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Micafungin in the treatment of invasive candidiasis and invasive aspergillosis.

Wiederhold NP, Cota JM, Frei CR - Infect Drug Resist (2009)

Bottom Line: Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects.Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis.Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations.

View Article: PubMed Central - PubMed

Affiliation: University of Texas at Austin College of Pharmacy, Austin, Texas, USA;

ABSTRACT
Micafungin is an echinocandin antifungal agent available for clinical use in Japan, Europe, and the United States. Through inhibition of β-1,3-glucan production, an essential component of the fungal cell wall, micafungin exhibits potent antifungal activity against key pathogenic fungi, including Candida and Aspergillus species, while contributing minimal toxicity to mammalian cells. This activity is maintained against polyene and azole-resistant isolates. Pharmacokinetic and pharmacodynamic studies have demonstrated linear kinetics both in adults and children with concentration-dependent activity observed both in vitro and in vivo. Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations. This review will focus on the pharmacology, clinical microbiology, mechanisms of resistance, safety, and clinical efficacy of micafungin in the treatment of invasive candidiasis and invasive aspergillosis.

No MeSH data available.


Related in: MedlinePlus

Linear profile of the Fks1p subunit in Candida albicans and loci containing amino acid substitutions associated with reduced echinocandin susceptibility. Adapted with permission from Park S, Kelly R, Kahn JN, et al. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother, 49:3264–73, and from Balashov SV, Park S, Perlin DS. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother, 50:2058–63. Copyright © 2005 and 2006 American Society for Microbiology.
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f1-idr-1-063: Linear profile of the Fks1p subunit in Candida albicans and loci containing amino acid substitutions associated with reduced echinocandin susceptibility. Adapted with permission from Park S, Kelly R, Kahn JN, et al. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother, 49:3264–73, and from Balashov SV, Park S, Perlin DS. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother, 50:2058–63. Copyright © 2005 and 2006 American Society for Microbiology.

Mentions: As the clinical use of the echinocandins continues to grow, reports of echinocandin failure associated with elevated MIC values continue to appear in the literature. Currently, the most established mechanism for reduced echinocandin susceptibility is an alteration in the glucan synthase enzyme complex. Genetic studies in Saccharomyces cerevisiae and C. albicans first suggested that alterations within this essential component of glucan synthase cause a reduced affinity of the echinocandins to this enzyme and could account for elevated MICs to this class of agents (Douglas et al 1994; Douglas et al 1997). These studies identified several single nucleotide polymorphisms (SNPs) that may occur within FKS1, the gene encoding for Fks1p, a subunit of the glucan synthase enzyme complex that is inhibited by the echinocandins (Balashov et al 2006). These SNPs occur within two regions of FKS1, and result in single amino acid substitutions within highly conserved regions of Fks1p. The first region associated with decreased echinocandin activity spans approximately 10 amino acids while the second region comprises 20 amino acids (Figure 1). Substitutions within these regions have been associated with increased echinocandin MICs in spontaneous laboratory C. albicans mutants and clinical isolates (Park et al 2005). These amino acid changes also resulted in a significant increase in the echinocandin 50% inhibitory concentration (IC50) against glucan synthase activity (Douglas et al 1997). In C. albicans, mutations within the highly conserved hot spot regions of FKS1 have been reported to lead to codon changes F641S, S645F, S645Y, S645P, and R1361H (Park et al 2005; Balashov et al 2006). Similar changes have been reported in a number of clinical non-C. albicans isolates with reduced echinocandin susceptibility (Table 2) collected from patients who experienced clinical failure while receiving an echinocandin (Kahn et al 2007; Cleary et al 2008; Garcia-Effron et al 2008b). In C. glabrata, SNPs in FKS1 and FKS2 result in amino acid changes that confer reduced susceptibility and have been documented in patients failing echinocandin therapy (Cleary et al 2008; Thompson et al 2008). Interestingly, a recent study has demonstrated that the reduced potency of echinocandins against C. parapsilosis and the closely related species C. orthopsilosis and C. metopsilosisis due to a naturally occurring proline-to-alanine substitution at amino acid 660 (P660A) at the end of one of the highly conserved hot spot regions within Fks1p (Garcia-Effron et al 2008a). Other mechanisms that may result in reduced echinocandin susceptibility include overexpression of the Golgi protein Sbe2p, which is involved in cell wall component transport (Osherov et al 2002), up-regulation of the cell wall integrity pathway (Wiederhold et al 2005), and increases in cell wall chitin content (Pfaller et al 1989; Stevens et al 2006; Cota et al 2008). The clinical significance of these other mechanisms is unknown.


Micafungin in the treatment of invasive candidiasis and invasive aspergillosis.

Wiederhold NP, Cota JM, Frei CR - Infect Drug Resist (2009)

Linear profile of the Fks1p subunit in Candida albicans and loci containing amino acid substitutions associated with reduced echinocandin susceptibility. Adapted with permission from Park S, Kelly R, Kahn JN, et al. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother, 49:3264–73, and from Balashov SV, Park S, Perlin DS. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother, 50:2058–63. Copyright © 2005 and 2006 American Society for Microbiology.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108724&req=5

f1-idr-1-063: Linear profile of the Fks1p subunit in Candida albicans and loci containing amino acid substitutions associated with reduced echinocandin susceptibility. Adapted with permission from Park S, Kelly R, Kahn JN, et al. 2005. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob Agents Chemother, 49:3264–73, and from Balashov SV, Park S, Perlin DS. 2006. Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1. Antimicrob Agents Chemother, 50:2058–63. Copyright © 2005 and 2006 American Society for Microbiology.
Mentions: As the clinical use of the echinocandins continues to grow, reports of echinocandin failure associated with elevated MIC values continue to appear in the literature. Currently, the most established mechanism for reduced echinocandin susceptibility is an alteration in the glucan synthase enzyme complex. Genetic studies in Saccharomyces cerevisiae and C. albicans first suggested that alterations within this essential component of glucan synthase cause a reduced affinity of the echinocandins to this enzyme and could account for elevated MICs to this class of agents (Douglas et al 1994; Douglas et al 1997). These studies identified several single nucleotide polymorphisms (SNPs) that may occur within FKS1, the gene encoding for Fks1p, a subunit of the glucan synthase enzyme complex that is inhibited by the echinocandins (Balashov et al 2006). These SNPs occur within two regions of FKS1, and result in single amino acid substitutions within highly conserved regions of Fks1p. The first region associated with decreased echinocandin activity spans approximately 10 amino acids while the second region comprises 20 amino acids (Figure 1). Substitutions within these regions have been associated with increased echinocandin MICs in spontaneous laboratory C. albicans mutants and clinical isolates (Park et al 2005). These amino acid changes also resulted in a significant increase in the echinocandin 50% inhibitory concentration (IC50) against glucan synthase activity (Douglas et al 1997). In C. albicans, mutations within the highly conserved hot spot regions of FKS1 have been reported to lead to codon changes F641S, S645F, S645Y, S645P, and R1361H (Park et al 2005; Balashov et al 2006). Similar changes have been reported in a number of clinical non-C. albicans isolates with reduced echinocandin susceptibility (Table 2) collected from patients who experienced clinical failure while receiving an echinocandin (Kahn et al 2007; Cleary et al 2008; Garcia-Effron et al 2008b). In C. glabrata, SNPs in FKS1 and FKS2 result in amino acid changes that confer reduced susceptibility and have been documented in patients failing echinocandin therapy (Cleary et al 2008; Thompson et al 2008). Interestingly, a recent study has demonstrated that the reduced potency of echinocandins against C. parapsilosis and the closely related species C. orthopsilosis and C. metopsilosisis due to a naturally occurring proline-to-alanine substitution at amino acid 660 (P660A) at the end of one of the highly conserved hot spot regions within Fks1p (Garcia-Effron et al 2008a). Other mechanisms that may result in reduced echinocandin susceptibility include overexpression of the Golgi protein Sbe2p, which is involved in cell wall component transport (Osherov et al 2002), up-regulation of the cell wall integrity pathway (Wiederhold et al 2005), and increases in cell wall chitin content (Pfaller et al 1989; Stevens et al 2006; Cota et al 2008). The clinical significance of these other mechanisms is unknown.

Bottom Line: Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects.Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis.Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations.

View Article: PubMed Central - PubMed

Affiliation: University of Texas at Austin College of Pharmacy, Austin, Texas, USA;

ABSTRACT
Micafungin is an echinocandin antifungal agent available for clinical use in Japan, Europe, and the United States. Through inhibition of β-1,3-glucan production, an essential component of the fungal cell wall, micafungin exhibits potent antifungal activity against key pathogenic fungi, including Candida and Aspergillus species, while contributing minimal toxicity to mammalian cells. This activity is maintained against polyene and azole-resistant isolates. Pharmacokinetic and pharmacodynamic studies have demonstrated linear kinetics both in adults and children with concentration-dependent activity observed both in vitro and in vivo. Dosage escalation studies have also demonstrated that doses much higher than those currently recommended may be administered without serious adverse effects. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. Furthermore, the clinical effectiveness of micafungin against these infections occurs without the drug interactions that occur with the azoles and the nephrotoxicity observed with amphotericin B formulations. This review will focus on the pharmacology, clinical microbiology, mechanisms of resistance, safety, and clinical efficacy of micafungin in the treatment of invasive candidiasis and invasive aspergillosis.

No MeSH data available.


Related in: MedlinePlus