CONTENTS

Antifungal agents

• Fungal antibiograms
• Azoles:
  • Voriconazole
  • Isavuconazole
  • Posaconazole
  • Fluconazole
  • Itraconazole
• Echinocandins (caspofungin, micafungin, anidulafungin)
• Liposomal amphotericin
• Flucytosine (5-FC)

Antiviral agents

• Acyclovir
• Ganciclovir
• Anti-viral therapy for influenza ➡️
  • Neuraminidase inhibitors (oseltamivir, peramivir) ➡️
  • Baloxavir ➡️

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fungal antibiograms

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There may not be a single fungal antibiogram to rule them all. Here is a selection:  

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voriconazole

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contraindications, drug interactions, side effects 👎

contraindications

• ⚠️ QTc prolongation.
• ⚠️ 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).
• ⚠️ Renal failure? (GFR <50 ml/min might be a relative contraindication, but this is probably safe – see the discussion under the “pharmacology” section).

drug-drug interactions

• [1] Drugs that affect voriconazole levels:
  • Voriconazole is usually metabolized by 2C19 >> 3A4 and 2C9.
  • Inducers of 2C19, 3A4, and 2C9 may lower voriconazole levels.
  • Inhibitors of 2C19 will increase voriconazole levels.
• [2] Voriconazole affects other medications:
  • Strong 3A4 inhibitor.
  • Moderate 2C19 inhibitor.
  • Weak 2C9 inhibitor.

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, suggesting 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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indications, 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, Exserohilum,  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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dosing & monitoring

voriconazole dosing

• Dosing for invasive aspergillosis:
  • 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. However, it should be taken an hour before or after a meal to improve absorption. (Paw & Shulman 2025)
• 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).
• Morbid obesity: Dose based on lean body weight. (Erstad 2022)

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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pharmacology

• Absorption: Generally well absorbed (>90%) if taken at least one hour before or after a meal. (36836260) Fatty foods may decrease absorption by ~30%.
• Distribution:
  • Protein binding in the blood is moderate, at 58%.
  • The volume of distribution is large, at 4.5 L/kg.
  • Good penetration of CSF and eye (fluconazole & voreconazole penetrate CNS).
  • Doesn't penetrate the urine well (not useful in fungal urinary tract infections).
• Metabolism:
  • Metabolized via CYP2C19 > CYP3A4.
  • Slow CYP2C19 metabolizers may accumulate higher levels of voriconazole, which is more common in patients with Asian or Pacific Islander ancestry. Alternatively, ultrarapid CYP2C19 metabolizers are unlikely to achieve therapeutic voriconazole levels. (34016281)
• Half-life is 6 hours. Pharmacokinetics are nonlinear and may be difficult to predict.
• 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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isavuconazole

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contraindications, drug interactions, side effects 👎

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: center around CYP3A4

• Normally, isavuconazole is primarily metabolized by CYP 3A4.
• Drugs that affect isavuconazole levels: Any medications affecting CYP 3A4.
• Isavuconazole affects other drugs:
  • Moderate CYP 3A4 inhibitor – seems to drive most drug-drug interactions.
  • Mild inhibitor of 2C9 and 2C19.
  • Mild P-glycoprotein inhibitor (may slightly increase digoxin levels).
  • Compared to voriconazole, isavuconazole has fewer drug-drug interactions.

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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indications, 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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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).

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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pharmacology

• Absorption: Oral bioavailability is ~100%, allowing oral dosing to be used interchangeably with intravenous dosing.
• Distribution:
  • Protein binding is 98-99%.
  • 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)
• Metabolism:
  • [1] Isavuconazole is administered as a prodrug (isavuconazonium sulfate), which is rapidly hydrolyzed in the blood to the active form (isavuconazole).
  • [2] Isavuconazole is primarily metabolized by CYP 3A4 into inactive metabolites.
• Elimination:
  • <1% excreted in urine, so isavuconazole may have little use in treating urinary tract infections. (29725999)
  • Half-life is ~80-120 hours.

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posaconazole

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contraindications, drug interactions, side effects 👎

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

• Drugs that affect posaconazole levels:
  • [1] UDP glucuronosyltransferase (UGT1A4) induction can significantly decrease posaconazole levels (e.g., rifampin, phenytoin, carbamazepine). Normally, only approximately 15% of posaconazole is metabolized by the UDP system, so UDP inhibition is less likely to have a significant impact.
  • [2] Posaconazole may be affected by drugs that impact the P-glycoprotein system, e.g.:
    • P-glycoprotein inducers (e.g., phenytoin, rifampin) decrease posaconazole levels.
    • P-glycoprotein inhibitors will elevate drug levels.
  • [3] PPIs may reduce the absorption of some formulations (discussed further below).
  • Examples:
    • Drugs that induce UGT and P-glycoprotein, leading to reduced levels: Rifampin, phenytoin, carbamazepine, phenobarbital, efavirenz.
    • Drugs that inhibit P-glycoprotein, leading to reduced levels: lopinavir/ritonavir, erythromycin.
• Posaconazole affects the levels of other drugs:
  • [1] Strong CYP 3A4 inhibitor.
  • [2] Mild-moderate P-glycoprotein inhibitor.

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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indications, advantages 👍

• 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, with 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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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)

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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pharmacology

• Absorption:
  • Absorption is improved by administration with food (especially high-fat food).
  • 🏆 Delayed-release tablet has a bioavailability of 54%; it may be less affected by food or gastric acid. (32722455)
  • Oral suspension: variable bioavailability with saturable absorption. (32722455) Antacid administration does not substantially affect the bioavailability of tablets, but it may reduce the absorption of oral liquid suspensions. (32000291)
• Distribution:
  • Protein binding: >98%.
  • The volume of distribution is large, suggesting extensive penetration into peripheral tissues (studies vary in the range of ~500 liters; 7-25 L/kg). (32000291, 32478597, 40113496) Its octanol/water partition coefficient is 5.5. (32478597) Concentrations in alveolar cells are ~32 times higher than blood concentrations. (36836260)
• Metabolism:
  • Unlike other azoles, posaconazole is not metabolized by the CYP enzyme system.
  • Normally, only ~15% is metabolized in the liver via UDP-glucuronosyltransferase (UGT) 1A4.
  • Half-life is ~24-35 hours.
• Elimination:
  • Posaconazole is primarily excreted unchanged in the feces (~70%). It is a substrate for the P-glycoprotein efflux transporter.
  • Some posaconazole is excreted in the urine (~15%) mostly as inactive glucuronide conjugates (with only trace amounts of unchanged drug). (32478597)
• Half-life & duration of action:

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fluconazole

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contraindications, drug interactions, side effects 👎

contraindications

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

drug-drug interactions

• Drugs that affect fluconazole levels:
  • Strong CYP 3A4 inducers (e.g., rifampin) can cause a mild reduction in fluconazole AUC (~20%).
  • Hydrochlorothiazide reduces renal fluconazole clearance.
• Fluconazole's effects on other drugs:
  • Strong inhibitor of CYP2C9.
  • Moderate inhibitor of CYP3A4.
  • Moderate-weak inhibitor of CYP2C19.
  • Inhibitor of uridine diphosphate-glucuronosyltransferase (UGT).

fluconazole: toxicity

• Fluconazole is generally well-tolerated, even when used chronically.
• Gastrointestinal side-effects: Nausea, vomiting, abdominal discomfort, diarrhea.
• 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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indications, spectrum/use 👍

• 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 meningitis: Fluconazole is the agent of choice for patients with CNS involvement due to excellent CNS penetration.

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dosing

fluconazole dosing

• Candidal infections:
  • 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).
  • Oropharyngeal or esophageal candidiasis: 200 mg load, followed by 100 mg daily.
• 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)

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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pharmacology

• Absorption: 
  • Oral bioavailability is 90-100% (unaffected by gastric pH or food).
  • IV and oral doses are interconvertible.
• Distribution:
  • Fluconazole is only 12% protein-bound. Unlike other azoles, fluconazole circulates mainly as a free drug. (32000291)
  • The volume of distribution is ~0.7 L/kg (much lower than other azoles).
  • Good penetration of the eye and CNS (fluconazole & voreconazole penetrate 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 (only azole to achieve high urinary penetration).
• Metabolism: 
  • Minimal hepatic metabolism (<10%). There may be a small amount of metabolism by CYP3A4 that can be induced by strong CYP-inducers.
• Elimination: 
  • Excreted unchanged in the kidney.
• Half-life & duration of action:
  • Half-life is ~30 hours (prolonged in renal failure).

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itraconazole

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contraindications, drug interactions, side effects 👎

contraindications

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

drug-drug interactions include

• Drugs that affect itraconazole level:
  • Itraconazole is predominantly metabolized by CYP 3A4.
  • Itraconazole levels are elevated by CYP 3A4-inhibitors and reduced by CYP 3A4-inducers.
  • 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).
• Itraconazole affects the level of other drugs:
  • [1] Strong inhibitor of CYP 3A4.
  • [2] Strong P-glycoprotein inhibitor.

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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indications, 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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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)

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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pharmacology

• Absorption: Oral absorption is discussed above (in terms of the different formulations).
• Distribution:
  • Protein binding: 99.8%
  • Volume of distribution is 11 L/kg. (40113496)
  • Negligible CSF or ocular concentrations.
  • High concentrations (~400 ng/mL) in bronchial fluid. (36836260)
• Metabolism:
  • Metabolized by the liver (mostly CYP3A4).
  • The primary metabolite is hydroxy-itraconazole, which has the same antifungal activity as itraconazole.
• Elimination:
• Half-life & duration of action:
  • Half-life: 32-42 hours.

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echinocandins (micaFUNGIN, caspoFUNGIN, anidulaFUNGIN)

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contraindications, drug interactions, side effects 👎

contraindications

• Acute hepatic failure with deteriorating liver function tests (since this renders monitoring of liver function tests impossible).

drug-drug interactions

• Caspofungin:
  • Strong CYP3A4 inducers may accelerate caspofungin metabolism (e.g., rifampin, carbamazepine, dexamethasone, phenytoin). This may require using a higher maintenance dose (70 mg instead of 50 mg).
  • Caspofungin may reduce tacrolimus levels (mechanism unclear, may involve mild CYP3A4 induction by caspofungin).
• Anidulafungin has few drug-drug interactions due to its spontaneous degradation physiology, which does not interact with any hepatic enzymes.
• Micafungin has relatively few drug-drug interactions. However, it may increase levels of sirolimus, cyclosporine, itraconazole, or nifedipine.

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, hypomagnesemia.
• Phlebitis at the infusion site.
• Fever.
• Neutropenia is rarely reported.

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indications, spectrum/use 👍

• All three agents have similar spectra and utilities. They are generally considered to be clinically interchangeable.
• [1] Candida:
  • Echinocandins cover nearly all Candida species. However, some resistance may be found among C. parapsilosis and C. guilliermondii. Resistance may rarely 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)
• [2] Adjunctive therapy:
  • Aspergillus: May be used for adjunctive therapy (discussed here: 📖)
  • Pneumocystis pneumonia: Echinocandins may be used as an adjunctive therapy. 📖

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dosing & monitoring

dosing

• 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 including rifampin, carbamazepine, dexamethasone, phenytoin). (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.

monitoring

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

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pharmacology

• Bioavailability: Requires IV administration.
• Distribution:
  • Protein binding:
    • Caspofungin: 92-97%.
    • Anidulafungin: 99%.
    • Micafungin: 99.95 %.
  • Penetration
    • Vd of 10 L/kg (caspofungin), 30-50 L/kg (anidulafungin), or 18 L/kg (micafungin). (40113496)
    • Adequate penetration of most organs (including lungs, liver, and spleen). (36836260)
    • Minimal CSF, urine, or eye penetration. However, the choroid and retina are highly vascularized, so it is possible that biological activity in the eye might be sufficient. (40113496)
• Metabolism:
  • Caspofungin: Minor CYP3A4 substrate; also undergoes spontaneous chemical degradation.
  • Anidulafungin: chemical degradation.
  • Micafungin: Minor CYP3A4 substrate. (40113496)
• Elimination: No active drug is cleared by the kidney; no need for renal dose-adjustment.
• Half-life:
  • Caspofungin: 8 hours initially, with a terminal half-life of 27-50 hours.
  • Anidulafungin: 40-50 hours.
  • Micafungin: 13-20 hours.

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liposomal amphotericin

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contraindications, drug interactions, side effects 👎

contraindications

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

drug-drug interactions

• No pharmacokinetic interactions (eliminated via the reticuloendothelial system).
• Pharmacodynamic interactions: (32000291)
  • Nephrotoxins.
  • Hypokalemia-promoting medications.
  • QT prolonging medications.
  • Flucytosine (may increase toxicity). (Wellington 3e)
  • Zidovudine (synergistic bone marrow toxicity).

toxicity

• Infusion reactions:
  • Amphotericin activates toll-like receptor 2, causing inflammation.
  • Features may include flushing, urticaria, fever, chills, rigors, bronchospasm, nausea/vomiting, hypotension, tachycardia, chest pain, abdominal pain, dyspnea, and tachypnea.
• Acute renal failure:
  • Renal failure is much less common with liposomal amphotericin B, as compared to prior amphotericin formulations (amphotericin deoxycholate).
  • Mechanisms of renal failure may include:
    • Afferent arteriolar vasoconstriction that results from tubuloglomerular feedback (due to the high ionic load within the renal tubules). (Erstad 2022)
    • Direct tubular epithelial injury. (36836260)
  • Nephrotoxicity is dose-related, with the cumulative total dose being a key factor.
  • Renal failure is usually nonoliguric and reversible.
• Type IV renal tubular acidosis due to back-leak of hydrogen ions in the distal renal tubule:
  • Hypokalemia.
  • Hypomagnesemia.
  • Metabolic acidosis.
• Hepatotoxicity:
  • Hepatitis and cholestasis can occur.
  • This is relatively rare, so routine monitoring of liver function tests generally isn't necessary. (29304209)

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indications, advantages 👍

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)
• Pathogens that aren't covered by amphotericin include: (34016281)
  • Candida lusitaniae, Candida haemulonii, and some Candida auris.
  • Aspergillus terreus.
  • Scedosporium apiospermum.
  • Trichosporon spp.
  • Lomentospora prolificans.
  • Some Fusarium spp. (36836260)

indications

• Mold infection, including:
  • Aspergillus species that are resistant to azoles.
• Induction therapy for patients with dimorphic fungi (although increasing evidence suggests that voriconazole may often be adequate therapy here).
• Induction therapy for Cryptococcus neoformans.
• Candida species that are resistant to fluconazole and echinocandins (rare!).
• 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.

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dosing & monitoring

dosing

• The dose is usually 3-5 mg/kg 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 recommends 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? 
  • Saline co-administration has been shown to reduce nephrotoxicity associated with prior formulations of amphotericin (amphotericin deoxycholate).
  • Liposomal amphotericin is much less nephrotoxic than amphotericin deoxycholate.
  • It is unknown whether saline co-administration is beneficial for liposomal amphotericin. There is no high-quality evidence regarding this. Based on the lower base rate of nephrotoxicity, it may be harder to design an adequately powered trial. (34016281)
  • Many guidelines and review articles continue to recommend co-administration of saline with liposomal amphotericin, based on older data obtained with amphotericin deoxycholate.
  • Ultimately, this decision should be individualized based on assessment of the patient's volume status.
• Renal or hepatic dysfunction: No dose adjustment.
• Obesity: Consider dosing based on ideal body weight (rather than total body weight).

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 monitoring the QTc interval if prolonged at baseline.

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pharmacology

• Absorption:
  • Requires IV administration.
  • Amphotericin is water-insoluble (hence requiring the liposomal formulation).
• Distribution:
  • Protein Binding in the blood is 95-99%.
  • Volume of distribution of ~0.1-0.2 L/kg.
  • 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.
• Metabolism: No apparent hepatic metabolism.
• Elimination:
  • Liposomal amphotericin is eliminated via the reticuloendothelial system. This doesn't appear to be affected by renal or hepatic dysfunction.
• Half-life & duration of action:
  • 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.

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flucytosine (5-FC)

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contraindications, drug interactions, side effects 👎

contraindications

• Renal dysfunction: use cautiously (potential for nephrotoxicity and requires dose adjustment).
• Severe bone marrow suppression (e.g., leukopenia, thrombocytopenia).
• Known dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
• Severe hepatic impairment.

drug-drug interactions

• Nephrotoxins, including amphotericin (increase flucytosine levels).
• Myelosuppressive medications (e.g., ganciclovir).
• Azoles: Flucytosine may reduce the efficacy of azole antifungal agents.

toxicity includes:

• Myelosuppression (e.g., thrombocytopenia, neutropenia, pancytopenia, aplastic anemia).
• Gastrointestinal: nausea, vomiting, diarrhea, hemorrhagic colitis, acute hepatic injury including hepatic necrosis.
• Nephrotoxicity (including crystalluria, renal failure).
• Neurologic toxicity: ataxia, seizures, peripheral neuropathy, Parkinsonism.
• Cardiotoxicity: rare but may cause myocardial dysfunction and arrhythmias.
• Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis.
• Other: hypoglycemia, hypokalemia.

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indications, advantages 👍

• Cryptococcal meningitis is the primary indication for flucytosine.
• Flucytosine is generally used as an adjunctive agent as part of a combined treatment regimen for a known fungal infection.
• Flucytosine displays time-dependent pharmacodynamics.
• Fungi metabolize Flucytosine into 5-fluorouracil, which is an antimetabolite.

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dosing & monitoring

dosing

• Cryptococcal meningitis: The standard induction dose for flucytosine is 100 mg/kg/day in four divided doses (i.e., 25 mg/kg q6hr). The FLOOR trial evaluated a lower dose and found inferior results (discussed further here).
• Renal failure: Dose reduction.

monitoring

• Follow flucytosine levels:
  • Monitor peak levels, obtained two hours after a dose.
  • Target a peak level of ~30-80 ug/mL.
  • >100 ug/mL may correlate with elevated toxicity.
  • Monitor more frequently in renal dysfunction (e.g., q2-4 days).
• Crystalluria may occur, so monitor urine output and aim to maintain a robust urine flow.
• Monitor creatinine.
• Monitor LFTs at baseline and every ~3-5 days.
• Monitor complete blood count to evaluate for any cytopenias.

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pharmacology

• Absorption:
  • Only available as an oral medication. Bioavailability is excellent (>80%).
• Distribution:
  • Low protein binding (<5%).
  • Vd of 0.6-0.8 L/kg (distributes into the extracellular fluid).
  • High penetration of the CNS and the eye.
• Metabolism:
  • Minimal absorption.
• Elimination:
  • >90% is excreted unchanged in the urine.
• Half-life & duration of action:
  • The half-life is usually 3-5 hours, but it is increased in cases of renal dysfunction.
• Mechanism of action:
  • Binds to the sterol component of the cell membrane, leading to increased permeability and cell death.

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acyclovir

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contraindications, drug interactions, side effects 👎

contraindications

• [1] Hypersensitivity to acyclovir or valacyclovir.
• [2] Renal dysfunction (relative contraindication; discussed further below in the section on dosing).

drug-drug interactions

• [1] Drugs competing for renal tubular secretion:
  • Probenecid.
  • Mycophenolate mofetil.
• [2] Coadministration with other nephrotoxins increases the risk of renal injury.
• (Concomitant use of similar antivirals (e.g., ganciclovir, foscarnet, zidovudine) may increase drug levels and cause overlapping toxicities.)

side effects

• Nephrotoxicity (discussed below in the section on dosing).
• Neurotoxocity (discussed in the paragraph below in more detail).
• Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain (more problematic with oral formulations), hepatitis.
• Hepatic: Hepatitis, hyperbilirubinemia.
• Hematologic: anemia, leukopenia, thrombocytopenia (including TTP/HUS).
• Dermatologic: Erythema multiforme, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, phlebitis.

side effects: neurotoxicity

• Epidemiology:
  • Incidence is ~1% (so this is rare but will happen). (Wellington 3e)
  • Risk factors:
    • Renal dysfunction is the primary risk factor (preventing excretion of the metabolite 9-carboxymethoxymethylguanine, aka CMMG, responsible for neurotoxicity).
    • Pre-existing neurological pathology.
    • Older age.
    • High-dose IV therapy (e.g., for HSV encephalitis).
    • Concurrent neurotoxic medications.
• Clinical features may include:
  • Tremors, myoclonus, seizures.
  • Confusion, lethargy, agitation, obtundation, coma.
• Diagnosis:
  • This is largely a diagnosis of exclusion.
  • High serum or CSF levels of 9-carboxymethoxymethylguanine (CMMG) are highly predictive of neurotoxicity. (30531673) However, measuring this metabolite appears to be difficult. Elevated acyclovir levels might function as a surrogate level for toxicity (available as a Mayo Clinic lab). 
• Management:
  • Discontinue acyclovir.
  • Dialysis may be required to remove acyclovir.
  • Treatment of seizures (e.g., EEG, antiepileptic medications).
  • Improvement should occur within a few days. (32943113)

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indications, advantages 👍

• Activity against:
  • HSV (types I and II).
  • VZV.
  • EBV (limited activity).

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dosing

[#1/3] Dose adjust based on GFR:

• HSV encephalitis: The typical dose of acyclovir in HSV encephalitis is 10 mg/kg IV q8 hours for a 14-21 day course. However, this dose may need to be adjusted based on renal function:
  • Augmented renal clearance: Consider dose escalation to 15 mg/kg IV every 8 hours. (38364888)
  • GFR >50 ml/min: Standard dose of 10 mg/kg IV q8 hours.
  • GFR 25-50 ml/min: 10 mg/kg IV q12 hours.
  • GFR 10-25 ml/min: 10 mg/kg IV q24 hours.
  • GFR <10 ml/min: 5 mg/kg IV every 24 hours is often recommended; however, this dose may be too high in certain situations (e.g., anuria without dialysis, peritoneal dialysis). (30531673)
• Varicella pneumonia, or VZV infection in an immunocompromised host: Same dose as above for HSV encephalitis.

[#2/3] Dosing in obesity (BMI >30)

• ⚠️ Do not use actual body weight.
• It is controversial whether to use an ideal body weight or an adjusted weight. Dosing based on ideal body weight may reduce the risk of nephrotoxicity (because lower doses will be used). However, dosing based on adjusted body weight may be more likely to ensure therapeutic drug levels.
• The selection of ideal vs. adjusted body weight could be personalized based on:
  • How robust the renal function is (e.g., GFR 55 ml/min vs 120 ml/min).
  • How high the index of suspicion is for HSV encephalitis (e.g., rule-out vs definite infection).
• Overall, an adjusted body weight probably most closely approximates usual drug levels. (26824940)

[#3/3] Additional measures to avoid nephrotoxicity

• Mechanisms of nephrotoxicity:
  • [1] Intratubular crystal deposition is the primary mechanism. In severe cases, this may even cause hematuria and flank pain.
  • [2] Direct toxicity to renal tubules (e.g., tubular injury can occur without crystal formation).
  • [3] Tubulointerstitial nephritis (can be associated with other symptoms such as fever and rash).
• Prevention of nephrotoxicity:
  • [a] Adequate volume resuscitation & promotion of urine output. For example, initiate an infusion of LR at 100 cc/hr and aim for a net even fluid balance.
  • [b] Avoidance of acidic urine might also reduce crystal formation. However, acyclovir crystallization is less pH-dependent than that of other medications (e.g., trimethoprim), so this may have limited value.
  • [c] Infuse acyclovir slowly over 2 hours. Especially after the initial dose, subsequent doses may be administered more slowly. To optimize the pharmacodynamic efficacy of acyclovir, it has been suggested that we target an adequate trough level (trough >50% of the minimum inhibitory concentration, MIC). (38364888) This implies that slower infusion of acyclovir could improve PK/PD target attainment while simultaneously reducing nephrotoxicity.
  • [d] Dose adjustments based on renal dysfunction (as above).
  • [e] Avoid concurrent use with other nephrotoxins.
  • [f] Limit treatment duration if possible.

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pharmacology

• Absorption: 
  • Oral valacyclovir has a bioavailability of ~50%.
  • For critical care applications, IV acyclovir is generally utilized.
• Distribution:
  • Vd (0.7 L/kg) corresponds more closely with lean body weight than total body weight.
  • Protein binding is low (~15%).
  • Acyclovir does penetrate the blood-brain barrier (CSF levels are ~50% of serum levels).
• Metabolism:
  • Acyclovir is only minimally metabolized by the liver (oxidized by alcohol dehydrogenase and aldehyde oxidase to 9-carboxymethoxymethylguanine, aka CMMG). Accumulation of this metabolite in patients with renal dysfunction may promote neurotoxicity.
• Elimination:
  • 60-90% excreted unchanged in the urine.
  • In addition to glomerular filtration, acyclovir is cleared via tubular secretion.
• Half-life & duration of action:
  • The half-life is ~3 hours but extends with renal dysfunction (up to 20 hours in anuric patients).
• Mechanism of action:
  • Acyclovir is a synthetic purine nucleotide analog. It incorporates into viral DNA, blocking DNA synthesis.

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ganciclovir

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contraindications, drug interactions, side effects 👎

contraindications

• Neutropenia.
• Severe thrombocytopenia (e.g., platelets <25,000). (Wellington 3e)
• Severe renal impairment (relative).

drug-drug interactions

• Few pharmacokinetic interactions.
• Pharmacodynamic interaction with other myelosuppressive agents (e.g., zidovudine, mycophenolate mofetil, trimethoprim-sulfamethoxazole, cytotoxic chemotherapy).

side effects

• Hematologic toxicity:
  • Neuropenia (up to 40% of patients).
  • Anemia.
  • Thrombocytopenia.
  • Pancytopenia.
• Nephrotoxicity:
  • Ganciclovir is considered nephrotoxic, but it's less nephrotoxic than acyclovir, foscarnet, or cidofovir.
  • The primary mechanism of nephrotoxicity may be crystal nephropathy.
• Other side-effects:
  • Neurotoxicity: Seizures, delirium, or tremors may occur.
  • Fever.
  • Impaired fertility (e.g., inhibition of spermatogenesis).

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indications, advantages 👍

• The primary use is the treatment/prevention of CMV.
• Ganciclovir is a broader-spectrum agent than acyclovir. It is highly active against CMV, HHV-6, and HSV 1/2. It also has some activity against VZV, EBV, and possibly adenoviruses. (Cunha & Cunha 2024)

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dosing & monitoring

dosing

• Dosing weight: Generally, total body weight is used as the dosing weight. However, if the total body weight exceeds 120% of the ideal body weight, the adjusted body weight should be used instead.
• Treatment dose for CMV:
  • GFR >70 ml/min: 5 mg/kg q12hr x14-21 days, followed by maintenance of 5 mg/kg daily.
  • GFR 50-69 ml/min: 2.5 mg/kg IV q12 hrs x14-21 days, then 2.5 mg/kg q24hr.
  • GFR 25-49 ml/min: 2.5 mg/kg IV q24 hr x14-21 days, then 1.25 mg/kg q24hr.
  • GFR 10-24 ml/min: 1.25 mg/kg IV q24 hr x14-21 days, then 0.625 mg/kg q24. (MedScape, UCSF, Cunha & Cunha 2024, Hopkins Antibiotic Guide, Paw & Shulman 2025, Wellington 3e)
• Prophylaxis (Note that an initial induction dose may be used, which resembles the treatment dosing for CMV as listed above for one week):
  • GFR >70 ml/min: 5 mg/kg q24hr.
  • GFR 50-69 ml/min: 2.5 mg/kg IV q24 hrs.
  • GFR 25-49 ml/min: 1.25 mg/kg IV q24 hr.
  • GFR 10-24 ml/min: 0.625 mg/kg IV q24 hr. (UCSF)

monitoring

• Renal function (ganciclovir clearance is strongly dependent on renal function).
• Complete blood count with differential (monitor the absolute neutrophil count).
• Liver function tests (ganciclovir can cause liver injury).
• Serum ganciclovir levels:
  • Trough and peak levels can be measured (especially useful in renal dysfunction, critical illness, or unpredictable pharmacokinetics).
  • Typical target levels: 1-3 mg/L (prophylaxis) or 2-4 mg/L (treatment).
• CMV DNA PCR viral load may be used to assess response to therapy.

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pharmacology

• Chemical properties:
  • Molecular weight: 255 g/mol.
  • LogP: -1.7
• Absorption:
  • Valganciclovir (a prodrug) has a bioavailability of 60-80%, with peak levels reached after 2-4 hours.
• Distribution:
  • Protein binding is low (<2%).
  • Vd is ~0.7 L/kg (consistent with total body water).
  • CSF penetration is ~24-70% of plasma levels. Standard induction doses for CMV seem to be adequate to treat CNS CMV disease.
• Metabolism:
  • Minimal hepatic metabolism.
• Elimination:
  • Eliminated unchanged (80-100%) in the urine. Excretion occurs via both glomerular filtration and tubular secretion.
  • Hemodialysis removes about half of the drug, requiring post-dialysis administration.
• Half-life & duration of action:
  • The half-life is 3-5 hours in individuals with normal renal function. In renal failure, the half-life may extend to 11-24 hours.

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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.
• 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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