CONTENTS

• Azoles:
  • Voriconazole
  • Isavuconazole
  • Posaconazole
  • Fluconazole
  • Itraconazole
• Echinocandins (caspofungin, micafungin, anidulafungin)
• Liposomal amphotericin

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voriconazole

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1) voriconazole: contraindications & drug-drug interactions

contraindications

• ⚠️ QTc prolongation.
• ⚠️ Renal failure? (GFR <50 ml/min might be a relative contraindication, but this is probably safe – see the discussion under the “pharmacology” section).
• ⚠️ Active hepatitis with deteriorating liver function tests (renders monitoring of liver function tests impossible) or severe liver disease (e.g., Child-Pugh class C cirrhosis).

drug-drug interactions include

• CYP inducers (e.g., rifampin, phenytoin) may reduce voriconazole levels.
• Voriconazole is metabolized by CYP2C19, so inhibitors of that enzyme may increase voriconazole levels.
• Voriconazole inhibits CYP2C9 weakly, CYP2C19 moderately, and CYP3A4 strongly. This may increase levels of other medications.

More common drug-drug interactions are discussed below. However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.

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2) voriconazole: dosing & monitoring

voriconazole dosing

• Dosing for invasive aspergillus:
  • IV: Load with 6 mg/kg q12 hours on day #1, then decrease to a maintenance dose of 4 mg/kg q12 hours.
  • PO: Load with 400 mg q12hr on day #1, then maintenance therapy at 200 mg PO q12hr.
  • Oral absorption is excellent and may reduce the risk of nephrotoxicity.
• Hepatic dysfunction (Child class A & B): Same loading dose, reduce maintenance dose by 50%. Follow liver function tests and voriconazole drug levels. Avoid voriconazole in patients with severe liver disease. (36836260)
• Renal dysfunction: No dose adjustment. Renal failure might be a relative contraindication to the intravenous form of voriconazole, but this is debatable (discussed in the “pharmacology” section).
• More information: 📚 Medscape monograph on voriconazole

voriconazole monitoring

• Monitoring liver function tests may be advisable in chronic therapy (e.g., baseline, after two weeks, and then every month).
• If prolonged at baseline, consider following the QTc interval.
• Therapeutic drug monitoring should be utilized when treating invasive fungal infections, especially in the ICU. (36823543) Trough levels may be checked after ~4-5 days of therapy and repeated the following week (or, more frequently, PRN). (22761409, ESCMID18)
  • Target trough level is ~2-6 mg/L for patients with multifocal disease or disseminated aspergillosis.(ESCMID18)
  • Trough levels below <1-2 mg/L are associated with treatment failure, so consider dose escalation.
  • Trough levels over ~5.5-6 mg/dL are associated with an increased risk of delirium and hepatotoxicity.
  • EUCAST defines >1 mg/L as the breakpoint for voriconazole sensitivity among Aspergillus fumigatus. (36836260)

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3) voriconazole: pharmacology

• Oral bioavailability:
  • Generally well absorbed (>90%) if taken at least one hour before or after a meal. (36836260)
  • Fatty foods may decrease absorption by ~30%.
• Protein binding in the blood is moderate, at 58%.
• Half-life is 6 hours. Pharmacokinetics are nonlinear and may be difficult to predict.
• Elimination is via hepatic metabolism (by CYP2C19 > CYP3A4). Slow metabolizers may accumulate higher levels of voriconazole (more common in patients with Asian or Pacific Islander ancestry). Alternatively, ultrarapid CYP2C19 metabolizers are unlikely to achieve therapeutic voriconazole levels. (34016281)
• Penetration:
  • The volume of distribution is large, at 4.5 L/kg.
  • Good penetration of CSF and eye.
  • Doesn't penetrate the urine well (not useful in fungal urinary tract infections).
• Intravenous voriconazole is solubilized with sulfobutylether-beta-cyclodextrin (SBECD), the same cyclodextrin vehicle used to solubilize remedsivir.
  • Among patients with GFR <50 ml/min, SBECD can accumulate and possibly cause kidney injury. However, there is no strong evidence that SBECD is nephrotoxic. (34016281)
  • Oral voriconazole is definitely safe in patients with renal dysfunction (since it doesn't contain SBECD).

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4) voriconazole: toxicity

• RCTs comparing voriconazole to either isavuconazole or posaconazole for the treatment of aspergillosis have found a higher rate of adverse events with voriconazole.
• QTc prolongation.
• Visual disturbance:
  • Transient, infusion-related hallucinations rarely require discontinuation of voriconazole (typically resolves in the first week of therapy).
  • Occurs in ~25% of patients. Seems related to serum concentrations. (34016281)
• Neurotoxicity may include hallucinations, delirium, agitation, or myoclonus (dose-related, suggests excessive voriconazole levels).
• Hepatitis (mostly reversible, but severe liver injury is possible. Along with itraconazole, this is one of the more hepatotoxic azoles). (36836260)
• Hypoglycemia.
• Pneumonitis.
• Nausea, vomiting, or abdominal discomfort may occur.
• Adrenal insufficiency (all azoles except for isavuconazole). (34016281)

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5) spectrum & use

• Candida
  • Voriconazole has anti-Candida activity similar to that of fluconazole. (31789904)
  • It may be used as step-down therapy for fluconazole-resistant isolates (e.g., Candida glabrata or Candida krusei).
• Aspergillus
  • Voriconazole is front-line therapy for invasive aspergillosis (with better outcomes than amphotericin in one RCT). (12167683)
  • Some rare Aspergillus species are intrinsically resistant to voriconazole (e.g., A. calidoustus, A. pseudodeflectus, A. lentulus, A felis, A viridinutans, A, hiratsukae, A tsurutae). (36836260)
• Other molds:
  • Voriconazole is active against dematiaceous molds (e.g., Alternaria, Bipolaris, Exerohilum,  Scedosporium angiospermum) and hyaline molds (including Fusarium, Talaromyces, and Paecilomyces spp). (36836260) 
  • Voriconazole doesn't cover Zygomycetes (e.g., Mucorales spp.) – so it's not ideal as an empiric anti-mold agent in patients with longstanding immunosuppression.
• Endemic fungi, including coccidioidomycosis, histoplasmosis, and blastomycosis. (19139290) Although voriconazole hasn't traditionally been used for these infections, it may be helpful in selected cases (e.g., patients with CNS involvement or contraindications to amphotericin).

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isavuconazole

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1) isavuconazole: contraindications & drug-drug interactions

contraindications

• ⚠️ Congenital short QT syndrome (unlike most azoles, isavuconazole shortens the QT interval!).
• ⚠️ Active hepatitis with deteriorating liver function tests is a relative contraindication (since this renders monitoring of liver function tests impossible).  However, isavuconazole is less hepatotoxic than other azoles (e.g., itraconazole, ketoconazole), so isavuconazole may be utilized among patients with mild transaminase elevations. Isavuconazole has been well-tolerated in patients who discontinued posaconazole due to liver toxicity. (30230043)

drug-drug interactions include

• Isavuconazole levels are affected by medications that affect the CYP3A4 system (e.g., rifampin reduces isavuconazole levels by 90%, and lopinavir/ritonavir doubles isavuconazole levels). (29725999)
• Isavuconazole affects levels of various agents handled via numerous systems (e.g., CYP3A4 system, P-glycoprotein system, organic anion transport systems, and CYP2C9).
• The table below shows some notable drug interactions. (However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.)

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2) isavuconazole: dosing & monitoring

isavuconazole dosing

• Typical dosing scheme
  • Loading dose: 372 mg isavuconazonium sulfate (a.k.a., 200 mg isavuconazonium base) PO/IV q8 hr x6 doses for two days.
  • Maintenance dose: 372 mg isavuconazonium sulfate (a.k.a., 200 mg isavuconazonium base) PO/IV q24hr.
  • Doses should be infused slowly over one hour to avoid an infusion reaction.
  • Note: The medication itself is given as isavuconazonium sulfate, a pro-drug metabolized into isavuconazole (the active drug). 372 mg isavuconazonium sulfate is equivalent to 200 mg isavuconazonium base.
• No dose adjustment is needed for renal or hepatic impairment (although this hasn't been studied for severe hepatic dysfunction).
• More information: 📚 Medscape monograph on isavuconazole

isavuconazole monitoring

• Therapeutic drug monitoring generally isn't needed.
• Monitoring liver function tests may be advisable in chronic therapy (e.g., baseline, after one month, then every 1-2 months).

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3) isavuconazole: pharmacology

• Oral bioavailability is ~100%, allowing oral dosing to be used interchangeably with intravenous dosing.
• Protein binding is 98-99%. This gives isavuconazole a long half-life and also prevents drug clearance by hemodialysis.
• Half-life is ~80-120 hours.
• Elimination is via hepatic metabolism (including uridine diphosphate glucuronosyltransferase and CYP3A4).
  • <1% excreted in urine, so isavuconazole may have little use in treating urinary tract infections. (29725999)
• Penetration
  • The volume of distribution is 6.5 L/kg.
  • Isavuconazole penetrates extensively into tissues, including the brain and eye. (32000291) However, CSF levels are low. (29551442)

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4) isavuconazole: toxicity

• Gastrointestinal side-effects (most commonly reported adverse events are nausea, vomiting, and diarrhea).
• Severe hepatic impairment may rarely occur.
• It may reduce the QT interval (!), but this is rarely an issue clinically.
• Hypokalemia, peripheral edema.
• Infusion reactions (chills, dyspnea, and hypotension).

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5) spectrum & use

• The spectrum of activity is similar to voriconazole with a few differences:
  • Active against Mucorales (including Rhizopus arrhizus, Lichtheimia, and Rhizomucor spp).  However, activity is weaker against Mucor circinelloides and other Mucor spp. (36836260)
  • (Aspergillus spp. resistant to voriconazole will often be resistant to isavuconazole as well). (36836260)
• Advantages of isavuconazole over voriconazole:
  • (1) Broader spectrum of activity, including Mucorales species (involved in mucormycosis).
  • (2) More favorable safety profile (especially regarding QT prolongation). In the SECURE trial, isavuconazole was non-inferior to voriconazole against invasive aspergillus or other filamentous fungi, yet isavuconazole was better tolerated. (26684607)
  • (3) Isavuconazole causes fewer drug-drug interactions (voriconazole interacts with more hepatic CYP enzymes than isavuconazole does). (31102782)
• Uses of isavuconazole include:
  • Empiric therapy for invasive mold infection: isavuconazole has the advantage of covering both Aspergillus and Mucorales species if the causative mold is unknown.
  • Potential use as induction therapy for endemic fungi? This remains unclear, being supported only by a single-arm study. (27169478) In vitro, isavuconazole appears to have favorable coverage of endemic fungi compared to other azoles, supporting a potential therapeutic role. (29534853)
  • Isavuconazole might be used for invasive candidiasis in selected situations. However, one study suggested inferior outcomes compared to echinocandins, so isavuconazole cannot be considered as a front-line agent against Candida spp. (30289478)

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posaconazole

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1) posaconazole: contraindications & drug-drug interactions

contraindications

• ⚠️ Active hepatitis with deteriorating liver function tests.
• ⚠️ QTc prolongation, but the effect on QTc seems to be small (e.g., QT prolongation noted in only 4% of one trial). (17251531)
• ⚠️ Interaction with essential medication (listed below).

drug-drug interactions include

• Posaconazole strongly CYP3A4, which will increase levels of drugs metabolized by CYP3A4, most notably:
  • Amiodarone.
  • Calcium channel blockers metabolized by CYP3A4 (diltiazem, verapamil)
  • Cyclosporine, tacrolimus, sirolimus (increases sirolimus levels by ~9 fold).
  • Ergot alkaloids.
  • Ibrutinib.
  • Midazolam.
  • Statins.
  • Vardenafil.
  • Vinka alkaloids.
• Other interactions:
  • Causes increased levels of Venetoclax (used to treat CLL or small lymphocytic lymphoma).
  • Two-way interaction with phenytoin (reduced posaconazole levels, increased phenytoin levels).
  • Increased posaconazole levels: rifabutin, efavirenz, fosamprenavir.
• More common drug-drug interactions are discussed above. However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.

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2) posaconazole: dosing & monitoring

posaconazole dosing

• Standard dose: 300 mg PO BID on day #1, then 300 mg PO daily. Administration with food may improve absorption.
• Renal adjustment:
  • Oral administration is safe without any dose adjustment. (31617055)
  • Intravenous posaconazole contains a sulfobutylether-beta-cyclodextrin (SBECD) vehicle that could accumulate among patients with GFR <50 ml/min.
• Hepatic adjustment: No adjustment is needed for cirrhosis, even Child-Pugh class C.
• Obesity: consider increasing the dose to 400 mg among patients >140 kg and possibly 500 mg among patients >190 kg. (31971567)
• More information: 📚 Medscape monograph on posaconazole

posaconazole monitoring

• Monitoring liver function tests may be advisable in chronic therapy (e.g., baseline, after one month, then every 1-2 months).
• If prolonged at baseline, consider following the QTc interval.
• Therapeutic dose monitoring may be considered since ~20% of patients may have subtherapeutic drug levels even using the tablet formulation. (32478597) Given the long half-life, a steady state is reached after about a week. 
  • Target trough >1 mg/L to treat invasive aspergillosis. (36836246) Higher levels may be needed to treat Mucorales, Fusarium, and Scedosporium spp. (36836260)
  • Target trough >0.7 mg/L for antifungal prophylaxis.
  • Higher levels of posaconazole don't appear to correlate with any higher risk of adverse events. (32478597)
  • The EUCAST posaconazole breakpoint for A. fumigatus is >0.25 mg/L. (36836260) Notably, most of the drug is in the tissues, so the serum level may not be very high.

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3) posaconazole: pharmacology

• Oral bioavailability:
  • Absorption is improved by administration with food (especially high-fat food).
  • Delayed release tablet has a bioavailability of 54%. (32722455)
  • Oral suspension: variable bioavailability with saturable absorption. (32722455) Antacid administration doesn't affect the bioavailability of tablets substantially, but it may reduce the absorption of oral liquid suspension. (32000291)
• Protein binding in the blood: >98%.
• Half-life is ~24 hours.
• Elimination
  • Only ~15% is metabolized in the liver via UDP-glucuronosyltransferase (UGT) 1A4.
  • Posaconazole is mostly excreted unchanged in the feces (70%).
  • Some posaconazole is excreted in the urine (~15%) mostly as inactive glucuronide conjugates (with only trace amounts of unchanged drug). (32478597)
  • Unlike other azoles, posaconazole is not metabolized by the CYP enzyme system.
• Penetration: The volume of distribution is large, suggesting extensive penetration into peripheral tissues (studies vary in the range of ~500 liters). (32000291, 32478597) Its octanol/water partition coefficient is 5.5. (32478597) Concentrations in alveolar cells are ~32 times higher than blood concentrations. (36836260)

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4) posaconazole: toxicity

• Posaconazole is generally better tolerated than voriconazole.
• Gastrointestinal side effects are more common with the oral suspension than with the delayed-release pill (e.g., anorexia, emesis, diarrhea).
• Other side effects may include:
  • Rash.
  • Fever.
  • Abnormal liver function tests; hepatitis.
  • Mineralocorticoid excess (causing hypertension, hypokalemia) due to inhibition of 11-beta-hydroxysteroid dehydrogenase inhibition.
  • Neutropenia. (32000291)

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5) spectrum & use

• Spectrum of activity:
  • Overall, it is similar to voriconazole, with a few salient differences:
  • Added efficacy against Mucor.
  • Lower MIC against. A. fumigatus.
  • Higher MIC against. A. niger. (36836260)
• Advantages of posaconazole over voriconazole:
  • Posaconazole is better tolerated, including fewer CNS side effects.
  • Activity against Mucorales.
• Uses of posaconazole include:
  • Prevention of fungal infection in patients with hematologic malignancies.
  • Mold infections including invasive pulmonary aspergillosis, mucormycosis, and fusariosis.
  • Endemic mycoses including histoplasmosis, blastomycosis, cryptococcosis, and cocciodomycosis. (32722455)

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fluconazole

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1) fluconazole: contraindications & drug-drug interactions

contraindications

• ⚠️ QTc prolongation.
• ⚠️ Active hepatitis with deteriorating liver function tests (renders monitoring of liver function tests impossible).

drug-drug interactions include

• CYP inducers (e.g., rifampin and phenytoin) may reduce fluconazole levels.
• Fluconazole is a strong inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4 and CYP2C19. This may increase levels of other medications (e.g., warfarin, phenytoin, cyclosporine, tacrolimus). Fluconazole also inhibits uridine diphosphate-glucuronosyltransferase (UGT).

More common drug-drug interactions are discussed below. However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.

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2) fluconazole: dosing & monitoring

fluconazole dosing

• Dose for various infections:
  • Oropharyngeal or esophageal candidiasis: 200 mg load, followed by 100 mg daily.
  • Systemic candidiasis: 800 mg IV load, followed by 400 mg IV daily (or 12 mg/kg and 6 mg/kg, respectively; see the section on obesity below).
  • Blastomycosis: 400-800 mg/day, but not generally preferred. (34364529)
  • Coccidioidomycosis: range of 400-1,200 mg/day.
    • 400-800 mg/day may be used for primary pulmonary infection.
    • 800-1,200 mg/day may be used for patients with CNS involvement.
• Renal adjustment:
  • GFR 11-50 ml/min: reduce dose by 50%.
  • Hemodialysis: replace dose after dialysis.
• Hepatic dysfunction: No dose adjustment.
• Obesity: Consider adjusting the dose based on actual body weight (load with 12 mg/kg, then maintenance dose 6 mg/kg daily). (31617055) The DALI study found that at least 5 mg/kg should be administered to reach therapeutic drug levels. (25888060) Consequently, the ESICM recommends weight-based dosing for invasive candidiasis. (30911804)
• More information: 📚 Medscape monograph on fluconazole

fluconazole monitoring

• Monitoring liver function tests may be advisable in chronic therapy (e.g., baseline, after one month, then every 1-2 months).
• If prolonged at baseline, consider following the QTc interval.

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3) fluconazole: pharmacology

• Oral bioavailability is 90-100% (unaffected by gastric pH or food). IV and oral doses are interconvertible.
• Protein binding in the blood: Fluconazole is only 12% in the blood. Unlike other azoles, fluconazole circulates mostly as free drug. (32000291)
• Half-life is ~30 hours.
• Elimination is mainly via the kidney, where it is excreted unchanged.
• Penetration:
  • The volume of distribution is ~0.7 L/kg.
  • Good penetration of the eye and CNS.
  • Excellent pulmonary penetration (levels in lung tissue are ~130% of plasma levels). (21502769)
  • Excellent urinary concentrations since fluconazole is primarily excreted unchanged in the urine.

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4) fluconazole: toxicity

• Fluconazole is generally well tolerated (even when used chronically).
• Gastrointestinal side-effects (nausea, vomiting, abdominal discomfort).
• Transaminase elevation can occur. Rarely, fluconazole may cause severe hepatic injury.
• QTc prolongation.
• Adrenal insufficiency (all azoles except for isavuconazole). (34016281)

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5) spectrum & use

• Fluconazole is only active against yeasts (whereas other azoles are active against both yeasts and molds).
• Candida species: fluconazole covers most, but not all (missing Candida glabrata and Candida krusei).
  • Fluconazole may be used as initial therapy for mild infection (e.g., candida esophagitis).
  • Fluconazole shouldn't be used as empiric therapy for invasive Candida infection acquired in the ICU. However, fluconazole may be used as a step-down therapy, following empiric treatment with an echinocandin (if the Candida species is sensitive to fluconazole). (31617055)
• Cryptococcus neoformans: Fluconazole is the agent of choice for patients with CNS involvement due to excellent CNS penetration.

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itraconazole

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1) itraconazole: contraindications & drug-drug interactions

contraindications

• ⚠️ Heart failure (may impair systolic heart function).
• ⚠️ QT prolongation.

drug-drug interactions include

• Numerous CYP interactions (itraconazole is a potent inhibitor and substrate of CYP3A4).
• Avoid co-administration of tablets with proton pump inhibitors or H2-blockers due to reduced absorption (the oral liquid may be utilized in this situation).

More common drug-drug interactions are discussed below. However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.

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2) itraconazole: dosing & monitoring

itraconazole dosing

• Absorption:
  • Original capsules should be taken with food or an acidic beverage (e.g., cola). Absorption is variable (~55) and requires gastric acidity.
  • The oral liquid should be taken on an empty stomach. This may be useful for patients who require gastric acid suppression or if capsules fail to achieve adequate itraconazole levels. Overall, itraconazole liquid is often preferred due to superior bioavailability (80%, about 30% higher than capsules) and less inter-patient variability. (36836260)  However, it may have more gastrointestinal side effects. (35233706)
  • Super-BioAvailable (SUBA) capsules have improved bioavailability compared to original capsules. Bioavailability isn't affected by gastric pH. (34016286)
• Typical dosing regimen:
  • Loading dose of 200 mg TID for three days, followed by 200 mg twice daily.
  • 💡 Itraconazole has a half-life of about 40 hours so that it won't reach a steady state immediately. When transitioning from amphotericin to itraconazole, consider beginning the loading doses of itraconazole before discontinuing amphotericin. (36675937) 
• Renal dysfunction: no adjustment.
• Hepatic dysfunction: no adjustment, but monitor for hepatotoxicity. (36836260)
• 📚 Medscape monographs on itraconazole.

itraconazole monitoring

• Monitoring liver function tests may be advisable in chronic therapy (e.g., baseline, after one month, then every 1-2 months).
• If prolonged at baseline, consider following the QTc interval.
• Therapeutic drug monitoring:
  • Most laboratories test this using HPLC (high-performance liquid chromatography), which reports both the itraconazole and hydroxy-itraconazole concentrations. Since hydroxy-itraconazole has the same antifungal activity as the parent drug, the sum total of these two compounds should be considered as the total concentration of the active drug.
  • Drug levels should be measured after two weeks of therapy.  The target trough level is 2-5 mcg/mL. (36675937; 36836350)
  • Aspergillus is considered sensitive to itraconazole if the MIC is 1 mg/L. (36836260)

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3) itraconazole: pharmacology

• Protein binding: 99.8%
• Absorption: discussed above
• Half-life: 32-42 hours.
• Elimination: Metabolized by the liver (mostly CYP3A4). The main metabolite is hydroxy-itraconazole, which has the same antifungal activity as itraconazole.
• Distribution:
  • Negligible CSF or ocular concentrations.
  • High concentrations (~400 ng/mL) in bronchial fluid. (36836260)

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4) itraconazole: toxicity

• Gastrointestinal side-effects (nausea, vomiting, diarrhea, abdominal discomfort).
• Hepatotoxicity (can occur with any azole, but risk is highest with itraconazole or voriconazole). (36836260)
• Heart failure.
• QT prolongation.
• Hearing loss, neuropathy.
• Rash.
• Effects on steroid hormone biosynthesis:
  • Pseudohyperaldosteronism (hypertension, sodium retention, hypokalemia, metabolic alkalosis). In some patients, this may cause heart failure exacerbation and/or hypertension.
  • Adrenal insufficiency (rarely occurs due to chronic use; this is a potential side effect of all azoles except for isavuconazole). (34016281)

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5) spectrum & use

• Spectrum of coverage:
  • Aspergillus (however, doesn't cover mucormycosis).
  • Candida (including C. krusei, C. glabrata, and C. tropicalis).
  • Cryptococcus.
  • Endemic mycoses (blastomycosis, histoplasmosis, coccidiomycosis).
• Clinical uses:
  • (1) Indolent, non-CNS infection with endemic fungi (blastomycosis, histoplasmosis, coccidiomycosis).
  • (2) ABPA (allergic bronchopulmonary aspergillosis).

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echinocandins (micaFUNGIN, caspoFUNGIN, anidulaFUNGIN)

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1) contraindications & drug-drug interactions

contraindications

• Consider avoiding in acute hepatic failure with deteriorating liver function tests (since this renders monitoring of liver function tests impossible).

drug-drug interactions

• Caspofungin: Metabolism of caspofungin may be accelerated, leading to lower caspofungin levels by strong inducers of CYP3A4 (e.g., rifampin, carbamazepine, dexamethasone, phenytoin). This may require using a higher maintenance dose of caspofungin (70 mg instead of 50 mg).
• Anidulafungin has few drug-drug interactions due to its physiology of spontaneous degradation (without interacting with any hepatic enzymes).
• Micafungin has relatively few drug-drug interactions. However, it may increase sirolimus, cyclosporine, itraconazole, or nifedipine levels.
• Check for interactions using 🧮 MedScape's drug interaction checker.

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2) dosing & monitoring

• Caspofungin: 70 mg loading dose, then 50 mg daily (or possibly 70 mg daily if weight >80 kg or simultaneous use of potent inducers of CYP4A4, such as carbamazepine, phenobarbital, phenytoin, and rifampin). (31617055)
• Anidulafungin: 200 mg loading dose, then 100 mg daily.
• Micafungin:
  • Invasive candidiasis: 100-150 mg IV q24hr.
  • Invasive aspergillosis: 150 mg IV q24hr.
  • Less ill ICU patients weighing >100 kg may be at risk of inadequate micafungin dosing. (28971861) 
• No adjustment for renal or hepatic dysfunction.
• Other indications (e.g., esophageal candidiasis or antifungal prophylaxis) may involve lower doses.
• More information: 📚 Medscape monographs on caspofungin, anidulafungin, and micafungin.

monitoring

• Liver function test monitoring (more frequently with micafungin than with others).

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3) pharmacology

• Protein binding:
  • Caspofungin: 92-97%.
  • Anidulafungin: 99%.
  • Micafungin: 99.95 %.
• Half-life:
  • Caspofungin: 8 hours initially, with a terminal half-life of 27-50 hours.
  • Anidulafungin: 40-50 hours.
  • Micafungin: 13-20 hours.
• Elimination
  • Caspofungin: Metabolized by N-acetylation in the liver and spontaneous chemical degradation (independent of the CYP system).
  • Anidulafungin: Spontaneous degradation in the plasma.
  • Micafungin: Hepatic metabolism by the CYP system.
• Penetration
  • The volume of distribution is low (~0.3-0.6 L/kg) for all.
  • Adequate penetration of most organs (including lungs, liver, and spleen). (36836260)
  • Minimal CSF, urine, or eye penetration (these are large molecules; see figure below).

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4) toxicity

Echinocandins overall have a relatively favorable safety profile (generally superior to either amphotericin or azoles). (29304209)

• Anaphylactoid reactions may result from rapid administration. (36836260)
• Liver function test abnormality (especially with micafungin).
• Hypokalemia.
• Phlebitis at the infusion site.
• Fever.
• Neutropenia is rarely reported.

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5) spectrum & use

• All three agents have similar spectrum and utility. They are generally considered to be clinically interchangeable.
• Clinical efficacy is largely restricted to Candida and Aspergillus.
• Candida:
  • Echinocandins cover nearly all Candida species. However, some resistance may be found among C. parapsilosis and C. guilliermondii. Resistance rarely may be detected among C. glabrata (especially strains that are resistant to fluconazole).
  • Echinocandins are generally the agent of choice for empiric treatment of candidemia in the ICU. Echinocandins may be uniquely effective against Candida embedded in biofilms (e.g., surrounding prosthetic devices), a context where fluconazole or amphotericin-B may be less effective. Echinocandins are fungicidal against Candida (unlike azoles, which are fungistatic). (32722455)
• Aspergillus: may be used for adjunctive therapy (discussed here: 📖)

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liposomal amphotericin

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1) contraindications & drug-drug interactions

contraindications

• ⚠️ Renal failure.
• ⚠️ Hepatic failure.
• ⚠️ QT prolongation.

drug-drug interactions

• Based on its elimination via the reticuloendothelial system, there aren't any direct drug-drug interactions. However, synergistic toxicity may occur if amphotericin is co-administered with drugs that have the following effects:(32000291)
  • Hypokalemia
  • Torsade de Pointes, QT prolongation
  • Nephrotoxicity
  • Zidovudine use with Amphotericin may lead to synergistic bone marrow toxicity
  • Check for interactions using 🧮 MedScape's drug interaction checker.

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2) dosing & monitoring

• The dose is usually 3-5 mg/kg liposomal formulation IV q24 hours
  • Invasive aspergillosis: 3-5 mg/kg.(27365388) The AmbiLoad trial comparing 3 mg/kg versus 10 mg/kg found equivalent efficacy between both doses but greater toxicity with the higher dose. Furthermore, survival after 12 weeks trended to be higher among patients treated with 3 mg/kg (72% vs. 59%, not statistically significant). (17443465)
  • Mucormycosis: usually started at 5 mg/kg/day. In severe infections that are refractory to this dose, the dose can be increased to 10 mg/kg/day. (Murray 2022) The European Confederation for Medical Mycology Guidelines recommend 10 mg/kg/day for patients with CNS involvement. (31699664)
  • Blastomycosis: 3-5 mg/kg IV q24 hours (use 5 mg/kg if CNS involvement or severe disease).
  • Coccidiomycosis: 3-5 mg/kg IV q24 hours. (35233706)
  • Histoplasmosis: 3-5 mg/kg IV q24 hours (use 5 mg/kg if CNS involvement). (36836350)
  • Candidemia without suspicion of CNS involvement: 3 mg/kg daily.
• Saline co-administration? Administration of normal saline along with amphotericin has been proposed to reduce the risk of nephrotoxicity. However, there is a lack of evidence demonstrating the benefit of this strategy (especially with newer liposomal formulations). (34016281)
• No dose adjustment for renal or hepatic dysfunction.
• In morbid obesity, consider dosing based on ideal body weight (rather than total body weight).
• More information: 📚 Medscape monograph on liposomal amphotericin.

monitoring

• [1] Follow renal function.
• [2] Follow volume status (especially if saline is being co-administered with amphotericin).
• [3] Follow electrolytes, calcium, and magnesium.
• [4] Consider following QTc interval, if prolonged at baseline

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3) pharmacology of liposomal amphotericin B (LAMB)

• Protein Binding in the blood is 95-99%, with a volume of distribution of ~0.1-0.2 L/kg. Amphotericin is water-insoluble (hence requiring the liposomal formulation).
• Half-life the initial half-life after a single dose is ~7-10 hours, but the terminal half-life following multiple doses is ~150 hours.
• Elimination is via the reticuloendothelial system. This doesn't appear to be affected by renal or hepatic dysfunction.
• Penetration
  • High drug levels within macrophages and the reticuloendothelial system (e.g., liver, spleen). (36836260) 
  • Poor CNS or ocular penetration.
  • Low concentrations are detected in the lungs and kidneys. (32000291)
• Penetration: Comparison of liposomal amphotericin vs. amphotericin deoxycholate:
  • Brain/CSF, eye, heart, liver: similar penetration.
  • Kidney/urine: Amphotericin deoxycholate has better penetration.
  • Lung: Liposomal amphotericin has better penetration.

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4) toxicity

• Infusion reactions – may include flushing, urticaria, fever, chills, rigors, bronchospasm, nausea/vomiting, hypotension, tachycardia, chest pain, abdominal pain, dyspnea, and tachypnea (amphotericin activates toll-like receptor 2, causing inflammation).
• Acute renal failure:
  • Caused by vasoconstriction of afferent arterioles. (36836260)
  • Nephrotoxicity is dose-related in terms of cumulative total dose.
  • Renal failure is usually nonoliguric and reversible.
• Type IV renal tubular acidosis (hypokalemia, hypomagnesemia, metabolic acidosis).
• Hepatotoxicity (however, this is relatively rare, and monitoring of liver function tests isn't generally necessary). (29304209)

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5) spectrum & use

Liposomal amphotericin has largely replaced older deoxycholate formulations, as liposomal amphotericin is less toxic but equally effective. (29304209)

spectrum of amphotericin

• Dimorphic fungi and Cryptococcus neoformans: Amphotericin is generally used initially for induction therapy.
• Mold: Traditionally, amphotericin was used as an empiric anti-mold agent (to cover either Aspergillus or Mucorales species). However, isavuconazole is a safer option here if it is available.
• Invasive Candida: Amphotericin had equivalent efficacy to micafungin in one study and meta-analyses, but amphotericin caused greater side effects. (17482982, 30257597)
• Some pathogens that are not covered by amphotericin: (34016281)
  • Candida lusitaniae, Candida haemulonii, and some Candida auris.
  • Aspergillus terreus.
  • Scedosporium apiospermum.
  • Trichosporon spp.
  • Lomentospora prolificans.
  • Some Fusarium spp. (36836260)

niche roles for amphotericin:

• Amphotericin is increasingly being replaced by newer, safer agents. However, amphotericin continues to have niche roles in situations where other agents cannot be used, such as:
• Aspergillus species that are resistant to azoles.
• Patients with acute hepatic failure or hepatitis (azoles and echinocandins can cause hepatic dysfunction). Note, however, that patients with stable Child's class A-B cirrhosis may be treated with azoles or echinocandins.
• Induction therapy for patients with dimorphic fungi (although increasing evidence suggests that voriconazole may often be adequate therapy here).
• Candida species that are resistant to fluconazole and echinocandins (rare!).

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questions & discussion

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Amphotericin has a high rate of nephrotoxicity, so reserve this for situations where it is truly necessary.
• Azole antifungals are generally well tolerated but are involved in numerous drug-drug interactions. Look carefully for interactions before initiating these (use a drug-interaction tool such as 🧮 MedScape's drug interaction checker.)
• For critically ill patients with a high likelihood of fungal infection, consider empiric initiation of therapy prior to definitive diagnosis. Relatively nontoxic and broad-spectrum agents exist that can be initiated early, with a favorable risk/benefit ratio.

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