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
Targets of Antifungal Therapy
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
Posaconazole (Noxafil®)
• 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
Posaconazole (Noxafil®)
• 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
Targets of Antifungal Therapy
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
Targets of Antifungal Therapy
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