INTRODUCTION — Azole antifungal agents have added greatly to the therapeutic options for treatment of systemic fungal infections. The azoles that are available for systemic use can be classified into two groups: the triazoles (fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) and the imidazoles (ketoconazole).
An overview of the use of azole agents for the treatment of various systemic fungal infections will be reviewed here.
Detailed disease-specific treatment and prophylaxis recommendations are presented elsewhere:
●Candidiasis (see "Management of candidemia and invasive candidiasis in adults" and "Oropharyngeal candidiasis in adults" and "Candida vulvovaginitis in adults: Treatment of acute infection" and "Candida infections of the bladder and kidneys")
●Aspergillosis (see "Treatment and prevention of invasive aspergillosis" and "Chronic pulmonary aspergillosis: Treatment")
●Cryptococcosis (see "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention" and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus gattii infection: Treatment")
●Histoplasmosis (see "Diagnosis and treatment of pulmonary histoplasmosis" and "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients" and "Treatment of histoplasmosis in patients with HIV")
●Blastomycosis (see "Treatment of blastomycosis")
●Coccidioidomycosis (see "Primary pulmonary coccidioidal infection" and "Coccidioidal meningitis" and "Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis")
●Prophylaxis of invasive fungal infections (see "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients")
OVERVIEW OF CLINICAL USES — Members of the triazole family are some of the most widely used antifungal agents . The drugs in this class offer activity against many fungal pathogens without the serious nephrotoxic effects observed with amphotericin B. Newer azole agents have emerged as first-line therapies for several severe fungal diseases, such as invasive aspergillosis, for which voriconazole has become the standard of care.
There are currently five members of the triazole class licensed for use in the United States (fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole). It is important for clinicians to appreciate the unique characteristics of each member of this class in order to use azoles appropriately.
Agents within the azole class vary importantly with regards to spectrum of activity, pharmacokinetic profiles, and toxicities. For example, fluconazole has excellent activity against yeasts but offers no protection against molds. An extended spectrum is provided by itraconazole, but inconsistent bioavailability limits use of this agent in severely ill patients. Voriconazole is one of the first-line agent for the treatment of invasive aspergillosis, but its bioavailability is unpredictable and genetically determined, it is associated with unique side effects, and it lacks activity against the Mucorales, the agents of mucormycosis. Among the azoles, posaconazole and isavuconazole have the broadest spectrum of activity. Both are available as intravenous (IV) and oral formulations.
The azoles have significant drug-drug interactions, but the magnitude of each interaction varies with the individual azole. Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate. A general discussion of relevant drug interactions is presented below. (See 'Drug interactions' below.)
The systemic use of earlier azoles, such as ketoconazole, has largely been replaced by the triazoles because of superior pharmacokinetics, improved safety profiles, and higher efficacy for the treatment of systemic mycoses.
MECHANISM OF ACTION — The azole antifungals work primarily by inhibiting the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase . This enzyme is necessary for the conversion of lanosterol to ergosterol, a vital component of the cellular membrane of fungi. Disruptions in the biosynthesis of ergosterol cause significant damage to the cell membrane by increasing its permeability, resulting in cell lysis and death. Despite this mechanism of action, the triazoles are generally considered fungistatic against Candida species. For voriconazole, fungicidal activity against Aspergillus species has been demonstrated .
MICROBIOLOGIC ACTIVITY — Each member of the azole class exhibits a unique spectrum of activity, although fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole all demonstrate similar activity against most Candida species . For detailed discussions of the clinical use of these agents, see the appropriate topic for specific fungal infections.
●Fluconazole has activity limited to yeasts and some clinical activity against the endemic fungi (Histoplasma, Blastomyces, Coccidioides, and Paracoccidioides spp), although it is not as potent as itraconazole for the endemic fungi. In general, it has excellent activity against Candida species but has less activity against C. glabrata and no activity against C. krusei. It has excellent activity against Cryptococcus species.
●Itraconazole offers a broader spectrum of activity than fluconazole, including endemic fungi, Sporothrix schenckii, and Aspergillus species. It is also active against the dematiaceous (brown-black) molds.
●Voriconazole has enhanced activity against Aspergillus species and other hyalohyphomycoses, including Scedosporium apiospermum and Fusarium species. It also has activity against dematiaceous molds. Voriconazole demonstrates superior activity in vitro against fluconazole-resistant C. glabrata and against C. krusei.
PHARMACOKINETICS — No two triazole agents offer the same pharmacokinetic profile. Understanding the differences among the members of this class with regards to metabolism and elimination is essential in order to safely and effectively administer these agents in the complex patient populations at risk for fungal infection. It is important to appreciate the differences in bioavailability, metabolism, and toxicities among these agents, as well as among different preparations of a given drug, since inconsistencies do exist (table 1) .
Fluconazole — Available in both oral and intravenous (IV) preparations, fluconazole is very hydrophilic and is almost completely absorbed following oral administration; the reported bioavailability is over 90 percent (table 1) . Fluconazole's absorption is not affected by the presence of food or gastric pH. There is also an IV preparation, which is useful if gastrointestinal absorption or motility is impaired.
A single dose of fluconazole is widely distributed into body fluids and tissues, with only 10 to 12 percent being protein bound . High concentrations can be measured in urine as well as prostatic tissues.
Fluconazole distributes well into the cerebrospinal fluid (CSF), with levels reaching 60 to 80 percent of serum levels [11,12]. Fluconazole achieves concentrations in the vitreous body of 20 to 70 percent that in the serum [13,14].
The long serum half-life (approximately 24 hours) allows once-daily dosing. Fluconazole is metabolized to a minimal extent; greater than 80 percent of a single dose is excreted unchanged in the urine. Thus, dose adjustments are necessary in patients with compromised renal function . Dose adjustments may also be needed in obese patients with severe, invasive fungal infections .
Itraconazole — Itraconazole is widely available as a capsule and an oral solution (table 1). An IV formulation, available in some countries, is no longer available in the United States. In 2018, a new formulation designed to enhance bioavailability, SUBA itraconazole, was approved by the US Food and Drug Administration (FDA) .
The bioavailability of itraconazole is highly variable. The capsule formulation has a bioavailability of approximately 55 percent, whereas the bioavailability of the itraconazole solution (containing cyclodextrin) in fasting state is approximately 30 percent greater than with capsules . Due to differences in bioavailability, none of the itraconazole formulations can be used interchangeably, and the solution is preferred. However, gastrointestinal upset is more common with the solution, and some patients cannot tolerate this formulation. There are potential pharmacokinetic advantages to the SUBA itraconazole formulation, but studies to demonstrate improved exposure to itraconazole and efficacy in patients with invasive fungal infection are ongoing .
The optimal conditions for administration of each formulation differ:
●Itraconazole capsules require food and an acidic gastric pH for solubilization . Absorption can be increased by concurrent ingestion of cola [20,21] or cranberry juice, and is impaired by drugs that interfere with gastric acidification. Impaired absorption is greatest with proton pump inhibitors , which should be avoided; intermediate with histamine H2 receptor blockers [20,23,24]; and least with antacids, which have a short duration of action.
●In contrast, the bioavailability of the oral solution is not altered by gastric pH. It should be administered on an empty stomach for optimal absorption; even in the presence of food, higher serum concentrations are achieved with the oral solution than with the capsule [24,25].
●The SUBA itraconazole formulation uses a solid dispersion of itraconazole in a polymeric matrix to allow better intestinal absorption. It is reported to have better serum drug exposure compared with itraconazole capsules (173 percent relative bioavailability) . This formulation needs to be administered with food and requires a different dosing regimen than other formulations of itraconazole.
Hydroxypropyl-beta-cyclodextrin is used to solubilize the IV and oral formulations. This vehicle is known to accumulate in patients with impaired renal function and, therefore, use of the IV preparation is limited to patients with a creatinine clearance (CrCl) >30 mL/min. Since the cyclodextrin vehicle is not absorbed from the oral solution, patients should be converted to either oral formulation as soon as is feasible.
Itraconazole has a relatively long half-life, approaching 25 to 50 hours, and thus allows for once-daily dosing if using up to 200 mg daily. However, when 400 mg daily is required, dosing should be split into two divided doses to optimize absorption.
Approximately 99 percent of itraconazole and its active hydroxy metabolite are bound to plasma proteins. Unbound itraconazole is highly lipophilic and extensively distributed in human tissues, reaching high concentrations in the lungs, kidneys, and epidermis . High levels (greater than three times the corresponding serum levels) are observed in the skin, nails, liver, adipose tissue, and bone [28,29]. Only trace amounts are detected in the cerebrospinal fluid and the eye.
Metabolism of itraconazole is extensive in the liver (primarily via cytochrome P450 3A4), and excretion of inactive metabolites occurs primarily in the urine and feces . Active drug does not appear in the urine, and itraconazole cannot be relied upon to treat urinary tract infections. A hepatic metabolite, hydroxyitraconazole, is bioactive, with activity similar to that of the parent compound .
Voriconazole — The oral tablet formulation of voriconazole has a bioavailability of greater than 90 percent (table 1) . Oral bioavailability is reduced by approximately 30 percent when taken with a high fat meal. Administration on an empty stomach, one to two hours before or after a meal, is preferable [32,33]. The powder for suspension possesses equivalent oral bioavailability compared with the tablet. The oral formulations do not contain cyclodextrin . However, the IV preparation of voriconazole contains a sulfobutyl ether-beta-cyclodextrin vehicle, which is known to accumulate in patients with impaired renal function. Thus, use of the IV preparation is limited to patients who have CrCl >50 mL/min. However, it should be noted that in severe infections requiring IV administration, the IV formulation of voriconazole has been safely used .
Voriconazole is well distributed throughout the body as demonstrated by its large volume of distribution (4.6 L/kg) and ability to penetrate into the CSF [32,35]. Voriconazole undergoes extensive hepatic metabolism by the cytochrome P450 enzyme system. The specific enzymes involved are CYP2C19, 2C9, and 3A4 . Unlike itraconazole, there are no active metabolites. A 50 percent maintenance dose reduction, after a full loading dose, is recommended for patients with mild and moderate chronic hepatic insufficiency (Child-Pugh Classes A and B) [32,33].
CYP2C19 gene polymorphisms appear to play an important role in the interindividual variability that has been observed with voriconazole [36,37]. Slow metabolizers via CYP2C19 (including 15 to 20 percent of persons of Eastern or Southern Asian or Oceanian descent) exhibit significantly greater systemic exposure and therefore should be considered at elevated risk of dose-related adverse effects such as hepatotoxicity [32,38]. CYP3A4 gene polymorphisms also appear to affect voriconazole serum concentrations . (See 'Overview of CYP and other effects' below.)
Less than 2 percent of voriconazole is excreted in the urine as unchanged drug. Thus, urine concentrations of voriconazole do not reach therapeutic levels and should not be relied upon to treat urinary tract infections. Dose adjustments of oral voriconazole are not necessary for patients with renal dysfunction.
Voriconazole exhibits nonlinear pharmacokinetics . Increasing the dose of voriconazole by 50 percent can lead to a 150 percent increase in serum concentration and a significant increase in serum half-life. This is important to consider because some voriconazole-associated toxicities are associated with higher serum concentrations [41,42]. Furthermore, higher doses of voriconazole have not been associated with improved clinical outcomes. (See 'Voriconazole' below.)
Posaconazole — Posaconazole is available in various formulations: IV, delayed-release tablets, immediate-release oral suspension, and delayed-release oral suspension . The IV formulation (approved for patients two years of age and older) is useful for patients when oral administration is not a viable option or in cases in which absorption may be of concern. Among the oral formulations, we prefer the delayed-release tablets due to less pharmacokinetic variability between fed and fasting states compared with the oral suspension . The delayed-release tablets and oral suspension and the immediate-release oral suspension are all approved for patients two years of age and older. However, the delayed-release oral suspension is only approved for those who weigh ≤40kg.
Effective absorption of the oral suspension requires oral intake, optimally with a high-fat meal, and it may be impaired in the setting of gastrointestinal tract disruption (eg, graft-versus-host disease or mucositis) (table 1) [45-47]. For the delayed-release tablets, administration with food is recommended; however, this formulation demonstrates less variability in pharmacokinetic parameters related to food when compared with the oral suspension . The delayed-release tablets are therefore especially useful in patients who cannot eat a full meal because, under fasting conditions, at a dose of 300 mg daily, the exposure is higher than that seen in patients taking 200 mg three times daily of the oral suspension . A study of neutropenic patients at high risk for invasive fungal infection given either 200 mg or 300 mg posaconazole once daily (following a twice-daily loading dose on day 1 in both groups) without regard to food intake showed that on day 8, the pharmacokinetic exposure target was reached in 15 of 19 patients (79 percent) taking 200 mg once daily and in 31 of 32 patients (97 percent) taking 300 mg once daily . Other studies have shown that patients taking the delayed-release tablets achieve higher serum concentrations than patients taking the oral suspension [49,50].
Absorption of the oral suspension appears to saturate at a total daily dose of 800 mg/day and is maximized when divided into multiple daily administrations. When given as four daily doses, total serum concentration was greater than when the same total amount of drug was divided into two doses .
The elimination half-life of the active (parent) compound of the oral suspension is approximately 27 hours in patients with normal hepatic function . Approximately 15 percent of an administered dose of posaconazole undergoes non-cytochrome 450 (CYP) hepatic metabolism to inactive metabolites and is excreted in urine and feces [43,52]. The unchanged parent drug is primarily eliminated via the fecal route (77 percent). Therefore, only minimal amounts are recovered in the urine; the drug cannot be relied upon to treat urinary tract infections, and dose reductions are not required for patients with renal insufficiency . Posaconazole is an inhibitor of CYP3A4 metabolism and P-glycoprotein (P-gp) efflux. (See 'Drug interactions' below.)
Isavuconazole — Isavuconazole was approved by the US Food and Drug Administration in March 2015 . It is formulated as the prodrug, isavuconazonium sulfate, and it is available as an IV formulation and an oral formulation (capsules) [6,54]. Isavuconazole has a prolonged half-life (T½) of 130 hours, which enables once-daily dosing following two days of every eight hour dosing (six loading doses), and has as a large volume of distribution of about 450 L, suggesting a high degree of tissue penetration (table 1). The oral capsules are well absorbed with an absolute bioavailability of 98 percent that is essentially unaltered by food intake. Administration of opened capsules via enteral feeding tube results in similar concentrations to intravenously administered drug . Isavuconazole clearance is highly dependent upon hepatic CYP3A4 metabolism and thereby subject to significant drug interactions. (See 'Drug interactions' below.)
The oral and IV formulations are delivered as a water-soluble prodrug, known as isavuconazonium sulfate, which is rapidly and almost completely (>99 percent) converted by plasma esterases to the active moiety isavuconazole and an inactive cleavage product . The 186 mg isavuconazonium sulfate oral capsule provides 100 mg of isavuconazole base and the 372 mg isavuconazonium sulfate injection vial provides 200 mg of isavuconazole base. How the dose is expressed (ie, isavuconazonium sulfate salt, isavuconazole base, or both) can differ regionally. As an example, the available product in the United States is expressed primarily in milligrams of isavuconazonium sulfate salt, whereas the available product in Canada, Europe, and the United Kingdom is expressed primarily in equivalent amount of isavuconazole base. To avoid confusion, consult local labeling before prescribing.
The inactive cleavage product is rapidly eliminated by metabolism, does not appear to accumulate after repeated dosing, and represents 1.3 percent or less of the total exposure to isavuconazole. Neither IV nor oral formulations contain cyclodextrin, a solubilizing agent used in some other azoles (eg, voriconazole), which can accumulate in renal impairment following IV administration and potentially cause nephrotoxicity. (See 'Voriconazole' below.)
Ketoconazole — Ketoconazole is available as an oral formulation and as a cream, gel, foam, and shampoo for topical use. Elimination is biphasic with a half-life of two hours within the first 10 hours and eight hours thereafter . Approximately 13 percent of oral ketoconazole is excreted in the urine, of which only 2 to 4 percent is unchanged drug. The majority of the drug is excreted via the biliary system. Penetration into the CSF is poor.
Absorption of the oral formulation is highly variable among individuals . Ketoconazole requires an acidic gastric pH for optimal absorption. Absorption can be increased by administration with a cola beverage  and is impaired by drugs that interfere with gastric acidification. The effect is greatest with proton pump inhibitors (eg, omeprazole) ; intermediate with H2 receptor blockers; and least with antacids or sucralfate, which have a short duration of action [59-61].
ADVERSE EFFECTS — Triazoles are generally well tolerated. Gastrointestinal (GI) symptoms are most frequently reported, including nausea, abdominal pain, vomiting, and diarrhea. The latter is most notable with itraconazole oral solution and is caused by the cyclodextrin vehicle, which enhances its solubility . Ketoconazole also commonly causes GI distress.
Hepatotoxicity — Hepatic function abnormalities are associated with all of the azoles. These range from mild elevations in transaminases to severe hepatic reactions including hepatitis, cholestasis, and fulminant hepatic failure. The approximate incidence of mild transient transaminase abnormalities associated with azole drugs is reported to be from 2 to 12 percent. Hepatic inflammation may be exposure related, especially with voriconazole, but a clear dose or time course relationship is not well established. The toxicity is usually hepatocellular but may be cholestatic or both.
Hepatic abnormalities necessitating drug discontinuation have been reported in less than 1 to 8 percent of patients in postmarketing experience and clinical trials. In most cases in which azole drug therapy was discontinued promptly following the emergence of abnormal transaminases, normalization of values and resolution of symptoms, if any, occurred gradually over weeks. Close monitoring of transaminases is recommended, particularly in the first weeks and months of therapy. The decision to stop azoles when transaminase elevations occur is made by the clinician determining the risks versus the benefits for each patient.
Careful monitoring of liver enzymes is recommended for all patients receiving azole therapy, since this adverse effect does not appear to be associated with duration of antifungal therapy or other identifiable risk factors. High-dose therapy, drug interactions, and genetic polymorphisms that increase systemic exposure to azoles may increase the risk of hepatotoxicity. While the majority of cases of hepatic toxicity resolve after discontinuation of therapy, fatal events have been reported with each agent.
Drug-specific adverse effects — Each of the azoles carries a unique side effect profile, in addition to those seen with the entire class. Some of these are discussed briefly below.
Itraconazole — Itraconazole can cause a triad of hypertension, hypokalemia, and peripheral edema . Cases of heart failure have been described in patients receiving itraconazole . This agent should not be used for the treatment of simple conditions, such as onychomycosis, in patients with evidence of ventricular dysfunction or with a history of congestive heart failure .
The cyclodextrin vehicle that is used to solubilize the oral solution can cause gastrointestinal distress .
Voriconazole — Voriconazole is associated with several unique adverse reactions; these include transient vision changes, a photosensitivity rash, alopecia, and periostitis, which is seen only in those on long-term voriconazole therapy.
●Vision changes – Among 1655 patients included in trials of voriconazole, abnormal vision, including photopsia or flashes of light, was reported in 19 percent, photophobia in 2 percent, and color changes in 1 percent . These transient effects are temporally associated with drug dosing, occurring within 30 minutes of oral or intravenous (IV) administration. Symptoms usually last for approximately 30 to 60 minutes but, in some patients, can be prolonged for hours. Clinical trials suggest that visual abnormalities may be associated with higher dosing or serum concentrations. These effects generally subside with continued therapy over several weeks. Counseling patients regarding potential effects on operating a motor vehicle is warranted [32,66].
●Neurologic toxicity – A serious adverse effect that must be distinguished from minor vision changes, such as photopsia, is that of visual hallucinations which represent neurologic toxicity that has been linked to serum concentrations of voriconazole >5.5 mcg/mL . In addition to visual hallucinations, patients with neurologic toxicity may also have confusion, agitation, myoclonic movements, and auditory hallucinations. These effects disappear when the serum concentration is lowered to <5.5 mcg/mL. Some patients, even when they have appropriate serum levels, complain of having trouble thinking, an inability to focus on a task, or just not seeming themselves for several hours after taking voriconazole.
●Skin toxicity – A rash associated with voriconazole therapy was reported in approximately 7 percent of patients enrolled in clinical trials . One type of rash seen with voriconazole is a photosensitivity reaction. Sun avoidance should be encouraged in patients who have experienced photosensitivity reactions during voriconazole therapy or who are concomitantly using drugs associated with ultraviolet reactivation reactions (eg, methotrexate). The rash has precipitated discontinuation of voriconazole and abates with withdrawal of therapy. Rare cases of severe rash (Stevens-Johnson syndrome, toxic epidermal necrolysis) have also been reported .
An association has been observed between long-term use of voriconazole and the development of skin cancers, mostly squamous cell carcinomas but also melanomas; clinicians should therefore examine patients on long-term voriconazole for concerning skin lesions [68-75].
●Periostitis – Periostitis is an adverse event that has been observed in patients who have been taking voriconazole for many months [76-79]. It appears to be due to fluoride excess and typically presents as bone pain, elevated alkaline phosphatase, and characteristic findings along the periosteum of affected bones on plain radiographs and bone scans. The US Food and Drug Administration (FDA) recommends that voriconazole be discontinued in patients who develop skeletal pain and radiologic findings compatible with fluorosis or periostitis .
A case-control study and detailed analysis of serum fluoride concentrations in transplant patients on long-term voriconazole showed a significant correlation between fluoride levels and voriconazole use . Among three allogeneic hematopoietic cell transplant recipients who developed periostitis during long-term voriconazole use, cessation of treatment resulted in clinical improvement in all cases . Clinically relevant periostitis was associated with renal insufficiency and with substantial elevations in serum fluoride concentration. Two patients who developed clinically relevant periostitis had serum fluoride concentrations that were >10-fold higher (316 mcg/L and 363 mcg/L) than normal concentrations (<30 mcg/L). The median serum fluoride concentration in 20 patients receiving long-term voriconazole was 157 mcg/L.
●Cardiac toxicity – Cases of QT prolongation, torsades de pointes, cardiac arrest, and sudden death have been reported in patients receiving voriconazole [32,81,82]. These adverse effects were reported in severely ill patients with multiple comorbidities and/or concomitant use of other drugs that also could have prolonged the QT interval.
●Alopecia and nail changes – Alopecia and nail changes appear to be common problems in patients taking voriconazole for a prolonged period. In a survey of patients receiving voriconazole for at least one month, 125 of 152 patients (82 percent) reported alopecia, with 19 (15 percent) reporting wearing a wig or hat because of extensive hair loss . Alopecia developed a mean of 75 days after initiation of voriconazole. Of 114 patients who discontinued voriconazole at least three months earlier, hair loss had stopped in 94 (82 percent) and regrowth had begun in 79 (69 percent), including those who were switched to itraconazole or posaconazole. Nail changes or loss occurred in 106 patients (70 percent).
There has been concern about the potential for nephrotoxicity of IV voriconazole in patients with renal dysfunction because the IV formulation contains a cyclodextrin vehicle, sulphobutylether-beta-cyclodextrin (SBECD); SBECD is a solubilizing agent that is renally cleared and that has been associated with nephrotoxicity in rats as a result of renal tubule vacuolation [84,85]. The manufacturer has recommended that IV voriconazole be avoided in patients with renal insufficiency (creatinine clearance <50 mL/min) . However, in a retrospective study that evaluated renal function in 166 patients receiving IV or oral voriconazole (one-quarter of whom had a glomerular filtration rate <50 mL/min at baseline and received IV voriconazole), neither baseline renal function nor route of administration was associated with worsening renal function . Limitations of this study are that it was a small study and that few patients received voriconazole for ≥7 days; it is possible that a longer duration of therapy in patients with preexisting renal dysfunction is more nephrotoxic than a shorter course. Further study is necessary to determine whether IV voriconazole is nephrotoxic in patients with preexisting renal dysfunction.
Posaconazole — Available data suggest that the adverse effect profile of posaconazole is more favorable than other triazoles . Gastrointestinal symptoms are commonly noted with the oral suspension. A case of torsades de pointes has been reported in a patient who was taking posaconazole, although no QTc prolongation was observed in healthy volunteers receiving posaconazole [5,43]. Incidence of QTc prolongation was described as occurring in 1 percent of 428 patients treated for neutropenic fever or refractory invasive fungal infection in phase II and III clinical trials .
Similar to ketoconazole, posaconazole can interfere with the steroid synthesis pathway. In the case of posaconazole, this can present as adrenal insufficiency  similar to that of ketoconazole. A syndrome of apparent mineralocorticoid excess associated with hypertension, hypokalemia, and alkalosis due to posaconazole has also been described . The frequency of its occurrence is unknown, and it appears to be associated with higher serum posaconazole concentrations [87,88]. It is characterized by undetectable renin and aldosterone and is often associated with an elevated cortisol to cortisone ratio with increased levels of estradiol.
The IV formulation of posaconazole contains the cyclodextrin vehicle, SBECD, which can accumulate in the setting of renal dysfunction . Concerns about the potential nephrotoxicity of SBECD in patients with renal dysfunction are discussed in greater detail above. (See 'Voriconazole' above.)
Isavuconazole — The most common adverse reactions associated with isavuconazole are nausea, vomiting, diarrhea, headache, elevated transaminases, hypokalemia, and peripheral edema . Isavuconazole may also cause serious side effects including hepatotoxicity and infusion reactions (chills, dyspnea, and hypotension). The incidence of these adverse effects is not clear and is likely no more common than with other azoles and appears to be less common than with voriconazole. Infusion reactions are rare, appear unique to isavuconazole, and could possibly be related to particulates in the IV formulation.
In a phase II trial that compared isavuconazole with voriconazole for the treatment of mold infections, drug-related side effects were lower with isavuconazole than voriconazole (42 versus 60 percent) . In this study, isavuconazole-treated patients had lower frequencies of hepatobiliary, eye, and skin or subcutaneous toxicities. Isavuconazole has been used successfully in patients who are intolerant of other azoles .
Isavuconazole is associated with shortening of the QT interval (in contrast with most other azoles, which cause prolongation of the QT interval). The clinical significance of this effect remains unclear; isavuconazole is contraindicated in patients with familial short QT syndrome.
Unlike voriconazole and posaconazole, the IV formulation of isavuconazole does not contain the cyclodextrin vehicle, SBECD, which can accumulate in the setting of renal dysfunction . (See 'Voriconazole' above.)
Ketoconazole — Ketoconazole causes more gastrointestinal intolerance than the other azoles . Like the other azoles, oral ketoconazole can also cause hepatitis. In 2013, the FDA warned that ketoconazole can cause severe liver injury, which can result in liver transplantation or death, and that it can cause adrenal insufficiency by decreasing the body’s production of glucocorticoids .
Other adverse effects include headaches, dizziness, and pruritus.
Applied topically, severe irritation, pruritus, and stinging occur commonly. Abnormal hair loss, dry/oily scalp, or itching may be seen following the application of the shampoo.
PREGNANCY — During pregnancy, we avoid systemic azole therapy, particularly during the first trimester, because it may increase the risk of miscarriage and high doses appear to increase the risk of congenital anomalies. Given risks of fetal toxicity, use of any azole agent during pregnancy should be carefully weighed based on the risk-benefit ratio. This is discussed in greater detail separately. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)
SERUM DRUG CONCENTRATION MONITORING — In many centers, it has become standard of care to monitor serum azole concentrations (table 1). Guidelines are available for recommended itraconazole concentrations when this agent is used for the treatment of certain invasive fungal infections [93-95]. Measurement of voriconazole and posaconazole serum concentrations is increasingly performed to assure efficacy in the treatment of serious fungal infections [42,96-99] and, in the case of voriconazole, to avoid toxicity .
Itraconazole — Due to the unpredictable absorption of itraconazole, the Infectious Diseases Society of America guidelines recommend monitoring serum levels in patients receiving itraconazole for the treatment of aspergillosis, histoplasmosis, or blastomycosis [93-95]. (See "Treatment and prevention of invasive aspergillosis" and "Diagnosis and treatment of disseminated histoplasmosis in HIV-uninfected patients" and "Diagnosis and treatment of pulmonary histoplasmosis" and "Treatment of blastomycosis".)
Serum concentrations should be tested only after steady state has been achieved (after two weeks of therapy). By waiting until this point, a random concentration is sufficient and is much more convenient than a peak concentration for patients being seen in the ambulatory setting.
Serum concentrations are useful in determining whether or not individuals are absorbing itraconazole but also provide information when drug-drug interactions might be a problem and help define whether the patient is compliant with their medications. It is recommended that the measured serum itraconazole concentration for the treatment of invasive fungal infections, such as histoplasmosis and blastomycosis, should be at least 1 mcg/mL by high-performance liquid chromatography (HPLC) and 3 mcg/mL by bioassay [93,94]. Levels of at least 2 ug/mL by HPLC are preferred by some clinicians.
Itraconazole activity is due not only to the parent drug but also to its active metabolite, hydroxyitraconazole. Two common techniques for measuring itraconazole concentrations handle this factor differently:
●HPLC measures the quantity of each component separately. Most laboratories run HPLC assays for itraconazole and hydroxyitraconazole concurrently and the results of both tests should be considered when attempting to evaluate clinical activity. We advocate adding these two results together to get a sum of itraconazole activity.
●In contrast to HPLC, bioassay results represent the amount of both the parent drug and the active metabolite. Itraconazole concentrations measured by bioassay can be 2- to 10-fold higher than those obtained by HPLC [100,101].
A concentration-effect relationship between itraconazole levels and toxicity has been identified. In patients receiving itraconazole, concentrations >17.1 mcg/mL as measured by bioassay were associated with a high probability of toxicity (86 percent), whereas concentrations <17.1 mcg/mL were associated with a low probability of toxicity (31 percent) . The majority of patients were being treated for either chronic pulmonary aspergillosis or allergic bronchopulmonary aspergillosis. Thus, these results may not be applicable to immunocompromised patients with invasive fungal infections who may be at higher risk of toxicity due to the use of multiple agents and who also may not absorb the drug well enough to attain levels this high.
Voriconazole — There is substantial variability in voriconazole serum drug concentrations in patients receiving standard oral dosing [42,96,98,103,104]. Studies have correlated higher failure rates with low serum voriconazole concentrations and adequate levels with favorable response. In addition, higher concentrations are associated with neurotoxicity.
Voriconazole trough concentrations should be checked four to seven days into therapy for all patients who are receiving treatment for invasive fungal infections . A goal of achieving serum trough concentrations >1 mcg/mL and <5.5 mcg/mL has been suggested , but we prefer concentrations between 2 and 5.5 mcg/mL. Although debate remains over the optimal target concentration, available data suggest a therapeutic range of greater than 1 mg/L and less than 5.5 mg/L. Trough concentrations below 1 mg/L warrant an increase in the voriconazole dose and appropriate subsequent monitoring . On the other hand, serum drug concentrations above 5.5 mg/L warrant a reduction in the voriconazole dose, since higher concentrations have been associated with an increased risk of toxicity (particularly neurotoxicity, including hallucinations, delirium, and delusions) without documented clinical benefit [42,105-107]. It is important to note that decisions about dose modification based upon voriconazole concentrations must always be made within the context of the clinical status of the patient, which is the most essential element in determining what, if any, dose modification or change in therapy is appropriate.
The importance of appropriate serum voriconazole concentrations has been illustrated in the following studies:
●In a study of 52 patients who were serially monitored with voriconazole trough concentrations, among six nonresponding patients who also had low trough concentrations (less than 1 mcg/mL), clinical improvement was seen following an increase in voriconazole dose . However, 5 of 16 patients (31 percent) with serum voriconazole concentrations above 5.5 mcg/mL developed encephalopathy.
●In a population pharmacokinetic analysis that was performed on 505 plasma concentration measurements from 55 patients using multivariate analysis, an association was observed between voriconazole trough concentration and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85 percent probability of response) to 4.5 mg/L (<15 percent probability of neurotoxicity) .
●A randomized trial was performed to evaluate the effect of serum concentration monitoring on the safety and efficacy of voriconazole in 110 adults being treated for invasive fungal infections . Patients were randomly assigned to undergo or not undergo serum concentration monitoring. Among the patients who underwent serum concentration monitoring, the voriconazole dose was adjusted (target range 1.0 to 5.5 mg/L) according to the serum trough concentration measured on the fourth day of therapy. Although the incidence of adverse effects was the same in both groups (42 percent), the proportion of voriconazole discontinuation due to adverse effects was significantly lower in the group that underwent monitoring compared with the group that did not undergo monitoring (4 versus 17 percent). Furthermore, a complete or partial response was observed significantly more frequently in the group that underwent monitoring (81 versus 57 percent).
Posaconazole — Studies have suggested a relationship between posaconazole concentrations and both prophylactic efficacy and response rates for invasive aspergillosis [110-112] and other invasive fungal infections . Thus, in patients with serious infections such as invasive aspergillosis, monitoring serum concentrations is recommended, especially given that the absorption of posaconazole suspension is dependent upon its administration with a fatty meal.
Furthermore, absorption of posaconazole is highly variable in hematopoietic cell transplant recipients, especially those with acute graft-versus-host-disease . Among patients with hematologic malignancies receiving posaconazole prophylaxis, mucositis and lower caloric intake were independently associated with reduced posaconazole concentrations .
Also, given reports concerning drug-drug interactions between posaconazole and proton pump inhibitors, clinicians should monitor serum concentrations in patients receiving posaconazole concomitantly with drugs that increase the gastric pH, such as proton pump inhibitors, since these agents can result in decreased serum posaconazole concentrations . (See 'Drug interactions' below.)
Based upon the limited data available, if posaconazole concentration monitoring is desired, trough concentrations should be obtained after four to seven days of therapy . We suggest a trough concentration ≥0.7 mcg/mL for prophylaxis and at least 1.0 mcg/mL for the treatment of severe infections . A study of patients with invasive fungal infections refractory to other agents has shown that higher drug concentrations are associated with improved clinical responses .
Fluconazole — Serum drug concentration monitoring of fluconazole is rarely performed. The reliable bioavailability and benign toxicity profile of this agent obviate the need to measure serum concentrations in nearly all patients.
Isavuconazole — Data on isavuconazole serum drug monitoring have shown consistent serum drug concentrations indicating routine monitoring is not required . However, in select cases where there is concern for toxicity or lack of response, serum concentration monitoring is available. Optimal drug concentrations have not been established but most patients achieve levels >1 mcg/mL with standard dosing regimens; an upper limit associated with toxicity has not been established.
DRUG INTERACTIONS — The major drug-drug interactions associated with the azole antifungal agents involve oxidative drug metabolism via the cytochrome P450 enzyme system. All azole agents are both metabolized by and affect the hepatic cytochrome P450 (CYP) enzymes to varying degrees (table 2) [25,117].
Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate.
Overview of CYP and other effects — Fluconazole is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4. This is generally not a concern for doses <200 mg/day . It is also an inhibitor of uridine 5'-diphosphate glucuronosyltransferases (UGT) enzymes. Fluconazole is only a weak substrate of CYP450 enzymes.
Itraconazole is a strong inhibitor of CYP3A4. It is also a substrate of CYP3A4 and an inhibitor of p-glycoprotein.
Voriconazole is a strong inhibitor of CYP3A4. It is a moderate inhibitor of CYP2C19 and a weak inhibitor of CYP2C9 isoenzymes. Voriconazole is metabolized extensively by CYP2C19 and CYP3A4 and, to a lesser extent, by CYP2C9. Since CYP2C9 and CYP2C19 exhibit genetic polymorphism, wide variations in pharmacokinetics are observed among certain patient populations (ie, 15 to 20 percent of individuals of Asian descent and 3 to 5 percent of others who are poor metabolizers via this mechanism will have significantly elevated serum concentrations) (see 'Voriconazole' above). Voriconazole does not appear to be a substrate or inhibitor of p-glycoprotein.
Posaconazole is an inhibitor of CYP3A4 and P-glycoprotein (P-gp) . Posaconazole is not metabolized via the P450 enzyme system; about 17 percent of the administered dose is metabolized by uridine diphosphate glucuronidation, and 66 percent is excreted fecally as unmetabolized drug . Drug-drug interactions similar to those seen with other inhibitors of CYP3A4/P-gp can occur [119,120].
Isavuconazole itself is a moderate inhibitor of CYP3A4 [54,121]. Isavuconazole clearance is highly dependent upon CYP3A4 metabolism and coadministration of drugs that are either strong inducers or inhibitors of CYP3A4 metabolism is contraindicated. A list of drugs that are strong CYP3A4 inducers or inhibitors is provided separately (table 3).
Major drug interactions — Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate. Examples of the major interactions will be briefly reviewed here (table 2).
●CYP induction – In general, medications that induce hepatic CYP enzymes (eg, rifampin, rifabutin, phenytoin, carbamazepine, phenobarbital) can accelerate the metabolism of the azoles . Enzyme induction can require up to two weeks to achieve maximum effect and persists for up to two weeks after discontinuation of the interacting medication, potentially delaying the response to treatment or causing treatment failure. However, clinically significant effects can occur within hours to days of starting a CYP inducer [124-127]. If one of the other hepatic CYP inducers must be given concurrently, serum concentration monitoring of the azole agent is essential.
Rifampin has the greatest effect; it has been associated with undetectable levels of itraconazole in the serum [123,128] and significant decreases in fluconazole, voriconazole, isavuconazole, and ketoconazole concentrations [6,32,124,129,130]. Concomitant use of rifampin is contraindicated with voriconazole and isavuconazole, discouraged with itraconazole, and may warrant dose increases of fluconazole. Rifabutin may affect the azole agents to a lesser degree . Although no data are available specifically for posaconazole and rifampin, data with rifabutin suggest that similar precautions are warranted with posaconazole and any of the rifamycins.
The anticonvulsants also have significant effects on the azole agents. Carbamazepine is contraindicated with voriconazole due to the potential to significantly decrease serum concentrations of the azole; a similar effect is possible with itraconazole and ketoconazole . Voriconazole, itraconazole, posaconazole, and ketoconazole exposure is decreased with phenytoin administration. The use of phenytoin with voriconazole requires an increase in voriconazole dosing to 5 mg/kg every 12 hours for the intravenous (IV) preparation and 400 mg every 12 hours for oral administration .
Based upon a 97 percent decrease in isavuconazole plasma concentration-time curve observed when coadministered with rifampin, the use of any strong inducer of CYP3A4 metabolism (eg, carbamazepine, St. John’s wort) with isavuconazole is contraindicated . A list of strong inducers is included in the following Table (table 3).
●CYP inhibition – A significant CYP interaction should be anticipated when an azole exerts a strong inhibitory effect on an isoenzyme that is the major metabolism pathway for another drug being taken by the patient. This is particularly important if the concomitant drug has a narrow therapeutic index. As an example, the combined use of azoles (particularly fluconazole and voriconazole) and warfarin leads to an increase in the prothrombin time due to inhibition of CYP2C9 by the azole. CYP2C9 is the primary enzyme by which s-warfarin, the active form, is metabolized. Thus, dose reduction of warfarin is necessary when used in combination with azoles, and monitoring of INR around the time of azole initiation is recommended. (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.)
Posaconazole has been found to increase the plasma concentration and area under the plasma concentration-time curve of the human immunodeficiency virus (HIV) protease inhibitor, atazanavir, when used in combination with ritonavir via CYP3A4 inhibition; this was associated with increased serum total bilirubin concentrations .
Coadministration of a strong inhibitor of CYP3A4 metabolism (ketoconazole) increased isavuconazole plasma concentration-time curve by more than fivefold . The use of any strong inhibitor of CYP3A4 metabolism with isavuconazole is therefore contraindicated. A list of strong CYP3A4 inhibitors is included in the following Table (table 3). Isavuconazole itself is a moderate inhibitor of CYP3A4 and can increase exposure of coadministered sirolimus and tacrolimus by approximately twofold.
●P-glycoprotein interactions – P-glycoprotein (P-gp) is an important drug efflux transporter found throughout the gastrointestinal tract. P-gp substrates are structurally similar to substrates of CYP-3A4, and many CYP-3A4 inhibitors also inhibit P-gp. Therefore, there is a potential for interactions via P-gp and the azole antifungals. However, determining the specific contribution of P-gp to a drug-drug interaction can be difficult. Itraconazole, isavuconazole, ketoconazole, and posaconazole are P-gp inhibitors [25,43]. One of the best-characterized interactions via P-gp and azole antifungals is increased exposure of digoxin when given with itraconazole.
●Chelation with divalent cations or alterations in gastric pH – Ketoconazole tablets, posaconazole solution, and itraconazole capsules require gastric acidity for oral absorption. Drugs that increase gastric pH, including histamine-2 receptor antagonists, proton pump inhibitors, and antacids decrease serum levels of ketoconazole, posaconazole, and the capsule formulation of itraconazole but not fluconazole or the liquid formulation of itraconazole [122,133-135]. (See 'Itraconazole' above.)
●UGT pathway – Although less well studied than the interactions described above, a number of drugs utilize the uridine 5'-diphosphate glucuronosyltransferases (UGT; glucuronidation) pathway, which may also be affected by the azoles. An example is the posaconazole-phenytoin interaction, which significantly reduces posaconazole exposure and increases phenytoin concentrations [25,43]. Although CYP3A4 interactions probably play a part in this interaction, the increase in posaconazole clearance may result from induction of UGT by phenytoin.
Selected clinical effects — The following are examples of some of the serious toxicities that can occur; such interacting drugs should be avoided, if possible, in patients treated with an azole (table 2):
●Long QT syndrome and possible sudden cardiac death due to torsade de pointes with concomitant amiodarone, cisapride (which has limited availability), quinidine, haloperidol, or other agents that prolong the QT interval. As an example, all of the azoles except for fluconazole delay haloperidol metabolism by CYP3A4 and both drug classes can prolong the QT interval in an exposure-related manner. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●Rhabdomyolysis with coadministration of simvastatin, lovastatin, and atorvastatin, which are metabolized by cytochrome P450 3A4. Inhibition of metabolism by azole antifungals results in increased plasma concentrations of the statin drugs. The degree of inhibition varies for each statin-azole combination. Some combinations are contraindicated (eg, posaconazole with simvastatin, lovastatin, or atorvastatin) . Pravastatin, fluvastatin, or rosuvastatin, which are not metabolized by CYP3A4, are preferred during azole therapy, but if statins can be avoided while on azole therapy, that is preferred. (See "Statin muscle-related adverse events".)
Serum concentrations and toxicities of a number of other drugs metabolized by CYP can be increased by azole therapy. These include HIV protease inhibitors, warfarin, some hypoglycemic agents, quinidine, calcium channel blockers, tacrolimus, sirolimus, and cyclosporine. Patients taking these medications must be monitored appropriately and empiric dose adjustments are often necessary.
Combinations that deserve particular attention because of the frequent need for azoles in transplant recipients are the interactions between the azoles and immunosuppressive agents, such as sirolimus and the calcineurin inhibitors (cyclosporine and tacrolimus) .
Voriconazole increases sirolimus levels by approximately 10-fold, and posaconazole increases sirolimus levels by approximately ninefold [32,43]. This has led to the prescribing information for both voriconazole and posaconazole suggesting that sirolimus be avoided in patients receiving these agents. However, clinicians have sometimes coadministered these agents when clinically necessary. This practice can occur safely if the dose of sirolimus is reduced and sirolimus concentrations are monitored closely [138,139]. Doses of sirolimus have been reduced empirically by up to 90 percent when voriconazole is added [138,139]. Any change in sirolimus dose needs to include a careful review of multiple factors, including sirolimus concentration at the time of azole initiation as well the individual patient's immunosuppressive requirements. Studies are ongoing regarding specific dosing algorithms based on baseline sirolimus concentrations .
Dose reductions of cyclosporine and tacrolimus are also necessary when used in combination with azoles. Although significant interpatient variability is seen, current recommendations are to decrease tacrolimus doses to one-third of the total daily dose when administered with either voriconazole or posaconazole. Recommendations for cyclosporine differ from a 50 percent reduction when voriconazole is added to 25 percent when posaconazole is added. Less clear recommendations exist for fluconazole, itraconazole, and isavuconazole. Regardless of the specific azole used, close monitoring of immunosuppressant concentrations following the addition or discontinuation of azole therapy is necessary.
SUMMARY AND RECOMMENDATIONS
●Overview of clinical uses − The triazole family includes fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole, which have activity against many fungal pathogens without the serious nephrotoxic effects observed with amphotericin B. The agents within this class vary importantly with regards to clinical activity, pharmacokinetic profiles, and toxicities. Detailed disease-specific treatment and prophylaxis recommendations are presented elsewhere. (See 'Introduction' above and 'Overview of clinical uses' above.)
●Mechanism of action − The azoles cause significant damage to the cell membrane by increasing its permeability, resulting in cell lysis and death. Despite this mechanism of action, the azoles are generally considered fungistatic against Candida species; voriconazole is fungicidal against Aspergillus. (See 'Mechanism of action' above.)
●Pharmacokinetics − Understanding the differences among the members of this class with regards to absorption, metabolism, and elimination is essential in order to safely and effectively administer these agents in complex patient populations (table 1). Oral bioavailability of fluconazole and voriconazole is excellent, but posaconazole, itraconazole, and ketoconazole require special circumstances for maximum absorption. (See 'Pharmacokinetics' above.)
●Adverse effects − Triazoles are generally well tolerated. Gastrointestinal symptoms are most frequently reported. Gastrointestinal intolerance is most common with ketoconazole. Serious hepatotoxicity has been reported with the azoles, so monitoring of aminotransferases is recommended. (See 'Adverse effects' above.)
●Use in pregnancy − Azole use should be avoided during pregnancy. (See 'Pregnancy' above and "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)
●Serum drug concentration monitoring − The Infectious Diseases Society of America guidelines recommend monitoring serum levels in patients receiving itraconazole for the treatment of aspergillosis, histoplasmosis, or blastomycosis. It has become standard of care at many centers to perform therapeutic drug monitoring of voriconazole and posaconazole to assure efficacy in the treatment of serious fungal infections and, in the case of voriconazole, to avoid toxicity. Serum concentrations of voriconazole and posaconazole should be checked in all patients receiving treatment doses of these agents. (See 'Serum drug concentration monitoring' above.)
●Drug interactions − The azoles are involved in many important drug-drug interactions, the most important of which involve oxidative drug metabolism via the cytochrome P450 enzyme system (table 2). Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate. (See 'Drug interactions' above.)
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