CONTENTS
- Rapid Reference 🚀
- Overview
- Azoles
- (#1) Choosing your azole:
- (#2) Pharmacology, dosing, and drug levels:
- (#3) Toxicity & monitoring
- Echinocandins (caspofungin, micafungin, anidulafungin)
- Liposomal amphotericin
- Podcast
- Questions & discussion
- Pitfalls
antifungal agents:
azole interactions:
As we manage an increasingly complex population of critically ill patients, the burden of fungal infections is continually increasing. Thus, we need to understand antifungal medications and feel comfortable initiating them promptly. Infectious disease consultants will often be involved with these patients, but we shouldn't be calling them at 3 AM for guidance to start an echinocandin for management of candidemia.
Fortunately, this task isn't overly difficult. There are essentially five workhorse antifungal agents commonly used in critically ill patients (table above). Itraconazole and posaconazole are excluded here, due to lack of intravenous formulations and scant evidentiary support in critical illness.
spectrum & use – discussion by drug
voriconazole
- 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)
- 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 useful in selected cases (e.g., patients with CNS involvement, or contraindications to amphotericin).
isavuconazole
- 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 for 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)
fluconazole
- 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.
itraconazole
- Clinical uses:
- (1) Indolent, non-CNS infection with endemic fungi (blastomycosis, histoplasmosis, coccidiomycosis).
- (2) ABPA (allergic bronchopulmonary aspergillosis).
- Spectrum of coverage:
- Aspergillus (however, doesn't cover mucormycosis).
- Candida (including C. krusei, C. glabrata, and C. tropicalis).
- Cryptococcus.
- Endemic mycoses (blastomycosis, histoplasmosis, coccidiomycosis).
choice of azoles in some specific situations
histoplasmosis
- Itraconazole is the azole of choice for histoplasmosis. (34016287)
- Voriconazole may be utilized as a second-line agent if itraconazole cannot be utilized (e.g., due to lack of enteral access). Data is limited, but some case reports and one case series describe successful therapy with voriconazole following failure of standard therapy.(17438046)
- Fluconazole has a lower success rate than itraconazole, with some reports of emerging fluconazole resistance during therapy. (34364529)
blastomycosis
- Itraconazole:
- Itraconazole is generally utilized as front-line therapy for mild-moderate pneumonia (including chronic pneumonia) or as step-down therapy for severe pneumonia (following induction therapy with amphotericin).
- Variable bioavailability may limit the use of itraconazole, especially among intubated patients who are receiving continuous enteral nutrition.
- Voriconazole:
- Voriconazole has excellent in vitro activity against blastomyces and improved bioavailability compared to itraconazole.
- Voriconazole has traditionally been considered as a second-line azole for management of blastomycosis. However, voriconazole is the preferred azole among patients with CNS involvement (due to high activity and good CNS penetration). Retrospective studies support voriconazole in CNS blastomycosis. (20166817)
- Fluconazole:
- May be be considered for patients with CNS blastomycosis in whom voriconazole cannot be used, due to its excellent CNS penetration. Unfortunately, fluconazole is relatively ineffective against blastomycosis overall, so fluconazole may not actually have a substantial advantage over itraconazole (itraconazole has lower CNS penetration, but greater activity against blastomycosis).
- If fluconazole is used, success rates may be higher at relatively high doses (400-800 mg/day). (36675937, 34364529)
- Isavuconazole has in vitro activity against blastomyces and has been utilized. However, clinical data remains limited. (Fishman 2023)
coccidioidomycosis
- Itraconazole:
- Usually the preferred agent for Coccidioidomycosis pneumonia. Despite reported poor CSF and bone penetration, clinically itraconazole appears to be effective in CNS and bone infection. (35233706)
- Not recommended in seriously ill patients, due to variable oral bioavailability.
- Fluconazole:
- For primary pneumonia, fluconazole may be slightly inferior to itraconazole. However, fluconazole may be better tolerated than itraconazole.
- Advantages include high bioavailability (100% absorption), low side-effect profile, and good CNS penetration (superior to itraconazole or amphotericin). However, fluconazole usually has significantly higher minimum inhibitory concentration as compared to other azoles, suggesting that in serious infection other mold-active azoles may be superior. (34016286)
- Voriconazole, isavuconazonium:
- Both agents have excellent in vitro activity. They are generally used in patients refractory or unable to tolerate itraconazole or fluconazole. (34016286)
- Voriconazole has been effective in some patients with refractory chronic fibrocavitary disease. (34016286) Retrospective series have demonstrated efficacy in meningeal and non-meningeal infection. (34016286)
- Isavuconazonium is supported by less evidence. However, one case series did find efficacy for coccidioidal meningitis. (30559134)
cryptococcus neoformans
- Fluconazole is generally the azole of choice.
- Experience with other azoles is limited. For patients intolerant of fluconazole, itraconazole is the recommended alternative. (32000285)
contraindications & drug-drug interactions
More common drug-drug interactions are discussed below. However, it's always optimal to check for interactions using 🧮 MedScape's drug interaction checker.
voriconazole
- 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).
- Drug-drug interactions include:
- CYP inducers (e.g., rifampin, phenytoin) may reduce levels of voriconazole.
- 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.
isavuconazole
- 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 older azoles (e.g., itraconazole, ketoconazole), so isavuconazole may be utilized among patients with mild transaminase elevations.
- 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 a variety of different agents handled via numerous systems (e.g., CYP3A4 system, P-glycoprotein system, organic anion transport systems, and CYP2C9).
- A table below shows some notable drug interactions:
fluconazole
- 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, phenytoin) may reduce levels of fluconazole.
- 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).
itraconazole
- 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 tablet with proton pump inhibitors or H2-blockers due to reduced absorption (the oral liquid may be utilized in this situation).
voriconazole dosing & pharmacology
voriconazole dosing & drug levels
- Dosing for invasive aspergillus:
- IV: Load with 6 mg/kg q12 hours on day #1, then decrease to 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.
- 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).
- Therapeutic drug monitoring should be utilized when treating invasive fungal infections. 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 associate with treatment failure, so consider dose escalation.
- Trough levels over ~5.5-6 mg/dL associate with increased risk of delirium.
- More information: 📚 Medscape monograph on voriconazole
voriconazole pharmacology
- Oral bioavailability:
- Generally well absorbed (>90%).
- Fatty foods may decrease absorption by ~30%.
- Protein binding in the blood is moderate, at 58%.
- Half-life is 6 hours.
- 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:
- 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 infection).
- Intravenous voriconazole is solubilized with sulfobutylether-beta-cyclodextrin (SBECD), the same cyclodextrin vehicle used to solubilize remedsevir.
- Among patients with GFR <50 ml/min, SBECD can accumulate and possibly cause kidney injury. However, there is not strong evidence that SBECD is nephrotoxic. (34016281)
- Oral voriconazole is definitely safe in renal dysfunction (since it doesn't contain SBECD).
isavuconazole dosing & pharmacology
isavuconazole dosing & drug levels
- 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, which is a pro-drug that is metabolized into isavuconazole (the active drug). 372 mg isavuconazonium sulfate is equivalent to 200 mg isavuconazonium base. This is the same drug, but different countries refer to it differently.
- No dose adjustment is needed in renal or hepatic impairment (although this hasn't been studied in severe hepatic dysfunction).
- More information: 📚 Medscape monograph on isavuconazole
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 the treatment of urinary tract infections. (29725999)
- Penetration
fluconazole dosing & pharmacology
fluconazole dosing & drug levels
- 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 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 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 mostly via the kidney, where it is excreted unchanged.
- Penetration
- Volume of distribution is ~0.7 L/kg.
- Good penetration of eye and CNS.
- Excellent urinary concentrations, since fluconazole is primarily excreted unchanged in the urine.
itraconazole dosing & pharmacology
itraconazole dosing & drug levels
- Dose varies depending on the formulation (various tablets or oral solution may have slightly different pharmacokinetics). Oral solution may often achieve levels ~30% higher than capsule formulations.
- 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 it won't reach steady state immediately. When transitioning from amphotericin to itraconazole, consider beginning the loading doses of itraconazole before discontinuation of amphotericin. (36675937)
- Therapeutic drug monitoring:
- Most laboratories test this using HPLC (high performance liquid chromatography) which reports both the itraconazole concentration and the hydroxy-itraconazole concentration. 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 active drug.
- Drug levels should be measured after two weeks of therapy. The target trough level is 2-5 mcg/mL. (36675937; 36836350)
- 📚 Medscape monographs on itraconazole.
itraconazole pharmacology
- Protein binding: 99.8%
- Absorption:
- Original capsule should be taken with food or an acidic beverage (e.g., cola). Absorption is variable and requires gastric acidity.
- 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 has superior bioavailability. However, it may have more gastrointestinal side effects. (35233706)
- Super-BioAvailable (SUBA) capsule has improved bioavailability compared to original capsules. Bioavailability isn't affected by gastric pH.(34016286)
- 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.
toxicity & monitoring of azoles
monitoring of azoles
- Monitoring of liver function tests may be advisable in the context of chronic therapy (e.g., baseline, after one month, then every 1-2 months).
- Consider following QTc interval, if prolonged at baseline (all azoles except for itraconazole).
voriconazole
- QTc prolongation.
- Visual disturbance:
- Transient, infusion-related, rarely requires 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).
- Hypoglycemia.
- Pneumonitis.
- Nausea, vomiting, or abdominal discomfort may occur.
- Adrenal insufficiency (all azoles except for isavuconazole). (34016281)
isavuconazole
- Gastrointestinal side-effects (most commonly reported adverse events are nausea, vomiting, and diarrhea).
- Severe hepatic impairment may rarely occur.
- Short QT interval (!) – clinically this is rarely an issue.
- Hypokalemia, peripheral edema.
- Infusion reactions (chills, dyspnea, and hypotension).
fluconazole
- 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)
itraconazole
- Gastrointestinal side-effects (nausea, vomiting, diarrhea).
- Hepatotoxicity (can occur with any azole).
- Adrenal insufficiency (rarely, due to chronic use).
- 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 (all azoles except for isavuconazole). (34016281)
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 levels of sirolimus, cyclosporine, itraconazole, or nifedipine.
- Check for interactions using 🧮 MedScape's drug interaction checker.
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).
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
- Volume of distribution is low (~0.3-0.6 L/kg) for all.
- Minimal CSF, urine, or eye penetration (these are large molecules; see figure below).
4) toxicity
Echinocandins overall have a relatively favorable safety profile (generally superior to either amphotericin or azoles). (29304209)
- Infusion-related reaction may occur with rapid administration.
- Liver function test abnormality (especially with micafungin).
- Hypokalemia.
- Phlebitis at the infusion site.
- Fever.
- Neutropenia is rarely reported.
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 which 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
- Echinocandins are not recommended for monotherapy.
- Echinocandins do exert synergistic activity when combined with voriconazole. Combination antifungal therapy isn't usually recommended as front-line therapy, but it can be used in the following situations:
- Salvage therapy due to clinical failure of an azole.
- Known azole resistance.
- High regional rates of azole-resistance.
- Treating a species with higher rates of resistance (e.g., Aspergillus calidoustus).
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.
2) dosing & monitoring
- The dose is usually 3-5 mg/kg liposomal formulation IV q24 hours
- Invasive aspergillosis: 3-5 mg/kg.(27365388) A trial comparing 3 mg/kg versus 10 mg/kg found equivalent efficacy between both doses, but greater toxicity with the higher dose.(17443465)
- Mucormycosis: usually started at 5 mg/kg/day. In severe infections that are refractory to this dose, the dose can be increased as high as 10-15 mg/kg/day.(Murray 2022) Guidelines from the European Confederation for Medical Mycology 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 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
3) pharmacology
- Protein Binding in the blood is 95-99%, with a volume of distribution of 0.05-2.2 L/kg. Amphotericin is water insoluble (hence requiring the liposomal formulation).
- Half-life is roughly 24 hours.
- Elimination is via the reticuloendothelial system. This doesn't appear to be affected by renal or hepatic dysfunction.
- Penetration
- Poor CNS or ocular penetration.
- Low concentrations detected in the lungs and kidney.(32000291)
- Volume of distribution is 0.05-2 L/kg.
4) toxicity
- Infusion reactions – may include fever, chills, rigors, bronchospasm, nausea/vomiting, hypotension, tachypnea (amphotericin activates toll-like receptor 2, causing inflammation).
- Acute renal failure – dose-related in terms of cumulative total dose. 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)
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 compared to micafungin in one study and in meta-analyses, but amphotericin caused greater side effects.(17482982, 30257597)
- Some pathogens that are not covered by amphotericin: (34016281)
- Aspergillus terreus.
- Candida lusitaniae, Candida haemulonii, and some Candida auris.
- Scedosporium apiospermum.
- Lomentospora prolificans.
- Some Fusarium spp.
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 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 which are resistant to fluconazole and echinocandins (rare!).
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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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References
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