Expanding the Echinocandin Class: Eraxis® (Anidulafungin)
Abstract & Commentary
By Rick Ngo, PharmD Candidate, Jarrod Mills, PharmD Candidate, Paul Hsiao, PharmD, and Jessica C. Song, MA, PharmD
Rick Ngo and Jarrod Mills are PharmD Candidates at the University of the Pacific, Paul Hsiao is a PharmD Candidate and Clinical Pharmacist Specialist at Santa Clara Valley Medical Center, and Jessica C. Song is Pharmacy Residency Coordinator at Santa Clara Valley Medical Center, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA. Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.
Rick Ngo, Jarrod Mills, Paul Hsiao, and Jessica C. Song report no relevant financial relationship related to this field of study.
Introduction
Fungal infections are becoming more prevalent, as Candida spp. represent the fourth most common organism recovered from blood of hospitalized patients in the United States.1 This phenomenon can, in part, be attributed to the AIDS epidemic and to the growing number of immunocompromised patients as a result of cancer chemotherapy and organ transplants. Fungemia has been reported to be as many as 12% of HIV-infected patients who have chronic indwelling central venous catheters.1,2 Esophageal candidiasis often represents a sentinel event indicating the presence or progression of AIDS, as an estimated 12-16% of children under the age of 13 receive a primary diagnosis of AIDS by the presence of this condition.1,3 Candida-associated infections induce significant morbidity and mortality, as shown by mortality rates as high as 47-48% for nosocomial candidemia and peritonitis.4,5
Current Infectious Disease Society of America (IDSA)6 guidelines for the treatment of candidiasis recommend the utilization of intravenous (IV) amphotericin B, IV or oral fluconazole, IV caspofungin, or a combination of amphotericin B and fluconazole in non-neutropenic patients diagnosed with candidemia.6 Primary treatment options for patients suffering from mucocutaneous candidiasis include fluconazole, clotrimazole, and nystatin, while alternative agents include itraconazole, amphotericin B, caspofungin, and voriconazole. The prevalence of fluconazole resistance and the multitude of interactions amongst the other commonly used antifungals, including caspofungin, suggest a potential need for alternative agents possessing more desirable safety and efficacy profiles.
The echinocandin antifungals represent the newest class of agents to be used in the treatment of candidal infections. In addition to caspofungin (CancidasTM), there are 2 other echinocandins available in the United States: micafungin (MycamineTM) and anidulafungin (EraxisTM). These agents are generally fungicidal against candida, inhibiting the synthesis of b-(1,3)-D-glucan, an essential polysaccharide that is critical to fungal cell wall integrity. This leads to osmotic instability and, ultimately, cell lysis in susceptible fungi.7 Relative to the development of resistance, the fungicidal activity of echinocandins represents a significant advantage over other static antifungal agents.
Anidulafungin is a semi-synthetic antifungal of the echinocandin class derived from a fermentation product of the fungus Aspergillus nidulans.8 FDA (Food and Drug Administration) approval was granted on February 17, 2006, for candidal infections including candidemia, esophageal candidiasis, intra-abdominal abscesses, and peritonitis. This article will provide a review anidulafungin’s: 1) spectrum of activity, pharmacological and pharmacokinetic properties, 2) safety and efficacy profile, 3) dosage, interaction, and resistance patterns, 4) clinical efficacy, and 5) comparative efficacy relative to other available echinocandins.
Spectrum of Activity
An in vitro study by Ostrosky and colleagues9 showed susceptibility of several Candida spp. to the echinocandins. The minimum inhibitory concentrations (MICs) of anidulafungin, caspofungin, and micafungin are shown in Table 1.
Anidulafungin also showed good activity against fluconazole-resistant Candida strains (fluconazole MIC > 16 µg/mL) in a study by Cuenca-Estrella and colleagues, with MIC90s for C. glabrata (42 isolates), C. krusei (28 isolates), and C. tropicalis (15 isolates) at 0.12, 0.03, and 0.06 µg/mL, respectively.10 In addition, anidulafungin exhibited postantifungal effects to various Candida spp. above and below the MICs for the specific organisms.11 Of note, a case report by Laverdiere and colleagues revealed resistance acquired via an FKS1 gene mutation in C. albicans isolates from an HIV patient being treated for chronic esophagitis with micafungin. The C. albicans isolates from this patient showed cross resistance to other echinocandins (caspofungin, anidulafungin).12
Aside from expressing activity against Candida organisms, anidulafungin also has in vitro inhibitory activity against Aspergillus spp. (flavus, fumigatus, terreus, & niger), with MIC90s of b 0.06 µg/mL.8 A small study (n = 26) noted in vitro antagonism between anidulafungin and amphotericin B in the presence of A. flavus and A. terreus. Similar antagonism was noted with itraconazole in the presence of A. niger.13
The activity of micafungin against Aspergillus spp. (flavus, fumigatus, terreus, & niger) was very similar in a review by Carver and colleagues, with MIC90s ranging from 0.0078 to 0.25 µg/mL.14 Caspofungin has well-documented activity against Aspergillus spp., as it is licensed for use as salvage therapy for invasive aspergillosis.15
Pharmacological Properties
A summary of the pharmacologic, pharmacokinetic, and clinical properties of anidulafungin can be found in Table 2.7,16 Since anidulafungin is not a substrate or an inhibitor/inducer of most cytochrome p450 (CYP) isoenzymes (1A2, 2C9, 2D6, 3A4), it is unlikely to interact with other drugs.7 Similarly, micafungin has not been shown to interact with other drugs, with the exception of sirolimus and nifedipine.17 The combination of either of these drugs with micafungin resulted in minor increases in the AUC (area under the concentration-time curve) of sirolimus and nifedipine. Interestingly, simultaneous administration of carbamazepine, dexamethasone, efavirenz, nevirapine, phenytoin, or rifampin will result in decreased caspofungin serum concentrations. Consequently, patients who require caspofungin along with any of these medications should receive a higher maintenance dose of caspofungin (70 mg/d). In addition, since there is concern of enhanced hepatotoxicity with concomitant administration of caspofungin with cyclosporine, the prescribing information for caspofungin includes a warning against using this combination.15
Clinical Efficacy
Two pivotal, multicenter, randomized, double-blind, non-inferiority phase III clinical trials have assessed the utility of anidulafungin in patients with candidemia and esophageal candidiasis (see Table 3).18,19
Studies assessing the effectiveness of anidulafungin and IV fluconazole in candidemia patients (n = 256) suggest that anidulafungin is superior to fluconazole with respect to clinical cure rates (+15.4% at 2 weeks; 95% CI, 0.4%, 30.4%, no P value reported). Primary end points were assessed based on the absence of systemic infection. Patients in both arms were converted to oral fluconazole following a minimum 10 days IV therapy. Prior to oral conversion, patients were required to remain afebrile for least 24 hours. In vitro studies suggest the possibility of a marginal synergistic relationship between azoles and echinocandins, which may have attributed to the increased clinical success of patients receiving initial anidulafungin therapy prior to switching to oral fluconazole.19
Krause and colleagues compared anidulafungin to oral fluconazole in the treatment of 601 esophageal candidiasis patients with predisposing conditions. Primary end points of clinical response were assessed endoscopically at the end of therapy and at a 2 week follow-up visit. Initial success was similar in anidulafungin and fluconazole arms (97.2% vs 98.8%, respectively); however, fluconazole proved superior at the 2 week follow-up visit (95%; CI, - 32.5%, -17.8%, P < 0.001). Between 446 and 465 patients were diagnosed with active HIV, and the discrepancy in follow-up success may be attributable to the greater number of HIV patients receiving antiretroviral therapy in the fluconazole arm.18
Comparison of Echinocandins
All 3 echinocandins are indicated for use in esophageal candidiasis, while only anidulafungin and caspofungin have received approval for candidemia. Multiple blinded and randomized studies have shown micafungin and caspofungin to be as effective as fluconazole in the treatment of esophageal candidiasis.20,21 At present, there is evidence to indicate that one echinocandin is superior to another with respect to clinical outcomes. However, comparative studies of echinocandins for the treatment of esophageal candidiasis and candidemia have not been published, therefore making it difficult to compare the relative efficacies of caspofungin, micafungin, and anidulafungin. Caspofungin has been compared to amphotericin B in candidemia patients, and was shown to be non-inferior relative to resolution of clinical disease.22 As previously reported, anidulafungin’s effectiveness in the treatment of candidemia was assessed relative to fluconazole, and was shown to be superior from the end of treatment until 2 weeks post-treatment.19 According to current IDSA guidelines, both comparator agents and caspofungin represent first line therapy for non-neutropenic adults suffering from candidemia (IDSA guidelines). One difference between the candidemia trials was the exclusion of Candida krusei in the anidulafungin studies, although this is an infrequently isolated species. Conversely, caspofungin has reported in vitro activity against C. krusei, and C. krusei isolates were not excluded in the comparative trials that used amphotericin B as the comparator drug. Moreover, in one key clinical trial, no failures were noted in caspofungin-treated patients with C. krusei candidemia.22
Future Directions
A multicenter, open-label, dosage-escalation study of neutropenic pediatric patients (n = 24) assessed the safety and pharmacokinetic profile of anidulafungin as empiric treatment to prevent invasive fungal infections in immunocompromised, hospitalized children.23 Patients were first separated into 2 age groups (2 to 11 years and 12 to 17 years). Groups were further stratified into low- and high-dose arms, with each patient receiving a loading dose of 1.5 or 3.0 mg/kg and a maintenance dose of 0.75 or 1.5 mg/kg/day (low- and high-dose groups, respectively).
Drug plasma levels were determined after the loading (first) and maintenance (fifth) dose, showing similar pharmacokinetics in both cohorts. Steady state was achieved after giving a loading dose, and the half-life was determined to be approximately 20 hours in these children. Anidulafungin was well tolerated, although flushing and dyspnea related to infusion were reported in one patient in the high-dose arm. Symptoms were reversed by stopping the infusion and administering diphenhydramine. This study may suggest that anidulafungin can successfully prevent breakthrough fungal infections in neutropenic pediatric patients. However, the limited size of the patient population and brief duration of therapy (mean duration, 8.7 days) require that further research be conducted prior to recommending anidulafungin for neutropenic children patients.23
Conclusion/Summary
Anidulafungin represents the newest echinocandin antifungal for use in candidemia, esophageal candidiasis, and intra-abdominal infections due to Candida spp. (including peritonitis and intra-abdominal abscesses). Future investigations should focus on anidulafungin’s utility in aspergillosis, and effectiveness in immunocompromised pediatric patients should be further explored with larger patient populations. The scope of anidulafungin’s approved indications are limited relative to caspofungin, which is approved for use as empiric therapy for presumed fungal infections in febrile, neutropenic patients, candidemia, intra-abdominal abscesses, peritonitis, and pleural space infections due to Candida spp., esophageal candidiasis, and refractory invasive aspergillosis. Indications also differ from micafungin, which include treatment of esophageal candidiasis, and prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation.
Anidulafungin possesses a favorable safety and drug-drug interaction profile, offering an advantage over caspofungin in select patients, yet is similar to that of micafungin.
Dosing of anidulafungin is dependent upon the type of Candida infection being treated. Patients suffering from candidemia, intra-abdominal abscesses, or peritonitis should receive a loading dose of 200 mg, with subsequent 100 mg doses for the duration of therapy, while patients being treated for esophageal candidiasis should receive a 100 mg loading dose, with 50 mg daily doses thereafter. Consideration should be given when using anidulafungin concomitantly with other antifungals (ie, azoles, amphotericin B), as both synergistic and antagonistic relationships have been documented.
Use and formulary considerations for anidulafungin may be limited due to its narrow scope of indications, and though estimated acquisition and administration costs have yet to be released, pricing comparisons amongst the currently available echinocandins must be assessed in order to determine anidulafungin’s place in cost effective therapy.
References
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- Krause DS, et al. Phase 2, Randomized, Dose-Ranging Study Evaluating the Safety and Efficacy of Anidulafungin in Invasive Candidiasis and Candidemia. Antimicrob Agents Chemother. 2004;48:2021-2024.
- Benjamin DK Jr, et al. Safety and Pharmacokinetics of Intravenous Anidulafungin in Children with Neutropenia at High Risk for Invasive Fungal Infections. Antimicrob Agents Chemother. 2006;50:632-638.
- Gudlaugsson O, et al. Attributable Mortality of Nosocomial Candidemia, Revisited. Clin Infect Dis. 2003;37:1172-1177.
- Montravers P, et al. Candida As a Risk Factor for Mortality in Peritonitis. Crit Care Med. 2006;34:646-652.
- Pappas PG, et al. Guidelines for Treatment of Candidiasis. Clin Infect Dis. 2004;38:161-189.
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- Ostrosky-Zeichner L, et al. Antifungal Susceptibility Survey of 2000 Bloodstream Candida Isolates in the United States. Antimicrob Agents Chemother. 2003;47:3149-3154.
- Cuenca-Estrella M, et al. Susceptibility of Fluconazole-Resistant Clinical Isolates of Candida spp. to Echinocandin LY303366, Itraconazole and Amphotericin B. J Antimicrob Chemother. 2000;46:475-477.
- Ernst EJ, et al. Postantifungal Effects of Echinocandin, Azole, and Polyene Antifungal Agents Against Candida albicans and Cryptococcus neoformans. Antimicrob Agents Chemother. 2000;44:1108-1111.
- Laverdiere M, et al. Progressive Loss of Echinocandin Activity Following Prolonged Use for Treatment of Candida albicans Oesophagitis. J Antimicrob Chemother. 2006. [Epub ahead of print]
- Philip A, et al. In Vitro Synergy Testing of Anidulafungin with Itraconazole, Voriconazole, and Amphotericin B Against Aspergillus spp. and Fusarium spp. Antimicrob Agents Chemother. 2005;49:3572-3574.
- Carver PL. Micafungin. Ann Pharmacother. 2004;38:1707-1721.
- Caspofungin (CancidasTM) Prescribing Information. Whitehouse Station, NJ; 2005 February.
- Pfaller MA, et al. Effectiveness of Anidulafungin in Eradicating Candida Species in Invasive Candidiasis. Antimicrob Agents Chemother. 2005;49:4795-4797.
- Micafungin (Mycamine) Prescribing Information. Deerfield, Il: Astellas Pharma US. 2005 April.
- Krause DS, et al. A Randomized, Double-Blind Trial of Anidulafungin Versus Fluconazole for the Treatment of Esophageal Candidiasis. Clin Infect Dis. 2004;39:770-775.
- Data on File (Personal Communication, Dr. Andrews, Pfizer Pharmaceuticals).
- Villanueva A, et al. A Randomized Double-Blind Study of Caspofungin Versus Fluconazole for the Treatment of Esophageal Candidiasis. Am J Med. 2002;113:294-299.
- de Wet N, et al. A Randomized, Double-Blind, Parallel-Group, Dose-Response Study of Micafungin Compared with Fluconazole for the Treatment of Esophageal Candidiasis in HIV-Positive Patients. Clin Infect Dis. 2004;39:842-849.
- Mora-Duarte J, et al. Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis. N Engl J Med. 2002;347:2020-2029.
- Benjamin DK Jr, et al. Safety and Pharmacokinetics of Intravenous Anidulafungin in Children with Neutropenia at High Risk for Invasive Fungal Infections. Antimicrob Agents Chemother. 2006;50:632-638.
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