Expert Review of Anti-infective Therapy

ISSN: 1478-7210 (Print) 1744-8336 (Online) Journal homepage: http://www.tandfonline.com/loi/ierz20

Azole antifungals: 35 years of invasive fungal infection management David Allen, Dustin Wilson, Richard Drew & John Perfect To cite this article: David Allen, Dustin Wilson, Richard Drew & John Perfect (2015) Azole antifungals: 35 years of invasive fungal infection management, Expert Review of Anti-infective Therapy, 13:6, 787-798, DOI: 10.1586/14787210.2015.1032939 To link to this article: http://dx.doi.org/10.1586/14787210.2015.1032939

Published online: 05 Apr 2015.

Submit your article to this journal

Article views: 448

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierz20 Download by: [La Trobe University]

Date: 30 September 2016, At: 13:41

Review

Azole antifungals: 35 years of invasive fungal infection management Expert Rev. Anti Infect. Ther. 13(6), 787–798 (2015)

David Allen1, Dustin Wilson1,2, Richard Drew*1,3 and John Perfect3 1 Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA 2 Department of Pharmacy, Duke University Hospital, Durham, NC, USA 3 Division of Infectious Diseases, Duke University Hospital, Durham, NC, USA *Author for correspondence: Tel.: +1 919 681 6793 Fax: +1 919 681 7494 [email protected]

Prior to 1981, treatment options for invasive fungal infections were limited and associated with significant toxicities. The introduction of ketoconazole marked the beginning of an era of dramatic improvements over previous therapies for non–life-threatening mycosis. After nearly a decade of use, ketoconazole was quickly replaced by the triazoles fluconazole and itraconazole due to significant improvements in pharmacokinetic profile, spectrum of activity and safety. The triazoles posaconazole and voriconazole followed, and were better known for their further extended spectrum, specifically against emerging mold infections. With the exception of fluconazole, the triazoles have been plagued with significant inter- and intrapatient pharmacokinetic variability and all possess significant drug interactions. Azoles currently in development appear to combine an in vitro spectrum of activity comparable to voriconazole and posaconazole with more predictable pharmacokinetics and fewer adverse effects. KEYWORDS: albaconazole . antifungals . azole . isavuconazole . ravuconazole

The incidence of invasive fungal diseases has steadily increased over the past few decades. Along with this growth in invasive fungal diseases there has also been a shift in causative pathogen(s) and changes in antifungal susceptibility. For example, while Candida spp. remain the most common cause of invasive fungal diseases, there has been a shift from Candida albicans to non-albicans Candida species [1]. Furthermore, rates of ‘difficult-to-treat’ molds, including formerly rare non-Aspergillus molds, with high-level resistance to most antifungals have also been on the rise [2,3]. Prior to the azole antifungals, options for the treatment of invasive fungal infections were severely limited. Griseofulvin was the first antifungal available, but its spectrum of activity limited its utility by only effectively treating dermatophytes. Flucytosine, on the other hand, has activity against many important yeast species, but flucytosine monotherapy is limited due to a low barrier to developing resistance on therapy [4]. Despite this, flucytosine was (and still is) commonly used as a combination therapy for some invasive fungal infections, notably cryptococcal meningitis [5]. The standard of care for nearly all severe informahealthcare.com

10.1586/14787210.2015.1032939

invasive fungal infections prior to azoles was the polyene antifungal amphotericin B deoxycholate (AmBd). This agent was available only as an intravenous infusion and its host of significant adverse reactions (nephrotoxicity, infusion reactions and electrolyte wasting) significantly limited its use. Over the last 35 years, the azole drug class has made a significant impact on the management of invasive fungal infections. Use of the older imidazoles (ketoconazole, miconazole, clotrimazole) is limited primarily to the treatment of superficial mycoses. In response, the triazoles (fluconazole, itraconazole, voriconazole and posaconazole) were developed to meet a broad range of applications. Newer azoles are under development in an effort to combat resistant pathogens while improving upon the tolerability and ease of administration. The objective of this study is to review the history of the azole antifungal class and examine potential future members of the class under development. Imidazoles

Azole antifungals prevent the synthesis of ergosterol (a major component of fungal


2015 Informa UK Ltd

ISSN 1478-7210

787

Review

Allen, Wilson, Drew & Perfect

plasma membranes) by inhibiting the CYP450-dependent enzyme, lanosterol demethylase [6]. The first azoles, the imidazoles (clotrimazole and miconazole), were marketed in 1969 as topical alternatives to griseovulvin and nystatin for cutaneous and mucocutaneous infections due to dermatophytes and Candida spp. In response to the need for oral treatment alternatives to AmBd systemic use of the imidazoles was explored in order to minimize AmBd-related side effects. Clotrimazole’s in vitro spectrum of activity appeared comparable to AmBd for dermatophytes, yeasts and endemic dimorphics, as well as some filamentous fungi [7]. While initial case reports of successful treatments of serious systemic infections (such as pulmonary aspergillosis) were published, more robust data quickly accumulated demonstrating high failure rates despite large oral doses of up to 100 mg/kg [8]. Later attempts to circumvent the gastrointestinal intolerability by using intravenous clotrimazole were also limited due in large part to the drug inducing its own metabolism [4]. Significant neurologic adverse effects (including hallucinations, disorientation and depression) were common at high doses and further restricted the potential for systemic use [4]. In the setting of clotrimazole’s limited use for systemic infections, the use of systemic miconazole started to gain favor as a potential option to AmBd for disseminated disease. Miconazole’s in vitro spectrum of activity against yeasts was similar to clotrimazole, but lacked activity against many molds [9]. Low solubility also restricted the development of oral dosage forms of miconazole. However, in 1979 (10 years after the topical formulation was introduced), an intravenous formulation was approved [6]. Although there were some favorable reports of use in disseminated candidiasis and cryptococcal meningitis, intravenous miconazole was associated with frequent infusion reactions (such as nausea, fever and chills, rash, phlebitis and pruritus) which were often refractory to antihistamines [4,9–12] The adverse reactions were likely due, at least in part, to the formulation containing Cremophor EL to address miconazole’s limited solubility [13]. Another more important point of concern was the number of cases of cardiac arrhythmia and arrest when rapidly infusing large doses [13]. This was also one of the earliest indicators of cardiac toxicity associated with the azole class that can limit their use to this day. Early in vitro testing of ketoconazole demonstrated a spectrum of activity similar to miconazole, but its specific potency was difficult to characterize during this time period [14]. Quantitative MICs were unreliable due to the high dependence upon culture medium, inoculum size and incubation conditions [14]. Despite this limitation, the approval of oral ketoconazole in 1981 allowed it to quickly become the preferred alternative to amphotericin B for many non-severe systemic yeast infections. Compared to AmBd and intravenous miconazole, ketoconazole was better tolerated. Ketoconazole also exhibits a high degree of interpatient variability in absorption following oral administration, due, in part, to its dependence on gastric pH. Therefore, avoidance of concomitant acid suppressing medications is essential for adequate absorption [15]. 788

Ketoconazole, like the other imidazoles, is also commonly associated with significant gastrointestinal intolerability. With further use, studies established an association of ketoconazole with severe life-threatening hepatotoxicity resulting in an US FDAissued ‘black box warning’ [16,17]. Other serious adverse effects unique to ketoconazole are a dose-dependent reduction in testosterone and cortisol concentrations [18,19]. The mechanism for this is believed to be due to inhibition of CYP450dependent enzymes required for hormone synthesis and is an example of the lower selectivity of the imidazole class for fungal P450 enzymes compared to mammalian P450 enzymes [18]. The resulting side effects may include gynecomastia, decreased libido and hair loss [12,19]. Interestingly, this action has been used for its positive effects on hormonally controlled prostate cancer [20]. Finally, ketoconazole’s inhibition of CYP3A4 can result in many clinically significant drug–drug interactions that can seriously complicate its use [18]. Despite its numerous limitations, ketoconazole established itself as the preferred agent for chronic mucocutaneous candidiasis and as the best alternative to AmBd for many other non– life-threatening systemic yeast infections for nearly a decade [21,22]. However, the lack of an intravenous formulation, unreliable oral absorption poor CNS penetration and low activity in immunocompromised hosts limited its widespread use [21]. With the introduction of triazoles (most notably fluconazole and itraconazole), use of ketoconazole significantly declined. To further demonstrate its limitations, previously approved indications for use were removed by the FDA in 2013. Recommendations were that ketoconazole use should be restricted to patients who have failed or are intolerant to other therapies [23]. While the use of oral ketoconazole is now limited, topical formulations of ketoconazole and the other imidazoles remain the first-line options for the treatment of many superficial mycoses (TABLE 1) [24]. Triazoles

The early 1990s marked a major advancement in the management of fungal infections with the introduction of two landmark triazoles, fluconazole and itraconazole. Compared to ketoconazole, these first-generation triazoles provided a broader spectrum of activity and improved safety [21]. Most notable was fluconazole, whose spectrum of activity included many Candida spp. (notably C. albicans), Cryptococcus neoformans and dimorphic fungi [25]. When compared to ketoconazole, fluconazole demonstrated both superior pharmacokinetic and adverse event profiles. Oral absorption of fluconazole is high (nearly 100%) and is not affected by food or gastric pH. In contrast to ketoconazole, fluconazole’s high water solubility permitted formulation as an intravenous solution and facilitated its use in more severe fungal infections [21]. In addition, fluconazole exhibits a large volume of distribution with very high concentrations in both CNS and in the urine (~80%), a pharmacologic profile that has yet to be matched by newer azoles [25]. Throughout the 1990s and early 2000s, there was widespread use of fluconazole for both prevention and treatment of select invasive Expert Rev. Anti Infect. Ther. 13(6), (2015)

Azole antifungals

Review

Table 1. Summary of US FDA-approved formulations and indications for azole antifungals. Agent

Formulation(s)

FDA-approved indications

Comments

Clotrimazole

Oral troches

Prophylaxis and treatment of oropharyngeal candidiasis

Topical creams and solution

Vulvovaginal candidiasis, dermatophytosis, cutaneous candidiasis and other superficial dermatologic infections

Troches are not significantly absorbed, but may still cause drug interactions Topical cream also comes in combination with betamethasone

Buccal tablet

Oropharyngeal candidiasis

Topical creams, solutions, ointments, powders, sprays and suppository

Vulvovaginal candidiasis Tinea corporis, tinea pedis and tinea cruris

Oral tablet

Treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis and paracoccidioidomycosis

Topical shampoo, cream, foam, gel

Tinea versicolor, tinea corpis, tinea cruris, tinea pedis, cutaneous candidiasis and seborrheic dermatitis

Fluconazole

Oral tablets Oral suspension Intravenous

Vulvovaginal, oropharyngeal, esophageal and systemic candidiasis, candiduria, cryptococcal meningitis and prophylaxis of candidiasis in allogeneic BMT recipients

Well tolerated Reduced susceptibility to Candida glabrata; no activity against Candida krusei Requires renal dose adjustments

Itraconazole

Oral capsules

Histoplasmosis and blastomycosis Invasive aspergillosis (in patients who are intolerant of or refractory to AmBd therapy)

Oral solution

Oropharyngeal and esophageal candidiasis

Preferred therapy for histoplasmosis and blastomycosis Solution is preferred to oral formulation. but has poor gastrointestinal tolerability Serum concentration monitoring recommended

Voriconazole

Oral tablets Oral suspension Intravenous

Invasive aspergillosis, esophageal candidiasis, systemic Candida infections, salvage therapy for infections caused by Scedosporium apiospermum and Fusarium spp.

Preferred therapy for invasive aspergillosis High potential for drug–drug interactions and adverse events Serum concentration monitoring recommended

Posaconazole

Oral suspension Oral tablets Intravenous

All formulations Prophylaxis of invasive Aspergillus or Candida infections in HSCT recipients with GVHD and in patients with hematologic malignancy with prolonged neutropenia Oral suspension Oropharyngeal candidiasis

Expanded spectrum of activity, including zygomycetes Oral suspension should be administered with high-fat meal, nutritional supplement or acidic beverage to enhance absorption Monitoring of serum concentrations recommended

Miconazole

Ketoconazole

Buccal tablet adheres to gums and stays in place for an average of 15 h per administration Many vulvovaginal products are available with both a suppository for vaginal instillation and topical cream for relief of external symptoms In 2013, the FDA limited the use of oral tablets to instances when other antifungal therapy is not available or tolerated, due to high potential for adverse events when given orally Low pH is required for absorption

AmBd: Amphotericin B deoxycholate; BMT: Bone marrow transplant, GVHD: Graft versus host disease; HSCT: Hematopoietic stem cell transplantation.

fungal diseases. For instance, fluconazole provided an invaluable oral option for the treatment of oropharyngeal and esophageal candidiasis, invasive candidiasis and prophylaxis against invasive fungal diseases in patients with hematologic malignancies [26–28]. Due to its high CNS penetration and ability to concentrate in the urine, fluconazole became a mainstay of therapy for cryptococcal meningitis and urinary tract infections caused by susceptible Candida spp. [5,29]. Itraconazole was approved by FDA in 1992 and it expanded the in vitro spectrum of antifungal activity to include clinically relevant molds, most notably Aspergillus spp. [30]. Despite this wider spectrum of activity, itraconazole was hindered by both informahealthcare.com

pharmacokinetic and safety profiles. Similar to ketoconazole, reliable absorption of the two oral formulations of itraconazole is significantly influenced by the presence/absence of food and gastric pH. While optimal absorption of itraconazole capsules (the first oral formulation available for use) occurs in the presence of food and gastric acid [30], itraconazole oral solution (the currently preferred oral formulation) is absorbed best on an empty stomach [31]. An intravenous preparation (available in the late 1990s) was subsequently withdrawn in most countries [32]. The incidence of adverse events is increased with itraconazole (compared to fluconazole), most notably significant nausea and diarrhea associated with the oral solution [33]. 789

Review

Allen, Wilson, Drew & Perfect

Moreover, due to its negative inotropic effects on the heart, itraconazole is contraindicated in patients with ventricular dysfunction (such as congestive heart failure) [30]. Despite its limitations, itraconazole replaced ketoconazole as the treatment of choice for endemic mycoses, such as mild to moderate histoplasmosis and blastomycosis, in guideline-defining studies [34,35]. In addition, open studies demonstrated that itraconazole capsules were an effective alternative therapy for select patients with invasive aspergillosis [36]. In contrast, widespread use for other indications (such as treatment of oropharyngeal and esophageal candidiasis, and prophylaxis against invasive fungal diseases) was limited in the setting of fluconazole availability [37]. As with the imidazoles, the first-generation triazoles still had several important limitations. Similar to ketoconazole, drug– drug interactions were still observed with these new agents due to the cross-inhibition of human CYP450-dependant enzymes, most notably 3A4 [38]. There was a shift of infections caused by non-albicans Candida spp. (such as Candida glabrata and Candida krusei) which are less susceptible to fluconazole therapy [39]. Neither agent had documented antifungal activity against the less-common opportunistic fungal infections (e.g., Scedosporium spp., Fusarium spp. and Zygomycetes) [40]. In addition, azole-resistant strains of Candida spp. and Aspergillus spp. began to emerge [41]. Voriconazole, approved in 2002, is structurally similar to fluconazole with the exception of a fluoropyrimidine group in place of a triazole moiety [41]. Its in vitro spectrum of activity includes most Candida spp. (including C. glabrata and C. krusei), Scedosporium apiospermum, Fusarium spp., Cryptococcus spp. and dimorphic fungi, and it was specifically selected to have potent activity against Aspergillus spp. [42]. It is available as both oral and intravenous formulations. The oral formulation of voriconazole has excellent bioavailability when given on an empty stomach (>90%). In contrast to fluconazole (which is primarily renally eliminated), the hepatic CYP450 enzymes (most notably 2C19, 2C9 and 3A4) are responsible for the metabolism of voriconazole [42]. Use of voriconazole for prophylaxis of invasive fungal diseases in allogeneic stem cell transplant recipients became attractive due to its excellent activity against both Aspergillus spp. and most Candida spp. [43]. Voriconazole’s use also quickly surpassed AmBd as the treatment of choice for invasive aspergillosis after a Phase III study showed that voriconazole had improved outcomes at week 12 (53 vs 32%) as well as better survival (70.8 vs 57.9%) compared to AmBd [44]. In addition, voriconazole became a promising agent in the treatment of refractory mold infections caused by S. apiospermum and Fusarium spp. [45,46]. While voriconazole was indicated for various infections caused by Candida spp., its use was limited in cases of azolesusceptible infections by the safer and less-expensive alternative fluconazole. While voriconazole provided a much-needed broader spectrum of antifungal activity compared to the previous triazoles (fluconazole and itraconazole), concerns regarding cross-resistance in fluconazole-resistant Candida spp. arose [47]. 790

In addition, the potential for drug–drug interactions and adverse events with voriconazole remains substantial. Voriconazole is an inhibitor and substrate of the CYP2C19, 2C9 and 3A4 enzymes; thus, interactions with other drugs that are substrates/inhibitors/inducers of the same CYP450 enzymes are likely (such as antiretrovirals and immunosuppressants) [42]. The high incidence of adverse events is attributable to variable serum concentrations due to non-linear kinetics of the drug as well as the genetic polymorphisms of CYP2C19. CYP2C19 polymorphisms account for 30–50% of the interpatient variability observed with voriconazole [48]. In addition to the adverse events seen with the previous triazoles (e.g., nausea, vomiting, diarrhea, hepatic toxicity and QTc prolongation), voriconazole has also been associated with several unique adverse events including transient visual disturbances (e.g., flashes of light and hallucinations), skin reactions and mental confusion [42]. Most recently, there have been reports of longterm voriconazole use being associated with periostitis, alopecia, nail changes and cutaneous malignancies [49–51]. Posaconazole, approved in 2006, has a comparable spectrum of antifungal activity as voriconazole, and in addition has some antifungal activity against Mucorales [52]. In contrast, voriconazole treatment has frequently been associated with super infection with the species belonging to Mucorales. [53]. Similar to ketoconazole and itraconazole, optimal absorption of the oral formulation of posaconazole is affected by the presence of both food and gastric pH. Therefore, posaconazole suspension should be administered with a high-fat meal, nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) to enhance absorption [54]. In addition, concomitant use of posaconazole with certain acid-suppressive agents (e.g., proton pump inhibitors) should be avoided [55]. To further optimize absorption, it is recommended to divide the daily dose of posaconazole suspension into three to four doses (four doses if using as treatment) [55]. More recently, two new formulations have been approved for posaconazole: a delayed-release tablet and an intravenous preparation. The delayed-release tablet has demonstrated increased drug exposure in both the fed and fasted states in healthy individuals, compared to the oral suspension [56]. In addition, it appears that acid-suppressive agents do not have a clinically meaningful effect on the bioavailability of the delayed-release tablet [57]. It is likely that the delayedrelease tablet will become the primary oral formulation. Similar to voriconazole, the intravenous preparation of posaconazole is not recommended for use in patients with a creatinine clearance 0.5–1 mcg/ml (measured by HPLC) [70]. In contrast, numerous studies have linked voriconazole serum concentrations to both efficacy and toxicity (most notably neurotoxicity) [71]. For example, a randomized, controlled trial demonstrated that routine voriconazole TDM (target range: 1–5.5 mcg/ml) reduced the drug discontinuation due to adverse events (4 vs 17%; p = 0.02) as well as improved the treatment response in patients with invasive fungal diseases (81 vs 57%; p = 0.04) compared to patients receiving a fixed, standard dose [72]. Serum concentrations should be obtained in the first 7 days of therapy (preferably on days 5–7), with target troughs of >1 and 2 mcg/ml is often recommended for treatment of severe cases of invasive fungal diseases [70]. Studies have linked posaconazole serum concentrations to improved efficacy in the prophylaxis and treatment of invasive fungal diseases [73]. However, no association has been identified between posaconazole serum concentrations and toxicity [74]. It is recommended to obtain a trough serum concentration 7 days after initiation of the drug. Goal troughs are >0.7 mcg/ml and >1 mcg/ml for prophylaxis and treatment, respectively [70]. All the triazoles have been evaluated as combination therapy with other antifungal agents (e.g., amphotericin B, flucytosine, echinocandins). With the exception of cryptococcal meningitis, data supporting the routine use of these various combination therapies for invasive fungal diseases are mostly limited to in vitro studies, animal models, observational studies and anecdotal case reports [62]. The most successful triazole used in combination thus far has been fluconazole. Significant success has been obtained when using fluconazole in combination with amphotericin B or flucytosine for induction treatment of cryptococcal meningitis in immunocompromised and immunocompetent individuals [5]. Given the success of fluconazole, much attention has been placed on voriconazole in combination with an echinocandin for the treatment of invasive aspergillosis. In a post-hoc analysis, results from a randomized, double-blind trial evaluating the combination of voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis showed a significant reduction in 6 weeks mortality rates in the combination group for patients with probable invasive aspergillosis, based on radiographic abnormalities and positive galactomannan antigen (15.7 vs 27.3%; p = 0.037) [75]. A recent meta-analysis concluded that combination therapy (including voriconazole plus an echinocandin) improves outcomes over monotherapy for salvage treatment of invasive aspergillosis [76]. This is in concordance with published guidelines [65]. Similarly, given the high mortality rates associated with invasive mucormycosis, combination therapy with AmBd and posaconazole is often implemented as salvage therapy despite the lack of data from large clinical trials [77]. In a recent case series of patients with hematologic diseases receiving combination therapy (amphotericin B and posaconazole) for the treatment of invasive 792

mucormycosis, 56% of the patients achieved a favorable response [77]. This reported rate was comparable to rates previously published for this infection [61]. Unmet needs & new triazoles in development

The ideal antifungal agent combines the wide spectrum of voriconazole or posaconazole with the reliable pharmacokinetics, parenteral and oral dosage forms, and favorable adverse effect profile of fluconazole. The three agents furthest along in research at this time are isavuconazole, ravuconazole and albaconazole. Isavuconazole (Basilea Pharmaceuticals and Astellas Pharma) is currently in Phase III trials. It is the active drug formed following the administration of its water-soluble prodrug isavuconazonium, which is rapidly and completely converted by plasma esterases into the active moiety [78]. This allows for both an oral and intravenous formulation without the need of cyclodextrin for solubility. This is a clear advantage of isavuconazole over the intravenous formulations of posaconazole, voriconazole and itraconazole as it negates any concern of accumulation and nephrotoxicity that accompany cyclodextrin [79]. Absorption of oral isavuconazole is excellent and unaffected by food or gastric pH [79]. The drug is primarily hepatically metabolized with a half-life of 56–77 h after oral administration and 76–104 h after intravenous administration [80]. The potential exists for significant accumulation in patients with hepatic dysfunction. In one pharmacokinetic trial, mild hepatic impairment caused a doubling in the half-life while moderate impairment caused nearly a tripling [80]. Isavuconazole also displays a moderate level of CYP3A4 enzyme inhibition to a similar degree as posaconazole [81]. Isavuconazole is currently involved in three Phase III studies. The SECURE study was a double-blind randomized trial evaluating the safety and efficacy of isavuconazole versus voriconazole in the primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi [82]. Isavuconazole was non-inferior to voriconazole for the primary endpoint of mortality at day 42 in the intent-to-treat population (18.6–20.2%, respectively) with a significantly lower rate of study drug-related adverse events relative to voriconazole (42.4–59.8%, respectively) [82]. Subgroup analysis of this data showed that non-inferiority was maintained in patients with confirmed invasive Aspergillus, neutropenia and pulmonary disease [83–85]. A health economic outcome analysis of patients from the SECURE study favored isavuconazole compared to voriconazole with numerically fewer days of hospital stay (13 vs 15 days) and lower 30-day hospital readmission rates (18.3 vs 24.4%) [86]. The VITAL study was an open-label study of isavuconazole in the treatment of aspergillosis in patients with pre-existing renal impairment or patients with invasive fungal disease caused by Mucorales, yeasts or dimorphic fungi [87]. The overall response at the end of treatment in patients with invasive mucormycosis was 31.6% when treated with isavuconazole as the primary antifungal therapy and 36.4% in patients refractory to prior antifungal therapy [87]. The mortality found in the VITAL study was Expert Rev. Anti Infect. Ther. 13(6), (2015)

Azole antifungals

considered to be consistent with published data for amphotericin and posaconazole. Pooled analyses from both the SECURE and VITAL studies were done looking at the response rates of patients with Fusarium or Scedosporium [88]. Successful treatment was achieved in three of nine patients with Fusarium and one of three with Scedosporium [88]. While these numbers are too small to draw significant conclusions, they do lend feasibility to the consideration of isavuconazole for salvage treatment. The ACTIVE study which compares the safety and efficacy of intravenous and orally administered isavuconazole to caspofungin followed by oral voriconazole in the treatment of candidemia and other invasive infections caused by Candida spp. has not yet reported results [89]. Ravuconazole (Bristol-Myers Squibb) is currently in Phase II clinical trials. The drug has a similar spectrum of activity and potency to voriconazole, with an increased half-life similar to isavuconazole (76–202 h) [81]. Of particular interest is the enhanced potency ravuconazole demonstrated against Candida spp., including fluconazole-resistant isolates [90]. However, ravuconazole has limited activity against Fusarium, Scedosporium and Zygomycetes [81]. In a pharmacokinetic dose study in healthy subjects, plasma concentrations of ravuconazole were dose proportional up to a dose of 400 mg at a time, but higher doses had a reduced absorption similar to that seen with the posaconazole suspension. Bioavailability was excellent, but was increased further by high-fat meals. Ravuconazole is being studied as both an oral and intravenous formulation, which is made possible by the prodrug ravuconazole di-lysine phosphoester [91]. Current clinical data with ravuconazole are limited to Phase II data. The first trial examined 5 days of ravuconazole for the treatment of oropharyngeal candidiasis in HIV-positive subjects and found a rate of 85% of either cure or improvement [92]. The second trial examined the treatment of onchomycosis with 12 weeks of ravuconazole and found a significant effective cure rate of 56% compared to 15% in the placebo arm [93]. Another new triazole antifungal under development, albaconazole (GlaxoSmithKline), is currently in Phase II trials. Albaconazole thus far has demonstrated good pharmacokinetics and excellent oral bioavailability with a wide spectrum of activity and favorable adverse effect profile. In fact, albaconazole demonstrated greater in vitro activity than amphotericin B against most important filamentous fungi even including the notoriously resistant Scedosporium prolificans [94]. Also encouraging is albaconazole’s apparent lack of negative effects on QTc that has plagued other members of the azole class. In a tolerability trial in healthy adults, albaconazole did not demonstrate any significant QT prolonging effects at concentrations five-times those expected in clinical use [95]. Coupled with a long mean half-life of 79 h, albaconazole appears to be a very promising agent [96]. In one Phase II trial investigating its use for onchomycosis, it achieved a significantly higher cure rate than placebo with only once-weekly dosing. The highest cure rate observed was 54% after 36 weeks of total therapy [97]. Another Phase II trial compared the efficacy of a single dose of informahealthcare.com

Review

albaconazole to that of various doses of fluconazole in women with uncomplicated Candida vulvovaginitis. Rates of therapeutic cure seen were as high as 91% with albaconazole compared to 67% with fluconazole [98]. An interesting additional potential use for albaconazole and ravuconazole is for the treatment of Trypanosoma cruzi, the parasite responsible for Chagas disease. Both agents are potent in vitro, but ravuconazole had limited in vivo activity in mice. The discouraging murine data, however, is thought to largely be due to the dramatically increased clearance observed in murine models compared to humans [99]. Albaconazole has shown the potential to provide parasitological cure of both acute and chronic Chagas in dogs. The study investigating the in vivo activity of albaconazole against two strains of T. cruzi in dogs demonstrated trypanocidal activity capable of inducing radical parasitological cure. Unfortunately, natural resistance to albaconazole was also observed [100]. A major ‘Achilles heel’ for most azoles in clinical use has been drug–drug interactions and this is particularly true of populations at risk of complicated invasive fungal diseases where polypharmacy is commonplace. There has now been substantial progress in replacing the triazole metal-binding group found in current antifungal azoles with less-avid metalbinding groups in concert with potency-enhancing molecular scaffold modifications to create potent antifungal compounds with excellent pharmacokinetics and importantly very little interaction with human CYP enzymes. This strategy has created compounds like VT-1161, which has potent antifungal activity but likely few drug–drug interactions [101,102]. If successful, this strategy could potentially make the azoles even more useful in clinical practice. In other words, a good drug class has become even better. Conclusion

Over the past 35 years, the landscape of antifungal options for the treatment of systemic mycosis has evolved dramatically from the first reasonable AmBd alternative, ketoconazole, to the host of triazole agents currently available (see FIGURE 1). Despite the remarkable evolution the azole class has undergone, there is still significant room for improvement. The new azole agents under development are exciting not only for their potential for increased spectrum of activity, but also for their ease of use, predictable pharmacokinetics, safety and reduced propensity for drug–drug interactions. The long history of the azole class up to this point makes it clear that no matter how these new agents are utilized, further research and development will likely be warranted due to the challenge of ever-evolving resistance patterns. Expert commentary

For over half a century, azole antifungal compounds have dominated our pharmaceutical screens, integrated into our armamentarium of agricultural fungicides, veterinary antifungals, and (importantly) have been the backbone of our human fungal treatments (both locally and systemically). There has been a 793

Review 1960s

Allen, Wilson, Drew & Perfect

1970s

1969 Topical miconazole and clotrimazole

1980s

1990s

2000s

2013 2002 Posaconazole Voriconazole tablets oral and IV

1990 1981 Fluconazole Ketoconazole oral and IV tablets

2006 Posaconazole oral suspension

1992 Itraconazole capsules

1979 Miconazole IV

2010s

2014 Posaconazole IV

1997 Itraconazole oral solution

1999 Itraconazole IV†

Figure 1. Timeline of US FDA approval of azole antifungals. † Intravenous itraconazole is no longer available in some countries.

graded development in which the azoles became relevant for prophylaxis, empirical and therapeutic strategies. They were developed to have impressive pharmacokinetics (fluconazole) and substantial broad-spectrum antifungal activity (itraconazole, voriconazole and posaconazole). In many respects, they were much more facile to use and generally safer than their predecessor, the polyenes, but they probably sacrificed some direct fungicidal activity and resistance development compared to polyenes. Furthermore, they can still be problematic to be used in severely ill patients with invasive mycoses, given the direct organ toxicities and (most importantly) serious drug–drug interactions in patients frequently receiving a ‘polypharmacy’ of concomitant medications. Despite these limitations, it is clear that this class of agents has been responsible for saving the lives of many infected patients and allowed modern medicine to aggressively treat serious underlying diseases. It is exciting to consider that this class continues to be developed to either improve pharmacokinetics or creatively change the molecules in their P450 binding sites to substantially reduce drug–drug interactions. Even with these new directions, the azoles still have challenges. First, azole resistance continues to be observed and appears to be increasing, and might be a spillover from agricultural azole fungicides in the environment or the widespread use in our own clinics. Second, broader spectrum compounds are needed and with more potent fungicidal activity. Finally, continued study of azoles combined with other antifungal agents may be desirable for synergistic activity and

794

reduction of drug resistance. Challenges abound with azoles both today and tomorrow, but in all respects, this class of antifungal drugs represents a major achievement in the control and management of fungi both in our fields and in our clinics. Azoles save lives and allow us to practice ‘cutting-edge’ medicine. Five-year view . . . .

It is likely that azoles will continue to be the backbone of our antifungal armamentarium for prophylaxis and treatment. New azoles with less drug–drug interactions and improved pharmacokinetic profiles will become available. Antifungal combination therapy (including an azole) will be more common. Azole resistance will continue to require antifungal stewardship, and improved azoles or new classes of antifungal agents.

Financial & competing interest disclosure

J Perfect has received grants, acted as an advisory consultant and has been on the board for Pfizer, Merck, Astellas, Viamet, F2G, Tokoyama, Scynexis and Amplyx. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Expert Rev. Anti Infect. Ther. 13(6), (2015)

Azole antifungals

Review

Key issues .

The imidazole class (particularly ketoconazole) was a tremendous breakthrough and quickly became the drug of choice for many fungal infections for nearly a decade. However, imidazoles are currently limited to the treatment of superficial mycosis due to their limited spectrum of activity and significant toxicities.

.

The first-generation triazoles (fluconazole and itraconazole) were groundbreaking, with fluconazole displaying excellent tolerability and pharmacokinetics while itraconazole possessed a broader spectrum of activity.

.

Voriconazole is the drug of choice for aspergillosis despite significant interpatient variability, high potential for drug–drug interactions and extensive adverse effect profile.

.

Posaconazole has an excellent spectrum of activity, limited drug–drug interactions and tolerable safety profile. Its oral use was primarily limited by difficulties with absorption, but the new delayed-release tablet and intravenous formulation appear to have improved this aspect dramatically.

.

Therapeutic drug monitoring of itraconazole, voriconazole and posaconazole is generally recommended to ensure adequate concentrations of these agents due to their significant inter- and intrapatient variability.

.

Combination antifungal therapy with azoles is not common practice, but the situations where there are data to support this strategy are the use of fluconazole with amphotericin B deoxycholate or flucytosine for cryptococcal meningitis induction therapy, or the use of voriconazole plus an echinocandin for the treatment of aspergillosis.

.

Isavuconazole is in Phase III trials and appears to be as effective as voriconazole for aspergillosis with significantly less side effects while also demonstrating some activity against zygomycetes.

.

Ravuconazole and albaconazole are both in Phase II trials and appear to have a broad spectrum of activity, are well tolerated and demonstrate a long half-life.

.

VT-1161 represents improved drug design to optimize pharmacology with a specific emphasis on drug–drug interactions.

References

7.

Papers of special note have been highlighted as: . of interest .. of considerable interest

Shadomy S. In vitro antifungal activity of clotrimazole (Bay b 5097). Infect Immun 1971;4(2):143-8

8.

Sawyer PR, Brogden RN, Pinder RM, et al. Clotrimazole: a review of its antifungal activity and therapeutic efficacy. Drugs 1975;9(6):424-47

16.

Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy: analysis of 33 cases. Gastroenterology 1984;86(3):503-13

9.

Heel RC, Brogden RN, Pakes GE, et al. Miconazole: a preliminary review of its therapeutic efficacy in systemic fungal infections. Drugs 1980;19(1):7-30

17.

Yan JY, Nie XL, Tao QM, et al. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci 2013;26(7):605-10

10.

Bennett JE, Remington JS. Miconazole in cryptococcosis and systemic candidiasis: a word of caution. Ann Intern Med 1981; 94(5):708-9

18.

Gupta AK, Daigle D, Foley KA. Drug safety assessment of oral formulations of ketoconazole. Expert Opin Drug Saf 2015; 14(2):325-34

11.

Lutwick LI, Rytel MW, Yanez JP, et al. Deep infections from Petriellidium boydii treated with miconazole. JAMA 1979; 241(3):272-3

19.

Pont A, Williams PL, Loose DS, et al. Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 1982;97(3): 370-2

12.

Graybill JR. Antifungal agents used in systemic mycoses: activity and therapeutic use. Drugs 1983;25(1):41-62

20.

13.

Fainstein V, Bodey GP. Cardiorespiratory toxicity due to miconazole. Ann Intern Med 1980;93(3):432-3

Galsky MD, Simon K, Sonpavde G, et al. Ketoconazole retains activity in patients with docetaxel-refractory prostate cancer. Ann Oncol 2009;20(5):965-6

21.

Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect 2004;10(Suppl 1):1-10

.

Provides an in-depth view of the history of the azole class.

22.

Drouhet E, Dupont B. Chronic mucocutaneous candidosis and other superficial and systemic mycoses successfully

1.

Marr KA. Invasive Candida infections: the changing epidemiology. Oncology 2004; 18(14 Suppl 13):9-14

2.

Lewis RE, Kontoyiannis DP. Epidemiology and treatment of mucormycosis. Future Microbiol 2013;8(9):1163-75

.

Review of epidemiology, risk factors and clinical manifestations of mucormycosis.

3.

Petrikkos G, Skiada A, Lortholary O, et al. Epidemiology and clinical manifestations of mucormycosis. Clin Infecti Dis 2012; 54(Suppl 1):S23-34

4.

Medoff G, Kobayashi GS. Strategies in the treatment of systemic fungal infections. N Engl J Med 1980;302(3):145-55

5.

Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50(3):291-322

6.

Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev 1999;12(1): 40-79

14.

15.

informahealthcare.com

Heel RC, Brogden RN, Carmine A, et al. Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 1982;23(1-2):1-36 Van Der Meer JW, Keuning JJ, Scheijgrond HW, et al. The influence of

gastric acidity on the bio-availability of ketoconazole. J Antimicrob Chemother 1980;6(4):552-4

795

Review

Allen, Wilson, Drew & Perfect

treated with ketoconazole. Rev Infect Dis 1980;2(4):606-19 23.

24.

25.

26.

27.

28.

29.

FDA Drug Safety Communication. FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems, 2013. Available from: www.fda.gov/Drugs/DrugSafety/ ucm362415.htm Rotta I, Otuki MF, Sanches AC, Correr CJ. Efficacy of topical antifungal drugs in different dermatomycoses: a systematic review with meta-analysis. Rev Assoc Med Bras 1992;58(3):308-18 Diflucan [package insert]. Pfizer, New York, NY; March 2013. Available from: http:// labeling.pfizer.com/ShowLabeling.aspx? id=575 Laine L, Dretler RH, Conteas CN, et al. Fluconazole compared with ketoconazole for the treatment of Candida esophagitis in AIDS. A randomized trial. Ann Intern Med 1992;117(8):655-60 Anaissie EJ, Darouiche RO, Abi-Said D, et al. Management of invasive candidal infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 1996;23(5):964-72 Slavin MA, Osborne B, Adams R, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation: a prospective, randomized, double-blind study. J Infect Dis 1995;171(6):1545-52 Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48(5):503-35

30.

Sporanox [package insert]. Janssen-Cilag Pty Ltd; Macquarie Park, Australia: November 2014. Available from: www.janssen.com.au/ files/Products/Sporanox_Capsules_PI.pdf

31.

Sporanox [package insert]. Janssen-Cilag Pty Ltd; Macquarie Park, Australia: November 2014. Available from: www.janssen.com.au/ files/Products/Sporanox_Solution_PI.pdf

32.

Dolton MJ, McLachlan AJ. Optimizing azole antifungal therapy in the prophylaxis and treatment of fungal infections. Curr Opin Infect Dis 2014;27(6):493-500

33.

Pound MW, Townsend ML, Dimondi V, et al. Overview of treatment options for invasive fungal infections. Med Mycol 2011; 49(6):561-80

34.

Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the

796

management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Iinfect Dis 2007; 45(7):807-25 35.

Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008;46(12): 1801-12

46.

Lortholary O, Obenga G, Biswas P, et al. International retrospective analysis of 73 cases of invasive fusariosis treated with voriconazole. Antimicrob Agents Chemother 2010;54(10):4446-50

47.

Thompson GR 3rd, Lewis JS 2nd. Pharmacology and clinical use of voriconazole. Expert Opin Drug Metab Toxicol 2010;6(1):83-94

48.

Obeng A EE, Alsultan A, Peloquin C, Johnson J. CYP2C19 polymorphisms and therapeutic drug monitoring of voriconazole: are we ready for clinical implementation of pharmacogenomics? Pharmacotherapy 2014;34(7):703-18

36.

Stevens DA, Lee JY. Analysis of compassionate use itraconazole therapy for invasive aspergillosis by the NIAID Mycoses Study Group criteria. Arch Intern Med 1997;157(16):1857-62

37.

Wilson DT, Drew RH, Perfect JR. Antifungal therapy for invasive fungal diseases in allogeneic stem cell transplant recipients: an update. Mycopathologia 2009; 168(6):313-27

49.

Wermers RA, Cooper K, Razonable RR, et al. Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. Clin Infect Dis 2011; 52(5):604-11

38.

Lass-Florl C. Triazole antifungal agents in invasive fungal infections: a comparative review. Drugs 2011;71(18):2405-19

50.

39.

Diekema D, Arbefeville S, Boyken L, et al. The changing epidemiology of healthcare-associated candidemia over three decades. Diagn Microbiol Infect Dis 2012; 73(1):45-8

Malani AN, Kerr L, Obear J, et al. Alopecia and nail changes associated with voriconazole therapy. Clin Infect Dis 2014; 59(3):e61-5

51.

Sable CA, Strohmaier KM, Chodakewitz JA. Advances in antifungal therapy. Annu Rev Med 2008;59:361-79

Williams K, Mansh M, Chin-Hong P, et al. Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients. Clin Infect Dis 2014;58(7): 997-1002

52.

De Sarro A, La Camera E, Fera MT. New and investigational triazole agents for the treatment of invasive fungal infections. J Chemother 2008;20(6):661-71

Noxafil [package insert]. Merck & Co., Inc; Whitehouse Station, NJ: June 2014. Available from: www.merck.com/product/ usa/pi_circulars/n/noxafil/noxafil_pi.pdf

53.

Ambrosioni J, Bouchuiguir-Wafa K, Garbino J. Emerging invasive zygomycosis in a tertiary care center: epidemiology and associated risk factors. Int J Infect Dis 2010; 14(Suppl 3):e100-3

54.

Cornely OA, Helfgott D, Langston A, et al. Pharmacokinetics of different dosing strategies of oral posaconazole in patients with compromised gastrointestinal function and who are at high risk for invasive fungal infection. Antimicrob Agents Chemother 2012;56(5):2652-8

55.

Green MR, Woolery JE. Optimising absorption of posaconazole. Mycoses 2011; 54(6):e775-9

56.

Krishna G, Ma L, Martinho M, O’Mara E. Single-dose phase I study to evaluate the pharmacokinetics of posaconazole in new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother 2012;56(8):4196-201

57.

Kraft WK, Chang PS, van Iersel ML, et al. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in

40.

41.

42.

Vfend [package insert]. Pfizer; New York, NY: February 2014. Available from: http:// labeling.pfizer.com/ShowLabeling.aspx? id=618

43.

Strasfeld L, Weinstock DM. Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents. Expert Rev Anti Infect Ther 2006;4(3):457-68

44.

Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347(6):408-15

.

45.

Clinical study showing voriconazole had improved outcomes as well as better survival compared to amphotericin B deoxycholate in patients with invasive aspergillosis. Perfect JR, Marr KA, Walsh TJ, et al. Voriconazole treatment for less-common, emerging, or refractory fungal infections. Clin Infect Dis 2003;36(9):1122-31

Expert Rev. Anti Infect. Ther. 13(6), (2015)

Azole antifungals

healthy subjects. Antimicrob Agents Chemother 2014;58(7):4020-5 58.

Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356(4):348-59

59.

Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356(4):335-47

60.

Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007;44(1):2-12

61.

Van Burik JA, Hare RS, Solomon HF, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006; 42(7):e61-5

62.

Johnson MD, Perfect JR. Use of antifungal combination therapy: agents, order, and timing. Curr Fungal Infect Rep 2010;4(2): 87-95

63.

Andes DR, Safdar N, Baddley JW, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 2012;54(8):1110-22

.

64.

65.

66.

67.

68.

69.

Drew RH, Townsend ML, Pound MW, et al. Recent advances in the treatment of life-threatening, invasive fungal infections. Expert Opin Pharmacother 2013;14(17): 2361-74

70.

Ashbee HR, Barnes RA, Johnson EM, et al. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 2014;69(5):1162-76

78.

Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist 2013;6: 163-74

..

Guidelines from the British Society for Medical Mycology providing recommendations for therapeutic drug monitoring of various antifungal agents.

79.

71.

Seyedmousavi S, Mouton JW, Verweij PE, Bruggemann RJ. Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis. Expert Rev Anti Infect Ther 2013;11(9): 931-41

Schmitt-Hoffmann A, Roos B, Heep M, et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006;50(1):279-85

72.

Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis 2012;55(8): 1080-7

80.

.

First randomized, controlled study evaluating the clinical utility of routine therapeutic drug monitoring of voriconazole.

Schmitt-Hoffmann A, Roos B, Spickermann J, et al. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother 2009;53(11): 4885-90

81.

Pasqualotto AC, Denning DW. New and emerging treatments for fungal infections. J antimicrob Chemother 2008;61(Suppl 1): i19-30

..

Thorough review of data for newly emerging antifungal agents.

82.

Maertens J, Patterson T, Rahav G, et al. A phase 3 randomised, double-blind trial evaluating isavuconazole vs. voriconazole for the primary treatment of invasive fungal disease caused by Aspergillus spp. or other. filamentous fungi (SECURE). European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Barcelona, Spain; May 10–13, 2014; Poster presentation, O230a

83.

Patterson T, Selleslag D, Mullane K, et al. A phase 3, randomized, double-blind, non-inferiority trial to evaluate efficacy and safety of isavuconazole versus voriconazole in patients with invasive mold disease (SECURE): outcomes in neutropenic patients. ID Week, Pennsylvania, Philadelphia; October 8–12, 2014; Poster presentation, 109-AB

84.

Raad I, Mullane I, Selleslag D, et al. A Phase 3, randomized, double-blind, non-inferiority trial to evaluate efficacy and safety of isavuconazole vs. voriconazole in patients with Invasive Mold Disease (IMD): Outcomes in Patients with Pulmonary Infections. IDWeek, Pennsylvania,

73.

Review of clinical studies concluding that treatment with an echinocandin was associated with decreased mortality in patients with invasive candidiasis. Baden LR, Bensinger W, Angarone M, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw 2012;10(11):1412-45 Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the infectious diseases society of America. 2008;46(3):327-60 Perfect JR, Hachem R, Wingard JR. Update on epidemiology of and preventive strategies for invasive fungal infections in cancer patients. Clin Infect Dis 2014;59(Suppl 5): S352-5 Tortorano AM, Richardson M, Roilides E, et al. ESCMID and ECMM joint guidelines on diagnosis and management of hyalohyphomycosis: fusarium spp., Scedosporium spp. and others. Clin Microbiol Infect 2014;20(Suppl 3):27-46 Kim JH, Williams K. Posaconazole salvage treatment for invasive fungal infection. Mycopathologia 2014;178(3-4):259-65

informahealthcare.com

Review

Vaes M, Hites M, Cotton F, et al. Therapeutic drug monitoring of posaconazole in patients with acute myeloid leukemia or myelodysplastic syndrome. Antimicrob Agents Chemother 2012;56(12): 6298-303

74.

Dolton MJ, Ray JE, Marriott D, McLachlan AJ. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother 2012;56(6): 2806-13

75.

Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015;162(2):81-9

..

First randomized, controlled study evaluating the safety and efficacy of combination therapy for invasive aspergillosis.

76.

Panackal AA, Parisini E, Proschan M. Salvage combination antifungal therapy for acute invasive aspergillosis may improve outcomes: a systematic review and meta-analysis. Int J Infect Dis 2014;28c: 80-94

77.

Pagano L, Cornely OA, Busca A, et al. Combined antifungal approach for the

treatment of invasive mucormycosis in patients with hematologic diseases: a report from the SEIFEM and FUNGISCOPE registries. Haematologica 2013;98(10): e127-30

797

Review

Allen, Wilson, Drew & Perfect

Philadelphia; October 8–12, 2014; Poster presentation, 109-AB 85.

86.

87.

88.

89.

Kontoyiannis D, Giladi M, Lee M, et al. A phase 3, randomized, double-blind, non-inferiority trial to evaluate efficacy and safety of isavuconazole versus voriconazole in patients with invasive mold disease (SECURE): outcomes in invasive aspergillosis patients. ID Week, Pennsylvania, Philadelphia; October 8–12, 2014; Poster presentation, 109-AB Khandelwal N, Franks B, Shi F, et al. Health economic outcome analysis of patients randomized in the SECURE phase 3 trial comparing isavuconazole to voriconazole for primary treatment of invasive fungal disease caused by aspergillus species or other filamentous fungi. ID Week, Pennsylvania, Philadelphia; October 8–12, 2014; Poster presentation 827

90.

91.

U.S. National Institutes of Health. Isavuconazole (BAL8557) in the Treatment of Candidemia and Other Invasive Candida Infections. ClinicalTrials.gov Identifier: NCT00413218. 2014. Available from: https://clinicaltrials.gov/ct2/show/ NCT00413218? term=isavuconazole&rank=26

798

Olsen SJ, Mummaneni V, Rolan P, et al. Ravuconazole single ascending oral dose study in healthy subjects. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Canada, Toronto; September 17–20, 2000; Abstract 838

92.

Marino MR, Mummanei V, Norton J, et al. Ravuconazole exposure-response relationship in HIV-patients with oropharyngeal candidiasis. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Illinois, Chicago; December 16–19, 2001 ; Abstract J-1622

93.

Gupta AK, Leonardi C, Stoltz RR, et al. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis. J Eur Acad Dermatol Venereol 2005;19(4):437-43

Marty FM, Perfect JR, Cornely OA, et al. An open-label phase 3 study of isavuconazole (VITAL): focus on mucormycosis. ID Week, Pennsylvania, Philadelphia; October 8–12, 2014; Poster presentation, Hall BC Cornely OA, Ostrosky-Zeichner L, Rahav G, et al. Outcomes in Patients with Invasive Mold Disease Caused by Fusarium or Scedosporium spp. Treated with Isavuconazole: Experience from the VITAL and SECURE Trials. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Wasington, DC; September 5–9, 2014; Abstract M-1760

Messer SA, Jones RN, Fritsche TR. International surveillance of Candida spp. and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program. J Clin Microbiol 2006;44(5): 1782-7

94.

Capilla J, Ortoneda M, Pastor FJ, Guarro J. In vitro antifungal activities of the new triazole UR-9825 against clinically important filamentous fungi. Antimicrob Agents chemother 2001;45(9):2635-7

95.

Dietz AJ, Barnard JC, van Rossem K. A randomized, double-blind, multiple-dose, placebo-controlled, dose escalation study with a 3-cohort parallel group design to investigate the tolerability and pharmacokinetics of albaconazole in healthy subjects. Clinical Pharmacology in Drug Development 2014;3(1):25-33

96.

van Rossem K, Lowe JA. A Phase 1, randomized, open-label crossover study to evaluate the safety and pharmacokinetics of 400 mg albaconazole administered to healthy participants as a tablet formulation

versus a capsule formulation. Clin Pharmacol 2013;5:23-31 97.

Sigurgeirsson B, van Rossem K, Malahias S, Raterink K. A phase II, randomized, double-blind, placebo-controlled, parallel group, dose-ranging study to investigate the efficacy and safety of 4 dose regimens of oral albaconazole in patients with distal subungual onychomycosis. J Am Acad Dermatol 2013;69(3):416-25

98.

Bartroli X, Uriach J. A clinical multicenter study comparing efficacy and tolerability between five single oral doses of albaconazole and fluconazole 150 mg single dose in acute vulvovaginal candidiasis. Interscience Conference on Antimicriobial Agents and Chemotherapy (ICAAC), Washington, DC; December 16–19, 2005; Abstract M-722

99.

Urbina JA, Payares G, Sanoja C, et al. In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease. Int J Antimicrob Agents 2003;21(1):27-38

100.

Guedes PM, Urbina JA, de Lana M, et al. Activity of the new triazole derivative albaconazole against Trypanosoma (Schizotrypanum) cruzi in dog hosts. Antimicrob Agents Chemother 2004;48(11): 4286-92

101.

Hoekstra WJ, Garvey EP, Moore WR, et al. Design and optimization of highly-selective fungal CYP51 inhibitors. Bioorg Med Chem Lett 2014;24(15):3455-8

102.

Warrilow AG, Hull CM, Parker JE, et al. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother 2014;58(12):7121-7

Expert Rev. Anti Infect. Ther. 13(6), (2015)