Anidulafungin: a New Addition to the Antifungal Armamentarium

DRUG EVALUATION

Anidulafungin: a new addition to the antifungal armamentarium

John Mohr1† & Invasive fungal infections continue to be associated with high rates of morbidity and Luis Ostrosky-Zeichner1,2 mortality, primarily in the immunocompromised hosts. Candida and Aspergillus are the †Author for correspondence most common causes of invasive fungal disease; however, other fungi can also cause disease 1University of Texas Health Science Center Houston, in humans. Current therapeutic options for the management of invasive fungal infections Department of Infectious include the polyenes, triazoles and echinocandins. Anidulafungin is a new echinocandin Diseases, 6431 Fannin, antifungal drug with a favorable toxicity profile and minimal drug–drug interactions that MSB 2.112, Houston, TX 77030, USA has activity against Aspergillus and Candida, including azole-resistant strains. Tel.: +1 713 500 6742; Fax: +1 713 500 5495 E-mail: john.mohr@ uth.tmc.edu Despite large advances in the development of bone marrow transplant or in those patients with 2Tel.: +1 713 500 6734; Fax: +1 713 500 5495; antifungal drugs, invasive fungal infections con- cerebral involvement, the case fatality rate E-mail: luis.ostrosky- tinue to contribute greatly to the overall morbid- increases to nearly 90% [6]. [email protected] ity and mortality in immunocompromised With the widespread use of azoles in the man- patients [1]. Candida has been associated with a agement and prevention of fungal infections, there wide spectrum of disease, ranging from catheter- has been a shift towards an increase of non-albi- associated infections to disseminated, deep cans Candida species, primarily Candida glabrata, organ disease [2]. While hematological malignan- which has reduced susceptibility to the azoles [7]. cies and solid organ transplants are well estab- In addition, the use of azoles in prophylaxis of lished risk factors for fungal infections, fungal infections in high-risk patients has shifted prolonged stay in the intensive care unit, the the epidemiology towards invasive molds, such as presence of central venous catheters, prolonged Aspergillus. Newer antifungal agents with activity broad spectrum antibiotics, parenteral nutrition, against a broad spectrum of fungi and favorable recent surgery (particularly intra-abdominal sur- safety profiles are needed. Anidulafungin (Eraxis®, gery), diabetes, hemodialysis and pancreatitis Pfizer Inc., NY, USA) is the newest addition to the have also been identified as risk factors for inva- antifungal armamentarium, which has a broad sive candidiasis [3]. Oropharyngeal/esophageal spectrum of activity to include Aspergillus and candidiasis is the most common opportunistic Candida species (including fluconazole-resistant infection in patients with HIV, occurring in one strains) and a favorable safety and drug–drug in five infected patients. In addition, Candida interaction profile. has become the fourth most common cause of nosocomial-bloodstream infections with an Overview of the antifungal market attributable mortality as high as 40% [1,4]. There have been a large number of new antifun- Aspergillus is ubiquitous mold found in the gal drugs that have emerged since fluconazole environment capable of causing invasive fungal was US FDA approved in 1990. Currently, there infections in nearly every organ in the immuno- are four FDA-approved triazole antifungals avail- compromised host. However, the pulmonary able in the USA: fluconazole (Diflucan®, Pfizer system is most commonly affected [5]. The inci- Inc., NY, USA), itraconazole (Sporonox®, Ortho dence of invasive aspergillosis varies by the Biotech, NJ, USA), voriconazole (Vfend®, underlying host factors; however, it can occur in Pfizer, Inc., NY, USA) and posaconazole (Noxa- as many as 25% of patients with acute leukemia fil®, Schering-Plough, NJ, USA). Generally or undergoing lung transplantation [5]. In speaking, fluconazole has the narrowest spec- patients undergoing hematopoetic stem cell trum of activity, followed by itraconazole and Keywords: anidulafungin, transplantation (HSCT), especially those who voriconazole, which increase in spectrum to Aspergillus, Candida, echinocandins develop Graft-versus-host disease, Aspergillus has include Aspergillus, and finally posaconazole, emerged as a problem pathogen. The overall which has the activity of itraconazole and vorico- part of mortality rate of patients with invasive aspergil- nazole with the additional spectrum to include losis is 60%; however, in patients undergoing the Zygomycetes, such as Rhizopus and Mucor.

In addition to the triazoles, polyenes have also Since eukaryotic cells do not have cell walls, the been used to manage invasive fungal infections. direct cellular toxicity seen with the polyenes is The polyenes include amphotericin B and the absent with the echinocandins. In addition, lipid formulations amphotericin B lipid com- organisms that are resistant to the polyenes and plex (ABLC; Abelcet®, Enzon, NJ, USA), azoles may be susceptible to the echinocandins. amphotericin B colloidal dispersion (ABCD; Amphotec®, Three Rivers Pharmaceuticals, PA, Microbiology USA) and liposomal amphotericin B (LAmB; Interpretive breakpoints for anidulafungin have Ambisome®, Astellas Pharma US, Inc., IL, not been established by the Clinical and Labora- USA). The polyenes are the broadest spectrum tory Standard Institute (CLSI). The in vitro fungicidal compounds available in the antifun- activity of the anidulafungin may be related to gal armamentarium; however, any pharmaco- the β-glucan content of the organism [11]. Anid- logical advantage of amphotericin B is ulafungin has potent in vitro activity against overshadowed by the high rates of nephrotoxic- Candida albicans, C. glabrata, Candida tropicallis ity and infusion-related reactions. Although the and Candida krusei as well as Aspergillus fumiga- lipid formulations have a lower rate of nephro- tus. Although anidulafungin maintains potent toxicity than the deoxycholate formulation, the in vitro activity against strains of C. glabrata that lipid formulations still have higher rates of have elevated minimum inhibitory concentra- nephrotoxicity when compared with the azoles tions (MICs) to caspofungin, the clinical signifi- or the echinocandins [8,9]. cance of this finding is unknown [12]. The The echinocandins are the most recent class MIC50 and MIC90 for Candida parapsilosis is 2 of drugs to be added to the antifungal arma- and 4 µg/ml, respectively [13]. The higher MIC’s mentarium. Caspofungin acetate (MK991, with C. parapsilosis is consistent with what is Cancidas®, Merck & Co., Inc, NJ, USA), observed with caspofungin and micafungin, and micafungin sodium (FK463, Mycamine®, the clinical relevance is not known [14,15]. In Astellas Pharma US, Inc., IL, USA) and anidu- addition, anidulafungin does not demonstrate lafungin (LY303366, VER002, Eraxis®, Pfizer in vitro activity against Cryptococcus neoformans, Inc.) are the three currently FDA-approved Fusarium spp., Rhizopus spp. or Mucor spp. [16]. echinocandins available in the USA. All three Anidulafungin demonstrates variable activity agents have similar spectrums of activity and against Blastomyces dermatitidis and Hispt- toxicity profiles; however, they have slightly ospasma capsulatum with MICs of 2–8 and different pharmacokinetic profiles. Anidu- 2–4 µg/ml, respectively [17]. lafungin received FDA approval on February 21, 2006, for the treatment of Pharmacokinetics esophageal candidiasis and candidemia with A summary of the pharmacokinetic properties other forms of Candida infections, including of anidulafungin is presented in Table 1. Anidu- intra-abdominal abscess and peritonitis. lafungin is only available as a parenteral product. Upon intravenous injection, it is rapidly taken Introduction to anidulafungin up into the tissues after administration and then Chemistry slowly eliminated with a half-life of approxi- Anidulafungin is a semisynthetic lipopeptide mately 24 h [18,19]. The overall volume of distri- synthesized from a fermentation byproduct of bution of anidulafungin is between 30 and 50 l, Aspergillus nidulans (Figure 1). Unlike the pol- which is similar to total body fluid volume. yenes and azoles, which exert their antifungal Unlike micafungin and caspofungin, anidulafun- activity on the fungal cell membrane, anidu- gin is not metabolized by the liver. Instead, anid- lafungin acts by inhibiting the formation of ulafungin undergoes slow chemical degradation (1,3)-β-D-glucan, an integral component of the into a chemically inactive peptide whereby the fungal cell wall. The inability of the fungi to cleaved ring products are further broken down cross link (1,3)-β-D-glucan and (1,6)-β-D-glu- into peptidic degradants and eliminated [18]. The can results in loss of structural integrity of the majority of the excreted anidulafungin is through cell wall, resulting in rapid fungicidal activity the feces, with 10% excreted as intact drug and against Candida and fungistatic activity against less than 1% of the dosage eliminated in the Aspergillus [10]. The selective effects on the cell urine. The average dose for anidulafungin is wall rather than the cell membrane of the fungi 50–100 mg/day after a 100–200 mg loading are advantageous to the echinocandin class. dose, depending on the indication. Dosage

126 Therapy (2007) 4(2) futurefuture sciencescience ggrouproup Anidulafungin – DRUG EVALUATION

Figure 1. Anidulafungin.

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adjustments of anidulafungin are not recom- dosage group. Drug exposure correlated more mended in patients with hepatic insufficiency, with body weight than age. Anidulafungin 0.75 renal insufficiency or hemodialysis. and 1.5 mg/kg/day in children provided expo- The pharmacokinetics of anidulafungin have sures that were achieved with 50 and 100 mg/day been evaluated in children with neutropenia [20]. in adults with invasive fungal disease [17]. Patients aged 2–17 years were divided into two cohorts of patients (2–11 and 11–17 years) and Animal studies received anidulafungin 0.75 or 1.5 mg/kg/day for Anidulafungin has shown excellent in vivo activ- at least 5 days. Anidulafungin pharmacokinetics ity in a variety of animal models. Two recent were similar between the two cohorts within each studies on models of C. glabrata and Aspergillus fumigatus are discussed below as exam- Table 1. Pharmacokinetic parameters of anidulafungin in ples of the activity seen. The efficacies of flucona- healthy adults. zole, amphotericin B and anidulafungin were evaluated in a neutropenic murine model of dis- Parameter Value seminated candidiasis with three different strains * Cmax,ss (mg/l) 8.6 of C. glabrata [21]. Mice were inoculated via the * * AUCss (mg h/l) 112 lateral tail vein and sacrificed over a 96-h period Vd (l) 30–50 where the kidneys were harvested for determina- tion of fungal burden and drug concentrations. Protein binding 85–90% While amphotericin B produced a 4.12 log Hepatic metabolism None. Chemically degraded with 30% reduction at 24 h for the strain with an eliminated in the feces amphotericin B MIC of 0.25 µg/ml, there was no Renal excretion <1% effect on the strain that had an MIC of 2 µg/ml. Half-life (h) 24 Fluconazole produced a 1.33 log reduction for Clearance (l/h) 0.8–1.0 the fluconazole-susceptible strain, however, it did *200 mg loading dose, followed by 100 mg/day for 10 days. not have an effect on the susceptible dose-

AUCss: Steady state area under the plasma concentration curve; Cmax,ss: Steady state dependent nor -resistant strain. Anidulafungin maximum concentration in plasma; Vd: Volume of distribution. produced a 1.38–1.87 log reduction in kidney

futurefuture sciencescience groupgroup www.futuremedicine.com 127 DRUG EVALUATION – Mohr & Ostrosky-Zeichner

fungal burden and this effect was not dependent Candidemia on fluconazole or amphotericin B activity. In In an open-label evaluation of anidulafungin addition, there was a persistent fungal decline at predominantly in patients with candidemia (6% 96 h after a single dose of anidulafungin in this of patients had invasive candidiasis without evi- model, demonstrating excellent in vitro activity dence of candidemia), there was an 84, 90 and against C. glabrata. 89% overall clinical success rate at the end of Anidulafungin and amphotericin B were treatment with 50, 75 and 100 mg/day, respec- evaluated against amphotericin B-susceptible tively [24]. In a pivotal, Phase III, randomized and -resistant strains of Aspergillus fumigatus in (1:1), double-blind study of candidemia and a neutropenic murine model of invasive invasive candidiasis, anidulafungin 200 mg aspergillosis [22]. Mice were inoculated via the loading dose, followed by 100 mg/day was com- lateral tail vein and monitored for survival over pared with fluconazole 800 mg loading dose, 11 days. At day 11, surviving mice were sacri- followed by 400 mg/day for 14 days from the ficed, and their lungs and kidney’s were last positive blood culture [18,25]. This study was removed, homogenized and plated for colony conducted at over 60 centers in the USA, Can- counts. Anidulafungin produced a survival ben- ada and Europe. Patients in both study arms efit and a greater reduction in tissue colony were permitted to step down to oral fluconazole counts compared with amphotericin B. This after they received 10 days of intravenous ther- effect was dose dependent and was greater with apy, if clinically indicated. Patients included in the amphotericin-susceptible strain. Nonethe- this study were largely non-neutropenic (97%), less, anidulafungin was shown to be effective with 80% of the patients having Acute Physiol- against Aspergillus fumigatus in a murine model ogy and Chronic Health (APACHE II) scores of invasive aspergillosis and this warrants future less than 20 and the most common pathogen human clinical trials. isolated at baseline was Candida albicans. At the end of intravenous therapy, there was a 75.6% Clinical efficacy overall clinical response with anidulafungin Esophageal candidiasis compared with a 60.2% response with flucona- Anidulafungin 100 mg loading dose followed by zole. (Difference = 15.4%; 95% CI: 3.9–27.0; 50 mg/day has been compared with fluconazole p = 0.01) (Figure 2). This improved difference in 200 mg loading dose, followed by 100 mg/day efficacy with anidulafungin was maintained at maintenance dose in a randomized, double-blind 2 weeks after the end of treatment. The overall clinical trial in 601, predominantly HIV-posi- mortality at 6 weeks after the end of treatment tive, patients with esophageal candidiasis [23]. was higher in the fluconazole-treated patients Endoscopic resolution of lesions after compared with anidulafungin (33 vs 23%), 14–21 days of treatment was determined and however, this was not statistically significant. was graded as either cured (complete resolution of lesions) or improved. In addition, clinical Drug interactions response, defined as an absence or improvement Since anidulafungin is not a substrate for, in symptoms compared with baseline, was deter- inhibitor of, or inducer of the mined. Endoscopic cure or improvement at the cytochrome P450 isoenzyme system, it would end of treatment was present in 97.2 and 98.8% not be expected to interact with drugs metabo- of anidulafungin- and fluconazole-treated lized by these systems. In a study of 12 healthy patients, respectively, and clinical response adults receiving anidulafungin 100 mg/day for occurred in 98.8 and 99.6% of anidulafungin- 8 days after an initial loading dose of and fluconazole-treated patients, respectively. 200 mg, coadministration with cyclosporine However, at the 2-week follow-up, only 64.4% 1.25 mg/kg twice daily did not result in a of the anidulafungin-treated patients had a sus- change in Cmax of anidulafungin or tained endoscopic success compared with 89.5% cyclosporine [26]. The AUC0–24 of anidulafun- of fluconazole-treated patients (p < 0.001). gin was increased by 22%, which was consid- However, patients’ immune status was not con- ered clinically insignificant and the overall trolled for and more patients in the fluconazole exposure of cyclosporine was not affected. In a group received antiretroviral drugs for their HIV study of 17 healthy adults receiving concomi- compared with the anidulafungin group, poten- tant anidulafungin and voriconazole, the Cmax tially explaining the lack of sustained response and AUC of both anidulafungin and voricona- with anidulafungin. zole were not significantly altered with the

128 Therapy (2007) 4(2) futurefuture sciencescience ggrouproup Anidulafungin – DRUG EVALUATION

Figure 2. Anidulafungin versus fluconazole for the treatment of candidemia in the modified intent-to-treat population.

80 76 74

65 60 60 57 56 49 44 40

20 Patients with successful response (%) Patients

0 End of i.v. therapy End of all therapy* 2-week follow-up 6-week follow-up

Anidulafungin (n = 127) Fluconazole (n = 118)

*33 patients in each arm converted to oral fluconazole after at least 10 days of intravenous (i.v.) treatment. End of i.v. therapy: treatment difference: 15.4; 95% CI: 3.9–27.0. End of all therapy: treatment difference: 17.2; 95% CI: 2.9–31.6. 2-week follow-up: treatment difference: 15.4; 95% CI: 0.4–30.4. 6-week follow-up: treatment difference: 11.8; 95% CI: -3.4–27.0.

co-administration [27]. In three additional phar- compared with 50 out of 301 (16.6%) of macokinetic drug-interaction studies, anidu- patients receiving fluconazole 100 mg/day [23]. lafungin was coadministered with tacrolimus, The most common adverse events with anidu- LAmB and rifampin [19]. The coadministration lafungin were increases in γ-glutamyl transferase of anidulafungin with each of these compounds (1.3%), headache (1.3%), nausea (1%) and also did not demonstrate any changes of Cmax neutropenia (1%). However, these incidents or AUC. Overall, the very favorable drug inter- were similar in patients receiving fluconazole. action and pharmacokinetic profile of anidu- The number of subjects experiencing at least lafungin make it an attractive agent for the one adverse event in a Phase III clinical trial of treatment of invasive fungal infections, espe- anidulafungin 100 mg/day compared with flu- cially in the complex patient receiving concom- conazole 400 mg/day for the treatment of can- itant cytochrome P450 inhibitors, inducers didemia was 32 out of 131 (24.4%) and 33 out and/or substrates. of 125 (26.4%), respectively [18]. The most fre- quent adverse events were diarrhea (4/131; Safety & tolerability 3.1%), hypokalemia (4/131; 3.1%) and The most common adverse events with anidu- increased alanine aminotransferase (ALT; lafungin compared with fluconazole in the 3/131; 2.3%), which were no different than esophageal candidiasis and candidemia clinical those seen with the comparator. There have trials are summarized in Table 2. In a Phase III been several reports of infusion-related toxici- clinical trial of anidulafungin compared with ties, including hypotension and flushing, with fluconazole for the treatment of esophageal can- anidulafungin [24]. However, the overall inci- didiasis, 43 out of 300 (14.3%) of the patients dence of infusion-related reactions can be mini- receiving anidulafungin 50 mg/day experienced mized by infusing anidulafungin at a rate not at least one treatment-emergent adverse event exceeding 1.1 mg/min [18]. futurefuture sciencescience groupgroup www.futuremedicine.com 129 DRUG EVALUATION – Mohr & Ostrosky-Zeichner

Table 2. Possible or probable treatment-emergent adverse events in patients receiving anidulafungin or fluconazole for the treatment of candidemia or esophageal candidiasis. Adverse event Anidulafungin Fluconazole Anidulafungin Fluconazole 100 mg/day 400 mg/day 50 mg/day 100 mg/day (n = 131) [18] (n = 125) [18] (n = 300) [23] (n = 301) [23] Increased ALT 2.3% 3.2% - 1% Increased AST 0.8% 2.4% 0.3% 2.3% Neutropenia 1% Hypokalemia 3.1% 2.4% Diarrhea 3.1% 1.6% Nausea 1% 1% Headache 1.3% 1% Vomiting 0.7% 1% Deep-vein 0.8% 2.4% thrombosis Phlebitis/ 1.3% 1.3% thrombophlebitis ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Expert commentary However, further clinical trials are required to The development of new antifungal drugs pro- confirm this finding, as this was a single nonin- vides some light at the end of the tunnel since the feriority trial and it was not designed to show overall outcomes of patients with invasive fungal superiority in its primary analysis. Of note is the infections has historically been quite poor. This fact that these data cannot be extrapolated to may be related to the type of hosts that develop patients who are neutropenic, as less than 4% of invasive fungal infections or related to suboptimal patients in the trial had an absolute neutrophil pharmacological treatments available to date. count (ANC) less than 500 cells/mm3. However, a critical evaluation of the evidence Other clinical trials comparing echinocandins must be undertaken before complete integration with polyenes demonstrated noninferiority with into the clinical arena. regards to clinical outcomes; however, the poly- As a class, the echinocandins have demon- ene-treated patients (both amphotericin B deox- strated utility in the management of invasive ycholate and LAmB) had a higher rate of fungal infections, primarily candidiasis and nephrotoxicity [9,14]. aspergillosis. Despite in vitro activity against A conservative conclusion, with respect to Aspergillus spp. and animal models of dissemi- invasive candidiasis, is that the echinocandins nated aspergillosis, human trials with anidu- provide the activity of the polyenes with the lafungin for aspergillosis are lacking and safety of the azoles. Currently, there is insufficient therefore, it cannot be recommended as a treat- data to date to support the position that one echi- ment option for patients at this time. However, nocandin is superior to another for the treatment investigations with anidulafungin alone and in of invasive candidiasis [28]. Anidulafungin offers a combination with other drugs for invasive safe and effective option with minimal to no aspergillosis are currently being conducted [101]. concerns of drug–drug interactions. Anidulafungin has demonstrated efficacy in the treatment of esophageal candidiasis at the Future perspective end of therapy. However, patients treated with A recent analysis of the treatment of invasive can- anidulafungin had a higher relapse rate than didiasis demonstrates the importance of avoid- those treated with fluconazole [23]. The reason ing delays in therapy and that early initiation of and clinical significance of these relapse rates are therapy is associated with improved patient unknown and may be more related to the host outcomes [29]. While this concept has not been immune function that to the drug. demonstrated with invasive aspergillosis, intui- Anidulafungin has demonstrated numerical tively, it should hold true and investigations are superiority over fluconazole for the treatment of needed to confirm this presumption. Nonethe- candidemia and invasive candidiasis [18,25]. less, the approach of early treatment stresses the

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importance of empiric or pre-emptive antifun- of a combination regimen with either a polyene gal therapy. Empiric antifungal therapy is given or an anti-aspergillus azole antifungal, will to patients who are at risk for invasive fungal likely be a popular combination for the treat- infections and have signs and symptoms of ment of invasive aspergillosis due to the differ- infection, despite treatment with appropriate ent mechanisms of action. In fact, in vitro antibiotics [30]. Pre-emptive therapy is similar studies demonstrate voriconazole or itracona- to antifungal prophylaxis; however, the patient zole in combination with anidulafungin are is at high risk, is not demonstrating any signs synergistic against Aspergillus [32]. or symptoms of disease, and has a positive sur- While we can foresee the importance of early veillance culture or has a positive test for a fun- diagnosis for candidiasis and aspergillosis and the gal antigen [31]. Fungal antigen tests role of combination therapy for invasive aspergil- (galactomannan and β-D-glucan) are performed losis, we should not be without concern. There on serum to provide additional evidence of an will need to be continued evaluation of newer invasive fungal infection, either candidiasis or antifungal agents with novel targets in addition to aspergillosis. These antigen tests have the continued searches for other fungal antigens, potential to provide an early and rapid diagno- including polymerase chain reaction. This sis, followed by early initiation of antifungal approach, in conjunction with rational antifungal therapy, which is likely to be the key to reducing use, including anidulafungin, will provide the the overall mortality associated with invasive tools to optimize the overall management of fungal infections. patients with invasive fungal infections. The echinocandins, including anidulafungin, will probably be at the forefront of these Disclosure approaches and there will undoubtedly con- Pertinent to this article, the authors have served as advisors tinue to be an emergence of azole-resistant and speakers for, and have received research grants from, Candida. In addition, echinocandins, as a part Pfizer, Inc.

Executive summary

• Anidulafungin is a new parenteral echinocandin antifungal drug.

• Anidulafungin demonstrates in vitro activity against strains of Candida spp., including strains that are resistant to fluconazole.

• In patients with candidemia, anidulafungin was associated with a significantly higher overall success rate compared with patients treated with fluconazole.

• The pharmacokinetic profile supports single daily dosing, without dose adjustments for geriatric age, race, concomitant administration of medications that are known inhibitors/inducers/substrates of the cytochrome P450 isoenzyme system or liver and/or renal insufficiency.

• The most common adverse events associated with anidulafungin are related to the gastrointestinal system.

Bibliography intensive care unit: approach to developing 7. Pappas PG, Rex JH, Lee J et al.: A Papers of special note have been highlighted as of practical criteria for systematic use in prospective observational study of interest (•) or of considerable interest (••) to antifungal prophylaxis trials. Med. Mycol. candidemia: epidemiology, therapy, and readers. 43, 235–243 (2005). influences on mortality in hospitalized adult 1. Falagas ME, Apostolou KE, Pappas VD: 4. Edmond MB, Wallace SE, McClish DK, and pediatric patients. Clin. Infect. Dis. 37, Attributable mortality of candidemia: a Pfaller MA, Jones RN, Wenzel RP: 634–643 (2003). systematic review of matched cohort and Nosocomial bloodstream infections in 8. Walsh TJ, Petraitis V, Petraitiene R et al.: case-control studies. Eur. J. Clin. Microbiol. United States hospitals: a three-year Experimental pulmonary aspergillosis due to Infect. Dis. 25, 419–425 (2006). analysis. Clin. Infect. Dis. 29, 239–244 Aspergillus terreus: pathogenesis and 2. Rex JH, Walsh TJ, Anaissie EJ: Fungal (1999). treatment of an emerging fungal pathogen infections in iatrogenically compromised 5. Denning DW: Invasive aspergillosis. Clin. resistant to amphotericin B. J. Infect. Dis. hosts. Adv. Intern. Med. 43, 321–371 Infect. Dis. 26, 781–803 (1998). 188, 305–319 (2003). (1998). 6. Lin SJ, Schranz J, Teutsch SM: Aspergillosis 9. Ruhnke M, Kuse E, Chetchotisakd P, 3. Paphitou NI, Ostrosky-Zeichner L, Rex JH: case-fatality rate: systematic review of the Buell D: Comparison of micafungin and Rules for identifying patients at increased literature. Clin. Infect. Dis. 32, 358–366 liposomal amphotericin B for invasive risk for candidal infections in the surgical (2001). candidiasis. Presented at: 45th Interscience

futurefuture sciencescience groupgroup www.futuremedicine.com 131 DRUG EVALUATION – Mohr & Ostrosky-Zeichner

Conference on Antimicrobial Agents and 17. Espinel-Ingroff A: Comparison of in vitro 26. Dowell JA, Stogniew M, Krause D, Chemotherapy, Washington, DC, USA. activities of the new triazole SCH56592 Henkel T, Weston IE: Assessment of the December 16–19, 2005 (Abstract M- and the echinocandins MK-0991 safety and pharmacokinetics of 722C). (L-743,872) and LY303366 against anidulafungin when administered with 10. Denning DW: Echinocandins: a new class opportunistic filamentous and dimorphic cyclosporine. J. Clin. Pharmacol. 45, of antifungal. J. Antimicrob. Chemother. 49, fungi and yeasts. J. Clin. Microbiol. 36, 227–233 (2005). 889–891 (2002). 2950–2956 (1998). 27. Dowell JA, Schranz J, Baruch A, Foster G: 11. Odabasi Z, Paetznick VL, Rodriguez JR, 18. Eraxis®, prescribing information. Pfizer, Safety and pharmacokinetics of Chen E, McGinnis MR, Inc., NY, USA (2006). coadministered voriconazole and Ostrosky-Zeichner L: Differences in β- 19. Dowell JA, Knebel W, Ludden T, anidulafungin. J. Clin. Pharmacol. 45, glucan levels in culture supernatants of a Stogniew M, Krause D, Henkel T: 1373–1382 (2005). variety of fungi. Med. Mycol. 44, 267–272 Population pharmacokinetic analysis of 28. Betts R, Rotstein C, D Talwar et al.: (2006). anidulafungin, an echinocandin antifungal. Comparison of micafungin and 12. Cota J, Carden M, Graybill JR, Najvar LK, J. Clin. Pharmacol. 44, 590–598 (2004). caspofungin for candidemia or invasive Burgess DS, Wiederhold NP: In vitro 20. Benjamin DK Jr, Driscoll T, Seibel NL candidiasis. Presented at: 46th Interscience pharmacodynamics of anidulafungin and et al.: Safety and pharmacokinetics of Conference on Antimicrobial Agents and caspofungin against candida glabrata intravenous anidulafungin in children Chemotherapy. CA, USA, September isolates, including strains with decreased with neutropenia at high risk for invasive 27–30, 2006 (Abstract M-1308a). caspofungin susceptibility. Antimicrob. fungal infections. Antimicrob. Agents 29. Garey KW, Rege M, Pai MP et al.: Time to Agents Chemother. 50, 3926–3928 (2006). Chemother. 50, 632–638 (2006). initiation of fluconazole therapy impacts 13. Ostrosky-Zeichner L, Rex JH, Pappas PG 21. Gumbo T, Drusano GL, Liu W et al.: mortality in patients with candidemia: a et al.: Antifungal susceptibility survey of Anidulafungin pharmacokinetics and multi-institutional study. Clin. Infect. Dis. 2,000 bloodstream Candida isolates in the microbial response in neutropenic mice 43, 25–31 (2006). United States. Antimicrob. Agents with disseminated candidiasis. Antimicrob. •• Retrospective cohort study that Chemother. 47, 3149–3154 (2003). Agents Chemother. 50, 3695–3700 (2006). demonstrated the importance of early • Large, multicenter susceptibility testing 22. Verweij PE, Oakley KL, Morrissey J, initiation of fluconazole in patients with survey that evaluated minimum Morrissey G, Denning DW: Efficacy of candidemia. While C. albicans was the inhibitory concentrations for multiple LY303366 against amphotericin most common species identified in this Candida species, including rarer species B-susceptible and -resistant Aspergillus study, the utility of fluconazole may isolated from patients bloodstream fumigatus in a murine model of invasive become limited due to increasing against amphotericin B, flucytosine, aspergillosis. Antimicrob. Agents fluconazole resistance. The authors fluconazole, itraconazole, voriconazole, Chemother. 42, 873–878 (1998). highlight the importance of avoiding posaconazole, caspofungin, micafungin 23. Krause DS, Simjee AE, van Rensburg C delays in antifungal therapy. and anidulafungin by broth et al.: A randomized, double-blind trial of 30. Pappas PG, Rex JH: Therapeutic approach microdilution. anidulafungin versus fluconazole for the to candida sepsis. Curr. Infect. Dis. Rep. 1, 14. Mora-Duarte J, Betts R, Rotstein C et al.: treatment of esophageal candidiasis. Clin. 245–252 (1999). Comparison of caspofungin and Infect. Dis. 39, 770–775 (2004). 31. Maertens J, Deeren D, Dierickx D, amphotericin B for invasive candidiasis. 24. Krause DS, Reinhardt J, Vazquez JA et al.: Theunissen K: Preemptive antifungal N. Engl. J. Med. 347, 2020–2029 (2002). Phase II, randomized, dose-ranging study therapy: still a way to go. Curr. Opin. 15. Colombo AL, Perfect J, DiNubile M et al.: evaluating the safety and efficacy of Infect. Dis. 19, 551–556 (2006). Global distribution and outcomes for anidulafungin in invasive candidiasis and 32. Philip A, Odabasi Z, Rodriguez J et al.: Candida species causing invasive candidiasis: candidemia. Antimicrob. Agents In vitro synergy testing of anidulafungin results from an international randomized Chemother. 48, 2021–2024 (2004). with itraconazole, voriconazole, and double-blind study of caspofungin versus 25. Reboli A, Rotstein C, P Pappas, Schranz J, amphotericin B against Aspergillus spp. amphotericin B for the treatment of invasive Krause D, Walsh T: Anidulafungin vs. and Fusarium spp. Antimicrob. Agents candidiasis. Eur. J. Clin. Microbiol. Infect. Dis. fluconazole for treatment of candidemia and Chemother. 49, 3572–3574 (2005). 22, 470–474 (2003). invasive candidiasis. Presented at: 45th 16. Espinel-Ingroff A: In vitro antifungal Interscience Conference on Antimicrobial Agents Website activities of anidulafungin and micafungin, and Chemotherapy, Washington, DC, USA. 101. Clinical trials licensed agents and the investigational December 16–19, 2005 (Abstract M-718). www.clinicaltrials.gov/ct/search;jsessionid=0 triazole posaconazole as determined by •• Pivotal Phase III clinical trial comparing 09996FA8165B04A3B8D2198B3D2BB2E NCCLS methods for 12,052 fungal anidulafungin with fluconazole for the ?term=anidulafungin isolates: review of the literature. Rev. treatment of candidemia and invasive Iberoam. Micol. 20, 121–136 (2003). candidiasis.

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