Azoles (Clotrimazole, Fluconazole, Itraconazole, Ketoconazole, Miconazole, Voriconazole, Posaconazole)

Updated January, 2011

Andreas H. Groll, M.D., Hedwig Kolve, Pharm.D., Thomas J. Walsh, M.D.

CLASS

               The antifungal azoles are synthetic compounds with one or more five-membered azole rings, in which each ring contains either two (imidazoles) or three (triazoles) nitrogen atoms. Antifungal activity of an azole derivative was first described in 1944, but systematic investigation of this class of compounds only began in the early 1970s. Overall, the azoles have become a major addition to the antifungal armamentarium, displaying less toxicity than amphotericin B, activity against a variety of different fungi, and comparable clinical efficacy under many circumstances.

               In comparison to the imidazoles, the triazoles offer increased stability as systemic drugs and have a broader spectrum of activity. In addition, they have greater selectivity for fungal as opposed to mammalian target enzymes, which renders them less toxic. The advantages of the triazoles have significantly reduced the indications for the imidazoles in the treatment of invasive fungal infections. However, the imidazoles are used as topical therapy for superficial fungal infections of the mucosa, the skin and appendages with the exception of tinea capitis (15,16,104,143).

ANTIFUNGAL IMIDAZOLES

ANTIFUNGAL ACTIVITY

Chemical Structure

               The imidazole compounds have side chains, which convey considerable differences in pharmacokinetic properties (Figure 1). Of these compounds, only ketoconazole is commonly used as an agent for systemic infection. Miconazole was an early azole developed for systemic use, but toxicity of its intravenous solubilizer has limited its use for the most part to topical indications. The lack of a parenteral formulation has also limited the remaining imidazole compounds to topical use for skin and mucosal infections. These agents include clotrimazole, which is used topically for oral, vaginal, and skin indications, and a variety of other topical agents used for vaginal, oral mucosa and skin infections (15,16).

MECHANISM OF ACTION

               The imidazoles are considered fungistatic antifungal agents. They bind to the heme moiety of the fungal cytochrome P-450 dependent enzyme lanosterol 15-alpha -demethylase. Inhibition of 15 alpha--demethylase blocks formation of ergosterol and leads to the buildup of toxic methylated -sterols and depletes ergosterol in the cell membrane (Figure 2) (285). Both effects serve to inhibit fungal cell growth. With topical use, fungicidal effects against some organisms may be seen due to the achievement of extremely high local concentrations (143). When systemically administered, the imidazoles also interact with the mammalian cytochrome P450 enzyme system. These interactions are responsible for their increased hepatic toxicity as compared to the newer triazoles and disruption of mammalian sterol synthesis, which can result in decreased cortisol and testosterone concentrations. Interactions with the cytochrome P450 enzyme system are also responsible for potential drug-drug interactions with compounds that are metabolized through the cytochrome P450 CYP3A4 pathway (44,104).

Spectrum of Activity

               The imidazoles have a broad spectrum of activity which encompasses many yeasts, dermatophytes and dimorphic moulds (104) (Table 1). Similar to fluconazole and itraconazole, ketoconazole and clotrimazole have less activity against some yeasts other than C. albicans such as C. glabrata and C. krusei (130). In vitro activity against some fluconazole-resistant yeasts has been demonstrated, although the clinical efficacy of an imidazole in that setting is not established (264). Ketoconazole is the only imidazole which may be used for therapy of non-life-threatening invasive infections (i.e., non-meningeal infections by endemic moulds in immunocompetent patients). Clotrimazole is not well-absorbed and undergoes extensive first-pass metabolism. Clotrimazole should be considered topical therapy even when used as oral troches. Miconazole has largely been replaced in its use by the newer triazoles due to its potential for serious toxicity. The imidazoles do not possess useful activity against Aspergillus spp., hyalohyphomycetes, phaeohyphomycetes and the Zygomycetes (104).

MECHANISM OF RESISTANCE

               In vitro and clinical resistance to the imidazoles was reported initially in patients with mucocutaneous candidiasis receiving long-term ketoconazole therapy (124). While mycological resistance to the imidazoles continues to occur, it is significantly less common than with the newer triazole antifungals (75). Molecular mechanisms of resistance include alterations in the target enzyme, decreased permeability of the fungus to the azole, and activation of efflux pumps which decrease intracellular drug concentrations (226, 286, 287). Other potential mechanisms for resistance include alterations in the alpha5,6desaturase and decrease in the ergosterol content in the cell wall (119,308). Fungal resistance may develop from mutations in a single strain or from replacement of the original isolates with inherently less susceptible strains or species (168, 194, 206). It is also important to distinguish mycological from clinical resistance. In many cases, clinical failure relates to the fact that the host is severely immunosuppressed or that the drug has not been effectively delivered to the site of infection (245, 278). Some fungi will develop cross-resistance between the newer triazoles and the imidazoles (130,264).

KETOCONAZOLE

Ketoconazole (Figure 1) is a cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxyl]phenyl] piperazine and was the first successful oral azole antifungal. Ketoconazole is soluble at a pH of 3. There is no intravenous formulation. Systemic administration is through the oral route as 200 mg tablets. Ketoconazole is also available as a 2% cream or shampoo for topical use. Ketoconazole has in vitro activity against many yeasts, including Candida spp. and Cryptococcus, dermatophytes, and the dimorphic moulds (104).

PHARMACOKINETICS

Absorption

               Pharmacokinetic parameters of oral ketoconazole are summarized in Table 2. Following administration of 200 mg of ketoconazole, peak serum levels are generally 1-4 ug/ml (52), although significant individual variation occurs. The half-life is generally 7-10 hours. Absorption is dramatically decreased in patients with decreased gastric acidity, including patients who are receiving antacids, H2-histaminergic receptor blocking agents (such as cimetidine, ranitidine), or omeprazole or having achlorhydria following gastric surgery, after chemotherapy or with advanced HIV-infection (41,100,109,197). The administration of ketoconazole with an acidic cola beverage (Coca-Cola Classic which has a pH of 2.5) has been shown to increase gastrointestinal absorption by approximately 65% (39).

Routes of Elimination

Ketoconazole undergoes extensive hepatic metabolism and is excreted in the form of inactive metabolites mainly into the bile. Only minor amounts of unchanged drug are found in the urine (104). Ketoconazole is highly bound to plasma proteins and penetrates poorly into CSF (52). Drug concentrations in salivary secretions are low, which may be responsible for the lesser activity of ketoconazole as compared to fluconazole in esophageal candidiasis (78). Vaginal concentrations are similar to those in plasma (16). Keratinocyte concentrations are also high and active drug is found in sweat, which may increase its activity in superficial mycoses of the skin.

DOSAGE

Adults and Children

               Systemic therapy for mucosal infections, such as oropharyngeal candidiasis, and cutaneous infections may be begun at doses of 200 mg/day and be continued for 2 weeks. For more extensive mucosal infection, such as Candida esophagitis, 400 mg/day are appropriate. When ketoconazole is used for therapy of non-meningeal non-life-threatening endemic mycoses, the usual dosage recommendation is 400 mg/day, continued for an extended course of 6-12 months. The dosage may be increased to 600-800 mg/day or more in patients who fail to respond, but toxicity is greatly increased at those doses with minimal increase in efficacy (85,180,265).

Ketoconazole is not approved for pediatric patients. A single daily dose of 3.3 to 6.6 mg/kg has been used in small numbers of children; however, the drug should not be used in children unless benefits outweigh risks.

Pregnancy

               Because ketoconazole is teratogenic in animals, its use during pregnancy is contraindicated during pregnancy. Since ketoconazole is probably excreted in breast milk, mothers who are receiving therapy should not breast feed (16,104).

Renal and Hepatic Failure

The dose of ketoconazole does not need to be adjusted in patients with altered renal function. Dose adjustment is also unnecessary in patients with moderate hepatic dysfunction (104).

ADVERSE EFFECTS

               Common adverse effects associated with ketoconazole are shown in Table 3. The most frequent side effects of ketoconazole are gastrointestinal, including nausea, vomiting and anorexia. These side effects are dose dependent, occurring in approximately 20% of patients receiving 400 mg/day and 30% of patients receiving 800 mg/d (265). Better tolerance is achieved with administration with food or, for the higher dose regimens, in divided doses. Rash occurs in <5%. Ketoconazole can decrease plasma testosterone concentrations and cause gynecomastia, decreased libido and impotence, menstrual irregularities and alopecia in females (104). In addition, at high dosages, ketoconazole may interfere with adrenal steroid synthesis and result in decreased plasma cortisol concentrations (85). Adrenal crisis following high dose ketoconazole therapy has also been reported.

Hepatic abnormalities are common. Approximately 5-10% of patients will have mild, asymptomatic elevations of liver transaminases, which return to normal without dose adjustment. However, symptomatic ketoconazole-induced hepatitis may occur, developing in an estimated 1 in 10,000 patients, and may potentially be fatal (15,52). The onset of symptoms is usually after a few days of therapy, but may occur after patients have been on therapy for weeks to months; 80% of the cases occur within the first 3 months of therapy (15).

MONITORING REQUIREMENT

               Patients should be advised regarding the possibility of hepatitis and liver function tests should be determined at baseline and monitored throughout treatment.

DRUG INTERACTIONS

               Drug-drug interactions of ketoconazole with other drugs are substantially more frequent than drug interactions with the newer triazoles, particularly fluconazole (Table 4) (104). Agents such as rifampicin, rifabutin, phenytoin, phenobarbital and isoniazid induce ketoconazole clearance through induction of hepatic enzymes (273). Cyclosporine A serum concentrations are markedly raised with the use of ketoconazole, presumably because both drugs are metabolized by the cytochrome P450 enzyme CYP3A4 (93,253,255). An additional impact in transplantation may be the increased AUC for methylprednisolone and prednisone by ketoconazole through uncertain mechanisms.

Ketoconazole elevates terfenadine, astemizole, and cisapride levels and metabolites to toxic concentrations, which can precipitate fatal torsade de pointes by prolonging the QT interval (122). Thus, the use of ketoconazole with terfenadine, astemizole, or cisapride is contraindicated. Other effects are less pronounced, including prolongation of the effects of warfarin, increase in digoxin levels, and increase in the activity of oral hypoglycemic agents. In addition, ketoconazole may increase serum concentrations of midazolam, triazolam, phenytoin, imipramine, and desipramine (104,256,273).

CLINICAL INDICATIONS

               The indications for ketoconazole are limited due to the increased efficacy and decreased toxicity of the newer azoles and the availability of terbinafine for dermatophyte infections. Ketoconazole is effective in non-meningeal endemic mycoses in non-immunocompromised, not gravely ill patients, including histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. Other potential indications include chronic mucocutaneous candidasis and oral, vaginal and esophageal candidal infections as well as tinea versicolor (due to Malassezia furfur) and dermatophytoses. Ketoconazole has limited or no clinical efficacy and no therapeutic role in mould infections, deeply invasive candidiasis including candidemia, cryptococcosis, meningeal coccidioidomycosis, and sporotrichosis (57,71,85,104,124,180,250,290).

MICONAZOLE

               Miconazole (Figure 1) (1-[2-(2,4-dichlorophenyl) methoxyl] ethyl]-1H-imidazole) was the first approved systemic azole. The compound has activity against a variety of yeasts, dermatophytes and selected moulds, such as Pseudallescheria spp. and other phaeohyphomycetes. While miconazole has evolved into a successful topical agent, limited efficacy and serious toxicities do no longer justify its systemic use (104). Toxicities of the intravenous formulation were mostly associated with the PEG 40 castor oil solubilizer and included serious hypersensitivity reactions, hyperlipidemia, anemia, and cardiopulmonary arrest secondary to cardiac conduction defects (70). In the past, intravenous miconazole has been used in patients intolerant of or unresponsive to standard antifungal therapies. However, with the availability of much better tolerated and effective therapeutic alternatives, the role for miconazole in the treatment of invasive fungal infections has been reduced to a historical consideration.

TOPICAL ANTIFUNGAL AGENTS

The topical imidazoles are used for the treatment of superficial and cutaneous infections including tinea corporis, tinea pedis, tinea cruris, and tinea versicolor, and cutaneous, vaginal and oropharyngeal Candida infections. They are not useful for tinea capitis. Mycological resistance to these agents is uncommon for the fungi causing superficial mycoses (16,151). The topical products are similar in their efficacy and tolerance so that selection of a specific agent should be based on cost, patient preferences and product availability. Many of these agents are available for over-the-counter use. In superficial dermatoses which have a high likelihood of a fungal etiology, an empiric trial of an inexpensive, but efficacious over-the-counter product may be the most cost effective (40). Generally these compounds should be applied twice daily for 3-6 weeks.

The imidazoles are also widely used for the treatment of vaginal candidal infections and are available in both over-the-counter and prescription preparations (251). They are available as vaginal creams, tablets, suppositories and ointments. Most are administered once daily at bedtime and are generally administered for 3 to 7 days. Higher dose preparations of clotrimazole tablet (500 mg) and ticonazole ointment have been developed which allow single dose administration. Antifungal resistance of vaginal isolates remains uncommon, but increasingly species of yeasts other than Candida albicansare being isolated as etiological agents of vaginitis. Some of these strains such as Candida glabrata will respond to topical imidazole therapy (250).

Of note, topical azole agents may be absorbed to a minor extent and can potentially interfere with the metabolism of concomitant drugs. For example, potentiation of the anticoagulatory effects of acenocoumarol has been noted after vaginal administration of miconazole capsules and after oral administration of miconazole gel (144).

CLOTRIMAZOLE

              The structure of clotrimazole is shown in Figure 1.

DOSAGE

Adults and Children

Clotrimazole is available in as oral, topical 10 mg troches, 100 mg and 500 mg vaginal tablets and 1% cream, and as a 1% cream, lotion or solution. Clotrimazole troches are only indicated for the treatment of oropharyngeal candidiasis. Clotrimazole is well tolerated as an oral agent, with patients sucking on the troches until they dissolve. Serum concentrations following doses of 200 mg per day are 0.2 to 0.35 ug/ml. The absorbed drug is hepatically metabolized. Adverse reactions to oral clotrimazole are uncommon, with mild gastrointestinal irritation occurring in approximately 5% of patients (15,16).

A problem with patient compliance is the fact that the recommended dosing regimen is for a 10 mg troche to be taken 5 times daily for 14 days. In patients with AIDS and in patients receiving chemotherapy, clotrimazole has been a useful antifungal regimen (91,99,137,233). Response rates in some series have approached 100%. Antifungal resistance has not been extensively evaluated but does not appear to commonly develop (200). However, patients with advanced AIDS and clinically refractory thrush are unlikely to respond to clotrimazole troches as are those with Candida esophagitis. The vaginal tablets have been advocated to allow increased doses to be administered less frequently but are difficult to palate.

Topical clotrimazole is applied to skin twice daily. Vaginal applications can be given for 7 days using the 100 mg vaginal tablets or for one dose of the 500 mg tablet. Clotrimazole cream is given for 7-14 days. The major adverse events are minor vaginal and urinary irritation in <2% of the patients. Overall response rates for cutaneous mycoses to clotrimazole therapy is from 80-100% (68,69), while vaginal response rates are expected to be at least 80% although relapses are common (16,76).

MICONAZOLE

DOSAGE

               Miconazole as a topical spray, powder, cream or ointment and as a vaginal cream or suppository continues to be a cost-effective therapy for superficial and vaginal mycoses (40). Only a minimal amount of miconazole is absorbed following vaginal or cutaneous administration. It is well tolerated with adverse events largely limited to local irritation that occurs in less than 5% of recipients. Response rates are similar to other therapies for topical mycoses. Generally efficacy rates well in excess of 70% are expected for most superficial and vaginal mycoses. In the treatment of tinea pedis, tinea cruris, and tinea versicolor, the response to miconazole may exceed 90% (2). In vulvovaginal candidiasis, cure rates range from 80-95% after 1 month of therapy. Decreased pruritus may be seen even after a single dose (11).

KETOCONAZOLE

DOSAGE

               In addition to its availability as an oral, systemic antifungal agent, ketoconazole is available as a 2% cream or 2% shampoo. It is used for tinea corporis, tinea cruris and tinea pedis caused by dermatophytes and yeasts (148). It is highly active against tinea versicolor, which is caused by Malassezia furfur, and seborrheic dermatitis.

ADVERSE EFFECTS

               The major reaction to this compound has also been skin irritation, which was reported in approximately 5% of patients. Occasionally allergic reaction may also occur.

Other Topical Azoles

               A number of other topical antifungal agents are available for clinical use, which have similar pharmacokinetic properties, efficacy and toxicities (15,16). Econazole is a derivative of miconazole. It is used primarily in cutaneous mycoses with excellent penetration of the skin. As with the other topical imidazoles, its major side effects are local irritation with minimal systemic absorption. It is applied twice daily. Tioconazole is marketed for Candida vulvovaginitis and is available as an ointment. Tioconazole is given as a single bedtime dose. Butoconazole is an azole similar to clotrimazole. It is used as a 2% vaginal cream for 3 days. Terconazole, is technically a triazole antifungal, but it is included here because of its activity in Candida vaginal infections. Terconazole is structurally similar to ketoconazole. As with the other topical agents, it can be administered as an 80 mg suppository given at bedtime for 3 or using the 0.4% cream which is continued for 7 days. Its efficacy and tolerance are similar to clotrimazole and the other topical imidazoles in vaginal candidiasis. Oxiconazole and sulconazole are both imidazoles, which are used for therapy of dermatophyte infections. Oxiconazole is applied as a cream while sulconazole is a solution.

ANTIFUNGAL TRIAZOLES

Antifungal Activity

The antifungal triazoles (Figure 3) are stable synthetic compounds with one or more five-membered azole rings containing three nitrogen atoms and -attached to one of the nitrogen atoms- a more or less complex side chain. Compared to the antifungal imidazoles, the triazole ring confers improved resistance to metabolic degradation, much greater preferential affinity for fungal than for mammalian targets, increased potency and an expanded spectrum of antifungal activity (95,96). Fluconazole, itraconazole and voriconazole, and posaconazole are the systemic antifungal triazoles licensed to date.

Spectrum

               The antifungal triazoles are principally active against dermatophytes, albicans- and non-albicans Candida species, Cr. neoformans, and dimorphic fungi such as Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatidis, Paracoccidioides brasiliensis and Sporotrix schenkii (67,95,96,129,131). Among non-albicans Candida spp., they are less active against Candida glabrata, and, with the exception of voriconazole, inactive against Candida krusei (214). Clinical useful activity against Aspergillus species and dematiaceous moulds is confined to itraconazole and voriconazole (6,193,234). Voriconazole and posaconazole are also active against Fusarium spp. and Scedosporium spp (57,129,193). With the exception of posaconazole, that has shown species- and strain dependent activity, the current triazoles are inactive against the Zygomycetes (Table 1).

MECHANISM OF ACTION

               The antifungal triazoles function by inhibition of the fungal cytochrome P450 3A dependent enzyme lanosterol 14-alpha-demethylase. This inhibition interrupts the conversion of lanosterol to ergosterol, leading to accumulation of 14-alpha methylsterols and depletion of ergosterol in the fungal cell wall (Figure 2). This in turn results in altered cell membrane properties and function with subsequently increased permeability and inhibition of cell growth and replication (285). Potential additional antifungal effects include an inhibition of cytochrome P450 enzyme systems of the fungal respiration chain (280), a toxic interaction with fungal membrane phospholipids and inhibition of transformation of yeasts to the mycelial form (44). It is important to note that interaction with the mammalian cytochrome P450 3A4 enzyme system is responsible for the majority of toxicities and drug interactions of this group of compounds.

MECHANISM OF RESISTANCE

               A steady stream of reports on treatment failures and improvements of methods of in-vitro susceptibility testing has led to greater discussion of resistance of Candida (212), and, more recently, Aspergillus species (295). Standardized methods for testing the in vitro susceptibility of yeasts (50,177) and filamentous fungi (178) to current antifungal agents have become available. Tentative breakpoints have been established for fluconazole and itraconazole vs. Candida spp. (177,213); these breakpoints appear to have similar predictive utility as observed with in vitro susceptibility testing of antibacterial agents (214). However, correlation of in vitro susceptibility with antifungal efficacy remains difficult, which is mainly due to the fact that host- and disease-related factors play such a prominent role in the outcome of immunocompromised patients with invasive fungal infections (190,211,214).

The molecular mechanisms of primary and secondary resistance to antifungal azoles include differences or alterations in the composition of membrane-associated sterols, alterations in the biosynthetic pathway of ergosterol, genetic changes in the target enzyme (mutation, overexpression, gene amplification), and enhanced efflux by ABC transporters and major facilitators (227,313). The classical example of primary resistance is C. krusei, which innately resistant to fluconazole. Secondary resistance of Candida spp. to azoles has been observed following prolonged exposure to azoles in the settings of chronic-recurrent oropharyngeal candidiasis (124,217), allogeneic hematopoietic stem cell transplantation (161,162,315,316) and cryptococcal meningitis (19,43,186) and is thought to be primarily due to the selection of resistant clones. Stepwise, cumulative molecular events that lead to progressively decreased susceptibility and stable resistance during exposure to current azoles are rarely encountered in patients but have been reported following longstanding exposure to azoles in conjunction with HIV-associated oropharyngeal candidiasis (149,313) and, less well characterized, chronic granulomatous disease (53). Nevertheless, these observations clearly underscore the potential epidemiological threats by uncritical azole use not only in medicine, but also in agriculture (120) and animal health (288).

Although cross-resistance of Candida spp. to antifungal azoles is common (173), it is not obligate: Patients with microbiologic and clinical fluconazole-resistant candidiasis may respond to itraconazole or voriconazole (108,114,192,221). In clinical practice, a microbiologic diagnosis should be attempted as feasible in suspected invasive infections, and the organism be identified at the species level. Because of the lack of its predictive value in other settings, the routine performance of in vitro susceptibility testing of azoles is currently reserved to Candida spp. vs. fluconazole. However, additional in vitro testing of other organism/drug combinations may be indicated in refractory infections and within surveillance programs (190,214).

FLUCONAZOLE

Fluconazole [(difluoro-2,4-phenyl)-2-bis (1H-triazole-1,2)-4-yl-1)-1,3propa-nol-2; Figure 3] is a low molecular weight, water-soluble, fungistatic bis-triazole that possesses very useful clinical efficacy against infections due dermatophytes, yeasts and certain dimorphic fungi both in immunocompetent and immunocompromised hosts. Fluconazole has comparable activity to that of ketoconazole in inhibiting fungal 14-alpha-demethylase but it is much less inhibitory toward mammalian demethylases (242).

Pharmacodynamics

Conventional time-kill assays performed over incubation periods of 24 to 48 hours in susceptible Candida spp and Cr. neoformans show fungistatic activity of fluconazole with variable concentration-related growth effects (135,136). With extended incubation for up to 14 days and under nonproliferating growth conditions, however, fungicidal activity has been observed against C. albicans (254). In serum-free growth media, fluconazole displays no measurable postantifungal effect against C. albicans and Cr. neoformans, but concentration-dependent postantifungal effects of 1 to 3.6 hours were observed in the presence of fresh serum (60,169). Pharmacodynamic studies in murine models of disseminated C. albicans infection collectively suggest that the area under the concentration-vs-time-curve and the minimum inhibitory concentration (AUC/MIC) ratio is the most predictive pharmacodynamic parameter of fluconazole (10,150).

PHARMACOKINETICS

               Fluconazole is available as oral and intravenous formulations, and its pharmacokinetic properties (Table 2) are independent of both route of administration and formulation (29,30). Only minor differences appear to exist between healthy and immunocompromised patient populations (92).The drug exhibits linear plasma pharmacokinetics which fit into two compartment pharmacokinetic models.

Absorption

Following oral administration, fluconazole is very well absorbed: Its absolute bioavailability exceeds 90%. Absorption is not affected by food or intragastric pH and plasma concentrations peak 1-2 hours after ingestion. In healthy volunteers, peak plasma concentrations of 2 to 7 ug/ml are obtained after a single oral or parenteral dose of 100 and 400 mg, respectively. Multiple dosing leads to an increase in peak plasma concentrations 2.5 times of that achieved with single dosing. Steady state is generally reached within 4 to 7 days during once daily dosing but can be rapidly attained by doubling the dose on the first day (20,29,81,92,93,243).

Distribution

Fluconazole is minimally (12%) bound to serum proteins; most of the compound circulates as free drug. The volume of distribution approximates that of total body water and the drug penetrates well into virtually all tissue sites and body fluids (29,125,243,300). Of particular note is the ability of fluconazole to effectively penetrate the Central Nervous System (CNS): Several studies both in laboratory animals and humans have shown that the cerebrospinal fluid (csf) to serum concentration ratio in healthy subjects is 0.5 to 0.9 % (12,80,191) and in between 0.8 and 0.9 in the setting of meningeal inflammation (277). In addition, excellent penetration into the parenchyma of the brain, vitreous humor and the choroid has been demonstrated (268,300).

Routes of Elimination

Fluconazole is comparatively stable to metabolic conversion. Its terminal half-life ranges from 27-37 hours. More than 90% of a dose are excreted via the kidneys with approximately 80% recovered in urine as unchanged, active drug and 11% recovered as inactive metabolites (27,28,81,243).

Pediatric Pharmacokinetics

The pharmacokinetics of fluconazole in pediatric age groups reflect developmental changes characteristic for a water soluble drug with minor metabolism and predominantly renal elimination (101). In comparison to adults, children older than 3 months of age display an increased volume of distribution, increased plasma clearance and a shorter half-life in the range of 16-20 hours (28,146,238). Dosages at the high end of the recommended dosage range are therefore necessary for the treatment of invasive mycoses in these age groups. While no published pharmacokinetic data exist for term neonates, the situation is complex in premature neonates, in which the volume of distribution may reach up to 2.60 L/kg and elimination is slow with mean terminal half-lives ranging from 89 hours at birth and 55 hours at 2 weeks to 21 hours at 3 months (28,231).

DOSAGE

Adults and Children

               In adults, the recommended dosage range for treatment of invasive infections is 400 to 800 mg once daily, and 100 to 400 mg once daily for prophylaxis (44,93,101). In pediatric patients of all age groups, the recommended dosage range of fluconazole is 3 to 6 mg/kg once daily in the prophylactic setting, and 6 to 12 mg/kg once daily for treatment of invasive infections (28,101,302). In view of the faster clearance rate, the larger volume of distribution and the favorable safety profile, however, 12 mg/kg once daily may be the appropriate dosage for treatment of serious infections in term neonates, infants, and children (101). In premature neonates, based on a study in the prophylactic setting (231), a 72-hour dosing interval at the same dosage as in older children has been recommended for the first two weeks of life, followed by a dosing interval of 48 hours during week 3 and 4 (28). However, given the extreme variability in extravascular water content and renal function particularly in very-low-birth-weight infants, predictably effective and safe treatment with fluconazole may not be possible in this patient population during the first days of life.

Renal Failure

As the excretion of fluconazole parallels the glomerular filtration rate, dose adjustment of the maintenance dose is necessary in patients with renal failure: A 50% reduction of dosage is recommended in subjects with a creatinine clearance of 50-21 ml/min, and a 75% reduction of dose with a creatinine clearance < 21ml/min (93). The initial loading dose needs not to be adjusted (18). Fluconazole is removed by hemodialysis, arteriovenous and venovenous hemofiltration and, to a lesser extent, by peritoneal dialysis. In patients undergoing regular hemodialysis, 100% of the target dose is given after each dialysis session; in patients with continuous renal replacement therapy, clearance depends on the flow rate and may require higher dosages and pharmacokinetic monitoring. In patients with peritoneal dialysis, the compound can be administered either systemically or intraperitoneally; a dose of 150 to 200 mg in a single 2 liter dialysis bag every second day has been used for continuous ambulatory peritoneal dialysis (51,58,95,174,181,199,235,269).

Hepatic Failure

Although dose adjustment in patients with hepatic insufficiency (liver cirrhosis) appears not necessary (218), thoughtful use of fluconazole with close monitoring of toxicity is warranted under these circumstances.

Obesity

No systematic data exist on pharmacokinetics of fluconazole in obese persons or patients with fluid accumulation in the third space. As the volume of distribution of the drug approximates total body water and no accumulating tissue compartment is known, dosing on a mg/kg basis would be a rational approach in such circumstances.

Pregnancy

Fluconazole is teratogenic in rats (165) and at least three cases with craniofacial, limb, and cardiac defects as congenital anomalies have been described in humans after exposure to fluconazole during the first trimester (203). Thus, the drug is contraindicated during pregnancy. Fluconazole is secreted into human milk at concentrations similar to plasma (79) and should preferably be avoided in nursing mothers.

ADVERSE EFFECTS

Fluconazole is generally well tolerated at the usual dose range of 100 to 400mg/day and even at daily doses of up to 1200mg (6,44,95). Dose escalation to 1600mg/day resulted mainly in increased hepatotoxicity, and dose-limiting neurotoxicity was observed at 2000mg/day (6). Compilated data from adult patients who received the drug at dosages of 100-400mg/day over at least 7 days indicate an overall incidence of possibly related adverse effects of 16%; significant adverse effects or laboratory abnormalities leading to the discontinuation of the drug were noted in overall 2.8% (95). Nausea, vomiting and other gastrointestinal symptoms are seen in <5%, skin rashes and headaches in <2%, and usually reversible, asymptomatic hepatic transaminase elevations in up to 7% of adult patients (44,95) (Table 3).

In pediatric patients of all age groups, fluconazole is generally well tolerated without differences in profile and frequency of adverse events in comparison to adults (102,182). In children older than 3 months of age with predominantly cancer or HIV- infection who received fluconazole at doses ranging from 1 to 12mg/kg/day, treatment-related adverse effects were observed in 10 %, with gastrointestinal symptoms and increases in hepatic transaminase levels occurring in seven and five percent, respectively, and skin reaction in approximately 1%. Significant adverse effects or toxicities, leading to the stop of treatment, occurred in overall 3.2 % (182).

Marked increases in hepatic transaminases (to > 8 times the upper limit of normal) are seen in approximately 1% of patients treated with fluconazole, but more severe hepatic injury or hepatitis are rare (44,95,101). Exfoliative skin reactions have been reported in patients with AIDS; however, the exact role of fluconazole in these reactions is unclear (95). No evidence for myelotoxicity has derived from studies in the marrow transplant setting (94,124), although prolonged neutropenia was observed in cancer patients receiving the drug as antifungal prophylaxis during cycles of intensive chemotherapy (232). Finally, in contrast to ketoconazole, fluconazole does not appear to affect the synthesis of steroid hormones at currently recommended dosages (44).

DRUG INTERACTIONS

               Although drug interactions of fluconazole in general are similar to those of other azoles, the number of relevant interactions occurring with fluconazole appears to be substantially lower than with ketoconazole, itraconazole and voriconazole (Table 4).

Nevertheless, the combination of fluconazole with cisapride and certain antihistaminic drugs such as terfenadine or astemizole can lead to serious cardiac arrhythmias due to inhibition of the metabolism of these drugs potentially resulting in QTc-prolongation, and is therefore strictly contraindicated (197). By similar mechanisms, fluconazole can precipitate phenytoin toxicity (170), may lead to increased plasma concentrations of cyclosporin, tacrolimus, and all trans retinoic acid (146,184,236) and may potentiate the effects of warfarin, sulfonylurea drugs, rifabutin, and benzodiazepines (146,175,183). At variable magnitude, fluconazole can decrease the plasma clearance of theophyllin and zidovudine (73,138,224).

On the other hand, drugs that are classical polyfunctional hepatic enzyme inducers (i.e., phenytoin, phenobarbital, carbamazepime, rifampin, rifabutin, and isoniazid) may lead to decreased fluconazole levels and therapeutic failure as the ultimate consequence (44,73,95). In addition, the potential for added hepatotoxicity must be monitored when fluconazole is given in combination with these compounds (95,175).

Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy. 2010 Aug;30:842-54.

CLINICAL INDICATIONS

               Fluconazole is highly effective against superficial infections due to dermatophytes and Pityrosporum spp. (111), and has excellent activity in the treatment of vaginal, oropharyngeal, esophageal and chronic mucocutaneous candidiasis (74,95,111,116,158,314).

Fluconazole is effective in the treatment of candidemia in non-neutropenic patients who have not received organ transplants and who do not have AIDS (196,210). Limited data suggest that the compound can be an acceptable alternative to amphotericin B in stable neutropenic and non-neutropenic cancer patients with acute, presumed or proven invasive Candida infections or chronic disseminated candidiasis (4,5,7,132,301). In settings where fluconazole is given as antifungal prophylaxis, however, its role as therapeutic agent is very limited. A randomized, controlled study comparing fluconazole 800mg/d plus placebo versus fluconazole 800mg/d plus amphotericin B (0.7mg/kg/d) for treatment of non-neutropenic candidemia revealed a trend toward more rapid clearance of the blood stream and improved antifungal efficacy, but also increased toxicity of the combination (215).

Fluconazole has demonstrated useful efficacy in focal Candida urinary tract infections and symptomatic funguria (92,298); in asymptomatic or minimally symptomatic hospitalized patients, however, the benefit of fluconazole therapy is less clear (252). The compound has been used successfully in Candida peritonitis, endocarditis, osteomyelitis, meningitis and endophthalmitis (2,44,302).

Fluconazole is effective for primary (64,166,219,284), and maintenance treatment of cryptococcal meningitis (26,220), and is the current drug of choice in coccidioidal meningitis (83); it is effective against non-meningeal coccidioidomycosis (35,62,84), but to a lesser extent than itraconazole (84). Although not as active as itraconazole, fluconazole is effective against paracoccidioidomycosis, blastomycosis, histoplasmosis and sporotrichiosis (62,164,185). High-dose fluconazole in combination with amphotericin B and flucytosine is a valid therapeutic approach to disseminated trichosporonosis in the immunocompromised host (302).

Given prophylactically, fluconazole has proven effectiveness in decreasing the occurrence of invasive Candida infections (94,247) and reducing crude and excess mortality (247) in patients with acute leukemia or undergoing bone marrow transplantation. In the latter study, there was persistent protection against invasive candidiasis and Candida-related death, a decreased frequency of severe, gut-related GVHD, and an overall survival benefit of 17% in fluconazole-treated patients at 8 years after completion (161). In less risk-selected patients with hematological malignancies undergoing remission-induction chemotherapy, fluconazole (400mg QD) has been shown to be effective in preventing systemic infection and death due to Candida spp. (216,317). In liver transplant patients, prophylactic fluconazole (400mg QD) reduced the incidence of invasive Candida infections and deaths from fungal infection, but did not improve overall survival (318). Prophylaxis with fluconazole reduced the incidence of invasive Candida infections (189) and intra-abdominal candidiasis (65) in high-risk surgical patients and invasive Candida infections in critically ill, ventilated medical and surgical intensive care patients (87) and in premature very low birth weight (VLBW) infants (133,157), but it had no impact on infection-related and overall mortality in these settings.

Fluconazole has comparable efficacy as conventional amphotericin in neutropenic cancer patients  who have persistent or recurrent fever despite treatment with broad-spectrum antibacterial agents (153,319). Because of its lack of efficacy against filamentous fungi, however, fluconazole may not be used in patients at substantial risk for invasive mould infections (105).

Fluconazole is effective for primary prevention of cryptococcosis and histoplasmosis in HIV-infected patients with very low CD4+ counts, and for secondary prevention of cryptococcosis and coccidioidomycosis in HIV-infected patients (281). Of note, continuous therapy in HIV-infected patients with oropharyngeal candidiasis reduced relapses as compared to intermittent therapy, and was not associated with an increased frequency of microbiological resistance (209).

ITRACONAZOLE

Itraconazole ((±) -cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,2-dioxolan-4-yl]methoxy]phenyl]-1-piperzinyl]phenyl]-2,4-dihydro -2-(1-methylpropyl)-3H-1,2,4-triazole-3-one) is a high molecular weight, highly lipophilic, fungistatic bis- triazole (Figure 3). Structurally closely related to ketoconazole, it has a broader spectrum of clinical useful activity, including superficial infections due to dermatophytes and yeasts, and infections by Aspergillus spp. and Penicillium spp., various phaeohyphomycetes and the dimorphic fungi (Table 1). Itraconazole binds more avidly to fungal cytochrome P-450 than does ketoconazole but, unlike the latter, binds only weakly to the mammalian cytochrome P-450 3A enzyme system, which results in reduced toxicity (96).

Pharmacodynamic Effects

Itraconazole exerts species- and strain-dependent fungistatic or fungicidal activity in vitro. Time-kill experiments have demonstrated concentration-independent fungistatic activity against Candida spp. and Cr. neoformans (31,32,154). Against Aspergillus spp., however, itraconazole displayed time- and concentration-dependent fungicidal activity with greater than 87 to 97% killing within 24 hours of drug exposure (154). It remains to be determined which pharmacodynamic parameter best predicts antifungal efficacy in vivo (103).

PHARMACOKINETICS

Itraconazole is commercially available as capsules, as oral solution in hydroxy-propyl-beta-cyclodextrin (HP-beta-CD), and as parenteral solution that also uses HP-beta-CD as carrier. Itraconazole is soluble only at low pH, as it prevails in the normal gastric environment. Absorption of the encapsulated formulation is dependent on a low intragastric pH and compromised in the fasting state, in patients receiving concurrent treatment with H2-receptor antagonists, omeprazole or antacids and becomes erratic in granulocytopenic cancer patients or HIV-infected patients with hypochlorhydria (25,117,248,270). Absorption is improved when the capsules are taken with food or a cola beverage (112,113,291). In comparison to the capsule form, the oral HP- beta -CD itraconazole suspension confers enhanced oral bioavailability with a mean increase in the AUC0-24h of approximately 30% (13); an additional 25 to 30% increase in oral bioavailability and increased peak plasma concentrations can be achieved, when the suspension is taken in the fasting state (284). The carrier has minimal to absent systemic effects due to the lack of systemic absorption. It may, however, exert osmotic activity in the intestinal lumen, which may lead to gastrointestinal intolerance, in particular at dosages exceeding 400mg (89,262).

Absorption

Following oral administration, peak plasma concentrations in healthy as well as in immunocompromised adults are attained within 1 to 4 hours (Table 2). With once daily dosing, steady state is achieved after 7-14 days, but can be reached more rapidly by oral loading (i.e., 200mg tid for 3 days) (44). Following administration of intravenous HP-beta-CD itraconazole, drug and carrier rapidly dissociate and follow their own disposition. Peak plasma levels of itraconazole and its carrier occur immediately after completion of the 1-hour infusion. The carrier HP-beta-CD is not significantly metabolized, and is virtually 100% eliminated from plasma within 24 hours in unchanged form by glomerular filtration (127,259). The carrier may accumulate in patients with significantly impaired renal function to potentially toxic concentrations (127).

Distribution

Independent of the formulation, itraconazole displays dose-dependent plasma pharmacokinetics with hyperproportional increases in the AUC, implying saturable metabolic processes (96,201). In blood, itraconazole is highly (95%) protein bound and only 0.2% is available as free drug with the remainder being bound to blood cells (Table 2) (117). It has a comparatively high volume of distribution and accumulates preferentially in skin, fat tissue, liver, bone marrow, kidney and lung (117). While concentrations of itraconazole in non-inflamed body fluids including the CSF are negligible, the drug is detectable in brain tissue, although at low concentrations (283). Of note, recent experimental work in rodents suggests that para-glycoprotein (P-gp) in capillary endothelial cells participates in a process of active efflux of itraconazole from the brain (171). The clinical impact of this observation, however, is unknown.

Routes of Elimination

Itraconazole undergoes extensive metabolization by the liver and is excreted in the form of inactive metabolites almost exclusively into bile and urine (96). Its major metabolite, hydroxy-itraconazole, possesses antifungal activity similar to itraconazole. After oral dosing, the plasma concentrations of hydroxy-itraconazole at steady state are 1.5 to 2 times higher than those of the parent compound (44), whereas they are considerably lower than those of itraconazole after intravenous dosing (24,322). It is important to understand that plasma concentrations of itraconazole measured by bioassay are different from those determined by HPLC (307), because the latter method usually does not account for hydroxy-itraconazole. The elimination of itraconazole from plasma follows a biexponential pattern. In comparison with single dosing, independent of the route, the elimination half-life at steady state is about twice as long, reflecting the dose dependent disposition of the drug (113).

DOSAGE

Adults and Children

               The recommended dose range of oral itraconazole in adults is 100 to 400 mg per day (capsules) and 2.5 mg/kg twice a day (HP-beta-CD solution). For life-threatening infections, however, more aggressive dosing is necessary. For such conditions, the authors recommend a loading dose of 600 to 800 mg/day for three to five days followed by a maintenance dose of 400 to 600 mg/day, respectively, and monitoring of serum concentrations. The approved dosages of intravenous HP-beta-CD itraconazole are 200 mg twice a day for 2 days, followed by 200 mg once daily for a maximum of altogether 14 days (24,54).

Itraconazole is not approved for patients under 18 years of age; based on the available pharmacokinetic data, a starting dosage of 2.5 mg/kg twice a day of oral HP-beta-CD itraconazole can be advocated (56,77,108). The recommended dosage range for the capsule formulation is 5 to 8 mg/kg/d with a loading dose of 4 mg/kg three times a day for the first 3 days. Data on the pharmacokinetics and dosage of intravenous HP-beta-CD itraconazole are currently lacking (101).

The dosage of oral itraconazole does not need to be adjusted in patients with renal insufficiency or undergoing hemo- or continuous ambulatory peritoneal dialysis (21). Because the elimination of HP-beta-CD parallels the glomerular filtration rate, however, intravenous itraconazole is contraindicated in patients with a creatinine clearance of less than 30 mL/min; no data are available for its use in patients undergoing dialysis or other renal replacement therapies. In patients with severe hepatic insufficiency, the elimination half-life of itraconazole can be prolonged and additional hepatic toxicity or possible drug interactions should be monitored carefully (54).

While detailed information in humans is lacking, itraconazole was embryotoxic and teratogenic in rodents (283). The drug is therefore contraindicated in pregnancy except for life threatening fungal infection with no therapeutic alternative. Itraconazole is excreted into human milk and expected benefits for the mother should be weighed against the unknown risks to the infant (128).

Therapeutic Monitoring

               Although experimental studies have provided evidence for a relationship between plasma concentrations and efficacy (17), the main rationale for monitoring of plasma levels has been the erratic oral bioavailability of itraconazole, particularly in neutropenic patients. Historically, the target plasma level of itraconazole was estimated at 0.25 ug/mL (HPLC) at trough based on the MIC90 of a large set of clinical isolates (54,101). More recent clinical data from a large cohort of patients undergoing intensive chemotherapy for acute leukemia and receiving antifungal prophylaxis with itraconazole, however, have demonstrated a significant statistical association of trough concentrations less than 0.5 ug/ml with the occurrence of invasive fungal infections (90). The authors and other experts recommend rapid achievement and maintenance of trough levels of greater or equal 0.5 ug/mL when itraconazole is given for prevention or treatment of invasive fungal infections.

ADVERSE EFFECTS

               Itraconazole is usually well tolerated with a similar spectrum and frequency of adverse effects as fluconazole ( Table 3) (36,276). In 189 patients treated for systemic mycoses with oral doses of 50-400mg/day for a median of 5 months, the overall rate of possibly related adverse reactions was 39%; most of the observed reactions were transient, and included nausea and vomiting (<10%), hypertrigliceridemia (9%), hypokalemia (6%), elevated liver transaminases (5%), skin rash and/or pruritus (2%), headache or dizziness (<2%) and pedal edema (1%). In 4% of the patients, toxicity led to the discontinuation of the drug; there were no deaths attributable to itraconazole toxicity (276). At doses of up to 400mg daily, the compound is almost devoid of effects on mammalian steroidogenesis (240,276,283). However, a Conn syndrome like combination of mild hypertension and hypokalemia observed in four and reversible adrenal insufficiency in one out of eight patients receiving 600mg daily for refractory invasive fungal infections over a mean duration of 5.5 months indicates that 600mg per day is approaching the upper limit of tolerability for long-term treatment (240). Gastrointestinal intolerance seems to be exceedingly frequent with oral HP-beta-CD itraconazole at dosages exceeding 400 mg and day (89).

Only a few cases of more severe hepatic injury or hepatitis have been described (145). Itraconazole can exert negative inotropic effects; because of a low but possible risk of cardiac toxicity, itraconazole should not be administered to patients with ventricular dysfunction (1).

Oral HP-beta-CD itraconazole was safe and well tolerated in the reported phase I/II pharmacokinetic studies in pediatric patients (56,108). Vomiting (12%), abnormal liver function tests (5%) and abdominal pain (3%) were the most common adverse effects in 103 neutropenic pediatric cancer patients who received the drug at 5 mg/kg once daily or 2.5 mg/kg twice a day for antifungal prophylaxis; 18% of the patients withdrew from the study because of adverse events (77).

DRUG INTERACTIONS

In comparison to fluconazole, both propensity and extent of drug-drug interactions are substantially greater (Table 4) (100,109).

Itraconazole is a substrate of CYP3A4, but also interacts with the heme moiety of CYP3A4, resulting in non-competitive inhibition of oxidative metabolism of many CYP3A4 substrates and increased and potentially toxic concentrations of coadministered drugs. Most important, the coadministration of cisapride, terfenadine, astemizole, mizolastine, dofetilide, quinidine, pimozide with itraconazole can lead to QTc prolongation with serious cardiac arrhythmias and is thus stricly containdicated (123,197). Similarily contraindicated is the coadministration of cholesterol-lowering agents such as lovastatin, simvastatin and atorvastatin which has been associated with rhabdomyolysis (128,179). Potentially toxic levels or effects of the coadministered drug can also be reached when itraconazole is given along with triazolam, midazolam, alprazolam, brotizolam, other benzodiazepines, phenytoin, carbamazepine, cyclosporine, tacrolimus, rapamycin, methylprednisolone, buspirone, alfentanil, ebstin, reboxetin calcium channel blockers such as dihydropyridine and verapamil, digoxin, quinidine, warfarin, sulfonylurea compounds, rifampin, rifabutin, ritonavir, indinavir, saquinavir, vincristine, busulphan, docetaxel and trimetrexate (22,100,109,128,139,183,197,223,292).

Increased metabolism of itraconazole resulting in decreased plasma levels can be induced by rifampin, rifabutin, isoniazide, carbamazepin, phenobarbital and phenytoin (197,273). In turn, inhibition of CYP3A4 by ritonavir, indinavir, clarithromycin and eryhromycin can lead to increased exposure to itraconazole (100,109)

As a consequence, patients who receive itraconazole along with one of the listed drugs should be followed closely and plasma concentrations of ideally both compounds as well as hepatic function should be monitored carefully. Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy. 2010 Aug;30:842-54.

CLINICAL INDICATIONS

               Itraconazole has useful clinical activity against dermatophytic infections and against pityriasis versicolor (96), against acute and chronic vaginal candidiasis (36,188,270) and HIV-associated oral and esophageal candidiasis including fluconazole-refractory infections (34,82,90,108,195,221,260,314). The clinical efficacy of itraconazole in candidemia and deeply invasive Candida infections, however, has not been systematically investigated.

Experience with oral itraconazole in the primary treatment of cryptococcal meningitis is scant (55,61,296); however, the drug has demonstrated effectiveness for consolidation or maintenance treatment of this condition in HIV-infected patients (220,289).

Itraconazole is approved as second line agent for treatment of invasive Aspergillus infections; only little data exist on ist use for first line treatment in neutropenic patients (33,59,261). The compound can lead to improvement of corticosteroid-dependent allergic bronchopulmonary aspergillosis without added toxicity (263). Itraconazole may be useful in the management of infections by certain dematiaceous moulds (239,240). It has been used successfully for adjunctive treatment of infections by entomophthorales  (152) but it has no documented activity against infections by mucorales and against fusariosis. Itraconazole is currently the preferred agent for treatment of lymphocutaneous sporotrichosis (207,241), and nonmeningeal, non-life-threatening histoplasmosis, blastomycosis and paracoccidioidomycosis (37,63,176,310,311,312). The drug also is effective against meningeal and nonmeningeal coccidioidomycosis (97,274,275). A randomized, double-blind clinical trial suggests that itraconazole may be superior to fluconazole against progressive non-meningeal coccidiodomycosis (84).

In comparison to fluconazole, intravenous and oral itraconazole reduced the incidence of proven invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients without effect on overall mortality rates (160,321). Prophylactic oral itraconazole may reduce the incidence of proved or suspected invasive fungal infections in neutropenic patients with hematological malignancies (167), but prophylactic efficacy against invasive aspergillosis has not been convincingly demonstrated . Itraconazole was at least as effective as conventional amphotericin B and superior with respect to its safety profile as empirical antifungal therapy in persistently febrile neutropenic patients (23), which has led to the approval of this indication by the FDA. 

In patients with advanced HIV infection and geographic exposition, itraconazole was effective as primary prophylaxis in reducing systemic cryptococcosis and histoplasmosis (163), and as primary (38) and secondary (266) of Penicillium marneffei infections. Itraconazole is as effective as fluconazole for prevention of invasive fungal infections in liver transplant patients (320) and has been shown to be an effective and well-tolerated treatment to reduce the frequency of fungal infections in chronic granulomatous disease (86).

Queiroz-Telles F, Goldani LZ, et al.  An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis.  Clin Infect Dis 2007;45(11):1462-1469.

VORICONAZOLE

Voriconazole ((2R,3S)-2,4-difluorophenyl)-3(5-fluoropyrimidine-4-yl)-1-(1,2,4-triazole-1-yl)butan-2-ol); Figure 3] is a low molecular weight, water-soluble triazole with a chemical structure that is very similar to that of fluconazole. In comparison to fluconazole, voriconazole has enhanced affinity to 14-alpha-demethylases of filamentous fungi and certain yeasts, including C. glabrata and C. krusei while maintaining specificity to the fungal target. Voriconazole possesses a broad spectrum of antifungal activity (Table 1), including Candida albicans and non-albicans Candida spp., Cr. neoformans, Aspergillus spp., Fusarium spp. and other hyaline, dematiaceous and dimorphic moulds. A notable exemption are the zygomycetes, against which voriconazole is intrinsically inactive (101,121,131).

Pharmacodynamic Effects

               Voriconazole exerts species-and strain-dependent cidal activity in vitro against opportunistic filamentous fungi but, based on currently accepted testing methods, is generally believed to be static against yeast-like fungi (42,67,129,134,154,193). Against C. albicans, a concentration-dependent postantifungal effect of 0.2 to 4.1 hours has been observed for voriconazole in the presence of serum (88). In a murine kidney target model of disseminated candidiasis, the AUC/MIC ratio was the pharmacodynamic parameter that correlated best with efficacy. Using ten Candida albicans isolates of different voriconazole susceptibilities , the free drug AUC/MIC ratios were similar in all of the organisms studied and similar to those observed for other azoles (8). Since voriconazole has non-linear pharmacokinetics and underlies considerable inter-individual variability in metabolization, assessment of concentration-effect relationships continues to be a challenge (103).

Neely M, Rushing T, et al. Voriconazole Pharmacokinetics and Pharmacodynamics in Children. Clin Infect Dis. 2010 Jan 1;50:27-36.

Walsh TJ, et al.  Pharmacokinetics, Safety, and Tolerability of Voriconazole in Immunocompromised Children.  Antimicrob Agents Chemother 2010;54(10):4116-4123.

PHARMACOKINETICS

Absorption

               Voriconazole is available in oral and intravenous formulations. In adults, following oral administration, peak plasma levels occur within 1 to 2 hours, and bioavailability exceeds 90% in the fasted state, independent of gastric acidity.

Dodds AES, Zaas AK, et al.  Comparative pharmacokinetics of voriconazole administered orally as either crushed or whole tablets.  Antimicrob Agents Chemother 2007;51(3):877-80.

Distribution

               The compound has nonlinear pharmacokinetics, leading to hyperproportional increases in exposure with increasing dosages. Plasma protein binding is 58%, and the mean volume of distribution accounts for approximately 4 L/kg. Tissue and CSF levels may exceed those of trough plasma levels severalfold.

Routes of Elimination

               The plasma half-life is 6 hours, with elimination primarily occurring by oxidative metabolism to at least 8 metabolites that are eliminated via the urine; less than 2% of a dose of voriconazole are excreted in unchanged form into the urine (Table 2). The major isoenzyme involved in voriconazole metabolization is CYP2C19, but CYP2C9 and CYP3A4 also contribute. There is a wide between-subject variability in the disposition of voriconazole, that is at least in part related to a polymorphism in the CYP2C19 genes (101,131,202,297,303).

DOSAGE

Adults and Children

               The recommended IV dosages for patients 12 years and above are 6mg/kg BID on day 1, followed by 4 mg/kg BID. The oral dosages in adults are 400mg BID on day 1 (< 40kg: 200mg BID), followed by 200mg BID (<40kg: 100mg BID). Pediatric patients < 12 to 1 year have a higher capacity for elimination of voriconazole per kilogram of body weight than adult healthy volunteers, resulting in a lower, potentially non-therapeutic exposure at similar dosages (303). Based on a population-based pharmacokinetic analysis of an intra-individual dosage escalation study exploring higher dosage regimens of voriconazole in this patient population, an IV dosage of 7 mg/kg BID and an oral dosage of 200 mg BID (oral suspension) without loading dosages is currently suggested for children < 12 to >1 years of age (299).

Renal Failure

In patients with renal insufficiency, no dosage adjustment is needed for the PO formulation. Because of the glomerular renal clearance of the intravenous cyclodextrin carrier, however, patients with a creatinine clearance of < 50mL/min should receive voriconazole by the oral route.

Hepatic Failure

In patients with mild to moderate hepatic function abnormalities (Child-Pugh category A and B), half of the daily maintenance dosage is recommended after the initial loading dose. Recommendations for severe liver failure (Child-Pugh category C) are lacking (101,297).

Pregnancy

Voriconazole is teratogenic in animals, and may cause fetal harm when administered to a pregnant woman; secretion into human milk has not been investigated. Therefore, the compound should not be used during pregnancy and in nursing mothers (101).

Therapeutic Monitoring

               A high inter-individual variability in exposure in patients has been noted by several investigators (126,271). While the manufacturer states the absence of concentration-effect relationships in clinical trials (297), mean random plasma concentrations of <250 ng/mL appeared to correlate with treatment failure in patients with invasive aspergillosis (60); similarly, in patients monitored for disease progression or toxicity, random plasma concentrations >2000 ng/mL seemed to be associated with favorable responses, whereas concentrations <2000 ng/mL correlated with disease progression (249). The analysis of close to 3000 samples from approximately 1000 patients enrolled on clinical trials of the manufacturer revealed relationships between voriconazole concentrations and visual disturbances and abnormalities in AST, alkaline phosphatase and bilirubin values (267), and similar observations were made by others (60,126). Based on these still limited observations and the highly variable disposition in patients, voriconazole clearly is a candidate to explore potential benefits of therapeutic drug monitoring. However, more systematic investigations on concentration- effect relationships including definition of target values are required before any recommendation can be made.

ADVERSE EFFECTS

               Voriconazole has an acceptable safety profile (Table 3). The clinical data accrued thus far indicate that side effects mainly include four distinct clinical categories: Transient liver enzyme abnormalities (10-20%), skin reactions (< 10%), hallucinations or confusion (<10%) and transient, dose-related visual disturbances (altered or enhanced perception of light, blurred vision; photophobia; <30%). For the latter, no morphologic correlation was found in animal models, and the underlying mechanism remains to be elucidated (131,297). Serious potentially related adverse effects requiring the discontinuation of voriconazole were infrequent in comparative clinical trials (2-13%) (3,115,305).

Of note, serious hepatic reactions including hepatic failure have been observed during treatment with voriconazole; therefore, evaluation of liver function tests before and during treatment with voriconazole is advised. Azole therapy has been associated with QTc prolongation; for this reason, voriconazole should be administered with caution to patients with proarrhytmic conditions (101).

Voriconazole has been administered safely and with success to a number children < 12 years of age without therapeutic alternative. Of 58 immunocompromised children with proven or probable invasive fungal infection refractory to or intolerant of conventional antifungal therapy, four (7%) were discontinued because of intolerance. A total of 23 patients had voriconazole-related adverse events, most commonly elevation in hepatic transaminases or bilirubin (n = 8), skin rash (n = 8), abnormal vision (n = 3) and photosensitivity reactions (n = 3) (304).

DRUG INTERACTIONS

               Voriconazole is both substrate and inhibitor of CYP2C19, CYP2C9, and CYP3A4, and therefore, a number of clinically relevant drug-drug interactions need to be considered (Table 4). Voriconazole significantly increases exposure to cyclosporin, tacrolimus, benzodiazepins, vinca-alkaloids, the statins, omeprazole, warfarin, sulfonylurea drugs, phenytoin, protease inhibitors other than indinavir, non-nucleoside reverse transcriptase inhibitors, requiring dosage adjustment and/or monitoring. Voriconazole exposure is significantly decreased by phenytoin, rifabutin, carbamazepine, rifampin, phenobarbital. Concurrent use of the three latter enzyme-inducers with voriconazole is contraindicated (risk subtherapeutic levels of voriconazole) as is the concurrent use of terfenadine, astemizole, cisapride, quinidine, pimozid (risk of QTc-prolongation due to increased exposure to these agents), ergotamin (risk of ergotism due to increased exposure) and sirolimus (increased exposure). Dosage adjustment of voriconazole is necessary when it has to be used concurrently with phenytoin or rifabutin (101,131,297).

Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy. 2010 Aug;30:842-54.

Mori, et al. Drug interaction between voriconazole and tacrolimus and its association with the bioavailability of oral voriconazole in recipients of allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2012; Mar30.

CLINICAL INDICATIONS

               Voriconazole has demonstrated excellent clinical efficacy in a non-comparative phase I/II study in HIV-infected patients with oropharyngeal candidiasis (114) and, at a dosage of 200mg BID, was as effective as fluconazole (200mg QD) for treatment of esophageal candidiasis in a double blind, randomized multicentre trial (3). In salvage studies in patients with refractory or intolerant-to-treatment fungal infections, complete and partial responses were seen in 43-48% of patients with invasive aspergillosis (60,192,304), in 45-52 % of patients with invasive candidiasis (192), in 30-63% of patients with scedosporiosis (192,304), in 45% of patients with fusariosis (192) and in 38% of patients with cryptococcosis (192).

A large multinational, randomized phase III clinical trial of voriconazole and conventional amphotericin B followed by other licensed antifungal therapy for primary therapy of invasive aspergillosis revealed superior outcomes in voriconazole treated patients (115): At week 12, successful outcomes were noted in 52.8% of the patients in the voriconazole group and in 31.6% of those in the amphotericin B group (absolute difference, 21.2 percentage points; 95% C.I., 10.4 to 32.9). The survival rate at 12 weeks was 70.8% in the voriconazole group and 57.9% in the amphotericin B group (hazard ratio, 0.59; 95% C.I., 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events. A randomized comparative study of voriconazole versus conventional amphotericin B followed by fluconazole for treatment of candidemia in non-neutropenic patients showed similar response rates and end of treatment and similar survival at three months (142): Twelve weeks after the end of treatment, successful outcomes were observed in 41% of patients in both treatment groups (95% CI for difference -10.6% to 10.6%). Voriconazole cleared blood cultures as quickly as amphotericin B/fluconazole and there were significantly fewer serious adverse events and cases of renal toxicity than in the amphotericin B/fluconazole group.

In a large international collaborative study of voriconazole versus liposomal amphotericin B for empirical therapy, voriconazole did not meet the prespecified statistical endpoint for non-inferiority in a composite endpoint but was associated with significantly fewer breakthrough invasive fungal infections, particularly those due to invasive aspergillosis (305).

Clinical data also indicate the usefulness of voriconazole for treatment of invasive aspergillosis of the central nervous system (237), the bone (172), chronic pulmonary aspergillosis (225) and invasive Aspergillus terreus aspergillosis (258). Favorable observational data on voriconazole in combination with echinocandins (159,244) provide the basis for a planned randomized clinical trial of such a combination for treatment of invasive aspergillosis. Voriconazole has been administered with success to children < 12 years of age with proven or probable invasive fungal infection refractory to or intolerant of conventional antifungal therapy (304) and to patients with cystic fibrosis and allergic bronchopulmonary aspergillosis (118).

Gubler C, Wildi SM, et al.  Disseminated Invasive Aspergillosis with Cerebral Involvement Successfully Treated with Caspofungin and Voriconazole.  Infection. 2007;35(5):364-6.

Queiroz-Telles F, Goldani LZ, et al.  An open-label comparative pilot study of oral voriconazole and itraconazole for long-term treatment of paracoccidioidomycosis.  Clin Infect Dis 2007;45(11):1462-1469.

POSACONAZOLE

Posaconazole (4-[4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-(1-ethyl-2-hydroxy-prophyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; C37H42F2N8O4; molecular weight: 700.33; trade name: Noxafil®) is a chirally and chemically stable, lipophilic second-generation antifungal triazole with a molecular structure similar to that of itraconazole [Figure 1] (14).

Posaconazole has potent and broad-spectrum in vitro activity against opportunistic, endemic, and dermatophytic fungi. This activity extends to organisms that are often refractory to existing triazoles, amphotericin B or echinocandins such as Candida glabrata, Candida krusei , Aspergillus terreus, and Fusarium spp. (222). In vivo, a large variety of animal models of invasive fungal infections has provided consistent evidence of therapeutic efficacy against these organisms in normal and in immunocompromised animals (107). Importantly, posaconazole possesses activity against zygomycetes both in vitro and in vivo, distinguishing it from all available azoles (106,222).

Pharmacodynamic Effects

               Posaconazole is considered fungistatic against Candida- and fungicidal against Aspergillus spp. (106). In time-kill assays, posaconazole showed concentration- and time dependent fungicidal activity against A. fumigatus (155,156). In vivo, in a neutropenic kidney target murine model of C. albicans infection, the AUC/MIC ratio was the parameter that was most predictive of antifungal efficacy (9).

PHARMACOKINETICS

               Posaconazole is available as oral suspension only and achieves optimal exposure when administered in 2 to 4 divided doses given with food or a nutritional supplement. The compound has dose-proportional pharmacokinetics in the 50- and 800-mg dose range, with saturation of absorption occurring above 800 mg; following repeat dosing, steady state is achieved after 7 to 10 days with a 6 to 8 fold accumulation of plasma concentrations (46). Posaconazole has a large volume of distribution in the order of 5 L/kg and a prolonged elimination half-life of approximately 20 hours. It is not significantly metabolized through the cytochrome P450 enzyme system but primarily excreted in unchanged form in the feces. The drug is inhibitory against cytochrome P3A4, but has no effects on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes, and therefore, a limited spectrum of drug-drug interactions can be expected (Table 2) (106,140,309). Posaconazole is a substrate and inhibitor of P-glycoprotein (P-gp). However, investigation of the relationship between MDR1 mRNA expression and posaconazole exposure showed no correlation. Thus, the moderate variability in the compounds pharmacokinetics is unlikely to be due to inter-individual differences in P-gp expression (47).

DOSAGE

               The recommended daily dosage of posaconazole for salvage treatment is 400 mg BID given with food; for patients not tolerating solid food, a dosage of 200 mg QID is recommended, preferentially together with a nutritional supplement. The dosage for primary treatment of OPC is 100 mg QD (day 1: 100 mg BID) and 400 mg BID refractory disease; for prophylaxis of invasive Candida- and Aspergillus infections, the recommended dosage is 200 mg TID.

Current data indicate no need for dosage adjustments based on differences in age, gender, race (230), renal or hepatic function (48,49). The pharmacokinetics of posaconazole in pediatric patients (<18 years of age) have not been studied yet. Very limited data obtained in 12 pediatric subjects ≥8 years of age appear to indicate no fundamental differences in trough plasma concentrations as compared to adults (141).

As a member of the class of antifungal azoles, posaconazole may be teratogenic and embryotoxic; secretion into human milk has not been investigated. Therefore, the compound should not be used during pregnancy and in nursing mothers.

Therapeutic Monitoring

Data generated in patients with invasive aspergillosis enrolled on the phase II clinical salvage trial (306) suggest a correlation between exposure and response to treatment with a threshold average plasma concentration of approximately 500 ng/mL. However, this correlation needs further validation and should not be used to advocate uniform therapeutic drug monitoring in the therapeutic situation.

Lebeaux D, Lanternier F, et al. Therapeutic Drug Monitoring of Posaconazole: A Monocentric Study with 54 Adults. Antimicrob Agents Chemother. 2009 Dec;53:5224-9.
 

ADVERSE EFFECTS

               Posaconazole appears to be well tolerated in a manner comparable to fluconazole (Table 3). The overall safety of posaconazole has been assessed in more than 400 patients with invasive fungal infections from two open label clinical trials who received posaconazole suspension (800 mg/day in divided doses). Treatment-related adverse events occurred in 38% of patients (164/428); the most common were nausea (8%), vomiting (6%), headache (5%), abdominal pain (4%), and diarrhea (4%). Treatment-related abnormal liver function test results were observed in up to 3% of patients. There were no clinically significant differences in mean QTc interval change from baseline. Serious adverse events considered possibly or probably related to posaconazole occurred in 35 (8%) patients. The most common severe adverse events were altered drug level, increased hepatic enzymes, nausea, rash, and vomiting (1% each). No significant trends related to age, sex, or race were observed, and no unique treatment related adverse events were identified in patients during long-term exposure (>6 months) compared with those identified during shorter-duration therapy (187,205). Of note, in two large, prospective, randomized comparative clinical trials investigating posaconazole for prevention of invasive fungal infections in high risk patients with leukemia or hematopoietic stem cell transplantation, posaconazole was well-tolerated and the rate of study drug discontinuations in posaconazole treated subjects was not different from that in subjects in the control cohort receiving fluconazole or itraconazole (45,279).

DRUG INTERACTIONS

               Posaconazole is not significantly metabolized through the cytochrome P450 enzyme system, and cytochrome P450-mediated drug-drug interactions will have limited potential to impact posaconazole pharmacokinetics (140) (Table 4). Posaconazole is inhibitory against cytochrome P3A4, but has no effects on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes (309). The drug-drug interaction potential of posaconazole has been investigated in seven open label, cross-over drug interaction studies. No dose adjustments are needed when posaconazole is coadministered with glipizide, zidovudine, and lamivudine, whereas dosages of ritonavir and indinavir may need to be lowered. Monitoring of cyclosporine and tacrolimus blood concentrations is mandatory, and dose adjustments should be made accordingly. Due to a relevant decrease in posaconazole concentrations, concomitant use with rifabutin, phenytoin, or cimetidine should be avoided. As with other azoles, caution is advised when posaconazole is coadministered with CYP3A4 substrates that have the potential to prolong the QTc interval (228,229).

Dodds-Ashley E. Management of drug and food interactions with azole antifungal agents in transplant recipients. Pharmacotherapy. 2010 Aug;30:842-54.

CLINICAL INDICATIONS

Posaconazole has been targeted for prevention and treatment of serious infections caused by opportunistic and endemic fungal organisms.

Posaconazole has demonstrated strong antifungal efficacy in phase II clinical trials in immunocompromised patients with primary or refractory oropharyngeal and esophageal candidiasis (246,293). In a randomized, comparative phase III trial, posaconazole (100mg daily (day 1: 200mg) was as effective as fluconazole (100mg daily (day 1: 200mg) in the primary treatment of HIV-associated oropharyngeal candidiasis: 155/169 (91.7%) patients receiving posaconazole vs. 148/160 (92.5%) of patients receiving fluconazole achieved a complete clinical response (cure). The relapse rate at day 42 was greater in fluconazole recipients than in posaconazole-treated subjects (38.2.vs. 31.5%, P=0.038) (294).

Posaconazole (800 mg in divided doses) also was investigated as salvage therapy in a large phase II study including 330 patients with invasive fungal infections intolerant to or refractory to standard therapies and a contemporaneous external control of 279 patients (204). Most patients (86%) were refractory to previous therapy. Successful outcomes at end of treatment in the posaconazole and in the contemporaneous external control cohorts were 42 vs. 26% in aspergillosis (107 and 86 pts.; separately published (306)), 39 vs. 50% in fusariosis (18 vs. 4 pts.), 56 vs. 50% in zygomycoses (11 vs. 8 pts.), 69 vs. 43% (16 vs. 7 pts.) in coccidioidomycosis, 52 vs. 53% in candidiasis (23 vs. 30 pts), 48 vs. 58% in cryptococcosis (31 vs. 64 pts.) , 81 vs. 0% in chromoblastomycosis (11 vs. 2 pts.), and 64 vs. 60% in other invasive fungal infections (30 vs. 20 pts.), including histoplasmosis (208). In a subset analysis of 39 patients with mostly refractory proven or probable CNS infections, posaconazole proved efficacy against cryptococcal meningitis (success rate in 29 patients: 48%) and against infections caused by opportunistic or endemic molds (5 of 10 patients, 50%) (198). These data are in agreement with the compound’s extended spectrum of activity in vitro and demonstrate efficacy for treatment of refractory invasive opportunistic and endemic mycoses. Of note, in a retrospective analysis of the manufacturer’s compassionate use program including 91 patients with proven or probable zygomycosis refractory or intolerant to prior antifungal therapy revealed a 60% success rate (complete and partial responses) at 12 weeks after initiation of therapy, providing first evidence for the clinical utility of posaconazole as second line or consolidation therapy of zygomycosis (282).

Two preventative randomized phase III studies in high risk patients with hematopoietic stem cell transplantation (HSCT) and graft-vs.-host disease (GVHD) (292) and acute leukemias (45) have been completed. In the first study, patients received either posaconazole 200 mg tid or fluconazole 400mg QD, respectively, with the start of immunosuppression for a total of 16 weeks. Treatment with posaconazole led to a decreased incidence of invasive fungal infections at 16 weeks (5 vs. 9%, p=0.07), with a statistically significant decrease in invasive Aspergillus infections (2 vs. 7%, p=0.006). Seven days post end of treatment, fewer patients had invasive fungal disease (2 vs. 8%, p=0.004), and fewer patients had invasive aspergillosis (1 vs. 6%, p=0.001). There were no differences in overall mortality at 12 weeks (292). In the second study, patients received either posaconazole 200 mg tid and either fluconazole 400mg QD or itraconazole 200 mg BID, respectively. Treatment was started with each cycle following drop of the ANC to ≤500 uL for up to 12 weeks. Significantly less patients enrolled in the posaconazole arm developed an invasive fungal infection at day 7 post end of treatment as compared to the comparator arm (2 vs. 8%, P<0.01); most importantly, treatment with posaconazole resulted in a significant decrease in the rate of invasive aspergillosis (1% vs. 7%, P<0.001). At day +100 post randomization, the rate of invasive fungal infections was 5% and 11% (P<0.01), and patients treated with posaconazole had a significantly improved survival probability (p=0.035) (45). These two landmark studies demonstrate the preventative efficacy of posaconazole in particular against invasive Aspergillus infections in high risk patients.

Acknowledgement: Author for First Edition: Thomas F. Paterson, M.D.

Raad II, Hanna HA, et al.  Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin.  Leukemia 2007 Dec. 20 [Epub ahead of print].

TABLES AND FIGURES

Table 1: Principal Activity Of Ketoconazole, Itraconazole, Fluconazole, Voriconazole and Posaconazole Against Human Fungal Pathogens.

Table 2: Pharmacokinetic Parameters of Ketoconazole, Itraconazole, Fluconazole, Voriconazole and Posaconazole  in Healthy Adult Volunteers at Steady State After Oral Daily Dosing with 200 mg.

Table 3a:  Profile of Common or Important Adverse Effects of Itraconazole and Posaconazole in Adults at Usual Dosages (≤ 400mg/Day And 800 Mg/Day) and Dose-Limiting Toxicity

Table 3b: Profile of Common or Important Adverse Effects of Fluconazole and Voriconazole in Adults at Usual Dosages (≤ 400mg/day) and Dose-Limiting Toxicity

Table 4:  Drug-drug Interactions of Ketoconazole, Itraconazole, Fluconazole, Voriconazole and Posaconazole

Figure 1: Structural formulas of clotrimazole, miconazole and ketoconazole

Figure 2: Ergosterol-biosynthesis and the target of the class of antifungal azoles

Figure 3: Structural formulas of itraconazole, fluconazole, posaconazole and voriconazole

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