Since the 1980s there has been an increasing but limited discovery of antifungal agents [15, 16]. The three principal classes of antifungal agents are polyenes, azoles, and echinocandins. Details on pharmacokinetics are provided in Table 1. Table 2 summarizes the features of antifungals in patients with renal or liver failure.
Polyenes (amphotericin B and nystatin) act in the fungal membrane by binding to ergosterol and causing disruption of the membrane structure promoting extravasation of intracellular constituents and, consequently, cell death (Fig. 1) . They have a broad spectrum of action, fungicidal activity, and an activity against most Candida, most Aspergillus, and Mucorales species. However, many Candida lusitaniae and Aspergillus terreus strains are resistant to amphotericin B (Tables 3, 4).
The standard amphotericin B formulation is associated with renal toxicity, caused by the vasoconstriction of the afferent arteriole, resulting in reduced renal blood flow and glomerular filtration rate combined with tubular injury, causing loss of potassium, magnesium bicarbonates, and amino acids. To reduce renal injury, liposomal amphotericin B allows lower absorption of amphotericin B by the reticuloendothelial system, resulting in a longer stay in the bloodstream.
Amphotericin B is contraindicated in patients with renal failure. Liposomal amphotericin B and amphotericin B lipid complex are less nephrotoxic than conventional amphotericin B, allowing a higher dosage because their PK are very different . Since enteral absorption is negligible for all commercially available amphotericin B formulations, they must be administered by intravenous infusion.
Infusion-related adverse events include chills, rigor, fever, hypotension or hypertension, hypoxia, nausea, vomiting, and hypokalemia, and affect about half of patients treated with conventional amphotericin B. The adverse event mechanisms are driven by activation of proinflammatory pathways [21,22,23].
Azoles act by inhibiting ergosterol synthesis in the endoplasmic reticulum of the fungal cell (Fig. 1). They have fungistatic properties affecting cell growth and proliferation. Candida krusei and Candida glabrata strains may show resistance against azoles (Table 3) ; however, a large accumulation of toxic sterols can eventually lead to fungal cell death [25, 26].
Triazoles include fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. The most frequent side effects induced by triazoles include liver toxicity, prolonged QTc, and emerging resistance among fungal isolates . Moreover, triazoles inhibit most of the cytochrome P450 enzymes (including the CYP34A), inducing variable drug–drug interactions. This plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus . Thus, co-administration of a triazole with these immunosuppressant drugs increases the risk of toxicity, or upon discontinuation, increases the risk of rejection or graft-versus-host disease. Close therapeutic drug monitoring of both immunosuppressants and triazoles is therefore indispensable.
Fluconazole is available for intravenous and oral administration with high bioavailability. It is active on most Candida species and is usually well tolerated. ICU patients treated with fluconazole should receive a loading dose (12 mg/kg) followed by a maintenance dose (6 mg/kg) . This dosage is supported because of impaired target site penetration in septic patients . For obese ICU patients, fluconazole dosage should be based on actual body weight . For patients with renal failure (creatinine clearance 11–50 mL/min) it is necessary to reduce the maintenance dose by 50% because of delayed elimination . Large amounts of fluconazole are eliminated by renal replacement therapy.
Voriconazole has high bioavailability and is available for intravenous and oral administration. It has a broad antifungal spectrum and is active against most Candida and Aspergillus species. Voriconazole is recommended as first-line treatment for IA because it had better clinical outcomes than amphotericin B deoxycholate in an open-label randomized clinical trial .
Renal failure has no relevant influence on voriconazole PK, but a considerable accumulation of the solvent sulfobutylether-β-cyclodextrin (SBECD) was found in patients with renal failure requiring intravenous administration of voriconazole. This solvent is a large cyclic oligosaccharide that is potentially nephrotoxic at high concentrations. The manufacturer recommends oral administration in patients with a creatinine clearance below 50 mL/min. Of note, in solid organ transplant patients, the significant interaction of voriconazole with sirolimus contraindicates there concomitant use .
Posaconazole has a wide antimycotic spectrum, including activity against Mucorales, and is licensed for antifungal prophylaxis in selected hematological high-risk patient. For a decade, posaconazole was available only as an oral suspension that displayed poor and highly variable absorption. An intravenous formulation and a tablet with improved bioavailability are now available. Posaconazole is a strong inhibitor of CYP3A4, which is responsible for drug–drug interactions. In a study that included ICU patients, the majority had subtherapeutic serum concentrations during treatment with standard doses of oral suspension . Mild to moderate renal or liver impairment had no relevant influence on posaconazole’s PK.
Isavuconazole is a new triazole agent that can be given once a day and offers a wider spectrum of antifungal activity than voriconazole, including activity against most Mucorales. It has an excellent bioavailability and predictable PK. It can be used in patients with renal failure given the absence of cyclodextrin in the intravenous formulation. A large double-blind randomized clinical trial showed non-inferiority for isavuconazole versus voriconazole in terms of all-cause mortality when used as a primary treatment for invasive fungal disease caused by Aspergillus species or other filamentous fungi . In addition, a matched case–control analysis of isavuconazole versus amphotericin B provided evidence for the efficacy and superior safety profile of isavuconazole in the treatment of mucormycosis . The most commonly reported side effects include gastrointestinal disorders such as nausea, vomiting, and diarrhea. A recent double-blind randomized clinical trial did not show non-inferiority of isavuconazole to caspofungin for primary treatment of IC. Secondary endpoints were similar between both groups .
Gastrointestinal disorders and central nervous adverse effects are possible during isavuconazole treatment. Whereas prolongation of the QT interval is a common adverse effect of azole antifungals, shortening of the QT interval has been observed with isavuconazole . Because isavuconazole is a moderate CYP3A4 inhibitor, interactions with immunosuppressants are reported to be less pronounced than those with voriconazole. However, increased serum concentrations of cyclosporine A, tacrolimus, sirolimus, and mycophenolate mofetil must be anticipated when isavuconazole is co-administered.
The echinocandins belong to a class of semisynthetic lipopeptides that inhibit the synthesis of the 1,3-beta-d-glucan component of the fungi cell wall (Fig. 1). Echinocandins have a broad spectrum of fungicidal activity against the Candida species, and fungistatic activity against most Aspergillus species  (Tables 3, 4). Limitations for use of currently approved echinocandins include the absence of an oral formulation. Frequently reported side effects include headache, nausea, diarrhea, phlebitis, and pruritus. Severe side effects such as leukopenia, neutropenia, anemia, hypokalemia, and liver toxicity are rarely reported [40,41,42].
The standard dose is 70 mg as a single loading dose followed by a maintenance dose of 50 mg once a day or 70 mg once a day when body weight exceeds 80 kg. It displays linear PK. Immediately after infusion caspofungin undergoes rapid distribution into tissue, mainly the liver. About 95% of caspofungin is typically bound to plasma proteins and it is metabolized in the liver. For non-ICU patients with moderate hepatic impairment (Child–Pugh score 7–9), reducing the maintenance dose to 35 mg per day is recommended . ICU patients with moderate liver failure may achieve subtherapeutic caspofungin exposure with the adjusted dose of 35 mg per day. The authors ascribed the low concentrations to typical physiological alterations occurring in ICU patients (hypoalbuminemia)  and recommended standard doses. Since caspofungin elimination is largely independent from renal function, standard doses are suggested in patients with renal failure, even those with terminal renal failure requiring hemodialysis [45,46,47,48,49].
Anidulafungin is licensed for the treatment of IC in adult patients. The recommended dose is 200 mg once a day on day 1 (loading dose) and then 100 mg daily (maintenance dose). Renal failure has no influence on anidulafungin elimination . Unlike caspofungin, liver failure results in decreased exposure for anidulafungin; no dose adjustment is recommended. An increased degradation due to reduced protein binding and an enlarged volume of distribution has been suggested .
Micafungin was shown to be as effective as both l-amphotericin B and caspofungin in randomized clinical trials [51, 52]. However, the potential risk for developing liver tumors indicates that use should be restricted to when other antifungals are not appropriate.