Antifungal Therapy: New and Evolving Therapies

Yasmine Nivoix; Marie-Pierre Ledoux; Raoul Herbrecht

Disclosures

Semin Respir Crit Care Med. 2020;41(1):158-174. 

In This Article

Antifungal Triazoles

Systemic triazoles are commonly administered to immunocompromised patients to prevent and treat fungal infections. Two triazole antifungal agents, fluconazole and itraconazole, were introduced almost three decades ago and have been used extensively for the prophylaxis and treatment of fungal infections.[22] Voriconazole, posaconazole, and isavuconazole are more recent extended-spectrum systemic antifungal triazoles. These agents are associated with significant drug–drug interactions, particularly with drugs metabolized by the CYP enzyme system or with membrane transporters. This is a common issue in immunocompromised patients who often take many concomitant medications, which increases the potential for drug interactions.

Mechanism of Action and Antifungal Spectrum

The azoles exert their effect by inhibiting CYP-dependent C-14 α-demethylase, an enzyme involved in the conversion of lanosterol to ergosterol (Figure 1).[23] This leads to the depletion of ergosterol, the essential sterol of the fungal cell membrane, and, ultimately, compromises cell membrane integrity. The result is fungistatic activity.

Fluconazole. The main restriction on the use of fluconazole comes from the limitation in its spectrum of activity. Although it is active against Candida spp. (except C. krusei and to a lesser extent C. glabrata) and other yeasts such as Cryptococcus, fluconazole lacks activity against molds.[10]

Itraconazole. Itraconazole is active against yeasts including Candida spp. and Cryptococcus spp., molds including agents of dermatomycosis and Aspergillus spp., and dimorphic fungi.[10]

Voriconazole. Voriconazole has a broad spectrum of activity, including most pathogenic yeasts and various filamentous fungi such as Aspergillus spp. and, to a certain extent, Scedosporium spp. and Fusarium spp.[24] Voriconazole is the gold standard for the treatment of invasive aspergillosis.[3,14,25] However, voriconazole lacks activity against the agents of mucormycosis, and breakthrough yeast and mold infections have been reported during voriconazole therapy.[26–28]

Posaconazole. In addition to demonstrating activity against the most frequently isolated yeast and mold pathogens including Candida spp. and Aspergillus spp., posaconazole is also active against most fungi in the Mucorales order.[10]

Isavuconazole. In vitro, isavuconazole shows a broad spectrum of activity and is active against yeasts (C. neoformans and Candida spp. including C. glabrata, C. krusei, and C. guilliermondii) and molds such as Aspergillus spp. and Mucorales (Mucor, Rhizomucor, Rhizopus, and Cunninghamella), whereas its activity is lower against Scedosporium spp. and Fusarium spp.[29,30]

Clinical Pharmacokinetics of Systemic Antifungal Azoles

Chemically, all azoles are weak bases. Itraconazole and posaconazole are very lipophilic and generally not soluble in water.[31,32] Voriconazole is lipophilic and has limited water solubility.[33] In contrast, fluconazole and isavuconazole are more water-soluble.[34,35] Moreover, the systemic azoles are substrates and inhibitors of CYP isoforms to various degrees.[36–38] Some azoles are also substrates and/or inhibitors of drug transporters.[39–43] These physicochemical and metabolic properties are the basis of the pharmacokinetic differences and drug–drug interactions involving this class.

Fluconazole. Because fluconazole is water-soluble and more polar than the other systemic azoles, it can be formulated as an IV form without the use of a solubilizing agent. This chemical property also allows fluconazole to circumvent much of the hepatic metabolism required by the other azoles for elimination. Oral fluconazole formulations are rapidly and nearly completely absorbed, with a bioavailability in excess of 93%. Fluconazole absorption is not dependent on acidic gastric conditions or the presence of food.[44] In contrast to other azoles, fluconazole minimally binds proteins and thus circulates mostly as free drug.[34] Fluconazole also distributes extensively into a variety of body fluids and hepatic and renal tissues.[44]

Fluconazole undergoes minimal CYP-mediated metabolism. Fluconazole is distinct among systemic azoles since approximately 91% of an orally administered dose is excreted in the urine.[34] Most (80%) is excreted as unchanged drug and therefore has good activity against urinary tract infections due to yeasts. Two inactive metabolites account for the remaining 11%: a glucuronide conjugate of unchanged fluconazole and an N-oxide form.[45]

Itraconazole. Itraconazole is marketed as capsules containing itraconazole-coated sugar pellets and as a solution in a 40% hydroxypropyl-β-cyclodextrin solution for oral and IV use. The absolute bioavailability of the oral solution is 55%, approximately 30% higher than that of the capsule formulation.[46,47] Following oral administration, itraconazole is highly protein bound (99%) and widely distributed in the body.[47] Recently, a new capsule formulation has been developed and approved.[48,49] This formulation, called SUBA (SUper BioAvailability) itraconazole, is a solid dispersion of itraconazole in a pH-dependent polymeric matrix enhancing its dissolution and intestinal absorption.

Itraconazole exhibits dose-dependent elimination and is extensively metabolized in the liver into many metabolites by CYP3A4. The complete metabolic pathway of itraconazole is fully elucidated, and it may be acted on by additional isoforms.[47] The main metabolite, hydroxyitraconazole, has considerable antifungal activity.[47] Itraconazole and hydroxyitraconazole circulate at comparable concentrations.[31,47,50,51] Fecal excretion of the parent drug varies between 3 and 18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine.[52]

Voriconazole. Voriconazole is available in both IV and oral formulations. IV voriconazole is formulated with the solubilizing agent sulfobutyl ether β-cyclodextrin. Following oral dosing, voriconazole absorption is rapid and nearly complete, with a relative bioavailability of approximately 90%.[53] Voriconazole is moderately bound (58%) to plasma proteins and is widely distributed throughout the body.[54] Notably, unlike itraconazole, both fluconazole and voriconazole distribute into the cerebrospinal fluid and central nervous system tissues.[34,55–57]

Voriconazole undergoes extensive hepatic metabolism by CYP enzymes into eight metabolites that are inactive. The hepatic metabolism of voriconazole is more complex than other azoles and involves several different CYP enzymes: voriconazole is metabolized into its main N-oxide metabolite by CYP2C19, CYP3A4, and, to a lesser extent, CYP2C9.[58] CYP2C19 metabolism is the primary pathway, and this isoform exhibits a genetic polymorphism. The CYP2C19 polymorphism is most prevalent among Asian, Polynesian, and Micronesian populations, and results in a slower metabolism.[58,59] Voriconazole is also metabolized by CYP2C9, which also exhibits a polymorphism that, if expressed, is associated with reduced CYP2C9 activity. This polymorphism is most prevalent among Caucasians, less frequent among African-Americans, and absent in Asian populations.[58] To date, no significant polymorphism has been identified for the CYP3A4. Nonetheless, variability in CYP3A4 expression is widely documented and may contribute somewhat to interindividual variability in voriconazole pharmacokinetics. Less than 2% of an administered dose is excreted in the urine unchanged.[33]

Posaconazole. Posaconazole is marketed as an aqueous suspension for oral use, gastro-resistant tablets, and IV formulation.[32] Food consumption is the most critical factor that affects the bioavailability of the oral suspension of posaconazole. Previous studies have demonstrated that food, particularly high-fat meals, significantly increases posaconazole bioavailability.[60,61] Gastro-resistant tablets were designed to ensure a better and less variable bioavailability.[62] Under fasting or nonfasting conditions, antacid coadministration has no statistically significant effect on posaconazole oral bioavailability.[60] Posaconazole is highly protein bound (>98%), predominantly to albumin, and has a large apparent volume of distribution, suggesting extensive penetration into the peripheral tissues.[63]

Posaconazole is primarily metabolized in the liver, where it undergoes glucuronidation and transformation into other biologically inactive metabolites.[64] Approximately 14% of an administered dose is excreted as multiple glucuronidated derivatives in the urine; an additional 77% is eliminated as parent compound in the feces.[32] Minor amounts are excreted as parent compound in the urine. Unlike other azoles, posaconazole is not primarily metabolized by CYP enzymes.

Isavuconazole. Isavuconazole is the active moiety formed after oral or IV administration of isavuconazonium sulfate, and its chemical structure is similar to that of fluconazole and voriconazole. The oral absolute bioavailability of isavuconazole amounts to 98%, and IV and oral dosing can thus be used interchangeably.[65] Isavuconazole is highly protein bound (>99%), predominantly to albumin, and has a large apparent volume of distribution (300–500 L) and extensive penetration into the peripheral tissues, including sanctuary sites such as the brain.[66–68]

Isavuconazole undergoes hepatic metabolism by CYP (CYP3A4 and CYP3A5) enzymes and is subsequently metabolized by uridine diphosphate-glucuronosyltransferase (UGT). Urinary excretion of unchanged isavuconazole is less than 1% of the administered dose. Isavuconazole has a long elimination half-life (80–120 hours).[66,67] In Asians, clearance is approximately 36% lower than in Caucasians.[69]

Dosage and Adjustments

Fluconazole. The recommended dose of fluconazole in invasive candidiasis ranges from 400 to 800 mg/day and can be 100 to 200 mg/day for other indications (Table 3). In the case of renal impairment or in elderly patients, the dosage or interval between administrations should be adjusted for creatinine clearance. No adaptation in fluconazole dosage is needed for hepatic impairment.

Itraconazole. The recommended daily dose of itraconazole is 200 to 400 mg. With moderate renal impairment, an adjustment of dosage can be made with therapeutic drug monitoring (TDM). If creatinine clearance is lower than 30 mL/minute, another antifungal is preferred. For severe hepatic impairment or cirrhosis, prolonged drug half-life and clearance warrant serum level monitoring. In neutropenic and AIDS patients, low serum levels should prompt a higher dosage (400 mg/day). SUBA-itraconazole dosing is 130 to 260 mg/day. TDM is usually recommended after reaching a steady state, all the more so when factors influencing absorption are present (fasting, graft-versus-host disease, diarrhea, mucositis) or when itraconazole is administered with some enzyme inducers (e.g., phenobarbital, carbamazepine).

Voriconazole. Two loading doses of voriconazole at 6 mg/kg every 12 hours are recommended followed by 4 mg/kg every 12 hours both for treatment and prophylaxis. This dosage must be reduced in case of mild-to-moderate hepatic impairment and drug levels, and liver function be monitored carefully. No adjustment of dosage is needed in case of renal impairment, but the oral route should be used due to the nephrotoxic excipient of the IV formulation.

Posaconazole. Both tablet and IV formulations of posaconazole are dosed at 300 mg/day, with a loading dose of twice a day on day 1 for the tablets. The dosage for oral suspension is 800 mg/day, divided. No adaptation is needed in the case of renal impairment. Clinical hepatitis or elevated hepatic enzyme levels have been observed during posaconazole use. Monitoring of liver enzymes is therefore mandatory, especially bilirubin levels. Discontinuation is advised if hepatitis occurs.

Isavuconazole. The recommended dose of isavuconazole is 200 mg/day preceded by a loading dose of 200 mg every 8 hours for 2 days. No adjustment of dosage is needed in patients with mild, moderate, severe, or terminal renal impairment or mild-to-moderate hepatic impairment. No data are available on severe hepatic impairment.

Drug–Drug Interactions

Due to their physical and chemical properties, such as low water solubility, and their action on CYP, azole use can be difficult, with numerous drug–drug interactions.

Interactions Through Antifungal Absorption. Gastric pH can alter the absorption of itraconazole and posaconazole solution; the drugs are weak bases with an optimal dissolution in a pH ranging from 1 to 4. Fluconazole, voriconazole, and isavuconazole are stronger acids with a lower pKa, and their dissolution is not altered by a higher gastric pH. Absorption of the older capsule formulation of itraconazole is decreased if the drug is taken in the fasted state or with antacids, H2 antihistaminics, or proton pump inhibitors. Unlike with itraconazole capsules, absorption of oral itraconazole suspension is increased when given in the fasted state, and SUBA-itraconazole absorption is not markedly different in fed or fasted states.[48] Either formulation is preferred over the capsules due to improved absorption. Furthermore, absorption of SUBA-itraconazole is increased in the presence of proton pump inhibitors.[48] For all formulations, serum trough levels should be monitored.

The oral suspension of posaconazole demonstrates decreased absorption if taken with H2 antihistaminics or proton pump inhibitors, whereas the tablet formulation spares posaconazole from significant interactions relying on gastric pH and is therefore widely preferred over the suspension.

Interactions Through Metabolism. With phase 1 drug metabolism, all triazole antifungals are inhibitors of CYP3A4/5 enzymes (Table 4). Voriconazole and isavuconazole also inhibit CYP2B6, whereas CYP2C9 and CYP2C19 are targets of both fluconazole and voriconazole. With regard to phase 2 drug metabolism, posaconazole is a substrate of UGT, and both fluconazole and isavuconazole are inhibitors of this enzyme. P-glycoprotein (P-gp) acts as a membrane transporter for all currently used azoles except for voriconazole; itraconazole, posaconazole, and isavuconazole also inhibit P-gp. The breast cancer resistance protein membrane transporter is inhibited by itraconazole, posaconazole, and isavuconazole, with the latter also inhibiting organic cation transporter 2 (Table 4).

Given the complexity of interaction mechanisms, it can be difficult to define whether a drug–drug interaction is linked to CYP or to membrane transporters. Nevertheless, the consequences of coadministration of a systemic azole with a compound active on CYP or membrane transporters can be divided into the following three categories:

  • Alteration of azole metabolism by the associated drug.

  • Alteration of the associated drug metabolism by the azole.

  • Two-way interactions.

Knowledge of the underlying molecular mechanism of interactions helps predict the resulting changes in the plasma concentration of each drug. As this knowledge continues to evolve, one should keep in mind that an unexpected toxicity or failure of the azole could represent a missed interaction. Several clinically relevant interactions are explained in Table 5, which is, as foresaid, not exhaustive.

Therapeutic Drug Monitoring. For the management of clinically relevant drug–drug interactions and absorption issues, TDM is often needed to prevent under- or overdosage of antifungal triazoles. It is particularly indicated for itraconazole, voriconazole, and posaconazole. Target drug concentration can depend on indication, for instance, a level of 0.5 μg/mL is recommended for itraconazole prophylaxis but 1.0 μg/mL for the treatment of aspergillosis.

The role of underdosing voriconazole in the treatment failure of invasive mycoses has been well documented: failure has been reported in 46% of patients with a voriconazole plasma concentration of ≤1.0 μg/mL, as opposed to only 12% of patients with a concentration higher than 1.0 μg/mL.[70] Overdosage must be suspected and assessed in patients with unexpected toxicity: serum trough levels higher than 5.5 μg/mL have been associated with encephalopathy.[70]

Given the high variability of plasma concentrations of posaconazole oral suspension, low plasma levels (i.e., less than 0.5 μg/mL) are common, and in one study, up to 44% of prophylaxis patients and 22% of treatment patients had low levels.[71] Therefore, TDM is mandatory when using this formulation. Posaconazole tablets provide higher trough levels than oral suspension, but the inter- and intraindividual variabilities remain high.[72]

TDM for itraconazole, voriconazole, and posaconazole suspension is recommended by the Infectious Diseases Society of America guidelines.[14,73] Further studies are needed to address whether TDM is helpful for IV or oral tablet formulations of posaconazole or isavuconazole.

Tolerability

Fluconazole. Fluconazole is well tolerated in standard doses. Digestive disturbances are described, including nausea, abdominal pain, and flatulence. In AIDS and cancer patients, hepatic (cholestasis or cytolysis), renal, and hematological disorders are reported. Rare cases of severe liver injury due to fluconazole are reported. A known hepatic impairment must prompt laboratory monitoring when fluconazole is used, and prothrombin time and international normalized ratio should be followed if warfarin is coadministered, given the drug–drug interaction. Skin reactions have been observed, particularly in AIDS patients receiving concomitant medications, leading to severe exfoliation. If a rash seems related to the introduction of fluconazole, reintroduction is prescribed.

Itraconazole. In short-duration treatments (under 1 month), itraconazole is associated mostly with nausea, abdominal pain, headaches, dizziness, and allergic reactions. In longer-duration treatments, the incidence of side effects reaches 16%, mostly comprising digestive disorders. Episodes of hypokalemia have also been reported. Liver enzymes may increase with itraconazole therapy, and if there is significant elevation or if there are clinical symptoms of gastrointestinal or liver dysfunction such as anorexia, nausea, vomiting, asthenia, or dark urine, treatment should be modified or discontinued.

Voriconazole. Hepatic disorders may also be seen with voriconazole, and monitoring of liver enzymes is recommended. More specific to this azole are adverse effects on vision, including dyschromatopsia, blurred vision, and photophobia, affecting 30 to 40% of patients, usually transiently. The mechanism by which the visual symptoms occur remains unclear. Erythema, skin rash, and photosensitization, with an increased risk of skin carcinoma in case of prolonged treatment, are also specific side effects. They must be taken into account in the assessment of benefit–risk balance, and strict sun protection must be enforced in long treatments. Psychiatric side effects may also occur, such as hallucinations and confusion.

Posaconazole. The most common side effects of posaconazole are digestive disorders, xerostomia, headaches, dizziness, fatigue, and drowsiness. They are usually mild and reversible. Most frequent among them are diarrhea (11%) and neutropenia (7%). Long-duration treatments (more than a year) are usually well tolerated.

Isavuconazole. The safety profile of isavuconazole has yet to be fully understood, but it seems consistent with other azoles, including liver disorders and skin side effects. Most frequent in recent clinical studies are liver enzyme increases, nausea, vomiting, dyspnea, abdominal pain, diarrhea, injection-site reactions, headaches, and skin rashes. The overall long-term tolerability of isavuconazole requires further study.

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