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In This Article
 »  Abstract
 »  Introduction
 »  Mechanism of action
 »  Antifungal spectrum
 »  Pharmacokinetics
 »  Use in special p...
 »  Pharmacoeconomic...
 »  Conclusion
 »  References
 »  Article Tables

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EDUCATIONAL FORUM
Year : 2010  |  Volume : 42  |  Issue : 1  |  Page : 9-11
 

Echinocandins: A ray of hope in antifungal drug therapy


Department of Pharmacology, Bharati Vidyapeth University Medical College and Hospital, Sangli, Maharashtra, India

Date of Submission15-Aug-2008
Date of Decision06-Feb-2009
Date of Acceptance12-Mar-2010
Date of Web Publication12-Apr-2010

Correspondence Address:
Neeta D Grover
Department of Pharmacology, Bharati Vidyapeth University Medical College and Hospital, Sangli, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.62396

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 » Abstract 

Invasive fungal infections are on the rise. Amphotericin B and azole antifungals have been the mainstay of antifungal therapy so far. The high incidence of infusion related toxicity and nephrotoxicity with amphotericin B and the emergence of fluconazole resistant strains of Candida glabrata egged on the search for alternatives. Echinocandins are a new class of antifungal drugs that act by inhibition of β (1, 3)-D- glucan synthase, a key enzyme necessary for integrity of the fungal cell wall.
Caspofungin was the first drug in this class to be approved. It is indicated for esophageal candidiasis, candidemia, invasive candidiasis, empirical therapy in febrile neutropenia and invasive aspergillosis. Response rates are comparable to those of amphotericin B and fluconazole. Micafungin is presently approved for esophageal candidiasis, for prophylaxis of candida infections in patients undergoing hematopoietic stem cell transplant (HSCT) and in disseminated candidiasis and candidemia. The currently approved indications for anidulafungin are esophageal candidiasis, candidemia and invasive candidiasis.
The incidence of infusion related adverse effects and nephrotoxicity is much lower than with amphotericin B. The main adverse effect is hepatotoxicity and derangement of serum transaminases. Liver function may need to be monitored. They are, however, safer in renal impairment. Even though a better pharmacoeconomical choice than amphotericin B, the higher cost of these drugs in comparison to azole antifungals is likely to limit their use to azole resistant cases of candidial infections and as salvage therapy in invasive aspergillosis rather than as first line drugs.


Keywords: Anidulafungin, candidemia, caspofungin, echinocandins, esophageal candidiasis, invasive aspergillosis, invasive candidiasis, micafungin


How to cite this article:
Grover ND. Echinocandins: A ray of hope in antifungal drug therapy. Indian J Pharmacol 2010;42:9-11

How to cite this URL:
Grover ND. Echinocandins: A ray of hope in antifungal drug therapy. Indian J Pharmacol [serial online] 2010 [cited 2017 Aug 20];42:9-11. Available from: http://www.ijp-online.com/text.asp?2010/42/1/9/62396



 » Introduction Top


Candidemia is a major contributor to mortality in immunosuppressed patients (33 to 47%), due to a rise in invasive fungal infections. [1],[2] Although C. albicans is the most commonly found isolate, patients infected with C. albicans-show the highest mortality. [3] They also show a reduced susceptibility to azole antifungals. [2],[4] Fluconazole, which has been the mainstay of treatment till now, is losing ground due to increasing resistance by C.glabrata. [5]

Aspergillosis is a major cause of morbidity in patients with hematological malignancies and those undergoing transplants. [6] Amphotericin B, which is used against invasive fungal infections, has a very high frequency of infusion related adverse effects and nephrotoxicity. Voriconazole is the only azole antifungal drug licensed for use in invasive aspergillosis. The introduction of echinocandins, a new class of antifungals, against this backdrop, is a promising development in antifungal therapy.

Echinocandins are a group of semisynthetic, cyclic lipopeptides with an N-linked acyl lipid side chain. The drugs in the class are: caspofungin, micafungin and anidulafungin.


 » Mechanism of action Top


The echinocandins act as non competitive inhibitors of β - (1, 3) - D-glucan synthase, an essential component of the fungal cell wall that is not present in mammals. Inability of the organism to synthesize β - (1, 3) - D-glucan leads to osmotic instability and cell death. [7],[8],[9],[10]


 » Antifungal spectrum Top


Echinocandins exhibit good fungicidal activities against Candida albicans, Candida parapsilosis and Candida guilliermondii. Good activity is also shown against amphotericin B-resistant and fluconazole-resistant Candida glabrata. For Aspergillus species, echinocandins have fungistatic activity in contrast to amphotericin B and trizoles, which exhibit fungicidal activity. [11],[12],[13] Echinocandin resistance, though not common, has been reported in C. glabrata and C. parapsilosis.[14],[15]


 » Pharmacokinetics Top


All echinocandins have poor oral bioavailability and are administered only by the intravenous route. Since none of the drugs are excreted solely by the kidneys, the dose need not be altered in renal impairment. In moderate hepatic impairment, the dose of caspofungin needs to be altered but this adjustment is not needed for anidulafungin and micafungin. [16],1[7],[18]

Clinical studies

Clinical studies have been conducted with all three echinocandins in various fungal infections. Caspofungin was the first drug in the group to be tested clinically. Subsequently, micafungin and anidulafungin have also been studied extensively. The various indications in which echinocandins have been studied are described below. The Food and Drug Administration (FDA)-approved indications and doses are presented in [Table 1].

Adverse effects

Infusion related reactions (facial flushing, swelling, rash, pruritis, and fever) have been reported with all the echinocandins. [16],[17],[18],[19] They usually occur immediately after infusion and respond well to antihistamines. The drug need not be withdrawn but the rate of infusion should be decreased. Thrombophlebits may occur with all the three drugs. Overall, the infusion-related events seem to be much fewer than those due to amphotericin B. [20],[21] Derangement of hepatic transaminases has been observed in almost all the studies of adverse events of the echinocandins. [16],[17],[18],[19],[20] Liver function should be monitored, especially in case of caspofungin. However, the gross disturbance in creatinine clearance, as observed with amphotericin B, is not seen and these drugs are probably safer than amphotericin B in case of renal impairment. [16],[17],[18] Overall, the tolerability profile of echinocandins seems to be comparable to that of fluconazole [22],[23],[24],[25] and better than that of amphotericin B. [21],[26],[27]


 » Use in special populations Top


No dose adjustment is required for renal impairment including in patients on dialysis since echinocandins are highly protein bound and non dialyzable. [16],[17],[18] Patients with mild hepatic insufficiency do not require dose adjustment for caspofungin but reduction of dose to 35 mg is recommended in moderate hepatic insufficiency. [16] However, if clinical situation warrants, a 70 mg loading dose should still be administered on day one. No dose adjustment is needed for micafungin and anidulafungin in mild to moderate hepatic insufficiency. [17],[18] Patients developing abnormal liver function tests while on micafungin should be evaluated for the risk/benefit ratio of continued treatment with micafungin. [17] Anidulafungin is not metabolized by the liver and no increase in its serum levels has been observed with any level of hepatic impairment. [18]

Even though echinocandins have been studied in children, none of the three drugs has yet been approved for use in pediatric population. [28],[29],[30],[31] No dose adjustment is required for geriatric population. All echinocandins have embryo toxic potential and should be used in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.


 » Pharmacoeconomic evaluation Top


A cost effectiveness analysis of caspofungin versus liposomal amphotericin B has been carried out by Bruynesteyn et al.[32] Cost per day for caspofungin was estimated at £ 417 for the first day (70 mg) and £ 328 per day (50 mg) from the second day onwards. The cost for amphotericin B for a 77 Kg patient (3 mg / Kg / day) was £ 483 per day. Included in the overall analysis were toxicity related costs, length of stay and quality adjusted life years (QALY). It was found that patients of suspected fungal infections treated with Caspofungin had a lower mortality in comparison with liposomal amphotericin B. Treatment with caspofungin was predicted to save 0.55 additional life years per patient. The authors concluded that caspofungin was more economical than liposomal amphotericin B in terms of cost saving as well as QALY gains.

An economic analysis of micafungin versus liposomal amphotericin B, for the treatment of candidemia and invasive candidiasis, revealed that micafungin may be a more cost effective therapy in the treatment of these conditions. [33]

It seems that using echinocandins instead of liposomal amphotericin B may be more economical, especially in patients with an impaired renal profile. But echinocandins may not be preferred over the azole antifungals, especially voriconazole. [34] For azole resistant cases; they may be more economical than liposomal amphotericin B. Even in IA, voriconazole has been found to be more cost - effective than caspofungin. [34]


 » Conclusion Top


Keeping in mind the high cost of echinocandins in comparison to azole antifungals like fluconazole, these drugs are likely to remain as reserve drugs for most invasive candidial infections. They may be more useful in azole - resistant cases or in invasive aspergillosis as salvage therapy.

 
 » References Top

1.Gudlaugsson O, Gillespie S, Lee K, Vande Berg J, Hu J, Messer S, et al. Attributable mortality of nosocomial candidemia, revisited. Clin Infect Dis 2003;37:1172-7.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]  
2.Pappas PG, Rex JH, Lee J, Hamill RJ, Larsen RA, Powderly W, et al. A prospective observational study of candidemia: Epidemiology, therapy and influences on mortality in hospitalized adult and pediatric patients. Clin Infect Dis 2003;37:634-43.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]  
3.Viscoli C, Girmenia C, Marinus A, Collette L, Martino P, Vandercam B, et al. Candidemia in cancer patients: A prospective, multicenter surveillance study by the Invasive Fungal Infection Group (IFIG) of the European Organisation for Research and Treatment of Cancer (EORTC). Clin Infect Dis 1999;28:1071-9.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]  
4.Morris MI, Villmann M. Echinocandins in the management of invasive fungal infections, Part 1. Am J Health Syst Pharm 2006;63:1693-703.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Pfaller MA, Diekema DJ; International Fungal Surveillance Participant Group. Twelve years of fluconazole in clinical practice: Global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. Clin Microbiol Infect 2004;10:11-23.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Vazquez JA, Sobel JD. Anidulafungin: A novel echinocandin. Clin Infect Dis 2006;43:215-22.  Back to cited text no. 6      
7.Wiederhold NP, Lewis RE. The echinocandin antifungals: An overview of the pharmacology, spectrum and clinical efficacy. Expert Opin Investig Drugs 2003;12:1313-33.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Denning DW. Echinocandin antifungal drugs. Lancet 2003;362:1142-51.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Odds FC, Brown AJ, Gow NA. Antifungal agents: Mechanisms of action. Trends Microbiol 2003;11:272-9.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]  
10.Zaas AK, Alexander BD. Echinocandins: role in antifungal therapy, 2005. Expert Opin Pharmacother 2005;6:1657-68.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol 2005;43:5425-7.   Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. Global surveillance of in vitro activity of micafungin against Candida: A comparison with caspofungin by CLSI-recommended methods. J Clin Microbiol 2006;44:3533-8.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Messer SA, Diekema DJ, Boyken L, Tendolkar S, Hollis RJ, Pfaller MA. Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp. J Clin Microbiol 2006;44:324-6.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  
14.Hernandez S, López-Ribot JL, Najvar LK, McCarthy DI, Bocanegra R, Graybill JR. Caspofungin resistance in Candida albicans: Correlating clinical outcome with laboratory susceptibility testing of three isogenic isolates serially obtained from a patient with progressive Candida esophagitis. Antimicrob Agents Chemother 2004;48:1382-3.  Back to cited text no. 14      
15.Moudgal V, Little T, Boikov D, Vazquez JA. Multiechinocandin- and multiazole-resistant Candida parapsilosis isolates serially obtained during therapy for prosthetic valve endocarditis. Antimicrob Agents Chemother 2005;49:767-9.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]  
16.Caspofungin prescribing information. Whitehouse Station NJ: Merck and Co. Available from: http://www.cancidas.com/caspofungin_acetate/cancidas/hcp/product_information/pi/index.jsp [Accessed on 2007 Oct 15].   Back to cited text no. 16      
17.Micafungin prescribing information. Astellas Pharma US April 2005. Available from: http://www.mycamine.com/pi.php [Accessed on 2007 Oct 15].  Back to cited text no. 17      
18.Antidulafungin prescribing information. Pfizer Inc. NY. Feb 2006 Available from: www.pfizer.com/pfizer/download/uspi_eraxis.pdf [Accessed on 2007 Oct 15].  Back to cited text no. 18      
19.Vazquez JA. Anidulafungin: A new echinocandin with a novel profile. Clin Ther 2005;27:657-73.  Back to cited text no. 19      
20.Keating G, Figgitt D. Caspofungin: A review of its use in oesophageal candidiasis, invasive candidiasis and invasive aspergillosis. Drugs 2003;63:2235-63.  Back to cited text no. 20      
21.McCormack PL, Perry CM. Caspofungin: A review of its use in the treatment of fungal infections. Drugs 2005;65:2049-68.  Back to cited text no. 21      
22.Villanueva A, Gotuzzo E, Arathoon EG, Noriega LM, Kartsonis NA, Lupinacci RJ, et al. A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 2002;113:294-9.  Back to cited text no. 22  [PUBMED]  [FULLTEXT]  
23.deWet N, Llanos-Cuentas A, Suleiman J, Baraldi E, Krantz EF, Della Negra M, 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;39:842-9.   Back to cited text no. 23      
24.deWet NT, Bester AJ, Viljoen JJ, Filho F, Suleiman JM, Ticona E, et al. A randomized, double blind, comparative trial of micafungin (FK463) vs. fluconazole for the treatment of oesophageal candidiasis. Aliment Pharmacol Ther 2005;21:899-907.  Back to cited text no. 24      
25.Krause DS, Simjee AE, van Rensburg C, Viljoen J, Walsh TJ, Goldstein BP, et al. A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis. Clin Infect Dis 2004;39:770-5.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]  
26.Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: A phase III randomised double-blind trial. Lancet 2007;369:1519-27.   Back to cited text no. 26  [PUBMED]  [FULLTEXT]  
27.Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351:1391-402.  Back to cited text no. 27  [PUBMED]  [FULLTEXT]  
28.Wertz KK, Pretzlaff RK. Caspofungin in a pediatric patient with persistent candidemia. Pediatr Crit Care Med 2004;5:181-3.   Back to cited text no. 28  [PUBMED]  [FULLTEXT]  
29.Natarajan G, Lulic-Botica M, Rongkavilit C, Pappas A, Bedard M. Experience with caspofungin in the treatment of persistent fungemia in neonates. J Perinatol 2005;25:770-7.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]  
30.van Burik JA, Ratanatharathorn V, Stepan DE, Miller CB, Lipton JH, Vesole DH, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004;39:1407-16.  Back to cited text no. 30  [PUBMED]  [FULLTEXT]  
31.Benjamin DK Jr, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia a thigh risk for invasive fungal infections. Antimicrob Agents Chemother 2006;50:632-8.  Back to cited text no. 31  [PUBMED]  [FULLTEXT]  
32.Bruynesteyn K, Gant V, McKenzie C, Pagliuca T, Poynton C, Kumar RN, et al. A cost- effectiveness analysis of caspofungin vs. liposomal amphotericin B for treatment of suspected fungal infections in the UK. Eur J Haematol 2007;78:532-9.  Back to cited text no. 32      
33.Cornely OA, Sidhu M, Odeyemi I, van Engen AK, van der Waal JM, Schoeman O. Economic analysis of micafungin versus liposomal amphotericin B for treatment of candidaemia and invasive candidiasis in Germany. Curr Med Res Opin 2008;24:1743-53.  Back to cited text no. 33  [PUBMED]  [FULLTEXT]  
34.Domínguez-Gil A, Martín I, García Vargas M, Del Castillo A, Díaz S, Sánchez C. Economic evaluation of voriconazole versus caspofungin for the treatment of invasive aspergillosis in Spain. Clin Drug Investig 2007;27:197-205.  Back to cited text no. 34      



 
 
    Tables

  [Table 1]

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