hepatotoxicity risk (avoid if

possible)• Tacrolimus: reduced tacrolimus levels by 20% monitor tacrolimus trough levels

MD = 50 mg LD = 70 mg

Micafungin (Mycamine®)

• ADR profile• Phlebitis, pruritus• Diarrhea, nausea, vomiting• Pyrexia• Rash

• Drug-drug interactions (CYP3A4 weak inhibitor) – monitor for toxicity• Nifedipine: increased AUC (18%) and Cmax (42%) of nifedipine• Sirolimus: increased AUC (21%) of sirolimus• Itraconazole: increased AUC (22%) and Cmax (11%) of itraconazole

Anidulafungin (Eraxis®)

• ADR profile• Nausea, diarrhea, vomiting• Pyrexia• Peripheral edema• Hypokalemia• Dyspepsia• HA

• No clinically significant drug-drug interactions

Ibrexafungerp (Brexafemme®)

• Novel class called triterpenoids• Structurally-distinct glucan synthase inhibitors

• Active against Candida, Aspergillus, Pneumocystis• Including C. auris and echinocandin-resistant C. glabrata• Including azole-resistant strains of A. fumigatus

Ibrexafungerp (Brexafemme®)• Candida vulvovaginitis: 300 mg PO BID (for a total

of 600 mg) with food• Verify pregnancy status in females of childbearing age

prior to initiation• Use effective contraception during treatment and for 4

days after the last dose

• C/I: pregnancy• ADRs

• Abdominal pain, diarrhea, nausea, vomiting (less common), dizziness

• Metabolized by CYP3A4 and P-gp• Inhibits CYP3A4 and P-gp substrates

Antifungal Activity – Comparison

Azoles: Interactions in the GI TractDrug-pH

Portal vein

Gut wallTo feces

Metabolism

Metabolism

Absorption

Bioavailability

Liver

CYP

efflux P-gp

CYPCYP

CYP

CYP

CYPCYPCYP CYP

Proportion of Drugs Metabolized by CYP P450

Azole Drug InteractionsComponent Substrate(s) Inhibitors

2C9 VoriconazoleFluconazoleItraconazoleVoriconazole

2C19 Voriconazole FluconazoleVoriconazole

3A4

FluconazoleItraconazoleVoriconazoleIsavuconazole

FluconazoleItraconazoleVoriconazolePosaconazoleIsavuconazole

P-glycoprotein PosaconazoleItraconazole

PosaconazoleIsavuconazole

3A4

2C19 2D6 2C9

1A2 2E1 2A6 2B6 2C8

Fluconazole (~ 50%)Itraconazole (> 90%)Voriconazole (~ 90%)Isavuconazole (?)Ibrexafungerp (?)

Rifampin Phenytoin CarbamazepinePhenobarbital

Ritonavir will inhibit CYP3A4 substrates and can induce CYP1A2 and 2C9 substrates

Reduction in levels

Summary: Azoles’ Drug Interactions

• Antacids, H2RAs, omeprazole do NOT impact fluconazole or voriconazole bioavailability

• PPIs ↓ the oral bioavailability of posaconazole (suspension >> DR tablet)• Itraconazole’s absorption can also be ↓ by H2RAs and PPIs

• Rifampin (& potent enzyme inducers) increase both gut and hepatic metabolism of azoles resulting in ↓ azole serum levels

• Azoles (vori > posa > flu) inhibit CYP450 system increase levels of sirolimus, CSA, tacrolimus, BZDs, glucocorticoids, warfarin

Important Antifungal Drug-Drug InteractionsAntifungal Concerns Drugs to Avoid

Amphotericin B Associated nephrotoxicity Drugs with potential additive nephrotoxicity

Itraconazole*Posaconazole**

Impact of gastric acidity

Medications that alter gastric pH (eg, proton pump inhibitors and histamine-2 blockers)

Azole Class

Role as CYP450 enzyme substrates and inhibitors

Antiarrhythmics, antipsychotics, immunosuppressants, migraine medications, antibiotics, anticoagulants, antidepressants, antiepileptics, antiretrovirals, chemotherapies, antihypertensives, lipid-lowering agents, narcotics, sedatives, hormonal therapies, and diabetes drugs

Caspofungin Use of OATP-1B1 transporter

Immunosuppressants, antiepileptics, antiretrovirals, and rifampin

*Oral capsule; **oral solution.CYP450, cytochrome P450; OATP1B1, organic anion transporting polypeptide 1B1.

Summary – Key Takeaways

• Amphotericin B – monitor for electrolyte disturbances & nephrotoxicity• Infusion-related rxns: premedicate with APAP & diphenhydramine

• Fluconazole is effective against yeast infections (preferred for mucocutaneous, candiduria and meningitis)

• Voriconazole pharmacogenomics & adverse effect profile (visual disturbances/hallucinations and possible QT prolongation)

• Isavuconazole dose does not need to be adjusted in renal impairment• Flucytosine is used in combination therapy (i.e., ampho B) for synergistic

activity• Echinocandins are safer than polyenes for treatment of invasive

candidiasis and aspergillosis

Summary – Key Takeaways (cont’d)

• Voriconazole (and isavuconazole) are preferred for invasive pulmonary aspergillosis

• Posaconazole has the broadest spectrum of activity among the azoles• Ibrexafungerp is only approved for vulvovaginal candidiasis

• Active against multidrug-resistant pathogens, including azole- and echinocandin-resistant strains

• Azoles have the most drug-drug interactions compared to polyenes and echinocandins

Documents

Antifungals: Clinical Aspects